Explore the vast range of titles available.

Background and Objective Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d’Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. Methods Pharmacokinetic data from studies in Tanzania and Côte d’Ivoire in adolescents (aged 12–19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. Results Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate. Conclusions Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d‘Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted.

Our study in CDTI-naïve areas in Nord Kivu and Ituri (Democratic Republic of the Congo, DRC), Lofa County (Liberia) and Nkwanta district (Ghana) showed that a single 8 mg moxidectin dose reduced skin microfilariae density (microfilariae/mg skin, SmfD) better and for longer than a single 150μg/kg ivermectin dose. We now analysed efficacy by study area and pre-treatment SmfD (intensity of infection, IoI). Four and three IoI categories were defined for across-study and by-study area analyses, respectively. We used a general linear model to analyse SmfD 1, 6, 12 and 18 months post-treatment, a logistic model to determine the odds of undetectable SmfD from month 1 to month 6 (UD1-6), month 12 (UD1-12) and month 18 (UD1-18), and descriptive statistics to quantitate inter-interindividual response differences. Twelve months post-treatment, treatment differences (difference in adjusted geometric mean SmfD after moxidectin and ivermectin in percentage of the adjusted geometric mean SmfD after ivermectin treatment) were 92.9%, 90.1%, 86.8% and 84.5% in Nord Kivu, Ituri, Lofa and Nkwanta, and 74.1%, 84.2%, 90.0% and 95.4% for participants with SmfD 10-20, ≥20-<50, ≥50-<80, ≥80, respectively. Ivermectin's efficacy was lower in Ituri and Nkwanta than Nord Kivu and Lofa (p≤0.002) and moxidectin's efficacy lower in Nkwanta than Nord Kivu, Ituri and Lofa (p<0.006). Odds ratios for UD1-6, UD1-12 or UD1-18 after moxidectin versus ivermectin treatment exceeded 7.0. Suboptimal response (SmfD 12 months post-treatment >40% of pre-treatment SmfD) occurred in 0%, 0.3%, 1.6% and 3.9% of moxidectin and 12.1%, 23.7%, 10.8% and 28.0% of ivermectin treated participants in Nord Kivu, Ituri, Lofa and Nkwanta, respectively. The benefit of moxidectin vs ivermectin treatment increased with pre-treatment IoI. The possibility that parasite populations in different areas have different drug susceptibility without prior ivermectin selection pressure needs to be considered and further investigated. Registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

The increased incidence of dengue poses a substantially global public health challenge. There are no approved antiviral drugs to treat dengue infections. Ivermectin, an old anti‐parasitic drug, had no effect on dengue viremia, but reduced the dengue non‐structural protein 1 (NS1) in a clinical trial. This is potentially important, as NS1 may play a causal role in the pathogenesis of severe dengue. This study established an in‐host model to characterize the plasma kinetics of dengue virus and NS1 with host immunity and evaluated the effects of ivermectin, using a population pharmacokinetic–pharmacodynamic (PK–PD) modeling approach, based on two studies in acute dengue fever: a placebo‐controlled ivermectin study in 250 adult patients and an ivermectin PK–PD study in 24 pediatric patients. The proposed model described adequately the observed ivermectin pharmacokinetics, viral load, and NS1 data. Bodyweight was a significant covariate on ivermectin pharmacokinetics. We found that ivermectin reduced NS1 with an EC50 of 67.5 μg/mL. In silico simulations suggested that ivermectin should be dosed within 48 h after fever onset, and that a daily dosage of 800 μg/kg could achieve substantial NS1 reduction. The in‐host dengue model is useful to assess the drug effect in antiviral drug development for dengue fever.

Anopheles gambiae mosquitoes were fed on 25 volunteers randomized to receive ivermectin or nothing. In mosquitoes feeding on volunteers given ivermectin the previous day, mean survival was 2.3 days, compared with 5.5 days in the control group (P < .001, by log-lank test).Mosquitomortality was 73%, 84%, and 89% on days 2, 3, and 4 in the ivermectin group. In mosquitoes fed 14 days after treatment, no difference was found between groups. Ivermectin is safe and has significant short-term insecticidal properties. A systemic insecticide taken by humans could help to control malaria in areas where mosquitoes are exophagic or exophilic and drug resistance is an urgent threat.

