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Biomedical subjects

J L Blumer

Publications and source records attributed to J L Blumer.

At least 91 records · Page 5Linked to original sources
PubMed1990

Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates.

To determine the pharmacokinetics of amphotericin B and 5-fluorocytosine in neonates, we measured serum concentrations at first dose and after 5 days of therapy by high-performance liquid chromatography in 13 neonates (mean birth weight 1.2 +/- 0.8 kg). The dose of amphotericin B was serially increased from 0.1 to 0.5 mg/kg/day in 10 infants but was decreased from 0.8 to 1.0 to 0.5 mg/kg/day in three infants. Amphotericin B concentrations were not detectable in infants receiving 0.1 mg/kg/day. Amphotericin B cerebrospinal fluid concentrations were 40% to 90% of serum values obtained simultaneously. Serum concentrations after oral administration of 5-fluorocytosine (dose 25 to 100 mg/kg/day) were detectable in all infants. We found extreme interindividual variability for the half-life, volume of distribution, and clearance for both drugs. Four infants had minimal elimination for both drugs between doses, a finding that correlates with rises in serum creatinine (greater than 0.4 mg/dl, 40 mumol/L) and blood urea nitrogen (greater than 10 mg/dl, 3.6 mmol/L). We recommend that the dose of amphotericin B given on the first day of treatment be greater than the usual testing dose of 0.1 mg/kg/day. We also recommend an initial 24-hour dosing interval for amphotericin B and 5-fluorocytosine. Serum drug concentrations may need to be monitored in high-risk, low birth weight infants.

Amphotericin B↗
PubMed1990

Clinical pharmacology of imipenem and cilastatin in premature infants during the first week of life.

The first-dose and multidose pharmacokinetics of imipenem and cilastatin were evaluated in 41 premature infants during their first week of life. Premature infants (gestational age, less than or equal to 37 weeks) were assigned to receive 10-, 15-, 20-, or 25-mg/kg doses of imipenem-cilastatin (1:1) as a single- or multiple-dose regimen. A total of 39 infants received a single dose, whereas 18 infants received multiple doses. No differences were observed in pharmacokinetic parameter estimates for either agent relative to the dose administered or infant body weight; thus, the data were pooled. Elimination half-life, steady-state volume of distribution, and body clearance averaged 2.5 h, 0.5 liter/kg, and 2.5 ml/min per kg, respectively, for imipenem and 9.1 h, 0.4 liter/kg, and 0.5 ml/min per kg, respectively, for cilastatin. Similar values for these parameter estimates were observed after multidose administration, although substantial accumulation of cilastatin in serum was observed. A total of 21% of the imipenem and 43% of the cilastatin were excreted unchanged in the urine over a 12-h collection period. Corresponding renal clearances averaged 0.4 and 0.2 ml/min per kg for imipenem and cilastatin, respectively. Substantial differences were observed in the route by which imipenem was cleared from the body compared with data from adult volunteers. These data suggest that infants should receive an imipenem dose of 20 mg/kg administered every 12 h for the treatment of bacterial infections outside the central nervous system.

Cilastatin↗
PubMed1989

Pedigree analysis of aryl hydrocarbon hydroxylase inducibility in acute leukemia of childhood.

We determined lymphocyte aryl hydrocarbon hydroxylase (AHH) inducibility for members of 13 families with one or more children with acute lymphoblastic leukemia (ALL) and 12 control families. Pedigree analysis suggested that aromatic hydrocarbon responsiveness (i.e. inducibility) is a codominant trait. Heterozygotes were found to be moderately responsive with IR values intermediate between homozygous minimally responsive and homozygous highly responsive individuals. Homozygous recessive and heterozygous genotypes accounted for 54% and 36% of ALL children respectively. The risk of ALL among minimally aromatic hydrocarbon responsive children was twice that of highly responsive children.

Aryl Hydrocarbon Hydroxylases↗
PubMed1989

Pharmacology of new hormonal therapies in the treatment of pediatric endocrine disorders.

