key: cord-1004023-0kxm8vd9 authors: Kivrak, Arif; Ulaş, Berdan; Kivrak, Hilal title: A Comparative Analysis for Anti-viral Drugs: Their Efficiency AgainstSARS-COV-2 date: 2020-11-30 journal: Int Immunopharmacol DOI: 10.1016/j.intimp.2020.107232 sha: cc60fdaad77aab98d5629ef32c6dea313337d9a3 doc_id: 1004023 cord_uid: 0kxm8vd9 Coronavirus, known as the coronavirus pandemic, is continuing its spread across the world, with over 42 million confirmed cases in 189 countries and more than 1.15 million deaths. Although, scientist focuses on the finding novel drugs and vaccine for SARS-COV-2, there is no certain treatment for it. Antiviral drugs such as; oseltamivir, favipiravir, umifenovir, lopinavir, remdesivir, hydroxychloroquine, chloroquine, azithromycin, ascorbic acid, corticosteroids, are mostly used for patients. They prevent cytokine storm that is the main reason of deaths related to SARS-CoV-2. In addition, anti-inflammatory agents have critical roles to inhibit the lung injury and multisystem organ dysfunction. The combination with anti-viral drugs with other drugs displays high synergistic effects. In the present study, the drugs used for Covid-19 are analyzed and compare the efficiency for the Covid-19 patients from the different continents including USA, South Korea, Italy, Spain, Germany, Russia, Brazil, Turkey, China. Now days, all countries tried to find vaccine and new drug candidates for SARS-CoV-2, but anti-viral drugs may be the best candidates for the treatment of Covid-19 before finding novel anti-Covid drug. symptoms as dry cough, dyspnea, fever, and bilateral lungin-filtrateson imaging. Cases were all linked to Wuhan's Huanan Seafood Wholesale Market, trading in fish and a variety of live animal species including poultry, bats, marmots, and snakes. On 7 th January 2020, The causative agent was identified from throat swab samples conducted by the Chinese Centre for Disease Control and Prevention (CCDC) and was named Severe Acute Respiratory Syndrome Coronavirus2 (SARS-CoV-2). Furthermore, it was called as COVID-19 by the World Health Organization(WHO). 1 Infected patients have usually mild symptoms as dry cough, sore throat, and fever. Furthermore, most of the cases have been resolved and according to the sexuality and age symptoms degree alters. For instance, 54.3% of those infected with SARS-CoV-2 are male with a median age of 56 years and patients requiring intensive care support were older and had multiple comorbidities including cardiovascular, cerebrovascular, endocrine, digestive, and respiratory disease. Those in intensive care were also more likely tore-port dyspnoea, dizziness, abdominal pain, anorexia. 1 This respiratory disease is very severe and potentially fatal in some patients according to their age and chronic disease history. It has been reported that 15% of cases related to this disease are severe, and mortality rate varies between 1.5% and 10%. 2 As of May 25, 2020, over 5,43 million cases of COVID-19 were reported, with > 345,000 deaths. It was reported that 91.1% of cases were diagnosed with pneumonia 3 . The second most common diagnosis is acute respiratory distress syndrome (3.4%) 4 . Although the fatality rate of SARS-CoV-2 is lower than these of Middle East respiratory syndrome (MERS-CoV) and SARS-CoV, the higher contagiousness of SARS-CoV-2 is a significant risk for the healthcare system. Presently COVID-19 seems to spread from person to person as common cold or influenza viruses-ie, face to face contact with a sneeze or cough, or from contact with secretions of people who are infected. At present study, anti-viral drugs were analyzed to find the efficiency of the treatments of SARS-CoV-2 virus. It is known that countries used different drugs and drug combinations for patients. These therapy methods usually depend on the number of deaths and the number of patients used ventilation. Moreover, there is no certain treatments ways for COVID-19. In this study, different countries from all over the world were analyzed with their drugs which were used for COVID-19. We also displayed that total case numbers and deaths between January to September 2020. Interestingly, it was observed that second wave started before September 2020 all countries. After COVID-19 appeared in Wuhan on December 1, 2019, it spread rapidly to other countries. Following the spread of COVID-19 to all continents, a pandemic was declared by WHO on March 11, 2020 . The