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Biomedical subjects

K Tawara

Publications and source records attributed to K Tawara.

53 records · Page 3Linked to original sources
PubMed1981

Effect of probucol on serum lipoprotein levels in normal and dyslipoproteinemic mice.

The effect of probucol was studied on serum lipoprotein levels in normal and cholesterol-fed, hypercholesterolemic mice. In normal mice, probucol caused a significant reduction in LDL + VLDL cholesterol at daily doses above 25-50 mg/kg and also in HDL cholesterol at higher doses. In cholesterol-fed mice, probucol treatment decreased LDL + VLDL cholesterol at daily doses exceeding 200 mg/kg and also HDL cholesterol at a daily dose of 800 mg/kg. The ratio of LDL + VLDL cholesterol to HDL cholesterol was significantly reduced by treatment at 25-100 mg/kg in normal mice and at 200 mg/kg in hypercholesterolemic mice. The ratio was not reduced at doses above these ranges. These dose-effect relationships were not modified by duration of probucol treatment. These findings suggest that there is an optimum dosage of probucol to lower LDL + VLDL cholesterol and the atherogenic index, and that the actual optimum dosage for the beneficial effect depends on blood lipid levels or types of hyperlipidemia. This may be important in the clinical application of this drug, because a negative correlation has been demonstrated between HDL cholesterol levels and ischemic heart disease. Clofibrate treatment did not affect serum lipid levels significantly in either normal or cholesterol-fed mice. Probucol was again effective in lowering LDL cholesterol values in cholesterol-fed mice which had previously been treated with clofibrate for 2 weeks without any beneficial effect. In an additional experiment, it was found that the probucol-induced reduction in cholesterol returned to the pre-treatment levels gradually over several days, depending on the dose and without rebound elevation after withdrawal of the drug.

Animals↗
PubMed1981

Synthesis and in vitro antimicrobial property of o-carborane derivatives.

Various o-carboranes and nido-type dicarbollide anions have been synthesized and tested for antimicrobial activity. Nearly all of the dicarbollide monoanions investigated were active in vitro against fungi such as Candida albicans, Aspergillus fumigatus, and Tricophyton asteroides, as well as against Gram-positive bacteria. From a consideration of the structure-activity relationships, it seems most reasonable to conclude that the introduction of lipophilic alkyl or o-carboranyl groups to the hydrophilic dicarbollide anions leads to the antimicrobial activity.

Anti-Bacterial Agents↗
PubMed1980

Absence of changes in drug disposition and catecholamine sensitivity in the hyperthyroid dog.

1 In order to study the relative contribution of hepatic drug metabolizing enzymes and hepatic blood flow to the clearance of drugs in the hyperthyroid state, the disposition kinetics of two model compounds (antipyrine and propranolol) were examined in thyroid-fed dogs as compared to euthyroid and phenobarbitone-pretreated animals. 2 In hyperthyroid dogs, the possibility of catecholamine hypersensitivity was evaluated by assessing the chronotropic response to isoprenaline and by constructing a drug concentration-effect (beta-blockade) relationship. 3 The plasma propranolol half-life (0.97 +/- 0.12 h) of the hyperthyroid animals did not differ significantly from either the euthyroid group or the phenobarbitone-pretreated group. This was observed with no significant change in the apparent volume of distribution among the three experimental groups. 4 Phenobarbitone pretreatment accelerated significantly the elimination of antipyrine (half-life, 1.09 +/- 0.15 h, P less than 0.01) as compared to the euthyroid (2.84 +/- 0.35 h) and the hyperthyroid groups (2.58 +/- 0.13 h), respectively, without any changes in the apparent volume of distribution in any group. 5 Neither the chronotropic responses to exogenously administered catecholamine, nor the antagonist concentration-effect relationships support the concept that the hyperthyroid state potentiates sensitivity of the receptor-effect system of the heart. 6 The data obtained from the present study fit best with the view that thyroid hormone excess alters neither the disposition of the model compounds used nor the catecholamine-sensitivity examined.

Animals↗
PubMed1980

No enhanced elimination of propranolol in patients with hyperthyroidism.

