|Year : 2020 | Volume
| Issue : 4 | Page : 171-178
Emerging Pharmacotherapy for COVID-19 Treatment: An Integrative Review
Deepa Shaji Thomas1, Divya K Yesodharan2, Judie Arulappan1
1 Department of Maternal and Child Health, College of Nursing, Sultan Qaboos University, Al Khoud, Muscat, Sultanate of Oman
2 Department of Community and Mental Health, College of Nursing, Sultan Qaboos University, Al Khoud, Muscat, Sultanate of Oman
|Date of Submission||14-Jun-2020|
|Date of Decision||15-Jun-2020|
|Date of Acceptance||23-Jun-2020|
|Date of Web Publication||27-Oct-2020|
RN, RM, BSN, MSN, PhD, DNSc Judie Arulappan
Assistant Professor/HoD, Department of Maternal and Child Health College of Nursing, Sultan Qaboos University, P. O. Box 66, Al Khoud, Muscat
Sultanate of Oman
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: COVID-19 has become the global pandemic incapacitating the health systems and demanding investigation of possible pharmacotherapeutic options against SARS CoV-2. Although social distancing, hand sanitizing and supportive care remain as the preventive and management measures of COVID-19, clinical efficacy of various therapeutic agents is being tried out simultaneously to reduce the mortality associated with the disease. Objective: To ascertain the potential drugs/treatment for COVID 19 from the published literature across the world from its origin until June 2020. Methods: A literature search was done in CINAHL, Pub Med, Google Scholar, Science Direct, Springer, Wiley, EEEE, and Medline computerized repositories for complete texts from December 2019 until June 2020. The search terms used were COVID-19, treatment, antimalarial, antibiotics, antiretroviral, antiviral, plasma, immunoglobulin, heparin and immunosuppressant. The inclusion criteria adopted in the study were original research articles with current treatment process and potential drugs used in COVID 19 patients, primary data, published in English and full article available for free download. Results: There is no absolute single pharmacotherapeutic measure identified till date to cure this disease. The studies reviewed reported that the clinical improvement of the disease could be due to the result of other supportive measures and the results are inconclusive as the disease is impacted by various coexisting medical conditions. More clinical trials at large scales are needed to tackle this crisis at the earliest. Conclusion: Inventing a new vaccine or drug against coronavirus may take years to fully develop. However, clinicians are trying to treat this disease with already prescribed drugs for other diseases like H1N1, malaria, HIV, and SARS. It is important to note that there may be emergence of new clinical characteristics, treatment trials and outcome of COVID-19 as the disease evolves.
Keywords: COVID-19, emerging, pharmacotherapy, treatment
|How to cite this article:|
Thomas DS, Yesodharan DK, Arulappan J. Emerging Pharmacotherapy for COVID-19 Treatment: An Integrative Review. Int J Nutr Pharmacol Neurol Dis 2020;10:171-8
|How to cite this URL:|
Thomas DS, Yesodharan DK, Arulappan J. Emerging Pharmacotherapy for COVID-19 Treatment: An Integrative Review. Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2021 May 14];10:171-8. Available from: https://www.ijnpnd.com/text.asp?2020/10/4/171/299266
| Introduction|| |
Coronavirus Disease 2019 (COVID-19) is a moderate to severe respiratory illness caused by a novel coronavirus, now called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began in Wuhan, China, in December 2019, and has now spread worldwide. It was formerly called as 2019-nCoV, as it was first time seen in humans. As of May 24, 2020, it has infected 5,438,783 people worldwide with 344,585 deaths and 28, 19, 971 active cases and 2,274,227 recovered cases. On January 30, 2020, World Health Organization (WHO) has declared a corona virus outbreak as a Global Public Health Emergency and on March 11, 2020, it was declared as a global pandemic. The COVID-19 outbreak soared swiftly across China and spread to 215 countries/territories/areas outside China as of 25th May 2020.
The treatment for COVID-19 may vary across countries. WHO has given general guidelines for symptomatic management of COVID-19 and the precautions to be taken for the vulnerable group including children, elderly, pregnant women and people with co-morbidities. Although several therapeutic agents have been tried for the treatment of COVID-19, there is currently no medicines approved to cure COVID-19. Researchers across globe are working tirelessly to identify a vaccine or a medicine to cure COVID-19.
