Use of an experimental design method for studying the effect of proteolytic enzymes on the pharmacokinetics of antibiotics]

The effect of chemotripsin on the pharmacokinetics of ampicillin as dependent on the drug dose and the administration intervals was studied on rats using the method of the experiment design. With the use of the method it was found that intramuscular injections of chemotripsin to rats in doses of 3, 4.5, 6, 8 and 10 mg/kg, 0.5, 1, 1.5 and 2 hours before intramuscular administration of ampicillin in doses of 10, 20, 35, 75 and 100 mg/kg caused a simple effect inducing an increase in the antibiotic levels in the blood and organs, when the enzyme and antibiotic were present simultaneously in the animal organism for an hour. The increase in the antibiotic levels in the rat organs due to simultaneous presence of chemotripsin and ampicillin the animal organism for 2 hours was less pronounced     

Use of a physiological model of gentamicin pharmacokinetics for individual dosage of the antibiotic]

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)     

Clinical pharmacokinetics of kanamycin in endolymphatic therapy of peritonitis]

The pharmacokinetics of kanamycin in patients with peritonitis was studied after its intramuscular, endolymphatic and lymphotropic administration. Endolymphatic administration of kanamycin provided an increase in its activity in the inflamed tissues of the peritoneum and omentum and markedly prolonged its halflife as compared to those after the routine intramuscular administration of the drug. Lymphotropic administration of kanamycin failed to provide the same effect. Endolymphatic therapy of the patients during the postoperative period provided a decrease in the lethality, development of complications and the terms of the treatment in the hospital. The therapeutic effect of the endolymphatic administration of kanamycin to the patients with peritonitis proved to be high. The more efficient antibiotic therapy of the cases was likely due to favourable shifts in the pharmacokinetics of kanamycin after its endolymphatic administration.     

Pharmacokinetics of penicillins in the blood of dogs administered the combination preparation, ampiox, internally]

The pharmacokinetics of penicillins in the blood of dogs treated with ampiox, a combination of ampicillin and oxacillin at a ratio of 1 : 1 was studied. The drug was administered orally in single or repeated doses of 25, 50 and 100 mg/kg. The maximum levels of ampicillin in the blood serum were observed 1 hour after a single administration of the drug. The therapeutic concentrations of the antibiotic were preserved for 6 hours, its value being depended on the dose used. The maximum concentration of oxacillin was detected 1 hour after the drug administration in various doses and it was preserved in the blood at the therapeutic levels for 3 hours. The dynamics of circulation of ampicillin and oxacillin administered separately did not differ from that established for the use of ampiox. The regularities of the pharmacokinetics of ampiox on its repeated use remained practically unchanged.     

Pharmacokinetics and pharmacodynamics of terguride following intramuscular administration in cows and goats

The pharmacokinetics of intramuscular terguride (transdihydrolisuride) was evaluated in a single-dose study in cows (doses 100, 62 and 31 micrograms/kg b.w.) and goats (dose 100 micrograms/kg b.w.). A radioreceptor assay was used to quantitative plasma terguride concentrations. The peak plasma concentrations of terguride were attained within 0.6 h of the drug administration and then decreased monoexponentially with half-life of 1.3 h (cows) and 2 h (goats). The pharmacokinetics of terguride in cows is nearly linear. Pharmacodynamics of terguride was expressed as reduction in plasma prolactin levels. Maximal decline in prolactin was observed 3-4 h following terguride administration and the effect lasted for about 24 h.     

Accumulation of gentamicin in biological fluids, organs and tissues during regional lymphotropic therapy with antibiotics

Gentamicin distribution in biological fluids, organs and tissues, lymph nodes was studied on 70 dogs. Three administration routes were compared: lymphotropic, intramuscular and regional subcutaneous. The lymphotropic route for the drug administration was recommended not long ago. It was shown that the lymphotropic route provided the antibiotic accumulation mainly in some of the abdominal organs as compared to intramuscular administration. Regional lymphotropic administration of the antibiotic to the experimental animals resulted in higher gentamicin levels in the regional lymph nodes and regional organs as compared to the levels observed after the antibiotic regional subcutaneous administration in the same doses.     

