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An analysis of maximal and minimal serum concentrations of carbamazepine was performed in 40 children with convulsive syndrome. All the patients received the drug for a long period. Considerable case-to-case differences of serum concentrations in spite of practically equal doses were revealed. Serum drug concentrations were therapeutically optimal (6-8 mg/ml) only in one third of children. On the basis of pharmacokinetic parameters, mean optimal dosages sufficient for maintenance of effective and safe carbamazepine concentrations were calculated. As the child grows general clearance of carbamazepine decreases. Over the age of 9 years it is significantly lower in girls than in boys of the same age. Speed of carbamazepine elimination was higher in cases of combined treatment than in cases of monotherapy. Indications and optimal time for therapeutic drug monitoring of carbamazepine are determined and clinical illustrations are presented.

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Pycamilon was shown to be rapidly absorbed in the blood (tmax = 0.23 h), to penetrate well through the blood-brain barrier and to be intensively uptaken by the animal organs and tissues and to be eliminated mainly in the urine (t1/2 = 0.51 h). The drug bioavailability at oral administration to mice is 21.9%, and to rats from 53 to 78.9% (according to the urinary excretion data).

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The pharmacokinetics of theopec (TP) and theobiolong (TB) was studied and compared to theotard and durophylline in 24 bronchial asthma patients. The efficacy of the continuous use of TP and TB was examined in 64 patients. Theophylline (TPh) was absorbed from TP tablets according to the laws of the kinetics of the first order, i. e. one-third of the dose was absorbed rapidly whereas the remaining two-thirds 7.5 times were slowly. The kinetics of TPh absorption from TW was marked by the zero order at a constant rate of 45 mg/h. The volume of distribution, the elimination rate constant, the total clearance, and bioavailability of the drugs under comparison did not differ significantly. During continuous treatment with TP and TB, equiponderant concentrations of TPh were attained by the 4th day, the mean maximum concentration of TPh for TP was 10.6 +/- 1.8, that for TB 9.6 +/- 0.9 micrograms/ml. By the 7th day of the treatment with TP and TB a beneficial clinical effect was reached in 79 and 81% of the patients, respectively, in spite of the fact that there was no well-defined correlation with the changes in the volume of forced expiration per second. During TP and TB intake, the side effects common to TPh occurred equally often (in 19 and 23% of cases, respectively), but they were short-lived and disappeared by themselves or after correction of the dosage. As for TP, the side effects were mostly recorded on the part of the gastrointestinal tract whereas TB provoked tachycardia, cardialgia which should be taken into account in cases where the drug is prescribed to patients with concomitant diseases.

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Pharmacokinetics of theopek--a new original slow release formulation of theophylline--as compared with theotard and theodur was studied in patients with bronchial asthma. The pharmacokinetic parameters of this product were shown to be comparable. A significant correlation between blood theophylline concentration and the bronchodilating and diuretic effects in patients with bronchial asthma was revealed.

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Pharmacokinetic data obtained from 41 patients with paroxysmal atrial fibrillation were used to give quinidine therapy on an individual basis. The proposed approach made it possible to restore sinus rhythm in 80% of the patients and to identify patients having "true" resistance to the drug. To restore the rhythm, 24 and 48 hours were required for 24 and 9 patients, respectively. The application of the pharmacokinetic approach allows the total therapeutic dose of the agent to be reduced and, to a considerable extent, the risk of side and toxic effects to be lowered.

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A population study of quinidine half-elimination time distribution has demonstrated a trimodality of distribution that is due to different rates of metabolic quinidine oxidation. The ratio of permanent serum concentrations of 3-oxyquinidine (metabolite) to quinidine in the rapid oxidation group was elevated significantly, as compared to slow oxidation groups. The values obtained in these phenotypic groups show good correspondence to the Hardy-Weinberg law, with a 0.755 frequency of the allele controlling high monooxygenase activity, and a 0.244 frequency of the gene for the low activity. Effective daily doses should be 1.5-2 times as high in high oxidants (57% of the population) as they are in slow oxidants (37%), and 2.5-3 times as high, as compared to very slow oxidants (6%).