WHO has launched an international initiative for clinical trials named “Solidarity” along with multinational participation, which is 80% faster than any traditional clinical trial. Many clinical trials are currently underway to evaluate the effectiveness of drugs like anti-malarial, antibiotics, antivirals, interleukins, immunosuppressant, convalescent plasma, anticoagulants and many more. Few in vitro drugs have been shown to be effective in few observational and non-randomized trials against the SARS-CoV-2 virus. The controlled clinical experiments are currently under way to assess the effectiveness of treatment against COVID-19. Our integrative review discusses the existing medications/treatment available in the treatment of patients with COVID-19 from the emergence of the virus in December 2019 until June 2020.
| Aim|| |
The aim of this review is to identify the potential drugs/treatment used for COVID 19 across the world. Since COVID-19 evolved in the world, many treatments have been suggested across the world and resulted in controversies. This review attempted to identify the available research articles related to the probable treatment for the COVID-19 around the world since its origin.
An integrative analysis of the literature was carried out through an initial search of CINAHL, Pub Med, Google Scholar, Science Direct, Springer, Wiley, EEEE, and Medline computerized repositories having complete texts. The original quest has 590 articles. The search parameters included publications published between December 2019 and June 2020, in English, using the keywords COVID-19, treatments, antimalarial, antibiotics, antiretroviral, antiviral, plasma, immunoglobulin, heparin and immunosuppressant.
The inclusion criteria included original research articles with current treatment process and potential drugs used in COVID 19 patients, primary data with full-text articles published in English only and full article available for free download.
The authors excluded review articles about COVID 19 drugs and treatments, articles on animal trial and laboratory test reports, journal and advisory articles, duplicate publications and article which lacked sufficient information on treatment outcome.
Analysis of the findings
Three reviewers analyzed the papers and chose the qualifying publications separately. To filter the article, the author and year of study, drug used and its category, type of study, setting and time period of drug under trial, sample included, and major findings were recorded. When many papers from the same research have been written, only one with the most comprehensive details has been added in the review. Three investigators have retrieved the evidence and contradictions have been discussed through debate.
17 research papers between December 2019 and June 2020 discussing alternative COVID-19 therapies which met the review requirements were included. A total of 590 electronic articles were listed, of which 240 were excluded on the grounds of not meeting the requirements and 250 publications which met the inclusion criteria were included. Again, 233 articles were excluded; 158 articles based on full-text screening including studies like reviews, animal studies; 55 citation duplications, and 20 articles due to insufficient information on treatment of COVID 19 including journal and advisory studies. Finally, 17 publications which met the inclusion requirements with a thorough review were included. This review includes different potential medicines used in COVID-19 treatment worldwide. [Figure 1] demonstrates the analytical process done for this integrative review.
|Figure 1 Schematic representation of review process with PRISMA 2009 flow diagram|
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| Results|| |
A total of 590 papers were initially listed. After eliminating duplicates, verifying title, abstract and full text, 17 studies were found suitable for this review based on the defined exclusion and inclusion requirements. All the 17 papers included were original studies which were conducted to determine the efficacy of treatment of COVID-19 patients utilizing drugs. The international studies comprised of 12 from China and one each from France, Hong Kong, USA, Iran and Brazil. The studies were summarized under the following categories: Antimalarial & antibiotics; Antiretroviral; Antiviral; Plasma & immunoglobulins; Immunosuppressant and Heparin. The research studies utilizing potential drugs for curing COVID 19 patients are listed in [Table 1]. A hypothetical image of effect of pharmacotherapy drugs on COVID-19 is shown in [Figure 2]. 
|Figure 2 Hypothetical image of Passive immunization in COVID-19 using convalescent plasma. Image is adapted from Abraham, J. Passive antibody therapy in COVID-19. Nat Rev Immunology (2020). https://doi.org/10.1038/s41577-020-0365-7.|
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| Discussion|| |
A comprehensive search summary of original studies addressing the treatment for COVID-19 from December 2019 to June 2020 is discussed here. “Solidarity” is a multinational research project initiated by World Health Organization and collaborators to discover successful COVID-19 therapy.
Remdesivir, Lopinavir/Ritonavir, Lopinavir/Ritonavir, Interferon beta-1a and Hydroxychloroquine have originally been chosen as therapeutic alternatives based on evidence from the laboratory and clinical trials. To date, over 400 hospitals in 35 countries have actively recruited the patients and nearly 3500 patients have been enrolled from 17 countries for the clinical trial. On 24 May 2020, the registration of Hydroxychloroquine drug was indefinitely revoked despite data on the protection and effectiveness of Hydroxychloroquine as a cure for the patients with COVID-19 is found.