Propranolol, a widely used beta-adrenergic receptor blocking drug extracted mostly by the liver, plays an important role in the various aspects of managment of hyperthyroidism. If the elimination of this drug is enhanced in thyrotoxic patients, one may consider necessary a modification of the dosage regimien when treating patients with this dysfunction. We examined the disposition profiles of propranolol in four patients with hyperthyroidism before and after their thyroid states became euthyroid and compared them to those of the seven control subjects. The data indicated that the values (mean +/- SEM) of half-life (3.34 +/- 0.81 hr) and systemic availability estimated (28.2 +/- 3.5%) in the hyperthyroid state were comparable to those in the euthyroid state (2.98 +/- 0.32 hr and 29.2 +/- 5.1%) and these in the control subjects (3.20 +/- 0.32 hr and 29.0 +/- 4.0%). Although our observations were obtained from a small number of subjects, there appears to be no considerable difference in propranolol elimination from the plasma of hyperthyroid and euthyroid states or healthy subjects, and therefore adjustment of the dosage regimen seems unwarranted. Adjustment of propranolol therapy based on individual plasma levels might be useful in thyrotoxic patients who respond inadequately until additional data relating more precisely to propranolol disposition becomes available.

Adult↗
PubMed1979

Pharmacokinetic differences between single and multiple oral dosing with the guidance for beta-adrenoceptor blockade assessment.

The disposition profiles of a new beta-adrenergic-blocking drug, timolol, were investigated in healthy subjects after single oral doses, and in patients with mild or moderate essential hypertension given multiple doses. The t1/2 of timolol were different between the two groups, possibly due to the decreased plasma clearance after multiple administration. The dosage regimen calculations for patients indicated to receive the treatment for certain chronic diseases, should be determined by utilizing the disposition data obtained in steady-state conditions. The absolute reduction of exercise heart rate gave the best coefficient as a beta-blockade assessment. Applying a theory for translating the pharmacokinetics to the duration-action course of drug, pharmacokinetic t1/2 was proven to be much shorter than pharmacological t1/2. Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma-renin-suppressing action in different subject. However, the casual relationship between the drug plasma level, blood pressure fall and change in PRA was not so clearly disclosed. The pharmacokinetics of beta-blockers, particularly with the property of receiving extensive metabolism by the mechanism of hepatic first-pass effect should be studied between single- and multiple-dosing schedules in subjects with diverse clinical conditions.

Administration, Oral↗
PubMed1979

Relationship between pharmacokinetics and pharmacodynamics of the beta adrenergic blocking drug sotalol in dogs.

The relationship between pharmacokinetics and pharmacodynamics was studied in dogs using sotalol as a model. The t 1/2 of this drug (4.30 +/- 0.40 hr) in dogs was longer than that of other beta adrenergic blockers. The renal clearance of the drug (4.21 +/- 0.31 ml/min/kg) was approximately 90% of total plasma clearance together with an extensive fraction excreted unchanged (72 +/- 12% of dose) in urine. Significant beta blockade, assessed by the response to isoproterenol tachycardia, was observed without change in blood pressure during the experiments. The log plasma sotalol concentration correlated significantly with the beta blockade (P less than .001). In an attempt to obtain insight into drug concentration-effect-time data, we applied a theory for correlating the observed kinetic data with the pharmacological effects using the elimination rate constant (beta) and the slope of log concentration-effect relationship (m). The rate of decline of drug effects (Rd) derived from this application agreed well with that actually observed in the effect-time interrelations.

Animals↗
PubMed1978

Comparison of disposition and effect of timolol and propranolol on exercise tachycardia.

The kinetic disposition and beta-adrenergic blocking action in relation to plasma level of a single oral dose of either timolol or propranolol has been compared in healthy male volunteers. The disposition profiles clearly disclosed different properties of the two drugs, although their half-lives were similar. The available fraction of timolol in the systemic circulation was estimated to be approximately 60% of the dose, and 17.4% was exereted unchanged in urine. The logarithm of plasma concentration showed a significant correlation with the beta-blocking activity assessed by an exercise test. The mean potency ratios of timolol to propranolol as an antagonist of chronotropic effects on exercise tachycardia were 11 to 17 and 3.6 to 5.5 in dose- and concentration-effect relationships, respectively. The absolute reduction of exercise heart rate gave the best coefficient of all measures of beta-blockade. When drug action was measured as beta-blockade assessed by a given response to exercise tachycardia, the effect declined linearly with time, even though plasma levels fell exponentially. This results suggest that the pharmacokinetic t1/2 is much shorter than the pharmacological t1/2.

