Population pharmacokinetics of rifampin in the treatment of Mycobacterium tuberculosis in Asian elephants.

The objective of this study was to develop a population pharmacokinetic model for rifampin in elephants. Rifampin concentration data from three sources were pooled to provide a total of 233 oral concentrations from 37 Asian elephants. The population pharmacokinetic models were created using Monolix (version 4.2). Simulations were conducted using ModelRisk. We examined the influence of age, food, sex, and weight as model covariates. We further optimized the dosing of rifampin based upon simulations using the population pharmacokinetic model. Rifampin pharmacokinetics were best described by a one-compartment open model including first-order absorption with a lag time and first-order elimination. Body weight was a significant covariate for volume of distribution, and food intake was a significant covariate for lag time. The median Cmax of 6.07 µg/mL was below the target range of 8-24 µg/mL. Monte Carlo simulations predicted the highest treatable MIC of 0.25 µg/mL with the current initial dosing recommendation of 10 mg/kg, based upon a previously published target AUC0-24/MIC > 271 (fAUC > 41). Simulations from the population model indicate that the current dose of 10 mg/kg may be adequate for MICs up to 0.25 µg/mL. While the targeted AUC/MIC may be adequate for most MICs, the median Cmax for all elephants is below the human and elephant targeted ranges.

An in vitro study comparing the cytotoxicity of three platinum complexes with regard to the effect of thiol depletion.

The cytotoxicity of three platinum complexes, cis-diamminedichloroplatinum(II) (cis-platin), cis-dichloro-trans-dihydroxy-cis-bis (isopropylamine) platinum(IV), (CHIP) and diammine (1, 1-cyclobutane-dicarboxylato) platinum(II) (carboplatin) on Chinese Hamster ovary (CHO) and mouse sarcoma RIF-1 cells cultured in vitro has been compared. The tumour cell line was much more sensitive to the cytotoxic action of the three agents compared to the CHO cell line. CHIP and carboplatin gave similar dose-response curves, both being much less toxic than cis-platin. The effect of thiol modification on platinum toxicity was also investigated. Substantial reduction in the intracellular non-protein sulphydryl content markedly enhanced the cytotoxicity of CHIP but had much less effect on carboplatin and cis-platin. Thiol depletion by diethylmaleate had a negligible effect on cis-platin toxicity.

Pretibial myxoedema: stimulation of mucopolysaccharide production of fibroblasts by serum.

We have shown that sera from normal individuals and from patients with pretibial myxoedema contain a factor which simulates mucopolysaccharide biosynthesis in normal human skin fibroblasts cultured in vitro. This factor was present in larger amounts in sera of patients with pretibial myxoedema. The role of growth stimulating factors in serum is reviewed and a hypothesis is put forward that the fibroblast stimulating factor is somatomedin and that its presence in increased amounts in thyroid disease may lead to pretibial myxoedema.

An improved method of assessing topical corticosteroid activity.

Topical application of ointment bases causes varying degrees of epidermal thickening in guinea-pigs. This is reproducible and can be accurately measured. Suppression of these changes was produced by addition of beta-methasone 17-valerate, fluocinolone acetonide, fluocinonide and hydrocortisone acetate. The inhibitory effect of these steroids was related to the type of corticosteriod, its concentration and the ointment base. The effect was still evident at extremely high dilutions of the steroids and could be measured at concentrations as low as 5 X 10(-5) % of fluocinonide in FAPG. This technique has the merits of being reproducible, sensitive and accurate. It should find a place among existing methods in assaying the efficacy of topical corticosteroids and in aiding in the selection of bases most suitable for formulation of these preparations.