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Biomedical subjects

J L Blumer

Publications and source records attributed to J L Blumer.

At least 145 records · Page 8Linked to original sources
PubMed1983

Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response.

The pharmacokinetics of ceftazidime were assessed following a single-dose in 20 patients (8 to 30 years) with cystic fibrosis. All patients received 50 mg/kg (0.9 to 3.5 g) bolus over 30 to 60 sec. Multiple timed samples were obtained over 8 h and analysed by a sensitive HPLC technique. Two-compartment pharmacokinetic analysis revealed means (+/- S.D.) T 1/2 alpha, 0.45 (0.20) h; T 1/2 beta, 1.74 (0.63) h; Vd, 270.0 (50.0) ml/kg; Vc, 190.0 (50.0) ml/kg and Cl beta, 133.7 (22.8) ml/min/1.73 m2. Probenecid pretreatment in six patients was without effect on T 1/2 beta and Cl beta. Urinary excretion was (% of dose) 0 to 2 h, 65.4 (11.1); 2 to 4 h, 14.9 (3.4) and 4 to 8 h, 9.8 (5.8). Ceftazidime was used to treat pulmonary exacerbations in 12 adult cystic fibrosis patients with multiply-resistant Pseudomonas species. Each patient received 2 g iv 8-hourly for 14 to 35 days. Ten of 12 patients showed dramatic improvement as determined by increased appetite and weight gain and arterial pCO2. No hepatic, renal or bone-marrow toxicity was noted. Ceftazidime is an effective antipseudomonal agent possessing favourable pharmacokinetic characteristics with potential use in the treatment of pulmonary exacerbations in cystic fibrosis.

Adolescent↗
PubMed1983

Determination of ceftazidime in biological fluids by using high-pressure liquid chromatography.

Ceftazidime is a new beta-lactamase-stable third-generation cephalosporin with a broad spectrum of antimicrobial activity. To evaluate the biodisposition of the drug in infants and children, a rapid and simple high-pressure liquid chromatographic technique was developed. The method is useful for both serum and urine and involves methanol precipitation followed by reverse-phase chromatography on MicroPak MCH 10. The mobile phase, consisting of 20% methanol and an 80% aqueous solution of 50 mM ammonium dihydrogen phosphate and 117 microM perchloric acid, is pumped at 1 ml/min through the column which is maintained at 50 degrees C. The drug was detected at 257 nm with a variable-wavelength UV detector. A good linear correlation was observed between the peak area and the ceftazidime concentration at 0.3 to 500 micrograms/ml (r = 0.999). Since an equal volume of cold methanol is used to precipitate proteins from serum samples and only 20 microliters of the resultant supernatant is injected into the column, samples as small as 50 microliters may be routinely analyzed. This method has been used to study ceftazidime pharmacokinetics in more than 30 patients and has proven to be rapid and reproducible.

Ceftazidime↗
PubMed1983

Developmental pharmacokinetics of moxalactam.

A pharmacokinetic evaluation of moxalactam was performed with 30 infants and children with documented or suspected bacterial infections arising outside the central nervous system. Each child received 50 mg of moxalactam per kg infused intravenously over a period of 15 min every 8 h. A total of 26 children were studied after receiving the first dose; 20 of these, along with 4 additional patients, were evaluated after receiving continuous therapy for at least 3 days. After the first dose, the elimination half-life, apparent volume of distribution, and plasma clearance averaged 1.59 h, 0.331 liter/kg, and 100.9 ml/min per 1.73 m2, respectively. The biodisposition of the moxalactam epimers was also evaluated, with similar overall results. No differences in pharmacokinetic parameters were observed when the first-dose values were compared with those obtained at the steady state. Age-dependent changes in moxalactam elimination were observed for children of less than or equal to 1 year of age, suggesting that a dosage reduction may be necessary for children of less than or equal to 2 months of age.

Adolescent↗
PubMed1983

Efficacy and safety of ceftriaxone in serious pediatric infections.

Thirty-four patients aged 1 month to 19 years were treated with ceftriaxone for suspected bacterial infections. Bacterial pathogens were isolated from 25 children. The overall bacterial cure rate was 88%, with an overall clinical response rate of 96%. No side effects requiring cessation of therapy were observed. Ceftriaxone proved to be safe and effective in the treatment of serious infections in children.

Adolescent↗
PubMed1983

Prostaglandin E2 concentration in gastric secretions of critically ill, full-term, and premature infants.

