Brahmantya I. B. V, Purnamasidhi C. A. W, Sumardika I. W. COVID-19 Pharmacological Treatment at the Udayana University Hospital in April-May 2020. Biomed Pharmacol J 2021;14(2).

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Manuscript received on :04-03-2021
Manuscript accepted on :22-06-21
Published online on: 29-06-2021

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Ida Bagus Yorky Brahmantya¹, Cokorda Agung Wahyu Purnamasidhi² and I Wayan Sumardika³

¹Undergraduate and Medical Program, Faculty of Medicine, Udayana University, Denpasar, Indonesia, 80232,

²Department of Internal Medicine Udayana University, Udayana University Hospital, Badung, Indonesia, 80361,

³Department of Pharmacology and Therapeutic, Faculty of Medicine, Udayana University, Denpasar, Indonesia, 80232

Corresponding Author E-Mail: wsumardika@unud.ac.id

DOI : https://dx.doi.org/10.13005/bpj/2198

Abstract

Since the COVID-19 pandemic in Indonesia, pharmacological therapy for COVID-19 cases to date arecurrently based on clinician’s assessments of drugs, or what drug combinationsmight work in managingCOVID-19 cases, and not yet based on empirical evidence from clinical trial studies, which also limited available in the early of pandemic. This study aims to provide data on drugs utilized during the treatment of the COVID-19 cases and the rationalization of their use. This research is a cross-sectional descriptive study conducted at the Udayana University Hospital in April-May 2020. Demographic and treatment data were obtained through inpatient medical records, and research sample was selected by total sampling method. 95 cases of COVID-19 hospitalized during April-May 2020 were included in the study. The standard COVID- 19 drugs given were vitamin C (100%), chloroquine phosphate (61.1%), azithromycin (34.7%) or levofloxacin (5.3%), and oseltamivir (37.9%) or lopinavir-ritonavir (3.2%). Other drugs given were low molecular weight heparin (2.1%), alprazolam (1.1%), amlodipine (3.2%), clobazam (9.5%), meropenem (2.1%), and metformin (3.2%). Administration of high doses intravenous vitamin C was found to be beneficial, while chloroquine phosphate, antibiotics, and antivirals need to be reconsidered based on theirrisks and benefits in COVID-19 management.

Keywords

Azithromycin; Chloroquine Phosphate; COVID-19; Favipiravir; Oseltamivir; Vitamin C

Introduction

The first case of COVID-19 in Indonesia was reported in March 2019, since then the numbers of cases are increasing until today. Antiviral therapy that has proven efficacy against SARS-CoV-2 has yet to be found, as wellas evidence-based guidelines or management protocols for COVID-19.¹The main pharmacological management of COVID-19 cases to date is still based on clinician’s assessment regarding drugs, or what drugs combination might work in the COVID-19 case, and not yet based on empirical evidence from clinical trial studies.¹There are not many data regarding the drugs that are effective for COVID-19 based on Randomized Controlled Trial (RCT) especially in the early of pandemic. Until now, The Indonesian Ministry of Health has published the third edition of the COVID-19 management protocol in December 2020.² The first edition of the protocol released by the Indonesian Ministry of Health recommends several drug options for COVID-19 cases, ranging from cases with no symptoms to severe symptoms.³ However, it is not certain how the recommended pharmacological therapy options work and can help patients with COVID-19.

Apart from these problems, this protocol has become a guideline for specialized health facilities that treat COVID-19 in several regions in Indonesia. Udayana University Hospital is one of referral hospital for COVID-19 treatment in Bali, Indonesia. Even though the management protocol has been established, evidence-based medicine still needs to be applied in the treatment of COVID-19 patients. There is not much data on the drugs used in COVID-19 patients in Indonesia. Descriptive preliminary data can be a first step for the application of evidence-based medical science related to drugs in COVID-19, particularly in Indonesia.

Considering the need for evidence-based practice and data publication, this study aims to collect data on pharmacological treatmentgiven in COVID-19 patients at the Udayana University Hospital, and discuss the rationalism of its use, to provide an overview of the COVID-19 treatment development in Indonesia.

