COVID-19 Pandemisinde Kullanılan İlaçlar, Etki Mekanizmaları ve Etkililikleri

Yıl 2021, Cilt: 43 Sayı: 3, 297 - 307, 07.05.2021

Cansu Kılıç , Sule Aydın , Fatma Sultan Kılıç

https://doi.org/10.20515/otd.834991

Cited By: 2

Öz

Aralık 2019’ da Çin’ in Wuhan kentinde ortaya çıkan koronavirüs ailesinden olan COVID-19 tüm dünyada pandemiye yol açmıştır. Bu virüsün daha önce SARS-CoV ve MERS-CoV olarak salgın yapmış koronavirüsler ile genetik yakınlığı vardır. COVID-19 hastaları, ciddi akut respiratuvar sendrom (ARDS), ağır pnömoni tablosu, hematolojik bulgular, dissemine intravasküler koagülopati (DIC) ve sepsis gibi ağır tabloların yanısıra koku kaybı, bulantı, kusma, ishal gibi gastrointestinal sistem bulguları ya da sadece cilt döküntüleri ile de hastanelere başvurabilmektedirler. Akut dönemde makrofaj aktivasyon sendromu (MAS) ve sitokin fırtınası sebebiyle ağır inflamasyon tablosuna sebep olmaktadır. Tedavide, SARS-CoV ve MERS-CoV ile oluşan hastalık durumlarında kullanılan ilaçlar denenmektedir. Proflaksi ve tedavide klorokin, hidroksiklorokin kullanılırken ağır pnömoni durumlarında, ilave olarak azitromisin tedaviye eklenir. Hastalığın seyrine göre favipiravir, lopinavir, ritonavir, remdesivir, ribavirin gibi tedavide kullanılan/ denenen ilaçlara yardımcı ilaçlar olarak antisitokin-immunomodulatörler (tosilizumab, anakinra, sarilumab, bevasizumab, ekulizumab), kortikosteroidler, immünoglobilinler, interferonlar ve antiagregan-antiinflamatuvar (dipiridamol) ilaçlar kullanılır. Bu hastalığın seyri sırasında oluşabilecek koagülasyonu önlemek amacıyla profilaktik olarak düşük molekül ağırlıklı heparin (enoksaparin) kullanılabilir. COVID-19 semptomları mevsimsel ve semptomatik nedenlerle influenza ile karışabilir. İnfluenza olması durumunda tedavide oseltamivir kullanılır. Normal şartlarda herhangi bir tedavisi olmayan COVID-19 için aşı ve ilaç çalışmaları hız kazanmıştır. Ancak bu sürecin en az bir yıl kadar sürebileceğini söylemekte yarar vardır. Hatta bu hastalıkla mücadelede kök hücre çalışmaları da yapılmaktadır.

Anahtar Kelimeler

pandemi, koronavirüs, COVİT-19, , farmakolojik yaklaşımlar

Drugs Used in the Treatment of COVID-19 Pandemic, Their Mechanisms of Action and Efficacy

Öz

COVID-19, which belongs to a coronavirus family that emerged in Wuhan-China in December 2019, has caused pandemics worldwide. This virus has genetic affinity with previous coronaviruses, which have been outbreaks as SARS-CoV and MERS-CoV. COVID-19 patients have severe acute respiratory syndrome(ARDS), severe pneumonia, hematological findings, disseminated intravascular coagulopathy(DIC) and sepsis and also have signs of gastrointestinal system such as loss of smell, nausea-vomiting, diarrhea and sometimes only skin manifestations. In acute period, it causes severe inflammation due to macrophage activation syndrome(MAS) and cytokine storm. In treatment; drugs used in the treatments of SARS-CoV and MERS-CoV, are being tried. While chloroquine/ hydroxychloroquine are used in prophylaxis and treatment, in cases of severe pneumonia, azithromycin is additionally added to the treatment. According to the course of the disease, drugs which are used/being tried at the treatment such as favipiravir, lopinavir, ritonavir, remdesivir and ribavirin could be combined with adjuvant drugs such as anticytokine-immunomodulators (tocilizumab, anakinra, sarilumab, bevacizumab, eculizumab), corticosteroids, immunoglobulines, interferons and antiaggregant drugs (anti-inflammatory drugs) are used as auxiliary drugs. Heparin (enoxaparin) can be used prophylactically, to prevent coagulation in course of this disease. COVID-19 symptoms can be confused with influenza for seasonal and symptomatic reasons. In case of influenza, oseltamivir is used for treatment. Vaccine and drug studies have accelerated for COVID-19, which does not have any treatment under normal conditions. But it would be beneficial to mention that this process may take at least one year. In fact, stem cell studies are also carried out to combat this disease.

