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Serum free fractions of nifedipine, verapamil and some of their metabolites were measured in patients with ischaemic heart disease receiving single oral dose and chronic monotherapy and were compared with those obtained in vitro. The percentages of unbound nifedipine and verapamil in vitro (concentration range 50-200 and 150-400 ng ml-1, respectively) were 2.51 and 7.23%, respectively, and did not differ from those found on monotherapy with these drugs (2.05 and 8.08%, respectively), and after single dosing. It is suggested that, during treatment with nifedipine or verapamil, their serum metabolites do not affect binding of the parent drugs to serum proteins. [ABSTRACT FROM AUTHOR]

The influence of chronic verapamil treatment on antipyrine elimination was studied in eight angina patients. Antipyrine half-life (mean +/- s.d.) was 13.1 +/- 1.15 h at the start of therapy and 16.6 +/- 3.05 h (P less than 0.05) during chronic oral administration of verapamil (80- 120 mg four or three times daily for 4 to 7 months). There was a significant decrease in antipyrine clearance (mean +/- s.d, 43.2 +/- 16.8 ml min-1 vs 28.7 +/- 16.6 ml min-1, P less than 0.01) while the change of distribution volume was insignificant. Verapamil elimination was also found to be impaired after chronic dosing as compared to single administration. Half-lives measured from the concentration vs time and urinary excretion rate vs time curves were both prolonged and oral clearance was decreased. Our results suggest that the inhibition of drug-metabolizing enzymes accounts for the impairment of verapamil elimination on chronic administration. [ABSTRACT FROM AUTHOR]

The influence of a long-term treatment with losartan (50-100 mg o.d.) and captopril (25-50 mg b.i.d.) followed by the abrupt therapy cessation was studied in an open randomized placebo-controlled parallel group trial. The study was performed on a group of 22 essential (soft to moderate) hypertensive male patients, which entered the trial when a mean daytime diastolic blood pressure was BP > or = 90 Torr. The antihypertensive effect of losartan was more pronounced and homogeneous than the effect of an equivalent dose of captopril. The group-average trough/peak ratios upon the losartan treatment were 61.5 and 61.3% for the systolic and diastolic BP (against 21.2 and 26.9% for captopril), respectively. At the same time, the smoothness index values of the patients treated with losartan and captopril showed no significant difference. Neither treatment with any of the two drugs nor the therapy cessation affected the circadian BP profile or the BP variability. The abrupt termination of the drug administration did not cause a withdrawal syndrome: on the contrary, a significant effect of the captopril and losartan treatment (statistically reliable against the placebo control) persisted for at least four days after the therapy cessation. Taking into account poor homogeneity of the antihypertensive effect of captopril in patients with a stable moderate hypertension treated b.i.d., the drug administration is recommended according to the t.i.d. schedule. In this group of patients, losartan and captopril are probably more expediently administered in combination with other hypertensive drugs.

Aim: To investigate 24-h evenness of an antihypertensive effect of angiotensin II receptor blocker losartan vs captopril by four parameters of arterial pressure (AP) monitoring., Material and Methods: An open, cross-over, placebo-controlled trial was made in 22 patients with mild/moderate arterial hypertension (AH). Four parameters of AP monitoring were assessed: TPR, SI, rate of AP morning rise, index of AP morning rise., Results: In losartan treatment TPR for systolic and diastolic AP were 61.5 and 61.3%, respectively, IS made up 0.74 +/- 0.13 and 0.64 +/- 0.09, respectively. For captopril these values reached 21.2 and 26.9%, 0.51 +/- 0.14 and 0.47 +/- 0.10, respectively. Differences by SI between the two drugs were statistically insignificant. Both drugs did not raise the rate and index of AP morning rise significantly., Conclusion: When administered in a single daily dose 100 mg, losartan produced a regular antihypertensive effect throughout 24 hours. Captopril (twice a day in a dose 50 mg) effect was not regular enough. This means that some patients need a three-times-a day regimen of captopril. Of the four parameters, SI is most informative for evaluation of antihypertensive effect evenness.

