[Chronopharmacokinetics of nadolol in patients with arterial hypertension]. / Khronofarmakokinetika nadolola u bol'nykh arterial'noi gipertenziei.

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 pharmacokinetics of propranolol and its conjugated metabolites in patients with chronic ischemic heart disease and arterial hypertension with a one-time and course intake of the drug]. / Farmakokinetika propranolola i ego kon''iugirovannykh metabolitov u bol'nykh khronicheskoi ishemicheskoi bolezn'iu serdtsa i arterial'noi gipertenziei pri odnokratnom i kursovom prieme.

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.

[The prediction of enantiomeric differences in the pharmacokinetic parameters of drugs by using a physiological perfusion model]. / Prognozirovanie énantiomernykh razlichii v farmakokineticheskikh parametrakh lekarstvennykh veshchestv s pomoshch'iu fiziologicheskoi perfuzionnoi modeli.

A physiological perfusion pharmacokinetic model was used to assess the possible differences in the model-independent pharmacokinetic parameters of drug enantiomers (total clearance, mean retention time, half-life and stationary distribution volume), depending on differences in their blood binding and in the values of intrinsic hepatic clearance. The distribution in the organs and tissues and renal clearance of enantiomers were assumed to be equal. The maximally possible values of the relationships of the above parameters were found for enantiomers. The relative values of parameters vary irregularly with the increase in the values of intrinsic hepatic clearance: drastic changes occur in the range 0 to 100 liter/hour, but they do not take place in the range 100 to 1000 liter/hour. The differences in enantiomeric parameters also decrease as the blood binding of enantiomers drops.

[Proxodolol pharmacokinetics in rats and rabbits]. / Farmakokinetika proksodolola u krys i krolikov.

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 pharmacokinetic interaction of propranolol and nifedipine in patients with angina of effort]. / Izuchenie farmakokineticheskogo vzaimodeistviia propranolola i nifedipina u bol'nykh so stenokardiei napriazheniia.

A comprehensive study was undertaken to examine the pharmacokinetic and pharmacodynamic interaction of propranolol and nifedipine in 11 patients with stable angina of effort who were treated for a long time. It was shown that when the agents were given in combination, the patient's plasma generated the same profiles of their concentrations as used alone. This suggests that the propranolol + nifedipine combination is safe from the point of their pharmacokinetic interaction. The latter occurs at the level of their pharmacodynamic effects.

[The pharmacokinetics of propranolol when used with the propercuten transdermal therapeutic system (experimental data)]. / Farmakokinetika propranolola pri primenenii transdermal'noi terapevticheskoi sistemy properkutena (éksperimental'nye dannye).

The pharmacokinetic studies of propranolol following the application of the propercuten transdermal therapeutic system were performed in conscious rabbits previously assigned to 3 groups. Different forms of propercuten (forte and mite) were used in different groups, different areas of its application being employed. Pulsed intravenous injections of propranolol were given to Group 1 rabbits to conduct another series of pharmacokinetic studies. The rate of drug administration to the systemic bed was 0.08 mg/h per cm propercuten. The constant injection rate was maintained during 5 days, but when propercuten was withdrawn the elimination time of propranolol was 24 hours.

[Differences in hemodynamic effects of the cardioselective beta-adrenoblocker acebutolol and non-selective beta-adrenoblocker propranolol in long-term antihypertensive therapy]. / Osnovnye razlichiia gemodinamicheskikh éffectov kardioselektivnogo beta-adrenoblokatora atsebutolola i neselektivnogo beta-adrenoblokatora propranolola pri dlitelnoi antigipertenzivnoi terapii.

The cardioselective beta-adrenoblocker acebutolol used as a course therapy for 12 weeks was found to be a highly beneficial antihypertensive agent. The antihypertensive effect of the agent given in doses of 400-800 mg/day was as pronounced and prolonged as that of propranolol, 80-160 mg/day, though there is a tendency for acebutolol to show its complete or partial antihypertensive effect rather at the end of monotherapy than propranolol. At the same time the bradycardiac effect was more pronounced in propranolol therapy. The antihypertensive effect of acebutolol, 400-800 mg/day, was revealed after 2 weeks of its use and persisted within the entire 12 weeks of therapy. The drug was well tolerated. In contrast to propranolol, a non-selective beta-adrenoblocker having no intrinsic sympathomimetic activity, acebutolol failed to produce adverse effects, such as by decreasing cardiac output and increasing total peripheral vascular resistance. The agent had a less negative chronotropic effect.

