Journal of pharmaceutical sciences
-
The chemical stability of the novel anticancer agent carzelesin in aqueous buffer/acetonitrile (1:1, v/v) mixtures has been investigated utilizing a stability-indicating reversed-phase high-performance liquid chromatographic assay. The degradation kinetics of carzelesin has been studied as a function of pH, buffer composition, ionic strength, and temperature. Degradation of carzelesin follows (pseudo-) first-order kinetics. ⋯ The degradation rate of carzelesin was not significantly affected by buffer components and by the ionic strength. In addition to the formation of the degradation products U-76,073, U-76,074, and aniline in alkaline medium and in acetate buffer solution, another degradation product was formed in acetate buffer solution. In perchloric acid buffer solution (pH* < 3), U-76,073 and U-76,074 could not be detected as degradation products.
-
Postoperative fever occurs in many surgical patients, due to release of pyrogens into the circulation. Pyrogens and fever may influence the pharmacokinetics and effects of drugs. The aim of this study was to investigate the interactions of a pyrogen with the opioid analgesic alfentanil in an animal model. ⋯ The increase in volume of distribution and the lack of effect of endotoxin on elimination clearance were confirmed in the 120-min infusion experiments. Apparent concentration-effect relationships for the actions of alfentanil on arterial CO2, O2, and pH were not influenced by the endotoxin. Circulating pyrogens can thus influence the pharmacokinetics and, indirectly, the effects of alfentanil.
-
Comparative Study
Determination of free extracellular concentrations of piperacillin by microdialysis.
The tissue penetration and distribution of antibiotics is of great importance, since most of the infections occur in the tissue. At the infection site, the free, unbound fraction of the antibiotic is responsible for the antiinfective effect. These free extracellular concentrations can be measured by microdialysis. ⋯ Comparisons between calculated free concentrations in the peripheral compartment and measured free extracellular concentrations revealed excellent agreement. Microdialysis is a suitable method to evaluate unbound drug concentrations in the tissues. In case of piperacillin, predictions of the concentration time profiles of free drug in the peripheral compartment can be made on the basis of plasma data.
-
Although the mechanism of anesthetic action is not yet clearly understood, it was recently shown that the pure enantiomers of chiral inhalation anesthetic agents interact differentially with the ion channels in the central nervous system. This differential interaction was suggested to arise from stereospecific binding of chiral enantiomers to proteins. ⋯ From studies on circular dichroism in the vibrational transitions of desflurane (CF2HOCHFCF3), we found that (-)-desflurane has the (R)-configuration and (+)-desflurane has the (S)-configuration [corrected]. In addition, each enantiomer existed in two distinct conformations at room temperature.
-
Development of effect compartment model theory has greatly enhanced our understanding of the relationship between pharmacokinetics and pharmacodynamics. When effect versus concentration in serum (usually total concentration) is plotted and counterclockwise hysteresis is observed, an initial disequilibrium between receptor(s) and serum is generally presumed and an effect compartment model is used; alternatively, clockwise hysteresis may infer tolerance, which may be characterized by an adaptation model. In this simulation study, the influence of time-dependent binding to serum protein on the relationship between effect and concentration in serum was investigated. ⋯ Clockwise hysteresis, consistent with tolerance, occurred with a time-dependent increase in binding to serum protein. For both sets of simulations, no hysteresis was observed when response was plotted against concentration of free drug in serum. These results indicate that, when response is related to concentration of free drug, measurement of concentration of free drug may allow a clearer interpretation of the pharmacokinetic-pharmacodynamic relationship.