center of the pandemic that started in Asia shifted to Europe in mid-March and then to America. According to John Hopkins University, the total number of cases in the world was 54 On 31 January, the first two cases in Italy were confirmed in Rome. The fact that serious measures began to be taken 3 weeks after the first case appeared, caused the cases in Italy to spread rapidly. Then, various measures were put into effect by taking advantage of China's pandemic experience. It can be seen from Figure 1a that the number of daily cases reached their highest values, especially between 17-29 March and 3-7 November. On November 6, the highest number of cases was reached with 39,809 days of cases. Firstly, on February 23, entrance and exit restrictions were imposed to 11 towns in the north of Italy, and schools in this region were closed 5 . This restriction was expanded on 8 March by including the whole Lombardia region and 12 cities while quarantine measures applied to 16 million people were applied to the whole country on 9 March 6 . On March 11, the activities of businesses other than supermarkets, banks, and pharmacies were stopped, and these measures were further tightened 7 . Parks and many factories were closed on 19 and 21 March, respectively. It can be seen from Figure 1b that, thanks to these measures, the rate of case increase has decreased and the total number of cases has reached a plateau. While a total of 902,409 cases and 41,063 deaths were reported in Italy until 7 November, the fatality rate was reported as 4.6%.The normalization effects in Italy are clearly seen from Fig.1a The first case in Spain was confirmed on January 31, and no new cases were reported almost during February 9 . While 1,399,169 cases were reported from the beginning of the pandemic process until 7 November, the deaths and recovery numbers were reported as 38,833 and 150,376. It is seen that the daily increase rate of COVID-19 cases in Spain gradually decreased after April (Figure 2a) . This decrease can be explained by the declaration of a 15-day state of emergency by the Spanish government on March 13 and the implementation of quarantine conditions throughout the country 10 . The Spanish government has applied the Italian model in terms of social measures. Therefore, the daily number of cases in these two countries after the measures are parallel. In addition, the dramatic decrease in the number of daily cases in June is followed by the sharp increases in the number of daily cases as a result of the relaxation of quarantine conditions. This observed increase after 13 July can be clearly followed in Figure 2b . In Spain, the maximum daily number of cases in first wave and second waves were determined as 8271 and 20640, respectively. The much higher number of infected cases in the second wave can be directly attributed to the elimination of nationwide measures. November. As seen in Figure 3a , no significant decreases in the number of cases were observed due to the lack of a stable quarantine throughout the country and the early initiation of normalization due to economic concerns. Thanks to the measures taken to maintain social distance across the country, the number of cases from April 5 to June 8 was reported around 35,000 while the highest daily number of cases was observed with 130,623 as of November 7. Although the increase in the number of daily cases accelerated after 8 June, after November 1, the increase in the number of daily cases is out of control (average daily number of cases is about 100,000).This increase is thought to be caused by the rapid normalization of America. and Luxembourg were closed, while flights to many countries were banned. In the state of Bavaria, a partial curfew was imposed. As a result of these measures, a rapid decrease in the The daily number of cases on November 7 is 23,399 and continues to increase.Germany is distinguished from other European countries with a particularly low mortality rate. Many researchers attribute this low mortality rate to the lower average age of the diagnosed population compared to other European countries 19 . Remdesevir is used as an antiviral in the treatment protocol recommended by the Robert Koch Institute (RCI). According to this algorithm, the use of 200 mg Remdesevir on the first day and 100 mg on the following days was deemed appropriate for adults and adolescents. It is stated that the use of Remdesevir should be between 5 and 10 days. On the other hand, RCI does not recommend the use of hydroxychloroquine and Lopinavir/Ritonavir. It has been stated that the use of these antiviral drugs for COVID-19 is the responsibility of doctors. The detailed treatment procedure recommended by RCI is given in Figure 6 ). 