Aim: To clarify if pain-relieving action of acetylsalicylic acid (ASA) is associated with lowered sensitivity of anginal patients to pain due to myocardial ischemia., Materials and Methods: A double blind randomized placebo-controlled trial enrolled 10 males aged 42-69 years with stable effort angina (EA) of functional class II-III. When exposed to exercise tolerance test (treadmill, stress-system Sicard 460S, computed ECG), the patients developed EA attack with at least 1 mm decline of ST segment on ECG. The exercise test was made before, 2 and 4 hours after administration of ASA and placebo. Sensitivity to ischemia was estimated by the total depth of the ST segment decline in 11 ECG leads (sigma ST) registered at the attack onset. Tactile and pain thresholds (TT and PT) were studied with a highly reproducible technique. TT and PT were measured before, 2 and 4 hours after ASA and placebo administration., Results: 2 and 4 hours after intake of 100 mg of ASA, sigma ST and TT significantly rose compared to the baseline level and placebo. PT significantly rose vs the baseline level., Conclusion: ASA deteriorates sensitivity of anginal patients to myocardial ischemia, skin tactile and pain sensitivity and thus can deprive the EA patient of the pain attack signal. This leads to the risk of overexercising and emergence of painless myocardial ischemia.

We compared the effects of abrupt cessation of nifedipine and isosorbide dinitrate therapy in patients with stable angina pectoris. Eighteen males were studied. Each patient received isosorbide dinitrate and nifedipine continuously for 5 weeks by randomised cross-over technique. Exercise treadmill tests were performed before each treatment period, at the beginning of treatment, 4 weeks after initiation of treatment and on the first and eighth days of drug withdrawal. At the end of treatment the antianginal effect of both agents attenuated (versus acute administration). Abrupt cessation of isosorbide dinitrate caused only a tendency towards decrease in exercise tolerance versus pre-treatment level. Alternatively, abrupt cessation of nifedipine resulted in substantial deterioration in exercise tolerance, which was statistically significant 21 and 24 h after the last dose administration. The number of anginal attacks increased >25% in two patients after cessation of isosorbide dinitrate and in eight patients after cessation of nifedipine. In no patient rest angina episodes appeared after stopping of isosorbide dinitrate, however, after stopping of nifedipine rest angina episodes appeared in three patients. We conclude that withdrawal phenomenon of nifedipine is much more pronounced than that of isosorbide dinitrate and may emerge on the first day of drug cessation. Such a phenomenon may be evident even in patients in whom nifedipine effect have attenuated due to the development of tolerance.

Aim: Study of the tolerance and pharmacodynamic and pharmacokinetic characteristics of ascolong, a new buccal dosage form of aspirin containing a very low dose of acetylsalicylic acid (ASA): 12.5 mg., Materials and Methods: The study was carried out in 43 healthy men (assessment of the drug tolerance) and 19 male patients with coronary disease or cerebrovascular disorders. In 10 patients the antiaggregant efficacy of ascolong administered once or regularly (for 2 weeks) in a dose of 12.5 mg was compared with placebo, in 9 patients a random cross study of 2-week courses of ascolong and Russian aspirin tablets in a dose of 100 mg was carried out. Platelet aggregation was assessed on days 1 and 14 of each course before and 2, 4, and 24 h after the drug intake., Results: Ascolong containing a very low dose of ASA exerts a reliable antiaggregant effect after a single and regular intake, although this effect is less manifest than after aspirin tablets. Profiles of ASA concentrations in the blood were studied. Transbuccal entry of ASA in systemic circulation decelerated its metabolism into a less active metabolite, salicylic acid, due to which fact the ASA microdose had an expressed antiaggregant effect. The drug was sufficiently well tolerated., Conclusion: The new buccal film form of aspirin containing a very low dose of ASA possesses a good antiaggregant effect and is promising in subjects with contraindications to oral intake of aspirin.

Aim: To compare efficacy of diltiazem and nifedipine in single dose and long-term treatment., Materials and Methods: A randomised double-blind cross-over study enrolled 17 patients suffering from coronary heart disease (CHD) with stable angina of effort (SAE). For 1 month, each patient received diltiazem and nifedipine (60-90 mg 4 times a day and 20-30 mg 4 times a day, respectively). The effect was assessed by the pharmacodynamic test after the initial dose and in the end of each treatment course., Results: In 14 eligible patients both drugs reduced the number of SAE attacks and nitroglycerin tablets, diltiazem efficiency being somewhat higher. Single doses of diltiazem and nifedipine produced the same action. In long-term treatment nifedipine effect became shorter, diltiazem effect did not change. Before the morning dose of nifedipine (11.5 hours after the previous dose) exercise tolerance of this drug worsened. This may be due to withdrawal syndrome. As to diltiazem, its exercise tolerance improved., Conclusion: In long-term treatment of CHD with SAE diltiasem is more effective and safe than nifedipine.

