RESUMEN
Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80-90 mg/kg), higher dose (110-140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean Cmax 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.
Asunto(s)
Antiparasitarios/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Ivermectina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Administración por Inhalación , Animales , Antiparasitarios/farmacocinética , Antiparasitarios/farmacología , Conducta Animal/efectos de los fármacos , COVID-19 , Infecciones por Coronavirus/patología , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Ivermectina/farmacocinética , Ivermectina/farmacología , Pulmón/metabolismo , Pulmón/patología , Masculino , Necrosis , Pandemias , Neumonía Viral/patología , Prueba de Estudio Conceptual , Ratas , Ratas Sprague-Dawley , Trastornos Respiratorios/tratamiento farmacológico , Trastornos Respiratorios/patologíaRESUMEN
BACKGROUND: Mosquitoes that feed on animals can survive and mediate residual transmission of malaria even after most humans have been protected with insecticidal bednets or indoor residual sprays. Ivermectin is a widely-used drug for treating parasites of humans and animals that is also insecticidal, killing mosquitoes that feed on treated subjects. Mass administration of ivermectin to livestock could be particularly useful for tackling residual malaria transmission by zoophagic vectors that evade human-centred approaches. Ivermectin comes from a different chemical class to active ingredients currently used to treat bednets or spray houses, so it also has potential for mitigating against emergence of insecticide resistance. However, the duration of insecticidal activity obtained with ivermectin is critical to its effectiveness and affordability. RESULTS: A slow-release formulation for ivermectin was implanted into cattle, causing 40 weeks of increased mortality among Anopheles arabiensis that fed on them. For this zoophagic vector of residual malaria transmission across much of Africa, the proportion surviving three days after feeding (typical mean duration of a gonotrophic cycle in field populations) was approximately halved for 25 weeks. CONCLUSIONS: This implantable ivermectin formulation delivers stable and sustained insecticidal activity for approximately 6 months. Residual malaria transmission by zoophagic vectors could be suppressed by targeting livestock with this long-lasting formulation, which would be impractical or unacceptable for mass treatment of human populations.
Asunto(s)
Anopheles/efectos de los fármacos , Preparaciones de Acción Retardada/farmacocinética , Erradicación de la Enfermedad/métodos , Implantes de Medicamentos/administración & dosificación , Ivermectina/administración & dosificación , Malaria/prevención & control , África/epidemiología , Animales , Bovinos , Preparaciones de Acción Retardada/administración & dosificación , Implantes de Medicamentos/química , Humanos , Resistencia a los Insecticidas , Insecticidas/administración & dosificación , Insecticidas/farmacocinética , Ivermectina/farmacocinética , Malaria/epidemiología , Malaria/parasitología , Control de Mosquitos/métodos , Mosquitos Vectores/efectos de los fármacosRESUMEN
Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug-mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases.