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PLoS Neglected Tropical Diseases Jan 2024Lymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted by the World Health Organization for elimination as a public health problem (EPHP). Since 2000,...
BACKGROUND
Lymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted by the World Health Organization for elimination as a public health problem (EPHP). Since 2000, more than 9 billion treatments of antifilarial medicines have been distributed through mass drug administration (MDA) programmes in 72 endemic countries and 17 countries have reached EPHP. Yet in 2021, nearly 900 million people still required MDA with combinations of albendazole, diethylcarbamazine and/or ivermectin. Despite the reliance on these drugs, there remain gaps in understanding of variation in responses to treatment. As demonstrated for other infectious diseases, some urgent questions could be addressed by conducting individual participant data (IPD) meta-analyses. Here, we present the results of a systematic literature review to estimate the abundance of IPD on pre- and post-intervention indicators of infection and/or morbidity and assess the feasibility of building a global data repository.
METHODOLOGY
We searched literature published between 1st January 2000 and 5th May 2023 in 15 databases to identify prospective studies assessing LF treatment and/or morbidity management and disease prevention (MMDP) approaches. We considered only studies where individual participants were diagnosed with LF infection or disease and were followed up on at least one occasion after receiving an intervention/treatment.
PRINCIPAL FINDINGS
We identified 138 eligible studies from 23 countries, having followed up an estimated 29,842 participants after intervention. We estimate 14,800 (49.6%) IPD on pre- and post-intervention infection indicators including microfilaraemia, circulating filarial antigen and/or ultrasound indicators measured before and after intervention using 8 drugs administered in various combinations. We identified 33 studies on MMDP, estimating 6,102 (20.4%) IPD on pre- and post-intervention clinical morbidity indicators only. A further 8,940 IPD cover a mixture of infection and morbidity outcomes measured with other diagnostics, from participants followed for adverse event outcomes only or recruited after initial intervention.
CONCLUSIONS
The LF treatment study landscape is heterogeneous, but the abundance of studies and related IPD suggest that establishing a global data repository to facilitate IPD meta-analyses would be feasible and useful to address unresolved questions on variation in treatment outcomes across geographies, demographics and in underrepresented groups. New studies using more standardized approaches should be initiated to address the scarcity and inconsistency of data on morbidity management.
Topics: Humans; Elephantiasis, Filarial; Prospective Studies; Filaricides; Diethylcarbamazine; Albendazole; Ivermectin
PubMed: 38227595
DOI: 10.1371/journal.pntd.0011882 -
Fundamental & Clinical Pharmacology Jun 2024Benzothiazole derivatives have been reported to possess a wide range of biological activities, including antimalarial activity. This systematic review aims to summarize... (Review)
Review
BACKGROUND
Benzothiazole derivatives have been reported to possess a wide range of biological activities, including antimalarial activity. This systematic review aims to summarize and evaluate the antimalarial activities of benzothiazole analogs.
METHODS
We conducted an electronic search using nine databases in October 2017 and subsequently updated in September 2022. We included all original in vitro and in vivo studies that documented the antimalarial activities of compounds containing benzothiazole analogs with no restriction. The risk of bias of each included study was assessed by ToxRTool.
RESULTS
Twenty-eight articles were included in our study, which are in vitro, in vivo, or both. Of these, 232 substances were identified to have potent antiplasmodial activity against various strains of the malaria parasite. Benzothiazole analogs show different antimalarial mechanisms, including inhibition of Plasmodium falciparum enzymes in in vitro studies and inhibition of blood parasites in in vivo studies.
CONCLUSIONS
Benzothiazole derivatives are promising substances for treating malaria. The structure-activity relationship studies suggest that the substitution pattern of the benzothiazole scaffold plays a crucial role in determining the antimalarial activity of the analog.