Critically ill, full-term, and premature infants are at increased risk to develop gastric mucosal ulceration. The cytoprotective effects of prostaglandin E2 (PGE2) may be important in the preservation of gastric mucosal integrity in these patients. PGE2 concentrations in the gastric secretions of seven full-term and 16 premature infants with severe pulmonary disease were measured by radioimmunoassay. The mean PGE2 concentration was significantly greater in the full-term infants (460 +/- 94 pg/ml), (mean +/- S.E.M.) than in the premature infants (190 +/- 35 pg/ml), P less than 0.01. There was a linear correlation between gestational age and PGE2 concentration, r = 0.70, P less than 0.001. In the 11 infants greater than or equal to 35 wk gestational age there was a linear correlation between gastric pH and PGE2 concentration, r = 0.69, P less than 0.01.

Dinoprostone↗
PubMed1982

Alterations in gentamicin pharmacokinetics during neonatal exchange transfusion.

The effect of double volume exchange transfusion on the pharmacokinetics of gentamicin was studied in 7 neonates undergoing eight transfusions. The procedures were performed an average of 9.6 h following the previous dose of drug and required an average of 0.91 h to complete. Exchange transfusion decreased serum gentamicin concentrations by 18.5 +/- 4.2% and increased the elimination rate for gentamicin by 31.8%. Serum concentrations obtained an average of 3.3 h following the procedure showed a rebound increase in concentration compared to that obtained just at the end of the transfusion (2 cases), no change (1 case) or a decrease compared with the immediate posttransfusion period (5 cases). The results observed in the late posttransfusion period were found to be inversely related (r = -0.78) to the number of doses received by the patient prior to the procedure. A one-compartment pharmacokinetic model was found to be adequate in predicting the amount of drug removed by the procedure while a two-compartment model best described the posttransfusion alteration in elimination kinetics.

Exchange Transfusion, Whole Blood↗
PubMed1981

Role of cell-generated hydrogen peroxide in granulocyte-mediated killing of schistosomula of Schistosoma mansoni in vitro.

Human as well as murine granulocytes have been shown to kill the larval stages of helminth parasites; the mechanism of this cell-mediated cytotoxicity is, however, poorly understood. The present study was designed to assess the role of peroxidative processes in killing of schistosomula of Schistosoma mansoni by human granulocytes in vitro. The rate of H(2)O(2) production by human neutrophils, eosinophils, and basophils was measured upon incubation with schistosomula alone or in the presence of specific antibody or complement. Opsonized parasites (antibody and/or complement) increased the rate of H(2)O(2) production by neutrophils, eosinophils, and basophils by respective percentages of 500, 500, and 371. The rate of H(2)O(2) release was directly related to the number of granulocytes and to the proportion of cells attached to the surface of the schistosomula. Increased hydrogen peroxide release occurred by 10 min of incubation and was demonstrable up to 16 h after addition of leukocytes to schistosomula. The primary source of this oxygen product was found to be the granulocytes adherent to the schistosomula and not those that remained unattached. Hydrogen peroxide production by neutrophils and eosinophils was quantitatively similar (schistosomula coated with antibody plus complement stimulated 5 x 10(6) neutrophils and eosinophils to release H(2)O(2) at respective rates of 0.35 and 0.40 nmol/min). Granulocyte-mediated parasite killing correlated with rate of H(2)O(2) generation; both processes were inhibited by catalase. To define further the role of oxidative metabolites, neutrophils and eosinophils of two subjects with chronic granulomatous disease were used; marked reduction of granulocyte-mediated parasite mortality was observed. Peroxidase was required for H(2)O(2)-mediated killing. Addition of the peroxidase inhibitors azide (1 mM), cyanide (1 mM), or aminotriazole (1 cM) to neutrophilschistosomula mixtures significantly reduced parasite cytotoxicity (P < 0.01); similar reduction was observed when eosinophils were used (P < 0.01). Fixation of halide (iodide) to trichloroacetic acid-precipitable protein (2.4-6.0 nmol/h per 10(7) neutrophils) was demonstrated in the presence of granulocytes, opsonins, and parasites; this process was completely inhibited by 1 mM azide. These data indicate that contact between the surfaces of human granulocytes and schistosomula results in release of cellular hydrogen peroxide and iodination. The generation of H(2)O(2) and its interaction with peroxidase appear to be crucial in effecting in vitro granulocyte-mediated parasite cytotoxicity.

Animals↗
PubMed1981

Lymphocyte aromatic hydrocarbon responsiveness in acute leukemia of childhood.

