Moxidectin Treatment Research Articles

Community-level effects of ivermectin and moxidectin from cattle dung: zooplankton as study case

Context Ivermectin (IVM) and moxidectin (MOX), are widely used internal and external antiparasitic drugs for livestock. They enter into the aquatic environment because the treated animals metabolise only a small percentage of the administered doses, and the rest is eliminated through the faeces posing a risk to aquatic organisms. Aims This study aimed to evaluate the responses of zooplankton to environmentally relevant concentrations of IVM and MOX spiked in cattle dung in a short-term exposure. Methods We compared the composition of the community, density, species richness, diversity and total biomass between treatments with parasiticides and controls. Key results The presence of both antiparasitic drugs altered the zooplankton community structure, leading to a shift in species composition. Cladocerans were the most affected, with a drastic reduction in their density. Additionally, a decrease in the density of copepods and an increase in the density of rotifers were observed in the MOX treatments. Conclusions Both drugs caused a simplification of the zooplankton community as species richness and diversity decreased. Overall, MOX was more toxic than IVM. Implications Our results suggest that long-term consequences on ecosystem services could arise, which merits the development of control and livestock management tools for the protection of these environments.

Inefficacy of ivermectin and moxidectin treatments against Dictyocaulus viviparus in dairy calves.

The bovine lungworm Dictyocaulus viviparus negatively impacts bovine health and leads to substantial economic losses. Lungworm infections can be difficult to manage due to the unpredictable and severe nature of clinical outbreaks. Despite the widespread use of macrocyclic lactones (MLs) in grazing cattle in the UK, there have been no confirmed reports of resistant lungworms to date, with only one case of anthelmintic-resistant (ML) lungworm confirmed worldwide. Lungworm Baermann filtrations were conducted on first-season grazing dairy calves as part of a wider study investigating anthelmintic resistance in gastrointestinal nematodes in Scotland using the faecal egg count reduction test. Clinical signs and significant numbers of lungworm larvae in faeces were observed after treatment with either ivermectin or moxidectin. There are no established guidelines for the diagnosis of resistant lungworms in the field. Currently, resistance can only be diagnosed after a controlled efficacy test has been conducted. This limits the conclusions that can be drawn; however, they are highly suggestive of resistance. This short report describes the inefficacy of ivermectin and moxidectin against D. viviparus and is highly suggestive of ML resistance.

Delayed canine heartworm (Dirofilaria immitis) microfilarial reduction following Advocate™ for dogs (imidacloprid, moxidectin) treatment

Macrocyclic lactone (ML) anthelmintics are currently the only class of drugs available for canine heartworm prevention. Recent reports of Dirofilaria immitis infection occurring in dogs reportedly receiving ‘rigorous’ prevention in Queensland, Australia, coupled with the confirmation of ML-resistant isolates in the USA, has led to speculation about the potential emergence of ML-resistance in Australia. In this study, we describe two cases (Dog 1 and 2) of asymptomatic canine heartworm disease in Townsville, Australia, that were reportedly receiving ‘rigorous’ heartworm prevention according to the owners’ claims. We aimed to deploy currently available tools to assess the phenotypic and genotypic ML-resistance status of these two dogs. For phenotypic testing, we performed an in-vivo 7-day microfilariae suppression test using a dose of spot-on moxidectin (Advocate™ for Dogs, 100 g/L imidacloprid + 25 g/L moxidectin). This formulation is marketed as Advantage Multi® for Dogs in the USA, which claims a D. immitis microfilaricidal effect. For genetic testing, an Illumina amplicon metabarcoding approach was used to target single nucleotide polymorphisms (SNPs) previously associated with ML-resistance in D. immitis from the USA. Dog 1 and Dog 2 demonstrated <10 % and <40 % reductions in circulating microfilariae seven days after moxidectin treatment, respectively. These phenotypes were not corroborated by genetic SNP testing, as both dogs were classified as susceptible across all examined markers. To streamline testing of D. immitis SNPs, we developed a rhAmp™ SNP qPCR approach for rapidly genotyping suspect cases of ML-resistant infections at the two major loci (L15709_A and L30575). These findings illustrate a phenomenon shown in some heartworm cases outside the USA, whereby infected dogs are failing to see marked reductions in microfilaraemia after ML treatment but possess an ML-susceptible genotype.

