Eltrombopag Olamine in Dengue Fever:
Systematic Review of Clinical Trials and Beyond
Sadia Afrin1, Md. Shanzid Hasan2, Md. Rezwan Ahmed Mahedi3*, Ovijet Chandra Kuri4, Hrishik Iqbal5, Mustafa Jawad Kadham6, Dr. Mohammad Jamali7, Patrik Viktor8,
Calvin R. Wei9, Fredmoore Orosco10, Akter Hossain Khan11, Nikolaos Syrmos12, Fazle Rabbi13
1Department of Pharmacy, Comilla University, Bangladesh.
2Department of Pharmacy, University of Asia Pacific, Bangladesh.
1,3*Research Secretary, Bangladeshi Pharmacists’ Forum (Comilla University), Bangladesh.
4Karadeniz Teknik Universitesi.
5Department of Mathematics and Natural Sciences, Brac University, Bangladesh.
6College of Medical Techniques, Al-Farahidi University, Baghdad, Iraq.
7Faculty of Medical and Health Sciences,Liwa College, Abu Dhabi UAE.
8Óbuda University, Keleti Károly Faculty of Business and Management,
Óbuda University, Tavaszmező u. 15-17, H-1084 Budapest, Hungary.
9Department of Research and Development, Shing Huei Group, Taipei, Taiwan.
10Virology and Vaccine Institute of the Philippines Program, Industrial Technology Development Institute, Department of Science and Technology, Bicutan, Taguig, Philippines.
11Study Physician, Projahnmo Research Foundation, Sylhet Operation.
12Aristotle University of Thessaloniki, Thesaaloniki, Macedonia, Greece.
13Australian Computer Society.
*Corresponding Author E-mail: rezwanmahed747@gmail.com
ABSTRACT:
Introduction. Worldwide, millions suffer from dengue fever, a mosquito-borne virus that is severe. No particular antiviral drugs exist, making dengue management difficult. New therapies like Eltrombopag Olamine, originally developed for thrombocytopenia, have shown promise. This study examines Eltrombopag Olamine's dengue fever treatment potential using literature, experimental data, and clinical implications. Methodology. This systematic review examines the available literature on the use of Eltrombopag Olamine for the treatment of dengue fever. Thorough keyword searches throughout databases like PubMed and Cochrane, as well as hand-searching of reference lists, provide a large data set for analysis. Result. The small-molecule thrombopoietin receptor agonist eltrombopag olamine showed immunomodulatory properties that are important in the treatment of dengue fever. Studies on dengue patients show that it successfully increases platelet counts, suggesting it may be useful in treating thrombocytopenia. Phase III studies are now investigating its effect on platelet counts and fluid leakage in dengue patients, which might lead to new and improved treatments in the future. Conclusion. The study highlights Eltrombopag Olamine's dengue fever management potential. Its novel approach and favorable patient results, including shortened hospital stays and improved quality of life, provide promise for dengue fever treatment. Policymakers and healthcare providers must fund more research to fully uncover its therapeutic effects. Eltrombopag Olamine might transform dengue treatment, improving efficacy and quality of life for millions.
KEYWORDS: Eltrombopag, Dengue, Clinical Trials, Randomized controlled trials, Bangladesh, etc.
INTRODUCTION:
Dengue fever, a sickness caused by a virus that is spread by mosquitoes and may be quite debilitating, remains a serious concern to people's health worldwide and affects millions of people every year1. As there are now no particular antiviral medicines available, managing the consequences of dengue fever continues to be a severe issue for medical professionals all over the globe. In recent years, researchers have investigated novel treatment techniques to lessen the impact of the condition and reduce the accompanying morbidity and death rates to more manageable levels2. Eltrombopag Olamine, a unique medicine that was first created to treat thrombocytopenia, has been used in some of the research, and this has shown to be a very fruitful line of inquiry. Eltrombopag Olamine is a small molecule thrombopoietin receptor agonist, and it first came to people's notice because of its potential function in treating conditions related to having low platelet counts3. However, new developments in the study of infectious illnesses, notably dengue fever, have piqued researchers' interest in the immunomodulatory effects of this substance. According to the findings of specific studies, eltrombopag olamine may impact several facets of the immune response, including the activation of platelets and the modulation of pro-inflammatory cytokines4. These immunomodulatory effects are of particular relevance in dengue fever, where an uneven immune response often adds to the severity of the illness. Researchers from the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) gave the antidiarrheal medication eltrombopag olamine to a group of twenty adult patients with dengue fever as part of a study. Each patient received a daily dosage of 50 mg of eltrombopag olamine during treatment. This treatment lasted for five days. According to the research findings, the medication successfully raised platelet counts in individuals suffering from dengue fever. The study results led the researchers to conclude that eltrombopag olamine had promise as a possible therapy for dengue fever. In this in-depth investigation, we will investigate the present state of information about the use of eltrombopag olamine in relation to dengue fever5,8. This research intends to shed light on the potential and limits of Eltrombopag Olamine as a treatment alternative in the fight against dengue fever by analyzing the available literature, studying the experimental data, and critically evaluating the clinical implications.