[The absence of stereoselectivity in propranolol uptake by the lungs]. / Otsutstvie stereoselektivnosti zakhvata propranolola legkimi.

Propranolol (P) is known to be actively captured by the lungs of experimental animal and man. To elucidate the mechanism of the phenomenon, the authors studied the P enantiomeric ratio in the serum from the left ventricle 0-10, 10-20 and 20-30 s after bolus injection of P (0.5 mg) into the pulmonary artery of 8 patients catheterized for coronary angiography. The total P concentrations and enantiomeric ratio were measured by non-stereoselective and stereoselective high performance liquid chromatography. The solid-phase extraction method was used for extracting P from the serum. It showed a small, but significant increase is S(-)/R(+) ratio (to 1.18 +/- 0.12, P < 0.05 vs 1) which was, however, almost the same when measuring this after adding P to serum of the same patients (1.11 +/- 0.05, P > 0.05 vs 1.18). Thus, propranolol uptake by the lung during a single passage is not stereoselective and hardly involves some active process.

[The pharmacokinetics and pharmacodynamics of the prolonged-action beta-adrenoblocker nadolol at rest after a single administration to hypertension patients]. / Farmakokinetika i farmakodinamika beta-adrenoblokatora prolongirovannogo deistviia nadolola v pokoe posle odnokratnogo priema u bol'nykh gipertonicheskoi bolezn'iu.

The pharmacokinetics and pharmacodynamics of nadolol given in a single dose of 80 mg to 17 patients with mild hypertension were studied by echocardiography at rest. The major pharmacokinetic parameters for nadolol did not differ greatly from those reported in the literature and obtained from volunteers. No correlation was found between endogenous creatine clearance and renal nadolol clearance. How the hemodynamic effect developed and whether it was related to blood nadolol concentrations in time after single administration were followed up and discussed. There was a significant decline in blood pressure 2 hours after the drug. There was a clock-wise hysteresis in the relationship between the changes in cardiac output and nadolol levels. Changes in blood pressure were shown to significantly correlate with those in cardiac output.

[The polymorphism of pachycarpine oxidation]. / Polimorfizm okisleniia pakhikarpina.

The ratio of urinary excretory pachycarpine to its oxidized metabolites, 2- and 5-dehydropachycarpines (metabolic ratio) was determined in a selective group of 81 unrelated cardiac patients from a Moscow Caucasian population given pachycarpine in a dose of 25 g. The metabolic ratio distribution was shown to be bimodal. Ninety five per cent of the patients had the metabolic ratio lower than 28 while 4 (5%) patients higher than 70. In 25 patients of the group, the pachycarpine metabolic ratio was evaluated after quinidine, 50 mg. Twenty-two patients with a relatively low metabolic ratio showed a dramatic (several times) increase, while in 3 patients with the prior metabolic ratio higher than 70, the effect of quinidine was insignificant. The findings suggest that pachycarpine oxidation is genetically polymorphic and similar to the polymorphism of sparteine/debrisoquine oxidation. Pachycarpine may be used as a marker in phenotyping the population.

[The pharmacokinetics of the prolonged-action beta-adrenoblocker nadolol in hypertension patients after a single administration]. / Farmakokinetika beta-adrenoblokatora prolongirovannogo deistviia nadolola u bol'nykh gipertonicheskoi bolezn'iu posle odnokratnogo priema.

The pharmacokinetics of the beta-adrenoceptor blocker nadolol was studied in 30 patients suffering from mild hypertension given a single 80 mg dose of the drug. It has been shown that distribution of the pharmacokinetic parameters in this sample can be assumed normal. Their averages are similar to the reported data on healthy subjects. The mean retention time of nadolol in the body was estimated for the first time. The absorption of the drug was shown to be slow, which together with a low degree of bioavailability, may be associated with its low lipophility. A close correlation was demonstrated between the half-life and the mean absorption time estimates computed from blood serum and nadolol excretion with urine. The conclusion is made that glomerular filtration plays the key role in the drug elimination.

[Assessment of rate constants for isolating a metabolite by a model-independent method]. / Otsenka konstanty skorosti vyvedeniia metabolita model'no-nezavisimym metodom.

A model-independent method for estimating an elimination rate constant of a metabolite of exogenous substance is suggested as an alternative to known methods. The new method (named the initial slope method) uses blood (plasma) concentration-time data of both the substance and the metabolite obtained after an extravascular impulse input of the substance. The metabolite input is not needed substantially facilitating the experiment. The method is based upon the assessment of areas under the substance and metabolite concentration-time curves, the initial substance concentration, and the initial slope of the metabolite concentration-time curve. The method was tested using artificial data generated on the basis of a compartment model for the substance and metabolite kinetics. It was shown providing nonbiased estimates of a true metabolite elimination rate constant irrespective of the structure of the model used to generate data. Other methods failed to provide such estimates.