The pharmacokinetics of nadolol in blood serum and its excretion in the urine were studied in 6 male patients (aged from 35 to 59 years) with arterial hypertension for 48 h and, respectively, 72 h after a single per os administration of nadolol in a dose of 80 mg in the morning (9.00 a.m.), in daytime (15.00 p.m.) and in the evening (20.00 p.m.). The concentration of nadolol in the blood serum and urine was determined by high performance liquid chromatography with fluorescence detection. Analysis of the obtained data showed maximum blood serum nadolol concentration and the area under the concentration--time curve to be lower (93 ng/ml and 1786 ng h/ml) in the case of evening medication, and the peroral clearance and kinetic distribution volume to be higher (44.8 l/h and 940 l) than after morning medication (188 ng/ml, 2816 ng h/ml, and 28.4 l/h and 650 l, respectively). The corresponding parameters after daytime medication had intermediate values. The half-life period, mean retention time, and time of achievement of maximum blood serum nadolol concentration did not depend on the time of medication and were in the range of 15.2-15.8 h, 21.1-22.0 h, and 2.9-4.0 h, respectively. The pharmacokinetic parameters characterizing nadolol excretion with the urine were independent of the time of its intake. On the basis of the character of the detected circadian changes in the parameters of nadolol pharmacokinetics it is suggested that these changes reflect the circadian variations in the absorption of the drug in the gastrointestinal tract.

The data are presented on the absence of a stable positive trend in echocardiographic characteristics of the left heart and intracardiac hemodynamics after 8 months of controlled antihypertensive therapy, 12-month follow-up and uncontrolled outpatient treatment. 12 months after discontinuation of controlled antihypertensive therapy arterial pressure was much higher than it was at the end of the treatment in patients taking antihypertensive drugs irregularly or not taking them at all. Intracardiac hemodynamics returned to the baseline. As shown by echo-CG, frequency of left ventricular hypertrophy 12 months after the end of antihypertensive treatment rose from 25.8 to 45.2% (p < 0.01), of right ventricular hypertrophy from 14.5 to 17.7%.

Potential tolerance to isosorbide dinitrate (ID) and molsidomine (M) was studied in 18 ischemic heart disease (IHD) patients with stable angina of effort entered in a double blind cross-over trial. Each drug was administered for 3 weeks 4 times a day in individual effective dose. Single doses of ID and M were similar by effectiveness, but after 3 weeks of regular intake their efficacy fell, ID becoming less potent than M. For ID, tolerance after long-term intake manifested in 7 out of 18 patients, for M--in 5 out of 18. Complete tolerance was registered in 3 of 18 and 1 of 18 patients, respectively. Thus, tolerance is possible for the two drugs, but for M it is less pronounced.

Exercise tests were performed in 18 patients with stable angina of effort treated with isosorbide dinitrate (ID) or nifedipine (NF) to see whether sharp discontinuation of the above drugs may entail withdrawal syndrome. Exercise tolerance declined 21 and 24 hours after the last administration of NF, 13 and 18 hours after that of ID. Compared to NF, ID tolerance decreased in a less degree. Some of the patients experienced myocardial ischemia in the course of the exercise tolerance tests, there were more frequent anginal episodes, arterial pressure rose. For ID withdrawal syndrome manifested weaker than for NF.