Materials and Methods

This study was a descriptive cross-sectional study conducted in September 2020. All data on hospitalized COVID-19 patients at Udayana University Hospital in April-May 2020 were used in this study. Data on age, sex, drugs name, drugs dose, and duration of treatment were obtained from medical records. Univariate analysis was used to present the frequency and percentage of categorical data, as well as mean and standard deviation for normally  distributed numerical data, otherwise median and interquartile rangewere used. Statistical analyses were performed using SPSS version 17 for windows. The research protocol was approved by the Institutional Review Board.

Results and Discussion

Positive COVID-19 hospitalized cases in April-May 2020 were 95 cases. The age range of cases was 20-73 years, with a median of 32 years (interquartile range/IQR = 18 years).Malesare more dominant (72.6%) than the females (27.4%). The median length of treatment was 12 days (IQR = 11 days), with the fastest length of treatment was 5 days and the longest was 57 days. Referring to the first edition of the COVID-19 management protocol from the Indonesian Ministry of Health, the pharmacological treatment given during treatment is summarized in Table 1.Median duration of treatment for cases is presented in Table 2.

Table 1: Pharmacological treatment administered during treatment

Table 2: Median length of treatment by drug

Vitamin C

In this study, all cases received vitamin C. Vitamin C was known to be a potent antioxidant with anti-inflammatory and immuno-supportive properties.^4,5 The role of vitamin C in viral infections is to decrease the pro-inflammatory response, improve epithelial barrier function, clear alveolar fluid, prevent sepsis-related coagulation problems, and as an essential factor in the production of type I interferon as long as the immune system responds to the virus.^6,7Vitamin C has been found to be effective in the treatment of pneumonia and infections due to its direct inhibitory effect on pathogens, protects the respiratory tract mucosa, and helps improve complaints of upper respiratory tract infections.^8,9In relation to the severity of COVID-19 disease, vitamin C was found to reduce the mortality of complications such as ARDS and shock in COVID-19 patients, as well as shorten the length of treatment in the Intensive Care Unit (ICU).^10,11

The benefits given by vitamin C depend on the dosage. The plasma level required to achieve maximum function of vitamin C as an antioxidant is estimated to be>175 mg/L (1000 µmol/L), ten times higher than the normal physiological levels.¹² Oral administration results in lower plasma concentrations due to sodium-dependent vitamin C transporter-1 (SVCT1) regulation, making intravenous administration more desirable.¹²Oral administration of 3 grams of vitamin C supplementation is safe and effective in dealing with respiratory or systemic infections, but if consumed every 4 hours it will only produce a plasma concentration of around 220 µmol/L.^13,14 For therapeutic purposes, intravenous vitamin C doses of 10-16 grams per day result in plasma levels>1000 µmol/L and provide maximum benefits from vitamin C.¹⁵Based on our data in Table 1, the intravenous dose of vitamin C given was low, thus the benefits of vitamin C may not be as expected.

High doses of vitamin C are reported to have minimal side effects. Some studies reported that patients with pneumonia and sepsis, doses as high as 100 grams/day did not cause diarrhea and other side effects.^16,17In this study we found that 3 patients (3.2%) received metformin. It should be noted that high doses of vitamin C can affect the measurement of blood glucose with a glucometer, therefore blood glucose tests should be done in a central laboratory.¹⁸

Chloroquine

Chloroquine was given because of its role as an immunomodulator and antiviral. As an immunosuppressant, chloroquine accumulates in lysosomes and influences lysosomal and autophagosome activity in lymphocytes, causing inhibition of lymphocyte function in the immune system, therefore immune system activation does not occur.^19–23 Chloroquine also prevents toll-like receptor activation and inhibits cytokine production by mononuclear cells.^24,25 As an antiviral, previous in vitro studies of chloroquine on SARS-CoV found that chloroquine interferes with ACE2 terminal glycosylation, decreasing ACE2 and SARS-CoV S protein binding affinity, thereby inhibiting SARS-CoV infection.²⁶However, these findings indicate that chloroquine is more appropriate in the early stages of infection, before SARS- CoV-2 decreases ACE2 expression and activity.²⁷ In addition, chloroquine can inhibit replication of the virusesby interfering the entry of viruses that are mediated by endosomes.²⁸

