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A A Firsov

Publications and source records attributed to A A Firsov.

At least 91 records · Page 5Linked to original sources
PubMed1985

[Clinical pharmacokinetics of the antitumor antibiotic reumycin: an analysis of individual variability].

The pharmacokinetics of reumycin, an antitumor antibiotic, was studied with high performance liquid chromatography in patients with tumors of the brain and kidneys. The drug was injected intravenously in single doses of 30-300 mg. It was shown that the pharmacokinetics of reumycin was nonlinear and within every dose could be depicted by a three- or two-compartmental model. Its nonlinearity was due to saturation of the antibiotic binding to blood plasma proteins. 20-40 per cent of the intact antibiotic was excreted with the urine unchanged, which indicated a significant role of extrarenal excretion of the antibiotic. The dose dependence of the pharmacokinetic parameters and in the particular of the area under the reumycin blood concentration on the time curve and cumulative renal excretion varied with patients. Distribution of patients by these parameters was bimodal. This factor and the differences in renal excretion caused significant variability in the reumycin pharmacokinetics, which required individualization and control of the antibiotic use in patients. The reumycin half-life in man predicted with the use of the Dedrick pharmacokinetic time scale by the data of experiments on rats appeared close to that established in patients (41 and 33.5 hours, respectively).

Antibiotics, Antineoplastic↗
PubMed1985

[Sisomycin pharmacokinetics in the perilymph and blood serum--an approach to predicting its ototoxic effect].

To elucidate the possibility of predicting the level of aminoglycoside antibiotic penetration into the fluids of the internal ear by the antibiotic blood levels, the pharmacokinetics of sisomicin in the perilymph and blood serum was studied on guinea pigs. The antibiotic was administered to the animals subcutaneously in doses of 50, 100 and 200 mg/kg. On the basis of the comparison of the sisomicin concentrations in the perilymph normalized against the dose it was concluded that the pharmacokinetics of sisomicin in the perilymph and blood serum of the animals was linear. Comparison of the areas under the curves of the antibiotic concentration versus time in the perilymph (AUCp) and blood serum (AUCs) showed that the tissue availability of the antibiotic in this study characterized by its penetration into the perilymph and defined by the ratio of the AUCp to AUCs amounted to 55 per cent. In a two-compartment model it was not possible to predict the antibiotic levels in the perilymph by concentrations in the blood. However, by the antibiotic blood levels it was possible to characterize in a complex the pharmacokinetic behaviour of the antibiotic in the perilymph by predicting the areas under the respective curves of the antibiotic concentration versus time. The proportional relation between the values of the AUCp and AUCs suggested that the level of the antibiotic penetration into the internal ear and consequently the intensity of the potential ototoxic effect could be more reliably predicted not by separate values of the antibiotic concentration but by the areas under curves of aminoglycoside concentrations versus time.

Animals↗
PubMed1983

[Pharmacokinetic basis for using tobramycin and sisomicin in treating pyelonephritis of the transplanted kidney].

The pharmacokinetics of tobramycin and sisomicin in patients after kidney transplantations was studied. A significant variability of the pharmacokinetic parameters of tobramycin and sisomicin under conditions of the changing function of the kidney transplant was shown. This required individual control of the drug serum levels in such patients. Linear correlation between the exponent (beta) and the clearance of endogenous creatinine was observed. On the basis of this correlation a nomogram providing a decrease in the percentage of the errors in determining the dosage intervals was plotted.

Adolescent↗
PubMed1983

[Pharmacokinetic prediction of the efficacy of using sisomicin in wound infections].

The pharmacokinetics of sisomicin in the blood, infection foci and urine of patients with wound infections was studied comparatively. Higher blood levels of the antibiotic after intravenous injection as compared to those after intramuscular injection provided its more intensive penetration into the tissues of the wound edges and bottom. After intravenous injection the sisomicin concentration in the tissues was sufficient for inhibition of the strains of Staphylococcus, E. coli and Ps. aeruginosa detected in the patients, while after intramuscular injection the antibiotic levels were sufficient only for inhibition of the first two causative agents. Comparison of the data on the sisomicin pharmacokinetics in the blood and tissues of the wounds provided the characteristics of the level of the drug penetration into the focus of the infection ("therapeutic availability"). Since the levels of sisomicin in the blood and infection foci were highly variable in different individuals. It is recommended that the antibiotic be used under the control of its concentrations in patients. It was shown that the data on the sisomicin renal excretion might be used for the purposes of the pharmacokinetic control.

Humans↗
PubMed1983

[Simulation of the pharmacokinetics of aminoglycosides in the kidneys: single and continuous intake of sisomicin and gentamicin by rats].

