Hiroshi Zenda

Population pharmacokinetics of vancomycin in Japanese adult patients

Population pharmacokinetic parameters of vancomycin (VCM) in Japanese adult patients infected with methicillin-resistant Staphylococcus aureus (MRSA) were estimated using 1253 items of serum concentration data from 190 patients obtained in routine drug monitoring. The two-compartment linear model was adopted, and VCM clearance (CL) was correlated with the creatinine clearance (CLcr), which was observed or estimated by the Cockcroft-Gault equation. The population pharmacokinetic analysis program NONMEM with first-order conditional estimation method was used. The results showed VCM clearance to be linearly correlated with CLcr (CL [ml/min] = 0.797 x CLcr) when the estimated CLcr was <85 ml/min, but no linear relationship at higher than this level because of the lack of accuracy in the CLcr estimates. The interindividual variability of CL was 38.5%; K12 and K21 were 0.525 hr(-1) and 0.213 hr(-1), respectively. The distribution volume at steady state (V[SS]) was 60.71, with no significant dependence on the actual body weight. The interindividual variability of Vss was 25.4%. The calculated half-life (t1/2,beta) in a typical patient with CLcr of 85 ml/minute was 12.8 hours. Residual variability was 23.7%. These results were compared to those of healthy volunteers, and guidelines for dosage adjustment in VCM therapy are discussed.

Population pharmacokinetics of vancomycin in Japanese pediatric patients.

The population pharmacokinetic profile of vancomycin (VCM) in Japanese pediatric patients infected with methicillin-resistant Staphylococcus aureus was analyzed using 181 samples of serum concentration data from 49 patients obtained in routine drug monitoring. The one-compartment linear model was adopted, where the VCM clearance (CL) and the distribution volume (Vd) were correlated with covariates such as postnatal age (AGE) and body weight (BWT). The population pharmacokinetic analysis program NONMEM with the first-order conditional estimation method was used. The results showed that the population mean clearance normalized by BWT increases with AGE up to 1 year of age [CL(L/hour per kg) = 0.1 19 + 0.0619 x (AGE - 1)] and decreases with age over 1 year old [CL(L/hour per kg) = 0.119 + 0.00508 x (1 - AGE)]. The population mean of the distribution volume normalized by BWT was independent of AGE (Vd (L/kg) = 0.522). The interindividual variability of CL was 39.6%, and that of Vd was 18.8%. The intraindividual, residual variability was 34.6%. These results were compared with those in other articles, and a guideline for dosage adjustment in VCM therapy is discussed.

Different sympathetic–parasympathetic interactions on sinus rate and AV conduction in dog hearts

We investigated the sympathetic-parasympathetic interactions involved in SA nodal pacemaker activity and AV conductivity in the anesthetized dog heart. Stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAPS) and stimulation of the intracardiac parasympathetic nerves to the AV nodal region (AVPS) induced negative chronotropic and dromotropic responses, respectively. Cardiac sympathetic stimulation, aminophylline, 3-isobutyl-1-methylxanthine (IBMX, a relatively pure nonselective phosphodiesterase inhibitor) and methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-p iridine-5-carboxylate (Bay k 8644, a Ca2+ channel agonist) increased sinus rate and decreased AV conduction time. Sympathetic stimulation augmented the negative chronotropic response to SAPS but not the negative dromotropic response to AVPS, IBMX augmented both responses, Bay k 8644 augmented the chronotropic response and attenuated the dromotropic response, and aminophylline did not affect the chronotropic response to SAPS and inhibited the dromotropic response to AVPS. Additionally, when Bay k 8644 directly given via the AV node artery decreased AV conduction time, it attenuated the negative dromotropic response to AVPS and carbachol injected into the AV node artery. These results suggest that the differential sympathetic-parasympathetic interactions on sinus rate and AV conduction are at least partly induced by an interaction between changes in slow inward Ca2+ current or intracellular Ca2+ and the cardiac effects of acetylcholine in the heart in situ.

Vasoconstrictor effects of endogenous digitalis-like factors extracted from urine of hypertensive patients

SummaryThe vascular effects of endogenous digitalis-like factors (EDLFs) extracted from the urine of hypertensive patients were investigated in isolated and perfused intermediate auricular and mesenteric arterial preparations of dogs. EDLFs produced a transient vasoconstriction in a dose-related manner in intermediate auricular arteries but only a slight constriction in mesenteric arteries. Ouabain induced a long-lasting vasoconstriction with tachyphylaxis in intermediate auricular arteries, but it did not constrict mesenteric arteries. EDLF-induced vasoconstrictions were reproducible and were not modified by alpha-adrenoceptor blockade. They were slightly suppressed by a potent calcium entry blocker, verapamil, in doses which markedly suppressed KCl-induced vasoconstrictions. Noradrenaline- and KCl-induced vasoconstrictions were not significantly modified by either EDLF or ouabain.From these results, it is concluded that EDLF has clear vasoconstrictor properties which are not due to adrenergic or calcium entry mechanisms and that there are differences in the vasoconstrictor effects of EDLFs with respect to different vascular beds. This is similar to what was found with ouabain.