UC-NRLF 
 
 (vorm: E. Sobering) 
 
 BERLIN. 
 
flfcf 
 
MEDICINAL AGENTS 
 
 OF THE 
 
 CHEMICAL WORKS 
 
 (VORMALS E. SOBERING), 
 
 BERLIN. 
 
 1893. 
 

 

 
 CONTENTS. 
 
 I'ACE 
 
 PREFACE , v. 
 
 PlPERAZINE ... ... ... ... ... ... ... I 
 
 PHENOCOLL 29 
 
 Phenocoll and Piperazine in combination ... 43 
 
 CHLORALAMID ... ... ... ... ... ... ... 47 
 
 PARALDEHYDE ... ... ... ... ... .. 63 
 
 THE CHLORAL GROUP 71 
 
 Chloral Hydrate 71 
 
 Butyl-Chloral 72 
 
 Chloroform from Chloral ... ... ... ... ... 72 
 
 SALOL 73 
 
 SALICYLIC ACID AND SALTS ... ... ... ... ... 93 
 
 Bismuth Salicylate ... ... ... ... ... ... 94 
 
 Lithium Salicylate ... ... ... ... ... ... 95 
 
 STRONTIUM SALTS ... ... ... ... ... ... 97 
 
 POTASSIUM BROMIDE 101 
 
 THIOSINAMINE ' "103 
 
 DlABETIN ... ... ... ... ... ... ... ... 107 
 
 IODOFORM, ELECTROLYTIC 109 
 
 CRESIN in 
 
PREFACE. 
 
 The discovery of the DAGUERRE method of producing 
 pictures of natural objects in other words, the invention of 
 the art of photography gave an important stimulus to the 
 preparation of chemicals in a high state of purity, and 
 indirectly exerted an influence upon the synthesis of organic 
 compounds. The importance of the art was recognised by 
 ERNST SCHERING, founder of the Chemische Fabrik auf 
 Actien, who set himself the task of preparing the chemicals 
 used in it in a condition of the utmost purity. In thus sketching 
 in barest outline the origin of the firm, allusion may be made 
 to the historic interest that gathers round the design impressed 
 upon the title-page and cover of the volume. Though by no 
 means a conspicuous figure, it is associated with the earliest 
 history of the Fabrik, and has more significance than appears 
 at first sight. Those readers acquainted with alchemic lore 
 and symbols will recognise the superimposed forms represent- 
 ing fire and water as well as the central circle which stood for 
 the third of the " elements" of the ancients.' The part played 
 by the sun as a source of energy in chemical processes is 
 symbolised by the halo of rays streaming from the " star," 
 while the particular application of this curious group of signs 
 to the firm is indicated by the initials (E.S.) of the founder. 
 
vi. Preface. 
 
 This may be regarded as the commencement of the 
 manufacture of fine chemicals by this firm, which has now 
 attained the dimensions indicated by the number of products 
 described in the following pages products which are, with 
 few exceptions, all of recent introduction. 
 
 From the preparation of well-known compounds in 
 qualities distinguished by their high purity to that of entirely 
 new bodies of definite chemical nature was a natural transition. 
 The development of synthetical organic chemistry revealed 
 new and better methods of procedure, which were promptly 
 investigated and taken advantage of in the works, and the 
 inevitable result of the progressive tendency always kept alive 
 was that the firm of E. SCHEKING occupied the foremost place 
 among those chemical manufacturers engaged in the produc- 
 tion and investigation of new remedies. 
 
 It is noteworthy that the very first of the synthetical 
 remedies Chloral Hydrate was prepared in the chemical 
 works of the firm, and the prestige conferred by this achieve- 
 ment was again enhanced by the introduction of Salicylic 
 Acid. It may be remarked, in passing, that although since the 
 debut of these compounds the class of synthetical medicinal 
 compounds has enormously increased, they still maintain their 
 high position in materia medica, and, indeed, have become 
 almost indispensable in modern therapeutics. 
 
 It will be seen that the derivative of chloral, Chloralamid, 
 rivals the mother-substance in general importance, and in 
 
Preface. vii. 
 
 certain cases is preferable to it. The steadily-growing litera- 
 ture of the compound establishes its valuable hypnotic 
 properties and the freedom of its medicinal action from 
 unpleasant after-effects. This latter feature has attracted 
 general attention; to it is largely due the great strides 
 which Chloralamid has made in the favour of medical men 
 in all countries. 
 
 The monograph on Piperazine, the first remedy in the 
 gouty diathesis which organic chemistry has yielded, should 
 prove especially interesting. Although so recently introduced, 
 the peculiar chemical and chemico-physiological behaviour 
 of the base, especially in relation to uric acid and its com- 
 pounds, has procured for it a searching investigation and 
 extensive trial which enable a sound judgment as to its value 
 to be already formed. When combined with Phenocoll it 
 seems to form the most efficient remedy for the various forms 
 of gout which has hitherto been discovered. 
 
 The noteworthy points in the therapeutical uses of 
 Phenocoll are its comparatively ready solubility in water, and 
 its freedom from any deleterious action on the blood or 
 circulatory system generally. The medical practitioner will 
 not need to be reminded that the possession of both these 
 properties gives Phenocoll a marked advantage over all other 
 remedies of the same class. 
 
 Finally, the attention of the reader may be directed to the 
 chapters on Diabetin, Strontium Salts, and Thiosinamine, 
 
viii. Preface. 
 
 the latest comers among therapeutical novelties. It is not 
 possible, of course, to predict with certainty what position 
 these substances will finally attain in materia mcdica ; but it 
 may at least be said that they give promise of winning 
 recognition as real enrichments of the physician's armament 
 against disease. 
 
 Chemische Fatoft auf Actien 
 
 Yormals E, Sobering, 
 
 BERLIN, 
 
 February, 1893. 
 
PIPERAZINE. 
 
 An interesting paper was read in Berlin some months ago by 
 Finzelberg, which illustrates the chain of events by which Piperazine 
 was discovered and its therapeutical value established. It appears 
 that the father of the chemist just named died from uraemia caused 
 by renal stone, and this led his son to resolve to find, if possible, a 
 substance that by internal administration might either prevent the 
 formation of deposits of uric acid or effect their solution when 
 formed. 
 
 Consultation with other chemists as to the most likely means of 
 effecting this end led to a determination to experiment with all the 
 known organic bases, as regarded their solvent action on uric acid, in 
 the hope of discovering one that would produce the desired result 
 without producing any deleterious or toxic effect upon the organism. 
 
 Several years passed by during which the investigation was carried 
 on as opportunity presented, until general attention was directed to 
 the natural base, spermine, and to the synthetically prepared diethyl- 
 enediimine of Ladenburg, by the work of Schreiner and Professor 
 Poehl. 
 
 At first spermine and Ladenburg's base were believed to be identical, 
 but the different appearance of their bismuth iodide compounds under 
 the microscope convinced Schmidt and Majert that they were different 
 bodies. A purer preparation of the synthetical compound named 
 Piperazine a designation indicating its relationship with piperidine, 
 piperine, and pyrazine was subjected to careful investigation, the 
 upshot of which was the discovery of the remarkable properties detailed 
 in the following paragraphs. 
 
 PHYSICAL AND CHEMICAL PROPERTIES. 
 
 Piperazine is represented by the formula C 4 H IO N 2 . Crystallised 
 from water it assumes the form of glassy lustrous tables. When 
 
 B 
 
Piperazine. 
 
 exposed to the air it is deliquescent, the crystals rapidly absorbing 
 carbon dioxide and water, and becoming liquid. When subjected to 
 the action of heat it melts between 104 and 107 C., and boils at 
 i45 C. 
 
 The compound is very readily soluble in water, forming an almost 
 tasteless, strongly alkaline but non-caustic solution. 
 
 Hydrochloride of Piperazine, a salt of the base which has also been 
 used therapeutically, forms silky, lustrous, lanceolate crystals, very 
 easily soluble in water and, with more difficulty, in alcohol. 
 
 The most important chemical property of Piperazine is its power of 
 combining with a large proportion of uric acid, forming urate of 
 Piperazine, a salt distinguished by its ready solubility in water. Even 
 in the presence of an excess of the acid only the neutral salt is 
 formed. 
 
 The clearest idea of the action of Piperazine as a solvent of uric 
 acid is obtained by comparing it with that of lithia, the remedy 
 chiefly resorted to, prior to the discovery of the synthetical base, in 
 the treatment of uric acid diathesis where the primary indication was 
 to effect the solution and elimination of uric acid. Now when brought 
 together in the cold with aqueous solution of the acid, Piperazine 
 dissolves twelve times as much as the same weight of carbonate of 
 lithium under similar circumstances. Further, the salt formed by 
 the organic base was found to be much more soluble in water than 
 urate of lithia ; the latter requires 368 parts of water for solution, while 
 one part of Piperazine urate is taken up by 50 parts of water. 
 
 A number of observers have examined the chemical activity of 
 Piperazine as a solvent for uric acid, especially when in the form 
 of those concretions which, originating in the renal pelvis and 
 bladder, give rise to severe pain and other serious symptoms. 
 
 Dr. Finzelberg subjected to the action of Piperazine, urinary calculi, 
 consisting either of pure uric acid, or of that compound together with 
 ammonium urate, calcium phosphate, etc. He found that all these 
 forms of concretion dissolved freely and perfectly within a compara- 
 tively short time in a one per cent. Piperazine solution. In some 
 cases nothing remained but a light honeycombed skeleton, which 
 consisted of the hardened cementing mucus. It was particularly 
 
Pipe. 
 
 razme. 
 
 striking that the edges of the calculi, sometimes very sharp, dissolved 
 away rapidly in the Piperazine solution. 
 
 A similar research was carried out by Drs. Biesenthal and Schmidt. 
 The " stones " they had for experiment consisted of uric acid (or 
 urates), or were. of a composite nature, being made up of alternate 
 layers of uric acid and calcium oxalate or phosphate. The authors 
 recorded the observation that even large compact pieces belonging to 
 the first class, dissolved with extraordinary readiness in a solution of 
 Piperazine. 
 
 One series of experiments was especially interesting as showing the 
 comparative activity of Piperazine, sodium carbonate, lithium carbonate 
 and borax, in effecting the solution of uric acid stones. A " tophus" 
 was obtained of great hardness, made up of concentric layers of uric 
 acid. Cubical pieces, of as near as possible equal weight, were sawn 
 from this, and each suspended by means of test-tubes with fine 
 perforations at the end, in one per cent, solutions of Piperazine and 
 of the salts enumerated above. All the solutions were kept at blood- 
 heat and under exactly the same conditions. The results of the 
 experiment are shown in the following paragraphs : 
 
 1. PIPERAZINE SOLUTION. Two and a-half grns. of the stone, 
 
 after only six hours, was all dissolved save a scarcely per- 
 ceptible residue without stratification. The solution had 
 become yellow in consequence of the organic matter which 
 had also passed into solution. 
 
 2. LITHIUM CARBONATE SOLUTION. Three grns. of the stone 
 
 was not dissolved after 48 hours, a compact skeleton being 
 left, in which fine stratification was clearly recognisable. 
 This residue was removed to the Piperazine solution, where, 
 with the exception of a few scarcely visible flocks, it had soon 
 all dissolved. 
 
 3. SODIUM CARBONATE SOLUTION. After 48 hours immersion in 
 
 this, a fragment of the stone weighing 2^ grns. was unaltered 
 in bulk. A white crust of sodium acid urate had formed on the 
 stone, which, though at the most - 6 L -th of an inch thick, pre- 
 vented any further action of the soda solution. Beneath the 
 
 B 2 
 
Piperazine. 
 
 white coating, the stone was as hard as ever, but transferred 
 to the Piperazine solution it dissolved in a few hours. 
 4. BORAX SOLUTION. A fragment weighing grn. only dis- 
 solved after a digestion of 20 hours, and then the same 
 compact skeleton was left behind, as with lithium carbonate. 
 It rapidly and entirely dissolved in Piperazine, save a few 
 scarcely perceptible flocks. 
 
 The capability shown by the solution of Piperazine of dissolving a 
 part of the organic substances, which enter into the composition of 
 these stones, explains the rapidity with which they are broken down 
 and pass into solution when digested in it. 
 
 Experiments with other stones confirmed the observation of Finzelberg 
 that, long before complete solution takes place, sharp edges are broken 
 down and the concretion assumes a slippery character. It is shown 
 later that every feature of the behaviour of tophi with Piperazine 
 solution has been of significance in determining the therapeutical 
 application of the compound. 
 
 Drs. Biesenthal and Schmidt also carried out in the chemical 
 laboratory a series of experiments on the comparative diffusibility of 
 the urates of Piperazine, sodium and lithium through animal membrane. 
 The results demonstrated that Piperazine urate diffused more rapidly 
 than either of the other salts. This observation has also therapeutic 
 significance in view of the important part which osmosis is known to 
 play in nutritive and other processes in which the tissues are 
 concerned. 
 
 Among the experiments performed by Biesenthal and Schmidt was 
 the following : 
 
 A solution of Piperazine hydrochloride was placed in a fractionating 
 flask, provided with a small separating funnel, and the side tubulure 
 of which dipped into the bulb of a second similar flask containing 
 barium hydrate solution ; both the flasks were joined up with air-tight 
 fittings, and exhausted. Soda carbonate solution was allowed to fall 
 through the funnel, and the apparatus again made completely vacuous. 
 On warming the mixture to 40 C. (104 F.) and constantly shaking 
 the barium solution, the latter gradually became turbid, and a thick 
 layer of barium carbonate formed. 
 
Piperazine. 
 
 These phenomena were due to the double decomposition of sodium 
 carbonate and Piperazine hydrochloride with the formation of sodium 
 chloride and Piperazine carbonate, which latter, on warming, gave off 
 carbon dioxide. 
 
 The bearing of this experiment upon the behaviour of Piperazine 
 in the organism is evident ; it becomes largely converted into hydro- 
 chloride in the stomach, and this salt is brought into contact with 
 sodium carbonate in the alkaline juices of the tissues. 
 
 But it would be equally important to the efficient action of Piperazine 
 as a solvent of gouty secretions that the urate should not undergo 
 double decomposition with the sodium carbonate of the alkaline 
 juices; if this were the case Piperazine carbonate and the relatively 
 insoluble sodium urate would be formed and the latter re-deposited. 
 
 In order to test this question the authors above-named arranged 
 two fractionating flasks again as in the experiment just described. In 
 the one was placed 400 cc. of a solution of 24 grns. of Piperazine with 
 45 grns. of uric acid (from which all possible traces of carbon dioxide 
 had been removed by long boiling). The other contained barium 
 hydrate solution as before. The flasks were again exhausted, soda 
 carbonate solution introduced, and the whole system heated to 
 40 C. No trace of turbidity appeared, however, in the barium 
 solution, thus showing that no decomposition occurred and no 
 Piperazine carbonate was formed in the flask under conditions closely 
 approximating to those which obtain in the human body. 
 
 TESTS. 
 
 In order to ascertain the precise manner in which the remedy is 
 affecting the excretory functions, and to enable the physician to 
 control its action, it is necessary to be able to trace Piperazine in the 
 excretions, and particularly in the urine. The method of doing this is 
 as follows : 
 
 About 10 ccm. of the urine to be examined for Piperazine is 
 decomposed by few drops of concentrated soda and slightly warmed 
 
Piperazine. 
 
 for a short time. After cooling the liquid is filtered from the floccuient 
 precipitate of phosphates, etc., made decidedly acid by few drops of 
 hydrochloric acid (avoiding any large excess) and treated with a 
 solution of potassium-bismuth iodide. 
 
 The first effect is the formation of a dirty-coloured amorphous 
 precipitate which contains no Piperazine, but is produced by nucleo- 
 albumen, a constituent of normal urine. The mixture is warmed for 
 a short time to about 40 50 C., in order to cause the precipitate 
 described to aggregate, and then rapidly cooled and filtered. On 
 energetically rubbing with a glass rod, a pomegranate-red crystalline 
 compound appears in microscopic needles which assume a distinctive 
 arrangement. 
 
 When the proportion of Piperazine present is too small to be 
 detected in this way, another more refined modus procendi is 
 available : 
 
 The urine is made decidedly acid and evaporated ; a tenacious 
 brown residue is left behind which is rubbed down with caustic soda 
 in powder. The evolution of ammonia which occurs is due to the 
 decomposition of the urea. The mass is then mixed with about an 
 equal weight of sand and rapidly distilled in a retort with an efficient 
 condenser until no more water- vapour passes over. The Piperazine 
 present in the urine passes over in the distillate unchanged, but 
 organic nitrogenous bodies like sarcosin, creatine, and xanthine are 
 decomposed. The liquid, which collects in the receiver, has a strong 
 odour of alkylamines, is boiled for a short time in order to get rid of 
 the greater part of the ammonia, filtered, acidified with hydrochloric 
 acid, and tested with the double iodide solution referred to already. 
 
 A convenient but less striking process depends upon the character- 
 istic crystalline form of benzoyl-piperazine. Phosphates are separated 
 as in the first process outlined above, a drop of benzoyl-chloride is 
 added, and the whole powerfully agitated. After standing half a day 
 the dirty- white sediment is thrown on to a filter and extracted with 
 absolute alcohol ; the extract is evaporated on a watch-glass, and a 
 drop of the concentrated liquid examined under the microscope. The 
 benzoyl compound of Piperazine separates in characteristic trans- 
 parent rhombs of great regularity. 
 
Piperazine. 
 
 PHYSIOLOGICAL ACTION. 
 
 It has been already intimated that Piperazine was at first supposed 
 to be identical with the "Spermine" of Drs. Brown-Sequard and 
 Poehl ; hence it was primarily regarded as a nervous stimulant. 
 
 The earliest physiological examination of Piperazine was carried out 
 by Prof. Robert of the Dorpat Pharmacological Institute. The result 
 was to demonstrate the freedom of the compound from any injurious 
 or poisonous action. At the same time no evidence was obtained of 
 the stimulant action upon the nervous system anticipated. Similar 
 results were obtained by Bock, who concluded that Piperazine did not 
 possess any marked physiological action. 
 
 Light was thrown upon this apparent discrepancy by the discovery 
 that there was no identity between Piperazine and spermine. Then 
 attention was directed to the solvent power of the synthetical base 
 for uric acid, and on this property was based its employment in 
 medicine. 
 
 Dr. Vogt, in conjunction with the chemists Ferdinand Vigier and 
 Gautrelot, investigated the effects which Piperazine produces upon the 
 metastasis or tissue change continually going on in the animal body. 
 They confined their attention to the urine of patients undergoing 
 treatment with the synthetical compound. The excretion was ex- 
 amined two days before the administration, then after the substance 
 had been given three days and again two days after its use had been 
 discontinued. 
 
 The results of this work led the authors to conclude as follows : 
 
 1. That the percentage of urea in the dry residue had fallen about 
 
 a sixth during the treatment, but that it was higher two 
 days after the administration was discontinued than before it 
 was begun. 
 
 2. That the percentage of uric acid had decreased after three days 
 
 of the treatment, and still more so two days after suspension. 
 
 3. That the ratio of uric acid to urea also fell steadily and 
 
 continuously during the period of observation. 
 
Piperazine. 
 
 The interesting results are noteworthy, though they have not 
 received confirmation by other workers. As a matter of fact our 
 knowledge of the influence of Piperazine on metastasis is still far from 
 complete. It is appropriate that mention should be made here of the 
 experiments which Drs. Heubach and Kuh made upon themselves 
 with Piperazine. Taking as much as 2^ grammes daily they did not 
 observe any functional disturbances or any ill-effect upon the general 
 well-being, but in every experiment a slight increase was observed in 
 the amount of uric acid excreted. 
 
 Drs. Biesenthal and Schmidt (Berl. klin. Wochenschr., 1892, January) 
 turned their attention also to the harmlessness of Piperazine when 
 given internally. Daily doses of 15 to 45 grns. gave rise to no kind of 
 disturbance, and in some cases the compound was taken in ounces at 
 this rate without any unpleasant symptoms appearing. Further, they 
 convinced themselves that much larger doses even than these of 
 Piperazine could be given without any undesirable albuminous changes 
 occurring. This was proved by experiments on a healthy man, under 
 strict diet, to whom during six days i drms. of Piperazine was given, 
 and whose urine was carefully examined day by day. The urine main- 
 tained its acidity, but after the use of Piperazine this considerably 
 diminished ; the base was always present in the urine in large 
 quantities. 
 
 Further, it was of course necessary that such a remedy intended for 
 the solution of gouty concretions in the human tissues, should be 
 stable, as if split up during its passage through the organism, it would 
 be of no use as a solvent for uric acid deposits. It has, however, been 
 shown that such stability is possessed by Piperazine (tier, d. D. chem. 
 GeselL, 1891, pp. 243 and 3237). After a single dose of 75 grns. by far 
 the greater part is excreted with the urine in the course of 24 hours, 
 but even after six days the presence of Piperazine can be detected in 
 the urine, which would not of course be the case if it underwent 
 decomposition in the body. 
 
 It was one object of the research of Drs. Biesenthal and Schmidt 
 to trace Piperazine in its course through the digestive organs and the 
 circulatory system, until it arrived at the point where gouty deposits 
 had been formed. 
 
Piperazine. 
 
 They stated that when the base enters the stomach it is converted, 
 largely at least, into a hydrochloride. This salt, with the sodium 
 carbonate of the alkaline juices, undergoes double decomposition, 
 sodium chloride and Piperazine carbonate being formed. They 
 experimentally demonstrated the mutual decomposition of Piperazine 
 hydrochloride and sodium carbonate when brought into contact 
 (v. under *' Chemical Properties"). Piperazine carbonate has a solvent 
 power for uric acid similar to that of the base, and coming in contact 
 with the gouty deposits forms Piperazine urate, a compound which 
 is more stable to a marked degree than the hydrochloride, as shown 
 by the experiments of Biesenthal and Schmidt, detailed in the 
 previous chapter. 
 
 MEDICINAL PROPERTIES AND USES. 
 
 From the time of Pliny downwards, attempts have been made to 
 effect the solution of urinary stones by chemical means that is to say, 
 by the administration of agents which were believed to exert a solvent 
 action upon the concretions. This treatment was, however, first 
 placed upon a rational basis by the researches of Fourcroy and 
 Vauquelin, who proved that the stones were dissolved by alkalies if 
 consisting of urates, and by acids when made up of phosphates. 
 
 There has, however, always been the difficulty to contend with, that 
 substances used in the laboratory with success, proved of little value 
 when used clinically, because they underwent changes in the organism 
 and reached the seat of the disease in altered, and, for the purpose in 
 view, inert forms. Carbonate of lithium, for instance, which formed 
 the most soluble compound of uric acid known prior to the introduc- 
 tion of Piperazine, appeared in the urine mostly as insoluble chloride. 
 
 Other authors, such as Pfeiffer and Posner, tested the effect of 
 various remedies upon the solvent power of the urine for uric acid, 
 both pure and in the form of stones and gravel. With all these 
 remedies, it was observed that so long as they were used the uric acid 
 decreased, but as soon as they were discontinued, the proportion of 
 acid rose again. 
 
TO Piperazine. 
 
 A further disadvantage of these earlier remedies was that neither 
 the stomach nor the '. 'adder was capable of bearing the quantity of 
 alkali necessary for the . jlution of the concretions, while this class of 
 substances had other serious disadvantages. For instance, if given in 
 too large quantities, so that the urine became unmistakably alkaline, 
 phosphates were thrown out of solution and formed secondary layers, 
 increasing the size of the stones already formed. 
 
 Altogether the internal treatment of phosphate stones has been 
 associated with great difficulties. Injection of acid solution has 
 sometimes proved effective, but by that method alone their formation 
 cannot be prevented. This could only be done by assiduous catheter- 
 isation, drainage and washing out of the bladder, so as to prevent the 
 ammoniacal fermention of the urine. 
 
 Unfortunately the alkalies do not attack the organic foundation of 
 the stones, and, although theoretically the solution of a vesical stone is 
 conceivable enough, experience has not hitherto been able to record 
 a single well-authenticated case in which such an effect has been 
 attained in the human body. When sometimes physicians and patients 
 have believed that the use of such solvent remedies had improved the 
 disease, this was due either to a beneficial effect upon associated 
 symptoms (e.g., vesical catarrh) or to a spontaneous effort of nature. 
 
 Under these circumstances it should not excite surprise that the 
 introduction of a compound possessing such remarkable powers of 
 dissolving uric acid as Piperazine should have at once attracted 
 attention. 
 
 At the same time it must be noted that vesical and renal calculi are 
 not generally of the same composition chemically; vesical " stones" 
 consist almost always of calcium phosphate, or, more rarely, oxalate, 
 with the exception of the small nucleus that is always present, while 
 renal stones much more frequently are composed nearly entirely of 
 urates, though sometimes mixed with phosphates and oxalates also. 
 
 Any foreign body in the bladder may form the nucleus of a calculus, 
 especially if the patient's urine be loaded with phosphates or urates. 
 A small renal calculus may, of course, figure as a vesical stone by 
 subsequent deposition upon it of phosphates, oxalates, etc., unless it 
 
Piperazine. 1 1 
 
 be passed away with the urine immediately after arriving in the 
 bladder. 
 
 Further it is believed that the formation of both vesical and renal 
 calculi is accelerated by the continuous imbibition of large quantities 
 of strongly alkaline mineral waters ; these agents, in neutralising the 
 urine, give rise to eminently favourable conditions for the formation 
 of concretions. 
 
 In considering the extensive literature which has accumulated on 
 Piperazine, it will be convenient to give attention first to its employ- 
 ment in troubles of the urinary tract due to the formation of 
 concretions of the solid constituents of the urine. 
 
 IN RENAL AND VESICAL CALCULI, ETC. 
 (a] Internally. 
 
 Although Dr. Vogt made a special study of the physiological 
 behaviour of Piperazine, he also records its employment clinically in 
 cases of gravel (gouty) associated with severe renal pain. After the 
 administration of Piperazine had been continued a few days the pains 
 entirely ceased, and the urine gave evidence of an increase in the 
 amount of urea excreted, with a corresponding decrease in the amount 
 of uric acid. 
 