Topics: Antimalarials; Benzothiazoles; Plasmodium falciparum; Humans; Structure-Activity Relationship; Animals; Malaria
PubMed: 38146774
DOI: 10.1111/fcp.12974 -
Bioorganic Chemistry Feb 2024The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary,... (Review)
Review
The increasing resistance of various malarial parasite strains to drugs has made the production of a new, rapid-acting, and efficient antimalarial drug more necessary, as the demand for such drugs is growing rapidly. As a major global health concern, various methods have been implemented to address the problem of drug resistance, including the hybrid drug concept, combination therapy, the development of analogues of existing medicines, and the use of drug resistance reversal agents. Artemisinin and its derivatives are currently used against multidrug- resistant P. falciparum species. However, due to its natural origin, its use has been limited by its scarcity in natural resources. As a result, finding a substitute becomes more crucial, and the peroxide group in artemisinin, responsible for the drugs biological action in the form of 1,2,4-trioxane, may hold the key to resolving this issue. The literature suggests that 1,2,4-trioxanes have the potential to become an alternative to current malaria drugs, as highlighted in this review. This is why 1,2,4-trioxanes and their derivatives have been synthesized on a large scale worldwide, as they have shown promising antimalarial activity in vivo and in vitro against Plasmodium species. Consequently, the search for a more convenient, environment friendly, sustainable, efficient, and effective synthetic pathway for the synthesis of 1,2,4-trioxanes continues. The aim of this work is to provide a comprehensive analysis of the synthesis and mechanism of action of 1,2,4-trioxanes. This systematic review highlights the most recent summaries of derivatives of 1,2,4-trioxane compounds and dimers with potential antimalarial activity from January 1988 to 2023.
Topics: Antimalarials; Artemisinins; Heterocyclic Compounds; Plasmodium falciparum
PubMed: 38134523
DOI: 10.1016/j.bioorg.2023.107043 -
BMJ Global Health Dec 2023The optimal dosing of primaquine to prevent relapsing malaria in South Asia remains unclear. We investigated the efficacy and safety of different primaquine regimens to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The optimal dosing of primaquine to prevent relapsing malaria in South Asia remains unclear. We investigated the efficacy and safety of different primaquine regimens to prevent relapse.
METHODS
A systematic review identified efficacy studies from South Asia published between 1 January 2000 and 23 August 2021. In a one-stage meta-analysis of available individual patient data, the cumulative risks of recurrence at day 42 and 180 were assessed by primaquine total mg/kg dose and duration. The risk of recurrence by day 180 was also determined in a two-stage meta-analysis. Patients with a >25% drop in haemoglobin to <70 g/L, or an absolute drop of >50 g/L between days 1 and 14 were categorised by daily mg/kg primaquine dose.
RESULTS
In 791 patients from 7 studies in the one-stage meta-analysis, the day 180 cumulative risk of recurrence was 61.1% (95% CI 42.2% to 80.4%; 201 patients; 25 recurrences) after treatment without primaquine, 28.8% (95% CI 8.2% to 74.1%; 398 patients; 4 recurrences) following low total (2 to <5 mg/kg) and 0% (96 patients; 0 recurrences) following high total dose primaquine (≥5 mg/kg). In the subsequent two-stage meta-analysis of nine studies (3529 patients), the pooled proportions of recurrences by day 180 were 12.1% (95% CI 7.7% to 17.2%), 2.3% (95% CI 0.3% to 5.4%) and 0.7% (95% CI 0% to 6.1%), respectively. No patients had a >25% drop in haemoglobin to <70 g/L.
CONCLUSIONS
Primaquine treatment led to a marked decrease in recurrences following low (~3.5 mg/kg) and high (~7 mg/kg) total doses, with no reported severe haemolytic events.
PROSPERO REGISTRATION NUMBER
CRD42022313730.
