Enhancement of cyclosporin A solubility by d-alphatocopheryl-polyethylene-glycol-1000 succinate (TPGS)

The aqueous solubility of cyclosporin A (CyA) in the presence of various concentrations of TPGS ranging from 0.01 to 0.50 mM was studied at three temperatures (5, 20, and 37°C). Compared to previously reported solubility data in triple distilled water, solubility in the presence of TPGS was significantly increased at all temperatures. Surface tension and light scattering measurements showed that solubilization in TPGS multimers is the main mechanism responsible for the increased CyA solubility at 20°C and 37°C. In contrast, the increased CyA solubility at 5°C appears to be mediated by other mechanism(s), such as association of TPGS in patients CyA. These data substantiate the view that the enhanced bioavailability of CyA, when coadministered with TPGS in patients suffering from cholestasis, is due to the increased solubility of CyA in the presence of TPGS. © 1994

Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens

Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of ‘cytokine storm’ and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used. In this study, simulations were performed to identify the ability of dosage regimens to attain plasma levels in CVOID-19 patients, known to be generally safe and efficacious. Since renal and hepatic impairment, as well as, drug-drug interactions have been identified to be the most significant factors increasing colchicine toxicity, the impact of these interactions was assessed in the simulations. Some dosage regimens lead to high colchicine concentrations, while others result in sub-therapeutic levels. Additional dosage schemes were proposed in this study aiming to be applied in patients with clearance insufficiency. Colchicine administration of 0.5 mg twice daily, can be considered safe and effective. In cases of clearance impairment, doses as low as 0.25 mg thrice or twice daily should be applied. Colchicine is a narrow therapeutic index drug and dosage regimens tailored to patients’ needs should be designed. © 2021 Informa UK Limited, trading as Taylor & Francis Group

Modified HPLC analysis of diltiazem in plasma for pharmacokinetic studies

A simple procedure for determination of diltiazem in plasma using high-performance liquid chromatography (HPLC) is described. The method consists of extraction of the drug and the internal standard (loxapine) by using hexane-isopropanol (98:2) followed by solvent evaporation and redissolution of the residue in acetonitrile/0.5 M potassium dihydrogen phosphate (pH 2.5, 30:70). The procedure has a sensitivity limit of 2 ng/ml and a standard curve that is linear to 200 ng/ml. The method was applied to a pharmacokinetic study of diltiazem tablets. © 1990

Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients’ characteristics: a review of the literature and simulations

During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models were retrieved from the literature and after evaluation and assessment one was selected in order to perform simulations. The most commonly applied dosing schemes were explored for patients with different weights and different levels of HCQ clearance impairment. Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. For instance, the dosing scheme proposed for a 70 kg adult with moderate COVID-19 symptoms would be 600 mg upon diagnosis, 400 mg after 12 h, 300 mg after 24 h, 200 mg after 36 h, followed by 200 mg BID for 4 d, followed by 200 mg OD for 5 d. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients. © 2020 Informa UK Limited, trading as Taylor & Francis Group

Unusual solubility behaviour of cyclosporin A in aqueous media

Abstract— The solubility of cyclosporin A was determined in water and in Sorensen buffers at pH 1.2 and 6.6 at temperatures ranging from 5 to 37°C. No differences in solubility behaviour were observed among the three aqueous media. Solubility was found to be inversely proportional to the temperature in each medium, indicating that the heat of solution was exothermic in each case. 1991 Royal Pharmaceutical Society of Great Britai

Correlation between acinetobacter baumannii resistance and hospital use of meropenem, cefepime, and ciprofloxacin: Time series analysis and dynamic regression models

Acinetobacter baumannii is one of the most difficult-to-treat pathogens worldwide, due to developed resistance. The aim of this study was to evaluate the use of widely prescribed antimi-crobials and the respective resistance rates of A. baumannii, and to explore the relationship between antimicrobial use and the emergence of A. baumannii resistance in a tertiary care hospital. Monthly data on A. baumannii susceptibility rates and antimicrobial use, between January 2014 and December 2017, were analyzed using time series analysis (Autoregressive Integrated Moving Average (ARIMA) models) and dynamic regression models. Temporal correlations between meropenem, cefepime, and ciprofloxacin use and the corresponding rates of A. baumannii resistance were documented. The results of ARIMA models showed statistically significant correlation between meropenem use and the detection rate of meropenem-resistant A. baumannii with a lag of two months (p = 0.024). A positive association, with one month lag, was identified between cefepime use and cefepime-resistant A. baumannii (p = 0.028), as well as between ciprofloxacin use and its resistance (p < 0.001). The dynamic regression models offered explanation of variance for the resistance rates (R2 > 0.60). The magnitude of the effect on resistance for each antimicrobial agent differed significantly. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Pharmacokinetics of oral cefatrizine in pregnant and non-pregnant women with reference to fetal distribution

Objective: To investigate the effect of gestation on the pharmacokinetics of orally administered beta-lactams, choosing cefatrizine as the model antibiotic. Setting: A tertiary teaching hospital. Design: Prospective study. Methods: In 20 women with affected fetuses, 17 by beta-thalassemia major and 3 with congenital malformations, termination of gestation between 19 and 24 weeks was induced by intra-amniotic administration of prostaglandin F-2 alpha. Pharmacokinetics of cefatrizine in maternal and fetal blood were studied after the administration of three 1 g doses of oral cefatrizine, every 12 h. Twenty female non-pregnant volunteers consisted the control group. Results: Gestation was found to decrease substantially both cefatrizine oral bioavailability and maximum serum plasma concentration (42.8 and 44.5%, respectively) but increased elimination half-life. This effect can be attributed to a substantial increase of the apparent volume of distribution of cefatrizine in relation to a moderate increase of clearance that occurs during pregnancy. Fetal serum cefatrizine levels were lower for the first few hours after administration and then exceeded the corresponding maternal ones. Conclusions: Our results indicate that gestation decreases the oral bioavailability of cefatrizine. A delay in the maternal drug elimination compared to non-pregnant controls was more pronounced in the fetus. Copyright (c) 2007 S. Karger AG, Basel

Solubilization of cyclosporin A

This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (α-cyclodextrin [(αCD)] and hydroxypropyl-β-cyclodextrin[(HP\CD)] were used as solubilizing agents in this study