Solvatomorphism of Moxidectin.
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ABSTRACT:
SUBMITTER: Grell T
PROVIDER: S-EPMC8398095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination.
| S-EPMC3862425 | biostudies-literature
Project description:In animal farming, anthelmintics are regularly applied to control gastrointestinal nematodes. There is plenty of evidence that also non-target organisms, such as dung beetles, are negatively affected by residues of anthelmintics in faeces of domestic ungulates. By contrast, knowledge about possible effects on wild plants is scarce. To bridge this gap of knowledge, we tested for effects of the common anthelmintic formulation Cydectin and its active ingredient moxidectin on seed germination. We conducted a feeding experiment with sheep and germination experiments in a climate chamber. Three wide-spread plant species of temperate grasslands (Centaurea jacea, Galium verum, Plantago lanceolata) were studied. We found significant influences of both, Cydectin and moxidectin, on germination of the tested species. Across species, both formulation and active ingredient solely led to a decrease in germination percentage and synchrony of germination and an increase in mean germination time with the formulation showing a more pronounced response pattern. Our study shows for the first time that anthelmintics have the potential to negatively affect plant regeneration. This has practical implications for nature conservation since our results suggest that treatments of livestock with anthelmintics should be carefully timed to not impede endozoochorous seed exchange between plant populations.
| S-EPMC5112930 | biostudies-literature
Project description:Anthelmintic resistance has been increasingly reported in cattle worldwide over the last decade, although reports from Europe are more limited. The objective of the present study was to evaluate the efficacy of injectable formulations of ivermectin and moxidectin at 0.2 mg per kg bodyweight against naturally acquired gastro-intestinal nematodes in cattle. A total of 753 animals on 40 farms were enrolled in Germany (12 farms), the UK (10 farms), Italy (10 farms), and France (8 farms). Animals were selected based on pre-treatment faecal egg counts and were allocated to one of the two treatment groups. Each treatment group consisted of between 7 and 10 animals. A post-treatment faecal egg count was performed 14 days (±2 days) after treatment. The observed percentage reduction was calculated for each treatment group based on the arithmetic mean faecal egg count before and after treatment. The resistance status was evaluated based on the reduction in arithmetic mean faecal egg count and both the lower and upper 95% confidence limits. A decreased efficacy was observed in half or more of the farms in Germany, France and the UK. For moxidectin, resistance was confirmed on 3 farms in France, and on 1 farm in Germany and the UK. For ivermectin, resistance was confirmed on 3 farms in the UK, and on 1 farm in Germany and France. The remaining farms with decreased efficacy were classified as having an inconclusive resistance status based on the available data. After treatment Cooperia spp. larvae were most frequently identified, though Ostertagia ostertagi was also found, in particular within the UK and Germany. The present study reports lower than expected efficacy for ivermectin and moxidectin (based on the reduction in egg excretion after treatment) on European cattle farms, with confirmed anthelmintic resistance on 12.5% of the farms.
| S-EPMC4572401 | biostudies-literature
Project description:BACKGROUND:The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly. METHODS:Study 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×. RESULTS:Study 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045-37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs. CONCLUSIONS:PH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.
| S-EPMC6728954 | biostudies-literature
Project description:BACKGROUND:Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed. METHODOLOGY/PRINCIPAL FINDINGS:Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N?=?44), 4 mg (N?=?45) or 8 mg (N?=?38) moxidectin or 150 µg/kg ivermectin (N?=?45) with 18 months follow up. All ivermectin and 97%-100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ?5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01). CONCLUSIONS/SIGNIFICANCE:The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control programmes could help them achieve onchocerciasis elimination objectives. TRIAL REGISTRATION:ClinicalTrials.gov NCT00300768.
| S-EPMC4072596 | biostudies-literature
Project description:Demodex musculi is a prostigmatid follicular mite that has rarely been reported in laboratory mice. Although prevalence of this species has not been assessed formally, we have found that many imported mouse strains from noncommercial sources harbor Demodex mites. To assess whether an acaricide can be used to eradicate this mite, infested immunocompromised mice were provided ivermectin-compounded (12 ppm) feed without restriction for 8 wk (n = 10), were treated topically with moxidectin and imidacloprid (MI; 3 and 13 mg/kg, respectively) weekly for 8 wk (n = 10), or remained untreated (n = 10). Mice were confirmed to be mite-infested before treatment and were tested after treatment by using fur plucks (FP), deep skin scrapes (DSS), and PCR analysis of fur swabs. In addition, the presence of mites was confirmed through skin biopsies at 2 study endpoints (1 wk [n = 5] and 12 wk [ n = 5] after treatment). Samples collected before treatment and from untreated mice were positive for D. musculi at all time points and by all test modalities. After treatment, all ivermectin-treated animals remained infested, whereas mice treated with MI were repeatedly negative by all test modalities. An additional shortened treatment trial revealed that 4 wk of MI (n = 7) was insufficient to eradicate mites. Neither treatment produced any evidence of adverse effects according to hematology, serum chemistry parameters, behavior, body weight, and histopathology. Of the 70 PCR assays performed in treated mice, 14 were positive when FP+DSS was negative. In 6 cases where PCR results were negative, 5 were positive by FP+DSS and a single sample was positive on skin biopsy. Although PCR analysis has a high detection rate for D. musculi, FP+DSS can further enhance the detection rate. In conclusion, topical MI administered for 8 consecutive weeks can safely eradicate D. musculi from an immunocompromised mouse strain.