Although its mechanism of action has been studied, the latest publication of the World Health Organization (WHO) solidarity trial states that hydroxychloroquine has minimal or no effect in hospitalized COVID-19 patients.²⁹Apart from that, the side effects are quite alarming, including retinopathy, neuromyopathy, and cardiomyopathy. Chloroquine also is excreted slowly from our body and has long half-life. Based on these data and finding, the risks and benefits to patients must be taken into account when prescribing  chloroquine for COVID-19 cases.³⁰

The chloroquine dosage for COVID-19 cases is still inconclusive. China recommends a dose of 500 mg twice daily for 7 days for person who has bodyweight more than 50 kg, while for less than 50 kg, the recommendation dose is 500 mg twice daily on the first day followed by 500 mg once daily until day 7. This Chinese recommendation yields a total dosage of 4-7 grams of chloroquine.³¹ Indonesian protocol recommends chloroquine with  longer duration, ranging from 5-15 days.³ 

Due to the large volume of distribution and the long half-life of chloroquine (32-50 days), the duration of administration is not recommended to exceed 5 days to avoid accumulation in plasma and tissue.³²Administration of high doses is also avoided in severe or critical COVID-19 patients, especially those receiving azithromycin and oseltamivir.³³

Antibiotics

The administration of azithromycin and levofloxacin in the management protocol made them became of a standard treatment rather than based on the evidence of a bacterial infection.³ Until recently, the use of azithromycin has been widely reported in the literature, and is recommended in several COVID-19 management guidelines in various countries.^3,27,34–36 Apart from having antibacterial activity, azithromycin was found to have antiviral and immunomodulatory effects which made this drug a concern in the COVID-19 pandemic.³⁵

As an immunomodulator, azithromycin acts on the inflammatory cascade and signaling processes of cells. Azithromycin was found to decrease mucus hyper secretion and induce relaxation of contracted airway smooth muscle, as well as reduced hyper secretion of proinflammatory like cytokines and chemokines.^35,37The antiviral effect of azithromycin is beneficial for various viral infections (zika, ebola, and influenza) in vitro. However, the results of studies on SARS-CoV-2 are still inconclusive.³⁵

The optimal dose of azithromycin for SARS-CoV-2 infection is unknown, but its use is reported to be safe with minimal risk of severe side effects. Side effects of concern include prolonged QT interval, torsade de pointes, ventricular tachycardia, and sudden cardiac death.³⁵

Despite the benefits, the One Health organization seesthe prolonged use of antibiotics contributes to antibiotic resistance.³⁸Within WHO interim guidance, even antibiotics are not recommended as either treatment or prophylaxis, unless there is clinical sign of bacterial  coinfection.³⁹ In Indonesia, azithromycin and levofloxacin are still included in the December 2020 edition of the COVID-19 patient management protocol.²

Antiviral

The antiviral recommended in Indonesia is oseltamivir or favipiravir. Like antibiotics, this drugs administration is also a standard treatment in Indonesia.³While the administration of both drugs is not recommended by WHO other than for clinical trials, the Indonesian COVID-19 management protocol until the latest edition still includes the administration of oseltamivir or favipiravir.²³⁹

Oseltamivir works by inhibiting neuraminidase, unlike other viruses (such as influenza A and B), SARS-CoV-2 does not have neuraminidase.⁴⁰The study in Wuhan even reported that oseltamivir had no role and positive outcome for COVID-19 patients.⁴¹Guan et al. found oseltamivir did not reduce ICU admission rates, need for ventilators, and mortality rates for COVID-19 patients.⁴²On the other hand, favipiravir increased the degree of relieve, decrease the duration of fever, cough, and viral clearance (median 4 days).^43,44

The lopinavir-ritonavir combination (Aluvia) works specifically by inhibiting proteases, particularly the HIV-1 protease. The results of the latest randomized clinical trial showedthat lopinavir-ritonavir 400 mg/100 mg administration had no benefit in hospitalized COVID-19 patients. Additionally, side effects of diarrhea, nausea, and weakness were frequently reported in patients receiving this regimen.^45,46

Clobazam

In addition to the standard COVID-19 drugs, during treatment, 9 patients (9.5%) experienced anxiety disorders that required pharmacological treatment. In this condition, clobazam was given. The interaction between clobazam and chloroquine phosphate should be noted. Clobazam affects the hepatic metabolism of chloroquine phosphate by inhibiting the CYP2D6 enzyme. The consequence of this interaction is prolonged the choloroquine phospate’s half-life, which may increase the risk of chloroquine toxicity.⁴⁷ 

Conclusion

The COVID-19 pharmacological treatment given during treatment at the Udayana University Hospital is in accordance with the COVID-19 management protocol by the Indonesian Ministry of Health. Administration of chloroquine phosphate, antibiotics, and antivirals during treatment needs to be reconsidered by weighing the benefits and risks, thereby reducing the cost burden and unnecessary drug consumption.

