[Preclinical pharmacokinetics of pefloxacin]. / Doklinicheskaia farmakokinetika pefloksatsina.

The substance and tablets of pefloxacin mesilate manufactured by the Urals Polytechnical University and the National Research Centre of Antibiotics were studied on rats and dogs with the drug oral administration in single and multiple doses equivalent to the human ones. The bioavailability of the drug was good and its blood levels were efficient for a prolonged period (at least 24 hours) after a single oral administration. No cumulation of the antibiotic after its repeated use was observed. The pefloxacin mesilate tablets proved to be fully equivalent to the drug manufactured by Rhone-Poulenc-Rorer (France).

[Sulacillin in the treatment of bronchopulmonary diseases]. / Sulatsillin v lechenii bronkholegochnykh zabolevanii.

Antibiotic susceptibility of 279 strains of gram-positive and gram-negative isolates from patients with bronchopulmonary infections was tested. It was shown that the frequency of resistance to ampicillin and sulacillin amounted to 36.5 and 28.8 per cent respectively. The highest clinical efficacy of sulacillin was observed in the treatment of acute pneumonia (good and satisfactory results in 76.2 and 19 per cent of the cases respectively) and chronic nonobstructive bronchitis (good and satisfactory results in 80 and 16 per cent respectively). The clinical efficacy of sulacillin was somewhat lower in the treatment of chronic obstructive bronchitis (good and satisfactory results in 50 and 30 per cent of the cases respectively). In the treatment of chronic purulent bronchitis no clinical effect was detected in 30 per cent of the cases and in 70 per cent of the cases the results were satisfactory. The total frequency of adverse reactions to sulacillin amounted to 18.8 per cent.

[Analysis of ceftazidime and ampicillin tissue distribution using physiologic models of pharmacokinetics]. / Analiz raspredeleniia tseftazidima i ampitsillina v tkaniakh s pomoshch'iu fiziologicheskikh modelei farmakokinetiki.

Physiological models of ceftazidime and ampicillin pharmacokinetics were used to study accumulation of the antibiotics in the tissue interstitial space and to analyze the influence of the regional blood flow rate on the accumulation. For the control of the model adequacy, the published pharmacokinetic data on the distribution of ceftazidime and ampicillin in serum and "skin blister" fluid were used. The pharmacokinetic profiles calculated from the equations of the physiological models including Kp corresponded to the kinetics of the changes in the content of the cephalosporins and penicillins in the tissue homogenates. To estimate the antibiotic accumulation in the tissue interstitial space, it was necessary to use the equations where Kp = 1. Introduction of the coefficient regulating the regional blood flow rate to the equations made it possible to analyze the influence of the blood supply characteristics on the local pharmacokinetics.

[An animal experiment on transplacental transport of ceftazidime at various terms of pregnancy]. / Transplatsentarnyi perekhod tseftazidima v éksperimente u zhivotnykh v raznye sroki beremennosti.

The experiments on rats revealed good transplacental transfer of ceftazidime to the fetus. The level of the transfer increased with increasing of the pregnancy term. The antibiotic concentration in the fetal tissues exceeded the MIC for opportunistic organisms. The ceftazidime concentrations in the amniotic fluid were equal to the therapeutic ones at the early and late terms of the pregnancy. At the early terms of the pregnancy the antibiotic transferred to the amniotic fluid transplacentally. The data are in favour of recommending ceftazidime for prophylaxis and treatment of fetal intrauterine infections.

Use of gentamicin physiologically-based model for individual dosing.

A new approach to fixing initial doses of gentamicin (GM) for i.m. administration (that is most commonly used anyway) is discussed. This approach is based on a physiologically-based model allowing to reproduce individual patterns of GM concentration change in the patient's blood. This approach was used to reproduce the individual pattern of GM concentration change after the initial i.m. administration of 80 mg to 19 male patients (age-range 21 to 73 years, weight range 50-94 kg, creatinine concentration in the blood 0.4-1.6 mg/d). The GM concentration levels, obtained with the help of this model, were afterwards compared to the results of FPIA measurement of GM concentrations in the blood of the patients 0.5, 1, 2, 3, 5 and 7 h after administration. It proved that the average deviation of the predicted values from the actual was equal to 20 per cent for all the measuring time-points. For comparison we used individual patterns of GM distribution in blood calculated according to the one-compartment model from the same values of Vd, Cl and dose. In this case the error of pharmacokinetic prediction exceeded the 20 per cent and amounted to 43 per cent by 0.5 and 7 hours. Thus, the new approach with the physiologically-based model provides better accuracy for stable pharmacokinetic prediction for longer stretches of time upon administration, which is especially important for the correct establishment of dosing intervals.

