[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.

[Dynamics of the anti-anginal effect and of the concentrations of verapamil and its metabolites in the blood serum of patients with stenocardia of exertion]. / Dinamika antianginal'nogo éffekta i kontsentratsii verapamila i ego metabolitov v syvorotke krovi u bol'nykh so stenokardiei napriazheniia.

Anti-anginal effect of verapamil was examined in 17 patients with angina of effort (a 120 mg single dose in 10 patients and a 200 mg dose in 7), using repeated identical treadmill exercise with ECG monitoring. Serum levels of verapamil and its three primary metabolites were measured simultaneously. A correlation was demonstrated between verapamil's anti-ischemic effect and serum concentrations, while no significant contribution of the metabolites to the effect could be shown. In most patients, a marked anti-ischemic effect was observed where blood levels of verapamil exceeded 100 ng/ml. A considerable variability was noted in both the maximum concentrations of the drug and its individual concentrations corresponding to the same anti-anginal effect.

[Pharmacokinetics of nifedipine and its metabolite after a single oral dose of the drug in patients with stenocardia of effort]. / Farmakokinetika nifedipina i ego metabolita posle odnokratnogo priema nefedipina vnutr' u bol'nykh stenokardiei napriazheniia.

The pharmacokinetics of nifedipine and its primary metabolite 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine carboxylate was studied in 7 patients with angina of effort after a single oral administration of nifedipine ("Corinfar" tablets) in doses of 20 and 30 mg. The binding of nifedipine and its metabolite to blood serum proteins was determined. Nifedipine appeared in the blood serum of the patients 1.5-2 hrs after the drug intake, the maximal serum concentration was observed 1.13 hrs after the intake. The mean half-life period of nifedipine in the serum was 4.51 hrs. With an increase of the nifedipine dose, its pharmacokinetics underwent linear changes. Nifedipine and its metabolite were not detected in the urine. Binding to the blood serum proteins was 97.4% for nifedipine and 90.5% for its metabolite. 20 mg of nifedipine is suggested to be insufficient for the creation of the effective drug concentration in the blood.

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.

[Clinico-pharmacological study of a new Russian anti-angina preparation dinitrosorbilong]. / Kliniko-farmakologicheskoe izuchenie novogo otechestvennogo antianginal'nogo preparata dinitrosorbilonga.

Eighty patients with ischemic heart disease and stable angina pectoris of effort were examined for the efficacy of dinitrosorbilong (DNL), a new long-acting drug based on isosorbide dinitrate (ID). The anti-ischemic effect of DNL appraised with the aid of repeated exercise lasted about 8h, which was on the average 4 h longer as compared with the duration of the anti-ischemic effect of ID tablets. The regular intake of DNL favoured an appreciable decrease in the number of angina pectoris attacks making it possible to lower nitroglycerin consumption. DNL was well tolerated by the patients.

[Dinitrosorbilong--a new Soviet anti-angina preparation. Its comparative pharmacodynamic, pharmacokinetic and clinical study]. / Dinitrosorbilong--novyi otechestvennyi antianginal'nyi preparat. Sravnitel'noe farmakodinamicheskoe, farmakokineticheskoe i klinicheskoe izuchenie.

The efficacy of dinitrosorbilong (DNL)--a new long-acting isosorbid dinitrate (IDN) preparation applied to the gum--was evaluated in 72 coronary patients with stable angina of effort. Repeated treadmill tests revealed antianginal effect of DNL exceeding 8 hours. The degree and duration of DNL action significantly surpassed those of conventional oral IDN tablets and of some other long-acting IDN preparations. The results of pharmacokinetic studies show that DNL bioavailability is 491 +/- 240% as compared to conventional oral IDN tablets. Regular 7-day DNL administration resulted in a significant decrease in the frequency of anginal attacks and in the daily consumption of nitroglycerin tablets as compared not only to the control period but also to the period of conventional IDN tablet therapy.

[Cooperative study on the long-term use of anti-anginal preparations (methodologic questions)]. / Kooperativnoe issledovanie po dlitel'nomu primeneniiu antianginal'nykh preparatov (metodicheskie voprosy).

The development of a national collaborative program for the study of long-term effects of antianginal drugs initiated for the first time in our country is reported. The present communication is concerned with methodological approaches to the study. The collaborative effort has enabled a basically new scale of research. The principal methodological problems discussed are: how to select antianginal drugs; how to assess drug tolerance; and, possible changes in pharmacokinetic parameters of antianginal drugs used on a long-term basis. Studies along these lines are expected to contribute to the development of optimum regimens of antianginal treatment.

[Comparative clinical study of the effectiveness of the new anti-arrhythmia agents, trimecaine and pyrromecaine]. / Sravnitel'noe klinicheskoe izuchenie éffektivnosti novykh antiaritmicheskikh preparatov trimekaina i piromekaina.

The antiarrythmic effects of trimecain and pyromecain were studied in 53 patients with frequent ventricular premature beats. Trimecain was given to 22 patients and pyromecain was given to 31. The efficiency of both intravenous and oral drug administration was considered. Comparative drugs--lidocain, mexityl, procainamid were parallely used. The efficiency criterion was the decrease in mean ventricular premature beats per hour by 50% or more during ECG-monitoring. A positive antiarrhythmic effect of intravenous trimecain was observed in 35.3% of the patients, that of pyromecain was in 18.2% and after administration of a related compound lidocain, it was seen in 30.0% and 26.7%, respectively. Trimecain in tablets proved to be efficacious in 15.4% of the patients in a single dose and in 18.2% after its long-term therapy, while mexityl, a comparative agent was efficacious in 63.6%. Pyromecain in tablets did not lead to decrease in ectopia either during an "acute" test or during the long-term therapy whereas procainamid was effective in 37.3% of the patients studied.

[Pharmacokinetic characteristics of trimecaine compared to lidocaine in myocardial infarct patients]. / Farmakokineticheskie kharakteristiki trimekaina v sravnenii s lidokainom u bol'nykh infarktom miokarda.

The authors studied pharmacokinetics of trimecain and lidocain in 10 and 15 patients with myocardial infarction, respectively, after a single intravenous jet injection in the dose of 80 mg. The groups were comparable as to age, mass and surface of the body. In all patients the dependence of trimecain and lidocain concentrations on time was biexponential. Average individual values of distribution volumes in stationary condition and in the stage of elimination, clearance and half-life differed but insignificantly for trimecain and lidocain. The results obtained justify the conclusion that trimecain and lidocain are identical from the pharmacokinetic point of view.

[Prevention of ventricular fibrillation using lidocaine in the acute period of a myocardial infarct]. / Profilaktika fibrilliatsii zheludochkov s pomosch'iu lidokaina v ostrom periode infarkta miokarda.

Two randomized investigations have shown a possibility to prevent primary ventricular fibrillation in acute myocardial infarction by lidocain. The first investigation was conducted in an intensive care unit on 316 patients hospitalized on an average 6 hours after the onset of acute myocardial infarction. 155 patients were included into a control group. Since the hospitalization 161 patients had been receiving lidocain (trimecain) intravenously and then intramuscularly for a day. The second investigation was conducted in accordance with the program "Myocardial Infarction Register" in a small town for 28 years. The sudden death rates among the patients who had been emergency cases within the first year were control. In subsequent 1.8 years all these patients received lidocain intramuscularly. The findings suggest that lidocain significantly reduces the incidence of primary ventricular fibrillation without suppressing ventricular rhythm disturbances completely.