Acknowledgement

We thank the Director and all Udayana University Hospital authorities who have authorized and assisted in carrying out this research.

Conflict of Interest

The authors declare no conflict of interests.

Funding Source

This research did not receive any funding.

References

1. Paumgartten FJR, Oliveira ACAX de. Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues. Cien Saude Colet. 2020;25(9):3413–9.
   CrossRef
2. Erlina Burhan, Susanto AD, Nasution SA, Ginanjar E, Pitoyo CW, Susilo A, et al. Pedoman Tatalaksana COVID-19. 3rd ed. Jakarta; 2020.
3. Burhan E, Susanto AD, Nasution SA, Ginanjar E, Pitoyo CW, Susilo A, et al. Protokol Tatalaksana COVID-19. 1st ed. Jakarta; 2020.
4. Vera JC, Rivas CI, Velasquez F V., Rong Hua Zhang, Concha II, Golde DW. Resolution of the facilitated transport of dehydroascorbic acid from its intracellular accumulation as ascorbic acid. J Biol Chem. 1995.
   CrossRef
5. Carr AC, Maggini S. Vitamin C and immune function. Nutrients. 2017.
   CrossRef
6. Bharara A, Grossman C, Grinnan D, Syed A, Fisher B, DeWilde C, et al. Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome. Case Reports Crit Care. 2016.
   CrossRef
7. Kim Y, Kim H, Bae S, Choi J, Lim SY, Lee N, et al. Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection. Immune Netw. 2013;
   CrossRef
8. Wilson JX. Evaluation of Vitamin C for Adjuvant Sepsis Therapy. Antioxidants and Redox Signaling. 2013.
   CrossRef
9. Maggini S, Maldonado P, Cardim P, Newball CF, Sota Latino ER. Vitamins C, D and Zinc: Synergistic Roles in Immune Function and Infections. Vitam Miner. 2017.
   CrossRef
10. Fowler AA, Truwit JD, Hite RD, Morris PE, Dewilde C, Priday A, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients with Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. In: JAMA – Journal of the American Medical Association. 2019.
11. Hemilä H, Chalker E. Vitamin C can shorten the length of stay in the ICU: A meta-analysis. Nutrients. 2019.
    CrossRef
12. Jackson TS, Xu A, Vita JA, Keaney JF. Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circ Res. 1998.
    CrossRef
13. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: A rationale for vitamin C administration in severe sepsis and septic shock? Critical Care. 2015.
    CrossRef
14. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, et al. Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use. Ann Intern Med. 2004.
    CrossRef
15. Robitaille L, Mamer OA, Miller WH, Levine M, Assouline S, Melnychuk D, et al. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism. 2009.
    CrossRef
16. Hoang BX, Shaw DG, Fang W, Han B. A Possible Application of High Dose Vitamin C in the Prevention and Therapy for Coronavirus Infections. J Glob Antimicrob Resist [Internet]. 2020;23:256–62. Available from: https://doi.org/10.1016/j.jgar.2020.09.025
    CrossRef
17. Fowler AA, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014.
    CrossRef
18. Flannery AH, Bastin MLT, Magee CA, Bensadoun ES. Vitamin C in Sepsis: When It Seems Too Sweet, It Might (Literally) Be. Chest. 2017.
    CrossRef
19. Circu M, Cardelli J, Barr M, O’Byrne K, Mills G, El-Osta H. Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells. PLoS One. 2017.
    CrossRef
20. Ballabio A, Bonifacino JS. Lysosomes as dynamic regulators of cell and organismal homeostasis. Nature Reviews Molecular Cell Biology. 2020.
    CrossRef
21. Ghislat G, Lawrence T. Autophagy in dendritic cells. Cellular and Molecular Immunology. 2018.
    CrossRef
22. Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology. 2020.
    CrossRef
23. Rebecca VW, Nicastri MC, Fennelly C, Chude CI, Barber-Rotenberg JS, Ronghe A, et al. PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. Cancer Discov. 2019.
