Effect Of Moxidectin Research Articles

Can mass drug administration of moxidectin accelerate onchocerciasis elimination in Africa?

Epidemiological and modelling studies suggest that elimination of Onchocerca volvulus transmission (EoT) throughout Africa may not be achievable with annual mass drug administration (MDA) of ivermectin alone, particularly in areas of high endemicity and vector density. Single-dose Phase II and III clinical trials demonstrated moxidectin's superiority over ivermectin for prolonged clearance of O. volvulus microfilariae. We used the stochastic, individual-based EPIONCHO-IBM model to compare the probabilities of reaching EoT between ivermectin and moxidectin MDA for a range of endemicity levels (30 to 70% baseline microfilarial prevalence), treatment frequencies (annual and biannual) and therapeutic coverage/adherence values (65 and 80% of total population, with, respectively, 5 and 1% of systematic non-adherence). EPIONCHO-IBM's projections indicate that biannual (six-monthly) moxidectin MDA can reduce by half the number of years necessary to achieve EoT in mesoendemic areas and might be the only strategy that can achieve EoT in hyperendemic areas. Data needed to improve modelling projections include (i) the effect of repeated annual and biannual moxidectin treatment; (ii) inter- and intra-individual variation in response to successive treatments with moxidectin or ivermectin; (iii) the effect of moxidectin and ivermectin treatment on L3 development into adult worms; and (iv) patterns of adherence to moxidectin and ivermectin MDA. This article is part of the theme issue 'Challenges in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Abstract 3895: Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma

Abstract Pediatric glioblastoma multiforme (GBM) is considered to be the second most lethal childhood cancer type after leukemia. Recent preclinical, clinical and genomic studies have highlighted upon the role of Hippo-Yap pathway in the progression of pediatric GBM. In addition, recent studies have established the role of YAP in creating immune suppressive tumor microenvironment (TME) facilitating drug resistance, recurrence and metastasis of GBM tumors. Herein, we report that ‘moxidectin’ an anti-helminthic drug inhibits the proliferation of SF268, SF295, SF188 and CT-2A Luc GBM cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy studies show that moxidectin mediates its effects by inhibiting MEK-ERK pathway, a regulator of Hippo-YAP signaling. As a result, moxidectin suppressed the nuclear translocation and transcriptional activity of YAP/TAZ-TEAD complex. Oral administration of 3.5mg/kg moxidectin suppressed the growth of GBM tumors by 90% in intracranial tumor model. Ex-vivo analysis of excised tumors confirmed the observations made in in vitro studies. We further conducted immunophenotyping on the excised tumors from both control and moxidectin treated mice to evaluate the effect of moxidectin on immune cell markers in TME and Tumor Draining Lymph Nodes (TDLNs). Our analysis indicated that treatment with moxidectin suppressed the immune suppressive TME created by GBM tumor. Interestingly, moxidectin enhanced antigen presentation in the TDLN. Indicating that it might play a role in activating the peripheral immune response. Moxidectin is an FDA approved drug and any findings from our research will promote its further investigation as a potential therapeutic agent for GBM patients. Citation Format: Itishree Kaushik, Shreyas Gaikwad, Sanjay K. Srivastava. Moxidectin unravels the role of Hippo-YAP pathway in maintaining immunity of pediatric glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3895.

The effects of moxidectin nicotine-conditioned cue on nicotine-seeking behavior in mice

Current pharmacotherapies for nicotine abuse are few and relatively inefficient demonstrating the need for the development of new, effective remedies. Moxidectin is used as an anti-parasitic agent in both animals and humans, it also activates GABA receptors. The objective of the present investigation was to study the effect of moxidectin on nicotine-induced conditioned place preference (CPP) in male Swiss mice. Intraperitoneal (i.p.) route was used for nicotine (0.5mg/kg) administration for a 3-day conditioning program. The influences of moxidectin on the reinforcing characteristics of nicotine were tested in mice given i.p. treatment of moxidectin (5 and 10mg/kg) 30 minutes prior to per nicotine administration. CPP was extinguished by repeated testing, through which conditioned mice were daily given two doses of moxidectin (5 and 10mg/kg, i.p.). Subsequently, the potency of moxidectin in blocking the reinstatement of CPP provoked by priming given low-dose nicotine (0.1mg/kg, i.p.) was also evaluated. Moxidectin treatment illustrated a reserve of acquisition of nicotine-induced CPP. It was reduced priming nicotine-induced reinstatement and accelerated the extinction of CPP. Relatively nicotine enhanced the locomotor, motor activity but was not statistically significant. In conclusion, the outcomes demonstrate the potential for the development of moxidectin as a new pharmacotherapy for the treatment of nicotine addiction.