| S-EPMC6159677 | biostudies-literature
Project description:The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(-/-) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11-2.0 and 0.23-12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD(50)) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(-/-) mice, LD(50) was 0.46 and 2.3 µmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD(50) were, in Mdr1ab(-/-) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740-1380 pmol/g for MOX, indicating that higher brain concentrations are required for MOX toxicity than IVM. In rat ?1?2?2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans.
| S-EPMC3486876 | biostudies-literature
Project description:BackgroundAnthelmintic treatment is a risk factor for intestinal disease in the horse, known as colic. However the mechanisms involved in the onset of disease post anthelmintic treatment are unknown. The interaction between anthelmintic drugs and the gut microbiota may be associated with this observed increase in risk of colic. Little is known about the interaction between gut microbiota and anthelmintics and how treatment may alter microbiome function. The objectives of this study were: To characterise (1) faecal microbiota, (2) feed fermentation kinetics in vitro and (3) metabolic profiles following moxidectin administration to horses with very low (0 epg) adult strongyle burdens.HypothesisMoxidectin will not alter (1) faecal microbiota, (2) feed fermentation in vitro, or, (3) host metabolome.ResultsMoxidectin increased the relative abundance of Deferribacter spp. and Spirochaetes spp. observed after 160?h in moxidectin treated horses. Reduced in vitro fibre fermentation was observed 16?h following moxidectin administration in vivo (P?= 0.001), along with lower pH in the in vitro fermentations from the moxidectin treated group. Metabolic profiles from urine samples did not differ between the treatment groups. However metabolic profiles from in vitro fermentations differed between moxidectin and control groups 16?h after treatment (R2?=?0.69, Q2Y?=?0.48), and within the moxidectin group between 16?h and 160?h post moxidectin treatment (R2?=?0.79, Q2Y?=?0.77). Metabolic profiles from in vitro fermentations and fermentation kinetics both indicated altered carbohydrate metabolism following in vivo treatment with moxidectin.ConclusionsThese data suggest that in horses with low parasite burdens moxidectin had a small but measurable effect on both the community structure and the function of the gut microbiome.
| S-EPMC7807906 | biostudies-literature
Project description:BACKGROUND:In three randomized, controlled laboratory efficacy studies, the efficacy in the prevention of patent infections of a topical combination of imidacloprid 10%/moxidectin 1% (Advocate® spot-on formulation for cats, Bayer Animal Health GmbH) against larval stages and immature adults of Aelurostrongylus abstrusus, as well as the treatment efficacy of a single or three monthly treatments against adult A. abstrusus, were evaluated. METHODS:Cats were experimentally inoculated with 300-800 third-stage larvae (L3). Each group comprised 8 animals and the treatment dose was 10 mg/kg bodyweight (bw) imidacloprid and 1 mg/kg bw moxidectin in each study. Prevention of the establishment of patent infections was evaluated by two treatments at a monthly interval at three different time points before and after challenge infection. Curative efficacy was tested by one or three treatments after the onset of patency. Worm counts at necropsy were used for efficacy calculations. RESULTS:In Study 1, the control group had a geometric mean (GM) of 28.8 adult nematodes and the single treatment group had a GM of 3.4 (efficacy 88.3%). In Study 2, the control group had a GM of 14.3, the prevention group had a GM of 0 (efficacy 100%), while the treatment group had a GM of 0.1 (efficacy 99.4%). In Study 3, the GM worm burden in the control group was 32.6 compared to 0 in all three prevention groups (efficacy 100% for all of those groups). CONCLUSIONS:The monthly administration of Advocate® reliably eliminated early larval stages and thereby prevented lung damage from and patent infections with A. abstrusus in cats. Regarding treatment, a single application of Advocate® reduced the worm burden, but it did not sufficiently clear the infection. In contrast, three monthly treatments were safe and highly efficacious against A. abstrusus.
| S-EPMC7017503 | biostudies-literature
Project description:BackgroundMoxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies.MethodsA PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy).ResultsA two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively.ConclusionWe describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs.Trial registrationRegistered at ClinicalTrials.gov (NCT04056325).
| S-EPMC8761718 | biostudies-literature