 Though the first diagnosis turned out to be incorrect, yet a case of 
 presumptive gravel which came under the observation of Drs. W. 
 Ebstein and C. Sprague (Berl. klin. Wochenschr., 1891, No. 14) should 
 not pass without mention. The principal symptoms were cystic 
 spasm, local pain during urination and obscure transient pains in 
 various parts of the body. Piperazine was given in doses of 30 to 45 
 grns. daily for a fortnight, during which the patient was strictly 
 dieted, and the urine daily estimated for total nitrogen and for uric 
 acid. 
 
 It was found out later, thnt the urinary troubles of the patient were 
 due to a vesical ulcer, but the case is of interest as showing that 
 Piperazine may be given in considerable quantities for prolonged 
 periods without producing any disagreeable effects, even when the 
 epithelial coating of the bladder was the seat of a morbid process. 
 
1 2 Piperazine. 
 
 One of the cases described by Dr. Bardet, Paris, was of renal colic. 
 In the course of six days 75 grns. of Piperazine pur. were given. The 
 patient had had an attack of colic the day before the medicament was 
 begun. The treatment was followed by rapid excretion of small renal 
 stones, and the patient stated that micturition was more rapid and 
 easy than usual. 
 
 Drs. Heubach and Kuh had among their patients a man of 37 who 
 suffered from renal colic ; there was constipation, difficult urination, 
 urine with much sediment and some albumen. After a week's 
 treatment with the usual routine remedies, one tablespoonful of a 
 per cent, solution of Piperazine every two hours was prescribed. 
 On the third day of the treatment, violent pains in the region of the 
 left kidney appeared, which increased during defaecation. A little 
 later a uric acid concretion was passed with great pain and slightly 
 bloody urine. The " stone " resembled in size and form a medium 
 incisor tooth and weighed six grns. The surface bore signs of 
 corrosion. Since the passage of this stone the symptoms did not 
 reappear. 
 
 In a second case, gravel, consisting chiefly of uric acid, had existed 
 for years with frequent attacks of colic and haematuria. A table- 
 spoonful of the % per cent. Piperazine solution every two hours was 
 prescribed, and after the treatment had been continued ten days 
 there was an abundant discharge of small round uric acid concretions. 
 This lasted for several days and was followed by a cessation of the 
 colic and haematuria. 
 
 In a lengthy treatise on the treatment of the uric acid dyscrasia by 
 internal medication in general, and by Piperazine in particular, Dr. 
 Brik (Wien. med. Blatter, 1891, December) describes a case of an old 
 man who had suffered for 45 years from uric acid sediments. The 
 alkaline method of treatment had been chiefly followed, but this was 
 not successful in preventing for long the precipitation of uric acid. 
 The patient had been operated on for stone more than once, very 
 large concretions being removed each time. 
 
 Piperazine was prescribed in daily doses of 15 grns. The first 
 effect was increased diuresis and a manifest diminution of sediment. 
 The urine was always acid in reaction. As the Piperazine was con- 
 
Piperazine. 1 3 
 
 tinued the uric acid sediment disappeared altogether, and did not 
 again reappear in notable quantities for four weeks. A few days' use 
 of the remedy was sufficient to again free the urine from excess of 
 the acid. 
 
 The same. author had under treatment a boy of 14 years with 
 enuresis nocturna, for which a variety of treatment had b^en tried 
 during two years, but without success. The specific gravity of the 
 urine was 1*027, its reaction strongly acid, and 0*2 per cent, of albumen 
 was present. It deposited a sediment of uric acid in different forms 
 (such as are constantly seen in incipient calculosis renalis urica} and 
 also containing red and white blood-corpuscles and epithelial scales. 
 The urinary tract showed nothing abnormal. 
 
 Diagnosing the enuresis as due to incipient calculus formation, the 
 author ordered 15 grns. of Piperazine in six ounces of water, to be 
 taken in two days. From the second day the incontinence ceased, 
 and did not appear again during four successive nights, although the 
 medication was not repeated. Although the patient was not quite 
 cured, the result was characterised as exceedingly satisfactory, the 
 enuresis showing itself only once a fortnight or three weeks. 
 
 The combination of diabetes and uric acid dyscrasia presented 
 special difficulties under the ordinary methods of treatment. Such a 
 case was also recorded by Dr. Brik. The daily quantity of urine was 
 between five and seven pints, albumen was present in traces, sugar to 
 the extent of one to three per cent., and uric acid in large quantities. 
 After other remedies had been tried without success, Piperazine was 
 prescribed. The proportion of uric acid considerably decreased, and 
 for some time sank to zero ; subsequently it rose again to a high level, 
 to drop once more to nil after a few days. 
 
 In this case, and another of similar nature, no effect was observed 
 upon the excretion of urine and sugar, but the subjective well-being 
 was markedly improved and the accompanying joint pains disappeared. 
 The second diabetic patient referred to had also acetonuria, but this 
 abnormality was soon entirely removed. Without entering into further 
 detail, the author mentions that very similar results were obtained in 
 six other cases of excessive excretion of uric acid. 
 
14 Piperazine. 
 
 Dr. Brik spoke of Piperazine as the best uric acid solvent, and 
 svarmly recommended it, especially in the treatment of renal calculus 
 and in the various nervous disturbances which follow on such affec- 
 tions. When vesical stones were very large he considered it advisable 
 to operate and then combat the uric acid dyscrasia with Piperazine, in 
 order to prevent the re-formation of the calculi. 
 
 Dr. Schott, Philadelphia, had also under his care a case of renal 
 colic in which repeated hypodermic injections afforded only partial 
 relief. The attacks recurred day after day, and were exhausting the 
 patient's strength. In consequence an operation was proposed when 
 on the eighth day, unexpectedly, the cause of all the trouble was passed 
 in the form of a fair-sized stone. 
 
 Potash and lithium salts had been used with very little benefit, and 
 the author ascribed the fortunate issue of the case to the prescribing 
 of solution of Piperazine. The patient himself was also very enthusi- 
 astic about the remedy and the relief which it afforded him. Dr. Schott 
 added (Notes on New Remedies, 1891, Dec.,) that since attaining this 
 favourable result he had prescribed Piperazine in other similar cases. 
 
 An interesting case is reported by Dr. Pfeiffer, Wiesbaden. The 
 patient, a lady, suffered from violent pains in the region of the kidneys 
 extending along the course of the right ureter to the tipper part of 
 the thigh. There was also observed in the right iliocaecal region a 
 marked swelling, and the urine, passed in very small quantities at a 
 time, had a bright yellow appearance. When microscopically examined 
 it revealed the presence of a great quantity of flocculent mucous 
 matter with a number of epithelial cells. Although the examination 
 was repeated daily, no crystals of uric acid could be discovered, and 
 in the first instance the diagnosis was felt to be difficult, but 
 Dr. Pfeiffer concluded that uric acid and urate concretions were the 
 cause of the mischief, and acting on this belief he began a course of 
 treatment with Piperazine. 
 
 Before the course was begun, an attack of sickness came on, and 
 fever also developed ; the local pain increased to a very great extent, 
 so that the patient was unable to get quiet rest at night, in spite of 
 large doses of morphine hypodermically. All the usual uric acid 
 solvents lithium carbonate, alkaline waters, etc. had been tried 
 without success. 
 
Piperazine. 1 5 
 
 Piperazine was ordered in daily doses of 15 grns. in aqueous solution. 
 After the treatment had been continued four days a number of 
 fragments of uric acid were to be detected in the urine by the 
 naked eye. The administration of the remedy was also followed by 
 diminution of pain and fall of the febrile temperature to the normal 
 level, while the general condition of the patient improved, and rest 
 and sleep were obtained without difficulty. The hard swelling also 
 diminished and local pain practically ceased. 
 
 These results were taken as evidence of the correctness of the 
 diagnosis, Piperazine having rapidly effected the solution of concre- 
 tions impacted in the right ureter which the older remedies had failed 
 to move. Three daily doses of 15 grns. so far effected solution of the 
 concretion that the disintegrated fragments could pass into the bladder. 
 
 The patient was kept on 8-grn. doses//'*? die of the remedy, with the 
 result that the amount of uric acid excreted gradually diminished 
 to zero. 
 
 In previous cases of "stone" treated with the ordinary remedies, 
 Dr. Pfeiffer had always observed, on about the eighth day, a large 
 increase in the volume of urine, which then became loaded with uric 
 acid concretions, and assumed a marked red colour. 
 
 In the case treated with Piperazine, the peculiar red colour did not 
 appear. This he explained as due to the fact that the synthetical base 
 not only dissolved the uric acid, but the mucous and other matter 
 which held the constituents of the "stone" together. 
 
 This property of Piperazine of dissolving the organic cementing 
 material of urinary concretions, enables it, according to Biesenthal, to 
 disintegrate stones consisting almost entirely of calcium phosphate. 
 At the same time, it has the advantage of not rendering the urine 
 alkaline, and so leading to phosphatic deposits. 
 
 Dr. Biesenthal believed that the continued treatment of patients 
 suffering from the symptoms of uric acid dyscrasia, by large doses of 
 alkalies, was very risky an opinion which received confirmation in 
 the examination of a renal calculus 'taken from a patient who had been 
 treated for a prolonged period with an alkaline mineral water. The 
 calculus had only a small nucleus of uric acid, around which a fairly 
 thick deposit of calcium phosphate had accumulated. 
 
1 6 Piperazine. 
 
 The author had met with 47 cases in his own practice, and collected 
 from colleagues the details of 220 more, in which Piperazine had been 
 employed with extraordinary success. Cases of renal colic were 
 included as well as various haemorrhages from the ureters ; some of the 
 latter, even when they had existed for years, were completely relieved 
 by the use of Piperazine. 
 
 Dr. Volmer obtained specially gratifying results in the case of a 
 merchant who had suffered for a prolonged period from renal colic. 
 He had been through a course of alkaline waters, and concretions 
 were passed which contained uric acid. In spite of this relief and 
 continued treatment with ordinary remedies, fresh attacks of colic 
 appeared, followed in every case by haematuria of several days' duration. 
 
 Piperazine was given in doses of 15 grns. (combined with an equal 
 weight of Phenocoll), and after this dose had been maintained for 
 four weeks, the quantity was reduced one half. From the very first 
 the local symptoms improved, and the haemorrhage ceased to recur. 
 
 Excellent results in renal colic were also obtained by Professor 
 Schweninger, the diet and excretions of the patient being so regulated 
 as to hinder the formation and separation of uric acid in the system. 
 
 () By Local Irrigation. 
 
 Attention was called early in the history of Piperazine to its freedom 
 from caustic or irritating properties ; the special significance of this 
 fact lay in the possibility it opened up of applying Piperazine in 
 solution locally, where vesical stones had to be treated. It has been 
 already pointed out that not only are the alkalies inefficient solvents 
 when used in this way, but also that the bladder is incapable of bearing 
 the quantity of alkali necessary for the purpose. 
 
 Dr. Brik specially noted the suitability of Piperazine for injection 
 into the bladder, owing to the fact that it does not display any local 
 irritant action. Drs. Biesenthal and Schmidt used for irrigation of the 
 bladder one and two per cent, solutions, these being borne for pro- 
 longed periods without the slightest difficulty. Other observers found 
 that even five per cent, solutions could be borne without difficulty ; it 
 
Piperazine. 1 7 
 
 was believed that the necessary renewal of the solution surrounding 
 concretions would be brought about by the movements of the patients. 
 
 In this particular direction there is a field for the initiation of a new 
 method of treating vesical stones, which promises to be of excellent 
 service. At any rate the injection of solutions of Piperazine is 
 worthy of trial, both before proceeding to operative measures and 
 afterwards with the view of preventing the recurrence of the difficulty. 
 
 Summing up the unique properties which Piperazine displays in the 
 treatment of affections of the urinary tract due to uric acid dyscrasia, 
 it appears that : 
 
 1. Piperazine dissolves concretions not only of uric acid but 
 also of phosphates, etc., in consequence of its power of dis- 
 integrating the mucous or albumenoid cementing-material which 
 binds them together. 
 
 2. Piperazine relieves renal colic and other local pain 
 associated with the formation of concretions in the urinary tract 
 owing to its power of dissolving the sharp edges of calculi and 
 giving them a slippery character. 
 
 3. As a consequence of the effect indicated above Piperazine 
 determines the evacuation of " stones " from the kidneys, ureters, 
 or bladder, very soon after administration and before time has 
 elapsed for complete solution. 
 
 4. Piperazine is not only superior as a solvent of uric acid 
 and urates to all previous remedies, but also is free from their 
 disadvantages. 
 
 5. Piperazine does not render the urine alkaline and so 
 favour the deposition of phosphates. 
 
 6. Being free from caustic or irritant action, Piperazine has 
 been used successfully and without any ill-effects for the 
 irrigation of the bladder in the treatment of vesical stone. 
 
 II. IN THE GOUTY DIATHESIS. 
 
 It should be scarcely necessary to premise that medication alone 
 can scarcely be expected in every case to effect alone the cure of 
 
 c 
 
1 8 Piperazine. 
 
 gout. The affection is characterised by marked obstinacy to all 
 forms of treatment, and further there are factors in its etiology or 
 causation which have to be taken into account in combating its 
 symptoms. 
 
 Among these factors an important part is played by diet and habits 
 of living, and it is a well-recognised principle in the therapy of gout 
 that dietetics are almost equal, in the possibilities of improvement 
 they offer, to more purely medicinal measures. 
 
 Further it would seem to be necessary to point out that when a 
 patient has suffered for years from the gouty diathesis, when the 
 whole system is more or less saturated with excess of uric acid and 
 other abnormal constituents, it cannot be expected that a few doses 
 of any medicament, however powerful in action, will be sufficient to 
 effect a complete and permanent cure. 
 
 The pathological distinction between rheumatism and gout in their 
 pure forms is tolerably clearly denned, but there is a large 
 proportion of cases in which it is difficult to diagnose with certainty 
 whether they are rheumatic or gouty in nature. It is in such forms of 
 " rheumatic arthritis," as they are termed, that a trial with Piperazine 
 is specially recommended by the authors who have written upon the 
 properties and employment of the base. Sufferers from the uric acid 
 diathesis and its numerous sequelae fill the various watering places of 
 Europe, and are recommended to bathe in the alkaline waters, and to 
 take a certain quantity of them internally. 
 
 This treatment is, of course, not within the means of all, and it has 
 been, therefore, emphasised as a marked advantage of Piperazine that 
 a course can be gone through without leaving home or temporarily 
 abandoning the usual avocation. At the same time, as will be seen 
 from the following recorded cases, the newer remedy is superior in 
 efficacy to those hitherto employed. 
 
 The effects of the administration of Piperazine may be watched 
 and compared from time to time by examining the urine of patients 
 periodically for urate of the base, by the methods described in a 
 previous section. In this way the activity of the remedy in determining 
 the elimination of the excess of uric acid in the fluids of the body may 
 also be estimated. 
 
Piperazine. 1 9 
 
 Dr. Bardet tried i5-grn. doses of Piperazine in the case of a woman 
 suffering from gout, in whom the urine was heavily loaded with urates. 
 In the course of two days the urine cleared up, while the author was 
 able to detect a slight decrease in the amount of uric acid present 
 within 24 hours of beginning the treatment. 
 
 In a second case a gouty patient suffered from an ulcer of the elbow. 
 The first two days of the treatment i 1 grns. of Piperazine were 
 given daily (by injection) and afterwards 3 6 grns. every two days for a 
 week. The patient observed that the ulcer and redness, which circum- 
 scribed it, rapidly decreased simultaneously, while, further, pain was 
 promptly lessened in intensity. The proportion of uric acid in the 
 urine was 0*65 before the treatment and 0*52 on the last day of it. 
 
 Another man had gout of long standing and podarthritis. He had 
 been subject to intermittent attacks for five months and had rarely 
 been free from pain for two days together. Injections of 3 5 grns. 
 of Piperazine (hydrochloride) were made every two days in the 
 nates. Alleviation of pain was experienced after two days of the 
 treatment. 
 
 An exudation of inflammatory secretion from enormous swellings of 
 the joints produced by urates was a conspicuous symptom in a second 
 case of podarthritis, where extensive and unusual deformity in the limbs 
 had been produced by the disease. The treatment adopted was to 
 inject 3 5 grns. of Piperazine or i to i grns. of the hydrochloride 
 every second day. The patient affirmed that the injection facilitated 
 and accelerated the excretion of urates through the skin. 
 
 The following brief histories of four cases are from a lengthy 
 treatise by Drs. Biesenthal and Schmidt, on their clinical experience 
 with Piperazine (Berl. klin. Wochenschr. t 1892, No. 2). 
 
 The first was of a man 57^ years old, in whom gout was hereditary, 
 and who had suffered numerous attacks and undergone a number 
 of different treatments. During February and March of 1891, about 
 I S !S-grn. doses of Piperazine were given, and during that time 
 gravel and stones, often as large as a small bean, were discharged, 
 almost daily. In July the treatment was suspended for a time, when 
 new outbreaks occurred, and Piperazine was again resorted to and 
 kept up for about six months ; the joints, which had been severely 
 
 C 2 
 
2O Piperazine. 
 
 affected, gradually regained their normal size, the only abnormality 
 remaining being a slight painful swelling of the right ankle. The 
 patient was able to walk about, and felt well. 
 
 Anoiher man, of 35 years, came from a family which had been 
 gouty through the two preceding generations. He had about two 
 attacks each year, varying in duration from one to three weeks ; both 
 large toes and the adjacent tissues were the seat of gouty deposits. 
 The preparation known as Gout Water (r. p. 43 etseg.)was prescribed and 
 continued till about 30 bottles (each containing 15 grns. of Piperazine) 
 had been taken. Some months after the discontinuance of the treat- 
 ment a slight attack of gout appeared, but this was entirely cured by a 
 single day's use of the water. 
 
 A striking illustration of the prompt action of Piperazine is afforded 
 by the following case. The patient, a man of 43 not hereditarily 
 predisposed had attacks of gout usually in spring and autumn, which 
 obliged him to keep to his bed for a week or fortnight. In December 
 of 1891, an exceedingly severe attack set in, for which four grns. 
 of Piperazine were taken, followed by 12 grns. the next morning, and 
 15 grns. on the third day. Immediately after this last dose the 
 condition of the patient was so much improved that he could get up 
 and walk out ; the swollen and reddened joints reassumed their normal 
 colour and appearance. After 18 daily doses of 15 grns. of Piperazine, 
 every symptom of the attack had passed off, and the treatment was 
 stopped. 
 
 Hereditary predisposition was similarly lacking in the next case, a 
 gentleman of 65 years, who had suffered from uric acid dyscrasia for 
 some years. The same dosage of Piperazine was adopted as in the 
 preceding case, and with equally satisfactory results. 
 
 Dr. von Herget detailed an instructive case in a monograph specially 
 compiled by Dr. Biesenthal mentioned above. The patient, a woman, 
 of 38 years, without any hereditary taint, was attacked by gout during 
 her second pregnancy. The most obvious symptoms were inflammatory 
 processes in the wrists and forearms, which steadily increased after 
 delivery, when the lower extremities were also attacked. 
 
 The condition of the sufferer was such that the knee joints were 
 bent almost at right angles, the ankles and wrists much swollen, and 
 
Piperazine. 2 1 
 
 the upper limbs considerably deformed. Pain was very severe during 
 passive movement of the affected parts, and occasionally appeared 
 spontaneously. This condition became more aggravated as time 
 went on, so that the patient was quite helpless and bedridden. 
 
 Between February 24th and March 6th, 1892, Dr. Herget prescribed 
 a pint of Gout Water daily, to be taken in four portions. The 
 beneficial effects were observed in two or three days ; pain acutely 
 felt on the slightest movement sensibly diminished, and in con- 
 sequence more movement in the joints became possible, and the 
 patient felt generally better. 
 
 The influence of Piperazine also showed itself in increased 
 excretion of urine, the quantity rising from 24 35 ozs. during 24 
 hours to 42 48 ozs., while, at the same time, it had a different 
 appearance in consequence of the larger deposits of urates. The 
 increased elimination of uric acid was also established by analysis 
 which revealed the following results : 
 
 Before treatment . . 0*045 per cent, of uric acid. 
 On 3rd day of ditto .. 0-054 ,, ,, ,, 
 ., 9th .. 0-067 
 
 ,r I Oth , 0-059 ,, 
 
 Further, the solvent action of the Piperazine could be detected in 
 the deposits at the joints, which became less swollen, and the 
 overlying integument loose and wrinkled. 
 
 With two intermissions of about two weeks each, when alkaline 
 mineral water was taken, the Piperazine treatment was continued for 
 several months, with steady and continuous improvement both in the 
 general condition of the patient and the amount of uric acid 
 excreted. 
 
 Corroborative evidence of the value of Piperazine in arthritis was 
 obtained by Dr. Volmer from a series of unmistakable cases. He 
 prescribed 8 15 grns. daily to be continued for several weeks. The 
 subjective symptoms were relieved in a much shorter time, and no 
 injurious bye-effects were ever observed. 
 
2 2 Piperazine. 
 
 Over 150 cases of gout were treated successfully with Piperazine by 
 Professor Schweninger. From an extensive experience of the treat- 
 ment of such cases he looks upon the newer remedy as an exceedingly 
 valuable addition to materia medica. Speaking of the local action of 
 Piperazine upon uric acid and concretions in which it occurs, he 
 observes that its solvent effect appears to increase with the circulation 
 in the affected parts, while .not only is the uric acid eliminated but 
 secondary inflammatory necrotic changes in the tissues are avoided. 
 
 Professor Schweninger administered Piperazine both internally and 
 subcutaneously in doses of 15 to 30 grns. pro die. He always 
 obtained good results with the remedy, far superior to those yielded 
 by the ordinary methods of treatment, such as that based on the use 
 of alkalies, of colchicum, and so on ; at the same time he never 
 observed any drawbacks in the action of the substance. 
 
 After the acute symptoms had subsided, 8 15 grns. of Piperazine 
 were ordered every third day for months afterwards. Subcutaneously 
 i^ grn. in ten per cent, solution was employed, and in this way large 
 gouty concretions in the elbows, ears, and even eyelids, which 
 otherwise must have demanded surgical interference, were removed 
 by solution. 
 
 The injections were made two or three times a day in the neigh- 
 bourhood of the deposits, while simultaneously 8 30 grns. were given 
 internally per os. The author characterised his results as so markedly 
 beneficial that he hoped never again to be without the remedy. Most 
 of the cases which came under his care had been subjected to the 
 principal so-called cures in vain, and yet in these obstinate cases the 
 Piperazine treatment proved successful in 90 to 92 per cent, of the 
 number. Although he had had a wide experience of many acute and 
 chronic cases of gout during a number of years, and had tried all the 
 different remedies, none had given such satisfactory results as 
 Piperazine. 
 
 Dr. J. O. Ungerhaunen, writing from South Africa, stated that he 
 had used the Piperazine gout water in a few cases with unexpected 
 success; he looked upon it as a remedy worth more than any which 
 had been previously recommended for the same purpose. 
 
Piperazine. 23 
 
 III. IN SOME OTHER ALLIED DISEASES. 
 
 The reader will have noticed from the outlines of cases described 
 in the preceding sections that one effect of the administration of 
 Piperazine is an increased secretion of urine. This diuretic action 
 of the base is specially emphasised by Dr. Umpfenbach, who made 
 use of it in a variety of diseases where more active uropoesis was 
 indicated. 
 
 In a case of asthma in a paranoic patient, who also suffered from 
 fatty degeneration of the heart, with occasional exudation, dropsy, 
 oedema, etc., as well as oliguria and albuminaria, about f- of a grn. 
 of Piperazine subcutaneously afforded great relief. He breathed 
 more freely and slept well. The volume of urine increased from 
 1 6 1 8 ounces in the twenty-four hours to 66 70 ounces, while 
 the albuminaria fell off at the same time from 7 8 to % per cent. 
 
 As the amount of albumen rose again, and that of the urine 
 diminished, when the remedy was discontinued, it was held proven 
 that these effects were due to the Piperazine. 
 
 A similar increase in the volume of urine, with consequent 
 reduction of exudation, was produced in a case of severe oedematous 
 swelling and infiltration of the leg, following on fracture, in an old 
 man ; confirmatory evidence of the diuretic activity of the preparation 
 was also obtained in other cases, including one of chronic nephritis. 
 
 OTHER SEQUELAE OF THE URIC ACID DIATHESIS. Besides the 
 renal and vesical calculi, the gouty deposits and other symptoms of 
 the uric acid habit already referred to, there are some other affections 
 associated with the presence of uric acid in the blood, in which 
 Piperazine either has been used or would appear to be indicated. 
 
 Early in the literature of the remedy, Dr. Krakauer reported 
 (Aerztl. Central. Anz., p. 543), on its use in two cases, which did not 
 belong to the regular forms of gout, and where he obtained results 
 characterised as very satisfactory. 
 
 Dr. William S. Disbrow, Newark, N.J. (Notes on New Remedies, 1892) 
 expressed his experience with Piperazine as follows : "I have had 
 
24 Piperazine. 
 
 opportunity to employ Piperazine, and have noted successful results. 
 Not the least satisfactory effect of the remedy is the relief it affords in 
 pruritus. " Who is there among general practitioners who has not seen 
 the muddy-complexioned, dry-skinned itcher, the unfortunate whose 
 urinary excretion is filled with urates, and whose system is poisoned 
 with the toxic elements due to imperfect nitrogenous elimination ? 
 Why do gouty or rheumatic patients complain of this same symptom ? 
 You ask them where they itch. They show you, and you find no 
 evidence of local irritation they simply itch. In these cases I 
 have used the new synthetic remedy, Piperazine, with very satisfactory 
 results, in conjunction with diminished nitrogenous food and hydro- 
 chloric acid. The patient's itch may, of course, be due to various 
 causes; but I think I have clearly indicated one cause, and one 
 remedy with which I have achieved good results." 
 
 There are, besides those above-mentioned, other forms of disease 
 which are associated with the uric acid diathesis, or in which uric acid 
 is regularly present in the blood, or excreted in abnormal proportions. 
 In these affections a course of the Piperazine treatment is also 
 considered indicated. 
 