Efficacy of a spot-on formulation containing moxidectin 2.5%/imidacloprid 10% for the treatment of Cercopithifilaria spp. and Onchocerca lupi microfilariae in naturally infected dogs from Portugal

BackgroundOnchocerca lupi and Cercopithifilaria spp. are vector-borne filarioids of dogs, which harbour skin microfilariae (mfs), the former being of zoonotic concern. Proper treatment studies using compounds with microfilaricidal activity have not been performed. Therefore, this study aimed to assess the efficacy of a commercially available spot-on formulation containing moxidectin 2.5%/imidacloprid 10% for the treatment of O. lupi or Cercopithifilaria spp. skin-dwelling mfs in naturally infected dogs.MethodsPrivately owned dogs (n = 393) from southern Portugal were sampled via skin biopsies to identify and count mfs in 20 µl of skin sediment. A total of 22 mfs-positive dogs were allocated to treatment group (n = 11; G1) or left untreated as a control (n = 11; G2). As a pilot investigation to test the treatment efficacy, five dogs assigned to G1 were treated four times at monthly intervals with moxidectin 2.5%/imidacloprid 10% spot-on formulation on SDs 0, 28 (± 2), 56 (± 2), and 84 (± 2). Based on the negative results for both O. lupi and/or Cercopithifilaria spp. mfs of dogs in the pilot study from SD28 onwards, the remaining six dogs in G1 were treated at SD0 and assessed only at SD28.ResultsOf the 393 animals sampled, 78 (19.8%) scored positive for skin-dwelling mfs. At the pilot investigation, a mean number of 19.6 mfs for O. lupi was recorded among five infected dogs whereas no mfs were detected at SD28. At SD0, the mean number of Cercopithifilaria spp. larvae was 12.6 for G1 and 8.7 for G2. The mean number of mfs for G2 was 20.09.ConclusionsResults herein obtained suggest that a single treatment with moxidectin 2.5%/imidacloprid 10% spot-on formulation is efficacious against skin-dwelling mfs in dogs. The microfilaricidal effect of moxidectin could also be useful in reducing the risk of O. lupi infection for humans.Graphical

Effect of Moxidectin on Bed Bug Feeding, Development, Fecundity, and Survivorship.

The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), is a blood-feeding ectoparasite which experienced world-wide resurgence during recent decades. The control of bed bugs is often challenging, due to their cryptic nature and resistance to commonly used insecticides. In this study, we evaluated the effect of the antiparasitic drug moxidectin on bed bug survival, reproduction, and development. The LC50 (lethal concentration to kill half the members of a tested population) of moxidectin against bed bug male adults, female adults, and large nymphs were 52.7 (95% CI (confidence interval): 39.5–70.8), 29.3 (95% CI: 20.7–40.5), and 29.1 ng/mL (95% CI: 23.3–35.3), respectively. Moxidectin (≥ 25 ng/mL) reduced egg laying of bed bug females, but showed no significant effect on egg hatching. One time feeding on rabbit blood containing 20 and 40 ng/mL moxidectin showed no negative effects in bed bug feeding and blood meal ingestion, but significantly reduced digestion rates and nymph molting rates. Although moxidectin at concentrations of 20 and 40 ng/mL only caused moderate mortality in bed bugs, it significantly interrupted digestion, development, and oviposition of survived bed bugs for at least one week after feeding. Moxidectin is a promising supplement of the existing bed bug control materials if its use on humans can be approved in the future.

Efficacy and persistent activity of moxidectin against natural Muellerius capillaris infection in goats and pathological consequences of muelleriosis

The effect of moxidectin against natural Muellerius capillaris infection in goats was evaluated in this study. Long-acting moxidectin at a single dose of 1mgkg−1 body weight was administered to an entire flock (n=10) of goats. The individual faecal larval count reduction was applied as an indicator of treatment efficacy. A significant reduction (>98%) in larval counts was observed in all surveyed animals 14 days after drug administration. Moxidectin demonstrated persistent activity in this study; the mean faecal larval count reduction was 99.1%±1.8 on day 77 of the treatment. Macroscopic abnormalities and histological changes in the lungs of two infected goats were evident during the post-mortem examination. The pathological consequences of M. capillaris infection were observed even three months after parasite elimination. The results of this study indicate that moxidectin is a highly effective anthelmintic agent for the control of muelleriosis in goats. This drug provides animals with fifteen weeks of protections against M. capillaris reinfection.