Malaria elimination using current tools has stalled in many areas. Ivermectin (IVM) is a broad-antiparasitic drug and mosquitocide and has been proposed as a tool for accelerating progress towards malaria elimination. Under laboratory conditions, IVM has been shown to reduce the survival of adult Anopheles populations that have fed on IVM-treated mammals. Treating cattle with IVM has been proposed as an important contribution to malaria vector management, however, the impacts of IVM in this One Health use case have been untested in field trials in Southeast Asia. Through a randomized village-based trial, this study quantified the effect of IVM-treated cattle on anopheline populations in treated vs. untreated villages in Central Vietnam. Local zebu cattle in six rural villages were included in this study. In three villages, cattle were treated with IVM at established veterinary dosages, and in three additional villages cattle were left as untreated controls. For the main study outcome, the mosquito populations in all villages were sampled using cattle-baited traps for six nights before, and six nights after a 2-day IVM-administration (intervention) period. Anopheline species were characterized using taxonomic keys. The impact of the intervention was analyzed using a difference-in-differences (DID) approach with generalized estimating equations (with negative binomial distribution and robust errors). This intervention was powered to detect a 50% reduction in total nightly Anopheles spp. vector catches from cattle-baited traps. Given the unusual diversity in anopheline populations, exploratory analyses examined taxon-level differences in the ecological population diversity. Across the treated villages, 1,112 of 1,523 censused cows (73% overall; range 67% to 83%) were treated with IVM. In both control and treated villages, there was a 30% to 40% decrease in total anophelines captured in the post-intervention period as compared to the pre-intervention period. In the control villages, there were 1,873 captured pre-intervention and 1,079 captured during the post-intervention period. In the treated villages, there were 1,594 captured pre-intervention, and 1,101 captured during the post-intervention period. The difference in differences model analysis comparing total captures between arms was not statistically significant (p = 0.61). Secondary outcomes of vector population diversity found that in three villages (one control and two treatment) Brillouin's index increased, and in three villages (two control and one treatment) Brillouin's index decreased. When examining biodiversity by trapping-night, there were no clear trends in treated or untreated vector populations. Additionally, there were no clear trends when examining the components of biodiversity: richness and evenness. The ability of this study to quantify the impacts of IVM treatment was limited due to unexpectedly large spatiotemporal variability in trapping rates; an area-wide decrease in trapping counts across all six villages post-intervention; and potential spillover effects. However, this study provides important data to directly inform future studies in the GMS and beyond for IVM-based vector control.

Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. It is highly effective against many microorganisms including some viruses. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. Furthermore, there are some studies showing antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses. In vivo studies of animal models revealed a broad range of antiviral effects of ivermectin, however, clinical trials are necessary to appraise the potential efficacy of ivermectin in clinical setting.

Unchecked ivermectin use in the region is making it difficult to test the anti-parasite drug’s effectiveness against the coronavirus. Latin America’s embrace of unproven COVID treatment hinders drug trials Unchecked ivermectin use in region is making it difficult to test anti-parasite drug’s effectiveness against the coronavirus.

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain ‘wrist’ interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors. A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state. Glycine receptor mechanism Eric Gouaux and colleagues have determined the high-resolution electron cryo-microscopy structure of strychnine-sensitive glycine receptor (GlyR) from zebrafish, bound to agonists or antagonists to reveal the conformational changes that take place when the channel opens. GlyRs mediate neurotransmission throughout the spinal cord and brainstem and their dysfunction is linked to multiple neurological disorders, including autism and hyperekplexia. Also in this issue of Nature , Xin Huang et al . report the X-ray crystal structure of the human GlyR in the presence of the antagonist strychnine.

Over the past decade, the global scientific community have begun to recognize the unmatched value of an extraordinary drug, ivermectin, that originates from a single microbe unearthed from soil in Japan. Work on ivermectin has seen its discoverer, Satoshi Ōmura, of Tokyo’s prestigious Kitasato Institute, receive the 2014 Gairdner Global Health Award and the 2015 Nobel Prize in Physiology or Medicine, which he shared with a collaborating partner in the discovery and development of the drug, William Campbell of Merck & Co. Incorporated. Today, ivermectin is continuing to surprise and excite scientists, offering more and more promise to help improve global public health by treating a diverse range of diseases, with its unexpected potential as an antibacterial, antiviral and anti-cancer agent being particularly extraordinary.

AbstractUpdatesThis is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity.ObjectiveTo determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).DesignLiving systematic review and network meta-analysis (NMA).Data sourcesWHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022.Study selectionRandomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.MethodsAfter duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.ResultsThe second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation—risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence.ConclusionMuch of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects.Systematic review registrationThis review was not registered. The protocol established a priori is included as a supplement.FundingThis study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).