 In leucaemia, for instance, in which an absolute increase of uric acid 
 has been observed by Fleischer and Penzoldt, and a relative increase 
 compared with the amount of urea eliminated, Professor Hosier 
 reported that Piperazine exerted a very favourable influence on the 
 course of the disease. 
 
 An interesting series of experiments were also carried out by 
 Bartels with the remedy in chlorosis, and its use has been suggested by 
 other authors in croupous pneumonia, in which there is a constant 
 increase of uric acid, in pulmonary emphysema and in advanced cardiac 
 degeneration with oedema. 
 
 A review of the entire literature of Piperazine, of which a resume 
 necessarily brief has been given in the preceding pages, throws into 
 
Pip 
 
 erazne. 
 
 prominence the following salient features in the properties and uses 
 of the base: 
 
 1. Piperazine is non-toxic, however administered. 
 
 2. Piperazine passes through the organism without undergoing 
 
 decomposition," appearing as a salt (urate of Piperazine) in 
 the excretions. 
 
 3. When administered in the treatment of the uric acid diathesis 
 
 Piperazine arrives at the seat of the disease in a form (as 
 carbonate) which readily combines with uric acid (of gouty 
 deposits, etc.), the resultant compound being stable, and 
 excreted, as such, from the organism. 
 
 4. Piperazine has a greater power of dissolving uric acid, and 
 
 the compound formed is much more stable than is the case 
 with any substance yet employed for the same purpose. 
 
 5. In the treatment of calculi of the urinary tract, Piperazine has 
 
 the further advantage over the older agents employed, of 
 being able to dissolve the albumenoid substances which form 
 the foundation of the calculi, holding the earthy constituents 
 together. 
 
 6. Being free from caustic or irritant action on the mucous 
 
 membrane, Piperazine may be injected in solution (2 5 per 
 cent.) into the bladder for the relief of gravel and stone. 
 
 7. Piperazine acts beneficially not only in the more character- 
 
 istic and well-marked forms of uric acid dyscrasia, but also in 
 the remoter, secondary and sympathetic phenomena frequently 
 observed. 
 
 8. By its adaptability for local application, both as an irrigation 
 
 and as a subcutaneous injection, Piperazine has effected 
 excellent results in the treatment of cases of calculi and of 
 gouty tophi which otherwise would have necessitated 
 surgical interference. 
 
 9. Piperazine is worthy of trial in all affections which are accom- 
 
 panied by the presence in the blood or the excretions of an 
 excess of uric acid. 
 
26 Piperazine. 
 
 METHODS OF ADMINISTRATION AND 
 APPLICATION. 
 
 It will have become clear from a consideration of the foregoing that 
 an essential factor in the usefulness of Piperazine is that it should be 
 absorbed as promptly and completely as possible into the blood, and 
 circulate with it through all the tissues, being finally excreted with the 
 urine, carrying with it in firm combinaiion the uric acid, which is the 
 abnormal body to be got rid of. 
 
 For these reasons it is advisable, and even necessary, to administer 
 Piperazine in the form of solution, and not as pills and other less- 
 soluble preparations. Other considerations which would lead to the 
 selection of the solution as the most suitable, are the hygro scop i city 
 of the compound and the readiness with which it is taken up by 
 water. 
 
 An agreeable mode of taking Piperazine is in some simple aerated 
 water either by itself or in combination with an equal dose of Phenocoll 
 (v. p. 43). This plan has also the advantage of securing the adminis- 
 tration of the remedy in a sufficiently dilute form. It is a well- 
 recognised and familiar fact that the proportion of water in which a 
 soluble compound is taken is often an important factor in determining 
 the effectiveness of its action. 
 
 It may be repeated here, though already stated in the preceding 
 sections, that the routine dosage of Piperazine per os is 15 grns. pro 
 die, in divided portions ; this quantity may, of course, not only be 
 increased in severe and obstinate cases, but also may be reduced with 
 advantage when the more urgent symptoms of a case have been 
 successfully removed and the continuance of the remedy is necessary 
 only to complete the cure or ensure the avoidance of a relapse. 
 
 But Piperazine has also been administered with conspicuous success 
 by subcutaneous injection. It was used in this way dose i 5 grns. 
 as a diuretic by Dr. Umpfenbach (v. p. 23), by Dr. Bardet against 
 gout (v. p. 19), and by Dr. Schweninger in the local treatment of gout 
 
Piperazine. 2 7 
 
 concretions, which otherwise would have called for surgical operation 
 (v. p. 23). 
 
 The ready solubility of Piperazine in water renders its adminis- 
 tration in this way very convenient and simple ; solutions varying in 
 strength from 2 10 or even 20 per cent, have been employed, and 
 although not quite painless yet the local tenderness soon passes off 
 when the diluter solutions are employed. In the treatment of general 
 gout the injections were made in the nates, but as a matter of course 
 when the resolution of well-defined concretions was aimed at, the 
 injection was made at the seat of the disease. 
 
 Finally Piperazine was applied in solution as a compress, a 
 Priessnitz bandage being saturated with a lotion made as follows : 
 
 R. Piperazine pur grns. xv. xxx. 
 
 Spiritus 5ss. 
 
 Aquae giiss. 
 
 M. ft. Solutio. 
 
 Drs. Biesenthal and Schmidt report that this application had a 
 beneficial effect on gouty swellings, and formed a useful adjunct to 
 the internal treatment. 
 
 The prescription of Piperazine with Phenocoll a specially efficient 
 combination is separately treated in a chapter following the treatise 
 on Phenocoll (v. p. 43). 
 
PHENOCOLL 
 
 Of the various classes of remedies with which synthetical chemistry 
 has enriched our materia medica, none perhaps has assumed much 
 larger dimensions than that of antipyretics. The chief reason for this, 
 if one at all be sought, would probably be found in the fact that the 
 modern development of synthesis, as applied to the production of 
 medicaments, had its origin in attempts to build up in the laboratory a 
 substitute for the natural antifebrile alkaloid of cinchona. 
 
 In spite, however, of this multiplicity of antipyretics, it must be 
 added that they have not all succeeded in doing as much as they were 
 expected to, while not a few have proved, when carefully tested, to 
 possess serious drawbacks, such as a poisonous action upon the blood, 
 a tendency to bring about cyanosis, collapse, &c. 
 
 Further, the greater number of synthetical antipyretics are com- 
 paratively insoluble in water, or only slightly taken up by that solvent. 
 This lack of solubility in water is of course accompanied by a 
 corresponding slowness of absorption, so that the effect is likely to be 
 diffuse and unreliable. It is of course quite unnecessary to emphasise 
 the significance of this difficult assimilation in the treatment of severe 
 febrile temperatures. 
 
 The following pages, containing a brief resume of the literature 
 of Phenocoll, show that it is entitled to take a high rank among the 
 members of the class Antipyretica, by virtue of a number of well- 
 marked distinctive properties. 
 
 CHEMICAL NATURE AND PROPERTIES. 
 
 The researches of a number of physiologists and chemists have shown 
 that by the introduction of acid groups into the molecules of acetanilide 
 and phenacetine, compounds are produced which, whatever other pro- 
 perties they may display, do not possess any antipyretic virtues. A good 
 
30 PhenocolL 
 
 deal of work was carried out in the investigation of this question 
 which started with the observation of Ehrlich that the affinity which 
 certain substances had for the central nervous system disappeared 
 when one or more acid sulphone groups was introduced into the 
 molecule. 
 
 This difficulty was solved in the case of Phenocoll by the addition 
 to the phenetidine group, not of an acid, but of a basic group 
 namely, glycocoll. The relation of phenacetine and Phenocoll is 
 understood at once by a glance at the following formulae : 
 X OC 2 H 5 /OCsH* 
 
 CeH-iN^ CeH*^ 
 
 X NHCOCH 3 X NH.COCH 2 NH a 
 
 Phenacetine. Phenocoll. 
 
 Owing to the presence of the amide group (NH 2 ) in Phenocoll, it 
 is capable of uniting with acids to form salts, of which the hydro- 
 chloride has been chiefly used in medicine. 
 
 Phenocoll hydrochloride occurs in the form of a white micro- 
 crystalline powder, soluble at 17 C., in about 16 parts of water, 
 forming a neutral solution. When crystallised from hot water, it 
 assumes a cubical form, while from alcohol, in which it is soluble only 
 at a fairly high temperature, it separates in the form of needles. 
 
 The pure base, Phenocoll, is thrown out of combination in the salt 
 on the addition of ammonia or the fixed alkalies (or their carbonates) 
 to the solution. It forms white matted needles which melt at 95 C., 
 and contain one molecule of water of crystallisation. 
 
 The most noteworthy of these physical characters is the ready 
 solubility of the compound in water. This property distinguishes it 
 very markedly from phenacetine, which is chemically closely allied to 
 it, but is only sparingly soluble in water. 
 
 PHYSIOLOGICAL PROPERTIES. 
 
 Prof. R. Robert, in Dorpat, was the first to examine the physio- 
 logical properties of Phenocoll hydrochloride, and from the results of 
 his investigation concluded that it was not poisonous to animals, and 
 that it had no effect even on the blood. In this respect the new 
 
Phenocoll. 3 1 
 
 compound contrasted with the majority of synthetical antipyretics 
 previously used. 
 
 Experiments on rabbits and other animals with Phenocoll hydro- 
 chloride were also made by Professor v. Mering, who found that i 
 grammes (about 24 grns.) could be taken by a large rabbit without 
 any perceptible effect being produced. 
 
 Dr. Isaac Ott, Easton, Pa., also made a series of experiments with 
 the compound, and recorded that in frogs it manifested an influence 
 upon the cerebro-spinal axis, evidenced by a general paralysing effect. 
 In rabbits it produced a cyanotic condition of the ears, while the 
 force and frequency of the heart's action was reduced. Even when 
 given in very large doses, the compound does not kill by its effect 
 upon the blood or the heart, but through the centre of respiration. It 
 showed a tendency to diminish vascular tension, while upon the 
 temperature its effect was one of reduction. 
 
 These experiments, concluded the author, explained the utility of 
 the compound in rheumatic pains and in pyrexia. It was evidently a 
 drug of considerable power and rapid in its action. This drug seemed 
 to be worthy of a fair trial at the hands of the profession. 
 
 An elaborate and exhaustive research into the physiological action 
 o'f Phenocoll was carried out by David Cerna, M.D., Ph.D., and 
 William S. Carter, M.D., of the Pennsylvania University. They 
 worked at the same time with other synthetical antipyretics, but, as 
 will be seen below, their conclusions were decidedly in favour of 
 Phenocoll. 
 
 They pointed out early in the treatise (Notes on New Remedies, 1892, 
 September), that unless given in enormous amounts the action of 
 Phenocoll upon the circulation was not marked. At the same time 
 they expressed the belief that, in ordinary medicinal quantities, the 
 substance exerts a slight stimulant effect upon the circulatory system. 
 
 In the dogs used for the experiments the blood-pressure fell slightly 
 after the injections, but soon rose again to the normal level. Respira- 
 tion became somewhat shallow and diminished in frequency, and 
 respiratory failure was the cause of death when the administration was 
 pushed to that extent. These results, it will be noted, agree with 
 those obtained by Dr. Ott. 
 
32 Phenocoll. 
 
 The authors corroborate the finding of Professor Kobert that no 
 change could be detected in the character of the blood. 
 
 Long series of experiments were made upon the action of Phenocoll 
 in reducing the body-heat, both upon normal animals and those in 
 which fever had been artificially produced by repeated small injections 
 (five drops) of putrid blood. In this way a steady fever was brought 
 about, while single large doses of the decomposed liquid were followed 
 by intense febrile reaction, which soon reached its maximum and 
 again fell. 
 
 In order to throw light upon the precise manner in which Phenocoll 
 acted as an antipyretic, the normal heat production and dissipation 
 were carefully ascertained first. Then the compound was given and 
 these factors observed again. 
 
 Neglecting slight variations as being possibly due to accidental 
 causes or to the conditions of the experiment, the authors noted that 
 fever was brought about the first day by an increase of heat production ; 
 dissipation was scarcely disturbed. After the fever was established, 
 the former factor fell, but, being still in excess of the dissipation, the 
 temperature continued to rise. 
 
 In common with most synthetical antipyretics, Phenocoll did not 
 exhibit any effect upon the normal temperature. In the case of those 
 animals in which fever had been artificially produced, a decided 
 antipyretic effect was noted. Summing up the results of the two 
 series of experiments carried out upon the circulatory, and the heat 
 phenomena observed with Phenocoll, the authors expressed the 
 following opinions : 
 
 1. Phenocoll, in ordinary amounts, has practically no effect upon 
 
 the circulation. 
 
 2. Large doses diminish the blood-pressure by influencing the 
 
 heart. 
 
 3. Phenocoll reduces the pulse-rate by stimulating the cardio- 
 
 inhibitory centres. It then increases the rapidity of the 
 pulse by paralysing said centres. The final diminution is of 
 cardiac origin. 
 
 4. Upon the blood itself Phenocoll has no action. 
 
Phenocoll. 33 
 
 5. Phenocoll causes in fever a very decided fall in temperature, 
 which occurs the first hour after the administration of the 
 drug by the stomach. This reduction is the result of an 
 enormous diminution of heat production, without any 
 alteration of heat dissipation. 
 
 Drs. Cerna and Carter believe, judging from the results of their 
 work, that of the compounds they examined, the safest for practical 
 purposes, especially as regarded an action upon abnormal temperatures, 
 would be Phenocoll. In their opinion, its advantages are that it is 
 readily soluble, rapidly absorbed and undoubtedly promptly eliminated. 
 They found that it had a very decided power of reducing abnormally 
 high temperatures, and this in therapeutic doses without depressing 
 the circulatory system. 
 
 Phenocoll was therefore concluded to be superior as an antipyretic 
 to the other members of the same class investigated. 
 
 MEDICINAL PROPERTIES AND USES. 
 
 Phenocoll has been successfully employed in at least three principal 
 roles which may be advantageously considered separately. Its 
 primary use of course was as an agent for combating the high 
 temperature of fevers, and its activity in this field will therefore 
 naturally be dealt with first. 
 
 L AS AN ANTIPYRETIC. 
 
 The physiologist von Mering, who examined the effect of Phenocoll 
 in the animal organism under normal conditions, also tried the 
 substance in cases of pneumonia and typhus with the most satisfactory 
 results. He recorded that in doses of one gramme it lowered the 
 febrile temperature about 2 C. ; no cyanosis nor collapse was 
 observed. 
 
 Dr. Hertel was one of the earliest to publish detailed results 
 obtained with Phenocoll. He employed it as an antifebrile in 
 advanced pulmonary tuberculosis and stated (Deutsche med. Wochenschr.\ 
 1891, No. 15) that during the whole time of the application there 
 
 D 
 
34 PhenocolL 
 
 were no disturbances of any kind in the functions of the heart, lungs 
 or digestive organs. It was possible by judicious dosage to produce 
 in some cases almost complete apyrexia ; he thought, however, that 
 the effect upon the high evening temperature was more marked and 
 reliable than that upon the high diurnal temperature. 
 
 Reascension of the supernormal body-temperature occurred without 
 any unpleasant subjective symptoms, such as, for instance, shivering 
 or perspiration. 
 
 The author added some comments on changes which occurred in 
 the urine during administration of Phenocoll. It always had a 
 marked dark brownish-red colour, which deepened on long exposure 
 to air. The presence of indican and hydrobilirubin could be always 
 detected. The colour also became more intense with solution ef 
 sesquichloride of iron; it was partly cleared away by concentrated 
 sulphuric acid, but never entirely vanished. Viewed by transmitted 
 light, it revealed a peculiar green shade. 
 
 Experiments made on various types of fever by Dr. O. Jacobi, 
 showed that Phenocoll was specially effective in the treatment of that 
 characterised as hectic. In doses of 15 grns., it reduced the tempera- 
 ture in 2^- hours to the extent of 1*4 C. This effect was not attended 
 by any unpleasant subjective symptoms. 
 
 A lengthy communication by Dr. Benno Hcrzog to the Giessen 
 Medical Society, contained the record of 1 1 cases in which Phenocoll 
 was administered as an antifebrile. These included four cases of 
 phthisis, two of erysipelas, and one each of apical pulmonary infil- 
 tration, pleuritic exudation, pneumonia crouposa, abscess and febrile 
 cholelithiasis. 
 
 The remedy was given in doses of eight grns. at 9, 10, 1 1 a.m., and 12 
 noon, then 15 grns. at noon. On a subsequent occasion, the dosage 
 was altered to 4 8 grns. subcutaneously, while TOO--^O- grn. of 
 atropine was given internally ; by this method the temperature could 
 be kept sufficiently reduced without any outbreak of perspiration. 
 The pulse improved in frequency and general character, and the 
 patients felt well. There was no shivering when the temperature rose 
 again to a febrile level. 
 
PhenocolL 35 
 
 In the case of apical pulmonary infiltration, 32 grns. of Phenocoll 
 in four portions were given at first, but subsequently it was found that 
 15 grns. brought about a state of freedom from fever with little or no 
 sweating or rigors. In the other cases the same dosage sometimes 
 varied by the subcutaneous administration of eight grns. was followed 
 by equally beneficial results. In one of the cases of erysipelas, fever 
 permanently disappeared on the third day after three i5-grn. doses. 
 
 The conclusions of the author as to the value of Phenocoll in 
 combating fever were expressed as under : 
 
 1 . Phenocoll has no unpleasant effect upon the digestive tract. 
 
 The saline taste may be covered by administration in wafer. 
 
 2. In one emaciated consumptive, symptoms of dyspnoea, 
 
 cyanosis and heart-weakness were observed after 32 grns., 
 but otherwise even much larger doses never produced 
 similar symptoms. On the contrary, the patients were 
 gratified with the general feeling of well-being induced, 
 while the respiration and pulse improved both in frequency 
 and character. 
 
 3. The antifebrile action, though lacking after small doses, was 
 
 almost always evident after larger. Phenocoll appeared to 
 work best if given when the fever was at its height. Its 
 action was manifested as a rule in an hour, the minimum 
 temperature was reached in three to five hours, and the febrile 
 level again attained only after seven hours or (rarely) more. 
 
 4. Reduction of temperature was almost always accompanied by 
 
 perspiration, which, however, only reached a high degree in 
 patients with whom this symptom was present otherwise. 
 Further it could be controlled by the simultaneous adminis- 
 tration of T^Q- - eV gm. of atropine. 
 
 A most copious combination of reports upon the use of Phenocoll 
 in malaria was presented by Professor P. Albertoni to the Medical 
 
 D 2 
 
36 PhenocolL 
 
 Society of Bologna. Dr. Prati, who carried out a portion of the 
 work, gave details of twenty-two cases, and concluded that Phenocoll 
 was equal if not superior to quinine in therapeutical activity against 
 malaria, and said he had arrested by its means febrile attacks against 
 which quinine proved ineffective. In those isolated cases where no 
 effect was observed, the author believed that either the dosage was too 
 small, or the absence of effect was a matter of idiosyncracy. 
 
 He found that Phenocoll was well borne, doses of 30 grns., at 
 intervals of two hours, not being once followed by disturbance. The 
 taste was easily covered by sugar, and hence Phenocoll was superior 
 to quinine in the treatment of children. 
 
 Drs. Alfred Novie and Victor Venturini also reported upon eleven 
 cases, and expressed very favourable opinions as to the value of 
 Phenocoll in malarial fever. Out of the entire number of cases which 
 were treated by the Italian medical men, a cure was effected in 70 per 
 cent., while the result was negative in 1 5 per cent., and doubtful in as 
 many more. Like quinine, Phenocoll must be given a few days after 
 the attacks have ceased, in order to avoid relapse. 
 
 Five cases which illustrated the antipyretic virtue of Phenocoll, 
 were recorded by Dr. Paul Cohnheim (Therap. Monatsh.^ 1892, No. i), 
 who used the substance in the in-patient ward of the Jewish Hospital, 
 Berlin. The cases included two of ileo-typhus and three of phthisis. 
 In the former, eight-grn. doses were given, with the result of 
 bringing about a fall of temperature amounting, in some instances, 
 to 2-3 2-8 C. 
 
 In the cases of phthisis, the same doses were given, and the bodily 
 temperature kept within the limits of 37 and 39*7 C. In the second 
 case the patient often had spontaneous falls in the temperature, after 
 the use of the remedy had been discontinued. The pulse, which had 
 been dicrotic for weeks, was hardly at all affected by the medication. 
 
 In no case were unpleasant bye-effects, such as collapse, prostration, 
 sickness, tinnitus, etc., observed. The small doses adopted had no 
 appreciable influence on the urine. Pointing out that the results 
 corroborated those of Hertel and Herzog, Dr. Cohnheim urged that 
 Phenocoll is indicated as an antifebrile in fevers, especially of the 
 hectic type. 
 
Phenocoll. 37 
 
 Dr. Balzer studied the antipyretic action of Phenocoll in 15 cases of 
 various nature, namely, seven of abdominal typhus, four of advanced 
 phthisis, three of pneumonia, and one of erysipelas. 
 
 In all the cases of typhus, Phenocoll exerted a very favourable 
 influence upon the course of the fever, and after a few doses there was 
 a decided tendency for the temperature to remain low. A dose of 15 
 grns. sufficed to reduce and maintain the temperature at a normal level 
 for four to six hours even in the height of the fever. 
 
 Similar favourable results followed the administration of Phenocoll 
 in the cases of phthisis accompanied by intermittent hectic fever ; 
 when given in the morning the evening rise of temperature was delayed 
 for several hours. Corresponding to the antifebrile action, a slowing 
 of the pulse was generally observed, though this did not occur in the 
 same ratio. The remedy was always administered in capsules as 
 powder, and nausea was never produced. 
 
 In a case of erysipelas, Phenocoll was administered in the form of 
 a suppository, and although maintained in position only half-an-hour, 
 an antipyretic effect was produced, indicating that the absorption of 
 the compound from the intestines takes place very rapidly. 
 
 Phenocoll proved, in the hands of Dr. Rudolph Bum, a strong and 
 very reliable antipyretic in cases of phthisis, whilst in low fevers it 
 also exerted a beneficial influence. The maximum dosage adopted 
 was 75 grns. 
 
 II. AS AN ANTIRHEUMATIC. 
 
 Four cases of rheumatism figured among those described by 
 Dr. Hertel early in the history of the use of Phenocoll. In the first of 
 these, the joints of the right knee, the hip, elbow, hand and fingers, 
 were attacked, as well as the lower portion of the spinal column. All 
 the joints were highly swollen so that active movement was scarcely 
 possible. Antipyrine with morphine, sodium salicylate and acetanilide 
 having been given in vain, Phenocoll was prescribed in daily doses of 
 75 
 
38 Phenocoll. 
 
 On the second day of the treatment considerable improvement was 
 noted, with less swelling of the joints. Painfulness persisted in the 
 cervical vertebrae, but on the whole was so far reduced that active 
 movement of the body could be effected without particular difficulty. 
 By the evening of the fourth day every joint was painless and swelling 
 had passed off. 
 
 For about a fortnight after this, the stock of Phenocoll being 
 exhausted, ether remedies were resorted to, but pains reappeared in 
 various joints. Finally Phenocoll was again returned to, and the 
 symptoms permanently removed. 
 
 In the remaining cases, described by Dr. Hertel, the older remedies 
 were first administered without satisfactory results. Phenocoll in daily 
 doses of 45 75 grns. in separate portions of 15 grns. brought about 
 the cessation of joint-pain in two or three days. 
 
 Drawing general conclusions from his cases, the author stated that 
 in severe acute febrile articular rheumatism, partly with complications, 
 the remedy, in daily doses of 75 grns. had a good effect upon the 
 painful joint affections, but none immediately upon the temperature ; 
 the latter receded to the normal level only when the other symptoms 
 improved. These beneficial results were obtained after the ordinary 
 remedies had failed. 
 
 In a single case of chronic rheumatism of the left hip-joint, Dr. 
 Herzog made two subcutaneous injection of four grns. of Phenocoll 
 into the gluteal region. The diminution of pain was sufficiently 
 marked to enable the patient, who had previously gone on crutches, 
 to walk unaided, though, of course, with considerable difficulty. 
 
 Opportunity of observing the antirheumatic action of Phenocoll was 
 afforded Dr. Cohnheim by three cases, in two of which very striking 
 results were obtained. In both the disease was in the acute stage ; 
 one patient suffered with marked swelling and pains in the right 
 wrist and hand, while in the other the left knee was the seat of 
 the affection. 
 
 In the first case, after a single day of the treatment, free movement 
 of the affected joint was possible, and on the fourth day the patient 
 was entirely free from pain. In the second, pain was entirely got rid 
 of after n days of the treatment, but two days later there was a 
 
Phenocoll. 39 
 
 recurrence ; is-grn. doses were again resorted to and followed by an 
 almost immediate disappearance of pain, and the joints could be 
 freely moved without discomfort. Beyond copious perspiration and 
 consequent thirst, no unpleasant effects were noted, even when \\ 
 drms. were being taken daily. 
 
 The value of Phenocoll in rheumatic affections was most marked, 
 according to Dr. Balzer, in acute polyarthritis, and was particularly 
 useful in cases where salicylates were contra-indicated or did not 
 produce the desired effect. The action of the remedy was examined 
 in six cases of acute and two of chronic polyarthritis, and although 
 (like all antirheumatics) less active in the chronic forms, it produced 
 prompt relief in acute cases where the routine methods of treatment 
 had failed. Like most observers, Dr. Balzer noted that in rheumatic 
 affections larger doses were necessary than when employed as an 
 antifebrile. 
 
 III. AS AN ANTINEURALGIC. 
 
 Two instructive cases illustrative of the value of Phenocoll in the 
 treatment of neuralgic pains were recorded by Dr. Herzog. One 
 patient (a woman) suffered from otitis media with very violent head- 
 ache of the left side, which had only been relieved for a short time 
 by acetanilide. Phenocoll was prescribed in doses of four grns. with 
 the result that an hour later pain was annulled for an hour. On the 
 next day four grns. was given again and the headache disappeared 
 for two hours. 
 
 The second case was also of otitis media with very violent pains on 
 the left side of the head ; four grns. of Phenocoll dispersed the pain in 
 about two hours. On the three succeeding days the same dose was 
 repeated, being given once in the morning, once in the evening, and 
 the third day, an hour past noon. Then eight grns. was ordered, with 
 the result of effecting in each instance cessation of pain, followed after 
 varying periods by recurrence. 
 