High rates of benzimidazole-resistance-associated alleles in Haemonchus contortus and detection of resistance against macrocyclic lactones in strongylids from German alpaca herds

The population of South American camelids (SAC) has been steadily growing in Europe, where they are confronted with the regional endoparasite population of ruminants. As there are no anthelmintic drugs registered for use against nematode infections in SACs, anthelmintics (AH) available for ruminants or horses are usually applied. Reports indicating potential failures in administered AH are increasing. However, the generally low egg counts in SACs complicate the application of resistance tests in the field. The present study reports a follow-up study on SAC farms where anthelmintic resistance (AR) was suspected. The aims were (i) to repeat faecal egg count reduction tests (FECRTs) on potentially affected farms identified in a previous study with larger sample sizes, (ii) to verify suspected AR of Haemonchus contortus against benzimidazoles (BZ) by performing a single-nucleotide polymorphism (SNP) analysis using digital polymerase chain reaction (dPCR), and (iii) to apply the mini-FLOTAC technique for more reliable results at low egg counts in line with current recommendations. Seven farms (9–46 animals each) were examined by coproscopy, larval differentiation and SNP analysis. A FECRT was performed on six of these farms with moxidectin (three farms), monepantel (two farms) and ivermectin (one farm). The FEC was calculated according to the current World Association for the Advancement of Veterinary Parasitology (WAAVP) guidelines with the clinical protocol (a newly introduced variant of FECRT which can be used for smaller sample sizes and lower egg counts on the cost of sensitivity) and an expected efficacy of 99%. A high level (> 90%) of BZ-resistance-associated SNPs on codon 200 of H. contortus was observed on all farms. With the FECRT, resistance was demonstrated for ivermectin (74% FECR), while it remained inconclusive for one farm for moxidectin treatment. Sustained efficacy was demonstrated for the remaining treatments. This study showed an advanced level of BZ resistance in H. contortus of SACs and the development of AR against macrocyclic lactones on some farms. Thus, constant monitoring of AH treatment and sustainable worm control methods both need to be applied.Graphical

An Updated Economic Assessment of Moxidectin Treatment Strategies for Onchocerciasis Elimination.

Concerns that annual mass administration of ivermectin, the predominant strategy for onchocerciasis control and elimination, may not lead to elimination of parasite transmission (EoT) in all endemic areas have increased interest in alternative treatment strategies. One such strategy is moxidectin. We performed an updated economic assessment of moxidectin- relative to ivermectin-based strategies. We investigated annual and biannual community-directed treatment with ivermectin (aCDTI, bCDTI) and moxidectin (aCDTM, bCDTM) with minimal or enhanced coverage (65% or 80% of total population taking the drug, respectively) in intervention-naive areas with 30%, 50%, or 70% microfilarial baseline prevalence (representative of hypo-, meso-, and hyperendemic areas). We compared programmatic delivery costs for the number of treatments achieving 90% probability of EoT (EoT90), calculated with the individual-based stochastic transmission model EPIONCHO-IBM. We used the costs for 40 years of program delivery when EoT90 was not reached earlier. The delivery costs do not include drug costs. aCDTM and bCDTM achieved EoT90 with lower programmatic delivery costs than aCDTI with 1 exception: aCDTM with minimal coverage did not achieve EoT90 in hyperendemic areas within 40 years. With minimal coverage, bCDTI delivery costs as much or more than aCDTM and bCDTM. With enhanced coverage, programmatic delivery costs for aCDTM and bCDTM were lower than for aCDTI and bCDTI. Moxidectin-based strategies could accelerate progress toward EoT and reduce programmatic delivery costs compared with ivermectin-based strategies. The costs of moxidectin to national programs are needed to quantify whether delivery cost reductions will translate into overall program cost reduction.