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Certain approaches to analysis of the drug concentration-response relationship based on the mechanism of the effect realization and the results of their clinical trials are discussed. The studies are exemplified by a model for quantitative analysis of the concentration-response relationship developed for diuretics and by the results of the clinical trial of the principle of the maximum providing prediction of the steady-state level of the drugs in blood and estimation of the drug effect.

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The efficiency of digoxin in elderly and old patients with subacute myocardial infarction is dependent on the original disorders of left-ventricular systolic phase structure. Changes in systolic phase structural parameters in the presence of supporting digoxin therapy show correspondence to changes of these parameters in response to a single digoxin dose. Digoxin's positive inotropic effect was similar in patients with the sinus rhythm and those with atrial fibrillation. The positive inotropic action of digoxin is not associated with a negative chronotropic effect in patients with sinus rhythm and normal heart rate.

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Elderly and old patients with subacute myocardial infarction showed elevated gastrointestinal digoxin absorption rates and a tendency to increased bioavailability of the drug, as compared to similar parameters in infarction-free patients of the same age, so that blood digoxin peaks were higher in the former. The demonstrated absorption changes may be related to limited physical activity of the myocardial infarction patients examined. Digoxin pharmacokinetic patterns are analysed with reference to baseline myocardial contractility.

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The authors have developed algorithms and programs that permit introduction in the dialogue mode of the data pertinent to the time-course of changes in the concentrations and pharmacological effects, calculation of up to 20 pharmacokinetic parameters, establishment of the relationship between the effect and concentration, and prediction of the expected effects under different drug dosage regimens. The ASPID is based on the FORTRAN-IV language.

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The pharmacokinetics of ampicillin was studied in 38 patients with acute pyelonephritis in the second and third trimesters of pregnancy after the first and the last (28th-32nd) intramuscular injections of the antibiotic. The ampicillin levels in the blood and urine were determined with the agar diffusion method. The pharmacokinetic parameters were estimated in a one-compartmental model by computer The ampicillin levels in the blood and urine of the patients did not practically differ at all the investigation periods (0.5-6 hours after the antibiotic administration) in the second and third trimesters of pregnancy. During the treatment, the rate of ampicillin elimination from the host increased and the period of half-elimination from the blood decreased. The antibiotic levels in the urine within 4-6 hours after the last injection were practically lower in the second trimester of pregnancy as compared with the second trimester. The therapy resulted in an increase in the antibiotic renal clearance, which returned to normal in the second trimester of pregnancy and remained under normal in the third trimester of pregnancy. The increase was due to an approximately 2-fold acceleration of the rate of ampicillin secretion by the renal tubules. The total clearance of ampicillin practically increased in the second trimester of pregnancy and remained decreased in the third trimester of pregnancy. The estimation performed in accordance with the Krueger-Timmer principles on the basis of the characteristic features of the pharmacokinetics of ampicillin shown in the study provides recommendation of the following scheme for pyelonephritis treatment in pregnant women: 500 mg of ampicillin injected intramuscularly every 6 hours followed by gradual decreasing of the intervals between the injections to 4 hours as the rate of ampicillin elimination increases.

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The time-course of the antiexudative effect of the antihistaminic drugs diphenhydramine, phencarol and suprastin was studied in experimental dextran edema of the rat hind limb after intragastric administration of the drugs in a dose of 50 mg/kg. The data obtained were correlated to the time-course of the blood serum drug concentration measured by high pressure liquid chromatography. The relationship between the pharmacological action of the drugs and the mean maintenance dose was depicted by means of computer. It has been shown that the antiexudative activity of diphenhydramine and phencarol is approximately identical, whereas the efficacy of suprastin is several times less.

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The authors have estimated the effect of hemodialysis on the pharmacokinetics of digoxin instilled intravenously to patients with the terminal stage of chronic renal insufficiency. It has been shown that dialysis was associated with an almost double increase in the clearance constant of digoxin due to its additional elimination through the membrane of the dialyzer. Over five h of dialysis the body excretes 12.5% of the administered dose of digoxin which is only 3.8% more (by 19 micrograms) than the average amount eliminated without dialysis. The contribution of dialysis to the elimination of digoxin is insignificant and, therefore, the regimen of its administration on days when dialysis is performed should be left unchanged.

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