 In two cases of sciatica of the right side, subcutaneous injections 
 were made once or twice daily (dose 48 grns.) at the seat of the 
 disease. Pain was removed in both instances, though sometimes it 
 set in again in the night. 
 
4O Phenocoll. 
 
 Dr. H. Aronson, who made a chemico-pharmacological study of 
 Phenocoll and allied compounds, said at the conclusion of the article 
 in which his work was recorded, "As an antineuralgic it displayed, 
 in a few cases observed by me, a safe and prompt action." 
 
 Phenocoll was prescribed by Dr. Paul Cohnheim in neuralgias of 
 various parts associated with phthisis, neurasthenia, chorea, enteritis 
 acuta, hysteria and myelitis transversa. The remedy produced the 
 desired effect in all the cases save in the first and last two forms, 
 where also other usual remedies were without beneficial influence. 
 The author observed that after these trials Phenocoll was justly entitled 
 to a place among the recognised antineuralgic remedies. There were 
 no unpleasant bye-effects. Whilst small single doses were ineffectual, 
 the results of eight grns. three times a day were unmistakable. 
 
 The influenza epidemics offered a good field for testing the power 
 of Phenocoll over pain of nervous origin, and the literature relating to 
 its employment in these cases showed that it came well out of the 
 trial. Seven cases classed by Dr. Cohnheim under neuralgias were due 
 to influenza, and in these Phenocoll was given with success ; pain was 
 alleviated and sound sleep induced. In a few instances variations 
 were observed in the manner in which the pains of Influenza were 
 affected ; generally those in the back were relieved at once, while the 
 headache was only little or not at all affected. In all the cases, it 
 should be noted, the febrile stage had been passed before Phenocoll 
 was given against the pain. 
 
 The fact that influenza was liable to influence the heart and the 
 digestive organs, contra-indicated the use of a number of the ordinary 
 antipyretic and aritirheumatic remedies. For the same reason 
 Phenocoll was expected, upon a priori grounds, to prove a harmless 
 and efficient remedy in influenza, and the results of the practical 
 trials made with it showed this expectation to be perfectly well 
 founded. 
 
 Dr. Lazarus reported on the employment of Phenocoll against 
 influenza, to the Berlin Society, for internal medicine. He prescribed 
 it not purely as an analgesic, but also as an antipyretic and anti- 
 rheumatic. In doses of eight grns., very satisfactory results were 
 obtained, without any unpleasant bye- or after-effects. 
 
PhenocolL 4 1 
 
 Dr. C. W. Brandenburg, Brooklyn, New York, also treated a 
 number of cases of "la grippe" with Phenocoll, and recorded one 
 (Notes on New Remedies, 1891, Dec.) in which, by its means, an attack 
 which threatened to be of a severe type was successfully aborted. 
 The patient, when first seen, was suffering severely with frontal 
 headache and pains in the cervical and lumbar regions of the spine. 
 Other symptoms were considerable muscular soreness, a general 
 feeling of weakness and malaise, coryza and pain in the left ear. 
 The temperature was 103 F., and the pulse 120. 
 
 The author prescribed eight grns. of Phenocoll in water every two 
 hours, until four had been taken, and then one to be taken the 
 following morning. At the latter period, Dr. Brandenburg called on 
 the patient, expecting to find him in bed, but instead of this he was 
 away at business as usual. Shortly after the third powder perspiration 
 became marked, aches and pains disappeared, and sound sleep 
 followed until the morning, when the patient felt well enough to 
 attend to business. 
 
 Observations of a similar nature were made by Dr. J. O. 
 Ungerhausen, district surgeon of the Lion's River Division, South 
 Africa. It gave very satisfactory results in the treatment of influenza, 
 and also in the first stage of a common cold, when the mucous 
 membrane of the upper part of the respiratory tract was swollen and 
 inflamed. All stages were remarkably shortened, headache disappear- 
 ing, and catarrh setting in more rapidly, but not developing into so 
 severe a form. 
 
 In the Drasche Clinic, Vienna, Dr. Bum found that as an anti- 
 neuralgic, Phenocoll had a very marked beneficial influence upon 
 migraine, and unpleasant symptoms were seldom observed. 
 
 Similar observations were made by Dr. Balzer in three cases of 
 sciatica, in one of lumbar neuralgia, and two of uraemic cephalalgia. 
 In those of sciatica the favourable effect of the remedy was quite 
 manifest ; improvement took place gradually, and was not followed 
 by any relapse if the administration of Phenocoll was continued for 
 a few days. The results were not so satisfactory in the cases of 
 lumbar neuralgia and chronic nephritis, accompanied by uraemic 
 headache. The maximum dose pro di, was 60 grns., and the largest 
 
42 Phenocoll. 
 
 quantity taken by any single patient was i ounces. The author 
 expressed the opinion that Phenocoll was specially indicated in the 
 forms of neuralgia arising from chills. 
 
 DOSAGE AND METHODS OF USE. 
 
 It will not be necessary to deal with the dosage of Phenocoll at great 
 length here, since the subject has been included in the preceding 
 sections where the quantities appropriate in each form of disease were 
 indicated. It will be sufficient to say that the average dose as an anti- 
 pyretic was 75 grns. pro die divided into powders of 15 grns. each ; 
 sometimes 45 grns. during the day was found sufficient. The general 
 rule that advanced consumptives require smaller doses of antipyretic 
 remedies than the usual must of course be also adhered to in the 
 case of Phenocoll. Outbreaks of perspiration, when occurring to an 
 uncomfortable extent, may be prevented by the simultaneous adminis- 
 tration of atropine in doses of i- - - eV grn. 
 
 In malaria 30 grns. was given with intervals of two hours between 
 the doses. 
 
 Against rheumatism and neuralgia, full doses 75 grns. daily in 
 divided portions must be given in order to ensure satisfactory results. 
 
 The compound may be prescribed as powders to be taken in wafers 
 or in simple aqueous solution with some ordinary flavouring agents ; 
 the latter form is perhaps the best under usual circumstances, as the 
 absorption of the compound is more certainly ensured. 
 
 Hypodermically doses of 4 8 grns. were chiefly employed. Dr. 
 Herzog prepared a glycerine solution made by dissolving 15 grns. of 
 Phenocoll hydrochloride in 30 grns. of glycerine warming to 50 6oC. 
 This solution was determined chemically to contain exactly four grns. 
 in 1 6 minims ; it had to be warmed before use, as in about an hour it 
 became a compact white mass, similar to paraffin in appearance. By 
 using glycerine as the solvent it is possible to administer an appropriate 
 dose without having to inject too large a volume of liquid. 
 
Phenocoll with Piper azine. 43 
 
 PHENOCOLL AND PIPERAZINE 
 IN COMBINATION. 
 
 The pronounced analgesic properties of Phenocoll, particularly in 
 rheumatic conditions, in conjunction with its perfect harmlessness, 
 suggested the idea of giving it in combination with Piperazine for the 
 treatment of gout. While Piperazine would act as solvent for and 
 facilitate the elimination of uric acid, the Phenocoll would relieve the 
 symptoms of topical inflammation due to localisation of uric acid 
 deposits. 
 
 Owing to the established custom of taking aerated mineral waters 
 for the relief of the gouty diathesis, Piperazine was also largely 
 administered in carbonated water, when its value in the treatment of 
 gout became recognised. Hence the next step was naturally to 
 prepare a Phenocoll-Piperazine water, each pint of which should 
 contain a certain definite amount of each remedy. The amount 
 selected was eight grns., so that if two bottles were used daily the 
 quantities of the compounds taken would be considerably less than 
 had been administered for prolonged periods without any kind of 
 disturbance. 
 
 The employment t>f such a preparation was of course so simple and 
 safe that it was felt to be worthy of extended trial. Treatment with 
 such an aerated water could be carried on with but little of the 
 constant claim upon the physician's attention, which is necessary in 
 the case of many remedies, owing to the freedom of both the active 
 ingredients from any corrosive or poisonous action. Again, the 
 rapidity with which the compounds are secreted from the body 
 removed any apprehensions as to the production of unpleasant 
 cumulative effects. 
 
 The earliest report upon the action of this combination recorded 
 its value in the treatment of the uric acid diathesis. 
 
 (a) IN GOUTY AND RHEUMATIC DISEASES. 
 
 Dr. Ritter, of Dresden, described a number of cases characterised 
 by chronic gouty enlargements of the joints and various morbid local 
 
44 Phenocoll loith Piperazine. 
 
 changes. The Piperazine and Phenocoll were given in daily doses of 
 15 grns. in the form of solution in aerated water. 
 
 In the first case pain decreased after the treatment had been con- 
 tinued nine days and the swelling of the joints was reduced ; the urine 
 was clear and abundant, the colour of the skin improved. After four 
 weeks' treatment the patient could walk again and remained free from 
 pain. 
 
 In the second the swelling of the joints decreased after a week ; 
 there was evident improvement of the general well-being, the appetite 
 and the colour. The amount of uric acid excreted increased. 
 
 Pronounced excretion of urates through the skin was a conspicuous 
 symptom in the third case. After a fortnight, symptoms of swelling and 
 inflammation subsided. The total duration of the treatment was three 
 weeks, the same dosage being adopted as in the former cases. 
 
 In a case of hereditary gout, four weeks' treatment produced 
 excellent results. The great toe joint was rapidly reduced in size and 
 pain was markedly alleviated. The urine was clear and abundant, 
 vesical catarrh disappeared and urates increased. There was abundant 
 sticky perspiration, but the general feeling was excellent, and the 
 appetite good. 
 
 The Phenocoll and Piperazine combination was also tried by 
 Dr. Herget in gout, with the result that beneficial results were observed 
 in two or three days. The pains occasioned by the slightest move- 
 ment sensibly diminished, and, in consequence, movements of all the 
 joints became more free and easy, and the patient felt generally better. 
 The appetite did not suffer. During an interval of some days the 
 remedy was discontinued, and an ordinary mineral water given. The 
 pains, however, grew in intensity, and the combined treatment was 
 again resorted to, and followed by lessening pain, freer movements 
 and undisturbed sleep. 
 
 It was noticed that the medication had a further favourable influence 
 both on the quantity and character of the urine. The secretion 
 increased in activity, the volume passed during the 24 hours prac- 
 tically doubling ; at the same time, owing to the larger amount of 
 urates deposited, the fluid has a different appearance. The effect 
 
Phenocoll with Piperazine. 4.5 
 
 upon elimination of uric acid, as determined by chemical experiment, 
 was found to be as follows: 
 
 Before commencement of treatment, 0*045 per cent, uric acid. 
 On the third day of ,, 0-054 >, , 
 
 ,, ninth ,, ,, ,, 0*067 " 
 
 tenth 0-059 >. 
 
 Locally the solvent action of the combination was evidenced in the 
 reduction of the enlargements due to gouty deposits. So rapidly were 
 these deposits carried away that the skin covering them had not time 
 to adapt itself to the altered form of the parts, but became loose and 
 wrinkled. 
 
 (3) IN VESICAL AND RENAL STONE. 
 
 Among Dr. Ritter's cases was one of a man aged 64, who had 
 been operated on 14 years before for vesical stone. At the time of 
 observation there was evidence of the presence of gravel in the renal 
 pelvis and small stones. The principal symptoms were severe renal 
 colic and vesical catarrh. 
 
 The combination was prescribed in daily doses of 30 grns. and the 
 treatment continued for 20 days. The vesical catarrh was first to 
 yield, and the urine became clear and abundant. There was a slight 
 excretion of gravel. The patient felt much better in himself at the 
 end of the course. 
 
 (0 IN GASTRIC TROUBLES. 
 
 It would appear that certain forms of digestive disorder are sequelae 
 of the rheumatic or gouty habit. Such cases are by no means easy to 
 treat, since they are resistant to the ordinary remedies. Consideration 
 of the etiology of these gastric troubles indicates the administration 
 of specific remedies, and in this way excellent results may be obtained 
 in cases which other methods fail to improve. 
 
 An illustration of the truth of this view is afforded by the following 
 case recorded by Dr. Schott, Philadelphia (Notes on New Remedies, 
 1890, July). The patient, a lady of about 60 years, who had previously 
 
46 Phenocoll with Piperazine. 
 
 suffered much from rheumatism, sought relief from annoying pains, 
 due to irritability of the stomach, which always recurred after meals, 
 no matter how carefully the food was selected. Every kind of food 
 was rejected, and nourishment could be administered only in the form 
 of enemata of peptonised beef. 
 
 Dr. Schott ordered Phenocoll and Piperazine in is-grn. doses 
 of each, pro die, dissolved in carbonated water. Pain was relieved in 
 a very short time, and then the vomiting stopped. After taking the 
 combination for about six weeks, the patient seemed to have completely 
 recovered, and felt as well as she had ever done in her life. 
 
 Dosage and Prescription, 
 
 The minimum dose of the Phenocoll and Piperazine combination 
 is 30 grns. daily, that is, 15 grns. of each. This quantity may be 
 increased up to one drm. of each, pro die, if the smaller doses are not 
 efficient, or if the case be exceptionally severe. It has been already 
 shown that neither Phenocoll nor Piperazine has any disturbing 
 influence upon the heart or blood, and that they may be taken for 
 prolonged periods without affecting the vital functions of the body. 
 
 The best way to prescribe the combination is to order the dose to 
 be taken in a tumblerful of plain or aerated water. It is necessary to 
 point out that if plain water be selected as the vehicle, a certain 
 amount of turbidity may be produced. This, however, is at once 
 cleared up on the addition of aerated water. The medicament may 
 be taken with meals if desired, but seems to be more effective when 
 taken at frequent intervals between them. 
 
C LORALAMID 
 
 In earlier times the physician was chiefly dependent upon the 
 opium alkaloids, or upon chloral hydrate, in cases where a narcotic or 
 hypnotic was indicated. But these medicaments could not be safely 
 employed in every instance. The continued administration of opium, 
 for example, is soon followed by habituation on the part .of the 
 patients, so that the doses have to be constantly increased ; at the 
 same time there is the risk of producing the opium habit. Chloral 
 hydrate, again, is not always free from risk, as regards its action upon 
 the heart, nor from unpleasant after-effects, such as giddiness, 
 depression, an unpleasant taste in the mouth, etc. 
 
 It followed therefore that in the development of synthetical 
 chemistry, as regards the production of medicinal agents, which has 
 taken place of late years, the preparation of hypnotic remedies has 
 excited general interest, and each compound which displayed an action 
 of this kind was exhaustively and searchingly examined. 
 
 The advantages of Chloralamid among this class of remedies were, 
 in consequence, early recognised, and all the minute investigations of 
 its properties only served to establish it more firmly in the high 
 position it obtained among pure hypnotics capable of bringing about 
 a sleep indistinguishable in character from physiological slumber. 
 
 PHYSICAL AND CHEMICAL CHARACTERS. 
 
 Regarded as a chemical compound, Chloralamid is chloral 
 formamide, being an additive product of chloral anhydride 
 CC1 3 CHO and formamide CHO NH 2 . One of the hydrogen atoms 
 of the amide group (NH 2 ) forms hydroxyl (HO) with the oxygen 
 
48 Chloralamid. 
 
 atom of the chlorar, and the resulting compound has the constitution 
 represented by the formula 
 
 CCl CH/ H 
 
 X IMHCHO 
 
 It forms colourless lustrous crystals soluble in about 20 parts of 
 cold water and in i parts of 96 per cent, alcohol. It is partially 
 decomposed into chloral hydrate and ammonium formate by water 
 heated above 60 C. (140 F.), but under ordinary conditions, the 
 aqueous solution is quite stable. Alkalies bring about the same 
 dissociation as warm water, but dilute acids have no effect. It melts 
 at ii5C. 
 
 Chloralamid has a mild, feebly bitter taste, in no way pungent like 
 chloral. 
 
 PHYSIOLOGICAL ACTION. 
 
 The first contribution to our knowledge of the effect of Chloralamid 
 upon the healthy animal functions and tissues, was due to Dr. Eugen 
 Kny, of the Strassburg Psychiatric Institute. His work was too 
 lengthy to admit of detailed reference ; but generalising, it may be 
 stated that he found Chloralamid a somewhat less powerful hypnotic 
 than chloral, but with the marked advantage of being free from action 
 on the heart, or on the digestive tract ; and, further, on account of 
 its comparative tastelessness, much more readily taken. In addition, 
 Chloralamid was not attended by the symptoms of congestion and 
 unpleasant after-effects sometimes observed with chloral hydrate. 
 
 The author's experiments, carried out with the view of ascertaining 
 the fate of Chloralamid in the animal organism, showed that chloral 
 hydrate was set free from it ; he detected a large proportion of uro- 
 chloralic acid in the urine of a dog which had been given three drms. 
 of the hypnotic. 
 
 The problem had therefore to be solved why Chloralamid, even 
 when exerting its full effect, was without any prejudicial action on 
 the circulatory system, if, as seemed proved, it yielded chloral in the 
 
Chloralamid. 49 
 
 organism, which had been repeatedly shown, powerfully affected the 
 heart. 
 
 Dr. Kny suggested that the difference could be explained from two 
 points of view. In the first place, it might be that the compound was 
 only slowly split up by the free alkali of the circulating blood, so that 
 only small quantities of chloral were set free at any one time. In the 
 second place the depressant tendency of the chloral might be counter- 
 acted by the stimulant effect of the formamid, which,* like all amide 
 derivatives, had a stimulating action upon the vascular centre in the 
 medulla, and thereby raised the blood-pressure. 
 
 Professor A. Langgaard believed that he observed some effect upon 
 the vascular tension, though the heart's action remained vigorous, but 
 the reliability of his experiments was called in question by Professor 
 J. von Mering and N. Zuntz (Therap. Monatsh., 1889) who called 
 attention to the fact that even physiological sleep reduced blood- 
 pressure. Their own elaborate experiments satisfied them that 
 Chloralamid could be safely given, even in cases of disease in which 
 chloral hydrate, on account of its action on the heart and blood- 
 pressure, was contra-indicated. 
 
 Concordantly with Kny the authors observed that the effect of 
 chloral hydrate set in more rapidly than that of Chloralamid, but at 
 the same time the hypnotic effect passed off sooner. 
 
 Dr. John Gordon, Aberdeen University, having studied the 
 physiological action of Chloralamid, concluded (Brit. Med. Journ. y 
 1891, May 1 6th,) that, in small doses, it tended to increase the 
 elimination of urea, but that this factor fell off when the doses were 
 large enough to produce a hypnotic effect. The excretion of 
 phosphates was diminished in all doses. No irritation of the gastro- 
 intestinal tract was observed, and no thirst was complained of during 
 its administration. 
 
 Dr. H. C. Wood, Professor of Materia Medica and Therapeutics 
 and of diseases of the nervous system in the Pennsylvania University, 
 and Dr. D. Cerna, Assistant in Physiology of the same Institution, 
 carried out a research upon the physiological action of Chloralamid 
 quite recently (Notes on New Remedies, 1891, August isth). Dogs were 
 chiefly used for the experiments, of which some dozen were. performed. 
 
 E 
 
50 Chloralamid. 
 
 in order to ascertain the effect of the compound upon the nervous 
 system, the respiration and circulation. The conclusions arrived at 
 were expressed as follows : 
 
 1. Chloralamid has a slight local action, and in large doses tends 
 
 to produce mucous diarrhoea. 
 
 2. It acts more powerfully upon the cerebral cortex than upon 
 
 any other portion of the nervous system of voluntary life, 
 thereby causing sleep and muscular relaxation ; it is also a 
 feeble spinal depressant. 
 
 3. It has a powerful influence in moderate dose upon the 
 
 respiration, stimulating the respiratory rate by a centric 
 action and probably also increasing the actual amount of air 
 breathed ; in toxic doses it causes death by paralysis. 
 
 4. Its influence upon the circulation is very feeble, the changes 
 
 produced by small doses being probably secondary to other 
 effects of the drug ; toxic doses, however, depress the arterial 
 pressure by a direct action either upon the heart or upon the 
 muscular coats of the arterials. 
 
 The authors inferred from these physiological data that Chloral- 
 amid might be safely given in cases of feeble heart ; its stimulating 
 influence upon the respiration seemed to render it peculiarly suitable 
 in cases of nervous exhaustion. The observations of Drs. Wood and 
 Cerna throw light also upon the finding of Drs. Hagen and Hiifler, 
 referred to later, that Chloralamid is especially valuable in cardiac 
 asthma. 
 
 THERAPEUTICAL EMPLOYMENT. 
 (a) In Insomnia. 
 
 As already indicated in the preceding section, Chloralamid may be 
 considered a pure hypnotic without any secondary influence upon the 
 functional activity of the animal organism. Particulars of its action 
 in special cases will be given incidentally in considering the experience 
 of the authors who have employed it clinically, but it will be 
 interesting to present here, at the outset, some general features of its 
 therapeutical effects. 
 
Chloralamid. 5 1 
 
 Of course it is impossible to lay down any hard and fast rule as to 
 the time which intervenes between the administration of a dose of 
 Chloralamid and the appearance of its characteristic effects. Many 
 factors, including the mode of administration, personal idiosyncrasy, 
 etc., determine differences in this respect. The average limits may be 
 given, however, as a half to three hours. Out of 55 cases which 
 Lettow observed, with special attention to this point, the action set in 
 after one hour in 29 instances, after two hours in 23, and after three 
 hours three times. 
 
 Another interesting feature of the action of the remedy is the 
 duration of the sleep it induces. Broadly considered, the time may 
 vary between two and nine hours. In Lettow's experience this 
 author made a special study of these details the sleep lasted from 
 4 6 hours in 17 cases (out of 21), between 24 hours twice, and 
 twice it lasted only two hours. 
 
 Dr. Kny, who made the first physiological investigation of 
 Chloralamid referred to above, also tried the compound clinically in 
 31 cases, prescribing it in doses of 24 60 grns. He found that 
 excellent results were given in psychoses, not accompanied by too 
 active excitement. Regular sleep was also induced in chronic 
 alcoholics and in patients suffering from tabes dorsalis, even when 
 they had been taking large doses of morphine. In four cases of 
 sleeplessness in neurasthenics, satisfactory results were obtained, as 
 also in instances where the morbid condition was due to bodily pain 
 of not too great intensity. 
 
 Allusion has been already made to the work of Drs. Hagen and 
 Hiifler on Chloralamid. They believed that it produced a hypnotic 
 effect immediately, that is, by a direct action upon the centres regu- 
 lating the function. In this respect, however, they differed from 
 Professor Alt, who reached the conclusion that the effect of the 
 remedy was indirectly brought about. 
 
 Striking observations were recorded by the two co-workers above- 
 named in cardiac asthma. During the administration of Chloralamid, 
 the pulse rose and the attacks entirely ceased. These effects must be 
 ascribed in all probability to the stimulant effect of the compound 
 upon the respiratory centres. 
 
 E 2 
 
5 2 Chloralamid. 
 
 No less noteworthy were the results obtained by Alt in chorea with 
 Chloralamid. He prescribed 1 5 grns. three times a day, and in from 
 5 8 days the affection was almost entirely cured. 
 
 Speaking from a considerable experience with Chloralamid, Dr. K. 
 Schaffer pronounced it superior to the other synthetical hypnotics such 
 as chloral hydrate, sulphonal, amylene hydrate, paraldehyde. In 15 
 cases of progressive dementia paralytica, 30 grns. proved sufficient to 
 relieve the sleeplessness. Where there was slight excitement he gave 
 i \\ drms. or up to i drms. in more pronounced cases. In one 
 instance a morphine injection was simultaneously given. The author 
 specifically mentioned a number of varieties of dementia and delirium 
 in which Chloralamid was successfully given. In general he was 
 satisfied with the action of the compound as an hypnotic, and no 
 unpleasant bye-effects were observed ; even after doses of i \\ drms. 
 the patients did not complain of headache, nausea, or other unpleasant 
 symptom. The cases in which good sleep was obtained by means of 
 Chloralamid included one of hysteria and three of hystero-epilepsy. 
 
 At a meeting of the Practitioners' Society, New York, Dr. George 
 L. Peabody gave the results of his experience with Chloralamid (The 
 Medical Record, 1889, November i6th). Although the effect was 
 characterised as less energetic and prompt than that of chloral 
 hydrate, it proved useful in the most varied forms of sleeplessness, even 
 in alcoholics, and in a case of cerebral haemorrhage accompanied by 
 great restlessness. It effected great alleviation in two cases of neuralgia 
 with sleeplessness. No disquieting symptoms were ever observed. 
 Chloralamid had the advantages over chloral hydrate of being less 
 irritant to mucous membrane and of having a less unpleasant taste. 
 
 Dr. E. Schmidt employed the hypnotic subcutaneously in a case of 
 carcinoma of the rectum. Each ccm. of the solution used contained 
 o'O4 grm. of Chloralamid, and one or two syringefuls were sufficient to 
 induce quiet and refreshing sleep lasting eight hours, in spite of the 
 violent pains suffered by the patients. A similar result was obtained 
 in a case of violent hepatic colic. 
 
 Further evidence of the value of Chloralamid was furnished by Dr. 
 Umpfenbach, of the Andernach Lunatic Asylum, who prescribed it in 
 55 cases (23 men and 32 women). To begin with, 30 grns. of the 
 
Chloralamid. 53 
 
 remedy were prescribed, increasing up to i drms., pro dost and 
 pro die. 
 
 In 30 of the cases the desired effect was attained, while in 13 it was 
 only transient, and in 12 absent. The remedy proved most active in 
 hallucinations, paralysis, and the quickly passing excitement-stage of 
 epilepsy, while the less satisfactory results were obtained in the rest- 
 lessness of imbecility, recent psychoses and melancholia. The sleep 
 lasted a long time, and was unaccompanied by any remarkable 
 symptoms. On the whole, the remedy had no effect upon the gastric 
 functions, but was well borne even when administered for months 
 consecutively. No appreciable influence was observed upon the heart, 
 the vascular or the urogenital system, and collapse-like phenomena 
 were never observed. In a case of tremor essentialis, and another of 
 chorea hereditaria, the motor unrest was considerably reduced under 
 small doses of Chloralamid (830 grns. pro die]. 
 