Topics: Humans; Primaquine; Malaria, Vivax; Antimalarials; Plasmodium vivax; Recurrence; Asia, Southern; Hemoglobins
PubMed: 38123228
DOI: 10.1136/bmjgh-2023-012675 -
The American Journal of Tropical... Apr 2024Malaria remains a significant cause of morbidity and mortality, even in low-transmission settings. With the advent of longer acting, more effective, and well-tolerated... (Meta-Analysis)
Meta-Analysis
Malaria remains a significant cause of morbidity and mortality, even in low-transmission settings. With the advent of longer acting, more effective, and well-tolerated antimalarials, there is renewed interest in the efficacy of mass drug administration (MDA) to accelerate to elimination. We conducted a systematic review and meta-analysis to assess the efficacy of MDA to reduce the incidence and prevalence of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) infection. From 1,044 articles screened, 14 articles, including 10 randomized controlled trials (RCTs), were identified. Five included data on Pf only; five included Pf and Pv. Two of the Pf studies were conducted in areas of high-moderate transmission, the remainder were in areas of low-very low transmission. In higher transmission areas, MDA reduced incidence of Pf parasitemia (rate ratio = 0.61, 95% CI: 0.40-0.92; moderate certainty) 1 to 3 months after drug administration; no significant effect of MDA on Pf parasitemia prevalence was detected 1 to 3 months post-MDA (risk ratio [RR] = 1.76, 95% CI: 0.58-5.36; low certainty). In lower transmission settings, both incidence and prevalence of Pf parasitemia were reduced 1 to 3 months post-MDA (rate ratio = 0.37, 95% CI: 0.21-0.66; RR = 0.25, 95% CI: 0.15-0.41, respectively). Pv prevalence was reduced 1 to 3 months post-MDA (RR = 0.15, 95% CI: 0.10-0.24); there were no RCTs providing data on incidence of Pv. There was no significant effect of MDA at later time points. MDA may have short-term benefits; however, there was no evidence for longer term impact, although none of the trials assessed prolonged interventions.
Topics: Humans; Mass Drug Administration; Parasitemia; Antimalarials; Malaria; Malaria, Vivax; Plasmodium falciparum
PubMed: 38118174
DOI: 10.4269/ajtmh.22-0766 -
The American Journal of Tropical... Apr 2024Several temperate countries have used mass chemoprevention interventions with medicines of the 8-aminoquinoline class that prevent relapses from Plasmodium vivax before...
Several temperate countries have used mass chemoprevention interventions with medicines of the 8-aminoquinoline class that prevent relapses from Plasmodium vivax before peak transmission to reduce transmission of malaria. The WHO commissioned a systematic review of the literature and evidence synthesis to inform development of recommendations regarding this intervention referred to as "mass relapse prevention" (MRP). Electronic databases were searched, 866 articles screened, and 25 assessed for eligibility after a full-text review. Two nonrandomized studies were included, one from the Democratic People's Republic of Korea (391,357 participants) and the second from the Azerbaijan Soviet Socialist Republic (∼30,000 participants). The two studies administered a single round of primaquine over 14 days (0.25 mg/kg per day). From 1 to 3 months after the treatment round, the incidence of P. vivax infections was significantly lower in areas that received MRP than those that did not (pooled rate ratio [RR] 0.08, 95% CI 0.07-0.08). At 4 to 12 months after the treatment round, the prevalence of P. vivax infection was significantly lower in MRP villages than non-MRP villages (odds ratio 0.12, 95% CI 0.03-0.52). No severe adverse events were found. The certainty of evidence for all outcomes was very low and no conclusions as to the effectiveness or safety of MRP could be drawn. However, it is not likely that this intervention will be needed in the future as most temperate countries where P. vivax is transmitted are nearing or have already eliminated malaria.
Topics: Humans; Antimalarials; Plasmodium vivax; Secondary Prevention; Primaquine; Malaria, Vivax; Recurrence
PubMed: 38118171
DOI: 10.4269/ajtmh.22-0727 -
The American Journal of Tropical... Apr 2024Many countries pursuing malaria elimination implement "reactive" strategies targeting household members and neighbors of index cases to reduce transmission. These... (Meta-Analysis)
Meta-Analysis
Many countries pursuing malaria elimination implement "reactive" strategies targeting household members and neighbors of index cases to reduce transmission. These strategies include reactive case detection and treatment (RACDT; testing and treating those positive) and reactive drug administration (RDA; providing antimalarials without testing). We conducted systematic reviews of RACDT and RDA to assess their effect on reducing malaria transmission and gathered evidence about key contextual factors important to their implementation. Two reviewers screened titles/abstracts and full-text records using defined criteria (Patient = those in malaria-endemic/receptive areas; Intervention = RACDT or RDA; Comparison = standard of care; Outcome = malaria incidence/prevalence) and abstracted data for meta-analyses. The Grading of Recommendations, Assessment, Development, and Evaluations approach was used to rate certainty of evidence (CoE) for each outcome. Of 1,460 records screened, reviewers identified five RACDT studies (three cluster-randomized controlled trials [cRCTs] and two nonrandomized studies [NRS]) and seven RDA studies (six cRCTs and one NRS); three cRCTs comparing RDA to RACDT were included in both reviews. Compared with RDA, RACDT was associated with nonsignificantly higher parasite prevalence (odds ratio [OR] = 1.85; 95% CI: 0.96-3.57; one study) and malaria incidence (rate ratio [RR] = 1.30; 95% CI: 0.94-1.79; three studies), both very low CoE. Compared with control or RACDT, RDA was associated with non-significantly lower parasite incidence (RR = 0.73; 95% CI: 0.36-1.47; 2 studies, moderate CoE), prevalence (OR = 0.78; 95% CI: 0.52-1.17; 4 studies, low CoE), and malaria incidence (RR = 0.93; 95% CI: 0.82-1.05; six studies, moderate CoE). Evidence for reactive strategies' impact on malaria transmission is limited, especially for RACDT, but suggests RDA might be more effective.