[Use of a physiological model of gentamicin pharmacokinetics for individual dosage of the antibiotic]. / Ispol'zovanie fiziologicheskoi modeli farmakokinetiki gentamitsina dlia individual'nogo dozirovaniia antibiotika.

A new approach to fixing the initial doses of gentamicin (GM) for its intramuscular administration (the most commonly used anyway) is discussed. The approach is based on the physiological model reproducing the individual patterns of GM concentration change in patient's blood. Such parameters of the model as blood flow velocity and actual average volume of specific tissues as well as the tissue to the blood partition coefficient (Kp) are constant. They were used to calculate the volume of distribution in the body specific organs (Vs). The apparent distribution volume (Vd) and total clearance (Cl) are individual parameters. The Vd value was calculated individually for every particular patient depending on the body weight by the known equations. The difference between Vd and Vs was used to calculate the individual Kp for the organs and tissues which were not specially examined. When calculating Cl of GM, the patient's sex, age, weight and creatinine concentrations were taken into account. To evaluate the local velocity of blood flow after antibiotic intramuscular administration, it was important to consider the patient's sex and age. The approach was used to reproduce the individual patterns of GM concentration change after the initial administration of the antibiotic, 80 mg, to 19 male patients (age range, 21 to 73 years; weight range, 50 to 94 kg; blood creatinine concentration, 0.4 to 1.6 mg/dl). The GM concentrations attained with the use of the model were afterwards compared to the data on FPIA. (TDx, Abbott) by measuring the GM concentrations in the blood of the patients 0.5, 1, 5 and 7 hours after the administration.(ABSTRACT TRUNCATED AT 250 WORDS)

[Characteristics of pharmacokinetics of liposome-incorporated rifampicin in rats after intratracheal administration]. / Osobennosti farmakokinetiki rifampitsina, vkliuchennogo v liposomy, u krys pri vnutritrakheal'nom vvedenii.

Pharmacokinetics of rifampicin after its single intratracheal administration in the form of the liposome-encapsulated drug and its aqueous solution was studied on rats. It was shown that after the exposure to the liposome-incorporated rifampicin (10 mg/kg) the concentration-time curve in the blood and lungs was sigmoid with the retarded decrease in the blood drug concentration within 9 hours. The plateau segment of the curve provided at least a 4-fold longer maintenance of the rifampicin concentration in the blood and lungs at 3 to 4 micrograms/ml. The use of the liposome-incorporated antibiotic induced 2- and 1.5-fold increases in the AUC in regard to the lungs and blood, respectively.

[Use of rifamethoprim in acute and chronic respiratory tract diseases]. / Primenenie rifametroprima pri ostrykh i khronicheskikh zabolevaniiakh dykhatel'nykh putei.

Rifamethoprim is a new formulation containing rifampicin and trimethoprim. Its efficacy was studied in the treatment of a group of patients with various nonspecific diseases of the lungs. It was shown to be highly active against a broad spectrum of pathogens. With inclusion of trimethoprim to the formulation it appeared possible to markedly lower the bacterial ability to develop resistance to rifampicin, which solved the problem of long-term antibiotic use. The unique pharmacokinetic properties of rifampicin such as its capacity to penetrating into the sputum, lung tissues and cells make rifamethoprim be the drug of optimal choice in the treatment of respiratory diseases.

[The efficacy of using the Soviet antibiotic rifamethoprim in treating acute bacterial pneumonias and chronic bronchitis]. / Effektivnost' primeneniia otechestvennogo antibiotika rifametoprima v lechenii ostrykh bakterial'nykh pnevmonii i khronicheskogo bronkhita.

Rifametoprim (600 mg/day) was given to 64 patients with acute bacterial pneumonia, acute bronchitis and exacerbation of chronic bronchitis. 201 (83.4%) out of 241 isolates were sensitive to the action of the antibiotic. The treatment turned out effective in 84.4% of cases.

[Pharmacokinetics of cefotaxime and desacetylcefotaxime in the blood serum and bronchial secretion in patients with chronic bronchitis after administration of a single 24-hour dose]. / Farmakokinetika tsefotaksima i dezatsetiltsefotaksima v syvorotke krovi i bronkhial'nom sekrete u bol'nykh khronicheskim bronkhitom pri odnokratnom vvedenii sutochnoi dozy.

Concentrations of cefotaxime and its major active metabolite, desacetylcefotaxime, were determined in the serum and bronchial secretion of patients with chronic bronchitis aggravated after intramuscular injection of cefotaxime in a dose of 4 g once a day. Characteristic patterns of cefotaxime metabolism and high peak concentrations of desacetylcefotaxime in the serum (67.6 +/- 17.2 micrograms/ml) defined the prolonged retention of the metabolite both in the blood and bronchial secretion. The metabolite concentrations in more than half of the patients maintained within 2 micrograms/ml in the bronchial secretion by the 12th hour after the injection and in the blood serum by the 24th hour. Therefore, 4 g cefotaxime administered intramuscularly once a day provided the blood concentrations of the metabolite comparable with the MIC for the majority of the pathogens causing nosocomial infections of the respiratory tract practically within the whole period of the daily dosage. In the bronchial secretion such concentrations were attained within half of the period of the daily dosage.

[Pharmacokinetics of an antibiotic administered in cell carriers]. / Farmakokinetika antibiotika, vvodimogo v organizm v kletochnykh nositeliakh.

Tissue distribution of erythrocyte membrane-bound gentamicin was studied in non-inbred albino rats. Gentamicin was administered to the animals intravenously in single doses of 3.3 mg/kg as a free substance of the antibiotic or in carrier erythrocytes. The gentamicin concentration was determined in serum, blood and tissues of the liver, kidneys, lungs, spleen and the skeletal muscles by fluorescence polarization immunoassay (TDx, Abbott). Encapsulation of gentamicin in erythrocytes caused changes in its pharmacokinetics: the antibiotic half-life and mean retention time appeared to be higher and the antibiotic accumulation in the liver, spleen and kidneys increased 1.7-3.0, 19-27 and 1.5 times respectively depending on the technique of the carrier erythrocytes preparation. Exposure of the erythrocytes to tannin led to an increase in the rate of the antibiotic release from the carrier erythrocytes.

[Mathematical modeling of ampicillin pharmacokinetics in patients with altered excretory function of the kidneys]. / Matematicheskoe modelirovanie farmakokinetiki ampitsillina u liudei s izmenennoi vydelitel'noi funktsiei pochek.

A physiological model of ampicillin pharmacokinetics in man is proposed. Its design stems from the data characterizing the antibiotic distribution in rats. The model is useful in describing the pharmacokinetics of ampicillin after its intravenous and intramuscular administration. An adequate description of the antibiotic distribution in blood suggested an agreement with the real values of the estimated antibiotic concentrations in the tissues. The concentrations of ampicillin and sulbactam in the tissues after their intramuscular combined administration in doses of 1 and 0.5 g, respectively, were compared. The physiological model of the pharmacokinetics was applied to evaluation of a possible interval in changing of the antibiotic half-life. There was analytical relationship between the ampicillin half-life and efficiency of the renal function.

[The comparative pharmacokinetics of ceftriaxone in the blood and bronchial secretion in patients with different durations in the course of chronic bronchitis]. / Sravnitelnaia farmakokinetika tseftriaksona v krovi i bronkhial'nom sekrete u bol'nykh s razlichnoi dlitel'nost'iu techeniia khronicheskogo bronkhita.

The study on ceftriaxone penetration into bronchial secretion showed that in patients with a short-term history of chronic bronchitis (no more than 3 years) ceftriaxone used in a dose of 1 g once a day intramuscularly was detectable in the bronchial secretion within 10 hours after the administration, its concentrations being 0.67-2.41 micrograms/ml in 3 hours, 15.87 micrograms/ml in 4.5 hours, 4.58 micrograms/ml in 6.5 hours and 2.29 micrograms/ml in 10 hours. In patients with a long-term history of chronic bronchitis (mean 10 to 20 years) the presence of ceftriaxone in the bronchial secretion was detectable in a concentration of 0.51-3.75 micrograms/ml only in 2 hours after its administration. Beginning from the 5th hour after the administration its detection failed. This is indicative of lower ceftriaxone penetration into the bronchial secretion of such patients. The duration of chronic bronchitis did not influence ceftriaxone pharmacokinetics in blood. The contents of the antibiotic in serum and bronchial secretion were determined by HPLC (the resolving power of 0.5 micrograms/ml).