Effect of moxidectin on CYP3A4 activity as evaluated by oral midazolam pharmacokinetics in healthy subjects.

In order to evaluate the potential for CYP3A4 induction by moxidectin, midazolam pharmacokinetic (PK) parameters were compared before and after moxidectin administration. Healthy subjects received a single 8 mg dose of moxidectin and 3 single 7.5 mg doses of midazolam 3 days before, and 7 and 89 days after the moxidectin. Blood samples were taken for 24 hours to measure midazolam and metabolites in plasma, and for 89 days to measure moxidectin in plasma after dose administration. Noncompartmental PK analyses were performed for each analyte. Analysis of variance was performed on log-transformed midazolam parameters with treatment day as a fixed effect. Adverse events were recorded and laboratory tests, physical examinations, pulse oximetry monitoring, vital sign measurement, and electrocardiograms performed. Thirty-nine subjects were enrolled in the study; PK data were available for 37 subjects. Moxidectin PK parameters were similar to previous studies. There were no significant changes in PK for midazolam or its metabolites 7 or 89 days after moxidectin administration. Adverse events were generally mild and there were no relevant changes in safety assessments. Thus, 8 mg moxidectin does not induce CYP3A4 activity and other CYP3A4 substrates are unlikely to be affected by moxidectin co-administration.

The effect of moxidectin 0,1% vs ivermectin 0,08% on milk production in sheep naturally infected by gastrointestinal nematodes

BackgroundGastrointestinal nematode (GIN) infection is one of the main constraints to sheep production both in temperate and tropical countries. Economic losses caused by GIN are related to decreased production, treatment costs and even animal death. The present paper was aimed at assessing the anthelmintic efficacy (based on faecal egg count reduction) of moxidectin and ivermectin both admistered per os at dose rate of 0.2 mg/Kg body weight and the benefit of anthelmintic treatments on milk production in a commercial dairy sheep farms in central Italy whose animals were naturally infected by GIN.ResultsThe treatment with moxidectin was highly effective (> 98%) from day 7 until day 75, and effective (90-98%) until day 105. The treatment with ivermectin was highly effective (> 98%) from day 7 until day 14, effective (90-98%) at day 28 and moderately effective (80-89%) on day 45. The milk productions in the treated groups were significantly higher than those of the control group.ConclusionIn conclusion, the results of the present study demonstrated that moxidectin and ivermectin adminstered per os according to the manufacturer's instructions were both effective and safe anthelmintics in sheep. The total milk production was higher in the treated groups than the control group. Overall, animals treated with moxidectin had a milk production 40.8% higher than control group; whereas animals treated with ivermectin had a milk production 32.2% higher than control group.

Fly larvicidal activity in the faeces of cattle and pigs treated with endectocide products.

Bioassays were conducted to study the effect of a single therapeutic dose of injectable ivermectin, doramectin or moxidectin given to cattle and pigs and excreted in their faeces, against larvae of the housefly, Musca domestica L. (Diptera: Muscidae). Five cattle were treated with each of the test products. Cattle faecal samples were collected before treatment and on days 1, 2, 3, 6, 10, 16, 20, 23 and 28 after treatment. Three groups of pigs, each comprising 12-14 pregnant sows and gilts, were used in the experiment. Pig faeces was collected from each group before treatment and on days 1, 3, 5, 7, 9, 11, 13, 15 and 20 after treatment. Thirty, first-stage larvae were placed into 100 g of faeces. Five replicates were examined for each time-point and for each endectocide group. Evaluation was based on the number of larvae surviving to adult emergence. Low numbers of adults emerged from samples taken from cattle 1 day after treatment, indicating that ivermectin and doramectin were rapidly excreted in the faeces and affected the development of the house fly. A larvicidal effect of both drugs in cattle faeces was present for a period of about 3-4 weeks and lasted a few days longer in cattle treated with doramectin than with ivermectin. In cattle, the larvicidal activity of moxidectin was first observed in faecal samples collected 2 days post-treatment; however, it killed fewer larvae than the other two drugs. The larvicidal effect of moxidectin subsequently decreased. Ivermectin and doramectin exhibited a pronounced larvicidal effect against the house fly in the faeces of pigs. The effect of doramectin was of longer duration. Moxidectin gave the weakest larvicidal effect in pig faeces. The main difference between the results obtained for the two livestock species is that peak toxicity occurred relatively later and for a shorter duration in pig than in cattle faeces.