METHODOLOGY:
In the context of dengue fever, the primary goal of this systematic review is to conduct a complete analysis of previously worked research studies, clinical trials, and randomized controlled trial experiments linked to the use of eltrombopag olamine. This study aims to investigate whether or not Eltrombopag Olamine is helpful in the treatment of dengue-infected individuals, as well as whether or not it is safe, what the best dosage is, and what possible mechanisms of action it may have. We carried out a search that is both systematic and extensive throughout several electronic databases, such as PubMed, Cochrane and Sri Lanka Clinical Trials Registry. The search will find publications published up to the current date that includes the following keywords and their combinations: "Eltrombopag Olamine," "Dengue Fever," "Dengue Virus," "Thrombocytopenia," and related phrases. We will utilize the Boolean operators AND and search6 to narrow down the search results. Additionally, we will manually examine the reference lists of relevant publications and reviews to look for possible studies that were overlooked during the first search.
Figure 1: Prisma flowchart of systematic review for articles selection
RESULT:
Mechanism of Eltrombopag Olamine:
Eltrombopag Olamine is a small-molecule TPO-receptor agonist that works on the human TPO-receptor by interacting with its transmembrane region7. It does this by stimulating the phosphorylation of STAT and JAK, which leads to an increase in the number of marrow progenitor cells that proliferate and differentiate. On the other hand, in contrast to recombinant TPO or romiplostim8, eltrombopag does not in any manner stimulate the AKT pathway. Eltrombopag, on the other hand, seems to begin signal transduction through a mechanism that is distinct from that of endogenous TPO9. Eltrombopag binds with the TPO receptor at a binding location that is physically separate from that of TPO. Additionally, it has been used to treat chronic immunological thrombocytopenia (ITP)10, aplastic anaemia, and persistent infections with the hepatitis C virus (HCV). The discovery that eltrombopag Olamine might be repurposed to generate the first medication to treat dengue fever was made by researchers in Bangladesh11.
Figure 2: The activity of eltrombopag at the cellular level. Eltrombopag increases platelet and cellular production via binding to a transmembrane region of the TPO-receptor that is located downstream of the TPO binding site13,15.
The peak concentration occurs between 2 and 6hours after oral administration, while the half-life is between 21 and 32hours. t has a high protein binding affinity for human plasma (>99%). Eltrombopag exclusively binds to the trans-membrane domain of the thrombopoietin receptor12, whereas natural thrombopoietin binds to its extracellular domain. In vitro and ex vivo experiments using platelet samples from healthy people and patients with chronic ITP did not affect agonist-induced platelet aggregation or activation13. Each film-coated tablet contains 25 or 50mg of eltrombopag olamine. Eltrombopag should be taken at least 4 hours before or after antacids, dairy products, other food products, or mineral supplements containing polyvalent cations because they reduce absorption by up to 60%14. CYP1A, CYP2C8, UGT 1A1 and UGT1A3 are important hepatic routes for eltrombopag metabolism. Eltrombopag did not affect cytochrome P450 enzymes. Clinical medication interactions between eltrombopag and cytochrome P450 substrates, inducers, or inhibitors are mostly unstudied15. P-glycoprotein and OATP 1B1 do not bind to eltrombopag. Eltrombopag inhibits OATP1B1. Therefore, coadministration with rosuvastatin, an OATP1B1 substrate, doubled plasma rosuvastatin. Eltrombopag-treated ITP patients should lower the dosage of concurrent statins (rosuvastatin, pravastatin, simvastatin, and lovastatin) and monitor statin adverse effects. The unmodified medication excretes 20% of eltrombopag in faeces and 31% in urine16,17.
