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Loiasis (Loa loa filariasis) is often deemed to be a benign condition but individuals with high microfilarial densities (MFD) are at risk of encephalopathy following ivermectin administration (IVM). As onchocerciasis control programs are based on mass drug administration of ivermectin, these serious adverse events (SAE) hamper their deployment in Central Africa. This thesis aims to better characterize the risk (i) before treatment, by investigating the influence of individual factors on the level of risk, and (ii) after treatment to determine to which extent the pre-treatment MFD can be inferred from the MFD obtained after treatment. Methods: (i) data from two clinical trials conducted in 1995-1996 and 2005 in Cameroon were pooled to model the risk of SAE as a logistic function of age, sex, and MFD (as a fractional polynomial). (ii) Data from six clinical trials with pre- and post-IVM MFD measurements were used to calculate the sensitivity, specificity, and positive and negative predictive values of different post-IVM MFD cutoffs for classifying individuals according to the commonly used pre-treatment thresholds.Results: we outlined how individual factors (age and sex) can influence the level of risk of post-IVM SAE and showed that the threshold above which IVM should be contraindicated could be adapted according to these factors. We also show that the post-treatment threshold of 1,000 mf/mL used to impute the occurrence of a SAE to IVM and L. loa is probably too low, and propose abacuses that can be used to assess this imputability in mass or individual treatments. Conclusions: the therapeutic management of loiasis is still poorly defined. The recent demonstration of its impact on life expectancy should lead to the definition of adequate management strategies for loiasis and its complications after treatment, including in Northern settings.; La loase (filariose à Loa loa) est souvent considérée comme une maladie bénigne mais les individus présentant une forte densité microfilarienne (DMF) dans le sang risquent de développer une encéphalopathie après la prise d’ivermectine (IVM). Les programmes de lutte contre l’onchocercose étant basés sur le traitement de masse des populations par l’IVM, ces événements indésirables graves (EIG) entravent leur déploiement en Afrique centrale. Ce travail vise à mieux caractériser ce risque (i) avant traitement, en étudiant l’influence de facteurs individuels sur le niveau de risque, et (ii) après traitement, en évaluant dans quelle mesure les DMF pré-traitement peuvent être évaluées à partir des DMF mesurées après traitement. Méthodes : (i) les données de deux essais cliniques menés en 1995 et 2005 au Cameroun ont été combinées pour modéliser, par une régression logistique incluant l’âge, le sexe et la DMF (transformée par un polynôme fractionnaire), le risque d’EIG. (ii) Les données de six essais cliniques avec mesure des DMF avant et après traitement par IVM ont été utilisées pour calculer la sensibilité, la spécificité et les valeurs prédictives positive et négative de différents seuils de DMF post-traitement pour classer les individus dans les catégories de risque habituellement retenues avant traitement.Résultats : nous avons précisé comment certains facteurs individuels (âge et sexe) peuvent influencer le niveau de risque d'EIG post-IVM et montré que le seuil au-delà duquel l’IVM devrait être contre-indiquée pourrait être adaptéen fonction de ces facteurs. Nous montrons également que le seuil de DMF post-traitement (1.000 mf/mL) utilisé pour imputer à l’IVM et L. loa la survenue d’un EIG est probablement trop bas, et proposons des abaques qui peuvent être utilisées pour évaluer cette imputabilité lors de traitements de masse ou de traitements individuels.Conclusions : la prise en charge thérapeutique de la loase est encore mal définie. La démonstration récente de son impact sur l’espérance de vie devrait conduire à définir des stratégies de prise en charge adéquates de la loase et de ses complications après traitement, y compris dans les pays du Nord.

Background Ivermectin is known to cause severe encephalopathies in subjects infected with loiasis, an endemic parasite in Sub-Saharan Africa (SSA). In addition, case reports have described ivermectin-related serious adverse drug reactions (sADRs) such as toxidermias, hepatic and renal disorders. The aim of this study was to identify suspected sADRs reported after ivermectin administration in VigiBase, the World Health Organization’s global individual case safety reports database and analyze their frequency relative to the frequency of these events after other antinematodal drugs reported in SSA and other areas of the world (ROW). Methods All antinematodal-related sADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate nervous, cutaneous, psychiatric, respiratory, renal, hepatic and cardiac suspected sADRs reported after ivermectin and benzimidazole drug administration across the world, in SSA and RoW. Principal findings 2041 post-ivermectin or post-benzimidazole suspected sADRs were identified including 667 after ivermectin exposure (208 in SSA and 459 in the RoW). We found an increased reporting for toxidermias, encephalopathies, confusional disorders after ivermectin compared to benzimidazole drug administration. Encephalopathies were not only reported from SSA but also from the RoW (adjusted reporting odds ratios [aROR] 6.30, 95% confidence interval: 2.68–14.8), highlighting the fact these types of sADR occur outside loiasis endemic regions. Conclusion We described for the first time suspected sADRs associated with ivermectin exposure according to geographical origin. While our results do not put in question ivermectin’s excellent safety profile, they show that as for all drugs, appropriate pharmacovigilance for adverse reactions is indicated., Author summary Ivermectin is a drug used worldwide for various indications: onchocerciasis, lymphatic filariasis, strongyloidiasis, human sarcoptic scabies, acarodermatitis and rosacea. In the early 1990s, it was discovered that ivermectin could induce severe encephalopathies in some patients with high parasite loads of Loa loa, a filarial nematode. This objective of this pharmacovigilance study is to summarize serious neurological and non-neurological post-ivermectin adverse drug reactions reported in the World Health Organization database called VigiBase. This study shows that reported serious adverse drug reactions associated with ivermectin are fairly consistent with those mentioned in the official product information of ivermectin but also provides some new signals. Serious post-ivermectin encephalopathies can also occur outside of Loa loa endemic regions but the understanding of the mechanism by which it occurs requires further studies. A new signal concerning two serious toxidermias (DRESS syndrome and acute generalized exanthematous pustulosis) is also described. A lack of reporting of adverse drug reactions is noticeable in some Sub-Saharan African countries, and actions are needed to increase the reporting rates of these adverse effects in these countries.