First identification of Strongyloides stercoralis infection in a pet dog in Argentina, using integrated diagnostic approaches

BackgroundStrongyloides stercoralis is a soil-transmitted intestinal nematode with a complex life cycle that primarily affects humans, non-human primates, dogs, and occasionally cats. This study presents, to the best of our knowledge, the first case of S. stercoralis infection and its genotyping in a domestic dog from Argentina.MethodsThe patient was a female wired-haired Teckel dog exhibiting recurrent coughing. Coproparasitological analysis using the Baermann technique revealed the presence of rhabditiform larvae morphologically compatible with S. stercoralis. To confirm this finding, molecular diagnosis (18S ribosomal RNA) and analysis of the cox1 gene were performed.ResultsWe identified a haplotype (HP20) that has previously only been related to S. stercoralis infection in dogs, but was found in the present study to be highly related to the haplotype (HP16) of a zoonotic variant and divergent from those previously described from human patients in Argentina. Furthermore, unlike in human cases following treatment with ivermectin, the dog was negative after moxidectin treatment according to polymerase chain reaction of the sampled faeces.ConclusionsThis case report shows the importance of further investigation into potential transmission events and prevalences of S. stercoralis in dogs and humans in South America. The results reported here should also encourage future work that examines different scenarios of infection with S. stercoralis in dogs and humans with the aim of integrating clinical management, diagnosis, treatment and follow-up strategies in the quest for new approaches for the treatment of this disease in animals and humans. The findings support the adoption of a One Health approach, which recognizes the interconnectedness between animal and human health, in addressing parasitic infections such as strongyloidiasis.Graphical

Strongyle egg reappearance periods following moxidectin treatment in horses in southeast England

Strongyle egg reappearance periods following moxidectin treatment in horses in southeast England

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'.

Strongyle egg reappearance periods following moxidectin treatment in horses in Southeast England

AbstractBackgroundA reduction in the egg reappearance period (ERP) has been suggested to be an early indication of emerging anthelmintic resistance in strongyles.ObjectiveTo measure the strongyle ERP following moxidectin treatment of horses in the southeast of England.Study designProspective study.MethodsHorses with a faecal egg count (FEC) of ≥400 strongyle eggs per gram (EPG) in a routine screening sample were enrolled into the study. Moxidectin (400 μg/kg) was administered per os and FEC tests repeated every 2 weeks for 16 weeks.ResultsForty‐eight horses completed the study. The mean EPG prior to treatment was 1047 (range 375–2137 EPG). In all but two horses, FEC was 0 EPG 2 weeks after moxidectin administration. In the remaining two, the FECs were each 12.5 EPG (97.8%–98.3% reductions compared to pre‐treatment FEC). At 4 weeks post‐treatment, 6 horses had positive FECs (96.6%–99.2% reductions). At 6 weeks, 11 horses had positive FECs (83.8% reduction in one horse; &gt;90% reduction in 10). At 8 weeks, 21 horses exhibited positive FECs (&lt;90% reduction in 2). At 10 weeks, 27 horses had positive FECs (&lt;90% in 6). At 12 weeks, 31 horses had positive FECs (&lt;90% reduction in 11). At 14 weeks, 34 horses had positive FECs (&lt;90% reduction in 13). At 16 weeks, 38 horses had positive FECs (&lt;90% reduction in 17).Main limitationsWeights of some horses were estimated using weigh tapes rather than a weighbridge. Dosing of the horses with moxidectin was carried out by owners.ConclusionsThe results indicated acceptable efficacy of moxidectin at 14 days after treatment; however, the ERP pattern measured across the group suggests that this anthelmintic has a considerably shorter suppressive effect on strongyle egg shedding than measured when it was first introduced (12–16 weeks).