The pharmacokinetics of sisomicin and gentamicin in the cortical and medullary layers of the kidneys was studied on rats. The antibiotics were administered daily in doses of 12.5 and 25 mg/kg a day. The levels of the antibiotics in the cortical layer were much higher than those in the medullary layer. The use of a twice as higher dose in the first case resulted in a less than a two-fold increase in the drug concentration, while in the second case the increase was more than two-fold. Prognosis of the pharmacokinetics of aminoglycosides used for 8-16 days was achieved with the help of the constants of the two-compartmental model. It was shown that the actual levels of sisomicin and gentamicin in the kidney medullary layer did not significantly differ from the estimated ones and the levels of the drugs in the cortical layer were much lower than the predicted ones. The distorted linearity of the aminoglycoside pharmacokinetics must be mainly due to saturation of the cortical layer with the drugs.

Animals↗
PubMed1983

[Graphic method of assessing the maximum cumulative excretion of a drug].

Inaccuracy in estimation of the maximum excretion of drugs (M infinity e) is the main cause of errors in determination of their pharmacokinetic parameters by the data of the cumulative excretion (Me(t)). It was shown that the M infinity e value could be determined analytically with the following equation: (formula; see text) where S0Me leads to t is the area under the cumulative excretion curve and ke1 is the elimination constant. The equation was derived from integration of the equation of the cumulative excretion of drugs, the pharmacokinetics of which could be formalized with the linear one-compartmental model. When the data were linearized on the coordinates S0Me leads to t/t - Me(t)/t, the M infinity e value was determined by the portion of the curve on the ordinate and the ke1 value was calculated by the negative reverse value of the regression coefficient. The advantage of the method is that collection of the excrete samples is not limited by the use of the method. The calculations may be performed with a calculator or manually. The possibilities of the method are illustrated with reference to an analysis of the simulated and experimental data.

Kinetics↗
PubMed1982

[Build up of a given concentration of tobramycin and sisomycin in the blood of young children by the intravenous infusion of the antibiotics according to a calculated regimen].

Three regimens for intravenous infusion of tobramycin and sisomicin in doses of 1.33 and 1 mg/kg, respectively were analysed theoretically with the use of the constants of a two-compartmental model characterizing the tobramycin pharmacokinetics in adults. The regimen implied administration of the antibiotics by means of a 12-hour infusion. The second regimen consisted of a jet injection of the initial dose simultaneously with the beginning of the maintenance infusion. The third regimen consisted of a rapid initial infusion followed by a slow maintenance infusion. It was shown that maintenance of the drug concentration at the required levels, i.e. 2-8 microgram/ml for tobramycin and 2-61 microgram/ml for sisomicin was most safely provided by the regimen of the subsequent infusions. This regimen was tried clinically in the treatment of 17 children aged 2 months to 2.5 years with severe forms of acute pneumonia. The rate of the 25-minute initial infusion of tobramycin was 22.2 microgram/kg . min and that of the subsequent 2.7-hour maintenance infusion was 4.85 microgram/kg . min, the total dose being 1.33 mg/kg. The rate of the 20-minute initial infusion of sisomicin was 21.7 microgram/kg . min and that of the subsequent 2.4-hour maintenance infusion was 3.88 microgram/kg . min, the total dose being 1 mg/kg. It was shown that the levels of both the antibiotics in the blood serum of the patients were within the required ranges.

Anti-Bacterial Agents↗
PubMed1982

[Elaboration of the procedures for the pharmacokinetic interpretation of aminoglycoside nephrotoxicity: the experimental evaluation of the safety of repeated gentamycin administration].

Nephrotoxicity and pharmacokinetics of gentamicin were studied on rats treated with the antibiotic for 30 days in doses of 6.25, 12.5 and 25 mg/kg administered daily. The pharmacokinetics of gentamicin and the time course of changes in the urea nitrogen levels of the blood serum were studied after the 1st, 5th, 8th and 30th injection. The analysis of the respective curves was used for calculation of the average integral values of the concentrations of the antibiotic (C) and urea nitrogen (E). After that the average integral values of these parameters ((CAVG and EAVG respectively) within the whole treatment couse with the use of every dose were calculated in the same way by using the curves of the dynamics of C and E changing. Comparison of the diagrams of E dependence on C for gentamicin and sisomycin showed that nephrotoxicity of sisomycin was 1.48 times higher than that of gentamicin.

Aminoglycosides↗
PubMed1981

[Pharmacokinetic analysis of the nephrotoxic effect of sisomycin].

The kinetics of the urea nitrogen in serum was studied on anesthetized cats with constant concentrations of sisomycin in the blood. A correlation between the nephrotoxic effect of sisomycin and its concentration in the blood serum was found. High nephrotoxicity of sisomycin as compared to that of gentamicin, kanamycin or streptomycin under conditions of their equal levels in the blood was revealed on the basis of the above correlation. Still, when the antibiotic concentrations in the blood serum were maintained at the respective therapeutic levels, the nephrotoxic effects of sisomycin and gentamicin were almost equal. The above correlation was used for calculation of the maximum value of the sisomycin safe concentration in blood serum. The safe concentration of gentamicin in blood serum is 8 micrograms/ml, while that of sisomycin in 6 micrograms/ml. This approach may be used in estimation of safe concentrations for new aminoglycosides.

