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Biomedical subjects

R San Roman

Publications and source records attributed to R San Roman.

5 recordsLinked to original sources
PubMed2001

Correlation between in vitro and in vivo activities of GM 237354, a new sordarin derivative, against Candida albicans in an in vitro pharmacokinetic-pharmacodynamic model and influence of protein binding.

The antifungal effect of GM 237354, a sordarin derivative, was studied in an in vitro pharmacokinetic (PK)-pharmacodynamic dynamic system (bioreactor) which reproduces PK profiles observed in a previously described model of drug efficacy against murine systemic candidiasis. Immunocompetent mice infected intravenously with 10(5) CFU of Candida albicans were treated with GM 237354 at 2.5, 10, and 40 mg/kg of body weight every 8 h subcutaneously for 7 days. Free concentrations in serum were calculated by multiplying total concentrations measured in vivo by 0.05, the free fraction determined in vitro by equilibrium dialysis. In the bioreactor the inoculum was approximately 10(6) CFU/ml; and a one-compartment PK model was used to reproduce the PK profiles of free and total GM 237354 in serum obtained in mice, and clearance of C. albicans was measured over 48 h. A good correlation was observed when the in vivo fungal kidney burden and the area under the survival time curve were compared with the in vitro broth "burden," although only when free in vivo levels in serum were reproduced in vitro. GM 237354 displayed a 3-log decrease effect both in vivo and in vitro. The very few reports available on in vitro-in vivo correlations have been obtained with antibiotics. The good in vitro-in vivo correlation obtained with an antifungal agent shows that the in vitro dynamic system could constitute a powerful investigational tool prior to assessment of the efficacy of an anti-infective agent in animals and humans.

Animals↗
PubMed2001

Animal pharmacokinetics and interspecies scaling of sordarin derivatives following intravenous administration.

Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine Candida albicans, Histoplasma capsulatum, and Coccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, < or =5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.

Animals↗
PubMed2000

Pharmacokinetics-pharmacodynamics of a sordarin derivative (GM 237354) in a murine model of lethal candidiasis.

Sordarins are a new class of antifungal agents which selectively inhibit fungal protein synthesis (FPS) by impairing the function of elongation factor 2. The present study investigates possible correlations between sordarin pharmacokinetic (PK) properties and therapeutic efficacy, based on a murine model of invasive systemic candidiasis, and provides a rationale for dose selection in the first study of efficacy in humans. A significant correlation between PK parameters and the in vivo activity of GM 237354, taken as a representative FPS inhibitor, was demonstrated in a murine model of lethal systemic candidiasis. Area under the concentration-time curve (AUC) and maximum concentration of drug in serum (C(max)) over 24 h were determined after a single GM 237354 subcutaneous (s.c.) dose (50 mg/kg of body weight) in healthy animals (no significant PK changes with infection were observed for other sordarin derivatives). These results have been used to simulate PK profiles obtained after several doses and/or schedules in animal therapy. A PK-pharmacodynamic (PD) parameter such as the time that serum drug concentrations remain above the MIC (t > MIC) was also determined. Treatment efficacies were evaluated in terms of the area under the survival time curve (AUSTC), using Kaplan-Meier survival analysis and in terms of kidney fungal burden (log CFU/gram) after s.c. doses of 2.5, 5, 10, 20, and 40 mg/kg every 4, 8, or 12 h (corresponding to total daily doses of 5 to 240 mg/kg). The results show all treatments to significantly prolong survival versus that of infected and nontreated controls (P < 0.05). Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but not C(max) or t > MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC(50) (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 microg. h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid E(max) and an inhibitory sigmoid E(max) PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 microg. h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.

Animals↗
PubMed1987

Pachydermoperiostosis. A case report.

A case of pachydermoperiostosis observed over a period of 4 years in a man aged 19 is reported. Its clinical features are described; these place it in the "incomplete" group, according to the classification of Touraine et al.. The authors also discuss the diagnostic criteria and the differential diagnosis from Pierre Marie disease, Ribing's syndrome, van Buchem's syndrome and acromegaly.

Adult↗