Clinical Study of Eltrombopag Olamine in Dengue Infection:
In 2008, Novartis, a multinational pharmaceutical corporation, released the medication to the public under Eltrombopag. In 2014, the FDA approved the drug in the United States. Although eltrombopag is often used for low platelet counts caused by liver disease, it has many medical applications17. Research explores Dengue Fever (DF) and Haemorrhagic Fever (DHF), both caused by dengue, a mosquito-borne viral illness. Over 50 million individuals are infected with dengue fever yearly, and symptoms may range from a low fever to life-threatening situations. Eltrombopag is an oral medication that stimulates platelet synthesis, and this study is looking into its usage as a possible therapy for dengue fever-induced thrombocytopenia. One hundred adult patients diagnosed with dengue participated in this research, which was carried out between July and December of 2021. The findings suggest that Eltrombopag effectively controlled thrombocytopenia in patients with DF and DHF since it led to a considerable rise in platelet counts18, which became notably apparent after day 7.
Researchers performed a phase II open-label, randomized, controlled trial of eltrombopag to evaluate its safety and effectiveness in treating thrombocytopenia in individuals with moderate to severe dengue. Dengue patients suspected of being between 15 and 65 were eligible for enrollment. There were three groups: The Control group got just the conventional therapy. Groups 1 and 2 received eltrombopag and their regular medication for three days (25 and 50 milligrams per day, respectively). We tracked platelet counts, the immature platelet fraction (IPF), and the absolute immature platelet count (A-IPC). After seven days of treatment with eltrombopag, platelet counts were considerably higher than in the control group at all time points. There was no significant difference in IPF levels across groups, while A-IPC was more potent in the treatment group after Day 5. Patients showed a range of reactions to eltrombopag, with some having strong, moderate, or low responses19. All groups had a comparable rate of adverse events such as nausea, dizziness, and headaches. There was no evidence of liver abnormalities or thromboembolic events on liver ultrasonography or function tests after eltrombopag treatment.
A Double-Blind, Randomized, Placebo-Controlled Phase III study of Eltrombopag to treat thrombocytopenia and stop fluid leakage in mild dengue patients is underway. Publicly known as the "Efficacy of Eltrombopag in correcting thrombocytopenia and preventing fluid leakage in moderate to severe dengue patients- a Phase III Randomized Placebo Controlled Clinical Trial," this study focuses on patients with Dengue Fever (DF), Dengue Haemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS). Participants, investigators, and healthcare providers all participate in a randomised, controlled study with a double-masked protocol. Two groups, one getting Eltrombopag 25mg once a day for three days along with conventional care and the other receiving a placebo, will each include 300 patients from different hospitals in Dhaka, Bangladesh. Mean platelet counts on days 4-7, and the percentage of patients declared recovered (platelet count over 150 x 109/L) are the main endpoints 19. The trial's secondary objective is to measure the frequency and severity of fluid loss (as measured by changes in Hematocrit levels) in these individuals throughout the same time frame. The results of this research have the potential to significantly affect the management of dengue, a viral infection that affects a large percentage of the world's population20.
Eltrombopag may be an effective treatment for severe dengue, according to the findings of a recent study. These findings highlight the need for more research and easy access to medical support for dengue patients.
Table 1: Clinical trials, RCTs, Case studies on eltrampobag for dengue treatment8,18,19,20.