23 The number of cases followed this decreasing trend until May 26, 2020. However, as a result of the normalization policy followed subsequently, a slight increase was observed in the number of daily cases. The daily cases, which increased again in August and September, was brought under control towards the end of September. For the moderate and severe cases, Central Clinical Task Force has suggested Lopinavir 400 mg/Ritonavir 100 mg twice a day or Hydroxychloroquine 400 mg/Chloroquine 500 mg orally per day 24 . In addition, Remdesevir was added to this treatment protocol, which lasted 7-10 days 25 . The details of this treatment protocol is summarized in Table 6 . Figure 7) . The total number of deaths and total recovered cases and mortality rates to date have been reported as 30,251, 1,342,814 and 1.72, respectively. The COVID-19 treatment procedure recommended by the Russian Ministry of Health is summarized in Table 7 . Accordingly, Recombinant interferon-alpha + Hydroxychloroquine and Umifenovir + Hydroxychloroquine are primarily used in the treatment of COVID-19 ( (Figure 8a) . The effect of normalization on the total number of cases is clearly seen in Figure 8b . As of 7 November, 391,719 total number of cases, 336,221 total recovered and 10,803 total deaths were reported while the mortality rate was calculated as 2.76. The Ministry of Health explains the relatively low mortality rate with the early initiation of antiviral medication. Chloroquine (alkylated 4-aminoquinolines) was synthesized in 1934, then it was used for the treatments of malaria in 1945 (Figure 10 ) 33 . It is a weak bases due to nitrogene atoms on the structure. Before chloroquine, the natural quinine, isolated from cinchona tree bark, was known as an antimalarial agent. Then, hydroxychloroquine (HCQ) sulfate was synthesized and found as new antimalarial drugs with less toxicity and less blood-retinal barrier permeability in 1946. HCQ has one more hydroxyl groups on the structures than CQ, so it created novel and more affectivity with more polarity and lower lipophilic effect. In addition, intracellular pH levels in Studies showed that HCQ could be critical roles in combination with other drugs, but it needs to be improved for clinical trials. HCQ and CQ display mild adverse effects included rash and headache. Ritonavir,known as antiretroviral, have been used as a protease inhibitors since 2000 35, 36 ( Figure 10) . The effects of protease inhibitors were described by the binding of lipoprotein particles or the blocking of their binding to the LDL receptor, which disrupts the mechanisms responsible for intracellular synthesis, storage and release of cholesterol. It have been used for the treatment of HIV-1 infection and improved its potantial medicine for COVID-19 37 (Figure 11 ). The drug concentration may be have critical roles for the treatments of diseases, so lopinavir is used with ritonavir. This combination creates more activity against COVID-19. On the other hand, there is a gastrointestinal effects in patients. Remdesivir, developed by Gilead Sciences, is a member of antiviral drugs with broad-spectrum some adverse effect such as; hepatic enzymes, diarrhea, rash, renal impairment, hypotension, organ-dysfunction syndrome, septic shock, acute kidney injury, hypotension. Recently, Oxford University announced that Dexamethasone, corticosteroid, is the most effective drug for the treatments of COVID-19 40 (Figure 10 the severe systemic inflammatory response such as lung injury, ARDS, and multisystem organ dysfunction. Therefore, anti-inflammatory effects of corticosteroid therapy could be eliminating these viral complications. On the other hand, dexamethasone was used more than 14 days; it did not reduce the mortality 42 . Some case reports displayed that high dose of corticosteroids could be multi-organ dysfunction and a potentially increased risk of deaths. As a result, the therapy of dexamethasone is not clear for the treatments of SARS-CoV-2, but it may be applied with combination with other anti-viral drugs. Favipiravir ( first day) could be the best way for the decreasing corona effects, followed by