Objective: To examine by Holter electrocardiographic monitoring the effect of abruptly stopping nitrate treatment in patients with stable angina pectoris., Patients: 12 men with confirmed ischaemic heart disease and stable exertional class 3 angina (Canadian). All had episodes of horizontal or down sloping ST segment depression during 24 hour electrocardiographic monitoring. All were nitrate responders., Design: Each patient was given isosorbide dinitrate (10-30 mg four times a day) and placebo (four times a day) for three days in a randomised crossover trial. There was a washout period of 3-5 days between the two treatment periods. Holter monitoring was performed on the third day of isosorbide dinitrate and placebo administration and on the first day of their withdrawal., Results: When treatment with isosorbide dinitrate was stopped there was a significant increase in the total number and duration of painless episodes of myocardial ischaemia. During placebo and isosorbide dinitrate administration 8 patients had episodes of painless myocardial ischaemia whereas after isosorbide dinitrate cessation they were recorded in all 12 patients. Episodes of silent myocardial ischaemia at rest appeared in 4 patients after isosorbide dinitrate withdrawal., Conclusion: Abrupt cessation of short-term continuous nitrate treatment in patients with severe angina may cause a rebound increase in myocardial ischaemia which is predominantly silent.

The aim of the study was to evaluate feasibility of emergence of nitrate withdrawal syndrome consequently to discontinuation of short-term nitrate administration for coronary heart disease. 12 males with stable effort angina functional class III were subjected to 24-h Holter ECG monitoring. In a randomized cross-over trial each patient received for 3 days isosorbide dinitrate (10-30 mg 4 times a day) followed by 3-day course of placebo. The monitoring was performed on day 3 of the drug or placebo administration and on the first day of their withdrawal. Isosorbide dinitrate discontinuation had no negative effects on the patients' condition though significantly increased the number and duration of episodes of asymptomatic myocardial ischemia. 4 patients developed episodes of asymptomatic myocardial ischemia at rest which were not observed in placebo application. It is believed that much caution should be used in planning interrupted regimes of nitrates therapy in patients with severe angina pectoris.

This multicenter trial included 205 males aged 30-60 years with stable mild and moderate hypertension. 140 patients were from Moscow (140 patients), St. Petersburg, Kursk, Rostov (Russia); Kharkov, Donetsk (Ukraine); Baku (Azerbaijan). Group 1 patients received captopril, group 2 nifedipine, group 3 hydrochlorothiazide, group 4 propranolol.

Pharmacokinetics of propranolol (P), 4-hydroxy-propranolol sulfate (4HOP-Sulf), and glucoronides of pharmacologically active S-enantiomer P (S-PG) and ballast R-enantiomer of P (R-PG) in the blood serum of 21 patients with chronic ischemic heart disease and/or arterial hypertension has been studied at a single and course oral P administration. The values od AUC and T1/2 for potentially active 4HOP-Sulf were significantly higher than those for unchanged P at a single and course administration. The values od AUC and T1/2 for for S-PG were approximately three times higher than those for P-PG after both a single and course administration. Thus the results presented show that potentially active 4HOP-Sulf and S-PG (which undergoes a partial deconjugation in an organism at oral administration) may contribute essentially to the value and duration of the P pharmacological effect.

Isosorbide-5-mononitrate (IMN) concentration-antianginal effect relationships were studied in 14 coronary heart diseases patients with stable exertion-induced angina after administration of Efox (Schwarz-Pharma) as two dosage forms: routinely acting tablets (20 mg) and long-acting capsules (50 mg). The antianginal effect index was an increase of treadmill exercise duration (sec) as compared with placebo, the concentration and effect were measured in points 0, 1, 3, and 7 hours after administration, in some patients, investigations were conducted 12 and 24 hours. The two formulations were found to be highly effective drugs whose action lasted 7 hours, by that time the effect of the tablets substantially decreased, which was associated with decreases in drug concentrations. The efficiency of the capsules at this point was significantly higher than that of the tablets. The use of the capsules resulted in tachyphylaxis--rapid decreasing responses to IMN. Following 7 hours of their administration there is a significant decrease in their effect with an increase in IMN concentrations.

This paper provides the basic advances made in studying the clinical pharmacology of antianginal agents (AAs), demonstrates the contribution of current tools for evaluating their antianginal effects, namely pharmacodynamic studies using pair bicycle ergometry and repeated treadmill exercises, 24-hour ECG monitoring, pharmacokinetic studies. It shows that AAs can be chosen on an individual basis. The authors present pharmacodynamic characteristics of a number of new AAs from nitrates (trinitrolong, dinitrosorbilong, etc.), calcium antagonists, beta-adrenoblockers (proxodolol, etc.). They have developed a method for assessing the biological equivalence of AAs. The paper discusses the tolerance that can be developed to nitrates and how it can be prevented. It first demonstrates that nifedipine tolerance can develop and that the withdrawal syndrome can occur if nitrates and calcium antagonists are discontinued. There are screening data on various combinations of AAs. A two-stage scheme for choosing an AA therapy is given.