Development of a new version of the Liverpool Malaria Model. I. Refining the parameter settings and mathematical formulation of basic processes based on a literature review

Artesunate (AS) is a clinically versatile artemisinin derivative utilized for the treatment of mild to severe malaria infection. Given the therapeutic significance of AS and the necessity of appropriate AS dosing, substantial research has been performed investigating the pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA). In this article, a comprehensive review is presented of AS clinical pharmacokinetics following administration of AS by the intravenous (IV), intramuscular (IM), oral or rectal routes. Intravenous AS is associated with high initial AS concentrations which subsequently decline rapidly, with typical AS half-life estimates of less than 15 minutes. AS clearance and volume estimates average 2 - 3 L/kg/hr and 0.1 - 0.3 L/kg, respectively. DHA concentrations peak within 25 minutes post-dose, and DHA is eliminated with a half-life of 30 - 60 minutes. DHA clearance and volume average between 0.5 - 1.5 L/kg/hr and 0.5 - 1.0 L/kg, respectively. Compared to IV administration, IM administration produces lower peaks, longer half-life values, and higher volumes of distribution for AS, as well as delayed peaks for DHA; other parameters are generally similar due to the high bioavailability, assessed by exposure to DHA, associated with IM AS administration (> 86%). Similarly high bioavailability of DHA (> 80%) is associated with oral administration. Following oral AS, peak AS concentrations (Cmax) are achieved within one hour, and AS is eliminated with a half-life of 20 - 45 minutes. DHA Cmax values are observed within two hours post-dose; DHA half-life values average 0.5 - 1.5 hours. AUC values reported for AS are often substantially lower than those reported for DHA following oral AS administration. Rectal AS administration yields pharmacokinetic results similar to those obtained from oral administration, with the exceptions of delayed AS Cmax and longer AS half-life. Drug interaction studies conducted with oral AS suggest that AS does not appreciably alter the pharmacokinetics of atovaquone/proguanil, chlorproguanil/dapsone, or sulphadoxine/pyrimethamine, and mefloquine and pyronaridine do not alter the pharmacokinetics of DHA. Finally, there is evidence suggesting that the pharmacokinetics of AS and/or DHA following AS administration may be altered by pregnancy and by acute malaria infection, but further investigation would be required to define those alterations precisely.     

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.     

Pharmacokinetics of long acting oxytetracycline in the laboratory rat

Pharmacokinetic parameters of a slow release form of oxytetracycline were determined in the rat. Triexponential pharmacokinetics were displayed after intravenous administration. The half-life of the distribution phase was 0.097 hours, the rapid elimination half-life was 3.74 hours and the slow elimination half-life was 27.26 hours. Subcutaneous and intramuscular injection resulted in a rapid elimination half-life of 6.09 and 6.02 hours, respectively. In comparison, a standard form of oxytetracycline given subcutaneously had a rapid elimination half-life of 4.22 hours. The slow release form of oxytetracycline has a half-life in the rat long enough to maintain serum levels greater than the minimum inhibitory concentration of Mycoplasma pulmonis with a dose interval of 72 hours.     

A new method of calculating tissue/blood distribution coefficient in physiological models of pharmacokinetics

An original simple method for evaluating the tissue/blood distribution coefficient for physiological models of drug pharmacokinetics on the basis of minimal information on the content of a xenobiotic in tissues (one time point) is described. For its testing, the literature data on the pharmacokinetics of sulbactam, ampicillin, THR-221 and NY-198 were used.     

An evaluation of ampicillin pharmacokinetics and toxicity in guinea pigs

Sodium ampicillin was administered subcutaneously to 350-550 g male Dunkin Hartley guinea pigs at doses of 6, 8 and 10 mg/kg tid for 5 days. Over a period of 12 days, the lowest ampicillin dose appeared to be tolerated well. However, significant body weight reduction and mortality occurred with the two higher dosage regimens. Cecal cultures of dead animals confirmed the presence of Clostridium difficile, an organism associated with antibiotic-induced enterotoxemia. Assay of serum collected from ampicillin-treated animals revealed ampicillin concentrations of approximately 10 micrograms/ml at 5 minutes post-dosing which fell precipitously to less than 0.2 micrograms/ml at 60 minutes. Determination of biliary ampicillin levels during the 60 minutes after administration of a single 10 mg/kg SQ dose revealed concentrations ranging from 18 micrograms/ml to 90 micrograms/ml. Estimates of total urinary ampicillin content after a single 10 mg/kg SQ dose were less than 500 micrograms/animal at 7.5 minutes, but increased to greater than 2000 micrograms/animal at 60 minutes after dosing. Results of this study indicated that due to its short serum half-life, sodium ampicillin probably has little systemic therapeutic efficacy in guinea pigs. Because high concentrations of ampicillin accumulated in the urine and bile, the antibiotic probably would have therapeutic efficacy for urinary and intestinal infections. However, its associated toxicity at large doses probably precludes its use. In view of the rapid clearance of ampicillin in guinea pigs in comparison to other species, the pharmacokinetics of other antibiotics, especially those reported to be less toxic for guinea pigs, should be considered.     