Animals↗
PubMed1981

[Clinical pharmacokinetics and the optimal intravenous ampicillin administration regimen in children].

Nineteen children aged 3 months to 3 years were treated with ampicillin for acute pneumonia. The drug pharmacokinetics after a single intravenous administration in a dose of 25 mg/kg was studied. The data of the antibiotic pharmacokinetics in blood serum specimens collected within 3 hours after the drug injection were approximated with the use of the two-compartmental model, which proved to be more adequate than the one-compartmental model. The average period of the antibiotic half-life was 37 minutes and the value of the total clearance was 7.3 ml/min . kg. The optimal regimen for ampicillin administration, i. e. intravenous infusion of the antibiotic at a rate of 70 microgram/min . kg and its administration in a loading dose of 3.5 mg/kg was calculated with the use of the constants of the two-compartmental model. Clinical trials of the above regimen showed satisfactory conformity of the factual and calculated levels of the antibiotic in the blood serum of 7 children.

Ampicillin↗
PubMed1981

[Cephalexin pharmacokinetics].

The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours).

Animals↗
PubMed1981

[Comparative characteristics of the methods for assessing aminoglycoside extraction with the artificial kidney tobramycin clearance and dialyzability].

The pharmacokinetics of tobramycin after its intravenous or intramuscular injection in a dose of 80 mg for 60 minutes was studied in 8 patients with chronic glomerulonephritis in the terminal stage of chronic renal insufficiency. The drug levels wee determined in the arterial (CA) and venous (CV) blood and dialyzates (CD) during the hemodialysis (6 hours) and 13-70 hours before the hemodialysis. The antibiotic was administered simultaneously with connection of the "artificial kidney" apparatus (KIIL) or 1 hour after it. The values of the clearance (CID) and dialyzing (D) of tobramycin were calculated with the following equations: (CID)1 equals Q(CA minus CV)/CA; (CID)4 equals FCD/CA; (D)2 equals Q(CA minus CV)/(CA minus CD); (D)5 equals FCD/(CA minus CD), where Q and F are the rates of the blood and dialysate flow respectively. In all cases the values of CID and D correlated and the difference between them was not significant. During the hemodialysis the values of (CID)1 varied to a greater extent than those of (CID)4. Irrespective of the procedure for estimation of CID the above variation was not pronounced, when tobramycin was administered simultaneously with initiation of the hemodialysis or during it than long before connection of the "artificial kidney" apparatus. In this connection it is recommended that antibiotic extraction be characterized by determination of (CID)4 on the drug administration long before the initiation of the hemodialysis. When Q equals 200 ml/min and F equals 600 ml/min, the average value of CLD for tobramycin was equal to 64 ml/min and the extraction coefficient was equal to 35 per cent.

Adult↗
PubMed1981

[Sisomicin pharmacokinetics in rat tissues in single and long-term administration].

The pharmacokinetics of sisomicin administered intramuscularly to rats in daily doses of 12.5 and 25 mg/kg for 30 days was studied. After a single administration of the drug in the above doses the highest and the lowest levels of sisomicin were observed in the kidney cortical layer and liver, respectively. The antibiotic level in the tissues rose with an increase in the antibiotic dose and duration of the drug use. The two-fold rise in the dose resulted in an elevation in the sisomicin level in the kidney cortical layer by 1.7 times, in the medullary layer by 3 times, and in the blood serum, lungs and spleen by 2.3, 1.2 and 1.5 times, respectively. After treatment with a dose of 25 mg/kg for 8 days the antibiotic level in all tissues studied was higher than that after the first administration of the drug: in the cortical and medullary layers of the kidneys by 5-7 times and in the blood serum and other tissues by 1.2-2 times. When sisomicin was used repeatedly in any dose, stabilization of or some decrease in the mean integral concentration of the antibiotic in the kidney cortical layer and a continuous increase of this value with respect to the medullary layer (up to the 30th day) were noted. The difference between the antibiotic levels in the kidney layers after the repeated administration of the drug was less pronounced than that after a single administration of the drug. The cumulation index of sisomicin in the kidney cortical layer persisted at the same level and that in the medullary layer gradually increased. In this connection it is concluded that correlation between the sisomicin nephrotoxic effect and the level of the antibiotic in the kidney cortical layer is more pronounced than that in the medullary layer.

Animals↗
PubMed1980

[Pharmacokinetic basis of the nephrotoxic action of sisomycin. The pharmacokinetics of sisomycin in single and multiple administrations to rats].