The antihypertensive effect of daily doses of three beta-adrenoblockers (Bisoprolol, 10 mg once a day, propranolol, 80 mg twice a day, and methoprolol, 100 mg twice a day), and placebo was examined in 14 patients with persistent mild and moderate hypertension during a double blind cross-over study by using 24-hour monitoring of blood pressure and its routine measurements. The latter made by a mercury sphygmomanometer indicated that the antihypertensive and negative chronotropic effect of Bisoprolol in a dose of 10 mg remained 24 hours after its administration and it did not significantly differ from that of the two other agents given in the above doses. The application of 24-hour blood pressure monitoring allows a more pronounced antihypertensive effect of bisoprolol to be revealed during 24 hours than that displayed by the two agents. Bisoprolol is an effective and safe antihypertensive agent.

A multicenter randomized controlled trial was performed to compare antihypertensive effects and tolerance of captopril monotherapy with those of reference drugs from three other main groups of antihypertensive drugs: propranolol, hydrochlorothiazide, nifedipine. The trial included 345 males with essential hypertension stage I-II by WHO criteria. Evaluable patients after 8 months of treatment comprised 85.8%. 8-month monotherapy with captopril, nifedipine, hydrochlorothiazide and propranolol was completed by 53.49%, 75.28%, 45.78% of patients, respectively. An antihypertensive effect was reached in 57.97% of patients on monotherapy. Normalization of arterial pressure took place in 51.3%. The 4 drugs in the given doses produced a significant and similar effect in relation to the action on arterial pressure (absolute value). As for individual effects (complete and partial), captopril and propranolol were equal, nifedipine was more beneficial than hydrochlorothiazide. Side effects in captopril monotherapy arose 1.5-2 times less frequently than in response to propranolol or nifedipine and were similar to those of hydrochlorothiazide.

A multicenter, controlled, open, randomized trial of antihypertensive and life quality (LQ) effects of monotherapy with captopril vs propranolol, hydrochlorothiazide and nifedipine included 345 males aged 35-60 years with mild and moderate hypertension. The results of 8-month treatment provided the conclusions: the drugs were much alike by antihypertensive efficacy, LQ parameters proved more beneficial in the group on captopril than those on nifedipine and propranolol, hydrochlorothiazide failed to improve life quality, captopril is an effective and safe antihypertensive drug superior to the drugs of 3 other antihypertensive drug groups by positively affecting LQ.

The effect of abrupt discontinuation of nifedipine (N) on exercise tolerance and myocardial ischemia was studied in 7 patients with stable angina pectoris of effort (AP). N was administered in a dose of 20 mg 4 times a day for 34 days. Exercise treadmill tests were performed before N therapy in placebo treatment, on N treatment day 1, 28, on the first day after abrupt N discontinuation and 8 days after the latter. Upon acute and regular administration N produced a significant improvement in exercise tolerance before the onset of AP, development of moderate AP and up to 1 mm depression of ST-segment. Abrupt N discontinuation resulted in substantial deterioration in exercise performance pronounced more definitely on hour 21 and 24 after the last dose intake. A substantial increase in the sum of ST-segment depression at the onset of AP and at the development of AP of moderate severity occurred on the first day of N withdrawal. 8 days after N cessation all the exercise parameters returned to the baseline levels. We conclude that abrupt cessation of regular N therapy may cause a withdrawal syndrome which manifested with a decrease in the exercise tolerance and an increase in exercise-induced myocardial ischemia.

The new original Russian drug proxodolol having alpha- and beta-adrenoblocking activities in a ratio of 1:100 was examined at Stages I and II of clinical trials. The drug was given to 29 male patients aged 30-63 years who suffered from Stages I and II persistent hypertensive disease with a baseline diastolic blood pressure of >95 mm Hg. Proxodolol as 10- and 40-mg tablets was demonstrated to be an effective antihypertensive agent, its antihypertensive effects being revealed in acute and chronic uses. The drug was well tolerated by the patients, causing no significant adverse reactions. Further comprehensive comparative controlled studies of proxodolol including larger patient groups will define the contribution of the drug in long-term antihypertensive prophylaxis.

