In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever DOI Creative Commons
Junjie Ding, Dumrong Mairiang,

Dararat Prayongkul

et al.

CPT Pharmacometrics & Systems Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

The increased incidence of dengue poses a substantially global public health challenge. There are no approved antiviral drugs to treat infections. Ivermectin, an old anti-parasitic drug, had effect on viremia, but reduced the non-structural protein 1 (NS1) in clinical trial. This is potentially important, as NS1 may play causal role pathogenesis severe dengue. study established in-host model characterize plasma kinetics virus and with host immunity evaluated effects ivermectin, using population pharmacokinetic-pharmacodynamic (PK-PD) modeling approach, based two studies acute fever: placebo-controlled ivermectin 250 adult patients PK-PD 24 pediatric patients. proposed described adequately observed pharmacokinetics, viral load, data. Bodyweight was significant covariate pharmacokinetics. We found that EC

Language: Английский

Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial DOI Creative Commons
William HK Schilling, Podjanee Jittamala, James A Watson

et al.

The Lancet Infectious Diseases, Journal Year: 2023, Volume and Issue: 24(1), P. 36 - 45

Published: Sept. 28, 2023

Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different treatments using rate viral clearance as measure effect.

Language: Английский

Citations

62
Clinical antiviral efficacy of favipiravir in early COVID-19 (PLATCOV): an open-label, randomised, controlled, adaptive platform trial DOI Creative Commons
Viravarn Luvira, William HK Schilling, Podjanee Jittamala

et al.

BMC Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(1)

Published: Jan. 15, 2024

Abstract Brief summary In early symptomatic COVID-19 treatment, high dose oral favipiravir did not accelerate viral clearance. Background Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir been recommended for the treatment of some countries. Methods a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with were randomised one ten arms including (3.6g on day 0 followed by 1.6g daily complete 7 days treatment) or no study drug. The primary outcome was rate clearance (derived under linear mixed-effects model from log 10 densities standardised duplicate oropharyngeal swab eluates taken over 8 [18 swabs per patient]), assessed modified intention-to-treat population (mITT). safety included all who received at least allocated intervention. This ongoing registered ClinicalTrials.gov (NCT05041907) 13/09/2021. Results final analysis, mITT contained data 114 and 126 concurrently Under fitted density estimates first randomisation (4,318 swabs), there difference between given receiving drug; -1% (95% credible interval: -14 14%) difference. High well-tolerated. Interpretation does COVID-19. estimated quantitative measurements eluate assesses efficacy drugs vivo comparatively few studied patients.

Language: Английский

Citations

17
Nipah virus disease: what can we do to improve patient care? DOI
Md Zakiul Hassan, Tahmina Shirin, Syed Moinuddin Satter

et al.

The Lancet Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(7), P. e463 - e471

Published: Jan. 4, 2024

Language: Английский

Citations

12
Temporal changes in SARS-CoV-2 clearance kinetics and the optimal design of antiviral pharmacodynamic studies: an individual patient data meta-analysis of a randomised, controlled, adaptive platform study (PLATCOV) DOI Creative Commons
Phrutsamon Wongnak, William HK Schilling, Podjanee Jittamala

et al.

The Lancet Infectious Diseases, Journal Year: 2024, Volume and Issue: 24(9), P. 953 - 963

Published: April 24, 2024

Effective antiviral drugs prevent hospitalisation and death from COVID-19. Antiviral efficacy can be efficiently assessed in vivo by measuring rates of SARS-CoV-2 clearance estimated serial viral genome densities quantitated nasopharyngeal or oropharyngeal swab eluates. We conducted an individual patient data meta-analysis unblinded arms the PLATCOV platform trial to characterise changes kinetics infer optimal design interpretation pharmacometric evaluations.

Language: Английский

Citations

6
Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV) DOI Creative Commons
Podjanee Jittamala, William HK Schilling, James A Watson

et al.

