[Sublingual nitroglycerin: the pharmacokinetic changes following long-term treatment with trinitrolong and nitroderm-TTS]. / Sublingval'nyi nitroglitserin: izmenenie farmakokinetiki posle dlitel'nogo lecheniia trinitrolongom i nitrodermom-TTS.

The effect of the long-term use of prolonged medicinal forms containing nitroglycerin (NG)--trinitrolong and nitroderm-TTS on the pharmacokinetics of sublingual NG was studied. A significant change of the pharmacokinetic parameters at the sublingual use of NG both after the long-term treatment with trinitrolong and after therapy with nitroderm was observed: in both cases the time of half-release of NG from plasma and the average time of retention increased, the area under the curve of concentration-time significantly increased and the drug clearance decreased (for trinitrolong the difference in the clearance parameter is significant). While combining the data on both drugs the difference in the last two parameters also becomes significant. The observed slowing of elimination is probably the cause of the development of tolerance to NH at the long-term treatment, since according to the modern notions the degree of the effect is determined by the rate of NG metabolism.

[An analysis of the concentration-effect relation of glyceryl trinitrate in patients with stenocardia of effort after its single use in prolonged-release drug forms]. / Analiz sviazi kontsentratsiia--éffekt trinitrata glitserina u bol'nykhstenokardiei napriazheniia posle odnokratnogo primeneniia v lekarstvennykh formakh s prolongirovannym vysvobozhdeniem.

There is a correlation between the plasma concentrations of glycerol trinitrate and the antianginal effects of trinitrolong (application on the gingival mucosa) and nitroderm-TTS (application on the skin) in patients with angina pectoris by Hill's formula. The lower limit on the gingival mucosa) and nitroderm-TTS is 0.5-0.6 ng/ml.

[Methodological approaches to the evaluation of the effectiveness of anti-anginal preparations in patients with stenocardia by 24-hour ECG monitoring]. / Metodicheskie podkhody k otsenke éffektivnosti antianginal'nykh preparatov u bol'nykh so stenokardiei s pomoshch'iu sutochnogo monitorirovaniia EKG.

Scientific rationale are given for methodological approaches promoting improved reproducibility of 24-hour ECG monitoring data, for the method to be used repeatedly in assessing patient's condition. Repeated 24-hour-ECG monitoring in identical motor conditions (a standard mobility regimen) has been shown to improve considerably the reproducibility of its results. Criteria for the efficiency of antianginal therapy in patients with angina of the 2nd and 3d functional classes, as evidenced by 24-hour ECG monitoring, have been developed and substantiated. They are a drop in the number of ST depression episodes (by 3 and more) and in the total depth of depression (by 50% and more). The sensitivity of the assessment of each of the two indicators of myocardial ischemia or their combination was 70%, and the specificity was 77.8% and 88.9%, respectively.

[Relation of the anti-anginal effect of nitroglycerin and its blood level in patients with stable exertion-induced stenocardia]. / Zavisimost' antianginal'nogo effekta nitroglitserina ot kontsentratsii ego v krovi u bol'nykh so stabil'noi stenokardiei napriazheniia.

In 8 patients with coronary heart disease and stable angina pectoris of effort, a relationship was examined between nitroglycerin antianginal effects and blood concentration when it was topically applied to the gum (trinitrolong, TNL) and to the skin (nitroderm, ND). A close correlation was found between the antianginal effects and blood concentration (r = 0.97 for TNL and r = 0.81 for ND). The individual correlation coefficients were 0.61 to 0.84 for TNL and 0.31 to 0.79 for ND). In all cases but one, the antianginal effect was demonstrable when blood NG concentration reached 0.75 ng/ml, while in some cases (23%) at a concentration of 0.5 ng/ml or less.

[Study of anti-ischemic effects of verapamil and nifedipine after long-term treatment of patients with exertion-induced stenocardia]. / Izuchenie vyrazhennosti antiishemicheskogo éffekta verapamila i nifedipina pri dlitel'nom lechenii bol'nykh so stenokardiei napriazheniia.