[Variability of ceftazidime pharmacokinetics in children with suppurative-septic diseases]. / Variabel'nost' farmakokinetiki tseftazidima u detei s gnoino- septicheskimi zabolevaniiami.

Marked variability of the ceftazidime pharmacokinetics (Cmax and T1/2) was observed in 3 newborns and 2 infants with purulent septic infections. The patients were under complex treatment in a reanimation unit (artificial pulmonary ventilation, infusions). It was recommended to perform the treatment with monitoring the antibiotic plasma concentrations to prevent the drug failure because of the changes in the distribution and excretion patterns. The use of HPLC for the purpose is advisable.

[Validation of a new procedure for calculating tissue/blood distribution coefficient]. / Obosnovanie ispol'zovaniia novogo metoda dlia rascheta koéffitsienta raspredeleniia tkan'/krov'.

An economic procedure for calculating the tissue/blood distribution coefficient (Kp) for physiological models of pharmacokinetics is substantiated. It stems from evaluation of Kp vs. the drug concentration in tissue and blood specimens. The estimate of the time for collecting biosubstrates for assay of the drug content in them is inverse of the constant of the blood drug elimination rate: Kp = Ct/Cb, where Ct and Cb are the drug concentrations in tissues and blood at the time moment equal to 1/kel. In this procedure the estimates of Kp agree with the values calculated by the AUC procedure which is the most exact but much more labour-consuming.

[Physiological model of sulbactam pharmacokinetics in rats and humans. Distribution of sulbactam in the tissues after intravenous and intramuscular administration]. / Fiziologicheskaia model' farmakokinetiki sil'baktama u krys i cheloveka. Raspredelenie sul'baktama v tkaniakh posle vnutrivennogo i vnutrimyshechnogo vvedeniia.

A 10-compartment physiological model of sulbactam pharmacokinetics is described. The model provides simulation of the pharmacokinetic profiles of the drug observed after its intra-muscular and intravenous administration in rats and humans. The adequate description of the drug distribution in human blood suggested that the model was applicable in designing rational schemes of sulbactam use.

[Physiologic model of NY-198 pharmacokinetics using a new method of determining tissue/blood distribution coefficient]. / Fiziologicheskaia model' farmakokinetiki NY-198 s ispol'zovaniem novogo metoda opredeleniia koeffitsienta raspredeleniia tkan'/krov'.

A 10-compartment physiological model of pharmacokinetics of NY-198, a new pyridone carboxylic acid, with antibacterial activity is described. In its construction an original rapid method based on measuring xenobiotic concentration in one particular time point was used for determining the tissue/blood distribution coefficients. The results of simulating the antibiotic pharmacokinetic profiles by the Kd values known from the literature and the values estimated with the proposed method were compared.

[Hypotension caused by intravenous infusion of rifampicin and its relation to the administration schedule]. / Gipotenziia, vyzyvaemaia vnutrivennym vvedeniem rifampitsina, i ee zavisimost' ot rezhima primeneniia antibiotika.

It was shown in studies on animals that bolus administration of rifampicin induced hypotension whose severity depended on the rate of the antibiotic administration. When the antibiotic was administered in the 5-, 10- or 15-minute regimen in a dose of 10 mg/kg the maximum decrease in blood pressure was 44, 34 or 21% of the initial level and the maximum antibiotic concentration attained in the blood was 34.4, 27.2 or 22.6 micrograms/ml, respectively. With the infusion for 30 minutes, the maximum antibiotic concentration in the blood was 17.6 micrograms/ml and the blood pressure did not undergo any significant changes. When the rate of the antibiotic infusion was high there was pharmacokinetic heterogeneity of the blood serum and biophase which could lead to unpredictable results. After repeated administrations of rifampicin to the same animals pronounced tachyphylaxis to the antibiotic was noted, which manifested itself in decreasing of hypotension, though the serum antibiotic level was 1.5 to 2 times higher that the initial one. It was concluded that administration of rifampicin in the therapeutic dose equal to 10 mg/kg for 30 minutes was the most sparing regimen for the antibiotic bolus intravenous infusion. Gradual increase in the antibiotic dose and administration rate in patients is possible under careful control of blood pressure and pharmacokinetic studies.