Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 μg/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 μg/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels. TA-3090 appears to be an effective coronary and peripheral vasodilator with demonstrated coronary selectivity, and to possess a prolonged duration of action compared with diltiazem.Key words: TA-3090, diltiazem, vasodilation, coronary, plasma levels.
To gain insight into whether ondansetron treatment induces changes in total cholecystokinin (CCKT) plasma levels before and after administration of the cholecystokinin tetrapeptide (CCK-4) panic challenge procedure in healthy men.Thirty-eight volunteers received a 50-microgram bolus of CCK-4 60 minutes after a single oral dose (acute treatment) and multiple oral doses (chronic treatment) of ondansetron or placebo.Results showed no difference in CCKT plasma levels of CCKT elimination rate constant between the ondansetron and the placebo groups after either acute or chronic treatment.Results from this study suggest that total CCK plasma levels are not influenced by either acute or chronic treatment with ondansetron. However, the effect of ondansetron on the different CCK component fractions still needs exploration.
Abstract A sensitive and specific gas chromatographic method, using an electron capture detector, for the measurement of plasma concentrations of loprazolam (HR‐158) is described. Retention times of the hydrolysis product of loprazolam (2‐amino‐2′‐chloro‐5‐nitrobenzophenone) and of the internal standard (2‐amino‐2′‐ fluorobenzophenone) were, respectively, 9 and 7 minutes. The sensitivity of the assay was 1.0 ng ml −1 of plasma, and for drug concentrations ranging from 1.0 to 15 ng ml −1 the mean recovery from plasma was 94.4 per cent and the mean coefficient of variation 9.8 per cent. This method was used to determine some pharmacokinetic parameters of loprazolam after administration of 2 × 1 mg capsule doses to nine healthy. fasted volunteers. The mean t 1/2 was 6.4 h. mean AUC x 65.42 ng.h ml −1 , and the mean clearance 0.51 l min −1 .
Maximal blood concentration (Cmax), time to concentration peak (Tmax), area under the serum concentration-time curve (AUC infinity) and half-life (t1/2) after the oral administration of zopiclone 7.5 mg were compared in patients with severe renal failure (group I), with moderate renal insufficiency (group II), and in healthy volunteers (group III) over a 72-h period. Cmax did not differ from one group to the other but Tmax was significantly longer in group II. Half-lives were longer in renal patients than in healthy volunteers and AUC infinity s tended to increase with the degree of renal failure. Hemodialysis of the severely ill renal patients did not increase the plasma clearance of zopiclone. Finally, only small amounts of drug were found in urine in the three groups. Overall, results allow the conclusion that zopiclone may be safely used in patients with various degrees of renal impairment.
Exposure to chlordecone (CD, Kepone) is known to increase the hepatotoxicity of chloroform (CHCl 3 ) in rats. A time-course analysis was conducted relating several indices of biotransformation capacity with the ability of CD to potentiate CHCl 3 -induced hepatotoxicity. Male Sprague–Dawley rats were given a single administration of corn oil alone or CD (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8, 16, 20, 24, or 32 days posttreatment, groups of rats were killed and their livers were analyzed for (i) cytochrome P-450, NADPH-dependent cytochrome c reductase, cytochrome b 5 and glutathione content or (ii) in vitro irreversible binding of 14 CHCl 3 -derived radiolabel to microsomal protein. Similarly treated rats were challenged (2–32 days posttreatment) with CHCl 3 (0.5 mL/kg po); 24 h later, liver damage was assessed by plasma alanine aminotransferase (ALT), plasma ornithine carbamyl transferase (OCT), plasma bilirubin, and hepatic glucose-6-phosphatase. CD potentiation was maximal 2 days posttreatment; and enhanced susceptibility to CHCl 3 persisted up to 20–24 days post-CD treatment. In a parallel study animals treated with chlordecone were killed 8, 16, 20, 24, or 32 days later. Blood, kidney, liver, and adipose tissue samples were taken and analyzed for chlordecone content. The results suggest that a general temporal correlation exists between biotransformation rate (microsomal 14 C binding), chlordecone content, and the severity of liver injury; the other parameters monitored do not appear to relate directly to the potentiation.
Atrial and atrioventricular conduction variables were studied at control and at the end of each of six consecutive 45-min diltiazem administration periods in eight closed chest-anesthetized dogs. Diltiazem was given as a bolus (50 micrograms/kg, i.v.) followed by an infusion (0.5 micrograms X kg-1 X min-1); doses were doubled in subsequent periods. The plasma concentrations, measured by gas-liquid chromatography, ranged from 8 to 1400 ng/mL and correlated strongly with the doses (r = 0.92; p less than 0.01). The Wenckebach cycle length, basic conduction time, and functional refractory period of the atrioventricular (AV) node increased proportionally with plasma concentration (respective r = 0.90, 0.89, 0.80; p less than 0.01). The minimum mean plasma concentrations affecting these variables significantly were 37, 83, and 175 ng/mL, respectively. Second or third degree AV blocks developed in all dogs for plasma concentrations between 379 and 1400 ng/mL. In four dogs which were given isoproterenol (0.2 micrograms X kg-1 X min-1), these blocks disappeared within 1 min. Atrial conduction time and functional refractory period were slightly but significantly shortened by diltiazem with mean plasma concentrations of 175 ng/mL and over. His-Purkinje intervals were not significantly changed by diltiazem. Systolic and diastolic arterial pressures were decreased by diltiazem (r = -0.64, r = -0.79; p less than 0.01) starting with a mean plasma concentration of 83 ng/mL. We conclude that AV nodal conduction variables are progressively prolonged with increasing plasma concentrations of diltiazem; plasma concentrations affecting blood pressure and AV nodal variables overlap; and the AV blocks produced by toxic concentrations of diltiazem can be corrected by isoproterenol.
A sensitive and specific gas chromatographic method using a nitrogen detector for the measurement of trimipramine plasma concentrations is described. This method was used to determine the relative bioavailability and some pharmacokinetic parameters of two formulations, tablets and capsules, in healthy volunteers. It was concluded the tablet and capsule formulations were pharmacokinetically equivalent.