Adrenergic beta-Antagonists↗
PubMed1977

[Studies on the pharmacokinetics and effects of beta-adrenergic blocking agents, sotalol (author's transl)].

Present investigation was undertaken to elucidate what pharmacokinetic parameters in animal experiment could be of more predictable for human clinical trial of beta-blocking agents. Sotalol was administered as a model drug to dogs, rats, and men. Dog experiments disclosed that the apparent volume of distribution of sotalol was about 4 times larger than the space of total body water and the plasma level of sotalol was 1.0-2.0 and 2.3-3.4 microgram/ml when the beta-blocking index showed 50 and 100% to the intravenous bolus injection of isoproterenol (0.1-1.0 microgram/kg). The clearance studies of dogs and men suggested that the elimination of sotalol depended essentially on renal excretion. The regression coefficient of beta-blocking index and plasma level of this agent in dog experiment using 0.1 microgram/kg isoproterenol was nearly equal to that of human study in which maximal exercise test was performed. Rat experiments showed a large apparent volume of distribution as well as in human study and high concentrations of sotalol in various tissues of rats. The plasma level of sotalol was well correlated with the content of the drug in such organs as heart, lung, liver, and kidneys.

Administration, Oral↗
PubMed1975

On the diuretic action produced dibutyryl cyclic AMP in dogs.

Experiments were undertaken on order to elucidate the mechanism of diuresis induced by dibutyryl cyclic AMP in dogs. Intravenous injections of dibutyryl cyclic AMP produced an increase in urine flow in dogs hydrated with saline. It was also noted that dibutyryl cyclic AMP produced an increase in myocardial contraction, renal blood flow and glomerular filtration rate; In addition, unilateral injection of dibutyryl cyclic AMP into the left renal artery produced diuresis bilaterally. Based on the above findings it was suggested that the diuretic action induced by dibutyryl cyclic AMP is associated with its hemodynamic effect.

Animals↗
PubMedDate not supplied

Clinical pharmacologic observations on timolol. I. Disposition and effect in relation to plasma level in normal individuals.

The disposition profiles of a new beta-adrenergic blocking drug, timolol, were investigated at 11 different times in normal individuals after a single oral dose. The disposition of timolol follows first-order kinetics and may be adequately described by a one-compartment model. The pharmacokinetic data were not significantly different among the three dose levels examined. After the single oral doses, overall elimination half-life was 3.2 +/- 0.2 hours (mean +/- S.E.M.), with an observed peak time of 2.0 +/- 0.2 hours; extrapolated volume of distribution was 1.81 +/- 0.15 liter/kg; and the total plasma clearance was 557 +/- 61 ml/min. Approximately 20 per cent of elimination from the human body was dependent on the kidney. The area under the curve from zero to infinity and the peak concentration observed were dose dependent. A linear relationship was found between timolol plasma concentrations and beta-adrenergic blocking effects (per cent inhibition), as estimated from exercise-induced tachycardia. Timolol is a beta blocker which must await further clinical trials for the assessment of therapeutic implications in relation to plasma levels.

Adult↗
PubMedDate not supplied

Clinical pharmacologic observations on timolol. II. Antihypertensive effect and kinetic disposition on twice-daily dosing in patients with mild or moderate hypertension.

Timolol given on a twice-daily schedule has shown both antihypertensive effectiveness and plasma renin-suppressing action in eight patients with mild or moderate hypertension. However, the causal relationship between the drug plasma level, blood pressure fall, and change in plasma renin activity was not so clearly demonstrated in the present study. The disposition profiles of timolol at the steady state show an elimination half-life of 4.7 +/- 0.7 hours and a total plasma clearance of 225 +/- 21 ml/min. These values are found to be different from those of our previous observations obtained in normal individuals. Although the range of mean timolol concentrations at steady state varies to a certain extent among different patients, the dosage regimens for patients who will receive treatment for certain chronic disease states (e.g., arrythmias, obstructive cardiomyopathy, and angina pectoris, but not hypertension) in relation to plasma levels should be based on the disposition data obtained under steady state conditions. Bronchospasm developed in one of eight patients whose timolol level was found to be higher than the average of other patients given the same dosage.

Adult↗