The effects of verapamil and nifedipine taken as single doses and regular treatment, its mean duration being 2.9 and 2.8 months, respectively, were compared by means of repeated standard treadmill exercise in 22 patients with stable angina of effort. Verapamil taken as a mean standard dose of 413 +/- 18 mg was shown to produce anti-ischemic effect in the whole group that, in most cases, increased in relation to longer duration of treatment. Regular use of nifedipine (a mean daily dose of 86 +/- 5 mg) was associated with decreasing effect of the drug. Moreover, different patients showed different trends in terms of treatment efficiency (constant, growing or declining effect) both with verapamil and nifedipine.

[Pharmacokinetics of verapamil and its N-dealkylated metabolites in patients with chronic ischemic heart disease undergoing long-term monotherapy]. / Farmakokinetika verapamila i ego N-dealkilirovannykh metabolitov u bol'nykh khronicheskoi ishemicheskoi bolezn'iu serdtsa v usloviiakh dlitel'noi monoterapii.

Pharmacokinetics of verapamil (VP) and its main N-dealkylated metabolites (nor-VP, D-617 and D-620) was studied in 10 patients with chronic ischemic heart disease after administration of the first and last doses of the course of treatment (80-120 mg of VP 3-4 times per day for 4-7 months). The antipyrine test was used in 8 patients simultaneously with the study of pharmacokinetics of VP and its metabolites. At the end of the course a decrease of oral clearance of VP as compared with its beginning (from 3.02 to 1.57 l/min, p less than 0.01) and an increase of the drug half-life (from 6.48 to 9.49 hrs, p less than 0.01) were found. Half-lives of nor-VP and D-617 at the end of VP course (12.1 and 19.7 hrs, respectively) were also higher than at its beginning (8.7 and 14.2 hrs, respectively), half-life of D-620 underwent no significant changes (29.5 hrs at the beginning and 31.6 hrs at the end of VP course). At the end of VP course the patients exhibited a decrease of antipyrine clearance (to 28.7 versus 43.2 ml/min at the beginning of VP course, p less than 0.01) that indicates a reduced activity of oxidative microsomal enzymes of the liver due to long-term VP therapy. It is presumably one of the causes of decreased VP clearance at the course administration.

[Pharmacokinetics of glycerin trinitrate (nitroglycerin) after sublingual administration in patients with chronic ischemic heart disease]. / Farmakokinetika glitserina trinitrata (nitroglitsein) posle sublingval'nogo priema u bol'nykh khronicheskoi ishemicheskoi bolezn'iu serdtsa.

Pharmacokinetics of nitroglycerin was studied in 22 patients with ischemic heart disease associated with angina of effort after sublingual intake of 0.5 mg standard granules. The maximal blood plasma concentration of the drug was shown to occur on the average in 4.4 minutes and was 2.56 ng/ml. The half-life in plasma was on the average 6.0 minutes, apparent clearance was 21.9 l/min. The mean retention time of nitroglycerin was 9.5 minutes. Significant fluctuations of pharmacokinetic parameters during repeated examinations in the same patient as well as between the patients were revealed. A sharp asymmetry of distribution of these parameters was observed that makes it necessary to use the mean arithmetical for characterization of the pharmacokinetic parameters.

[Comparison of the verapamil concentration of human blood serum and saliva]. / Sopostavlenie kontsentratsii verapamila v syvorotke krovi i sliune u cheloveka.

Verapamil concentrations were measured in the samples of blood serum and saliva taken at the same time in patients with angina of effort within 0.5-24 hr after administration of a single dose of the drug (14 persons) or the last dose of the course (10 persons). A mean ratio of saliva verapamil concentration to blood serum concentration was 0.85 +/- 0.09 (from 0.19 to 2.69) after a single administration and 0.77 +/- 0.04 (from 0.29 to 1.09) after the course treatment. A statistically significant (p less than 0.001) positive correlation was revealed between verapamil concentrations in blood serum and saliva after a single administration (r = 0.69) and course treatment (r = 0.80). It is suggested that determination of verapamil concentration in the saliva of patients on long-term verapamil medication should be used for a reference estimation of its level in the blood.

The effect of oral verapamil therapy on antipyrine clearance.

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.

[New approaches to pharmacodynamic research on anti-angina agents]. / Novye podkhody k farmakodinamicheskim issledovaniiam antianginal'nykh lekarstv.

Methods of evaluating efficacy of antianginal drugs with exercise tests are described. The use of the methods makes it possible to choose adequate antianginal therapy for most patients with ischemic heart disease and stable effort angina and also to control efficacy of treatment with the chosen drug at its regular administration.