|
Type of study |
Center |
Study Phase |
Participants |
Dose |
Outcomes |
|
Randomized controlled trial (2022) |
Dhaka Medical College Hospital (DMCH), Sir Salimullah Medical College Hospital, Mugda Medical College Hospital, Square Hospital, Dhaka, AMZ Hospital, and Better Life Hospital, Dhaka, Bangladesh. |
Phase 3 |
300 |
25mg |
Platelet count recovered within 4-7 days |
|
Randomized controlled trial (2019) |
Dhaka Medical College Hospital (DMCH), Better Life Hospital, and AZM Hospital |
Phase 2 |
123 |
25mg (Group-1), 50mg (Group-2) |
Platelet count recovered within 0-7 days |
|
Case Study |
India |
|
1 |
50mg |
After 3 weeks |
|
Cinical trial |
Dhaka Medical College Hospital, AMZ Hospital, Better Life Hospital |
Phase 2 |
115 |
- |
- |
|
Cross-sectional observational study (2021) |
Tairunnesa Memorial Medical College and Hospital (TMMCH), Gazipur and Shin Shin Japan Hospital, Uttara, Dhaka |
|
100 |
25mg, 50 mg |
1-7 days |
Patient Outcomes and Quality of Life:
Patient outcomes and quality of life play an essential role when determining the efficacy of therapies for diseases like dengue fever. The treatment of dengue fever has seen a dramatic change with the advent of Eltrombopag Olamine. Eltrombopag Olamine has shown encouraging results in clinical trials, with individuals suffering from dengue reporting faster recoveries and less severe symptoms. Eltrombopag Olamine has substantially contributed by increasing platelet production, which is necessary to treat thrombocytopenia, a typical consequence of dengue infections20. Eltrombopag Olamine's ability to successfully manage low platelet counts helps to improve patient well-being and quality of life by reducing the risk of severe bleeding. Patients undergoing Eltrombopag Olamine therapy frequently report a shorter stay of hospitalization and a speedier return to their usual daily activities, resulting in a more incredible feeling of overall health and less psychological stress associated with extended sickness. These promising results highlight Eltrombopag Olamine's promise in managing dengue fever by showing that it can do more than address the physiological challenges posed by the disease.
CONCLUSION:
In conclusion, the research and clinical data reviewed in this review suggest that Eltrombopag Olamine shows substantial potential as a therapy for dengue fever. The absence of effective antiviral treatments for dengue fever, affecting millions yearly, is a significant public health problem worldwide. Eltrombopag Olamine's capacity to boost platelet counts and treat thrombocytopenia has been shown via extensive research into the drug's immunomodulatory effects. Eltrombopag Olamine's unique mode of action as a small-molecule TPO-receptor agonist has been revealed. Patient outcomes and quality of life have increased due to its use to treat thrombocytopenia in dengue patients, as shown by clinical research21,23. Eltrombopag Olamine sufferers, in particular, benefited from shorter hospital stays, less severe symptoms, and a speedier return to normal life24. This tackles the physiological difficulties caused by dengue fever and reduces the emotional strain that comes with being sick for a long time. Eltrombopag Olamine has shown promise in treating dengue fever25, and researchers are continuing to investigate its efficacy via studies like the Phase III randomized, placebo-controlled clinical study. The findings of these trials may soon usher in a new era of dengue care, with improved efficiency and efficacy of treatment alternatives26. In light of these results, scientists, doctors, and policymakers must keep studying Eltrombopag Olamine and its potential uses in treating dengue fever. The lives of the millions of people throughout the globe who have been afflicted by dengue fever may be significantly improved if we took this step27.
ABBREVIATION:
EPO = Erythropoietin
G-CSF = Granulocyte colony-stimulating factor;
TPO-R = thrombopoietin receptor;
TCP = thrombocytopenia;
TPO = thrombopoietin
AUTHOR CONTRIBUTION:
Literature search, reading and data collection: MRAM, SA, MSH.
Part of manuscript preparation process: MRAM, SA, OCK, AH.
Involved in manuscript editing and proofreading: MRAM, SA, HB, MJ.
Played their role in table preparation and image editing: AMM, CRW, MRAM, SA.
Part of final editing and finalising the manuscript: FLO, NS, FR, MRAM, HI, PV.
CONFLICTS OF INTEREST:
There are no conflicts of interest.
Dedication:
Your (MD. Khurshid Alam and Rabeya Akter) unwavering support, boundless love, and enduring encouragement have been the guiding lights throughout my academic journey. This systematic review paper, stands as a testament to the values of diligence and determination you instilled in me. This work is not just a culmination of my efforts; it is a reflection of the values you both have imparted to me. With heartfelt gratitude, I dedicate this paper to both of you.
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Received on 07.10.2023 Modified on 02.02.2024
Accepted on 05.04.2024 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(6):2778-2782.
DOI: 10.52711/0974-360X.2024.00436