The Journal of Infectious Diseases, Journal Year: 2023, Volume and Issue: 228(10), P. 1318 - 1325

Published: July 19, 2023

Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted varying treatment guidelines.In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 8 arms including intravenous (200 mg followed by 100 daily for 5 days) or no study drug. The primary outcome was rate severe acute respiratory syndrome 2 (SARS-CoV-2) clearance (estimated under linear model fit log10 viral densities, days 0-7) standardized duplicate oropharyngeal swab eluates, modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907).The enrolled 131 (remdesivir n = 67, drug 64) and estimated rates from median 18 samples per patient (a total 2356 quantitative polymerase chain reactions). Under model, compared contemporaneous control arm (no drug), accelerated mean 42% (95% credible interval, 18%-73%).Parenteral accelerates COVID-19. Pharmacometric assessment therapeutics using method described can determine vivo clinical antiviral efficacy rapidly efficiently.

Language: Английский

Citations

13
Repurposing Anthelmintic Drugs for COVID-19 Treatment: A Comprehensive Meta-Analysis of Randomized Clinical Trials on Ivermectin and Mebendazole DOI Creative Commons
Shakta Mani Satyam, Mohamed El‐Tanani, Mohamed Anas Mohamed Faruk Patni

et al.

Antibiotics, Journal Year: 2025, Volume and Issue: 14(5), P. 459 - 459

Published: April 30, 2025

Background: The COVID-19 pandemic necessitated the urgent exploration of therapeutic options, including drug repurposing. Anthelmintic drugs such as ivermectin and mebendazole have garnered interest due to their potential antiviral immunomodulatory properties. However, conflicting evidence from randomized clinical trials (RCTs) necessitates a comprehensive meta-analysis determine efficacy safety in management. Objective: This evaluates treating by analyzing impact on viral clearance, symptom resolution, hospitalization duration, profiles. Methods: A systematic search Scopus, PubMed, Embase, Cochrane Library was conducted following PRISMA guidelines identify RCTs published up February 2025. Eligible studies included adult patients with confirmed who received or compared placebo standard care. Data extraction risk bias assessment were performed using Risk Bias Tool. Statistical heterogeneity evaluated I2 statistic, pooled effect sizes calculated for primary outcomes. Results: Twenty-three (n = 12,345) included, twenty-one two mebendazole. analysis suggested no statistically significant improvement clearance (p 0.39), duration 0.15), resolution 0.08) individual indicated benefits, particularly mebendazole, reducing load inflammation. Both exhibited favorable profiles, increase adverse events. Conclusions: promising propensities observed selected underscore adjunct therapies COVID-19. With well-established effects, affordability, these present strong candidates further exploration. Advancing research through well-designed, large-scale will help unlock full expand treatment options fight against

Language: Английский

Citations

0
Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV) DOI Creative Commons
Podjanee Jittamala, Simon Boyd, William HK Schilling

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 18, 2024

Abstract Background The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro , observational clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended guidelines vivo has characterised. Methods PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform running Thailand, Brazil, Pakistan, Laos. We recruited low-risk adult outpatients aged 18-50 with symptomatic (symptoms <4 days). Patients assigned using block randomisation one eleven arms including oral (40mg/day 7 days), or no study drug. Uniform ratios applied across active groups while drug group comprised ≥20% patients at all times. primary endpoint was rate oropharyngeal viral clearance assessed a modified intention-to-treat population (>2 days follow-up). estimated under Bayesian hierarchical linear model fitted log10 densities standardised duplicate swab eluates taken daily over week (18 measurements per patient). This ongoing registered ClinicalTrials.gov ( NCT05041907 ). Findings Between 5 April 2022 8 May 2023 271 concurrently randomised either (n=120) (n=151). Fluoxetine well tolerated accelerated relative arm by 15% (95% credible interval (CrI): 2% 34%). In pooled meta-analysis unblinded substantially less than ritonavir-boosted nirmatrelvir-85% increase CrI: 61 112%); remdesivir 35% (14 59%), molnupiravir 37% 60%), casirivimab/imdevimab 29% (10 48%). Interpretation against SARS-CoV-2. Although level efficacy other currently available drugs, might still be useful prophylaxis where effect required. Funding Wellcome Trust Grant ref: 223195/Z/21/Z through Therapeutics Accelerator. Evidence before this proposed as therapeutics initially observational, evidence. reports suggested that taking had reduced probability developing dying. searched PubMed EMBASE studies English up until 30 th November search terms “fluoxetine”, “fluvoxamine” “COVID-19” restricted controlled trials (RCTs). Eight outpatient RCTs identified. There outpatients. A compatible moderate reduction hospitalisation death risk ratio 0.80 CI: 0.62,1.01). Added value showed illness SSRI weak . antivirals such nirmatrelvir molnupiravir. approach described here provides quantitative measure effects tractable sample sizes. Implications COVID-19. insufficient but, required prevent infection, could beneficial prophylaxis.

