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Made available in DSpace on 2021-06-25T10:22:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-04-01 A magnetic enteric-coated tablet containing diclofenac sodium was produced, and its performance under physiological and disturbed gastrointestinal motility was assessed through pharmacomagnetography analysis. In vitro studies were performed using conventional methods and in vivo studies were conducted on healthy volunteers before (control) and after domperidone administration. The magnetic tablet's gastrointestinal (GI) transit and disintegration process were monitored using the Alternating Current Biosusceptometry sensors combined with drug plasmatic concentration. The Gastric Residence Time, Colon Arrival Time, Small Bowel Transit Time, Disintegration Time and the pharmacokinetics parameters were calculated. The pH-dependent polymers used to coat the magnetic tablets were able to avoid the premature drug release on gastric or small intestine simulated medium. Gastric Residence Time was accelerated compared with the control group (p < 0.01). No significant differences were found regarding small bowel transit, colon arrival, disintegration process, or pharmacokinetics parameters. A strong correlation between magnetic monitoring and pharmacokinetics parameters analysis was determinant to evaluate the efficiency in the drug delivery at a specific site in the human gastrointestinal tract. In addition, a tablet with a damaged coating was used as a proof of concept to show the suitability of our methodology to evaluate the tablet. Our study showed that pharmacomagnetography is a multi-instrumental approach towards assessing drug delivery and bioavailability. São Paulo State University – UNESP Department of Biophysics and Pharmacology Institute of Biosciences Alagoas State University of Health Sciences- UNCISAL Center of Integrative Sciences São Paulo State University – UNESP Department of Biophysics and Pharmacology Institute of Biosciences

Remdesivir is an antiviral drug that results in clinical improvement after five days of treatment and accelerates recovery by 31%. No studies have discussed the pharmacokinetic analysis of remdesivir in patients with severe COVID-19 requiring extracorporeal membrane oxygenation (ECMO). A 63-year-old American man who underwent mechanical ventilation and ECMO for severe COVID-19 was administered remdesivir for ten days. The loading dosage was 200 mg at 7 PM on day 12 and 100 mg daily at 0:00 PM from day 13–21, administered within 1 h. The pharmacokinetic analysis was performed. The serum creatinine concentration was within the normal range of 0.5–0.7 mg/dL during treatment. According to the pharmacokinetic analysis, the plasma concentrations of remdesivir and GS-441524 4 h after administration (C4) were 662 ng/mL and 58 ng/mL, respectively, and the concentrations 18 h after administration (C18) were 32 ng/mL and 44 ng/mL, respectively. Therefore, the half-life of remdesivir and GS-441524 was 3.2 and 35.1 h, respectively. Monitoring the plasma concentrations of remdesivir and GS-441524 in patients undergoing ECMO may be necessary., Highlights • A COVID-19 patient undergoing ECMO was administered remdesivir. • The loading dosage was 200 mg at 7:00 PM on day 12. • From days 13–21, it was 100 mg daily at 0:00 PM administered within 1 h. • The half-lives of remdesivir and GS-441524 were 3.2 and 35.1 h, respectively. • Plasma concentrations of remdesivir and GS-441524 must be monitored during ECMO.

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

Echinococcosis is a serious helminthic zoonosis with a great impact on human health and livestock husbandry. However, the clinically used drugs (benzimidazoles) have a low cure rate, so alternative drugs are urgently needed. Currently, drug screenings for echinococcosis are mainly phenotype-based, and the efficiency of identifying active compounds is very low. With a pharmacophore model generated from the structures of active amino alcohols, we performed a virtual screening to discover novel compounds with anti-echinococcal activity. Sixty-two compounds from the virtual screening were tested on Echinococcus multilocularis protoscoleces, and 10 of these compounds were found to be active. After further evaluation of their cytotoxicity, S6 was selected along with two active amino alcohols for in vivo pharmacodynamic and pharmacokinetic studies. At the two tested doses (50 and 25 mg/kg), S6 inhibited the growth of E. multilocularis in mice (14.43 and 9.53%), but no significant difference between the treatment groups and control group was observed. Treatment with BTB4 and HT3 was shown to be ineffective. During the 28 days of treatment, the death of mice in the mebendazole, HT3, and BTB4 groups indicated their toxicity. The plasma concentration of S6 administered by both methods was very low, with the Cmax being only 1 ng/ml after oral administration and below the detection limit after intramuscular administration. In addition, the plasma concentrations of BTB4 and HT3 in vitro did not reach high enough levels to kill the parasites. The toxicities of these two amino alcohols indicated that they are not suitable for further development as anti-echinococcal drugs. However, further attempts should be made to increase the bioavailability of S6 and modify its structure. In this study, we demonstrate that pharmacophore-based virtual screenings with high drug identification efficiency could be used to find novel drugs for treating echinococcosis.

Assessment of mitochondrial oxidative metabolism has wide-ranging importance, from pharmacokinetic analysis to studies in cell viability and apoptosis. Here we present the Perfusion File Analyzer (PFA) application for the real-time analysis of spectral data to measure cytochrome c reduction, cytochrome a3 reduction, and other parameters important to cellular metabolism, which are collected during tissue perfusion experiments. Our current efforts are focused on quantitating changes in mitochondrial function by normalizing baseline drift of spectral data while addressing two major challenges: (1) a lack of real-time feedback from the system when aiming is compromised, and (2) an inability to adjust calculated data in the event of spectral shift. PFA has been developed to address these issues, and is currently used for quality assessment of human islets prior to clinical transplantation.