Anahtar Kelimeler

Pandemic, coronavirus, COVID-19, pharmacological approaches

Kaynakça

• 1.Zhu N, Zhang D, Wang W, Li X, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-33.
• 2.Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. Jama. 2020.
• 3.Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.
• 4.Morra ME, Van Thanh L, Kamel MG, et al. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis. Rev Med Virol. 2018;28(3):e1977.
• 5.Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003;3(11):722-7.
• 6.Zhou D, Dai SM, Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother. 2020.
• 7.Devaux CA, Rolain JM, Colson P, et al. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55(5):105938.
• 8.Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020;14(1):72-3.
• 9.Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020
• 10.Jun C, Danping L, Li L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVİD-19). J Zhejiang Univ (Med Sci). 2020;49(215-219 ).
• 11.Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020;55(4):105932.
• 12.Osadchy A, Ratnapalan T, Koren G. Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature. J Rheumatol. 2011;38(12):2504-8.
• 13.Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020. Jul 28;71(15):732-739
• 14.Kalil AC. Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. Jama. 2020 May 19;323(19):1897-1898. doi: 10.1001/jama.2020.4742.2020.
• 15.Peter Horby MM, Louise Linsell, Jennifer L Bell, et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. N Engl J Med. Oct 8:NEJMoa2022926. doi: 10.1056/NEJMoa2022926. Online ahead of print. PMID: 33031652 2020.
• 16.Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;383(6):517-25.
• 17.Sissoko D, Laouenan C, Folkesson E, et al. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med. 2016;13(3): e1002009. doi: 10.1371 18.Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther. 2020;209:107512.
• 19.Chinello P, Petrosillo N, Pittalis S, et al. QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient. PLoS Negl Trop Dis. 2017;11(12):e0006034.
• 20.Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Jul;583(7816):459-468. doi: 10.1038/s41586-020-2286-9. Epub 2020 Apr 30. Nature. 2020.
• 21.Nagata T, Lefor AK, Hasegawa M, Ishii M. Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep. 2015;9(1):79-81.
• 22.Chang Chen YZ, Jianying Huang, Ping Yin, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial www.medrxiv.org2020
• 23.Pilkington V, Pepperrell T, Hill A. A review of the safety of favipiravir - a potential treatment in the COVID-19 pandemic? J Virus Erad. 2020;6(2):45-51.
• 24.Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59(3):252-6.
• 25.de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875-84.
• 26.Yao TT, Qian JD, Zhu WY, et al. A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option. J Med Virol. 2020;92(6):556-63.
• 27.Chan KS, Lai ST, Chu CM, T et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J. 2003;9(6):399-406.
• 28.Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-99.
• 29.Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395(10238):1695-704.
• 30.Siegel D, Hui HC, Doerffler E, et al. Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. J Med Chem. 2017;60(5):1648-61.
• 31.Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71.
• 32.Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222.
• 33.Jacobs M, Rodger A, Bell DJ, et al. Late Ebola virus relapse causing meningoencephalitis: a case report. Lancet. 2016;388(10043):498-503.
• 34.Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10):929-36.
• 35.Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-78.
• 36.McMahon JH, Udy A, Peleg AY. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020;383(10):992-3.
• 37.Foolad F, Aitken SL, Shigle TL, et al. Oral Versus Aerosolized Ribavirin for the Treatment of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients. Clin Infect Dis. 2019;68(10):1641-9.
• 38.Arabi YM, Shalhoub S, Mandourah Y, et al. Ribavirin and Interferon Therapy for Critically Ill Patients With Middle East Respiratory Syndrome: A Multicenter Observational Study. Clin Infect Dis. 2020;70(9):1837-44.
• 39.Altınbas S, Holmes JA, Altınbas A. Hepatitis C Virus Infection in Pregnancy: An Update. Gastroenterol Nurs. 2020;43(1):12-21.
• 40.Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Jama. 2020;323(11):1061-9.
• 41.Kadam RU, Wilson IA. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017;114(2):206-14.
• 42.Khamitov RA, Loginova S, Shchukina VN, et al. [Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures]. Vopr Virusol. 2008;53(4):9-13.
• 43.Wang Z, Yang B, Li Q, et al. Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China. Clin Infect Dis. 2020.
• 44.Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149-50.
• 45.Coleman CM, Sisk JM, Mingo RM, et al. Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion. J Virol. 2016;90(19):8924-33.
• 46.Dyall J, Gross R, Kindrachuk J, et al. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies. Drugs. 2017;77(18):1935-66.
• 47.Pfefferle S, Schöpf J, Kögl M, et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog. 2011;7(10):e1002331.
• 48.de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin A inhibits the replication of diverse coronaviruses. J Gen Virol. 2011;92(Pt 11):2542-8.
• 49.Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-5.
• 50.Ni YN, Chen G, Sun J, Liang BM, et al. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019;23(1):99.
• 51.Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020.
• 52.Coronavirus Disease 2019 (COVID-19)Treatment Guidelines https://www.covid19treatmentguidelines.nih.gov
• 53.Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4.
• 54.Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62.
• 55.Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5.
• 56.Chen L, Xiong J, Bao L, et al. Convalescent plasma as a potential therapy for COVID-19. Lancet Infect Dis. 2020;20(4):398-400.
• 57.Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect. 2004;10(7):676-8.
• 58.Arabi Y, Balkhy H, Hajeer AH, et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:709.
• 59.Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis. 2011;52(4):447-56.
• 60.Cao W, Liu X, Bai T, et al. High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease 2019. Open Forum Infect Dis. 2020;7(3):ofaa102.
• 61.Tang N, Bai H, Chen X, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-9.
• 62.Liu X, Li Z, Liu S, et al. Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction. medRxiv; 2020.
• 63.Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020.
• 64.Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. Jama. 2020;323(24):2493-502.
• 65.Joan-Ramon Laporte DH. In the midst of the SARS-CoV-2 pandemia, caution is needed with commonly used drugs that increase the risk of pneumonia https://www.isdbweb.org2020