Pentameric ligand-gated ion channels (pLGICs), which mediate chemo-electric signal transduction in animals, have been recently found in bacteria. Despite clear sequence and 3D structure homology, the phylogenetic distance between prokaryotic and eukaryotic homologs suggests significant structural divergences, especially at the interface between the extracellular (ECD) and the transmembrane (TMD) domains. To challenge this possibility, we constructed a chimera in which the ECD of the bacterial protein GLIC is fused to the TMD of the human α1 glycine receptor (α1GlyR). Electrophysiology in Xenopus oocytes shows that it functions as a proton-gated ion channel, thereby locating the proton activation site(s) of GLIC in its ECD. Patch-clamp experiments in BHK cells show that the ion channel displays an anionic selectivity with a unitary conductance identical to that of the α1GlyR. In addition, pharmacological investigations result in transmembrane allosteric modulation similar to the one observed on α1GlyR. Indeed, the clinically active drugs propofol, four volatile general anesthetics, alcohols, and ivermectin all potentiate the chimera while they inhibit GLIC. Collectively, this work shows the compatibility between GLIC and α1GlyR domains and points to conservation of the ion channel and transmembrane allosteric regulatory sites in the chimera. This provides evidence that GLIC and α1GlyR share a highly homologous 3D structure. GLIC is thus a relevant model of eukaryotic pLGICs, at least from the anionic type. In addition, the chimera is a good candidate for mass production in Escherichia coli , opening the way for investigations of “druggable” eukaryotic allosteric sites by X-ray crystallography.

International audience; Self-licking behaviour in cattle has recently been identified as a determinant of the kinetic disposition of topically-administered ivermectin. In the present study, we document the occurrence and extent of transfer between cattle of three topically-administered endectocides, as a consequence of allo-licking. Four groups of two Holstein cows each received one pour-on formulation of doramectin, ivermectin, or moxidectin, or no treatment. The cows were then kept together in a paddock. Systemic exposure to each topically-administered endectocide was observed in at least five of six non-treated cattle. Plasma and faecal drug concentration profiles in non-treated animals were highly variable between animals and within an animal, and sometimes attained those observed in treated animals. Drug exchanges were quantified by measuring plasma and faecal clearances after simultaneous i.v. administration of the three drugs as a cocktail. Plasma clearances were 185+/-43, 347+/-77 and 636+/-130ml/kg/day, faecal clearances representing 75+/-26, 28+/-13, and 39+/-30% of the plasma clearance for doramectin, ivermectin and moxidectin, respectively. The amount of drug ingested by non-treated cattle attained 1.3-21.3% (doramectin), 1.3-16.1% (ivermectin), 2.4-10.6% (moxidectin) of a pour-on dose (500 microg/kg). The total amount of drug ingested by all non-treated cattle represented 29% (doramectin), 19% (ivermectin), and 8.6% (moxidectin) of the total amount of each drug poured on the backs of treated animals. The cumulative amounts of endectocide ingested by each non-treated cow ranged from 1.3 to 27.4% of a pour-on dose. Oral bioavailability after drug ingestion due to allo-licking was 13.5+/-9.4, 17.5+/-3.5 and 26.1+/-11.1% for doramectin, ivermectin and moxidectin, respectively. The extent of drug exchange demonstrated here raises concerns for drug efficacy and safety, emergence of drug resistance, presence of unexpectedly high residue levels in treated and/or untreated animals and high environmental burdens. Moreover, scientific and regulatory aspects of clinical and bioequivalence trials for topical drug administration in cattle should be explored.