    CrossRef
24. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature. 2008.
    CrossRef
25. Van Den Borne BEEM, Dijkmans BAC, De Rooij HH, Le Cessie S, Verweij CL. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-α, interleukin 6, and interferon-γ production by peripheral blood mononuclear cells. J Rheumatol. 1997.
26. Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005.
27. Wu R, Wang L, Kuo HCD, Shannar A, Peter R, Chou PJ, et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Reports. 2020;6(3):56–70.
    CrossRef
28. Cassell S, Edwards J, Brown DT. Effects of lysosomotropic weak bases on infection of BHK-21 cells by Sindbis virus. J Virol. 1984.
    CrossRef
29. Pan H, Peto R, Karim QA, Alejandria M, Henao-Restrepo AM, García CH, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. medRxiv [Internet]. 2020;(October 15):2020.10.15.20209817. Available from: http://medrxiv.org /content/early/2020/10/15/2020.10.15.20209817.abstract
30. Juurlink DN. Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection. CMAJ. 2020.
    CrossRef
31. China National Health Comission. Chinese clinical guidance for COVID-19 pneumonia diagnosis and treatment, 7th ed. 2020.
32. Nugrahaningsih DAA, Purnomo E. Chloroquine and hydroxychloroquine for COVID-19 treatment. J Med Sci [Internet]. 2020;52(3):11–20. Available from: http://dx.doi.org/10.19106/JMedSciSI005203202002
    CrossRef
33. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw open. 2020.
    CrossRef
34. Agarwal AD. Azithromycin in coronavirus disease-19: What we know? Open Access Maced J Med Sci. 2020;8(T1):92–6.
    CrossRef
35. Echeverría-Esnal D, Martin-Ontiyuelo C, Navarrete-Rouco ME, De-Antonio Cuscó M, Ferrández O, Horcajada JP, et al. Azithromycin in the treatment of COVID-19: a review. Expert Rev Anti Infect Ther [Internet]. 2020;00(00):1–17. Available from: https://doi.org/10.1080/14787210.2020.1813024
    CrossRef
36. Bleyzac N, Goutelle S, Bourguignon L, Tod M. Azithromycin for COVID-19: More Than Just an Antimicrobial? Clin Drug Investig [Internet]. 2020;40(8):683–6. Available from: https://doi.org/10.1007/s40261-020-00933-3
    CrossRef
37. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 — Final Report. N Engl J Med. 2020.
38. Miranda C, Silva V, Capita R, Alonso-Calleja C, Igrejas G, Poeta P. Implications of antibiotics use during the COVID-19 pandemic: present and future. J Antimicrob Chemother. 2020;(Figure 1):2–5.
    CrossRef
39. World Health Organization. Clinical Management of COVID-19: Interim guidance [Internet]. 2020. Available from: https://apps.who.int/iris/rest/bitstreams/1278777/retrieve
40. Instiaty, Darmayani IGAAPS, Marzuki JE, Angelia F, William, Siane A, et al. Antiviral treatment of COVID-19: a clinical pharmacology narrative review. Med J Indones [Internet]. 2020;29(3):332–45. Available from: http://dx.doi.org/10.13181/mji.rev.204652
    CrossRef
41. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA – J Am Med Assoc. 2020.
    CrossRef
42. Guan W, Ni Z, Hu YYH, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020.
    CrossRef
43. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis. 2020.
    CrossRef
44. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv [Internet]. 2020 Jan 1;2020.03.17.20037432. Available from: http://medrxiv.org/ content/early/2020/04 /15/2020. 03.17.20037432.abstract
45. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020.
46. Horby PW, Mafham M, Bell JL, Linsell L, Staplin N, Emberson J, et al. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020.
    CrossRef
47. Asadi-Pooya AA, Attar A, Moghadami M, Karimzadeh I. Management of COVID-19 in people with epilepsy: drug considerations. Neurol Sci. 2020.
    CrossRef