The pharmacokinetics of sisomicin was studied on Wistar rats. The antibiotic was used in single or repeated doses of 12.5 and 25 mg/kg. The kinetic data of the antibiotic titration in blood serum within 1 and 24 hours of intramuscular administration of the drug were formalized with the use of a linear two-compartment model. The average values of the elimination constant and the constants of sisomycin transfer from the central compartment into the peripheral one were 0.64, 0.34 and 0.13 hours-1 respectively. The value of the apparent distribution volume in the central compartment was 0.38 ml/kg and that of the stationary and kinetic distribution volumes was 1.37 and 3.06 1/kg respectively. The value of the general clearance was 0.24 1/(kg.hour) and that of the sisomicin half-life was 8.7 hours. Comparison of the antibiotic levels estimated with a model and actually measured in the blood after repeated administrations revealed the drug cumulation. When the antibiotic was used in a dose of 25 mg/kg daily, its cumulation was observed earlier (by the 5th--8th day) than on its use in a dose of 12.5 mg/kg (by the 30th day). Irrespective of the dose, sisomicin cumulation was accompanied by prolongation of the antibiotic half-life in the rats.

Animals↗
PubMed1980

[Pharmacokinetic validation of the nephrotoxic action of sisomycin. The relationship between nephrotoxicity and sisomycin concentration in the blood serum of rats].

The kinetics of urine nitrogen in the blood serum and morphological changes in the kidneys after a single and repeated intramuscular administrations of the antibiotic in doses of 12.5 and 25 mg/kg a day were studied in Wistar rats. When sisomycin was administered in a dose of 12.5 mg/kg, the increase in the urine nitrogen level after 1--30 injections was reversible, whereas at a dose of 25 mg/kg it became irreversible already after the 5th injection. Maximum deviations in the urine nitrogen level observed within 3--6 hours after each injection of sisomicin were recorded after the 5th injection of the drug in a dose of 12.5 mg/kg and even after the 1st injection of the drug in a dose of 25 mg/kg. The deviations increased up to the 5th and 16th injection of sisomycin in doses of 12.5 and 25 mg/kg respectively. Later the deviations were less pronounced. Regardless of the dose, adipose degeneration in renal tubules was registered after 8--16 injections of the drug. By the 30th and 16th days of the drug administration in doses of 12.5 and 25 mg/kg respectively, the above changes also decreased. On the whole, pronounced functional and morphological changes in the kidneys correlated with the antibiotic dose. Relationship between the time from the beginning of sisomycin administration and the moment when the average integral concentration of the urine nitrogen increased to the upper limit of normal and the logarithm of the average integral concentration of the antibiotic in the serum was found. The safety of the clinical schemes for the use of sisomicin was estimated with the help of this relationship with respect to its nephrotoxic effect.

Animals↗
PubMed1980

[Pharmacokinetic interpretation of the myorelaxant effect of kanamycin].

Changes in the neuromuscular conductivity and pharmacokinetics of kanamycin in the blood serum were studied in parallel on anesthetized cats treated with the antibiotic administered intravenously in a dose of 85 mg/kg or by means of infusion at a rate of 6.5-8 mg/kg . min. Combination of the logistic equation of the effect kinetics with the bioexponential equation of kanamycin pharmacokinetics resulted in analytical interrelations between the rate of the neuromscular conductivity suppression and kanamycin concentrations in the central and peripheral compartments of the two-compartmental model. The concentration-response curves in the first case were of the same S-shaped form, while in the second case they were of an irregular character. This suggested that the biophase was attributed formally to the central compartment of the model. However, the values of kanamycin concentrations in this compartment corresponding to the same level of the effect at the period of its development was always higher than those for the period of its extinction. This was indicative of the kinetic heterogeneity of the central compartment and biophase. Irrespective of the kanamycin administration regimen, the character of the effect-concentration relationship was the same and the antibiotic blood level determined after intravenous and infusion administration of the drug and corresponding to 50% reduction of the neuromuscular conductivity were close. Administration of kanamycin by means of infusion is more convenient, since it prevents development of undesirable respiration arrest in the animals.

Animals↗
PubMed1979

[Dependence of the nephrotoxic effect of kanamycin on its concentration in the blood (an experimental study)].

The kinetics of changes in the urea nitrogen level of the serum was studied experimentally on narcotized cats with constant blood levels of kanamycin. A relationship between the intensity of the nephrotoxic effect of kanamycin and its blood level was found. On the basis of this relationship lower nephrotoxicity of kanamycin as compared to that of gentamicin and streptomycin under conditions of their constant blood levels was shown. However, the concentrations of gentamicin and kanamycin provided in the blood by their use in therapeutic doses differeing 3--4 times allow a conclusion that the nephrotoxic effect of kanamycin and gentamicin to be practically the same.

Animals↗