Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model.

BACKGROUND: Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. METHODOLOGY/PRINCIPAL FINDINGS: Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26-100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite's entire life cycle and enabling long-lasting efficacy. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies.

Efficacy of sainfoin (Onobrychis viciifolia) pellets against multi resistant Haemonchus contortus and interaction with oral ivermectin: Implications for on-farm control.

The worldwide spread of resistance to anthelmintic (AH) drugs in gastrointestinal nematodes (GINs) imposes to explore alternative solutions. Amongst those, the possible use of tannin-containing nutraceuticals appears as a relevant option to replace (or decrease the frequency of) chemical-based treatments. Our objectives were to test the AH efficacy of sainfoin pellets against a multiresistant strain of Haemonchus contortus in experimentally infected lambs and to examine possible interaction between ivermectin (IVM) and condensed tannins (CT)-rich ressource. In vivo study was performed with twenty-four lambs were inoculated (Day 0) with multiresistant H. contortus infective larvae. On D21 Post-Infection, the lambs were assigned to two dietary treatments (sainfoin vs lucerne control pellets). On D39, half of the animals per group received 0.25ml/kg of an oral ivermectin treatment. On D47, animals were slaughtered to count worms. The consumption of sainfoin was associated with higher packed cell volume (PCV) values (P<0.05) and reduced faecal egg counts (FECs) (P<0.05). For the experimental feeding period, FECs were overall reduced by 50% in the sainfoin group. The diet did not have significant effect on the worm number but sainfoin significantly reduced female fertility. Decrease in plasma IVM concentrations was observed in the sainfoin-fed animals and was associated with a decrease of IVM efficiency when compared with the control group. Incubating tannin in vitro with ivermectin and rumen fluid showed a blocking of ivermectin by the tannins. This suggests that tannins lower the IVM intestinal absorption compromising thereby drug plasma bioavailability and efficacy. Tannin-containing nutraceuticals alter the biology of multiresistant nematodes, thus representing an option for their sustainable control. In vivo and in vitro interactions between nutraceuticals and chemicals impose caution when both tannin-rich diet and drug-based treatments are combined. Further studies are required to clarify the mechanisms that support such interactions.

Contribution of lymphatic transport to the systemic exposure of orally administered moxidectin in conscious lymph duct-cannulated dogs.

Moxidectin, a macrocyclic lactone (ML), is a potent parasiticide widely used in veterinary medicine and currently under development for use in humans. The contribution of the lymphatic route to the intestinal absorption and transport of moxidectin to the systemic circulation was evaluated in lymph duct-cannulated dogs. Beagle dogs were operated for lymph duct cannulation and were orally dosed with 38g of corn oil and moxidectin (0.2mg/kg, n=3). The lymph and plasma were collected over 24h and moxidectin and triglyceride concentrations were measured. Similarly, control dogs (n=5) were dosed orally with moxidectin and oil and subsequently with moxidectin intravenously. Pharmacokinetic parameters were calculated for moxidectin in the plasma of the dogs. Moxidectin readily accumulated in the lymph and reached a plateau 8h post-administration, paralleling triglyceride appearance. The percentage of moxidectin recovered in lymph was 22+/-3% of the total administered dose with 92% being associated with triglyceride-rich particles. The systemic bioavailability of oral moxidectin coadministered with lipid was only 40% in the lymph duct-cannulated dogs compared with 71% in the controls. Our data clearly indicate that the lymphatic transport process contributes significantly to the post-prandial intestinal absorption of moxidectin and subsequently to its systemic bioavailability. The lymphatic transport of moxidectin offers potential strategies based on lipid formulations to improve the bioavailability of MLs when administered orally.

Enhancement of oral moxidectin bioavailability in rabbits by lipid co-administration.

Moxidectin is a member of the macrocyclic lactone family of drugs widely used for the control of internal and external parasites. Because moxidectin is highly lipophilic, we suspect that lymphatic transport influences the intestinal absorption of oral formulations of the drug. We studied the influence of lipid co-administration on the pharmacokinetics of an oral formulation of moxidectin in rabbits. Ten rabbits were orally administered 0.3 mg kg(-1) moxidectin with or without sunflower oil. Moxidectin and triglyceride were analyzed in plasma over 23 days. Sunflower oil co-administration significantly increased the area under the plasma concentration-time curve of moxidectin (98%, P<0.05) and prolonged its mean residence time from 1.52 days to 2.12 days (P<0.04). Simultaneously, an increase in plasma triglyceride was observed in response to oil administration. It is suggested that lipid administration increases the systemic availability of oral moxidectin by enhancing the extent of intestinal lymphatic transport of the drug. Lipid-based formulations should improve the bioavailability of moxidectin in rabbits.