 Dr. G. Genersich, Klausenberg, considered that Chloralamid had 
 established its right to be classed among useful hypnotics, and added 
 that in doses of 45 to 60 grns. the action was reliable and lasting, 
 sleep supervening in from a quarter to one hour after the dose. 
 Secondary symptoms were only unimportant, and the digestive and 
 urinary functions were unaffected. Although the pulse increased in 
 rapidity and became softer, no serious subjective symptoms were 
 experienced by the patients. 
 
 Dr. Chas. H. Steele, Professor of Materia Medica and Therapeutics, 
 of the Cooper Medical College, stated (Pacific Medical Journal] that 
 Chloralamid was successfully employed in combating insomnia, 
 particularly the simple or idiopathic form not due to excitement or 
 severe pain. It was, furthermore, possible for the wakeful patient to 
 enjoy several nights of natural sleep after a single dose. The best 
 results occurred when the drug was used in insomnia due to nervous- 
 ness, neurasthenia, hysteria, spinal disease, or old age. When 
 administered in phthisis it was found that the troublesome night 
 sweats disappeared. 
 
 Dr. W. Hale White, Guy's Hospital, London, gave Chloralamid in 
 twenty cases of various illnesses in which insomnia was a troublesome 
 symptom. He found (British Medical Journal, 1889, p. 1,326) that 
 
5 4 Chloralam id. 
 
 the compound produced comfortable sleep in all the patients except 
 two; one of these was suffering from delirium connected with cerebral 
 haemorrhage, and the other with rheumatic fever complicated by 
 delirium tremens and salicylic poisoning. Some of the other patients 
 were suffering from extremely painful diseases, and yet Chloralamid 
 produced sleep. A woman who had a thoracic aneurysm preferred it 
 to morphine, and another patient who had carcinoma of the stomach 
 also slept better with Chloralamid than with morphine. 
 
 Other striking cases were of carcinoma of the liver with intense 
 pain and of cerebral softening; both dozed comfortably after Chloral- 
 amid. The sisters and nurses, who saw the patients frequently during 
 the night, told the author that those who took Chloralamid not only 
 slept well and comfortably but better than after any of the hypnotics 
 which had been introduced during the past few years. 
 
 In none of the patients did any effects follow that could be looked 
 upon as contra-indications to its use. No depressing results nor 
 headache were observed to be caused by it. Dr. White concluded 
 that in Chloralamid we had a safe hypnotic which did not produce 
 indigestion, and very rarely gave rise to any unpleasant results ; the 
 author illustrated his conclusions with brief details of the twenty 
 cases he treated with the hypnotic. 
 
 Great care was taken to avoid the disturbing influence of suggestion 
 by Dr. Ed. Reichmann (Deutsch Med. Wochenschr.^ 1889, No. 31) either 
 by keeping .the patients entirely in the dark as to the effects of the 
 medication, or where the patient had become acquainted with the 
 same, by makmg control experiments with inert substances. 
 
 Among the cases detailed by the author were patients suffering from 
 bronchitis and cephalalgia, from chlorosis with mitral insufficiency, 
 from endocarditis aortae et mitralis, ecstasia ventriculi, renal colic and 
 neuralgia. When 30 grns. of Chloralamid were administered during 
 the day, even if actual sleep did not follow, a feeling of fatigue and 
 sleepiness was induced. More satisfactory results were obtained by 
 doses of 45 grns. ; in illustration of this, Reichmann mentions two 
 cases of obstinate insomnia of alcoholism where morphine had hardly 
 any effect, but Chloralamid produced sound sleep. 
 
 The question whether Chloralamid could be employed as a hypnotic 
 
Chloralamid. 55 
 
 with success had therefore, according to Dr. Reichmann, to be 
 answered in the affirmative ; and further, he experimentally demon- 
 strated the still more important fact that the remedy had no influence 
 in \ i-drm. doses upon the circulation. He ventured to say that 
 Chloralamid fulfilled all the requirements of a hypnotic, had a safe, 
 prompt action, and was free from disturbing bye-effects. 
 
 Similar conclusions were formed by Professor S. Rabow (Centralbl. 
 f. Nervenheilkunde^ 1889, No. 15) from experience of the employment 
 of Chloralamid in cases of mental disease. It proved reliable in the 
 large majority of cases of sleeplessness following indulgence in 
 alcohol, as well as in the so-called nervous form of neurasthenia, 
 hysteria, etc. 
 
 An exhaustive paper on the value of Chloralamid as a hypnotic was 
 written by Dr. D. R. Paterson (Lancet, 1889, Oct. 26th). Observations 
 made on the various vital functions during the use of Chloralamid 
 gave negative results. One patient with simple insomnia was an old 
 woman of 64 who used to spend the night sitting up in bed ; 30 grns. 
 of the remedy on consecutive nights, induced, after an interval of 30 
 to 40 minutes, a tranquil sleep lasting eight and nine hours respec- 
 tively. When the dose was reduced to 15 grns. the onset of sleep 
 was somewhat more delayed, but it lasted an equal length of time, 
 and was not followed by the slight unpleasant effects which were 
 experienced after the larger dose. An old man of 60, convalescent 
 from an attack of jaundice, and complaining much of resting badly at 
 night, was given 30 grns. on several occasions. Sleep ensued in from 
 40 to 75 minutes after administration, and lasted eight hours. The 
 slumber was unbroken, very sound, and removed a dull headache from 
 which the patient had been suffering. 
 
 Dr. Paterson described other cases paroxysmal cough, insomnia of 
 phthisis, heart disease, aneurysm of the aorta in which good results 
 were obtained by administration of Chloralamid. He confirms the 
 opinion of other authors that the hypnotic had no action on the 
 digestive organs ; the appetite remained unimpaired. 
 
 Dr. George P. Cope made a valuable addition to the literature of 
 Chloralamid in the Dublin Journal of Med. Science, 1890, Feb. After 
 describing the cases in which he prescribed the compound, he 
 
56 Chloralamid. 
 
 expressed the opinion that they demonstrated the hypnotic value of 
 Chloralamid, the sleep brought about lasting five to eight hours, and 
 appearing sound and refreshing. A dose of 25 to 35 grns. was 
 sufficient to cause sleep in patients suffering from melancholia and 
 chronic mania. No recognised evil effects followed the continued use 
 of the remedy for eight days, and only one out of twenty-five persons 
 suffered from gastric disturbance. 
 
 According to the observations of Dr. Cope, Chloralamid appeared 
 to be free from the dangers which accompanied the action of chloral 
 hydrate, and in explanation of the distinction, he quoted the words 
 of Dr. D. Leech (Brit. Med. Journ., 1889, Nov. 2nd): "It seems 
 probable that the formamide element, containing as it does a substitute 
 NH 2 group, will stimulate the circulatory and respiratory centres in 
 the medulla, thus tending to counteract the depressing influence of 
 chloral on them." 
 
 Dr. Cope corroborated the opinion of Dr. C. Norman, that the chief 
 disadvantages of sulphonal were its bulkiness, insolubility, slowness of 
 action, and high price, and pointed out the Chloralamid formed a 
 contrast in every particular. 
 
 Speaking of the indications for the exhibition of Chloralamid, 
 Dr. John Aulde, Philadelphia College, directed attention to the fact 
 that ordinarily large doses did not affect the heart and circulation ; in 
 diseased conditions of the system the remedy appeared to be borne 
 with a remarkable degree of tolerance, and after-effects were not 
 objectionable. 
 
 Dr. J. M. Thompson, Boston, prescribed about 30 grns. of 
 Chloralamid for a dose, to be taken dry in powder and followed by 
 milk. One patient was a neurotic, subject to sleeplessness, in whom 
 sulphonal produced unpleasant after-effects ; 30 grns. of Chloralamid 
 at bedtime brought on sleep in about half-an-hour, which was not 
 followed by any unpleasant after-effects. An habitue* of morphine, 
 who had almost entirely discarded the drug, could not get sound sleep ; 
 even the use of chloral, bromides and sulphonal was ineffectual. 
 Comfortable sleep was brought on by 30-grn. doses of Chloralamid, 
 lasting four to five hours, and without disagreeable after-symptoms. 
 
Chloralamid. 57 
 
 Similar satisfactory results were obtained in cases of influenza, 
 followed by delirium tremens, in sleeplessness due to overwork, in 
 angina pectoris, varicose ulcer and alcoholic neuritis. Dr. Thompson 
 said : " I can safely recommend Chloralamid in any case where a 
 hypnotic is indicated, and feel sure that it is the best, safest, and most 
 reliable in use up to date." 
 
 Dr. P. Naecke made a number of comparative experiments with 
 Chloralamid, hyoscine and amylene hydrate as hypnotics, which 
 showed that the first-named gave the best results. In his hands it 
 proved free from risk for women suffering from chronic mental 
 diseases, and for epileptics, and did good service not only in nervous 
 agrypnia, but also in cases of excitement. It was best given shortly 
 before the patient's time for sleeping. Though slower in action than 
 chloral, the author thought it might also be more sure, and was 
 confident that it was less dangerous, and that the sleep produced 
 was more refreshing than in the case of chloral. 
 
 In three cases put on record by Dr. J. S. Ridge (Notes on New 
 Remedies, 1891, No. 8), Chloralamid did even more than was expected 
 of it. The first patient was a consumptive, 60 years of age, to whom, 
 in consequence of insomnia, morphine, bromidia and sulphonal, had 
 been given with only partial success. Chloralamid, in a dose of 
 30 grns., gave the patient eight hours' sound sleep, without any ill 
 after-effects. This dose always ensured good rest. 
 
 In a case of painful vaginal fistula, seven or eight hours' good 
 sound sleep was always induced by 15 grns. of Chloralamid; the 
 patient awoke refreshed. 
 
 The third of these cases was one of acute gastritis in an opium 
 habitue". Morphia was prescribed without success ; but 45 grns. of 
 Chloralamid was followed by seven hours' sound sleep. Refreshing 
 slumber, free from bad after-effects, was always induced by the same 
 dose of the hypnotic. 
 
 Professor M. Charteris, Glasgow University, having administered 
 Chloralamid in many cases of insomnia, where pain was not a chief 
 factor, pronounced it an excellent and safe hypnotic, superior in every 
 way to sulphonal. If it were dispensed in a complete state of 
 solution, it would be found to answer well in cases of sleeplessness. 
 
58 Chloralamid. 
 
 Comparing Chloralamid with sulphonal, Dr. John Gordon, Aberdeen 
 University, said (Brit. Med.Journ., 1891, May i6th) : "It was frequently 
 noticed that, following a dose of sulphonal, the hypnotic action did not 
 take place for a number of hours, so that sleep was projected into the 
 following day, whereas with Chloralamid, sleep, if it supervened at all, 
 came quickly and passed off within six or eight hours. Another claim 
 for Chloralamid over sulphonal is the fact that sleep is more speedy in 
 its onset after administration. The comparatively easy solubility of 
 the substance may so far explain its more rapid action. It was given 
 in doses of 25, 30, 40 and 45 grns." 
 
 Nine cases are described in more or less detail by Dr. Gordon, the 
 insomnia against which the hypnotic was given originating in senile 
 changes, heart disease, neurasthenia, phthisis and alcoholism, chronic 
 bronchitis, hysteria and locomotor ataxy, with characteristic "lightning 
 pains." In an old man (84 years) suffering from dilated heart and 
 general anasarca, zo-grn. doses of sulphonal produced what the 
 patient described as " feelings of intoxication," followed by one or 
 two hours of sleep. Thirty grns. of ammonium bromide were without 
 effect, and twenty-five minims of nepenthe gave short uneasy sleep, 
 with dry tongue and headache in the morning. Chloralamid was then 
 resorted to, and a dose of 25 grns. prescribed, with the result that in 
 half-an-hour sleep set in that lasted five hours. On awakening, there 
 was no confusion or headache, but marked refreshment. The same 
 medication was given repeatedly, and continued to act .well. 
 
 In the case of neurasthenia, the patient stated that on the right 
 succeeding the taking of the powder he slept well, without a fur her 
 dose. This experience does not stand alone; other observers have 
 recorded cases in which the like phenomenon has been observed. 
 
 On the basis of his investigations, both physiological and therapeu- 
 tical, Dr. Gordon concluded that the results were highly reliable in 
 painless insomnia, and fairly so in insomnia accompanied only by 
 moderate pain. The hypnotic effect followed, as a rule, within half- 
 an-hour of the dose the sleep induced was tranquil, pleasant and 
 natural and the awakening free from mental confusion or depression. 
 He further concluded that there was no deferred action, nor was any 
 craving for the remedy excited. 
 
Chloral amia. 59 
 
 The Therapeutic Committee of the British Medical Association 
 undertook, among other work, the investigation of the value of 
 Chloralamid, and in the report (Brit. Med. Journ., 1890, Aug.), gave 
 details of some half-dozen cases in which the diseases associated 
 with insomnia were cardiac affections, phthisis, neuralgia and acute 
 melancholia. The members of the Committee who recorded the 
 cases were Drs. Charles Angus, William Bullock, and John Gordon, 
 under the direction of Professor T. Cash, F.R.S., Aberdeen. 
 
 Save in the case of acute melancholia, doses of 25 40 grns. of 
 Chloralamid produced a refreshing slumber of five to twelve hours 
 duration, and not followed by any bad after-effects. Some of the 
 patients had been previously dosed with opium and other hypnotic 
 remedies without satisfactory results. 
 
 Dr. C. R. Hexamer, Stamford, Conn., had among his patients two 
 suffering from alcoholic tremor and insomnia. Doses of 30 to 45 
 grns. were prescribed with unmistakably beneficial results. 
 
 A noteworthy contribution to the literature of Chloralamid was 
 made by Dr. E. Lanphear, Kansas University Medical College, who 
 called attention to its usefulness in quieting the nervous system, and 
 producing sleep after an operation of magnitude. He had convinced 
 himself that it was not always pain which caused restlessness and 
 insomnia in these cases, but the impression made upon the nervous 
 system and on the mind. The usual practice of ordering a morphine 
 injection he considered unjustifiable, and chloral had a dangerous 
 depressing action upon the heart ; bromides with hyoscyamus some- 
 times answered, but most stomachs rebelled against it. 
 
 Dr. Lanphear believed that in these cases Chloralamid fulfilled 
 every requirement. It was "the ideal sedative, giving prompt and 
 satisfactory action, reliable results, and absolute freedom from evil- 
 side- or after-effect" (Notes New Remedies, 1891, May). 
 
 Dr. J. B. Mattison, Brooklyn, had a case of a lady, aged 37, who, 
 when first seen by him, was suffering from weakness, anorexia, 
 depression, and sleeplessness. She had been taking chloral regularly, 
 but this was withdrawn at once and 40 grns. of Chloralamid given. 
 A full night's sleep was obtained without any ill after-effects. Com- 
 parative trials with a number of hypnotics showed that Chloralamid 
 
60 Chloralamid. 
 
 was by far the best always procuring refreshing slumber lasting 
 several hours. 
 
 In the treatment of the insomnia of delirium tremens, Chloralamid 
 proved the remedy, par excellence, in the hands of Dr. T. A. Helm. It 
 brought about the quiet and refreshing sleep so desirable, and even 
 essential, to the successful treatment of the malady named. 
 
 k Among the medical men in various parts of the United States who 
 also emphasised the superiority of Chloralamid to other hypnotics, 
 in the insomnia of nervous and mental diseases, were Drs. J. C. Reeve, 
 J. O. Jenkins, C. R. Phillips, R. M. Brady. 
 
 Dr. S. H. Dupon called attention to the value of the hypnotic as a 
 sedative in uterine troubles, especially in aggravated cases with 
 hysterical convulsions. The first dose of 10 grns. frequently gave 
 immediate relief with no return of pain. One of the cases where 
 Chloralamid yielded good results had previously resisted all kinds 
 of remedies. 
 
 In the case of an old lady who had suffered from heart disease eight 
 years, and who sought relief from dyspnrea, cough and consequent 
 insomnia, Dr. J. A. Patterson (Therap. Gazette, 1891, Aug.) used 
 Chloralamid with great success. He first tried morphine, but this had 
 to be given in such large doses that the author was afraid to continue 
 with it. The synthetical hypnotic in lo-grn. doses, gradually increasing 
 to 40 grns., good rest and sleep in a recumbent posture was obtained. 
 The pulse improved at the same time. 
 
 It will be unnecessary to cite all the authors who have found 
 Chloralamid advantageous in insomnia from the most diverse causes. 
 They agreed in praising the readiness with which it lent itself to 
 administration in mixture form and the freedom of its action from 
 unpleasant bye- or after-effects. 
 
 () In Sea -sickness. 
 
 Chloralamid, especially in combination with potassium bromide 
 (forming the solution termed "Chlorobrom"), has taken a foremost 
 position among the really serviceable prophylactics against, and cures 
 for, the much dreaded sea-sickness. 
 
Chloralamid: 61 
 
 One of the chief points in the effect of this compound which has 
 been an important factor in its usefulness in the affection referred to, 
 is, that it is readily retained by the stomach, allaying irritation and 
 arresting nausea. Professor M. Charteris recommended that the 
 remedy should be given after the stage of active vomiting had passed, 
 and stated that at that time it had invariably proved successful, 
 removing all distress, depression, etc., and securing by sleep the 
 gastric and mental repose so urgently required. 
 
 Without referring in detail to the reports of the various practitioners 
 who have successfully prescribed the Chloralamid and potassium 
 bromide solution, it may be said that their testimony confirms the 
 experience of Professor Charteris, and shows further that in many 
 cases the complaint may be altogether warded off by taking ordinary 
 precautions to avoid upsetting the digestive organs and resorting 
 to the Chloralamid solution on the appearance of any disturbing 
 symptoms. 
 
 A case recently recorded by Dr. Geo. Macdonald, Glasgow (Brit. 
 Med. Journ., 1892, Sept. lyth), is noteworthy, because the patient (a 
 young lady) was suffering from gastric ulcer, which made it the more 
 imperative to check the retching of sea-sickness, owing to the danger 
 of rupturing the stomach. Half an ounce of the solution of Chlor- 
 alamid (equivalent to 15 grns. of the remedy) was given immediately, 
 and in twenty minutes sound sleep was induced, which lasted for eight 
 hours. With careful subsequent dieting the patient improved steadily 
 during the voyage. The case is a striking illustration both of the 
 safety of Chloralamid and of its reliability in allaying sickness. 
 
 METHODS OF ADMINISTRATION. 
 
 Among the earliest formulae given for Chloralamid mixtures were 
 the following : 
 
 "Sf. Chloralamidi .. grns. 45. 
 
 Acid hydrochl. dil gtt. v. 
 
 Syr. Rub. idaci ss. 
 
 Aq. destill. ad gij. 
 
 M. ft. mist. To be taken as a draught. 
 
62 Chloralamid. 
 
 !. Chloralamidi 3iiss. 
 
 Syr. Rub. idaei 3J. 
 
 Aq. destill. 3iv. 
 
 M. ft. mist. Two, three or four tablespoonfuls to be taken before going to rest. 
 
 IJ. Chloralamidi grns. 45. 
 
 Ac.hydrochl.dil. gtt. ii. 
 
 Spirit vini rect m. 15. 
 
 Aq. destill. ad giij. 
 
 M. ft. mist. For an enema. 
 
 It is important to remember that although Chloralamid is somewhat 
 slowly soluble in water, heat should never be employed to facilitate 
 solution. Either time. must be given for the compound to be taken 
 up in the cold or it must be prescribed with some spirituous preparation 
 in which it can be readily dissolved, and then diluted with water ; 20 
 grns. of Chloralamid dissolves in a drm. of rectified spirit in 15 
 minutes and then water may be added without throwing the compound 
 out of solution. 
 
 Dr. Hale White said a good way of giving the hypnotic was to 'tell 
 the patient to dissolve it in a little brandy, add water to liking, and 
 drink it shortly before going to bed. 
 
 Dr. John Aukle cited the formula given under as convenient and 
 agreeable : 
 
 Ifc. Chloralamidi 3iv. 
 
 Spts. frumenti giij. 
 
 Elix. aurantii ad Jiv. 
 
 M. Sig. Take one tablespoonful in water every four to six hours, as directed. 
 
 Beer and wine have also been used as menstrua for Chloralamid, 
 and spiced wine proved in Dr. Rabow's experience especially agreeable. 
 
 Chloralamid should not be given in powder, as, under these 
 circumstances, its absorption may be delayed, and the result con- 
 sequently less satisfactory. The method adopted by some authors of 
 prescribing the remedy to be taken dry on the tongue, or with milk, is 
 is not therefore to be commended. The desired result may be 
 attained in this way, but it is not so certain and reliable, nor so 
 agreeable as when the mixture form is selected. 
 
PARALDEHYDE. 
 
 Nearly all the members of the aldehyde group of synthetical 
 remedies possess hypnotic properties, though they exhibit differences 
 in the degree of this effect produced, and also in the character and the 
 prominence of the secondary effects which accompany the primary 
 action. 
 
 There is another property which may be characterised as common 
 to the members of the aldehyde group of compounds namely, a 
 tendency to form condensation products, by virtue of which the 
 molecule becomes more complex, without undergoing any change in 
 the relative proportions of the constituent atoms. That is, the 
 analysis of one of these substances, yields the same figures for the 
 percentage composition as that of the mother substance, possessing a 
 much simpler molecule. 
 
 This brings us to the consideration of the 
 
 PHYSICAL AND CHEMICAL NATURE 
 
 of Paraldehyde. Ordinary ethyl or acetic aldehyde has the formula 
 CH 3 CHO, that is, it is alcohol CH 3 CH 2 OH, from which two atoms 
 of hydrogen have been removed. Graphically, the formulae of these 
 compounds might be displayed as follows : 
 
 H-C-C-O-H H-C-C? 
 
 H H H H 
 
 Alcohol. Aldehyde. 
 
 Now, if aldehyde, which is a volatile liquid with a peculiar, some- 
 what suffocating odour, a sp. gr. of 0-807 at o C., and boiling point 
 
64 Paraldehyde 
 
 at2iC., be acted upon at ordinary temperatures by polymerising 
 agents, such as acids (HC1, SO 2 ) and certain salts (especially ZnCl 2 ), 
 it undergoes condensation contracting in volume and evolving heat. 
 The product, Paraldehyde, has a vapour density which corresponds to 
 the formula C 6 H 12 O 3 , from which it appears that it is formed by the 
 condensation into one molecule of three molecules of aldehyde, the 
 union taking place through the medium of the oxygen atoms in 
 the latter. Its constitution is represented thus : 
 
 H H 
 
 The physical and chemical properties of Paraldehyde compared 
 with those of the mother substance briefly given above correspond 
 closely with the nature of the change by which it is formed that is, 
 they are those of a more condensed body. 
 
 Paraldehyde, when pure, is a colourless liquid with a sp. gr. of 
 0-998 at 15 C. and boiling at i24C. Subjected to a low tempera- 
 ture it solidifies to a crystalline form and melts again at io'5C. At 
 1 3 C. it dissolves in eight parts of water ; unlike most substances, its 
 solubility is not increased by raising the temperature of the water, on 
 the contrary an aqueous solution saturated at the ordinary temperature 
 becomes turbid when heated, and a large proportion of the dissolved 
 Paraldehyde separates out. 
 
 Though fairly stable under normal conditions, Paraldehyde as the 
 chemist would expect from the mere consideration of its structure 
 is somewhat easily split up. It is very sensitive to oxidising agents, 
 and is partly reconverted into ordinary aldehyde by mere ebullition ; 
 in the presence of a small quantity of sulphuric acid the change is 
 complete on boiling. 
 
 In common with aldehydes generally, Paraldehyde is a powerful 
 reducing agent, forms an aldehyde resin with warm potassium hydrate, 
 and so on. 
 
Paraldehyde. 65 
 
 The Importance of Purity 
 
 is generally recognised in the domain of medicine, and it is owing 
 to the spread of this principle that the use of medicinal agents of 
 definite chemical composition has attained such large dimensions of 
 late years. Bodies which have an unvarying chemical composition 
 and well-defined physical characters are more likely to produce 
 reliable and exact effects than preparations of which no two batches are 
 ever exactly similar in composition and therapeutical activity. 
 
 But in the case of Paraldehyde it is especially important that the 
 substance used in medicine should be absolutely pure. It has been 
 repeatedly found that specimens described as " Paraldehyd. purum " 
 contained not only ordinary aldehyde, but also amylaldehyde. 
 
 Now even only small quantities of these impurities are sufficient 
 to render the Paraldehyde unfit for medicinal use. Ordinary acetal- 
 dehyde, as stated above, has a pungent, almost suffocating odour, 
 and amylaldehyde is poisonous to an unmistakable degree. 
 
 No doubt it was the consequence of the introduction of specimens 
 containing these impurities into medicine, which prevented the com- 
 pound in the earlier days from attaining that prominent position 
 among hypnotics which it deserved. Hence the necessity of empha- 
 sising the importance of seeing that patients get only such a brand of 
 Paraldehyde as is really absolutely pure, not only in name but in fact. 
 
 The physical factors sp. gr., boiling point, congealing point men- 
 tioned above, are valuable tests of the purity of the compound. The 
 odour, however, is frequently sufficient in itself to indicate the presence 
 of impurities. Pure Paraldehyde has a spicy aromatic odour, and when 
 3j. or 3 ij- are evaporated gently on a water-bath, no unpleasant 
 smelling residue (higher aldehydes from fousel oil occurring in the 
 spirit from which the preparation was made) should be left. 
 
 PHYSIOLOGICAL ACTION. 
 
 It seems to have been assumed at first that Paraldehyde would have 
 the same effect upon the animal organism as aldehyde. The careful 
 
 F 
 
66 Par aldehyde. 
 
 work of Dr. Vincenz Cervello, Strassburg Pharmacological Laboratory, 
 showed the unsoundness of this view. 
 
 Doses of about - f- drm. produced in rabbits of average size 
 narcosis, lasting six or seven hours, not preceded by any stage of 
 excitement. On awakening, the animals were at first a little unsteady 
 on their legs, but soon regained their normal certainty. No further 
 disturbances were noted ; the animals seemed perfectly well, and took 
 food eagerly. 
 