The first report of macrocyclic lactone resistant cyathostomins in the UK

In recent years, resistance to the benzimidazole (BZ) and tetrahydropyrimidine (PYR) anthelmintics in global cyathostomin populations, has led to reliance on the macrocyclic lactone drugs (ML-of which ivermectin and moxidectin are licensed in horses) to control these parasites. Recently, the first confirmed case of resistance to both ivermectin (IVM) and moxidectin (MOX) was reported in the USA in yearlings imported from Ireland. This suggests that ML resistance in cyathostomins has emerged, and raises the possibility that regular movement of horses may result in rapid spread of ML resistant cyathostomins. Resistance may go undetected due to a lack of surveillance for ML efficacy. Here, we report anthelmintic efficacies in cyathostomins infecting UK Thoroughbreds on four studs. Faecal egg count reduction tests (FECRT) were performed to define resistance (resistance = FECR <95% lower credible interval (LCI) < 90%). Stud A yearlings had FECRs of 36.4–78.6% (CI:15.7–86.3) after three IVM treatments, 72.6% (CI: 50.8–85.2) after MOX, and 80.8% (CI: 61.9–90.0) after PYR. Mares on stud A had a FECR of 97.8% (CI: 93.3–99.9) and 98% (95.1–99.4) after IVM and MOX treatment, respectively. Resistance to MLs was not found in yearlings or mares on studs B, C or D with FECR after MOX OR IVM treatment ranging from 99.8 to 99.9% (95.4–100); although yearlings on studs B, C and D all had an egg reappearance period (ERP) of six weeks for MOX and stud C had a four-week ERP for IVM. This study describes the first confirmed case of resistance to both licensed ML drugs on a UK Thoroughbred stud and highlights the urgent need for a) increased awareness of the threat of ML resistant parasites infecting horses, and b) extensive surveillance of ML efficacy against cyathostomin populations in the UK, to gauge the extent of the problem.

Pre-established anthelmintic protocols in horses: low efficacy and unnecessary treatments highlight the need for strategic deworming

Context Deworming all horses with commercial anthelmintics on a rotational basis every 90 days is still popular worldwide. Aims To investigate anthelmintic resistance and therapeutic requirements of adult horses on the basis of faecal examinations after a rotation between commercial anthelmintics commonly used in Brazil. Methods We followed up faecal egg counts and coprocultures of 29 horses for 7 months, after pre-established anthelmintic treatments, every 3 months (August and November 2019 and February 2020). The following commercial anthelmintics were used respectively: moxidectin (1), ivermectin + praziquantel (2) and trichlorfon + mebendazole (3). Faecal egg count (FEC), FEC reduction tests (FECRT) and coproculture were performed before (Day 0) and after 14 days for each of the three treatments. Wilcoxon test (95% confidence level, P &lt; 0.05) was used to test the efficacy of the treatment on the FECRT and the occurrence of resistance to the treatments used. Results The FEC results and percentage of individual FECRT indicated parasite resistance, and 82 of 87 (94%) deworming treatments were unnecessary. The efficacy rate was 78%, 34% and 53% for Treatments 1, 2 and 3 respectively. In the coprocultures before deworming, 98.5% were small strongyles, 1.1% Strongylus equinus and 0.4% Gyalocephalus capitatus. After deworming, 98.7% of parasites were small strongyles and 1.3% Dictyocaulus arnfieldi. FEC values at Day 0 and 14 days after anthelminthics were different (lower) only for the moxidectin treatment (U = 271.5; P-value &lt;0.01). For both ivermectin + praziquantel (U = 373; P-value &gt;0.05) and mebendazole + trichlorfon (U = 391; P-value &gt;0.05) treatments, there was no difference in FEC between Day 0 and Day 14 at 95% confidence level. Conclusions The anthelmintics used in the deworming protocol of this study had reduced efficacy against the parasites identified in the coprocultures and the pre-established treatments were probably unnecessary in 93% of the horses with a low level of infection. Implications This study has highlighted not only the issue of the indiscriminate use of anthelmintics regarding parasitic resistance, but also the exposure of horses to unnecessary treatments. Such widespread use is a costly waste of resources and further reinforces the discontinuation of schedule rather than strategic deworming protocols.