Effet de traitement par injection de moxidectine sur la prévalence et la production d’oeufs de strongles chez des bovins dans un système de pâturage communal en Ouganda

L’effet de la moxidectine sur la prévalence des infections par les nématodes chez les bovins, ainsi que sur la production d’oeufs des fèces et la contamination sur des pâturages collectifs a été évalué dans le district de Tororo en Ouganda. Dans le premier essai, un groupe traité et un autre non traité de 40 bovins chacun ont été suivis pendant une période de 12 semaines, alors que dans le deuxième essai un groupe traité et un autre non traité de 30 bovins chacun ont été suivis pendant sept mois. Dans le premier essai, la prévalence d’infection par les nématodes ainsi que le nombre moyen d’oeufs des fèces du groupe traité sont restés significativement (p < 0,05) moins importants que ceux du groupe non traité du 7e au 84e jour. Dans le deuxième essai, les traitements stratégiques ont d’abord entraîné une réduction du nombre d’oeufs de 100 p. 100 chez les bovins traités, alors que cette réduction a été de 82 p. 100 chez les bovins non traités. Par la suite, le nombre moyen d’oeufs des fèces du groupe traité est resté en dessous de 60 pendant six mois, alors que celui du groupe non traité a fluctué en fonction de la pluviométrie entre 63 et 400. De plus, la contamination au pâturage par des larves infestantes des bovins traités a été significativement (p < 0,05) plus faible que celle du groupe non traité pendant la saison humide. Les infestations au pâturage par Haemonchus spp., Bunostomum spp., Oesophagostomum spp. et Trichostrongylus spp. ont été respectivement trois fois, cinq fois, quatre fois et deux fois moins importantes chez les bovins traités que chez les bovins non traités. La moxidectine pourrait être utilisée dans la lutte stratégique contre les parasites dans les conditions de gestion communale des pâturages en Afrique tropicale par le traitement sélectif des groupes d’âges de bovins les plus affectés à la mi- et à la fin de la saison des pluies pour réduire la contamination au pâturage.

The reappearance of strongyle eggs in the faeces of horses after treatment with moxidectin

Summary The reappearance of strongyle eggs in the faeces of horses treated with moxidectin (0.4 mg/kg of body weight) was compared with that in the faeces of horses treated with ivermectin (0.2 mg/kg of body weight). The study was performed from December 1995 till June 1996. Horses were infected naturally in the preceding grazing period. Two groups of 24 horses each were treated with moxidectin and ivermectin respectively at week 0. No side effects were seen after treatment. Horses were housed from week ‐1 till week 17. From week 17 onwards the horses were on pasture. Faecal samples were taken from each horse at week ‐1, week 0 and weekly from week 3 to week 25. The ivermectin treated horses had to be retreated in week 17 to prevent pasture contamination. For this reason this group was withdrawn from the trial in week 17. Individual faecal egg counts and group faecal cultures and larval differentiation were performed. In the ivermectin treated group strongyle eggs were seen for the first time after treatment in week 8. A steady rise in the mean number of eggs per gram faeces (EPG) was seen from week 8 till week 15. After week 15 a plateau was reached. In the moxidectin treated group mean egg counts remained very low throughout the study. A plateau was reached in week 19, with egg counts varying from 10 to 30 EPG between week 19 and week 25. The difference between the egg output after moxidectin‐ and lvertnectin treatments can be explained by a higher efficacy of moxidectin against mucosal stages or by a longer residual effect of moxidectin than ivermectin.

Controlled dose confirmation study of a 2% moxidectin equine gel against equine internal parasites in The Netherlands

The efficacy of a 2% moxidectin equine gel at adosage rate of 0.4 mg kg −1 was evaluated in a controlled trial at Utrecht University. Twelve yearling castrated male Shetland ponies grazed a pasture of 2 ha from May 1994 until housing in November. Six ponies were treated with moxidectin, whereas the others served as non-treated controls. Necropsy was carried out 35 days after treatment. Greater than 99% efficacy of moxidectin was observed on faecal egg output. No effect of moxidectin was observed on mucosal inhibited early cyathostome L3 (EL3) or on the total numbers of mucosal developing stages. However, a 89.6% reduction was observed on large mucosal fourth stage larvae (L4). Moxidectin treatment probably triggered resumption of development of EL3. Moxidectin appeared to be highly effective (95–100%) on lumenal L4 cyathostomes, adult strongylids, Strongylus vulgaris larvae from the arteries, S. edentatus larvae from the abdominal wall and Trichostrongylus axei. Moxidectin had relatively poor efficacy against Gasterophilus intestinalis and had no effect on Anoplocephala perfoliata. No side-effects of moxidectin treatment were observed.