Topics: Humans; Malaria; Antimalarials; Incidence; Prevalence
PubMed: 38118166
DOI: 10.4269/ajtmh.22-0720 -
Biomedicine & Pharmacotherapy =... Jan 2024Development of therapeutic agents that have fewer adverse effects and have higher efficacy for diseases, such as cancer, metabolic disorders, neurological diseases,... (Review)
Review
Development of therapeutic agents that have fewer adverse effects and have higher efficacy for diseases, such as cancer, metabolic disorders, neurological diseases, infections, cardiovascular diseases, and respiratory diseases, are required. Recent studies have focused on identifying novel sources for pharmaceutical molecules to develop therapies against these diseases. Among the sources for potentially new therapies, animal venom-derived molecules have generated much interest. Various animal venom-derived proteins and peptides have been isolated, identified, synthesized, and tested to develop drugs. Venom-derived peptides have several biomedical properties, such as proapoptotic, cell migration, and autophagy regulation activities in cancer cell models; induction of vasodilation by nitric oxide and regulation of angiotensin II; modification of insulin response by controlling calcium and potassium channels; regulation of pain receptor activity; modulation of immune cell activity; alteration of motor neuron activity; degradation or inhibition of β-amyloid plaque formation; antibacterial, antifungal, antiviral, and antiprotozoal activities; increase in sperm motility and potentiation of erectile function; reduction of intraocular pressure; anticoagulation, fibrinolytic, and antithrombotic activities; etc. This systematic review compiles these biomedical properties and potential biomedical applications of synthesized animal venom-derived peptides reported in the latest research. In addition, the limitations and areas of opportunity in this research field are discussed so that new studies can be developed based on the data presented.
Topics: Animals; Male; Venoms; Sperm Motility; Peptides; Angiotensin II
PubMed: 38113629
DOI: 10.1016/j.biopha.2023.116015 -
BMC Infectious Diseases Dec 2023Scrub typhus is a bacterial mite-borne disease associated with poor clinical outcomes if not treated adequately. The study aimed to compare the time to defervescence,... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Scrub typhus is a bacterial mite-borne disease associated with poor clinical outcomes if not treated adequately. The study aimed to compare the time to defervescence, clinical failure, mortality and treatment-related adverse effects of two common drugs (doxycycline and azithromycin) used for its treatment.
METHODOLOGY
This was a systematic review and meta-analysis. All studies up to 20.03.2023 were screened for eligibility in Pubmed and Embase using a search string containing terms related to scrub typhus, doxycycline and azithromycin. After two phases of screening, all comparative studies where doxycycline and azithromycin were used to treat scrub typhus were included. The studies were critically appraised using standardised tools, and a meta-analysis was performed for time to defervescence (primary outcome), clinical failure, mortality and treatment-related adverse effects.
RESULTS
Of 744 articles from two databases, ten were included in the meta-analysis. All but two studies had a high risk of bias. The meta-analysis for time to defervescence had a high heterogeneity and did not show any significant difference between doxycycline and azithromycin arms [Mean difference of -3.37 hours (95%CI: -10.31 to 3.57), p=0.34]. When the analysis was restricted to studies that included only severe scrub typhus, doxycycline was found to have a shorter time to defervescence [mean difference of -10.15 (95%CI: -19.83 to -0.46) hours, p=0.04]. Additionally, there was no difference between the two arms concerning clinical failure, mortality and treatment-related adverse effects.