Pharmacokinetics of the antitumor antibiotic bleomycetin in cancer patients given the preparation by different methods

The pharmacokinetics of bleomycetin, a new antitumor antibiotic prepared in the USSR, was studied microbiologically. The less the extent of the main tumor in the patients, the higher the antibiotic blood levels in them. This might be associated with the adsorption capacity of the tumor tissue. The dependence of the bleomycetin kinetics on the intensity of renal clearance was shown. The characteristics of the drug distribution in the blood after intravenous, intramuscular and intrapleural administration are presented.     

Pharmacokinetics of rifamycin

Rifamycin pharmacokinetics was studied on experimental animals after the antibiotic administration by various routes. Parenteral use of the antibiotic resulted in its high levels in rats and rabbits. Irrespective of the administration route, i. e. intravenous, intramuscular or oral rifamycin satisfactorily penetrated into the rat tissues. The highest antibiotic levels were found in the animal liver. In small amounts the antibiotic was excreted with the urine (about 6 per cent for 4 hours). The extrarenal clearance of rifamycin was lower than the plasmic clearance only by 3 per cent and higher than the kidney clearance almost by 40 times. Rifamycin was bound in close amounts by the blood serum of humans, oxen and rabbits, i. e. by 68, 64 and 56 per cent respectively. The rat organ homogenates bound the antibiotic by 34--72 per cent.     

Effect of furosemide on the pharmacokinetics of benzylpenicillin and its penetration through the hematoencephalic barrier in experimental and clinical meningococcic meningitis]

Pharmacokinetics of sodium benzylpenicillin after intramuscular administration in a dose of 250 000 gamma/kg and simultaneous intramuscular injection of furosemid (lazix) in doses of 0.5--1--2 mg/kg was studied in experiments on a model of meningococcal meningitis of rabbits and in clinics on patients with meningococcal meningitis. A pronounced effect of furosemid on pharmacokinetics of benzylpenicillin as dependent on a number of factors was found. Furosemid and meningococcal endotoxin had a synergic effect and decreased benzylpenicillin excretion with urine resulting in prolongation of the antibiotic effect in the blood. An increase in benzylpenicillin blood levels and inflammation of the soft brain membranes increased permeability of the hemato-encephalic barrier for the antibiotic.     

Effect of a modified terrilytin on ampicillin pharmacokinetics in experimental peritonitis

The effect of modified terrilytin, a new enzyme of the microbial origin on the pharmacokinetics of ampicillin in experimental peritonitis was studied on 16 pubertal rabbits. Peritonitis was caused by laparotomy and administration of a 15 per cent fecal suspension into the abdominal cavity. The drugs were injected intramuscularly: the enzyme in a dose of 5 PU/kg and the antibiotic in a dose of 10 mg/kg. The ampicillin levels in the blood and peritoneal exudate were determined with the agar-diffusion method. The specimens were collected 30 minutes, 1, 1.5 and 2 hours after administration of the drugs. The animals were divided into 2 groups: control (not treated with the enzyme) and experimental. An increase in the antibiotic levels in the blood and peritoneal exudate by 50--54 per cent was observed. The maximum increase was recorded 30 minutes after simultaneous administration of the drugs.     

Experimental study of the pharmacokinetics of an amphotericin B derivative

Absorption, distribution and excretion of a new water soluble derivative of amphotericin B (NWSDA) were studied after its administration by different routes. After the antibiotic intravenous administration the therapeutic concentrations in blood, organs and urine were shown to remain for prolonged periods. The likely sites of NWSDA deposition were detected with microbiological and radionuclide methods. The most prolonged periods of antibiotic preservation were stated in the renal cortex, spleen and lungs. The ways of NWSDA excretion were studied in operated animals. Only 3.5 per cent of the antibiotic was excreted with urine and bile for 24 hours. The pharmacokinetic parameters of NWSDA after its intravenous administration were estimated. The bioavailability of the antibiotic after its intramuscular and oral administration was found to be low.     