In non-inbred rats, the pharmacokinetics of proxodolol was studied after its intravenous administration in a dose of 1 mg/kg or oral use in a dose of 50 mg/kg as 1% aqueous solution, in Chinchilla rabbits, it was examined after intravenous administration in a dose of 1 mg/kg as 1% aqueous solution and oral use in a dose of 40-50 mg/kg as 40-mg tablets. The equilibrium dialysis method was applied to explore proxodolol binding to human and rat serum proteins in vitro. Proxodolol was demonstrated to be slightly distributed in the rat peripheral tissues and more actively in the rabbits (the stationary distribution volume was 0.264 and 2.27 1/kg, respectively). After intravenous injection, the total proxodolol clearance in the rats and the rabbits was 0.229 and 2.24 1/h/kg, the area beneath the concentration-time curve was 5702 and 964 ng/h/ml, the terminal half-life was 1.44 and 1.49 h, the mean retention time was 1.16 and 1.52 h, respectively. The pattern of rabbit serum proxodolol concentration curves after intravenous infusion suggests that the drug shows enterohepatic recirculation. After oral administration, the drug was rapidly absorbed from the gastrointestinal tract; the maximum concentration time was 0.58 h in rats and 0.70 h in rabbits. The mean absorption time was 0.77 and 0.64 h in rats and in rabbits, respectively. The absolute proxodolol bioavailability was determined to be 3.51 and 3.02% in rats and in rabbits, respectively. The in vitro serum protein-binding of proxodolol was 34% in rats and 66% in man.

The comparative efficacy of single and regular doses of the new Russian alpha- and beta-adrenoblocker proxodolol (Pd) and the beta-adrenoblocker propranolol (Pr) was studied in 12 male patients with stable angina on effort. The effect of single doses was evaluated with paired bicycle ergometries (PBE); that of course therapy was assessed with crossover randomized placebo-controlled tests of the two agents. During PBE, an adequate antianginal effect of Pd given in single doses of 0.04-0.08 g was seen in 66.5% and that of Pr used in the same doses was observed in 58.4% (p > 0.05). The exercise tolerance in patients given either agent in a single dose was similar. During 1-month course treatment with Pd in a mean daily dose of 186 +/- 24 mg, anginal episodes caused an over 3-fold reduction, which is similar to the clinical effect displayed by Pr, 182 +/- 25 mg/day. A single dose of Pd of 0.04 g produced a more pronounced chronotropic and antihypertensive effect than did the same dose of Pr. No differences were found during their course therapy. Pd was found to cause no orthostatic antihypertensive phenomenon.

The paper presents the results of the first phase of clinical trials of prodoxolol, a beta-adrenoblocker having alpha-adrenoblocking activity in a ratio of 100:1, in patients with coronary heart disease concurrent with stable exercise-induced angina pectoris. The tolerance of single proxodolol doses (10 mg in 4 patients, 20 mg in 2 and 40 mg in 2) was studied. In all cases, proxodolol reduced resting heart rate by 6-18 beats/min, which lasted for 5 hours or more. Four patients had a proxodolol-induced 20 mm Hg or more decrease in systolic blood pressure lasting for 5 hours. In 10 patients, the antianginal and anti-ischemic effects of proxodolol were evaluated by pharmaco-dynamic studies consisting in threshold treadmill exercise tests before and 30 min, 2 and 6 hours after single placebo (in 10 patients) and proxodolol (40 and 80 mg in 3 and 7 patients, respectively) administration. In addition, 7 patients underwent pharmacodynamic studies with propranolol, 80 mg. The efficacy was judged from the increased exercise duration before an anginal episode (antianginal effect) and from the decreased ST segment depression during the identical exercise (anti-ischemic effect). The antianginal effect of proxodolol began 30 min later, reaching its peak 2 hours later and retained 6 hours later. During all study periods it was more marked than that of propranolol. The anti-ischemic effect of proxodolol was similar to the antianginal effects and it did not correlated with its chronotropic one. Proxodolol was well tolerated with patients. Thus, proxodolol in single doses of 40 and 80 mg produced antianginal and anti-ischemic effects and its action was similar to that of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)