Shortened egg reappearance periods of equine cyathostomins following ivermectin or moxidectin treatment: morphological and molecular investigation of efficacy and species composition

Macrocyclic lactones have been the most widely used drugs for equine parasite control during the past four decades. Unlike ivermectin, moxidectin exhibits efficacy against encysted cyathostomin larvae, and is reported to have persistent efficacy with substantially longer egg reappearance periods. However, shortened egg reappearance periods have been reported recently for both macrocyclic lactones, and these findings have raised several questions: (i) are egg reappearance period patterns different after ivermectin or moxidectin treatment? (ii) Are shortened egg reappearance periods associated with certain cyathostomin species or stages? (iii) How does moxidectin’s larvicidal efficacy affect egg reappearance period? To address these questions, 36 horses at pasture, aged 2–5 years old, were randomly allocated to three treatment groups: 1, moxidectin; 2, ivermectin; and 3, untreated control. Strongylid fecal egg counts were measured on a weekly basis, and the egg reappearance period was 5 weeks for both compounds. Strongylid worm counts were determined for all horses: 18 were necropsied at 2 weeks post-treatment (PT), and the remaining 18 at 5 weeks PT. Worms were identified to species morphologically and by internal transcribed spacer-2 (ITS-2) rDNA metabarcoding. Moxidectin and ivermectin were 99.9% and 99.7% efficacious against adults at 2 weeks post treatment, whereas the respective efficacies against luminal L4s were 84.3% and 69.7%. At 5 weeks PT, adulticidal efficacy was 88.3% and 57.6% for moxidectin and ivermectin, respectively, while the efficacy against luminal L4s was 0% for both drugs. Moxidectin reduced early L3 counts by 18.1% and 8.0% at 2 or 5 weeks, while the efficacies against late L3s and mucosal L4s were 60.4% and 21.2% at the same intervals, respectively. The luminal L4s surviving ivermectin treatment were predominantly Cylicocyclus (Cyc.) insigne. The ITS-2 rDNA metabarcoding was in good agreement with morphologic species estimates but suggested differential activity between moxidectin and ivermectin for several species, most notably Cyc. insigne and Cylicocyclus nassatus. This study was a comprehensive investigation of current macrocyclic lactone efficacy patterns and provided important insight into potential mechanisms behind shortened egg reappearance periods.

Moxidectin use in Scottish sheep flocks suggests a need for clearer product labelling and communication of updated SCOPS guidelines.

Guidelines for sustainable use of moxidectin were established in 2020. This study aimed to identify how Scottish sheep farmers are using this key endectocide and estimate its effectiveness against gastrointestinal nematodes. Questionnaires were distributed to sheep farmers across Scotland, and analysis focused on moxidectin use in relation to Sustainable Control of Parasites in Sheep (SCOPS) guidelines. Farmers using moxidectin in their flock volunteered to submit post-treatment sheep faecal samples, which were analysed for the presence of gastrointestinal nematodes using faecal egg counts with polymerase chain reaction to determine species. Despite 70% of farmers using moxidectin in 2020, knowledge levels varied: 24% of farmers included other anthelmintics when asked about moxidectin use. Moxidectin was used for a wide variety of reasons, and most farmers did not consistently follow SCOPS guidelines. Despite only 2 of 76 farmers reporting failure of moxidectin treatment, gastrointestinal nematodes were found following moxidectin treatment on five out of six farms tested and included Teladorsagia circumcincta, Cooperia curticei, Haemonchus contortus and Nematodirus sp. Findings from this project indicate the need for improved anthelmintic product labelling and farmer support to encourage sustainable use. The presence of nematodes in treated animals is suggestive of anthelmintic resistance.

Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection.

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).

