Estimation of Pediatric Dosage of Antimalarial Drugs, Using Pharmacokinetic and Physiological Approach.

Most of the individuals who die of malaria in sub-Saharan Africa are children. It is, therefore, important for this age group to have access to the right treatment and correct dose. Artemether-lumefantrine is one of the fixed dose combination therapies that was approved by the World Health Organization to treat malaria. However, the current recommended dose has been reported to cause underexposure or overexposure in some children. The aim of this article was, therefore, to estimate the doses that can mimic adult exposure. The availability of more and reliable pharmacokinetic data is essential to accurately estimate appropriate dosage regimens. The doses in this study were estimated using the physiological information from children and some pharmacokinetic data from adults due to the lack of pediatric pharmacokinetic data in the literature. Depending on the approach that was used to calculate the dose, the results showed that some children were underexposed, and others were overexposed. This can lead to treatment failure, toxicity, and even death. Therefore, when designing a dosage regimen, it is important to know and include the distinctions in physiology at various phases of development that influence the pharmacokinetics of various drugs in order to estimate the dose in young children. The physiology at each time point during the growth of a child may influence how the drug is absorbed, gets distributed, metabolized, and eliminated. From the results, there is a very clear need to conduct a clinical study to further verify if the suggested (i.e., 0.34 mg/kg for artemether and 6 mg/kg for lumefantrine) doses could be clinically efficacious.

A Malawian pharmaceutical response to the COVID-19 Pandemic.

The COVID-19 pandemic has elicited swift and innovative responses due to the severity of the outbreak. Higher education institutions worldwide with pharmacy programs have identified vital gaps in COVID-19 care and has undertaken proactive steps to aid in the fight against the coronavirus. In Malawi, the Kamuzu University of Health Science's Department of Pharmacy initiated the production of a modified formulation of the World Health Organization's (WHO) recommended hand sanitizer. This manufacturing venture involved mobilizing the pharmacy faculty, identifying gaps in supplies and equipment, and utilizing evidenced-based information to create a high-quality sanitation product, which passed the requirements as tested by the Malawi Bureau of Standards. The department of pharmacy is expanding their distribution of the product to meet the needs of frontline healthcare workers and vulnerable populations. With historical issues of accessing care in Malawi and with COVID-19's spread among healthcare workers, this hand sanitizer venture is vital in the public healthcare's system response. The department of pharmacy will continue to lead the pharmacy profession in Malawi to provide targeted interventions in this unprecedented time.

Dose-dependent pharmacokinetics and tentative identification of urine metabolites from an isosteviol derivative with anti-hepatitis B activity in rats.

Compound 1 (ent-16-oxobeyeran-19-N-methylureido) is a semisynthetic isosteviol derivative that shows anti-hepatitis B virus activity in Huh7 cells by affecting viral DNA transcription and the Toll-like receptor 2/nuclear factor-κB signaling pathway. Thus, the pharmacokinetics and metabolite identification were studied as part of the discovery and development process of compound 1. The pharmacokinetics was evaluated after administration to rats at an intravenous dose of 2 mg/kg, and oral doses of 2, 5 and 10 mg/kg. Plasma concentrations were determined using LC-MS/MS. Moreover, urine samples from rats dosed at 10 mg/kg were scanned for metabolites using UPLC-QTOF-MS/MS. Results for the intravenously administered dose of 2 mg/kg showed that the area under the concentration-time curve was 65,223.31 ± 4269.80 ng min/mL, and the systemic clearance was 0.031 ± 0.0021 L/min. Oral pharmacokinetic parameters were dose-dependent, showing nonproportional increases in the oral AUCs with respective values of 4371.62 ± 3084.81, 22,472.75 ± 9103.33 and 135,141.83 ± 38,934.03 ng min/mL for 2, 5 and 10 mg/kg. The bioavailability was low at 1.5% for 2 mg/kg dose, and at 1.1% for both 5 and 10 mg/kg doses. Metabolites excreted in the urine indicate possible N-oxidation and glucuronide conjugation.

Development and validation of an LC-MS/MS method for quantification of NC-8 in rat plasma and its application to pharmacokinetic studies.

ent-16-Oxobeyeran-19-N-methylureido (NC-8) is a recently synthesized derivative of isosteviol that showed anti-hepatitis B virus (HBV) activity by disturbing replication and gene expression of the HBV and by inhibiting the host toll-like receptor 2/nuclear factor-κB signaling pathway. To study its pharmacokinetics as a part of the drug development process, a highly sensitive, rapid, and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for determining NC-8 in rat plasma. After protein precipitation extraction, the chromatographic separation of the analyte and internal standard (IS; diclofenac sodium) was performed on a reverse-phase Luna C18 column coupled with a Quattro Ultima triple quadruple mass spectrometer in the multiple-reaction monitoring mode using the transitions, m/z 347.31 â†’ 75.09 for NC-8 and m/z 295.89 â†’ 214.06 for the IS. The lower limit of quantitation was 0.5 ng/mL. The linear scope of the standard curve was between 0.5 and 500 ng/mL. Both the precision (coefficient of variation; %) and accuracy (relative error; %) were within acceptable criteria of <15%. Recoveries ranged from 104% to 113.4%, and the matrix effects (absolute) were non-significant (CV ≤ 6%). The validated method was successfully applied to investigate the pharmacokinetics of NC-8 in male Sprague-Dawley rats. The present methodology provides an analytical means to better understand the preliminary pharmacokinetics of NC-8 for investigations on further drug development.

Effects of metformin dose on cancer risk reduction in patients with type 2 diabetes mellitus: a 6-year follow-up study.

STUDY OBJECTIVE: To explore the effects of metformin dose on cancer risk reduction in patients with type 2 diabetes. DESIGN: Population-based cohort study. DATA SOURCE: National Health Insurance program Longitudinal Health Insurance Database. PATIENTS: A total of 65,754 age- and gender-matched patients without diabetes and no previous cancer diagnosis were extracted from the database. MEASUREMENTS AND MAIN RESULTS: We compared cancer risk among the subjects who had no diabetes, had type 2 diabetes but were not on diabetes drugs, used metformin only, used antidiabetic drugs other than metformin, or used metformin in combination with other antidiabetic drugs. Our results revealed dose-dependent effects of metformin on cancer risk and cancer onset times. A significant decrease in cancer risk was found in the monotherapy group who received more than 360 defined daily doses (DDDs) of metformin (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24-0.66). The greatest decrease in cancer risk was observed in patients who took more than 1080 DDDs (HR 0.27, 95% CI 0.09-0.84). Significantly greater dose-dependent effects were seen in patients who used metformin in combination with other antidiabetic drugs. CONCLUSION: The magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin, regardless of whether metformin was used alone or combined with other antidiabetic drugs.