key: cord-023585-n3lr9z3u
authors: Phillpotts, Robert
title: Interferon prophylaxis of the common cold
date: 2003-01-06
journal: Trends Pharmacol Sci
DOI: 10.1016/0165-6147(84)90509-1
sha: 
doc_id: 23585
cord_uid: n3lr9z3u

Interferon is a potential prophylactic agent for the common cold. But there are problems. The present levels of side-effects that have been observed don't justify its use in the long term. Robert Phillpotts describes the mechanism of interferon action and the future hopes and developments for its use in preventing colds.

MRC Common Cold Unit, Coombe Road, Solisbuty, Wil~chire SP2 8BW, UK, Interferon is a potential prophylactic agent for the common cold. But there are problems. The present levels of side-effects that have been observed don't justify its use in the long term. l~'obert Phillpotts describe~ the mechanism of interferon action and the future hopes and developments for its use in preventing colds.

Interferon appears to be the ideal antiviral drug for use in preventing colds; it is extremely potent, and active against a wide range of viruses. However, it is too toxic for systemic use in minor respiratory illnesses, and when taken in adequate doses intranasaHy it causes a mild inflammation of the mucosa. Current research is directed towards overcoming this problem.

For most people the common cold is a mild, self-limiting illness. However, the high incidence of colds, and their ability to cause an exacerbation of chronic underlying respiratory disease leads to considerable morbidity. Research has established that over 200 serologicaily distinct viruses can cause a cold, and there is little hope that infectica can be controlled by vaccination. Therefore control by means of a broad-spectrmn antivizal agent is the most rational approach, and interferon is without doubt the most pote=t, and broadly active antiviral agent yet discovered. C~ course there are limitations upon the k~nd of medication which could be used to prevent a cold. For example it should be cheap and easy to manufacture, as well as being highly effective, and virtually free from side-effects. I What is interferen? I Human interferons (HulFN) are pro-/ teins or glycoproteins of which there are: 3 principal types, a, 13, and "y. HulFN a and p: ~re both produced by cel~s after exposure to a virus: WN a by" leucocytes and LFN 13 by fibroblast,,,. HulFN ~ is also produced by fibroblasts exposed to double-stranded RNA, while IFN ~/is produced by lymphocytes only in response to an antigenic or mitogenic stimulus. Interferons do not directly inhibit virus growth, but exposure of :mittfected cells to interferon makes them resistant to attack by viruses, interferon is not internalized by cells but binds to cell surface receptors (there is one receptor for IFN a and [3, and another receptor for IFN y) triggering off a series of events within the cell. Multiple effects have been observed in cells, including the inhibition of penetration and maturation of certain viruses. However, the principal effect of interferon treatrnent seems to be to inhibit viral protein synthesis t. A system of interferoninduced enzymes has been described, some of which are activated by doublestranded RNA molecules such as those produced during the replication of RNA 'druses. The effect of these enzymes is to inhibit the initiation of viral protein synthesis, and to increase the rate at which viral mRNA is degraded within the cell (see Fig. 1 ). Future research will mldoubtedly disclose other mechanisms by which virus growth is prevented. "[here is already evidence to suggest that I[FN ~ has a different mechanism of ~K~tion from IFNs a and 13, as combinations of IFN ~ with IFN ct or IFN 13 (but not IFN a with IFN 13) exhibit synergy.

The potency of various interferon preparations may therefore be compared in terms of units of antiviral activity. There is species specificity in this process v ,'11, while not absolute, means in practice that human interferon must be used to treat human cells.

Human interferon may be produced from cells cultured in vitro. A partially purified human leucocyte (a) interferon is produced by the Finnish Red Cross from huffy coat cells (derived from blood donations) which have been stimulated with Sendal virus. However, this procedure is expensive, and the amount of interferon which can be produced is limited by the availability of buffy coat cells. More recently, DNA copies of the mRNAs coding of all 3 types of HulFN have been synthesized, and inserted into plasmid vectors downstream from a suitable prokaryotic promoter. Such plasmis are introduced into bacteria by transfection, where they multiply, and high levels of expression of the interferon gene sequence can be cheap, costs will undoubtedly be further reduced.

intranasal interferon prevents colds In an initial experiment at the Common Cold Unit in Wiltshire, UK, intranasal administration of partially purified human leucocyte interferon to volunteers was shown to prevent colds caused by rhinovirus type 4 (Ref. 5). Rhinoviruses cause approximately 50% of colds. However, leucocytes from 30-50 donations of blood were required to produce the 14 MU of interferon used to treat each volunteer. Furthermore, the use of partially purified material in which only about 1% of the protein was interferon also raised the question of whether interferon itself was responsible for preventing rhinovirus infection. Could the activity have been due to contaminating, biologically active molecules also derived from human leucocytes? This question was answered in a further experiment carried out in 1982, in which HulFN a, purified to virtual homogeneity on a monoclonal antibody affinity column was shown to prevent colds caused by another rhinovirus, type 9 (Ref. 6). A total dose of 90 MU was given intranasally to each volunteer over a period of 4 days (12 doses, 3 doses daily). Four doses were given before, and 8 after vixus challenge. There was a dramatic reduction in the frequency of colds in the interferon treated group (Table 1) . This was accompanied by lesser reductions in the number of volunteers who shed virus, or who had an increase in serum neutralizing antibody to the challenge virus. In a further experiment conducted under an identical protocol, closely similar results were achieved using highly purified, HulFN a-2, pro-duced in Escherichia coil 7 (manufactured by Schering Plough). This experiment clearly demonstrated that interferons produced in bacteria by recombinant DNA techniques could be as active as those produced by human celk.