Advances in genetic engineering will make possible treatment of many pediatric endocrine disorders with replacement therapy. Some of these conditions include short stature, precocious puberty, and diabetes mellitus. Although the availability of such hormonal replacement offers new treatment modalities, an understanding of their mechanism of action and pharmacologic characteristics is crucial to maximize their effectiveness while minimizing possible untoward effects. The clinician must evaluate potential risks and benefits as these substances come to market without definitive answers being available as to their long-term effects.

Child↗
PubMed1989

Role of microtubule assembly in phenytoin teratogenic action in the sea urchin (Arbacia punctulata) embryo.

We evaluated the role of microtubule assembly in phenytoin (5-5-diphenylhydantoin) teratogenic activity in the sea urchin embryo. Zygotes were exposed to phenytoin or one of several phenytoin analogs within 15 min of fertilization and the frequency of the resultant malformations was assessed at the cleavage and late gastrula (prism) stages. Concomitant studies of drug uptake into zygotes and drug effects on both microtubule assembly in vitro and spindle morphology in situ were also performed. Phenytoin, 5-p-methylphenyl-5-phenylhydantoin, and 5-p-methoxyphenyl-5-phenylhydantoin were teratogenic (approaching 100% affected embryos) at both developmental stages were concentrated rapidly by the zygotes, and induced a shortened mitotic spindle in situ. In a separate in vitro system using porcine brain microtubular protein, these analogs were shown to inhibit microtubule assembly directly. The major human metabolite of phenytoin, 5-p-hydroxyphenyl-5-phenylhydantoin was teratogenic at the prism stage but induced only a 20% incidence of abnormal embryos at the first cleavage. This was attributed to the slow rate of uptake of this analog. This compound inhibited microtubule assembly in the in vitro assay and also shortened the mitotic spindle to an extent proportional to its observed weak effect on the first cleavage. Another analog, 5-p-hydroxyphenyl-5-p'-methylphenylhydantoin was not teratogenic at concentrations up to the limit of its solubility (285 microM). If this analog were as potent inside the cell as either phenyltoin or 5-p-hydroxyphenyl-5-phenylhydantoin, the intracellular concentrations achieved should have been sufficient to induce abnormal cleavage. Thus, the lack of teratogenic efficacy of this analog was correlated with its observed lack of effects on either microtubule assembly in vitro or spindle formation in situ. The anticonvulsant drug ethotoin was not teratogenic at concentrations up to 2.93 mM, apparently due to either poor uptake or inability to inhibit microtubule assembly or both. Overall, these studies are consistent with a hypothesis that phenytoin may induce abnormal development in this system by a direct inhibition of microtubule assembly.

Animals↗
PubMed1989

Critical period of phenytoin teratogenic action in the sea urchin, Arbacia punctulata embryo.

We characterized the susceptibility of sea urchin embryogenesis to phenytoin developmental toxicity. Concentration-dependent effects were assessed by exposing embryos from fertilization through the late gastrula/prism stage and scoring abnormal development via light microscopy. Malformations were observed as early as the first cleavage, when asymmetric, incomplete and arrested cleavage were noted, and also at the prism stage. These effects were concentration-dependent with an EC50 value of approximately 40 microM at both the cleavage and prism stages. Several phenytoin analogs of varying toxicity were identified. Comparison of zygote uptake of phenytoin and one nonteratogenic analog found that toxicity was not limited by uptake as the analog achieved intracellular concentrations which would have been sufficient to induce abnormal development if it had an intracellular potency equal to that of phenytoin. Periods in sea urchin embryogenesis susceptible to phenytoin actions were identified by exposing embryos to phenytoin (120 microM) for discrete intervals after fertilization and scoring development at the prism stage. A critical period of unique susceptibility coincided with the cleavage and morula stages (0- approximately 64 cells/embryo, 0-5 hr after fertilization). Drug exposure after this period did not alter development. Studies examining phases of the cell cycle for susceptibility to phenytoin effects on cleavage found that drug exposure confined to M phase was necessary and sufficient to manifest developmental toxicity. Drug uptake was similar during the sensitive and insensitive developmental stages and cell cycle phases and thus was not responsible for the variations in susceptibility observed. We conclude that the direct effects of phenytoin on sea urchin embryogenesis are confined to the cleavage and morula stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Lack of unique ciprofloxacin pharmacokinetic characteristics in patients with cystic fibrosis.