 During the stage of profound narcosis the breathing became slower, 
 but the pulsation of the heart, so far as could be estimated by the 
 hand, remained strong. No change was perceptible in the pupils. 
 
 The effect upon dogs was similar, quiet sleep being induced without 
 previous excitement. The diminution in the frequency of the respira- 
 tion was not so considerable as in rabbits. That the compound was 
 absorbed very rapidly was shown by the fact that five minutes after 
 injection the gait of the dogs became unsteady and sleep soon 
 supervened. 
 
 Dr. Cervello's conclusions may be summarised as follows : 
 
 1. Paraldehyde acts principally upon the cerebrum and partially 
 
 upon the medulla oblongata and spinal cord. 
 
 2. In large doses it arrests the respiration, but the heart's action 
 
 continues. The animals could be restored by means of 
 artificial respiration. 
 
 3. There is no stage of excitement previous to the narcosis as in 
 
 the case of ordinary aldehyde, nor any subsequent functional 
 disturbance. 
 
 Cervello's researches left unanswered, however, the question whether 
 the preparation had any effect upon the digestive function or not. 
 Our knowledge of this side of the action of Paraldehyde we owe to 
 Dr. John Gordon, Aberdeen University, who carried out a series of 
 experiments, with the view of determining the action of hypnotics on 
 digestion. 
 
 Test-tubes were used of equal size and form, containing gramme 
 of stained fibrin, two decigrammes of pepsina porci, two ccs. of two 
 percent, hydrochloric acid, 15 ccs. of water, with varying quantities 
 of the drugs under examination. One tube without any medicament 
 
Paraldehyde. 67 
 
 was used for control purposes. The set of tubes was placed in an 
 incubator, and kept as near as possible at the normal body heat. 
 
 In the case of Paraldehyde, the test-tubes were capped with india- 
 rubber to prevent evaporation. The quantities of the hypnotic added 
 to the tubes were 0*3, 0*75 and 1*25 cc. respectively. The remarkable 
 result obtained was that in nine hours the digestion of the fibrin was 
 complete in the tubes containing the large quantities of Paraldehyde, 
 and well advanced in the third, while, in the control tube, very little 
 progress had been made towards digestion. 
 
 From a number of experiments, Dr. Gordon drew the conclusion 
 that the presence of Paraldehyde, even in minute quantities, ac- 
 celerated the digestion of fibrin, and that the greater the proportion of 
 the hypnotic present, the more rapid the peptonising process. 
 
 It was also observed that putrefaction was prevented by the larger 
 proportion of Paraldehyde, and delayed by the smaller. 
 
 MEDICINAL PROPERTIES AND USES. 
 
 The physiological examination of Paraldehyde outlined above in- 
 dicated its value as a harmless but efficient hypnotic. Dr. Cervello 
 described a case of sciatica, in which two drms. of Paraldehyde was 
 given as a three per cent, solution in three doses, with half-hourly 
 intervals. Two hours after the last portion was taken, the patient was 
 asleep, and did not awake till ten and a half hours later. No headache, 
 nausea, or other inconvenience was experienced. 
 
 Dr. Gugl used Paraldehyde 336 times, and found that in from half- 
 an-hour to three hours it produced calm, deep, and refreshing sleep, 
 closely resembling natural slumber. The duration of the sleep 
 varied from three to seven hours, or even ten hours, according to 
 dosage and individual idiosyncrasy. He obtained evidence that it 
 could be administered without hesitation in cases of heart disease, 
 even when of very pronounced gravity. The conviction forced itself 
 upon Dr. Gugl, that the best results were obtained in constitutional or 
 acquired neuropathic conditions in hysterical and neurasthenic, rather 
 than hypochondriacal cases. The author cites a number of illustrative 
 
 F 2 
 
68 Paraldehyde. 
 
 cases which also indicate the freedom with which Paraldehyde may be 
 given for prolonged periods without causing disturbances. 
 
 Good, and even, in some instances, brilliant results were obtained 
 in cases of alcoholism, and in the simple nocturnal restlessness of 
 dementia paralytica and senilis. When the hypnotic effect was not 
 marked, as was sometimes the case, an evident sedative action was 
 perceptible. 
 
 In a case of hystero-neurasthenia, with unusually painful spinal 
 affection, the patient declared that immediately after taking Paralde- 
 hyde, she always became sensible of an essential decrease in the 
 pains. 
 
 On the whole, the author concluded that Paraldehyde was a 
 powerful hypnotic, preferable in many cases to chloral, on account 
 of its freedom from danger, even when its use was long continued. 
 In mental diseases and neuro-pathology, the physician had gained, 
 in Paraldehyde, a powerful aid in combating sleeplessness. 
 
 Similar evidence was afforded by the cases under treatment by Dr. 
 J. Peretti (BerL klin. Wochenschr., 1883, Oct. ist); even decrepit and 
 paralytic persons could take the remedy without danger, and heart 
 disease was not a contra-indication to its use. In one case a patient 
 took over six ozs. in forty-two days ; and in another, nearly 5^ ozs. 
 was taken in forty-one days, without any injurious effect. 
 
 A very trifling fall of temperature was produced, and there was no 
 congestion or alteration of the pupils. The results of Dr. Gordon's 
 investigation of the effects of Paraldehyde on digestion outlined above 
 were clinically antedated by Peretti's observation that not only was 
 the hypnotic free from prejudicial action on the digestion, but some 
 persons were able to record an appreciable beneficial influence upon 
 the digestive function and the appetite. The after taste was not 
 sufficiently marked to give occasion for complaint, or to affect the 
 appetite. Further, even prolonged use did not interfere with the 
 digestive or intestinal functions. 
 
 The author expressed the advantages of Paraldehyde over chloral 
 hydrate, as follows : 
 
 i. Even in large doses Paraldehyde is free from dangerous action 
 on the heart. 
 
Paraldehyde. 69 
 
 2. The action of Paraldehyde is not cumulative. 
 
 3. Paraldehyde rapidly induces sleep without previous symptoms 
 
 of excitement or congestion. 
 
 4. Patients awakening from the sleep induced by Paraldehyde 
 
 do not experience any disagreeable sensations. 
 
 Prolonged experience convinced Prof. v. Krafft-Ebing that Paral- 
 dehyde was an efficient and safe hypnotic if given in suitable doses. 
 He warned medical men, however, against prescribing the compound 
 in doses exceeding the limit of safety. This warning is now less 
 necessary, since it has been found by various authors, and is specially 
 noted by Dr. E. M. Sympson, that Paraldehyde is effective in com- 
 paratively small doses. Dr. Sympson obtained good results in delirium 
 and various kinds of insomnia with the remedy. 
 
 By Dr. H. Dehio, Paraldehyde was characterised as " the sovereign 
 remedy " among hypnotics. In his experience it produced a sleep 
 frequently lasting seven or eight hours, and extraordinarily like natural 
 slumber ; no headache, giddiness, or other symptoms usual after 
 narcotics, were observed. Like the physiological sleep, that produced 
 by Paraldehyde was most profound during the first two hours. 
 
 Reference has been already made to the work of Dr. Gordon on 
 some points in the chemico-physiology of Paraldehyde. The author, 
 who is Assistant-Physician of the Aberdeen Sick Children's Hospital, 
 mentions incidentally that he used the compound clinically in a 
 number of cases, but does not give any details. 
 
 DOSE AND METHOD OF ADMINISTRATION. 
 
 The average dose of Paraldehyde is about a drm., but the limits are 
 given as 45 ms. to 2^ drms. ; not more than i^ drms. should be given 
 as a single dose, nor should the maximum quantity mentioned above 
 be exceeded during the twenty-four hours. 
 
 Owing to the occasional employment of inferior and impure 
 specimens of Paraldehyde, somewhat exaggerated statements were 
 made as to its flavour, and the odour it communicated to the breath 
 of the patients. It appears according to Dr. Dehio and others, that 
 
7O Paraldehyde. 
 
 the pure preparation is generally taken without any complaint or any 
 effect upon the appetite. 
 
 Paraldehyde may be conveniently taken with rum, milk or flavouring 
 essences, while aromatic bitters, like the tincture of orange, have been 
 favourite correctives. The tincture has the futher advantage of readily 
 dissolving the remedy. The following formulae yield agreeable 
 mixtures : 
 
 $. Paraldebyd 5iij. 
 
 Tinct. Aurantii 3vj. 
 
 Syrupi. simplic. Siij. 
 
 M. Sig. One Teaspoonful (15 ms. of Paraldehyde) for a dose. 
 $. Paraldehyd 
 
 Mucilag. Acac. aa 5iv. 
 
 Syrup. Amygd 53. 
 
 Aquae ad vi. 
 
 M. ft. Emulsio. Two Tablespocnfuls (40 ms. of Paraldehyde) for a dose. 
 
 Paraldehyde is very readily absorbed from the digestive tract, but in 
 some instances it has been administered subcutaneously. Mr. Keraval 
 employed a solution of 10 ms. each of Paraldehyde and cherry laurel 
 water made up to 40 ms. with distilled water. Before use he immersed 
 the bottle in warm water in order to ensure perfect admixture. 
 
 Ifc. Paraldehyd m. Ivi. 
 
 Spir. Menth. Pip. m.j. 
 
 Olei oliv. q.s. ad . m. cxij. 
 
 M. ft. solutio. 
 
 The solution prepared according to this formula was preferred bj 
 Drs. Langreuter and Strubisch. In any case the method seems to be 
 somewhat painful and, save in. very exceptional instances, would not 
 have any advantages over the usual mode of prescribing. 
 
4wgi^ 
 
 CHLORALS AND 
 
 CHLOROFORM. 
 
 CHLORAL HYDRATE was first recommended as a hypnotic and sub- 
 stitute for opium by Dr. O. Liebreich ; the mother substance chloral 
 was discovered by Liebig in 1832, having been prepared by him from 
 dry chlorine gas and alcohol. 
 
 One of the most important chemical properties of Chloral hydrate, 
 CC1 3 COH, H 2 O, is its hydrolysis in the presence of alkalies into 
 chloroform and formic acid, thus: 
 
 CC1 3 COH (H 8 0)=CHC1 8 + HCOOH. 
 
 This reaction is practically applied for the preparation of the purest 
 Chloroform (v. infra]. 
 
 In the use of Chloral hydrate as of each member of this group of 
 bodies the greatest care must be taken to ensure perfect purity, as 
 the organic compounds of chlorine are characterised by a powerful 
 physiological action, and aldehydes or oxidation products, as well as 
 free chlorine, either reduce the activity of the preparation or have a 
 marked local irritant effect. 
 
 It is quite unnecessary to describe the physiological or thera- 
 peutical action of Chloral hydrate in any detail, or to refer to the 
 enormous literature of its employment in medicine. Its chief 
 importance depends upon its hypnotic properties ; while it has some 
 disadvantages compared with opium preparations, it has also many 
 advantages and is not rarely efficacious where they fail. The best 
 results are yielded in delirium potatorum, in puerperal mania, 
 enuresis nocturna, convulsive affections (eclampsia, uraemic cramps, 
 epileptiform convulsions in children, tetanus, chorea, etc.). 
 
72 Chlorals and Chloroform 
 
 The unquestionable success of the remedy in gastro-intestinal 
 affections of children depends evidently upon its simultaneously 
 antiseptic and irritant action. The same is also true of most of its 
 external applications. 
 
 BUTYL-CHLORAL HYDRATE, which was at first regarded as the 
 chlorine substitution product of croton aldehyde, and therefore termed 
 croton-chloral, must be given in much larger doses than Chloral 
 hydrate, in order to attain the same degree of hypnosis. Comparative 
 experiments with Butyl-chloral and Chloral hydrate showed that the 
 narcosis of the former lasted only a third as long as that of the latter. 
 A peculiarity of the remedy is that it principally produces anaesthesia 
 of the cerebral nerves while it affects those of the body much less. 
 It is therefore especially serviceable in the treatment of trigeminal 
 neuralgia. It has, however, been successfully given in convulsive and 
 irritant cough and the neuralgic pains of tabetic patients. 
 
 As a sedative, Butyl-chloral hydrate is given in doses of ^ i drm., 
 preferably in solution. 
 
 CHLORAL-CHLOROFORM. Reference has been already made to 
 Chloral hydrate as a source of Chloroform (v. supra) and the equation 
 given illustrative of the process by which it is formed. The product 
 is characterised by its high standard of purity and absence of foreign 
 compounds. It answers satisfactorily to all tests and is appreciably 
 less prone to spontaneous decomposition than the ordinary chloro- 
 form of commerce. 
 
 Though the presence of oxidation products or foreign chlorinated 
 compounds is prejudicial to the value of all the members of this 
 group of compounds, it is especially so in the case of Chloroform, 
 which is principally used by inhalation. Hence the superiority of a 
 product which is made from a compound of definite chemical 
 character which can be readily obtained in a condition of great purity. 
 
SALOL 
 
 The important role which phenol played in antiseptic surgery and 
 medicine was only restricted by its poisonousness. When used inter- 
 nally, apart from its local caustic action, it was exceedingly liable to 
 produce symptoms of toxic action, which not only necessitated the 
 observance of great caution in its employment, but further absolutely 
 contra-indicated its use in a considerable number of cases. 
 
 At the same time, there is a fairly large group of diseases known to 
 be due to, or at least associated with, the presence of pathogenic 
 micro-organisms in different parts of the intestinal tract. These 
 called for the administration of compounds which, while free from 
 a general poisonous effect upon the organism, would yet be capable 
 of directly attacking in situ the bacteria which were keeping up the 
 disease. 
 
 The problem was, therefore, to find some combination of phenol 
 which should be free from its poisonous action but possessed of an 
 equal, or, at least, of a marked antiseptic power. Such a compound 
 was discovered in Salol, one of a group of aromatic esters first pre- 
 pared by Nencki in 1883. 
 
 CHEMICAL NATURE AND PROPERTIES. 
 
 Salol is systematically termed phenyl salicylate, being represented 
 by the constitutional formula 
 
 COOCsHs 
 
 It occurs in the form of white powder, seen under the microscope to 
 consist of tabular crystals ; or these crystals may be large enough to 
 make it necessary to describe the compound as being in crystalline 
 
74 Salol. 
 
 tables, which are well defined and transparent. Salol has a feeble 
 aromatic odour, but being practically insoluble in water, has little or 
 no taste. 
 
 In alcohol the compound is soluble in the proportion of i in 10, 
 while ether takes up rather more than three times its weight. When 
 an alcoholic solution of Salol is poured into water a liquid having the 
 appearance of an emulsion is produced, which really contains the 
 substance suspended in a fine state of division. It is also soluble to 
 a considerable extent in fatty and mineral oils, in turpentine, copaiba 
 balsnm and sandal-wood oil. It will be seen below that this solubility 
 of the compound in essential oils and oleo-resins has a practical value 
 in its administration. When subjected to the action of heat, Salol 
 melts at 42 43 C., and if the temperature be raised (the substance 
 being supported on platinum foil) burns away with a very smoky flame, 
 leaving no residue. 
 
 If an alcoholic solution of Salol be added to solution of ferric 
 chloride (perchloride of iron) the only result is the appearance of 
 turbidity; if, however, the process be reversed and the solution of 
 ferric chloride poured into that of the Salol, the characteristic bluish 
 or violet colour of phenol is produced. Bromine water precipitates a 
 monobromo compound that crystallises from alcohol in long needles. 
 
 PHYSIOLOGICAL PROPERTIES. 
 
 The discoverer of Salol, Professor Nencki, compared it in its 
 physiological relations to the fats; like these it was split up by the 
 pancreatic juice into free acid and an alcoholic group, that is into 
 salicylic acid and phenol. He also believed that the compound 
 passed through the stomach unchanged, because the feeling of 
 malaise which almost invariably follows the administration of sodium 
 salicylate was entirely absent when Salol was given. 
 
 A careful research into the destiny of Salol when administered by 
 the mouth was made by Dr. R. Sievers and Professor C. A. Ewald 
 (Therap. Monatsh., 1887, Aug.). In 25 experiments in which the 
 
SaloL 75 
 
 extracted gastric juice after a dose of the substance was tested every 
 half hour for free salicylic acid, negative results were uniformly 
 obtained. 
 
 On the other hand, it was observed that in contact with alkalies, 
 even at the normal temperature, and especially at that of the blood, 
 the compound was split up into its components. Since the pancreatic 
 juice and intestinal fluids are alkaline, it followed that when Salol, 
 having passed through the stomach unchanged, entered the intestines 
 it would be there split up into phenol compounds and salicylic acid. 
 
 It was experimentally proved by the authors that every part of the 
 intestinal tract was capable of effecting the dissociation of Salol. 
 They further found that wh'en Salol was brought into direct contact 
 with the intestinal mucous membrane, 20 30 minutes were required 
 before its constituents appeared in the urine. In healthy individuals 
 an hour proved to be the extreme limit of time between the adminis- 
 tration of the compound and its appearance in the urine. 
 
 About the same time Professor Sahli studied the dissociation of 
 Salol in the organism, and obtained results which corroborated those 
 of Drs. Sievers and Ewald. 
 
 In the well-known Pharmacological Institute of Dorpat, under the 
 direction of Professor Robert, G. Willenz carried out a searching 
 investigation of the conditions under which the substance split up 
 into its components. He found, like the preceding workers, that the 
 members of this class of compounds did not split up in the stomach, 
 but were resolved into their components only by the alkaline juices 
 of the intestines. Owing to their dilatory effects upon the vascular 
 system, the substances exerted an antifebrile effect. 
 
 In a research of later date than that mentioned above, Professor 
 Sahli adduced proofs that large doses of Salol could be taken doses 
 which corresponded to an amount of phenol far exceeding what 
 could be safely given as such without any symptoms of poisoning. 
 The author expressed the opinion that when given in large doses 
 Salol was possibly absorbed undecomposed, while further it might 
 be that the phenol was very gradually separated from combination 
 and excreted as fast as it was set free, or converted into harmless 
 compounds with sulphuric or glycuronic acid. 
 
76 Salol. 
 
 Experiments with Salol upon animals were carried out by Dr. 
 Hesselbach, which demonstrated, beyond doubt, that the dosage of 
 the substance should not be based upon that of phenol. It was 
 proved by the fact that the lethal dose of Salol for animals amounted 
 to 7-6 grms. per kilo (about 53 grns. per lb.), corresponding to a 
 dosage of 532 grins, for a man of 70 kilo (i54lbs.) weight. 
 
 BACTERIOLOGICAL EXPERIMENTS. 
 
 The most elaborate research on the antiseptic action of Salol was 
 conducted by Professor Sahli. The first series of experiments was 
 made on finely-minced pancreas, diluted with water to a pasty con- 
 sistence, and containing various proportions of Salol. It was found 
 that 2^ per cent, of the compound was sufficient to prevent the 
 process of putrefaction. 
 
 It was stated by Koch that the antiseptics were of no value when 
 used in oleaginous solution; under these circumstances they were, 
 according to his investigation, practically inert. Professor Sahli made 
 a special series of experiments, with a view of testing the truth of this 
 general statement in the case of Salol ; from these it appeared that 
 even in oleaginous solution, the compound exerted a powerful koly- 
 septic (or development hindering) action upon bacteria. Apparently 
 even it was more active when dissolved in almond oil than when 
 used in powder a result ascribed by the author to the more uniform 
 admixture of the antiseptic with the substance containing the 
 bacteria. 
 
 It is unnecessary to refer to all the work which has been done in 
 the investigation of the antiseptic activity of Salol. In the following 
 section, dealing with its use in medicine, a good deal of evidence of 
 its power in this direction will be met with. 
 
 THERAPEUTICAL USES. 
 
 Salol was recommended in the first instance as a substitute for 
 salicylic acid, presumably of more rapid effect, and free from irritant 
 
Salol. 77 
 
 action upon the stomach, as it was not separated into its components 
 until it had arrived in the duodenum. This view of the medicinal 
 function of the compound determined of course the mode of its 
 employment, and it will be perhaps advantageous to follow, to some 
 extent, in dealing with its various uses in medicine, the chronological 
 order of their development. 
 
 (a) INTERNALLY. 
 1. Against Rheumatism. 
 
 Salol was employed in 27 cases of typical articular rheumatism by 
 Dr. Bielschowsky, being given in capsules in doses of i drm. pro die 
 within five hours, and in one case, two drms. within eight hours. 
 Smaller doses of 30 45 grns. were given only for the after treatment 
 of some cases where slight pains persisted. Of the 27 cases, 19 were 
 rapidly and completely cured ; in two, the effect was only slight, and 
 the remaining six passed into the chronic form. 
 
 Relapse was observed only eight times, and in each case was cured 
 by returning to the use of Salol ; smaller quantities of the medicament 
 sufficed than in the first attack. 
 
 The smallest quantity which sufficed to remove the symptoms 
 amounted to 3^- drms., and, on the average, the treatment had to be 
 continued for from four to eight days before a cure was attained. Once, 
 the disease resisted for ten days, but in several cases every trace of the 
 affection disappeared after three days. In four of the patients, slight 
 disturbances of the cardiac activity appeared, but were no longer in 
 evidence when they were discharged. Three suffered from mitral 
 failure, in consequence of earlier attacks of rheumatism ; they were 
 not aggravated by the fresh onset of the disease. 
 
 The author concluded, from his cases, that Salol must be regarded 
 as a specific in acute rheumatism, having the advantage over salicylic 
 acid and the other usual remedies of being free from any bye-effects. 
 The most careful observation of the patients satisfied the author 
 that this was so ; neither exanthema, perspiration, nor digestive 
 disturbances were seen. 
 
78 Salol. 
 
 Almost simultaneously, clinical experiments with Salol in rheuma- 
 tism were carried out by Dr. Siegfried Rosenberg in the Jewish 
 Hospital, Berlin ; He reported (Therap. Monatsh., 1887, No. 2) that 
 on the whole, the effect was promptly exhibited ; as a rule fever 
 disappeared and the painfulness of the joints was alleviated after 
 twenty-four to forty-eight hours. The longest time which elapsed 
 before symptoms were removed was five days, and in a single case 
 only, and that of very severe nature, was the remedy entirely without 
 effect. 
 
 So long as fever and pain persisted in the joints, 1^2 drms. of 
 Salol were given daily in single doses of 15 grns. at intervals of one 
 or two hours. As soon as the patients were free from fever and pain, 
 the dose was reduced to i, i drm., 45 and 30 grns. pro die (always 
 in portions of 15 grns. each) in the hope of preventing relapse. 
 
 The colour of the urine assumed an olive-green shade, deepening 
 to blackish green. In a few patients it cleared up later in spite of 
 continued use of Salol, and exhibited a greenish coloration only on 
 the upper surface where it came in contact with the air. Unlike 
 the preceding observer, Rosenberg recorded tinnitus as sometimes 
 following the use of Salol, but agreed with him that malaise, eructation 
 and nausea were very rare, and that the persistent digestive dis- 
 turbances of salicylic acid were never produced. Salol was also 
 superior to salicylic acid in its freedom from any irritant effect upon 
 the mucous membrane of the stomach. 
 
 Dr. Herrlich gave Salol in 25 cases of acute rheumatism with 
 satisfactory results. He employed doses of 15 grns. frequently 
 repeated, and recommended this modus procendi as preferable to large 
 doses less often. 
 
 Concordant results were recorded (Berl. klin. Wochenschr., 1887, 
 No. 9-11) by Dr. F. E. Georgi, who also tried Salol in acute 
 rheumatism. Unpleasant secondary effects were not at all manifested. 
 The average dose adopted was ^\ 3 drms., and the writer believed 
 that thorough and lasting effects were attained by continuing the 
 administration of Salol in decreasing doses. 
 
 The crucial test of the safety of a remedy is its effect when adminis- 
 tered to children, who are most susceptible to the action of medicinal 
 
SaloL 79 
 
 agents. This test, as regards Salol, was carried out by Professor 
 Demme, of the Jenner Children's Hospital, Berne. 
 
 From 45 to 60 grns. of Salol daily, in doses of 15 grns., with intervals 
 of two to three hours, were given to two boys (of 8 and 13 years 
 respectively) so long as fever, swelling and pain persisted. In one 
 case the administration was continued in this way five days and in the 
 other seven days. As the symptoms were alleviated the dose was 
 reduced to 30 grns. and during convalescence to 15 grns. The dura- 
 tion of the attack did not exceed 14 and 16 days in these two cases. 
 
 In another instance the patient was a girl of seven years, with fever 
 and severely attacked joints ; the afebrile state and reduction of the 
 local swelling were attained in 48 hours, during which \\ drm. of 
 Salol was given. Here, as in the cases of the two boys above 
 mentioned, there was no relapse. 
 
 Salol had also a favourable influence upon two cases of endocarditis 
 and pericarditis which were of rheumatic origin. Before the specific 
 remedy was given, the abnormal frequency of the heart's action was 
 reduced, and the blood-pressure regulated by the administration of 
 digitalis. 
 
 The very markedly unpleasant after-effects of salicylic acid and 
 salicylate of soda induced Dr. Aufrecht to give Salol a trial, with note- 
 worthy results (Deutsche med. Wochenschr., 1888, No. 2). The remedy 
 was given in 30 cases, i^ 2 drms. daily in i5-grn. doses. One 
 patient (a woman) took half a pound of the substance in daily 
 quantities of i^ drm., and bore the treatment well. Dr. Aufrecht 
 formed the opinion that, in chronic rheumatism, Salol was undoubtedly 
 superior to salicylic acid. In acute cases he gave salicylic acid until 
 the fever was reduced (which required two or three days), and then 
 replaced it by Salol. 
 
 Dr. Lepine (Lyon Medical, 1886, July) found that Salol was more 
 effective than salicylic acid in relieving the pains of rheumatism. 
 Daily doses of one to two drms. were well tolerated. 
 
 Among American observers who have used Salol, Drs. C. J. Sauer, 
 Brooklyn, New York ; F. G. Dawnitz, St. Louis, Missouri ; and Wile, 
 of Danbury, Connecticut, may be mentioned. They all spoke very 
 highly of Salol as much superior to any of the salicylates, and as a 
 
8o Salol. 
 
 reliable remedy for gout and rheumatism. Dr. Wile used the 
 compound in rheumatism complicated with Bright's disease ; 15 grns. 
 of Salol was prescribed three times a day with a milk diet. The 
 improvement ws at once apparent and steadily progressed. 
 