maintenance doses ranging from 300 mg to 1800 mg next days 45, 46 . Moreover, favipiravir have high activity first five days after getting corona virus (Figure 11) . Interestingly, it was first approved anticovid drug in China. Nowadays, many countries improved its affectivity to prevent COVID- 19 .The side-effect of favipiravir is acceptable with asymptomatic hyperuricemia and reversible elevation in transaminases. The proposed mechanism of actions of anti-COVID-19 drugs was shown in Figure 12 . The treatments are depended on the life cycle of SARS-CoV-2 in host cell. 47 The detail mechanism could be summarized as; The human angiotensin-converting enzyme 2 (ACE2) is the main cell receptor for COVID-19, so SARS-CoV-2 entry into host cells by using ACE2 receptor on the cell membrane. 48 Recently researchers suggested that the S genetic code of the receptor binding spike protein plays critical roles to entry into the host cell. On the other hand, general functions including protein assembly, envelope generation, encasing the RNA, budding, and pathogenesis are controlled by the nucleocapsid (N), the small envelope (E) and membrane (M) proteins. When the antibodies against SARS-CoV-2, obtained by plasma cells, could be neutralize the virus to decrease its pathogenicity (Fig. 12) . 49 Thegenome of SARS-CoV-2 can be released after the process of membrane fusion. Hydroxychloroquine or chloroquine increase the pH of the intranuclear body, lysosome, and Golgi bod, genome replication, and assembly of mature viral particles. 50 The pH interferes with SARS-CoV-2 entry into endosomes and blocks viral-endosome fusion (Fig. 12) . The positive (+)-sense genomic RNA forms the synthesisof negative (−)-sense RNA, followed by the template to give the RNA chain of progeny virus. Remdesivir and Favipiravir are improved that they can be integrated into the RNA chain of progeny SARS-CoV-2 as the substrate of the RNA-dependent RNA polymerase (RdRp). Remdesivir and Favipiravir inhibit the replication of viral genomes (Fig. 12) . 51,52,53 The negative (−)-sense RNA is used as atemplate with mRNAs transcribed to direct the protein biosynthesis of SARS-CoV-2 in the cytoplasm. The enzyme 3-chymotrypsin-like protease (3CLpro) has a crucial role in processing this RNA.The 3CLpro is inactivated by Lopinavir/ritonavir (Fig. 12) . 54 The genomic RNA andvirion proteins are assembled to givethe infective form of SARS-CoV-2 ( Fig. 12) . Final step of the life cycle is releasing SARS-CoV-2 from the host cell via exocytosis (Fig. 12) . COVID-19 cause the 42 million case and 1.15 million deaths all over the world. The number of cases and deaths in many countries, especially Germany, France and Italy, reached the highest levels of after months. The highest number of cases was the USA with 7.5 million cases, flowed by India with 6.7 million cases and Brazil with 5 million cases. Interestingly, the number of new cases in Russia increase each day than other countries. Recent clinical reports displayed that the specific treatment methods for SARS-COV-2 is not known. However, some antiviral drugs and agents, such as oseltamivir, favipiravir, umifenovir, lopinavir, remdesivir, hydroxychloroquine, chloroquine, azithromycin, ascorbic acid, corticosteroids, have been used for the treatment of SARS-CoV-2. Some of them reduce cytokine storm that is main reason of mortality related to SARS-CoV-2.Moreover, they used as anti-inflammatory agents which prevent the lung injury and multisystem organ dysfunction. Many of these drugs are used in combination with anti-viral drugs to create synergistic effects, such as hydroxychloroquine and favipiravir; Lopinavir/Ritonavir and hydroxychloroquine etc. Many of them are more effective when used early stage of the SARS-CoV-2 infection. For example,favipiravir have highest activity against SARS-CoV-2 in the first 5 days. Today, there is no certain treatments ways for COVID-19. At the present study, we analyzed different countries from all over the world, and compare the drugs for the treatments of COVID-19. Total case numbers and deaths from January 2020 to November 2020 were also shown. It was observed that second wave started, so new drugs will be investigated for long term therapy. As a result, all countries tried to find new vaccine against SARS-CoV-2, and they also tried to find new drug candidates to prevent from virus. Anti-viral drugs may be best candidates for the treatments of