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EBioMedicine Nov 2023Ivermectin's mosquitocidal effect and in vitro activity against Plasmodium falciparum asexual stages are known. Its in vivo blood-schizonticidal efficacy is unknown.... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic male and female Gabonese adults - a pilot randomized, double-blind, placebo-controlled single-centre phase Ib/IIa clinical trial.
BACKGROUND
Ivermectin's mosquitocidal effect and in vitro activity against Plasmodium falciparum asexual stages are known. Its in vivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P. falciparum infections in Gabonese adults were assessed.
METHODS
The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P. falciparum parasitaemia (200-5000 parasites/μl) were enrolled. First, three groups of five participants received 200 μg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300 μg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051).
FINDINGS
Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0 h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]).
INTERPRETATION
Ivermectin was well tolerated in doses up to 300 μg/kg once daily for three days and asymptomatic P. falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples.
FUNDING
This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.
Topics: Adult; Female; Humans; Male; Antimalarials; Double-Blind Method; Ivermectin; Malaria, Falciparum; Pilot Projects; Plasmodium falciparum
PubMed: 37839134
DOI: 10.1016/j.ebiom.2023.104814 -
International Journal For Parasitology.... Apr 2024As etiological agents of malaria disease, Plasmodium spp. parasites are responsible for one of the most severe global health problems occurring in tropical regions of... (Review)
Review
As etiological agents of malaria disease, Plasmodium spp. parasites are responsible for one of the most severe global health problems occurring in tropical regions of the world. This work involved compiling marine cyanobacteria metabolites reported in the scientific literature that exhibit antiplasmodial activity. Out of the 111 compounds mined and 106 tested, two showed antiplasmodial activity at very low concentrations, with IC at 0.1 and 1.5 nM (peptides: dolastatin 10 and lyngbyabellin A, 1.9% of total tested). Examples of chemical derivatives generated from natural cyanobacterial compounds to enhance antiplasmodial activity and Plasmodium selectivity can be found in successful findings from nostocarboline, eudistomin, and carmaphycin derivatives, while bastimolide derivatives have not yet been found. Overall, 57% of the reviewed compounds are peptides with modified residues producing interesting active moieties, such as α- and β-epoxyketone in camaphycins. The remaining compounds belong to diverse chemical groups such as alkaloids, macrolides, polycyclic compounds, and halogenated compounds. The Dolastatin 10 and lyngbyabellin A, compounds with antiplasmodial high activity, are cytoskeletal disruptors with different protein targets.
Topics: Humans; Antimalarials; Plasmodium falciparum; Malaria; Alkaloids; Cyanobacteria; Plant Extracts
PubMed: 38447332
DOI: 10.1016/j.ijpddr.2024.100530 -
PloS One 2023Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying...
Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa.
Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.
Topics: Animals; Humans; Plasmodium falciparum; Antimalarials; Atovaquone; Folic Acid Antagonists; Malaria, Falciparum; Africa, Western
PubMed: 37494413
DOI: 10.1371/journal.pone.0284751 -
Frontiers in Cellular and Infection... 2023Over the last two decades, global malaria cases caused by have declined due to the implementation of effective treatments and the use of insecticides. However, the... (Review)
Review
Over the last two decades, global malaria cases caused by have declined due to the implementation of effective treatments and the use of insecticides. However, the COVID-19 pandemic caused major disruption in the timely delivery of medical goods and diverted public health resources, impairing malaria control. The emergence of resistance to all existing frontline antimalarials underpins an urgent need for new antimalarials with novel mechanisms of action. Furthermore, the need to reduce malaria transmission and/or prevent malaria infection has shifted the focus of antimalarial research towards the discovery of compounds that act beyond the symptomatic blood stage and also impact other parasite life cycle stages. Phenotypic screening has been responsible for the majority of new antimalarial lead compounds discovered over the past 10 years. This review describes recently reported novel antimalarial hits that target multiple parasite stages and were discovered by phenotypic screening during the COVID-19 pandemic. Their modes of action and targets in blood stage parasites are also discussed.
Topics: Humans; Antimalarials; Pandemics; Malaria; Plasmodium falciparum; COVID-19
PubMed: 38162576
DOI: 10.3389/fcimb.2023.1308193 -
Pathogens and Global Health Sep 2023Despite advances in modern human and veterinary medicine, gastrointestinal (GI) parasitic infections remain a significant health issue worldwide, mainly in developing...