 An interesting case of rheumatism, in which Salol was used, was 
 described in a medical journal of Japan, by Dr. J. Kimura. The 
 patient was attacked in both knee-joints, and had been long under 
 various treatments without good effect. At first 10, and later 2o-grn. 
 doses of Salol were prescribed. In about three months the pain had 
 entirely disappeared, and the patient, who had been quite unable to 
 walk, could move about very well with the aid of a stick. Previously 
 there had been habitual constipation ; but after the use of Salol, the 
 bowels became quite regular. 
 
 Thirty cases of articular rheumatism were treated in the Magdeburg 
 Town Hospital, by daily doses of i^ 2 drms. of Salol, under the 
 direction of Dr. Behm. The results were characterised as very 
 satisfactory, and there was a noticeable absence of unpleasant bye- 
 effects. Appetite nearly always remained good, and the amount of 
 perspiration produced was always less than that which accompanied 
 the use of salicylic acid. 
 
 2. In Diseases of the Genito- Urinary Tract. 
 
 While Dr. Rosenberg was examining the anti-rheumatic virtues of 
 Salol, Dr. L. Feilchenfeld, in the same institution (Jewish Hospital. 
 Berlin), tried it in vesical catarrh and pyelitis. Single doses oJ 
 1 5 grns. two or three times a day, produced good effects in all cases ; 
 the urine, when previously alkaline, became acid, its volume increased 
 while the amount of pus excreted decreased. 
 
 These favourable effects were especially marked in acute cases, and 
 in cystitis gonorrhoica. 
 
 In two cases of pyelitis the pus was unmistakably diminished in 
 amount to an extent not attainable by other means. Even when the 
 case was one of prostatic hypertrophy, the quality of the urine was 
 improved by the use of 45 grns. of Salol. 
 
Salol. 8 1 
 
 The dosage employed was not, as a rule, followed by any unpleasant 
 effects. The so-called carboluria was frequent, but soon passed off 
 again, although the remedy was uninterruptedly continued. Gastric 
 troubles were never observed. 
 
 Professor Demme (Ber. d. Jennerschen Kinderspital in Bern No. 20) 
 recorded beneficial results in two cases of vesical catarrh. In one 
 case the affection was the result of cantharidin-poisoning in a boy of 
 five years. From 20 40 grns. of Salol was prescribed, and on the 
 second day the previously alkaline urine became acid, and the diuresis 
 more abundant and painless ; after a fortnight's use of Salol, the boy 
 could be looked upon as cured. The second case was one of cystitis 
 following on measles, which passed into the chronic form ; here also 
 Salol did good service. 
 
 In writing on "The present position of the treatment of Cystitis" 
 (Therap. Monatsh., 1887, No. 2) Dr. Leopold Casper, Berlin, alludes 
 at length to the effect of internal medication with antiseptics, and 
 characterises Salol as one of the best. It was ordered in powder 
 form with sugar i 2^ drms. pro die. 
 
 A decidedly favourable issue was attained by Dr. B. Arnold (Ibid, 
 1888, No. 7) in the case of an old man of 80 years suffering from 
 paralysis of the expulsory muscles. The constant use of the catheter 
 was followed by cystitis, the urine being alkaline, turbid and containing 
 blood and fatty substances. These abnormalities of the urine persisted 
 in spite of all measures, until finally 15 grns. of Salol was prescribed 
 twice, and later as the compound was well borne by the stomach- 
 three times a day. 
 
 During the daily dosage of 30 grns. the urine gradually cleared up, 
 and when the quantity was increased by another 15 grns. it exhibited 
 at first a blackish green tinge, and then rapidly became clear ; the 
 sediment also steadily decreased in amount. 
 
 By continuing the use of the remedy, the diseased symptoms were 
 kept in abeyance, but any suspension of its administration was followed 
 by a return of the turbidity, etc. 
 
 The author observed that the small dose of 45, and then 30 grns. 
 daily, had the desired effect of preventing the ammoniacal fermentation 
 of the urine in the bladder, and so keeping it clear and acid. At the 
 
 G 
 
82 -Salol. 
 
 same time the remedy was very well borne ; the tongue, previously 
 thickly covered, cleared perceptibly, and the appetite decidedly 
 improved. 
 
 The fact (i) that Salol was split up in the organism into its 
 constituents, and (2) that it was excreted as salicyluric and phenyl- 
 sulphuric acids in the urine, led to its employment for attaining 
 antisepsis of the urinary tract by a number of French physicians also, 
 whose results corroborated those of the authors above mentioned. 
 
 Salol has also been used with excellent results in the treatment of 
 inflammatory processes of the urethra, both acute and sub-acute in 
 character, due to micro-organic activity. 
 
 Dr. Ch. Talamon, of the Paris Hospital, tried Salol in blen- 
 norrhagia. In two cases scalding had lasted a week, with abundant 
 green pus and nocturnal erections. By the second day of the Salol 
 treatment the excretion was thinner, and the scalding removed ; on the 
 fourth the discharge was milky, and by the seventh only a drop of 
 serous liquid could be obtained at the meatus by pressure. 
 
 In two other cases the discharge assumed a milky character three 
 days after the administration of Salol. In all these instances the cases 
 were recent, and had not been aggravated by the injections which 
 always tend to perpetuate the discharge. 
 
 Dr. Hirtz, of the same Institute, recorded similar results. In 20 
 cases the remedy checked the discharge at the end of a period varying 
 from eight to twelve days. The analgesic action was manifested early 
 in the history of the cases. By this author the combination of Salol 
 and copaiba balsam or sandal-wood oil was largely prescribed (v. p. 91). 
 
 Dr. Dreyfous treated seven cases of gonorrhcea with Salol in doses 
 of i 2 drms. (Brit. Med. Journal, 1889, Dec. 7th). The discharge 
 became less abundant, and in some cases a cure was effected in a few 
 days. The remedy was sometimes given alone and sometimes com- 
 bined with copaiba and cubebs in order to hasten the cure. Dr. 
 Dreyfous recommends Salol to surgeons about to operate on the 
 urinary organs ; it rendered the urine aseptic and innocuous when it 
 came in contact with wounded surfaces. 
 
 Mr. J. Ernest Lane, F.R.C.S., Out-Patient Surgeon of the London 
 Lock Hospital, gave the results of the administration of Salol in fifty 
 
Salol. 83 
 
 cases of gonorrhoea {Lancet, 1890, March 22nd); six were cured, 
 24 showed considerable improvement, 15 showed no change either 
 one way or the other, and in five the symptoms were aggravated. 
 The doses used were from 5 30 grns. taken three times a day, and 
 the beneficial effects manifested themselves in a very short time. 
 
 When improvement took place, the symptoms abated in from two 
 to seven days ; painful micturition was early alleviated, and, in cases 
 of more chronic nature, the discharge was materially lessened. 
 
 At first the author used injections at the same time as the Salol was 
 given in five-grn. doses, but, subsequently, he raised the dosage to 10, 
 20, and in a few cases, 30 grns., and relied upon it exclusively. Out 
 of 40 cases so treated, improvement was noticed in 20 within a week, 
 while, as already stated, six were completely cured. The author 
 believed that, in chronic cases, the cure would be materially hastened 
 by an astringent injection, and that more favourable results would have 
 been obtained had larger doses been used from the beginning. 
 
 Dr. William White described before the American Syphilographical 
 Society his experience with Salol in over 50 cases of inflammation of 
 the urethra. In 35 of these the discharge was completely arrested at 
 the end of a week. 
 
 Interesting cases, which may be classed under this heading, were 
 described by Dr. Vernon Jones in the British Medical Journal, 1892, 
 Feb. 1 3th. In the first, the patient, who had suffered from gonorrhoea 
 for some time, strained his knee slightly, in consequence of which 
 there was great pain and effusion into the joint ; the limb was put on 
 a splint, and all the usual remedies tried, without avail. The urethral 
 discharge continued, and the other knee also became involved. He 
 was then put on 1 5 grns. of Salol three times a day, and from that 
 time improvement set in ; the discharge diminished, pain ceased, and 
 eventually, by the aid of local measures, the effusion also subsided. 
 
 The second case was less instructive, as the author did not rely 
 upon Salol alone, but changed about with other agents. The case 
 recovered in the end. In the third instance recorded by Dr. Jones, 
 the patient was a woman, and, as might be expected on theoretical 
 grounds (from the shortness of the urethra), the action was very much 
 less marked in the female sex. 
 
 G 2 
 
84 Salol. 
 
 3. In Diseases of the Intestinal Tract. 
 
 In the account of the employment of Salol given by Dr. Georgi in 
 the Bcrl. klin. Wochenschr., 1887, Nos. 9-11, already referred to, there 
 is a section devoted to the consideration of the value of the remedy 
 in diseases where intestinal antisepsis is indicated. He found that 
 beneficial results were produced. 
 
 Dr. E. L. Vansant, Demonstrator of Pathological Histology, and 
 Chief of the Medical Clinic, Philadelphia, gave an account (Medical 
 Times, 1888, Oct. 15) of some dozen cases of diarrhoea and dysentery 
 treated by him with Salol, sometimes alone and sometimes with 
 bismuth subnitrate. The patients were of very varied ages, from 10 
 months up to 57 years, but in every case the remedy was well borne 
 and successful in bringing about the desired results. It was found 
 that much better results were obtained by prescribing the Salol every 
 three hours than by restricting it to three times a day. 
 
 Dr. R. B. McCall (St. Louis Medical Brief, 1888, Nov.) detailed a 
 case of dysentery in a delicate boy of five years. At first the fluid 
 extract of ergot did good, but delirium ensued, and so it was sub- 
 stituted by subnitrate of bismuth combined with paregoric. This 
 seemed to be having a good effect for a day or two, when the disease 
 suddenly resumed its first serious character. Then small doses of 
 calomel ( grn.) with i grn. of Dover's powder every five or six 
 hours, was prescribed, but obliged to be given up because of the 
 nausea produced. Under routine methods it was plain the boy could 
 not be saved, and Dr. McCall resolved to essay Salol. He ordered it 
 in 2-grn. powders every three hours, and by the end of the first day 
 there was evident improvement in the character of the evacuations, 
 diminution in their number, fall of temperature, and slowing of the 
 pulse; at the same time restlessness and fretfulness vanished as if by 
 magic. After the second day the dose was increased and improvement 
 continued, fever entirely disappearing, the tongue cleaning and 
 appetite returning. 
 
 In about 10 days nearly 200 grns. of Salol were taken by this child 
 without the least sign of oppression, disturbance of any kind, of 
 
Salol. 85 
 
 stomach, heart, kidneys or brain. The author expressed the convic- 
 tion that Salol was perfectly safe in suitable doses at any age. 
 
 Theoretical considerations induced Dr. A. H. Goelet, New York 
 (Medical Journal, 1887, Aug. 6th) to prescribe Salol in a bad case of 
 diarrhoea where bismuth, extract pancreatis and sodii bicarbonas, with 
 a milk diet, had proved ineffectual. Ten grns. of the remedy were 
 ordered to be taken every two hours. By the next morning the 
 patient reported himself all right. The motions ceased after the 
 second dose, as well as the pains and colic. A dose an hour before 
 each meal for two days was ordered with a practically unrestricted 
 diet. The motions continued natural in character and number, thus 
 . proving that the remedy had no constipating effect. 
 
 In a second case a fifteen months' child suffering from diarrhoea and 
 vomiting, one grn. was ordered every two hours dry on the tongue 
 with a teaspoonful of water after it. The vomiting ceased immediately, 
 and in six hours the diarrhoea had ceased as well ; on the next day the 
 stools were natural, and the Salol was discontinued. 
 
 The author expressed the opinion that Salol was the only purely 
 satisfactory remedy he had ever used in such cases. In typhoid fever, 
 every three hours, there was nothing better, while he could not say 
 that it shortened the attack, it annulled the excessively disagreeable 
 odour of the faeces, and relieved the tenesmus and flatulence due to 
 accumulated gases in the colon. He did not know of anything which 
 so satisfactorily relieved flatulence of any origin. 
 
 Other cases in which Dr. Goelet successfully prescribed Salol were 
 summer diarrhoea and dysentery of children ; under such treatment, 
 if seen early, and properly dieted, there was no need for appre- 
 hension. 
 
 Corroborative evidence was furnished by Dr. O. T. Osborne, New 
 Haven (New York Medical Journal, 1888, April yth). As indications 
 for Salol in bowel troubles, he cited vomiting, purging, cramps, and 
 all the symptoms of the so-called "summer diarrhoea" of children. 
 He used it in twenty- two cases of all kinds, including one of acute 
 dysentery, without a single failure. The dysenteric patient had as 
 many as sixty bloody and mucous stools daily. The treatment was 
 four grains of Salol internally every two hours with morphine, whiskey 
 
86 Salol. 
 
 and ice-water injections into the rectum. These latter failed, 
 however, to relieve the tenesmus or sanguinolent nature of the stools, 
 and were therefore substituted by a four per cent, solution of Salol in 
 alcohol, two teaspoonsful in water being injected as soon as the 
 tenesmus was felt to be coming on. Immediate relief followed the 
 first injection, and the next day no blood was passed, but faecal 
 matter appeared in the stools. 
 
 Except in a single case where an eruption occurred after the use of 
 Salol which could not be certainly traced to the remedy there were 
 no unpleasant symptoms due to its use. All the patients, save the 
 dysenteric, were cured without opium, and indeed without any other 
 medications at all, except the Salol. Although it is insoluble in the 
 gastric juice, the compound allayed vomiting ; this effect, conjectured 
 Dr. Osborne, might be due to an antiseptic action of Salol per se. 
 
 Dr. Kimura, whose paper on the use of Salol has been already 
 referred to, used the remedy against dysentery with good effect. 
 About five grns. were emulsified with water and injected into the 
 rectum; the most satisfactory results followed when the injection was 
 preceded with two or three quantities of lukewarm water. 
 
 Dr. Hirtz prescribed Salol in combination with salicylate of bismuth 
 in 35 cases of typhoid fever with great benefit. Combined with bicar- 
 bonate of soda, it arrested eructations, pyrosis, flatulence and diarrhrea, 
 so often witnessed in dyspepsia, due to dilation of the stomach. The 
 remedy was always well borne and had the advantage in typhoid of 
 effecting antisepsis simultaneously of the intestinal and urinary tract. 
 Similar results were obtained by Hesselmann. 
 
 In a lengthy treatise on "Intestinal Antisepsis" (Therap. Gazette, 
 1891, Aug.) Prof. Dujardin-Beaumetz recommended Salol particularly 
 as the best of intestinal antiseptics. He prescribed it for rectal cancer 
 with bismuth salicylate and sodium bicarbonate in five-grn. doses 
 before breakfast and dinner. He added, however, that the dose of 
 Salol might be increased to a drachm daily. 
 
 Dr. M. H. Fussell devoted an entire paper to the recording of his 
 experience with Salol in diarrhoea (Therap. Gaz., 1892, p. 508) and 
 
Salol. 87 
 
 generalised his results as follows : 
 
 1. Diarrhrea due to dietetic error, and that which is common 
 
 in adults and infants in summer, is well controlled by the 
 administration of Salol and bismuth or chalk. 
 
 2. Opium is rarely necessary where Salol is used. 
 
 3. Salol controls the abdominal pains equally as well as opium. 
 
 4. It is perfectly safe, having no bad after-effects. 
 
 5. It is especially useful in the diarrhoea of children. 
 
 6. It constantly corrects the foetor of the stools. 
 
 Dr. Mensi also adds his testimony to the value of Salol in the 
 diarrhoea of children (Therapist, 1892, Oct. ijth). Complete recovery 
 was obtained, with a single exception, by the use of Salol in 27 
 children suffering from the chronic form of the affection. The daily 
 dose to young children was 4 8 grns ; to elder children, 16 30 grns, 
 
 4. Salol in Cholera, 
 
 It was shown by Dr. W. Lowenthal (Le Progrcs Mid., 1889, No. 2) 
 (i) that the comma bacillus formed toxic ptomaines with the pan- 
 creatic juice, and (2) that the process of their formation could be 
 prevented by addition of a small quantity of Salol. Since this latter 
 was harmless to man, the author recommended it for the treatment of 
 cholera, and the suggestion was followed by Dr. Ferd. Hueppe, who 
 prescribed it in combination with bismuth salicylate, and reported 
 encouraging results from India. 
 
 Dr. James Couldrey (Brit. Med. Journ., 1892, Aug. 6th) also recom- 
 mended Salol against cholera, suggesting its prescription with tincture 
 of chloroform and morphine internally, with hypodermic injections of 
 ether in the relapse stage. , 
 
 Dr. Salvator, of Zambeles, Phillipine Islands, sent Prof. Lowenthal 
 the record of 53 cases of cholera treated with Salol. Only three- 
 received in very advanced stages of the disease terminated fatally. 
 Doses of 30 grns. were first given, followed by further doses of 8 15 
 grns. every hour or half-hour. 
 
88 Salol. 
 
 5. In Yellow Fever. 
 
 During an epidemic of yellow fever in Rio de Janeiro, Dr. Ferreira 
 tried Salol, being led to do so by the theoretical considerations based 
 on the symptoms of the disease, and on post-mortem revelations. He 
 reached the conclusion that the fever was intestinal in origin, and his 
 experience with Salol appeared to confirm the theory in the most 
 positive manner. He prescribed it in doses of five grns. every twc 
 hours in water, and regarded its value as beyond doubt, though the 
 number of cases in which it was tried was not large. Further trials 
 with Salol in this disease could not fail to be interesting, though it 
 seems that it must be given in considerable doses if success is to be 
 attained. 
 
 6. In Leprosy. 
 
 In the Biennial Report of the Board of Health to the Hawaiian 
 Government, Dr. Lutz, of Honolulu, stated that he had obtained a 
 very favourable impression as to the value of Salol in leprosy. In half 
 a dozen cases the leprous fever was almost immediately interrupted by 
 the daily use of i| 2 drms. divided into three or four equal doses. 
 In some cases the acute eruptions immediately and quickly disappeared 
 under the use of Salol, leaving the patient in complete health during 
 the next six months' observation. In another case a few tubercles 
 appeared, and even persisted during the use of the remedy, but the 
 author believed these would probably have been prevented by the 
 use of larger doses. 
 
 7. For Diagnostic Purposes. 
 
 Salol has done good 'service in the diagnosis of morbid conditions 
 of the upper digestive tract. This employment of the compound 
 depends upon the fact that it passes unchanged through the stomach, 
 and is resolved into its constituents and absorbed only in and from the 
 intestines. Drs. Sievers and Ewald established that in healthy indi- 
 viduals an hour is the extreme limit between the taking of the close 
 
Salol. 89 
 
 and the appearance of salicylic acid in the urine. Variations from 
 this standard would be due to pathological causes. On this basis the 
 diagnosis of changes in the motor efficiency of the stomach could be 
 readily and reliably made with the help of Salol. 
 
 Thus occlusion of the pyloris was successfully diagnosed in a case 
 where, after administration of Salol, no salicylic acid appeared in the 
 urine {Brit. Med. Journ., 1890, June i4th), and Drs. Sievers and 
 Ewald were able, in a number of instances, to diagnose in this way 
 dilatation and functional disorder of the stomach. 
 
 - 
 EXTERNALLY. 
 
 1. In Surgery and Skin Affections. 
 
 It will be unnecessary to reproduce extracts from all the literature 
 which has appeared upon the external application of Salol. As a 
 substitute for iodoform, the chief advantages which it has manifested 
 
 are 
 
 1. Freedom from odour. 
 
 2. Almost absolute non-toxicity. 
 
 3. Valuable drying properties. 
 
 Dr. Eugen Griitzer, Menchi (Therap. Monatsh., 1884, No. 9), 
 Corner (Journ. Amer. Med. Assoc., 1889, June 8th), Saalfeld, etc., 
 observed that when applied to raw or excoriated surfaces, it exerted a 
 powerful antiseptic and anodyne action. It was used in surgery in 
 the form of powder, either alone or mixed with starch or French 
 chalk, as liniment. Professor Demme obtained very good results in 
 burns ; Dr. Gratzer and others in abscesses of the leg and sycosis 
 parasitaria ; Saalfeld in impetigo, eczema ; and Professor Barduzzi in 
 various skin affections, especially those of syphilitic origin. 
 
 Very careful researches into the action of Salol externally as an 
 antiseptic were carried out by Dr. M. G. Patein (Surgical Review, 1887, 
 p. 519), who recorded its successful use in localised tuberculosis, in 
 the treatment of variolous pustules of the face (20 per cent, solution 
 in ether), and other diseases of a similar nature. In cases of epi- 
 thelioma of the nose, fistula of the breast, mammary and maxillary 
 
go Salol. 
 
 abscess, removal of diseased growths, caries of the sternum and rectal 
 abscess, the results were superior to those obtained with iodoform. 
 In an operation for a laryngeal cyst, requiring tracheotomy, the action 
 of Salol was remarkable. 
 
 Dr. M. Perrier observed very good results in local tuberculosis ; 
 where the bones were the seat of disease, this surgeon discarded 
 iodoform and used Salol alone. In several cases he filled the cavities 
 with gauze sachets containing varying amounts of Salol powder 
 without producing any symptoms of poisoning, while all septic action 
 was arrested. 
 
 2. In Rhino -larynology. 
 
 The successful treatment of 22 cases of inflammation of the soft 
 palate, of tonsillitis and pharyngitis by Salol was reported by 
 Dr. Gougenheim. Dr. Caport (Brussels) first called attention to the 
 remarkable value of Salol in the treatment of suppurative tonsillitis, 
 and the publication of his results led Dr. Gougenheim to test its value 
 in various forms of angina. On account of its insolubility, the remedy 
 was conveniently dispensed in mucilage 15 20 grns. three times a 
 day, and the diet almost exclusively restricted to milk. In all the 
 author's cases the dysphagia was cured with the most remarkable 
 rapidity, no matter what its cause. 
 
 Dr. Otto Seifert (Centralbl.f. klin. Med., 1887, No. 14) tried -Salol in 
 the local treatment of diseases of the mouth, nose, and larynx. He 
 praised it highly as a mouth wash and gargle one teaspoonful of a 
 six per cent, alcoholic solution in a glass of warm water in stomatitis, 
 ulceration of the mouth and pharynx, angina; in chronic diphtheria 
 the remedy did better service than potassium chlorate and salicylic 
 acid. 
 
 Dr. Thorner, Cincinnati (Lancet Clinic, 1887, Dec. loth), charac- 
 terised Salol as far superior to sodium salicylate, not only in certainty 
 and rapidity of effect, but also as regarded the relative smallness of 
 the dose. In those exceedingly painful cases of acute catarrhal 
 pharyngitis, involving the entire muscular system of the neck, the 
 pains rapidly disappeared under the use of 9 12 grns. of Salol three 
 
Salol. 9 1 
 
 times a day. The effects were nearly equal in phlegmonous and 
 follicular angina, pain disappeared after a few doses, the restless 
 patients fell into a refreshing sleep and were enabled to swallow 
 almost without pain. 
 
 Good results followed the internal use of Salol in nervous otalgia, 
 as well as in one case of otitis med. chronica purulenta. 
 
 In ozaena, Cozzolina recommends insufflation of a Salol powder 
 (30 per cent.) in combination with boric acid (15 per cent.), salicylic 
 acid (3 per cent.) and French chalk, with a minute quantity of 
 thymol. 
 
 In the treatment of diseased condition of the mouth with foetor, 
 Georgi recommended a mouth wash made by mixing 2 ^\ drms. of 
 a four to five per cent, alcoholic solution with six ounces of water. 
 
 FORMUL/E AND METHODS OF USE. 
 
 When prescribed as powders the slight taste of Salol may be masked 
 by oil of peppermint. As already repeatedly stated above, it has also 
 been given in wafers and emulsion. 
 
 When given in diseases of the genital tract tho solubility of Salol 
 in essential oils and oleo-resins enables it to be readily combined 
 with sandal-wood oil or balsam of copaiba. The employment and 
 efficiency of these combinations has been already described. 
 
 Externally in ulcers, skin affections, etc., the oleaginous solution is 
 effective, or an ointment (i 10 per cent, with lanolin). When 
 employed as a dusting powder it is best mixed with starch or French 
 chalk. 
 
 As a topical application against rheumatism it has been recom- 
 mended to dissolve four parts of Salol in an equal weight of ether 
 and add 30 parts of collodion. Painted on the affected areas this 
 application is a useful adjunct to the internal treatment. 
 
SALICYLIC ACID 
 
 AND ITS SALTS. 
 
 The value of Salicylic acid in the various forms of the rheumatic 
 diathesis needs no emphasis; it has obtained a well-recognised 
 position as possessed of what may be termed specific virtues in the 
 treatment of the class of affections above-named. 
 
 The reputation of the substance and its preparations was largely 
 built up upon results obtained with the product derived from the 
 vegetable kingdom, and especially from the oil of wintergreen, and 
 when Kolbe's method of synthesising Salicylic acid was first used for 
 the preparation of a medicinal article, doubts were entertained as to 
 its exact correspondence with the natural product. 
 
 Chemical investigation did show, as a matter of fact, that commercial 
 Salicylic acid contained foreign acids, and physiological work carried 
 out by Prof. M. Charteris and Dr. W. Maclennan indicated that a 
 dangerous and even fatal action on animals was produced by these 
 foreign constituents of the synthetical acid. Professor Charteris 
 extracted a substance from the acid which in doses of one grn. proved 
 fatal to a rabbit of 2 Ibs. weight. At the same time it was proved that 
 it was possible to purify the acid, and the physiological action of the 
 substance, thus freed from impurities, was not characterised by any of 
 the symptoms of paralysis or even of depression observed to follow 
 the administration of the impure article. 
 
 In consequence of this work Messrs. Schering turned their attention 
 to the subject, and adopted additional means of purification. Some of 
 the product of the modified process of manufacture was placed in the 
 hands of Prof. Charteris, who examined it physiologically, and stated 
 that he satisfied himself it was precisely similar to the acid obtained 
 from natural salicylates, and therefore of such purity as to be equally 
 eligible for medical use. 
 