[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 initial slope method for model structure: independent estimation of the elimination rate constant of a metabolite.

A model structure-independent method for calculating the true elimination rate constant of a primary metabolite is presented. It does not require direct metabolite administration and uses data on drug and metabolite blood (plasma) concentrations after a bolus drug input. The method has been tested and compared with the moment method and the area function method using errorless and errant data simulated on the basis of one- and two-compartment models of the metabolite kinetics. In contrast to known methods the proposed method provided exact estimates of the elimination rate constant in the case of errorless data of both one- and two-compartment models. However the estimates are sensitive to random errors in the concentration data.

[New drug forms of isosorbide dinitrate: the problem of an objective evaluation in patients with ischemic heart disease]. / Novye lekarstvennye formy izosorbida dinitrata: problema ob''ektivnoi otsenki u bol'nykh ishemicheskoi bolezn'iu serdtsa.

In 7 patients with ischemic heart disease and stable angina pectoris the efficacy of three oral isosorbide dinitrate (ID) formulations, nitrosorbide, isodinite and isodinite-retard, was compared. The antianginal and anti-ischemic effects were assessed in terms of exercise treadmill tests performed prior to and repeatedly after (2, 5 and 7 hours) single-dose administration (in comparison with placebo). The efficacy of isodinite-retard only slightly differed from that of placebo. Isodinite had a more pronounced effect than nitrosorbide, although the duration of isodinite effect was shorter than that of nitrosorbide. Plasma ID and its metabolite, isosorbide-5-mononitrate concentrations mirrored exercise duration changes. ID content in the tablets of all formulations studied corresponded to those indicated by the manufacturer. The differences in the efficacy of ID formulations can be attributed to the differences in their bioavailability. Thus, the method used permitted to reveal significant distinctions in the efficacy of different ID formulations. These distinctions must be taken into account in clinical practice.

[Comparative effectiveness and biological equivalency of new nifedipine preparations in patients with exercise-induced stenocardia]. / Sravnitel'naia éffektivnost' i bioékvivalentnost' novykh preparatov nifedipina u bol'nykh stenokardiei napriazheniia.

The effectiveness of fenigidin and cordafen was studied in comparison with placebo and corinfar after a single administration during pharmacodynamic investigations with tredmill in 14 patients with stable exertional angina. Blood nifedipine concentrations were also compared. The potency of fenigidin was shown to be weaker than that of corinfar. The effect of cordafen and corinfar did not differ significantly. The mean concentrations of nifedipine in the blood serum after administration of equal doses of cordafen and corinfar did not differ considerably, either. Thus the findings were indicative of the equal potency of the same single doses of cordafen and corinfar and of less marked potency of fenigidin due to lower bioavailability.

Development of tolerance to nifedipine in patients with stable angina pectoris.

1. The possibility of development of tolerance to the anti-ischaemic and anti-anginal effects of nifedipine during sustained administration for 2 months was studied in 15 patients with stable angina pectoris by means of repeated exercise tests on a treadmill. 2. After acute administration of nifedipine (20-30 mg) substantial anti-ischaemic and anti-anginal effects lasted for at least 4 h in all patients. 3. During sustained nifedipine treatment with a dose schedule which provided continuous anti-ischaemic effect during a day (mean daily dose 82.7 +/- 6.0 mg, range 60-120 mg) a substantial attenuation of this effect was registered. The duration of the anti-ischaemic effect was 5.4 +/- 0.3 h after acute administration, decreasing significantly to 3.6 +/- 0.4 h during sustained administration. 4. The attenuation of the nifedipine effect was not associated with worsening of the patients' condition. 5. Plasma concentrations of nifedipine and its metabolite were similar after acute administration and during sustained treatment. Protein binding of nifedipine also remained constant during the study. 6. There was marked interindividual variation in the degree of attenuation of the nifedipine effect during sustained administration. In five patients nearly complete loss of nifedipine efficacy was registered. Eight to ten days after stopping regular administration of nifedipine only partial restoration of nifedipine effect was observed. 7. We conclude that during sustained nifedipine administration tolerance to its anti-ischaemic, anti-anginal and circulatory effects develops in a substantial number of patients with stable angina pectoris.