Disposition kinetics and urinary excretion of verapamil and some of its primary metabolites after oral administration in patients with angina pectoris.

Pharmacokinetics of verapamil and of its three primary metabolites [norverapamil, 2-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaheptanitrile (D-617) and 2-(3,4-dimethoxyphenyl)-2-propylamino-3-methylbutyronitrile (D-260)] was studied after oral administration in 7 patients with stable angina pectoris. Serum levels of metabolites were found to be in the same range as that of the intact drug. Areas under the serum concentration time curves of each metabolite were higher and serum half-lives were significantly longer than those of verapamil. Half-life values obtained from urinary excretion data and from serum levels did not differ for the metabolites, but for the unchanged drug, the half-life from urinary excretion data was longer. Cumulative urinary excretion of verapamil, norverapamil, D-617 and D-620 up to 48 h postdose was averaged to 1%, 2.2%, 11.4%, and 6.7% of the dose administered, respectively. The extent of verapamil bioavailability was directly measured in one patient receiving an intravenous dose as well as an oral one and was found to be 42.3%. In other patients, bioavailability was assessed by means of a regression equation relating the reciprocal of bioavailability and oral clearance of the drug, and was averaged at 35.1%. The possibilities of contribution of the metabolites to verapamil effects in patients were discussed.

[Pharmacodynamics of the new beta blockader corgard (nadolol) in patients with stress-induced angina pectoris]. / Farmakodinamika novogo beta-blokatora korgarda (nadolola) u bol'nykh so stenokardiei napriazheniia.

Antianginal effect of a new beta-blocker corgard (nadolol) was studied in 17 male patients with stable stress angina, aged 42 to 56, in comparison to obsidan and placebo. An original method was used to assess the extent and duration of antianginal effect consisting in repeat identical treadmill exercise coupled with continuous ECG monitoring. Corgard was shown to produce a marked antianginal effect as reflected in significantly reduced ST depression and elevation of angina of effort for more than 24 hours after a single 80 mg dose. Compared to an adequate dose of propranolol, corgard is 20-25% more effective in terms of markedness, and at least 14 hours more effective in terms of duration of the effect.

[Calcium antagonists in stress angina pectoris (pharmacodynamic study)]. / Antagonisty kal'tsiia pri stenokardii napriazheniia (farmakodinamicheskoe issledovanie).

In 10 patients with stress stenocardia pharmacodynamics of Isoptin was studied with the aid of identical physical loads on the treadmill repeated with an hour's interval for 5-6 hours. A clearcut antianginal effect was recorded which consisted in the reduction of ST segment depression and of the pain syndrome for 5 hours after administration of 3 tablets over 5 hours and for 6 hrs 20 min after administration of 5 tablets of both drugs. The degree of effect increased considerably after the dose of isoptin was enhanced and was not changed after the dose of corinfar was enhanced. Difference in the haemodynamic effect of the drugs was found in their effect on the cardiac rate. Corinfar increased the cardiac rate, isoptin decreased it.

[Sustak pharmacodynamics in effort stenocardia]. / Farmakodinamika sustaka u bol'nykh so stenokardiei napriazheniia.

Sustak pharmacodynamics was studied in 32 patients with stable angina pectoris of effort during acute tests with dosaged physical exercises repeated a tone-hour intervals. The results were compared with those in placebo. It is shown that the duration and pronounced character of the antianginal sustak effect varies widely in different patients. The maximum effect of the drug in a dose of 6.4 mg was encountered one hour after medication and was characterized by reduced depression of the ST segment by 54% during physical exercise and alleviation of the pain syndrome. The drug caused a statistically significant reduction of arterial pressure, an increase in the pulse rate at rest and a decrease of this value during exercise. The antianginal effect of sustak was particularly manifest in patients with low tolerance of physical exertion and in patients in whom the attack of angina pectoris was attended by marked dyspnea.

[Comparative pharmacodynamics study of korinfar and isoptin in ischemic heart disease]. / Sravnitel'noe farmakodinamicheskoe izuchenie korinfara i izoptina u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The effect of Korinfar (30 and 50 mg) and isoptin (120 and 200 mg) on exercise tolerance was studied in 11 patients with angina pectoris of effort using the double blind crossover method. Both doses of Korinfar and 120 mg of isoptin increased cardiac output by 70--80% and 200 mg of isoptin--by 136%. Korinfar had a pronounced growth hypotensive effect and induced tachycardia, which is an increased dose hindered growth of exercise tolerance. The negative chronotropic effect of isoptin increased its efficacy. As a result of calcium antagonists action a stable threshold double product was established, and its was higher, than the control one.

[Method of studying the pharmacodynamics of anti-angina drugs by means of repeated exercise tests]. / Metod izucheniia farmakodinamiki antianginal'nykh preparatov s pomoshch'iu povtornykh nagruzovhnykh testov.

A method for studying the effect of anti-anginal agents was elaborated. It comprises the appraisal of ST segment depression dynamics in individually dosaged physical exercise repeated in the same volume at interval of one hour after a single dose of the agent that is studied had been taken. Continuous monitoring with subsequent computer treatment was used for ECG recording and analysing. The administration of placebo in 14 patients with angina of effort had no effect on the hemodynamic parameters determining the requirements of the myocardium for oxygen or on the depth of ST segment depression during physical exercise to which the patients were repeatedly exposed for 6 hours; at the same time, a statistically significant decrease in the severity of the pain syndrome was revealed. The average deviation in the magnitude of ST segment depression during repeated exercises was 11.2%. The method may be used in approbation of drugs and selection of effective anti-anginal therapy.

[Comparative pharmacodynamic study of Cordanum and obzidan in stress angina pectoris patients]. / Sravnitel'noe farmakodinamicheskoe izuchenie kordanuma i obzidana u bol'nykh stenokardiei napriazheniia.

The effect of different single doses of beta-blockers cordanum (talinolol) and obsidan was comparatively studied in 10 patients with angina pectoris of effort. The pharmacodynamic study was performed according to an original technique consisting in a sequence of monitored repeated identical treadmill exercise. The effect of the drug was evaluated by the reduction in ST-segment depression during exercise. Hemodynamic effect of cordanum was 1.7 lower than that of obsidan. The reduction of ST-segment depression effected by cordanum was 2.6 lower than in case of the corresponding doses of obsidan. The effect did not correlate with the heart rate and the double product; it terminated within 4--5 hrs.