Despite advances in modern human and veterinary medicine, gastrointestinal (GI) parasitic infections remain a significant health issue worldwide, mainly in developing countries. Increasing evidence of the multi-drug resistance of these parasites and the side effects of currently available synthetic drugs have led to increased research on alternative medicines to treat parasitic infections. The exploration of potential botanical antiparasitics, which are inexpensive and abundant, may be a promising alternative in this context. This study summarizes the / antiparasitic efficacy of different medicinal plants and their components against GI parasites. Published literature from 1990-2020 was retrieved from Google Scholar, Web of Science, PubMed and Scopus. A total of 68 plant species belonging to 32 families have been evaluated as antiparasitic agents against GI parasites worldwide. The majority of studies (70%) were conducted . Most plants were from the Fabaceae family (53%, = 18). Methanol (37%, = 35) was the most used solvent. Leaf (22%, = 16) was the most used plant part, followed by seed and rhizome (each 12%, = 9). These studies suggest that herbal medicines hold a great scope for new drug discoveries against parasitic diseases and that the derivatives of these plants are useful structures for drug synthesis and bioactivity optimization.
Topics: Humans; Plants, Medicinal; Antiparasitic Agents; Parasitic Diseases; Phytotherapy
PubMed: 36805662
DOI: 10.1080/20477724.2023.2179454 -
Antimicrobial Agents and Chemotherapy Jul 2023The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new...
The increasing burden and spread of resistant malaria parasites remains an immense burden to public health. These factors have driven the demand to search for a new therapeutic agent. From our screening, phebestin stood out with nanomolar efficacy against Plasmodium falciparum 3D7. Phebestin was initially identified as an aminopeptidase N inhibitor. Phebestin inhibited the multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains at IC values of 157.90 ± 6.26 nM and 268.17 ± 67.59 nM, respectively. Furthermore, phebestin exhibited no cytotoxic against human foreskin fibroblast cells at 2.5 mM. In the stage-specific assay, phebestin inhibited all parasite stages at 100 and 10-fold its IC concentration. Using 72-h exposure of phebestin at concentrations of 1 μM on P. falciparum 3D7 distorted the parasite morphology, showed dying signs, shrank, and prevented reinvasion of RBCs, even after the compound was washed from the culture. An study found that phebestin binds to P. falciparum M1 alanyl aminopeptidase (PfM1AAP) and M17 leucyl aminopeptidase (PfM17LAP), as observed for bestatin. evaluation using P. yoelii 17XNL-infected mice with administrations of 20 mg/kg phebestin, once daily for 7 days, resulted in significantly lower parasitemia peaks in the phebestin-treated group (19.53%) than in the untreated group (29.55%). At the same dose and treatment, P. berghei ANKA-infected mice showed reduced parasitemia levels and improved survival compared to untreated mice. These results indicate that phebestin is a promising candidate for development as a potential therapeutic agent against malaria.
Topics: Humans; Animals; Mice; Antimalarials; Aminopeptidases; Parasitemia; Chloroquine; Malaria; Malaria, Falciparum; Plasmodium falciparum; Plasmodium berghei
PubMed: 37314349
DOI: 10.1128/aac.01606-22 -
Global Health Action Dec 2023Malaria during pregnancy is a major global health concern, with approximately 10,000 pregnant women dying from malaria-related anaemia each year. The World Health...
Malaria during pregnancy is a major global health concern, with approximately 10,000 pregnant women dying from malaria-related anaemia each year. The World Health Organization has suggested intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) to avert malaria infection in pregnant women in malaria-endemic areas, but this intermittent preventive (IP) treatment is at risk of becoming ineffective due to parasite resistance and the contraindication in HIV-infected women. This paper argues that alternative IP treatments such as dihydroartemisinin-piperaquine (DP) should be explored, alongside the urgent need to investigate antimalarial cycling strategies. Additionally, the cost-effectiveness of IPTp-DP should be evaluated, as well as potential barriers to IP treatment such as medication stockouts, late attendance at antenatal clinics, lack of autonomy and freedom among women, and lack of knowledge about malaria prevention. Health education focusing on malaria prevention should be incorporated into routine antenatal care programmes to improve patient compliance. A comprehensive approach that includes the administration of IPTp-DP alone along with other measures such as insecticide-treated nets and medical education is the key to addressing the devastating effects of malaria infection in pregnant women.
Topics: Female; Pregnancy; Humans; Pregnant Women; Cost-Benefit Analysis; Antimalarials; Malaria
PubMed: 37459385
DOI: 10.1080/16549716.2023.2231257 -
Parasites & Vectors Jul 2023The American Heartworm Society canine guidelines recommend treatment with doxycycline prior to adulticide administration to reduce levels of Wolbachia and its associated...
BACKGROUND
The American Heartworm Society canine guidelines recommend treatment with doxycycline prior to adulticide administration to reduce levels of Wolbachia and its associated metabolites, which are known to be a leading cause of pulmonary pathology. Studies have determined that doxycycline administered at 10 mg/kg BID for 28 days is an effective dose for eliminating Wolbachia, but what has not been determined is the clinical relevance of this elimination. The current guidelines also recommend a 30-day wait period following administration of doxycycline to allow for clearance of metabolites, such as Wolbachia surface protein, and for further reduction in heartworm biomass before administration of adulticide. Reducing the doxycycline dose and eliminating the wait period may carry practical benefits for the animal, client, and practitioner.