The single-dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight-matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VSSF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty-two percent of the ciprofloxacin dose was excreted in the urine (0-48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolities were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P less than .05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24-hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.

Adolescent↗
PubMed1988

Alteration of methylcholanthrene-mediated suppression of cutaneous delayed hypersensitivity by benzoflavone treatment of C57BL/6J mice.

The potential role of the cytochromes P-450 in methylcholanthrene (MC)-mediated suppression of cutaneous delayed hypersensitivity (CDH) in C57BL/6J (B6) mice was evaluated indirectly by treating mice with agents known to induce or inhibit hepatic cytochromes P-450 prior to contact sensitization. Subsequent alterations in aryl hydrocarbon hydroxylase (AHH) activity and CDH, as measured by suppression of 2,4-dinitrofluorobenzene (DNFB)-induced ear swelling, were measured. MC administration resulted in a dose-dependent suppression of ear swelling and a concomitant dose-dependent induction of hepatic AHH activity. Treatment of B6 mice with phenobarbital (PB), 80 mg/kg daily X 3, a broad spectrum inducer of P-450, resulted in a 2.5-fold increase in benzo[a]pyrene (B[a]P) hydroxylase activity without affecting CDH. Animals treated with the same PB protocol prior to an ED20 dose of MC showed no difference in suppression of CDH compared to animals treated with MC alone. In contrast, successive treatment with the selective P1-450 inducer, 5,6-benzoflavone (beta NF), prior to and following an ED20 dose of MC significantly increased suppression of CDH (p less than 0.001) usually seen at this MC dose. Treatment with a known inhibitor of cytochrome P1-450 activity, 7,8-benzoflavone (alpha NF), did not prevent AHH induction when administered prior to and following MC (ED100) nor did it suppress CDH when administered alone. However, this alpha NF treatment completely prevented suppression of CDH usually seen at this MC dose. These data provide evidence suggesting that metabolic activation by cytochrome P1-450 is required for the expression of the immunosuppressive activity of MC.

Animals↗
PubMed1988

An evaluation of optimal sampling strategy and adaptive study design.

We have evaluated the utility of optimal sampling strategy coupled with adaptive study design in the determination of individual patient and population pharmacokinetic parameter values. In 9 patients with cystic fibrosis receiving a short (1 minute) infusion of ceftazidime pharmacokinetic parameter values were determined with a nonlinear least-squares estimator analyzing a traditional, geometrically spaced set of 12 postinfusion serum samples drawn over 8 hours. These values were compared with values generated from four sample subsets of the 12 obtained at optimal times and analyzed by nonlinear least-squares estimator, as well as a maximum a posteriori probability Bayesian estimator with prior distributions placed on beta and clearance. The four sampling times were determined according to an adaptive design optimization technique that employs sequential updating of population prior distributions on parameter values. Compared with the 12-point determination, the four optimal points analyzed with the maximum a posteriori probability Bayesian estimator faithfully reproduced both microscopic and hybrid pharmacokinetic parameter values for individual patients and, consequently, also produced accurate measures of population central tendency and dispersion. This has important implications in being able to more efficiently derive target patient population pharmacokinetic information for new drugs. This should also allow generation of better concentration-effect relationships in populations of interest.

Adolescent↗
PubMed1988

Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo.