CONCLUSION
The current data from studies with a high risk of bias did not find statistically significant differences in clinical outcomes between doxycycline and azithromycin for scrub typhus.
Topics: Humans; Azithromycin; Doxycycline; Anti-Bacterial Agents; Scrub Typhus; Patients; Drug-Related Side Effects and Adverse Reactions
PubMed: 38110855
DOI: 10.1186/s12879-023-08893-7 -
The Lancet. Global Health Jan 2024Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality... (Meta-Analysis)
Meta-Analysis
Post-discharge malaria chemoprevention in children admitted with severe anaemia in malaria-endemic settings in Africa: a systematic review and individual patient data meta-analysis of randomised controlled trials.
BACKGROUND
Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also have an increased risk of mortality or readmission after hospital discharge. We conducted a systematic review and individual patient data meta-analysis to determine the efficacy of monthly post-discharge malaria chemoprevention in children recovering from severe anaemia.
METHODS
This analysis was conducted according to PRISMA-IPD guidelines. We searched multiple databases on Aug 28, 2023, without date or language restrictions, for randomised controlled trials comparing monthly post-discharge malaria chemoprevention with placebo or standard of care among children (aged <15 years) admitted with severe anaemia in malaria-endemic Africa. Trials using daily or weekly malaria prophylaxis were not eligible. The investigators from all eligible trials shared pseudonymised datasets, which were standardised and merged for analysis. The primary outcome was all-cause mortality during the intervention period. Analyses were performed in the modified intention-to-treat population, including all randomly assigned participants who contributed to the endpoint. Fixed-effects two-stage meta-analysis of risk ratios (RRs) was used to generate pooled effect estimates for mortality. Recurrent time-to-event data (readmissions or clinic visits) were analysed using one-stage mixed-effects Prentice-Williams-Peterson total-time models to obtain hazard ratios (HRs). This study is registered with PROSPERO, CRD42022308791.
FINDINGS
Our search identified 91 articles, of which 78 were excluded by title and abstract, and a further ten did not meet eligibility criteria. Three double-blind, placebo-controlled trials, including 3663 children with severe anaemia, were included in the systematic review and meta-analysis; 3507 (95·7%) contributed to the modified intention-to-treat analysis. Participants received monthly sulfadoxine-pyrimethamine until the end of the malaria transmission season (mean 3·1 courses per child [range 1-6]; n=1085; The Gambia), monthly artemether-lumefantrine given at the end of weeks 4 and 8 post discharge (n=1373; Malawi), or monthly dihydroartemisinin-piperaquine given at the end of weeks 2, 6, and 10 post discharge (n=1049; Uganda and Kenya). During the intervention period, post-discharge malaria chemoprevention was associated with a 77% reduction in mortality (RR 0·23 [95% CI 0·08-0·70], p=0·0094, I=0%) and a 55% reduction in all-cause readmissions (HR 0·45 [95% CI 0·36-0·56], p<0·0001) compared with placebo. The protective effect was restricted to the intervention period and was not sustained after the direct pharmacodynamic effect of the drugs had waned. The small number of trials limited our ability to assess heterogeneity, its sources, and publication bias.
INTERPRETATION
In malaria-endemic Africa, post-discharge malaria chemoprevention reduces mortality and readmissions in recently discharged children recovering from severe anaemia. Post-discharge malaria chemoprevention could be a valuable strategy for the management of this group at high risk. Future research should focus on methods of delivery, options to prolong the protection duration, other hospitalised groups at high risk, and interventions targeting non-malarial causes of post-discharge morbidity.
FUNDING
The Research-Council of Norway and the Bill-&-Melinda-Gates-Foundation through the Worldwide-Antimalarial-Research-Network.
Topics: Child; Humans; Child, Preschool; Antimalarials; Patient Discharge; Aftercare; Artemether; Artemether, Lumefantrine Drug Combination; Malaria; Anemia; Drug Combinations; Kenya; Chemoprevention; Randomized Controlled Trials as Topic
PubMed: 38097295
DOI: 10.1016/S2214-109X(23)00492-8