Pharmacokinetics of gentamicin after its regional endolymphatic and lymphotropic administration to dogs

It was shown that intralymphatic+ inguinal administration of gentamicin provided its high concentrations in central lymph, blood and ++para-aortic lymph nodes and increased the antibiotic levels in the abdominal organs 2.33 to 6.66 times as compared with its intramuscular administration while lymphotropic retroperitoneal administration of gentamicin provided more prolonged maintenance of the antibiotic therapeutic concentrations in lymph of the thoracic lymphatic duct, central blood, ++para-aortic lymph nodes and the abdominal organs in comparison to its intramuscular administration. Intralymphatic+ inguinal administration of drugs providing the highest concentrations in all the organs of the abdominal cavity and the ways of the infection penetration is useful in therapy of severe inflammatory diseases of the abdominal organs inclined to generalization and lymphotropic retroperitoneal administration of drugs is useful in therapy of less severe purulent inflammatory processes in the abdominal cavity.     

Ampicillin inactivation in the caecum of axenic, gnotoxenic and conventional lambs: interaction with resistant or sensitive Escherichia coli

The fate of orally administered ampicillin was studied in axenic lambs, in gnotoxenic lambs given a complex microflora and a mixture of ampicillin resistant and/or sensitive strains of Escherichia coli, and in conventional lambs. In axenic lambs or animals with a sensitive microflora, antibiotic concentrations of 500-1600 micrograms ml-1 were detected in the intestine, and most of the ampicillin passed through the small intestine and entered the large intestine, within 12-15 h of administration. These antibiotic concentrations were sufficient to decrease the numbers of ampicillin-sensitive E. coli from 10(8)-10(9) bacteria ml-1 to about 10(5)-10(6) bacteria ml-1 by 8 h after ampicillin administration. Second and third doses of antibiotic had no further effect on the bacterial count. Administration of ampicillin to animals hosting ampicillin-resistant E. coli resulted in a significant inactivation of the antibiotic in the intestine. As might be expected there was little reduction in the numbers of these organisms. These results are similar to those observed in conventional lambs hosting resistant E. coli as the dominant colibacillary flora.     

Pharmacokinetics and tissue distribution of novel traditional Chinese medicine-platinum anticancer agents in rats

The pharmacokinetics and tissue distribution profiles of a novel series of traditional Chinese medicine-platinum (TCM-Pt) compounds [Pt(C(8)H(8)O(5))(NH(2)R)(2)]: 1 (where R=H), 3 (R=CH(3)) and 5 (R=C(6)H(10)), were studied in Sprague-Dawley rats following a single bolus intravenous (i.v.) injection. Platinum concentrations in total plasma, plasma ultrafiltrate, urine and tissues were measured by flameless atomic absorption spectroscopy. Pharmacokinetic studies showed that plasma concentrations of total and free platinum for the novel TCM-Pt compounds as well as cisplatin and carboplatin declined in a biexponential manner with a short distribution half-life (t(1/2alpha): 0.12-0.34h). Compared with cisplatin, the novel TCM-Pt compounds had a longer elimination half-life (t(1/2beta)), larger dose normalized area under the curve (AUC/D), larger volume of distribution at steady-state (V(ss)), slower clearance (CL) of free platinum and higher percentage of cumulative urinary excretion (CUE), which can be attributed to their lower chemical reactivities. In tissues, the highest Pt concentrations were found in the kidney, followed by the liver and the lowest in the heart; no Pt was detected in the brain. Twenty-four hours after drug administration, platinum concentrations in tissues were significantly lower for the novel TCM-Pt compounds. These findings suggest that the novel compounds might afford higher clinical efficacy and reduced systemic side effects, when compared with cisplatin.     

Reversal of drug resistance in Mycobacterium leprae by ampicillin/sulbactam.

The multiplication of Mycobacterium leprae in foot pads of experimentally-infected mice was suppressed by intramuscular administration of ampicillin combined with sulbactam or YTR-830H, two potent inhibitors of beta-lactamase in the bacteria. The antibiotic or the inhibitors by themselves were inactive. Ampicillin/sulbactam also inhibited the growth of drug-resistant M. leprae which grew in the presence of rifampin or dapsone. The finding provides a new approach to treat leprosy and to overcome drug resistance of the mycobacteria.