GABAA receptor agonist suppresses pediatric medulloblastoma progression by inhibiting PKA-Gli1 signaling axis

The Sonic hedgehog-activated subgroup of medulloblastoma (SHH-MB) is one of the most common malignant pediatric brain tumors. Recent clinical studies and genomic databases indicate that GABAA receptor holds significant clinical relevance as a therapeutic target for pediatric MB. Herein, we report that "moxidectin," a GABAA receptor agonist, inhibits the proliferation of Daoy, UW426, UW228, ONS76, and PFSK1 SHH-MB cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy demonstrated that moxidectin significantly induced GABAA receptor expression and inhibited cyclic AMP (cAMP)-mediated protein kinase A (PKA)-cAMP response element-binding protein (CREB)-Gli1 signaling in SHH-MB. Gli1 and the downstream effector cancer stem cell (CSC) molecules such as Pax6, Oct4, Sox2, and Nanog were also inhibited by moxidectin treatment. Interestingly, moxidectin also inhibited the expression of MDR1. Mechanistic studies using pharmacological or genetic inhibitors/activators of PKA and Gli1 confirmed that the anti-proliferative and apoptotic effects of moxidectin were mediated through inhibition of PKA-Gli1 signaling. Oral administration of 2.5mg/kg moxidectin suppressed the growth of SHH-MB tumors by 55%-80% in subcutaneous and intracranial tumor models in mice. Exvivo analysis of excised tumors confirmed the observations made in the invitro studies. Moxidectin is an FDA-approved drug with an established safety record, therefore any positive findings from our studies will prompt its further clinical investigation for the treatment of MB patients.

Investigation of the impact of antiparasitic drug moxidectin on the rewarding effects of alcohol.

Alcohol addiction or alcoholism constitutes a significant risk factor worldwide for morbidity and mortality. Moxidectin is a recently approved anthelmintic drug, which also activates the gamma-aminobutyric acid receptors. The objective of the present study was to examine the impact of moxidectin on rewarding effects of ethanol in the conditioned place preference (CPP) model in mice. In separate experiments, mice were administered intraperitoneal (i.p.) injections of moxidectin (5 or 10 mg/kg, i.p.) before a) acquisition of alcohol-induced CPP, b) each extinction session, and c) alcohol-induced reinstatement of CPP. The present experiments provide consistent data about ethanol place preference in mice (2 g/kg, i.p.), with mice in all tests spending significantly more time on the ethanol-paired side. The acquisition of the CPP response to ethanol was prevented by the administration of moxidectin at a dose of 10 mg/kg. Additionally, moxidectin treatment accelerated the extinction of ethanol CPP when given repeatedly during the extinction phase. Ethanol-induced reinstatement of CPP following an extinction phase was inhibited by moxidectin. Ethanol alone and co-administration with moxidectin did not change locomotor activity and motor coordination. In conclusion, we suggest that moxidectin may be a promising therapeutic candidate for prevention of ethanol-induced addiction and relapse as well as detoxification.

Optimizing moxidectin dosing for Strongyloides stercoralis infections: Insights from pharmacometric modeling.

Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability profile. Yet, owing to the unique life cycle of Strongyloides stercoralis (S. stercoralis) that entails internal autoinfection, a curative treatment would be desirable. Population‐based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure‐efficacy response relationship of moxidectin in treating S. stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post‐treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve‐receiver operating characteristic [AUC‐ROC] 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC0‐24 or maximum concentration [Cmax]) to baseline infection intensity. Pharmacometric simulations indicate that with a minimum dose of 4 mg a maximum cure rate of ~ 95% is established in the low infection intensity group (larvae per gram [LPG] ≥0.4–1), whereas in the moderate‐to‐high intensity group (LPG >1) the cure rate plateaus at ~ 87%, following an 8 mg dose. To enhance efficacy further, studies using repeated dosing based on the duration of the autoinfection cycle, for example a two‐dose regimen 3 weeks apart should be considered. Simulations revealed similar Cmax in both treatment courses of a two‐dose regimen; hence safety should not be a concern. Collectively, our results provide evidence‐based guidance for enhanced dosing strategies and should be considered when designing future treatment strategies.

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.