How can interferon be used in prm'tke?

In these experiments, interferon was given intranasally in large doses by a physidan. Therefore ffinterferon is to find application as a prophylactic against the common cold. two questions have to be answered. Firstly, could people treat themselves with interferon using a simple design of nasal spray? Sc-condly, what is the minimum quantity of interferon necessary to protect against infection with cold viruses? Answers to these questions were sought in a dose-ranging study, in which volunteers gave themselves various doses of HulFN a-2 using a finger-actuated nasal spray s . Interferon was given for one day before, and 3 days after, challenge with virulent human rhinoviruses. Not only was the dose of interferon varied, but also the time of virus challenge in relation to a dose, so that the period of maximum vulnerability to virus infection could be identified. The results of this study suggest that at least 3-4 MU of IFN a-2 self-administered intranasally 3 times daily are necessary to protect against experimental rhino~rus infection. Subsequent experiments have shown that 3-4 MU of HuiFN a-A (a similar molecule to HulFN a-, produced by Roche) can protect against experimental infect/on with a human respnratory coronavtrus (see Fig. 2 )". Coronaviruses are the ~econd most frequently encouatered cause of a L.oid. and are responsible for 15-20e/r of cases.

However. one more requirement must be. met by a prophylactic against the common cold -almost complete freedom from unpleasant snde-effects, it is here that research has run into difficulties. Further studies have shown that while regimens of IFN a similar to that proposed seem to he necessa~" for protection against natural colds, such doses are also toxi=, and produce a mild inflammation of the nasal mucosa. In a recent stuly from the University of Virginia, prclorge.d intranasal administration of the HulF?,~ or-2 was associated with muxr~d irritation in 23% ot recipients"L Histologically, marked epithelial acute t qfiammation with ulceration occurr,'d in 19%, and 58% had pronounced submucosal l.~anphoq,/tic and mononuclear cell ~filtrates. Although these abnormalities re'solved within 8 weeks after stopping treatment, long-term administration of IFN a would not be acceptable. However. there has been little sign of irritation of volumeers Wen interferon f~r 4 days. Therefore interferon prophylaxis could be used when the time of exposure to virus (or fear of exposure to virus) can be predicted. Examples of this situation would be contact with a cold sufferer, or before an examination or some other important event.

There is eveR' reason to believe that the problem of poor tolerance to intranasal interferon will be overcome. Only a very. small number of interferons have been tested for antiviral activity and toxicity in the nose, and it is conceivable that a molecular subspecies of HulFN c~. HuIFN t~ or HulFN -¢, or a hybrid interferon molecule prepared from these, may have an improved therapeutic ratio. Interferon could then be taken for prolonged periods as a prophylactic against the common cold by patients with underlying chronic respiratory disease, such as bronchitis or asthma. Not surprisingly therefore, the discovery of inteffemns with this desirable property is one of the major goals in common cold research today. The question of whether interferon can be used to treat a cold also remains open. The relatively short course of the illness suggests that virus replication in the nose oomns rapidly, and may even be essentially complete by the time symptoms have begun. However, this pessimistic view has yet to be confirmed, and there is some evidence to suggest that even a relatively we~k antiviral agent, such as Enviroxime (registered trade name, produced by Eli Lilly and Company), administered locally after virus infection can affect the course of a cold tt. Perhaps a suitable preparation of interferon, which could be over 1 000 times more potent than Enviroxime in vitro, could prove clinically useful. as modulators of appetite. The intiuen~es of other neurotransmitters and the physicochemical properties of food will, therefore, receive less prominence. At the outset it should be stres~d that the complexities of appetite regulation make it extremely unlikely that any single agent will prove to be the Holy Grail of appetite suppressants. Future pharmacological approaches will need to take cognizance of this fact and attempt to tailor the treatment to the individual rather than the individual to the treatment. This is particularly important in view of the fact that the majority of peptides appear to have multiple effects, making it likely that the indiscriminate use of these agents, in subjects in whom a deficit or an excess has not been demonstrated, will lead to an unacceptably high incidence of side effects. opuad reading m A large body of evidence has now accumulated supporting a role for opioid peptides in the modulation of feeding behavior t. In particular, the relatively specific opioid antagonist, naloxone, has been demonstrated to decrease fe~ding under a variety of conditions in many species including humans. In humans, however, the major effect o! opioid blockade with naloxone appears to be to reduce carbohydrate intake rather than to produce an absolute reduction in calories. This reduction is offset by an increase in fat intake. In addition, the first ion 8 term study in humans by Atkinson 2 using the long-acting opiate antagonist, naltrexone, produced disap-

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