Language: Английский

Citations

3
An Update on SARS-CoV-2 Clinical Trial Results—What We Can Learn for the Next Pandemic DOI Open Access
Edi Dharmana, Juliane Brun, Michelle L. Hill

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 354 - 354

Published: Dec. 26, 2023

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance preparedness. Due to lack approved antiviral drugs effective against coronaviruses at start pandemic, world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials date, as well selected in vitro data directly acting antivirals, host-targeting and immunomodulatory drugs. Overall, repurposing efforts evaluating antivirals targeting other viral families were unsuccessful, whereas several led clinical improvement hospitalised patients with severe disease. In addition, accelerated drug discovery during progressed multiple novel efficacy, including small molecule inhibitors monoclonal antibodies. We argue that large-scale investment is required prepare for future pandemics; both develop an arsenal broad-spectrum beyond build worldwide trial networks can be rapidly utilised.

Language: Английский

Citations

8
Binding behavior of receptor binding domain of the SARS-CoV-2 virus and ivermectin DOI Creative Commons

Kasidy R. Gossen,

Meiyi Zhang, Z̆ivko L. Nikolov

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Feb. 2, 2024

Abstract The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), sparked an international debate on effective ways to prevent and treat the virus. Specifically, there were many varying opinions use of ivermectin (IVM) throughout world, with minimal research support either side. IVM is FDA-approved antiparasitic drug that was discovered in 1970s found show antiviral activity. objective this study examine binding behavior rates association dissociation between SARS-CoV-2 receptor domain (RBD), IVM, their combination using aminopropylsilane (APS) biosensors as surrogates for hydrophobic interaction viral protein human angiotensin-converting enzyme (ACE2) receptors determine potential a repurposed prevention treatment. RBD, kinetics analyzed biolayer interferometry (BLI) validated multiple silico techniques including protein–ligand docking, molecular dynamics simulation, mechanics-generalized Born surface area (MM-GBSA), principal component analysis (PCA). Our results suggest increasing concentrations rate biosensor increases simultaneous decrease dissociation. Significant kinetic changes when combined only at concentration thousand times approved dosage over 35-min time period. suggests not preventative or treatment method currently dosage.

Language: Английский

Citations

2
Why Certain Repurposed Drugs Are Unlikely to Be Effective Antivirals to Treat SARS-CoV-2 Infections DOI Creative Commons

Selwyn J. Hurwitz,

Ramyani De, Julia C. LeCher

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(4), P. 651 - 651

Published: April 22, 2024

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential vivo efficacy. The 20 with highest ratios retested human Calu-3 Caco-2 cells, their CC50 was determined an expanded panel cell lines. Many inactive Antivirals controlled trials had Cmax/EC50 ≥ 6.8 or EC50 nucleoside analogs dependent. This approach earlier availability more relevant cultures could reduced number unwarranted trials.

Language: Английский

Citations

2