8 research outputs found
Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats
Ivermectin is a widely used antiparasitic drug with known efcacy against several single-strain RNA
viruses. Recent data shows signifcant 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 profle including behavioral and weight monitoring, full blood count, biochemistry,
necropsy and histological examination of the lungs was conducted. The pharmacokinetic profle
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
Nebulized ivermectin for COVID‑19 and other respiratory diseases, a proof of concept, dose‑ranging study in rats
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
Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae
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
Chaotic, memory and cooling rate effects in spin glasses: Is the Edwards-Anderson model a good spin glass?
We investigate chaotic, memory and cooling rate effects in the three
dimensional Edwards-Anderson model by doing thermoremanent (TRM) and AC
susceptibility numerical experiments and making a detailed comparison with
laboratory experiments on spin glasses. In contrast to the experiments, the
Edwards-Anderson model does not show any trace of re-initialization processes
in temperature change experiments (TRM or AC). A detailed comparison with AC
relaxation experiments in the presence of DC magnetic field or coupling
distribution perturbations reveals that the absence of chaotic effects in the
Edwards-Anderson model is a consequence of the presence of strong cooling rate
effects. We discuss possible solutions to this discrepancy, in particular the
smallness of the time scales reached in numerical experiments, but we also
question the validity of the Edwards-Anderson model to reproduce the
experimental results.Comment: 17 pages, 10 figures. The original version of the paper has been
split in two parts. The second part is now available as cond-mat/010224
Nebulized ivermectin for COVID‑19 and other respiratory diseases, a proof of concept, dose‑ranging study in rats
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
Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats
Ivermectin is a widely used antiparasitic drug with known efcacy against several single-strain RNA
viruses. Recent data shows signifcant 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 profle including behavioral and weight monitoring, full blood count, biochemistry,
necropsy and histological examination of the lungs was conducted. The pharmacokinetic profle
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
Combinatorial QSAR Modeling of human Intestinal Absorption
Intestinal drug absorption in humans is a central topic in drug discovery. In this study, we use a broad selection of machine learning and statistical methods for the classification and numerical prediction of this key endpoint. Our dataset is based on a selection of 458 small drug-like compounds with FDA approval. Using easily available tools, we calculated one- to three-dimensional physicochemical descriptors and used various methods of feature selection (best-first backward selection, correlation analysis, and decision tree analysis). We then used decision tree induction (DTI), fragment-based lazy-learning (LAZAR), support vector machine classification, multilayer perceptrons, random forests, k-nearest neighbor and Naïve Bayes analysis to model absorption ratios and binary classification (well absorbed and poorly absorbed compounds). Best performance for classification was seen with DTI using the chi-squared analysis interaction detector (CHAID) algorithm yielding corrected classification rate of 88%, (Matthews correlation coefficient of 75%). In numeric predictions, the multilayer perceptron performed best achieving root mean squared error of 25.823 and a correlation coefficient of 0.6. In line with current understanding is the importance of descriptors such as lipophilic partition coefficients (logP) and hydrogen bonding. However, we are able to highlight the utility of gravitational indices and moments of inertia, reflecting the role of structural symmetry in oral absorption. Our models are based on s diverse dataset of marketed drugs representing a broad chemical space. These models therefore contribute substantially to the molecular understanding of human intestinal drug absorption and qualify for a generalized use in drug discovery and lead optimization