International audience; Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administrations of ivermectin at a 3-5-month interval. For one pour-on administration, the twins were separated into an unrestrained group and a group where self- and allo-licking were prevented. Ivermectin concentrations in the plasma and faeces were determined by HPLC. Licking resulted in a high intra-and inter-individual variability of systemic exposure after topical application. By the means of pharmacokinetic modelling, we showed that 58-87% of the pour-on dose was ingested, while only 10% was absorbed percutaneously. Approximately 72% of the ingested ivermectin transited directly into the faeces, resulting in a 7-fold higher faecal excretion of the parent drug than in the non-lickers. We conclude that topical administration does not guarantee a controlled drug delivery in cattle. More importantly, the simulations revealed that non-treated cattle could get easily contaminated by allo-licking, raising the public health problem of unexpected drug residues in edible tissues.

International audience; The transepithelial intestinal elimination of ivermectin was studied using the intestinal closed-loop model in the rat. The common bile duct was cannulated, and duodenum, jejunum, and ileum were isolated in situ with their intact blood supplies. Following administration of 100, 200, or 400 microg/kg b.wt. ivermectin via the carotid artery, the elimination of parent ivermectin into the small intestinal lumen over 90 min was approximately 5-fold higher than in bile. The major amount of secreted ivermectin was recovered in the jejunum, but the duodenum showed a higher intestinal elimination capacity than the other intestinal segments with respect to the intestinal length. Systemic coadministration of the P-glycoprotein blocker verapamil significantly reduced the elimination capacity of jejunum by 50%, which resulted in a 30% decrease of ivermectin overall elimination by the small intestine. In contrast, verapamil did not significantly affect ivermectin secretion in duodenum, ileum, or bile in the same animals. Ivermectin small intestinal and biliary clearances were estimated to account for 27 and 5.5% of the total drug clearance, which was evaluated from a parallel in vivo experiment in which rats were given 200 microg/kg b.wt. ivermectin intra-arterially. In conclusion, intestinal secretion plays a greater role than biliary secretion in the overall elimination of ivermectin in the rat, providing major amounts of active drug to the intestinal lumen and to feces. This is discussed in terms of therapeutic efficacy against intestinal parasites in humans and animals and of ecotoxicity resulting from the contamination of livestock dung with parent drug.

International audience; Pour-on formulations of endectocides are extensively used to treat and control systemic parasitic diseases in cattle, worldwide. The purpose of the present study was to investigate the influence of the natural licking behaviour of cattle on the plasma and faecal disposition of topically administered ivermectin. Twelve Holstein cattle were given one single intravenous (i.v.) (200 microg/kg) and topical (500 microg/kg) administration of ivermectin at a 5-month interval. For the pour-on administration, the animals were allocated into two groups (n=6): one control group (lickers) and one group where licking was prevented (non-lickers). Ivermectin plasma (total) clearance (270+/-57.4 ml/kg/day) was very homogeneous among the 12 cattle. In contrast, major differences between lickers and non-lickers were observed following pour-on administration. Prevention of licking resulted in an extended terminal plasma half-life (363+/-16.2 vs. 154+/-7.4 h in lickers) and in a lower and less variable systemic availability of ivermectin (19+/-4.9 vs. 33+/-18.5% in lickers). More importantly, nearly 70% of the pour-on dose was recovered as parent drug in the faeces of lickers vs. only 6.6% in non-lickers. Altogether, these results are consistent with an oral rather than percutaneous absorption of topical ivermectin in control animals, the non-systemically available fraction of ingested ivermectin providing a major contribution (80%) to the drug faecal output. The consequences of licking on the disposition of pour-on ivermectin are discussed in terms of environment, given the known ecotoxicity of this drug, and of cross-contamination. Animals licking themselves and each other could result in unexpected residues in edible tissues of untreated animals and in possible subtherapeutic drug concentrations, a factor in drug resistance. According to the Precautionary Principle, these considerations elicit concern over the use of topical drug formulations in cattle.

International audience; We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human alpha7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl- currents. The concomitant increase in apparent affinity and cooperativity of the dose-response curve suggest that ivermectin acts as a positive allosteric effector. This interpretation is supported by the observation of an increase in efficiency of a partial agonist associated with the potentiation and by the differential effect of ivermectin on mutants within the M2 channel domain. Ivermectin effects reveal a novel allosteric site for pharmacological agents on neuronal alpha7 nicotinic acetylcholine receptors.

International audience; A study aimed at determining individual factors associated with participation in community treatment with ivermectin was conducted in a village hyperendemic for onchocerciasis in northern Cameroon. The respective influences of sex, age, place of residence, distance between the compound and the dosing point, compound size, and participation in treatment by authoritative individuals in the compound was evaluated using univariate and multivariate analysis. Participation in treatment was closely associated with the attitude of the compound heads. Participation of compound heads in treatment increased as the household size increased, and as the distance to the distribution point diminished. This may be explained by the fact that getting information on health programmes is easier in large households whose members are involved in various social activities, and in compounds located near the village centre. Staff involved in health education should take this issue into account, and try to ensure circulation of information particularly to those living in small or remote compounds.