Increase in the reproductive efficiency of primiparous and multiparous Nellore cows following moxidectin treatment at the onset of a fixed-time artificial insemination protocol

The aim of the present study was to evaluate the effects of moxidectin (MOX – 200 µg/kg/sc) administered on Day Zero of a fixed-time artificial insemination (FTAI) protocol on fecal egg counts and the reproductive efficiency of primiparous and multiparous Nellore beef cows kept in the pasture. A simulation was performed of the possible correlation between the fecal egg count and helminth load per animal (cow versus calf). An economic analysis was performed of the magnitude of the return over investment (ROI) of moxidectin treatment at the onset of the FTAI protocol. Three experiments were performed with a total of 6,320 Nellore females (primiparous and multiparous) and calves approximately 45 days old. The animals were subdivided into two groups: control and treated with MOX subcutaneously on Day 0 concomitant with the reproduction protocol adopted in the first FTAI. Egg counts per gram of feces (EPG) were performed on Days 0 and 11. Resynchronization of ovulation (RO) was performed in cows diagnosed with negative pregnancy 30 days after the first FTAI. Nellore bulls were used for natural service at a proportion of one bull per 25 Nellore cows 10 days after the second diagnosis of gestation (D92). The results of the three experiments indicated that treatment with MOX at the beginning of the FTAI protocol (Day 0) increased the pregnancy rate at the first FTAI and had no effect on the pregnancy rate at the second FTAI (RO), leading to a larger number of pregnant cows at the end of the breeding season, with an ROI of 44.9 and 19.0 for primiparous and multiparous cows, respectively. The mean parasite load (EPG) decreased significantly after treatment with moxidectin in both primiparous and multiparous cows. However, the statement that the difference in the pregnancy rate for the treated cows occurred due to the control of helminth infection should be interpreted with caution. Further studies are needed to gain an understanding the unknown physiological mechanisms of moxidectin that could be affecting the reproductive results.

Abstract LB254: PKA signaling: a friend or foe to pediatric medulloblastoma

Abstract Pediatric brain tumor is the leading cause of cancer-related deaths in pediatric patients ranging 0-19 years of age. Medulloblastoma is one of the most commonly occurring brain tumor in children. Sonic hedgehog (Shh) activated subgroup of medulloblastoma is considered to be highly aggressive and metastatic in nature. Recent studies and oncomine, a cancer microarray database has shown that GABAA receptor is down regulated in pediatric medulloblastoma. In this study, we have evaluated the anti-cancer effects of an anthelminthic drug ‘moxidectin' a GABAA receptor agonist. Treatment of medulloblastoma cells with moxidectin, resulted in reduced Protein kinase A (PKA) activity. Leading to the inhibition of Gli1, a major transcription factor of non-canonical Shh signaling. Moxidectin has inhibited the proliferation of Daoy, UW426, UW228, ONS76, and PFSK1 medulloblastoma cells and significantly induced apoptosis in a concentration and time dependent manner in all the cell lines. Western blotting and immunofluorescence microscopy demonstrated that moxidectin treatment significantly induced GABAA receptor expression and inhibited cAMP mediated PKA signaling. As a result, the non-canonical activation of Gli1 and its downstream effector molecules such as Pax-6, Oct-4, Sox-2 and Nanog were also inhibited by moxidectin treatment. Efficacy of moxidectin was also evaluated in subcutaneous and intracranial medulloblastoma tumor models. Our results demonstrated that daily oral administration of 2.5 mg/kg moxidectin suppressed the growth of medulloblastoma tumors by 55-70% in subcutaneous and intracranial models. Ex-vivo analysis of tumors by western blotting, IHC, TUNEL and H&amp;E staining revealed that moxidectin suppressed medulloblastoma tumor progression by inhibiting PKA/Gli1 signaling axis indicating the significance of this pathway in medulloblastoma progression. To our knowledge, this study for the first time focuses on GABAA receptor agonist mediated PKA/Gli1 signaling inhibition. Most importantly, moxidectin is an FDA approved drug and is already in clinical use for the treatment of river blindness in humans with an established safety record, therefore any positive findings from our studies will prompt further clinical investigation into repositioning moxidectin for the treatment of MB patients. Citation Format: Itishree Kaushik, Sanjay Srivastava. PKA signaling: a friend or foe to pediatric medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB254.