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The goal of the current work was to perform an integrated evaluation of monepantel (MNP) pharmacokinetics (PK) and pharmacodynamics, measured as anthelmintic efficacy, after its oral administration to calves naturally infected with GI nematodes resistant to ivermectin (IVM) and ricobendazole (RBZ) on three commercial farms. On each farm, forty-five calves were randomly allocated into three groups (n = 15): MNP oral administration (2.5 mg/kg); IVM subcutaneous (SC) administration (0.2 mg/kg); and RBZ SC administration (3.75 mg/kg). Eight animals from the MNP treated group (Farm 1) were selected to perform the PK study. Drug concentrations were measured by HPLC. The efficacy was determined by the faecal egg count reduction test (FECRT). MNP and MNP-sulphone (MNPSO2) were the main analytes recovered in plasma. MNPSO2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO2 metabolite (96.8 ± 29.7 ng/mL and 9220 ± 1720 ng h/mL) compared to MNP (21.5 ± 4.62 ng/mL and 1709 ± 651 ng h/mL). The MNPSO2 AUC value was 6-fold higher compared to the parent drug. Efficacies of 99% (Farm 1), 96% (Farm 2) and 98% (Farm 3) demonstrated the high activity of MNP (P

Geraniol (GNL) was effective against gastrointestinal nematodes in vitro; nevertheless, the anthelmintic effect of phytochemicals combined with synthetic drugs has been little explored in vivo. This article characterized in vitro / in vivo the pharmacological features of GNL in sheep as well as its pharmacokinetic interaction with albendazole (ABZ). Additionally, the in vivo efficacy of GNL against Haemonchus contortus was evaluated in lambs. Liver microsomes from lambs were incubated in the absence or presence of GNL to analyze CYP1A1, CYP1A2 and FMO metabolic pathways. The effect of GNL on the hepatic sulfoxidation and sulfonation of ABZ and the ruminal sulforeduction of albendazole sulfoxide (ABZSO) was assessed. The in vivo pharmacokinetic interaction of ABZ and GNL was evaluated in lambs. The effect of GNL on the fecal egg count was evaluated in lambs infected with a resistant isolate of H. contortus. In sheep liver microsomes, the presence of 2 mM GNL reduced the CYP1A1, CYP1A2 and FMO pathways by 77.9, 90.8 and 84.5%, respectively, with respect to control (P

Background: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. Methods: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. Findings: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59–77) versus untreated controls (42% IQR 31–73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. Interpretation: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. Funding: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.