Aryl hydrocarbon hydroxylase (AHH) activity and inducibility were examined in mitogen-stimulated cultured lymphocytes from children with acute leukemia in remission, with nonleukemic malignancies, and with no family or personal history of malignant disease. Neither morphological differences nor differences in mitogen responsiveness were observed among the three sources of cells studied. Levels of constitutive and dibenzanthracene-induced AHH activity were found to be similar among the three groups by analysis of variance. However, when results were analyzed in terms of inducibility ratios, it was found that cells from leukemic children were significantly less inducible (p less than 0.005) than cells from unaffected children or children with nonleukemic malignancies. The reason for this difference became apparent when statistical criteria were employed for the pheontypic separation of individuals who were highly aromatic hydrocarbon responsive and minimally responsive. A significantly larger proportion (p less than 0.001) of leukemic children than unaffected children or children with nonleukemic malignancy were found to be minimally aromatic hydrocarbon responsive. Moreover, in patients with acute lymphoblastic leukemia relapsing while on therapy, longer durations of the first remission were correlated (r = 0.63, p less than 0.05) with the highly inducible AHH phenotype.

Acute Disease↗
PubMed1981

Effect of genotype on mutagenicity of niridazole in nitroreductase-deficient bacteria.

The mutagenicity of niridazole for Salmonella typhimurium depends upon the enzymic reduction of the nitro function. The response of niridazole nitroreductase-deficient bacteria to niridazole is reduced to 4.4 and 0.19% that exhibited by the enzyme-proficient parent strain when the deficiency is the result of a base substitution and frame-shift mutation, respectively. The results are taken to indicate that the residual activity (4.4%) seen in the strain with a base substitution mutation reflects the activity of an enzyme with an amino acid substitution, while the basal level (0.19%) of activity indicates the action of a different nitroreductase with a low specificity for niridazole.

Genotype↗
PubMed1980

Relative importance of bacterial and mammalian nitroreductases for niridazole mutagenesis.

Niridazole is a nitrothiazole anthelmintic agent used to treat schistosomiasis. Its antibacterial activity was found to require the presence of the nitro group; a synthetic desnitro analog was completely inactive. Niridazole was mutagenic for Salmonella tester strains TA1538, TA98, and TA100, suggesting that it was both a frame-shift- and a base substitution-type mutagen. It was effective under both aerobic and anaerobic conditions, while similar testing of the desnitro niridazole produced consistently negative results. Addition of rat liver S-9 fraction under either aerobic or anaerobic conditions did not enhance mutagenicity. However, since bacterial killing limited the dose of niridazole to 0.33 microgram/plate in standard tester strains (1/20 Km for the mammalian liver enzymes), further studies were performed using niridazole-resistant, histidine-dependent mutants derived from strains TA98 and TA100. These mutants were found to be nitroreductase deficient and to resist the mutagenic effects of niridazole, in the presence or absence of S-9, up to concentrations of 10 microgram/plate. In addition, even at niridazole concentrations of up to 100 microgram/plate, rat liver S-9 was ineffective in enhancing the mutagenicity of niridazole. These results suggest that the mutagenicity of niridazole is dependent on its aromatic nitro group and a specific bacterial nitroreductase.

Aerobiosis↗
PubMed1980

Toxicogenetics of niridazole in inbred mice.

The lethal potency of the antischistosomal agent niridazole (NDZ) was compared in C57BL/6J (B6) and DBA/2J (D2) mice and in their F1 hybrid, backcross and F2 progeny. A daily i.p. dosage range was chosen so that the lethal effect, ascribed to central nervous system toxicity, did not occur before 4 to 5 days. Death was always preceded by a generalized tonic-clonic seizure which terminated in respiratory arrest. In B6 mice the LD50 was 202 mg kg-1 day-1 while in D2 mice the LD50 was 146 mg kg-1 day-1; the LD50 for NDZ in similarly treated F1 hybrid mice was found to be the arithmetic mean of the LD50 values for the parental strains (172 mg kg-1 day-1). Determination of the level of NDZ in the plasma and brains of B6 and D2 mice treated subacutely with the same daily dose of NDZ failed to reveal any strain differences. Moreover, there was no evidence of in vivo accumulation of NDZ with subacute treatment which suggests that a NDZ metabolite is responsible for the observed toxicity. An association between susceptibility to the lethal effects of NDZ and the Ah locus is suggested by experiments in backcross and F2 mice. The incidence of death observed after subacute treatment with 162 mg/kg-1 day-1 of NDZ matched that predicted on the basis of genotype, i.e., it was lethal to 72% of nonresponsive and 38% of aromatic hydrocarbon responsive mice.

Animals↗
PubMed1979

Effect of niridazole and niridazole immunoregulatory factor (NIF) on cutaneous delayed hypersensitivity in mice.