The safety and efficacy of a new topical antiinfective agent, mupirocin, was compared with that of oral erythromycin ethylsuccinate in the treatment of impetigo in children. Sixty-two children aged 5 months to 13 years with impetigo were assigned to be treated with either mupirocin in three daily applications or erythromycin ethylsuccinate (40 mg/kg of body weight per day divided into four doses) according to a randomized treatment schedule. On the initial visit, exudate or cleansed infected sites or both were cultured and therapy was begun. All patients were treated for 8 days. Patients were seen again on days 4 to 5 of therapy, at the end of therapy, and 7 days after the end of therapy. Sites of infection were comparable between the groups, as were bacteriologic responses. At the first visit, 24 of 30 children in the mupirocin group and 14 of 32 children in the erythromycin group were cured or had at least a 75% reduction in size of the lesions. At the end of the study, all 29 of the children in the mupirocin group who came to follow-up, compared with 27 of 29 in the erythromycin group, were cured. Side effects were few. Five children in the erythromycin group developed mild diarrhea. Thus, mupirocin appears to be safe and effective in treating impetigo in children. Our data show a trend toward more rapid clinical response with mupirocin than with erythromycin.

Administration, Oral↗
PubMed1988

The effect of exocrine pancreatic function on chloramphenicol pharmacokinetics in patients with cystic fibrosis.

The effect of exocrine pancreatic function on the pharmacokinetics of the choramphenicol oral capsule (CAP-base), chloramphenicol palmitate oral liquid (CAP-P), and chloramphenicol succinate intravenous (CAP-S) formulations was evaluated in 10 patients, aged 16-30 yr, with cystic fibrosis. Pancreatic insufficiency was assessed in each patient by measuring the absorption of p-amino-benzoic acid after oral administration of N-benzoyl-L-tyrosyl-p-aminobenzoic acid which requires chymotrypsin to cleave p-aminobenzoic from the parent molecule. In a controlled cross-over design, the overall biodisposition of each formulation was assessed in each patient with or without concurrent administration of oral pancreatic enzymes. The relative amounts of active chloramphenicol available in systemic circulation was CAP-base greater than CAP-S greater than CAP-P. Pancreatic enzyme replacement had little effect on the biodisposition parameters for the CAP-base and CAP-S formulation, but significantly increased the peak concentration and bioavailability of the CAP-P formulation. Although pancreatic enzyme replacement improved the absorption characteristics of the CAP-P formulation, absorption remained prolonged and unreliable. Serum concentration-time profiles for either CAP-base or CAP-S consistently exceeded the MIC of important nonpseudomonal pathogens. This finding was not observed after CAP-P administration independent of pancreatic enzyme replacement. The results of this study support the continued clinical use of either CAP-base or CAP-S, but the cautious use of CAP-P formulations in CF patients with concurrent pancreatic insufficiency.

Administration, Oral↗
PubMed1988

Optimal positive end-expiratory pressure therapy in infants and children with acute respiratory failure.

Positive end-expiratory pressure (PEEP) has become a mainstay in the treatment of hypoxemic acute respiratory failure (ARF). Whereas PEEP improves arterial oxygen tension by decreasing intrapulmonary shunting, it may also impair cardiac output and hence decrease systemic oxygen transport. Inasmuch as optimizing oxygen transport is a goal of therapy in ARF, we sought to determine if the level of PEEP that results in maximal oxygen transport could be estimated from measurements of compliance of the respiratory system (Crs) or PaO2. We studied the effects of PEEP application on cardiorespiratory parameters in 15 children who required mechanical ventilation for ARF. Static Crs, PaO2, central venous and arterial blood pressures, indicator dilution cardiac index (CI), and oxygen transport were determined at 0, 3, 6, 9, 12, and 15 cm H2O PEEP. PaO2 increased significantly at PEEP levels greater than or equal to 9 cm H2O (p less than 0.001), while CI fell by 15% between 0 and 15 cm end-expiratory pressure (p less than 0.02). Crs and oxygen transport did not change significantly with increasing levels of PEEP. The level of PEEP resulting in maximal oxygen transport ranged from 0 to 15 cm H2O, and in all patients it corresponded to PEEP of best CI. At levels of PEEP above that associated with maximal oxygen transport, CI and oxygen transport fell significantly, while PaO2 continued to rise. No relationship between Crs and oxygen transport was observed. In our normovolemic patients with ARF, neither PaO2 nor Crs predicted PEEP of maximal oxygen transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1988

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part I).