METHODS
To investigate these treatment practices, Dirofilaria immitis adults were surgically transplanted into each of 45 dogs, which were divided into nine study groups of five dogs each. Seventy-five days after transplantation, two groups each were administered 5, 7.5, or 10 mg/kg BID doxycycline orally for 28 days and 6 µg/kg ivermectin monthly, with three untreated groups serving as controls. Study animals were necropsied and examined prior to treatment as well as 30 and 60 days post-treatment.
RESULTS
Mean worm weight was unaffected by dosage but exhibited a significant increase at 30 days and significant decrease at 60 days post-treatment, including in control groups. Histopathology lesion scores did not significantly differ among groups, with the exception of the lung composite score for one untreated group. Liver enzymes, the levels of which are a concern in doxycycline treatment, were also examined, with no abnormalities in alanine aminotransferase or alkaline phosphatase observed.
CONCLUSIONS
No consistent worsening of tissue lesions was observed with or without the AHS-recommended 30-day wait period, nor did reduced dosages of doxycycline lead to worsening of pathology or any change in efficacy in depleting worm weight. Mean worm weight did significantly increase prior to, and decrease following, the wait period. Future work that also includes adulticide treatment (i.e. melarsomine) will study treatment recommendations that may improve both animal health and owner compliance.
Topics: Animals; Dogs; Dirofilaria immitis; Doxycycline; Dirofilariasis; Filaricides; Dog Diseases; Wolbachia
PubMed: 37491306
DOI: 10.1186/s13071-023-05858-2 -
Parasitology Jan 2024Leishmaniasis is a vector-borne parasitic disease caused by parasites with a spectrum of clinical manifestations, ranging from skin lesions to severe visceral... (Review)
Review
Leishmaniasis is a vector-borne parasitic disease caused by parasites with a spectrum of clinical manifestations, ranging from skin lesions to severe visceral complications. Treatment of this infection has been extremely challenging with the concurrent emergence of drug resistance. The differential gene expression and the discrepancies in protein functions contribute to the appearance of 2 distinct phenotypes: resistant and sensitive, but the current diagnostic tools fail to differentiate between them. The identification of gene expression patterns and molecular mechanisms coupled with antimony (Sb) resistance can be leveraged to prompt diagnosis and select the most effective treatment methods. The present study attempts to use comparative expression of Sb resistance-associated genes in resistant and sensitive , to disclose their relative abundance in clinical or selected isolates to gain an understanding of the molecular mechanisms of Sb response/resistance. Data suggest that the analysis of resistance gene expression would verify the Sb resistance or susceptibility only to a certain extent; however, none of the individual expression patterns of the studied genes was diagnostic as a biomarker of Sb response of . The findings highlighted will be useful in bridging the knowledge gap and discovering innovative diagnostic tools and novel therapeutic targets.
Topics: Leishmania; Antimony; Proteomics; Antiprotozoal Agents; Drug Resistance; Gene Expression
PubMed: 38012864
DOI: 10.1017/S0031182023001129 -
Biomedicine & Pharmacotherapy =... Aug 2023Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world health problem. The harsh reality of these infective diseases is the...
Leishmaniasis and Chagas disease, two of the most prevalent neglected tropical diseases, are a world health problem. The harsh reality of these infective diseases is the absence of effective and safe therapies. In this framework, natural products play an important role in overcoming the current need to development new antiparasitic agents. The present study reports the synthesis, antikinetoplastid screening, mechanism study of fourteen withaferin A derivatives (2-15). Nine of them (2-6, 8-10 and 12) showed a potent dose-dependent inhibitory effect on the proliferation of Leishmania amazonensis and L. donovani promastigotes and Trypanosoma cruzi epimastigotes with IC values ranging from 0.19 to 24.01 µM. Outstandingly, the fully acetylated derivative 10 (4,27-diacetylwithaferin A) was the most potent compound showing IC values of 0.36, 2.82 and 0.19 µM against L. amazonensis, L. donovani and T. cruzi, respectively. Furthermore, analogue 10 exhibited approximately 18 and 36-fold greater antikinetoplastid activity, on L. amazonensis and T. cruzi, than the reference drugs. The activity was accompanied by significantly lower cytotoxicity on the murine macrophage cell line. Moreover, compounds 2, 3, 5-7, 9 and 10 showed more potent activity than the reference drug against the intracellular amastigotes forms of L. amazonensis and T.cruzi, with a good selectivity index on a mammalian cell line. In addition, withaferin A analogues 3, 5-7, 9 and 10 induce programmed cell death through a process of apoptosis-like and autophagy. These results strengthen the anti-parasitic potential of withaferin A-related steroids against neglected tropical diseases caused by Leishmania spp. and T. cruzi parasites.
Topics: Animals; Mice; Antiprotozoal Agents; Parasitic Sensitivity Tests; Leishmania; Chagas Disease; Apoptosis; Mammals
PubMed: 37210899
DOI: 10.1016/j.biopha.2023.114879