94 Salicylic Acid and its Salts. 
 
 Subsequent researches, chemical and physiological, proved beyond 
 doubt that the Salicylic acid and salicylate of sodium, prepared by the 
 improved process referred to above were absolutely free from foreign 
 acids or other impurities, and consequently that they were indis- 
 tinguishable in their action upon the animal organism, whether in 
 health or disease, from the compounds obtained from natural sources. 
 
 Since the salicylates provided by nature are far from abundant and 
 difficultly isolated, so that high prices follow as a matter of course, 
 the importance of a means of artificially preparing them which is 
 comparatively simple and unlimited in productive capacity is self- 
 evident. But also it is essential that the synthetical body should be 
 absolutely pure, not only to chemical but to physiological tests as well. 
 The researches of Professor Charteris and the other workers have had 
 a very practical and valuable outcome in leading to the manufacture 
 of a Salicylic acid and compounds which can be used in every way as 
 freely and harmlessly as the preparations obtained from the vegetable 
 kingdom. 
 
 BISMUTH SALICYLATE. 
 
 Basic salicylate of bismuth is a definite compound with the formula 
 Bi (C 7 H 5 O 3 )3 Bi 2 O 3 containing 76 per cent, of bismuth oxide and 
 23 per cent, of Salicylic acid. It occurs as an amorphous yellowish 
 white powder, entirely insoluble in water. 
 
 Under the name salicylate of bismuth, however, preparations have 
 been introduced into medicine which were little else than mixtures of 
 Salicylic acid and oxide of bismuth ; as the free acid has a well- 
 marked irritant action when externally employed, it is necessary to 
 avoid the use of these articles. 
 
 It should be noted that neither water, alcohol, ether, nor chloro- 
 form, should extract anything from the true salicylate of bismuth. 
 Preparations which contain free Salicylic acid yield it to these solvents 
 and are thus detected. 
 
 The compound has been employed in medicine as a substitute for 
 iodoform in the treatment of wounds, ulcers, etc. Its value in these 
 
Salicylic Acid and its Salts. 95 
 
 cases depends upon the following properties : 
 
 1. It is antiseptic, rapidly removing foetor and arresting morbid 
 
 process due to micro-organic activity. 
 
 2. It is drying, diminishing secretion, and thus indirectly check- 
 
 ing bacterial development. 
 
 3. It is soothing and healing, healthy granulations quickly forming 
 
 during its use. 
 
 In internal antisepsis salicylate of bismuth has also played an 
 important part, both alone and in combination with other remedies 
 of the same class. Vulpian recommended it highly in morbid con- 
 ditions of the intestinal tract, especially of the rectum, and Dr. Solger 
 used it in affections of this kind with great success. 
 
 The best results were obtained in irritated and sub-inflammatory 
 conditions of the intestines, in which its mild antiseptic action gave 
 it great advantages over the nitrate of bismuth previously employed. 
 
 The pure bismuth salicylate, free from uncombined acid, is well 
 borne by the stomach, and can be continuously given for months 
 without ill-effect. It is, therefore, specially suitable in chronic 
 diarrhoeas, even when of most obstinate nature. Surgeons have also 
 found it useful to prescribe after operations upon the intestines, in 
 order to prevent faecal accumulation and development of gases which 
 endanger the results of the operations*. 
 
 Dr. Dujardin-Beaumetz recommended bismuth salicylate (Therap. 
 Gazette, 1891, Aug.) combined with equal doses of Salol in the 
 treatment of rectal cancer. He prescribed five-grn. doses of each of 
 the remedies to be taken before breakfast and dinner; the adjuncts to 
 this treatment were antiseptic rectal irrigations and a vegetarian diet. 
 Where the disease did not cause much local constriction he believed 
 quite satisfactory results could be obtained from the means indicated. 
 
 LITHIUM SALICYLATE. 
 
 This compound is a white crystalline powder, soluble in little more 
 than its own weight of water; it is also abundantly taken up by 
 alcohol. 
 
96 Salicylic Acid and its Salts. 
 
 The lithium salts have, as known, been used for years in the treat- 
 ment of gout and of diseases of the urinary tract. Salicylic acid also 
 won a high reputation in the treatment of many similar affections, 
 and, therefore, its combination with lithium promised to display 
 therapeutical properties most valuable against the uric acid diathesis. 
 
 Clinical trials with lithium salicylate showed that the expectations 
 formed as to its value were well founded. It manifested very valuable 
 properties in the treatment of acute rheumatism and the various affec- 
 tions due to, or associated with, an excess of uric acid in the blood. 
 
 Unlike the salicylates of the commoner alkali metals, lithium 
 salicylate does not produce any disagreeable effects upon the digestive 
 organs. The tendency of the ordinary salicylates to do this is a 
 contra-indication to their use in some cases, and in these especially 
 lithium salicylate appears to be very suitable. Over the carbonate of 
 lithium the newer salt has the advantage of being readily soluble, 
 and, therefore, its absorption and therapeutical effect are the more 
 reliable and prompt. The property of dissolving readily and entirely 
 in water is characteristic of the pure salt, and will serve as a rough test. 
 
 Dr. Vulpian found lithium salicylate equal in every case to 
 salicylate of sodium as regarded therapeutical effect, while, in some 
 instances, it was distinctly rriore efficient. This was especially 
 noticeable in some cases of acute rheumatism of the joints ; oc- 
 casionally, in this affection, the fever, though at a very low level, is 
 difficult to entirely remove, and sodium salicylate is by no means 
 always successful, even when its administration is long continued, in 
 bringing about complete apyrexia. In these cases the lithium salt 
 proved especially valuable. 
 
 In the chronic form of rheumatism, and particularly in rheumatic 
 affections of the tendons, lithium salicylate proved superior to the 
 sodium salt. 
 
 The medium daily dose for adults is one drm., though it may be 
 increased to about i| drms. pro die without any disagreeable results. 
 The compound appears to be worthy of more extended trial than it 
 has hitherto received, as it possesses a valuable combination ot 
 therapeutical virtues with a noteworthy absence of drawbacks. 
 

 STRONTIUM 
 SALTS. 
 
 Hitherto the so-called alkali earth metals have not yielded salts of 
 very marked therapeutical value, or, at any rate, where such have been 
 prepared and employed in medicine, their usefulness has depended 
 more upon the acidulous group in the salt than upon the metal itself. 
 This is easily verified in the case of such compounds as calcium 
 iodide, hypophosphite, etc. The barium compounds are well-known 
 to be characterised by a powerful poisonous effect, specially manifested 
 upon the circulatory system, and therefore they have been little or not 
 at all used. 
 
 The close chemical relationship existing between Strontium salts 
 and those of barium, as well as the difficulty of obtaining the former 
 perfectly free from traces of the poisonous barium compounds, led to 
 the impression that the Strontium salts were possessed of similar 
 dangerous properties. 
 
 Original investigations recently carried out in the hospitals of Paris, 
 and communicated to the French Academy of Medicine and to other 
 learned Societies, have conclusively proved that the 
 
 Strontium Salts are innocuous, 
 
 and not only so, but that they have a beneficial influence upon the 
 nutritive processes. 
 
 The first evidence of this kind was contained in a treatise by 
 Ismael Nassan, the effect of which was to lead to the preparation of 
 absolutely pure salts for use in medicine. These were employed 
 therapeutically by a number of experimenters, and with so much 
 success as to be considered worthy of special notice and emphasis. 
 
 H 
 
98 Strontium Sails. 
 
 THERAPEUTICAL USES. 
 
 BROMIDE OF STRONTIUM. This compound was found to have all 
 the useful properties of the alkaline bromides without their tendency 
 to produce digestive and nutritive disturbances. Dr. Constantine Paul 
 prescribed it in daily doses of i drms. to a young girl suffering 
 from hystero-epilepsy. Although the attacks had resisted potassium 
 bromide given perseveringly in drachm doses, they were entirely 
 arrested by the Strontium salt and did not recur. 
 
 Bromide of Strontium was prescribed by Deny for seven epileptics, 
 and under this treatment the patients had among them 246 attacks 
 in seven months. During the corresponding period of the preceding 
 year bromide of potassium had been administered, and the number of 
 attacks was 331, consequently the Strontium salt reduced the fits by 
 more than a quarter. Both compounds were given in exactly the 
 same doses. One of the patients who was most benefited by the 
 Strontium treatment, ceased to suffer from the maniacal excitement 
 after each epileptic seizure to which he had previously been 
 subject. 
 
 From the experience of Fr and Prof. Germain S6e, it appears that 
 pure Strontium bromide has no disastrous effect upon the stomach, 
 even when given in large doses. The latter authority employed the salt 
 with success in various gastric affections, and it also proved useful in 
 diabetes, causing a diminution in the amount of sugar excreted. 
 
 LACTATE OF STRONTIUM. Dr. Laborde first recorded the bene- 
 ficial action of this salt in obstinate painful dyspepsia, and his 
 observations were subsequently confirmed by other experimenters. 
 Dr. C. Paul found that it was well borne in daily doses of 2 3 drms., 
 and employed it with advantage in visceral congestion, and in Bright's 
 disease ; better results were obtained than with lithia. Though not 
 a diuretic, Strontium lactate brings about at once a diminution in the 
 amount of albumen excreted, and correspondently improves the 
 collateral symptoms. When the administration of the remedy was 
 suspended, the albumen reappeared in the urine, to again fall to zero 
 when the treatment was resumed. 
 
Strontium Salts. 99 
 
 Other affections of the urinary system associated with excretion of 
 albumen were similarly benefited. Dr. Dujardin-Beaumetz reduced 
 the proportion 50 per cent, within one to four days. He characterised 
 the salt as a valuable agent, both reliable and harmless. Laborde 
 prescribed the lactate as a taenifuge with success in drachm doses 
 repeated daily for about a week. 
 
 OTHER STRONTIUM SALTS which have been successfully used 
 therapeutically are the iodide, a one or two per cent, solution being 
 employed in scrofulous diseases ; the nitrate, given in doses of 
 % 4 drms. in articular rheumatism ; the phosphate, regarded by 
 Laborde as one of the most valuable nutritive and tonic medicaments 
 known ; and the acetate, which has also a reputation as an active 
 taenifuge. Altogether there is sufficient evidence that, if perfectly 
 pure Strontium salts are employed, they will prove a valuable enrich- 
 ment of materia medica, and increase the power of the physician to 
 control certain obstinate and obscure diseases. 
 
 H 2 
 
POTASSIUM 
 BROMIDE. 
 
 Although of late years materia medica has been enriched by a 
 considerable number of synthetical hypnotics and sedatives, which 
 may be described as products of organic chemistry, yet Bromide of 
 Potassium maintains its position as a most valuable remedy in nervous 
 diseases, whether due to abnormalities of the nerve centres them- 
 selves, or to excessive reflex sensibility. 
 
 It is necessary, however, to call attention to the desirability of care 
 in the selection of Potassium Bromide for use in medicine. The 
 standard to be aimed at is, of course, absolute purity, not only on 
 economic grounds, but because scientific medicine can only be based 
 upon the presumption that the substances administered or applied are 
 of definite composition and perfect purity. 
 
 Chemical analysis has shown, however, that there are brands of 
 Bromide of Potassium which are far from satisfying the requirements 
 of the high standard alluded to. The examination of commercial 
 specimens of the salt, carried out by Messrs. Helbing & Passmore, 
 showed that there are American brands which contain notable 
 amounts of impurities in the form of combined chlorine. 
 
 It is therefore necessary for prescribers and dispensers to exercise 
 care in the selection of Potassium Bromide for therapeutical use, in 
 order that the physician may be able to rely upon the constancy of 
 effect of the remedy he prescribes. Physiological research has shown 
 that apparently quite insignificant doses of compounds may have an 
 appreciable effect upon the organism, and there is sufficient difference 
 between the action of chlorides or bromates (another possible 
 contamination of commercial bromide) and bromides to render it 
 undesirable to administer a preparation which contains a relatively 
 large proportion of these compounds as impurities. 
 
THIOSINAMINE. 
 
 This substance is one of a group of bodies which may be regarded 
 as derivatives of urea. Systematically it is termed allylthiocarbamide 
 a name which indicates that in the urea nucleus the oxygen atom is 
 replaced by sulphur. The place of the allyl group in the body might 
 be occupied by almost any compound radical such as phenyl, ethyl, 
 etc., and most of the possible combinations thus brought about have 
 been experimentally examined physiologically and bacteriologically. 
 
 On the whole, Thiosinamine proved the most valuable member of 
 the group. 
 
 A lengthy treatise on the employment and action of the compound 
 has been written by Dr. H. v. Hebra. In this paper the formula of 
 Thiosinamine appears as 
 
 /NHC 3 l-b 
 CS< 
 
 X NH a 
 
 and it is described as prepared by acting on volatile oil of mustard 
 with ammonia in the presence of alcohol. As in the case of most 
 derivatives of mustard oil, water decomposes the compound, and 
 consequently alcohol or ether must be resorted to for the purpose of 
 preparing solutions of Thiosinamine. Such solutions administered 
 subcutaneously produce a smarting sensation, but this appears to be 
 of very short duration, and not sufficiently unpleasant to make patients 
 unwilling to persevere with their use. 
 
 THERAPEUTICAL USE. 
 
 Some three years ago Dr. v. Froschauer stated that animals could 
 be rendered immune to bacillary infection by subcutaneous injection 
 
IO4 Thiosinamim. 
 
 of allylsulphocarbamide. Careful repetition of the experiments 
 showed that this was not well-founded, but at the same time led to 
 the employment of the compound in some chronic cutaneous 
 diseases. 
 
 The medicinal value of Thiosinamine was made the subject of 
 careful study by Dr. Hebra. He found that a prominent feature of 
 its action was a well-marked local reaction, not accompanied by any 
 general constitutional disturbances. 
 
 About two hours after the injection the affected site reddened and 
 began to swell, the intensity of these symptoms depending upon the 
 extent of the disease and the dose injected. After some four or six 
 hours these phenomena subsided, and the normal colour was regained 
 about 1 8 to 20 hours later. No vesicles or serous exudation was ever 
 observed. 
 
 The majority of cases treated were lupus of various severity and 
 site. On the day following the reaction considerable desquamation 
 occurred, and all the diseased patches were covered with scales ; the 
 adjacent healthy skin remained smooth and unaltered. 
 
 As regarded the beneficial effects of the treatment a few injections 
 were sufficient to render this unmistakable. Lupus tumidus became 
 much less prominent, the whole area sinking considerably, while in 
 the ulcerated form the thickened margins decreased, and in a few 
 weeks' time the healing process was established, after vain endeavours 
 to effect it by external remedies. 
 
 The lupoid nodules offered the greatest resistance, owing, doubtless, 
 to the paucity of the blood supply. 
 
 The results, as regarded the cicatricial tissue following the spon- 
 taneous ulceration of lupus, or the application of caustics, were much 
 more striking. Whenever such tissue disturbed nutrition or impeded 
 movement, a complete softening and loosening was brought about 
 by the medication. Very striking cases, illustrative of this fact, are 
 described by the author. 
 
 Other cases in which favourable results were attained by the use of 
 Thiosinamine were those of chronic glandular swellings. Syphilitic 
 affections of the glands were not affected, and it was suggested that 
 this fact might be made use of for diagnostic purposes. 
 
Thiosinamine. 1 05 
 
 On the day of injection an excess of 7-318 ounces of urine was 
 passed, but no untoward effect upon the kidneys was ever observed ; 
 neither albuminaria nor any other morbid changes were detected, 
 though carefully watched for. The process of absorption generally 
 was promoted. 
 
 All the patients felt well during the treatment. Appetite increased 
 remarkably in every case, and coincidently with the administration of 
 the remedy ; as a natural consequence, nutrition and general body- 
 weight also improved. Experiments made on animals showed that 
 doses ten to twenty times as large proportionately as those given 
 to the human subject, caused only a slight lowering of the blood- 
 pressure, which was probably due to the solvent. 
 
 Dr. Hebra recommended that only old processes should be treated 
 with Thiosinamine, save in lupus and allied conditions. Carefully 
 employed, it seems to have a valuable action in clearing nebulae of 
 the cornea. 
 
 DOSAGE. 
 
 A 15 per cent, alcoholic solution was employed, two or three 
 divisions of a Pravaz syringe being injected twice weekly, so that 
 5 7 grns. of Thiosinamine were administered at each injection. In 
 cases of lupus the dose was increased in the third week to half a 
 syringeful, and in the fourth or fifth week to a whole syringeful of 
 15 percent, solution. In a few cases even more was given without 
 bad effect. 
 
DIABETIN. 
 
 The fact that the sugar excreted by diabetics is identical with 
 ordinary dextrose or grape sugar has always been held a sufficient 
 reason for cutting off from the dietary of such patients not only all 
 preparations containing dextrose, but also all farinaceous or starchy 
 foods which are known to be converted into that sugar by the action 
 of the digestive ferments. 
 
 To a large proportion of diabetics this restriction is a considerable 
 hardship, and numerous attempts have been made to substitute 
 ordinary sugar by some preparation which, while satisfying the craving 
 of the patients for sweetness, should at the same time be free from 
 any tendency to aggravate the disease. 
 
 The most successful of these substitutes, the benzene derivative 
 termed " saccharin," though meeting the latter requirement, since it 
 passes through the system unchanged, does not satisfy the craving 
 for the natural saccharine substance, sugar, because its taste is 
 altogether different to this. The sweetness of " saccharin " has a 
 cloying, nauseating character, that generally leads to its speedy 
 abandonment. 
 
 Although the chemical laboratory has failed then to satisfactorily 
 solve the difficulty alluded to, yet such an enormous variety of sweet 
 compounds is elaborated by Nature that it was recognised as extremely 
 probable that some of them would be suitable for the purpose in view. 
 
 The true sugars have, as known, a very close relation to one 
 another in chemical composition, but the progress of the study of 
 the alliance of chemical structure and physiological action has 
 revealed the fact that apparently insignificant constitutional differences 
 are accompanied by the widest variations of medicinal action. 
 
 Now dextrose, the sugar which appears in the urine of diabetic 
 patients, is one member of a group of compounds very closely allied 
 
io8 Diabetin. 
 
 among themselves, but also exhibiting certain important differences. 
 Laevulose is another member of the same class which, in constitution 
 and general reactions, is very similar to dextrose. Yet experiment has 
 shown that, as regards physiological destiny, when introduced into 
 the animal organism, the similarity does not hold, and for this reason 
 it is probable that laevulose will be available for use by diabetic 
 patients without aggravating the disease from which they surfer. 
 
 But although laevulose or "fruit sugar" is moderately abundant in 
 the vegetable kingdom, either free or combined, yet its preparation in 
 the pure state has presented very great difficulties. The only form in 
 which it was known, even to the chemist, was that of a sticky syrup 
 that could not be induced to crystallise, and was rarely colourless. 
 
 It may therefore be regarded as a triumph of technology, that a 
 method has now been elaborated, by which this sugar is obtained as a 
 pure white crystalline powder, as convenient for general use, as a food- 
 stuff, as any other of the sugars. This pure substance is distinguished 
 from the older product known as laevulose, by the name Diabetin. 
 
 The exact value of Diabetin, as a sweet food for diabetics, can of 
 course only be arrived at by an examination of its effects in a con- 
 siderable number of cases under experienced guidance. For this 
 purpose the attention of physicians is called to the preparation, so 
 that trials with it may be at once instituted, and the results recorded 
 in medical literature. * 
 
 At present, as a matter of course, Diabetin cannot be produced at 
 anything approximating to the price of ordinary cane sugar; but, 
 nevertheless, it can be produced at a figure which places it within the 
 reach of the majority of patients. 
 
IODOFORM 
 
 It is well known that lodoform, as ordinarily prepared, is obtained 
 from raw materials which inevitably vary in quality, and by the assist- 
 ance of different solvents for the purpose of recrystallisation. 
 
 The effect of these varying factors upon the appearance and even 
 quality of the product scarcely needs pointing out. That differences 
 in the purity of the materials from which a substance is prepared, 
 result in corresponding variations in the purity of the product, is 
 generally self-evident, and a very little consideration shows that where 
 processes are not precisely similar, exact resemblance is not to be 
 expected in the compound produced. 
 
 Thus, in the case of lodoform, the size, manner of aggregation, or 
 even form of the crystals, may depend upon the solvent employed, 
 while further, this factor has often an appreciable effect in modifying 
 the odour of the product, owing to the difficulty of removing the last, 
 traces of the mother liquor. 
 
 Modern progress in technical chemistry has been largely along the 
 lines of increasing the purity of the compounds manufactured, by 
 means of more refined methods of preparation or of purification, or 
 both. At the same time the practical applications of the various 
 forms of electricity have enormously increased, and it has been found 
 possible, by means of this force, to achieve results in numerous fields 
 which previously were unattainable. 
 
 The dynamo-electric current was pressed into the service of the 
 chemical manufacturer some time ago, experiments being made to 
 ascertain the practicability of its employment for the preparation of 
 fine chemicals, and to compare the quality and appearance of the 
 products with those of the ordinary chemical processes. 
 
 Among the compounds experimentally manufactured in this way 
 was lodoform, and the results in this case were regarded as being of 
 
1 o lodoform. 
 
 special interest, owing to the peculiar nature and importance of the 
 substance. 
 
 The new process started with absolutely pure materials instead of 
 the ordinary crude substances. Perfectly pure iodide of potassium 
 was the one reagent and the purest absolute alcohol (unmethylated, of 
 course,) the other. The interaction of these compounds, which, as 
 known, have not, under normal conditions, any noteworthy tendency 
 to react, was brought about by the dynamo-electric current. 
 
 In this way lodoform separated immediately in a state of absolute 
 purity, and so perfect in every respect that recrystallisation proved 
 unnecessary. Further, the product was found to be always absolutely 
 uniform in character, as indeed was to be a priori anticipated from 
 the premises that it constantly separated under precisely similar 
 conditions. 
 
 " Electrolytic lodoform," as it may be termed, has the form of 
 lemon yellow, soft and delicate scales, characterised by the absence of 
 sharp or hard edges. The odour is absolutely free from all pungency, 
 and can be described as mild compared with that of ordinary 
 commercial iodoform. 
 
 As regards its chemical nature, the product corresponds to a body 
 represented exactly by the formula CHI 3 . It stands the most 
 searching tests of those Pharmacopoeias which demand the highest 
 standard of purity. In its original form it can be applied in medicine 
 and surgery without producing the irritant effects of the ordinary 
 product (owing to its softness and delicacy), and if desired in a 
 powdered form can be readily reduced to an impalpable condition of 
 fineness. 
 
CRESIN 
 
 In the course of the exhaustive bacteriological researches which 
 have been made upon the compounds of the aromatic series of hydro- 
 carbons, it was found that the higher homologues of phenol, termed 
 "cresols," were more powerful disinfectants and antiseptics than 
 phenol itself. At the same time the noteworthy observation was made 
 that these compounds were free from the pronounced poisonous 
 properties of carbolic acid. 
 
 The natural conclusion was, therefore, that the cresols were much 
 more suitable for use as disinfectants than phenol and its derivatives. 
 But though this was undoubtedly the case, a serious practical hindrance 
 to their employment was found in the fact that they were very slightly 
 taken up by water. 
 
 This difficulty did not seem at first likely to be easily overcome, and 
 consequently, for some time after the powerful antiseptic virtues of 
 the cresols were discovered, the substances were not actually made 
 use of in therapy. 
 
 Accepting as almost insuperable the difficulty of getting the cresols 
 into solution in a form suitable for medicinal application, efforts were 
 made to render them available for use by emulsification. The 
 products thus obtained were, however, not free from objections, apart 
 from the fact that they did not really solve the problem of rendering 
 the cresols capable of employment in solution the only form in which 
 their pronounced germicidal properties could be taken advantage of 
 by the physician in their peculiar and unabated energy. 
 
 Subsequently attention was again directed to the desirability of 
 getting the cresols into true solution, and by following the principle 
 that the phenomenon of solution has often a close relationship with 
 similarity of chemical nature, the problem was at length satisfactorily 
 solved. 
 
112 Cresin. 
 
 It was found on experiment that the cresols, so insoluble in water, 
 were taken up by solutions of salicylates, of salts of oxybenzenecar- 
 boxylic acids generally, of oxybenzenesulphonic acids and other 
 allied compounds. 
 
 These solutions had the great advantage of being neutral, and 
 therefore specially suitable for use in surgery, etc., where of course 
 liquids varying in any marked degree from neutrality are very 
 objectionable. 
 
 Cresin is a solution of cresol in an aqueous solution of cresoxy- 
 lacetate of sodium ; it forms a clear brown liquid which contains 25 
 per cent, of the active ingredient. The cresol dissolved in this 
 preparation is, as already stated, markedly less poisonous than carbolic 
 acid, and yet at the same time its antiseptic power is four times as 
 great as that of phenol. 
 
 On these grounds Cresin is an excellent disinfectant and antiseptic, 
 which even in highly dilute solutions has a powerful deodorant action. 
 In one per cent, solutions it has done good service for the disinfection 
 of surgical instruments, of night-commodes, etc. 
 
 In the treatment of wounds and surgery generally, \ r per cent, 
 solutions further healthy granulation, and promote healing by first 
 intention without suppuration. Equally good results are obtained in 
 the treatment of torpid ulcers of the feet of long standing. In these 
 cases also \ r per cent, solutions may be advantageously used. 
 
 The preparation is also suitable for use in the local treatment ot 
 affections of the mucous membrane of the upper part of the respiratory 
 tract. For such purposes its freedom from irritating and poisonous 
 properties render Cresin especially useful. Solutions in water of the 
 strength of \-\ per cent, form gargles which are efficient without 
 being too unpleasant; the same liquids may also be employed as 
 sprays or for inhalation with advantage. 
 
 Although the liquid is not recommended for internal use at present, 
 it seems possible that it might be found suitable for employment in 
 this way in certain cases. Apart from the general fact that the cresols 
 are free from marked poisonousness, actual experiment has shown that 
 half a drachm given to a rabbit did not produce any functional 
 disturbances whatever. 
 
 M. S. RiCKEf.BV, Printer, 4, Walbrook, E.G. 
 
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