It has been suggested that the suppression of cell-mediated immune phenomena following niridazole administration is most likely due to a niridazole metabolite rather than the parent drug. This hypothesis was tested using two inbred strains of mice that manifest different rates of microsomal niridazole oxidation and reduction. DBA/2J mice were found to metabolize niridazole at a rate approximately 3-fold greater than C57BL/6J mice under both aerobic and anaerobic conditions. Niridazole was found to be more potent with respect to suppression of cutaneous delayed hypersensitivity in the former than in the latter. An immunosuppressive component was isolated from the urine fraction obtained from niridazole-treated rats. This component was found to be chromatographically pure; have a simple UV absorbance spectrum containing no 360 nm absorbing material characteristic of niridazole; to show no strain difference with respect to potency or efficacy in the ear-swelling assay for cutaneous delayed hypersensitivity; and to be 10(7) times more potent than niridazole with respect to the suppression of cutaneous delayed hypersensitivity.

Animals↗
PubMed1978

Genetic expression of microsomal electron transport in mice. Different patterns of dependence of constitutive cytochrome P-450 reductase activity of pyridine nucleotide concentrations.

Cytochrome P-450 reductase and aryl hydrocarbon hydroxylase activities were investigated in hepatic microsomes from untreated C57BL/6J, DBA/2J, B6D2F1, and (B6D2) D2 mice. The dependence of the rate of P-450 reduction on the concentration of added pyridine nucleotide (NADPH or NADH) was biphasic in DBA/2J microsomes but monophasic in C57BL/6J microsomes. Analogous strain-specific patterns were observed when the dependence of the rate of benzpyrene hydroxylation on NADPH concentration was examined. In crosses between the two inbred strains and between B6D2F1 mice and DBA/2J mice, the biphasic pattern for both the reductase and the hydroxylase activities was found to co-segregate with the recessive allele for aromatic hydrocarbon responsiveness. These results might reflect an architectural difference between the microsomal electron transport systems of responsive and nonresponsive mice.

Animals↗
PubMed1976

Accleration of autooxidation of human oxyhemoglobin by aniline and its relation to hemoglobin-catalyzed aniline hydroxylation.

Changes in the ultraviolet/visible spectrum of human oxyferrohemoglobin upon addition of aniline were indicative of a concentration-dependent interaction of aniline with hemoglobin, resulting in accelerated autooxidation of the hemoprotein. Oxygen was found to markedly inhibit this interaction of aniline with oxyhemoglobin. The dependence of the rate of autooxidation on aniline concentration followed saturation kinetics and showed a half-maximal response at 8 mM aniline. This value is equal to the value of Km for aniline as substrate for the O2-dependent, hemoglobin-catalyzed hydroxylation reaction which yields p-aminophenol (Mieyal, J. J., Ackerman, R.S., Blumer, J.L., and Freeman, L.S. (1976) J. Biol. Chem. 241, 3436-3441). Thus, an aniline-oxyhemoglobin complex is implicated in the overall catalytic reaction. No detectable p-aminophenol was formed when aniline was combined with oxyhemoglobin in the absence of an electron donor, but hydroxylation of aniline does occur when NADPH, NADPH plus P-450 reductase, or Na2S2O4 are also added.

Aniline Compounds↗
PubMed1976

Characterization of Enzyme-like activity of human hemoglobin. Properties of the hemoglobin-P-450 reductase-coupled aniline hydroxylase system.

Human hemoglobin was characterized as an enzyme in a reconstituted aniline hydroxylase system containing hemoglobin, NADPH, rat liver cytochrome P-450 reductase, aniline and atmospheric O2. This system catalyzed p-aminophenol formation (turnover number 0.2 mol/min/mol of hemoglobin) with an efficiency similar to that which has been reported for either microsomal cytochrome P-450 or cytochrome P-450 solubilized from rat liver. The rate of the reaction was linearly dependent on hemoglobin concentration up to approximately 1 nmol of hemoglobin/ml. This linear range of hemoenzyme concentration is also similar to cytochrome P-450-catalyzed reactions. Unlike the cytochrome P-450 system, the hemoglobin system did not require a lipid cofactor for maximal activity, and much less reductase was needed for maximal activity. Aniline displayed typical Michaelis-Menten saturation kinetics as substrate, and its Km (8 mM) was the same in the absence of presence of the reductase. Catalase essentially completely inhibited p-aminophenol formation in the absence or presence of reductase. In contrast, superoxide dismutase inhibited the reductase-mediated reaction only to a small extent (if at all). No detectable hydrogen peroxide accumulated during the course of the reaction in the absence of catalase. These findings suggested a hypothetical mechanism for hemoglobin-catalyzed hydroxylation of aniline involving a hemoglobin-bound form of hydrogen peroxide (aniline-Hb3+-OOH-) as an intermediate preceding the rate-determining formation of products.

Aniline Hydroxylase↗