For the treatment of COVID-19, several antiretroviral drugs are considered. Protease inhibitors have been considered as candidate therapy because they inhibit enzymes that activate the glycoprotein envelope as part of the process of viral cell entry. In patients receiving LPV/r-combination therapy, the time of return to normal body temperature was shorter than utilizing adjuvant therapy. It also reduced the pathological values of biological indices like ALT and AST proportion in the patients. Certain clinical symptoms had quicker remission too.
A triple mixture of injectable Interferon (interferon beta-1b), oral protease (lopinavir − ritonavir) and oral nucleoside precursor (ribavirin) was used when the symptoms began. As compared to the use of Lopinavir − ritonavir alone, the above-mentioned combination could suppress the release of SARS-CoV-2, not only in nasopharyngeal swab but in all clinical specimens. The combination therapy correlated with substantially shorter time to negative viral load in all specimens for the virologic test.
In critically ill COVID-19 patients, the introduction of Lopinavir-ritonavir along with standard supportive therapy was not linked to clinical improvement or mortality. Moreover, the number of recipients of Lopinavir-itonavir who suffered from significant problems or who needed artificial ventilation were smaller. These findings are speculative and need more research to see whether a specific stage of the disease will eliminate such symptoms in COVID-19.
The antiviral drug usage for the COVID-19 patients produced varied outcomes. Interferon alfa-2b (IFN-α2b) is an antiviral and antineoplastic drug. IFN-α2b therapy accelerates upper respiratory viral clearance in patients with COVID-19. Such results help the plausibility of IFN-α2b as a treatment for COVID-19 illness with the indicators of acute inflammation such as CRP and IL-6 associated with this reduced viral shedding.
The patients with COVID-19 obtaining Favipiravir (FPV) tend to be quicker in viral clearing and chest imaging than the patients receiving Lopinavir (LPV)/ritonavir (RTV). This study lacked clarity to define the relationship between the viral titer and its clinical prediction. Since this is not a controlled, double blind, and parallel trial, more well-designed and large scale confirmatory studies are needed.
The treatment with Umifenovir did not shorten the length of hospital stay in non-ICU hospital patients with COVID-19. Intravenous Remdesivir did not substantially increase the duration for clinical recovery, mortality or period for virus clearance in patients with extreme COVID-19 relative to placebo.
Convalescent plasmas therapy (CP) has been used for more than a century to help deter and cure a variety of infectious diseases like hemorrhagic fever such as Ebola, as well as other virus infection. It was reported that CP was used in the treatment of extreme acute respiratory syndrome (SARS), pandemic 2009 influenza A (H1N1), and air influenza A (H5N1). The possibility of CP therapy in COVID-19 was well endured, with the clinical symptoms improvement within 3 days, with rapid neutralization of viremia.
Anticoagulant therapy with low molecular weight heparin can benefit only those patients with significantly elevated D dimer. To validate this finding, more forward-looking experiments are required. Our review included the studies with the controversial drug Hydroxychloroquine. When comparing the effect of treatment with Hydroxychloroquine as a single drug and Hydroxychloroquine and Azithromycin combination, the combined dose was significantly effective in eliminating the virus.
In the patients treated with Hydroxychloroquine (HCQ), the time for recovery of body temperature and the time for cough remission were substantially shortened. In a two-week Iranian study using Hydroxychloroquine, Oseltamivir, and Lopinavir ritonavir, the mortality in the ICU reduced to 25% among ARDS patients. However, in critically ill patients with COVID-19, a higher Chloroquine diphosphate (CQ) dose is not to be recommended due to the potential safety hazards, especially in combination with Azithromycin and Oseltamivir.
In a wide range of patients, the risk of intubation or death in patients receiving Hydroxychloroquine was not substantially higher or lower than those without it. The increased frequency of ventricular arrhythmias and in hospital mortality are linked to either the prescription regimens of Chloroquine or Hydroxychloroquine alone or in conjunction with macrolide., Based on the above study results, considering the safety and efficacy of Hydroxychloroquine as a treatment for the COVID-19, the registration of Hydroxychloroquine was indefinitely revoked by World Health Organization.
| Conclusion|| |
Though there is a compelling need to control this global pandemic COVID-19, there is no absolute measures identified so far to cure or prevent this crisis. This integrative review has identified 17 original human trials with promising evidence on clinical improvement and safety except HCQ. The studies also reported that the clinical improvement could also be due to other supportive measures and they are inconclusive of its impact secondary to various coexisting medical conditions. We recognize at this juncture that no absolute conclusion can be drawn on the effectiveness of any particular group of drugs over the others with regard to its benefit or risks. Therefore, large multicenter urgent clinical trials are needed to tackle this crisis at the earliest.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]