COVID-19 before finding novel anti-Covid drugs. The author (A. Kivrak) would like to acknowledge networking contribution by the COST Action CA17104 "New diagnostic and therapeutic tools against multidrug resistant tumours". The mechanism of actions of anti-COVID-19 drugs was proposed. World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19) CoV-2: a storm is raging Kidney involvement in COVID-19 and rationale for extracorporeal therapies Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019 Early evidence that social distancing and public health interventions flatten the COVID-19 curve in Italy Effects of the COVID-19 Outbreak in Northern Italy: Perspectives from the Bergamo Neurosurgery Department Italian GovernmentPresidency of the Council of Ministers. Coronavirus, le misure adottate dal Governo Handbook for the care of people with disease-COVI 19 Prognostic factors in Spanish COVID-19 patients: A case series from Barcelona Comparecencia Sobre Las Actuaciones Desarrolladas En Relación Con El Coronavirus (COVID-19) Spanish Agency for Medicines and Health Products, Tratamientos disponibles sujetos a condiciones especiales de acceso para el manejo de la infección respiratoria por SARS-CoV National Institutes of Health, Characteristics of Potential Antiviral Agents Under Evaluation for Treatment of COVID-19 COVID-19 in Brazil COVID-19 in Latin America: The implications of the first confirmed case in Brazil Resposta imediata da Vigilância em Saúde à epidemia da COVID SciELO Public Health Intervenções não farmacológicas para o enfrentamento à epidemia da COVID-19 no Brasil Orientações Do Ministério Da Saúde Para Manuseio Medicamentoso Precoce De Pacientes Com Diagnóstico Da COVID-19 Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series Covid-19: Why Germany's case fatality rate seems so low Ständiger Arbeitskreis der Kompetenz-und Behandlungszentren für Krankheiten durch hochpathogene Erreger, Hinweise zu Erkennung, Diagnostik und Therapie von Patienten mit COVID-19 Transmission potential and severity of COVID-19 in South Korea Transmission potential and severity of COVID-19 in South Korea As Covid-19 cases rise, South Korea raises virus threat level to its maximum Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries Special import approved for COVID-19 treatment Organizational measures aiming to combat COVID-19 in the Russian Federation: the first experience COVID-19: Guidance for Employers in Russia Responses to the COVID-19 crisis in Russia Coronavirus in Russia: The Latest News. The Moscow Times2020. 30. Ministry of Health of Russia Chinese National Health Commission, Chinese Clinical Guidance for COVID-19 Pneumonia Diagnosis and Treatment Medical need, scientific opportunity and the drive for antimalarial drugs Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Antiretroviral Treatment of Adult HIV Infection 2010 Recommendations of the International AIDS Society-USA Panel Class-sparing regimens for initial treatment of HIV-1 infection A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Clinical trials for the prevention and treatment ofCOVID-19: current state of play An overview of the safety assessment of medicines currently used in the COVID-19 disease treatment Beyond dexamethasone, emerging immunothrombotic therapies for COVID-19 Postnatal corticosteroids and sensorineural outcome at 5 years of age Overview of the Pathogenesis and Treatment of SARS-CoV-2 for Clinicians: A Comprehensive Literature Review Favipiravir May Acts as COVID-19 Main Protease PDB ID 6LU7 Inhibitor: Docking Analysis Interactions Between Remdesivir, Ribavirin, Favipiravir, Galidesivir, Hydroxychloroquine and Chloroquine with Fragment Molecular of the COVID-19 Main Protease with Inhibitor N3 Complex (PDB ID:6LU7) Using Molecular Docking Tolerability of favipiravir therapy in critically ill patients with COVID-19: A report of four cases Current pharmacological treatments for SARS-COV-2: A narrative review Derivatization and combination therapy of current COVID-19 therapeutic agents: a review of mechanistic pathways, adverse effects, and binding sites Progress in the Research and Development of Anti-COVID-19 Drugs Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro The mechanism of resistance to favipiravir in influenza Molecular dynamic simulations analysis of ritronavir and lopinavir as SARS-CoV 3CL(pro) inhibitors The authors declare that they have no conflict of interest.