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Absorption↗
PubMed1988

Urologic pharmacology in the office setting.

The authors discuss two areas of therapeutics employed commonly in office practice, namely, anti-infective therapy and therapy for disorders of micturition. In anti-infective therapy, the pharmacodynamic aspects of drug action, as exemplified by the in-vitro susceptibility of various pathogens to antibiotics, are often known before the drug is administered to the patient. Thus, therapeutic failures generally result from a lack of knowledge of the individual patient's pharmacokinetics. In contrast, drug therapy for disorders of micturition is directed against a variety of often conflicting mechanisms and is seldom based on any pharmacokinetic tenets.

Ambulatory Care↗
PubMed1988

Once-daily cefadroxil versus oral penicillin in the pediatric treatment of streptococcal pharyngitis.

Thirty-two patients with pharyngitis were randomly assigned to receive either 30 mg/kg of cefadroxil every 24 hours orally or 15 mg/kg of penicillin V potassium every eight hours orally for ten days. Sera for antistreptolysin-O, streptozyme, and anti-DNAase were compared before and after treatment. Twenty patients finished the study and had a confirmed throat culture for the group A streptococcus and at least one fourfold antibody rise. Of these 20 patients, seven of eight in the penicillin group and all 12 in the cefadroxil group were cured at the end of therapy. One patient in the penicillin group had a positive culture at the end of therapy; one patient in each group was recolonized at follow-up culture 10 to 20 days after ending therapy. Seven other patients who finished the study had a positive throat culture but no antibody response and were presumed carriers; these included five in the penicillin and two in the cefadroxil group. One of these presumed carriers had a persistent infection and relapsed two days after the end of therapy. Both therapies appeared to be equally successful and no serious side effects occurred.

Adolescent↗
PubMed1987

High-performance liquid chromatography of ciprofloxacin and its metabolites in serum, urine and sputum.

A versatile and sensitive method requiring no internal standard was developed for quantitating ciprofloxacin in serum, urine and sputum by high-performance liquid chromatography with fluorescence detection. Acetonitrile and chloroform were employed to remove protein and lipophilic substances from an aqueous, ciprofloxacin-containing sample layer. The proportions of acetonitrile and 0.1 M potassium phosphate, pH 2.5, in the mobile phase were varied to suit the purpose of the assay. For the routine determination of ciprofloxacin pharmacokinetics, isocratic 19% acetonitrile was used. A gradient from 15 to 35% acetonitrile was chosen to show the appearance of metabolites which formed during the biodisposition of ciprofloxacin. In the latter case urine samples were diluted for assay and protein was precipitated from serum samples with trichloroacetic acid. Four fluorescent metabolites were observed in all patient specimens, and with tandem ultraviolet detection two additional ultraviolet-absorbing metabolites were readily found in urine specimens.

Biotransformation↗
PubMed1987

Model study on the bioreduction of paraquat, MPP+, and analogs. Evidence against a "redox cycling" mechanism in MPTP neurotoxicity.

The ability of paraquat, MPP+, and analogs to be reduced by chemical reductants and by NADPH, as catalyzed by liver microsomes or purified NADPH cytochrome P-450 reductase, is reported. The analogs span a range of electrochemical potential, including values in-between that of paraquat and MPP+. Analogs with an Eo below -.55 V (vs. NHE) are not reduced by either the NADPH-microsomes or NADPH-reductase systems. The inability of MPP+ to be bio-reduced or to stimulate the production of superoxide during aerobic reduction is evidence against a redox-cycling (oxidant stress) role of MPP+ in MPTP neurotoxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