Analysis of the variability in the pharmacokinetics and pharmacodynamics of bumetanide in critically ill infants.

OBJECTIVES: Account for the interindividual variability in the pharmacokinetics and pharmacodynamics of bumetanide after intravenous administration of single doses to critically ill infants. METHODS: This prospective open-label study was carried out in the pediatric intensive care unit of a university-based children's hospital. Fifty-three volume-overloaded critically ill infants (age range, 4 days to 6 months) were divided into two groups: those with heart disease (31 infants) and those with lung disease (22 infants). Each patient received a single intravenous bolus dose of bumetanide. Doses, selected in sequential order, ranged from 0.005 to 0.100 mg/kg. Age was used as a continuous variable to determine its effects on the variability in the pharmacokinetics and pharmacodynamics of bumetanide. Hierarchical multiple regression analyses were used to assess the effects of age, disease, and other drugs on the variability in the effects of bumetanide. RESULTS: Total clearance, renal clearance, and nonrenal clearance of bumetanide all increased with age (p < 0.05), but the ratio of renal clearance to total clearance remained constant at about 0.4. Half-life and mean residence time decreased markedly in the first month of life (p < 0.05). Bumetanide excretion rate normalized for dose also increased with increasing age. Patients with lung disease exhibited a significantly greater clearance and shorter half-life (p < 0.05) than those with heart disease, whereas volume of distribution was similar in both groups. The primary determinant of bumetanide excretion rate was the administered dose (73%). Dose-response curves for urine flow rate and electrolyte excretion were similar between disease groups. The time course of the effect of bumetanide excretion rate on pharmacodynamics responses was similar between disease groups, as was the duration of the diuretic effect. CONCLUSIONS: The pharmacokinetics of bumetanide were influenced significantly by age and disease. Differences in pharmacokinetics between patients with lung and heart disease were primarily due to differences in total clearance. The administered dose of bumetanide and age were positive determinants of bumetanide excretion rate and pharmacodynamic responses. Pharmacodynamic responses as a function of bumetanide excretion rate were not significantly different between disease groups.

Pharmacokinetics of bumetanide in critically ill infants.

OBJECTIVE: Define the pharmacokinetics of bumetanide after single intravenous doses in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in a group of 58 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single dose of intravenous bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Hematologic and serum chemistry studies were performed before and at 6 and 24 hours after bumetanide administration. Determinations of urine volume and chemistries were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine collected at time 0 and at 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Data were evaluated by standard noncompartmental pharmacokinetic techniques. RESULTS: Peak serum bumetanide concentrations occurred at 5 minutes after bumetanide administration. Area under the curve and peak serum bumetanide concentrations showed linear increases over the twentyfold dose range; whereas beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time values were independent of dose. Peak urinary excretion rates of bumetanide increased linearly with increasing doses. The mean percent of bumetanide recovered in the urine from 0 to 12 hours was 40% +/- 15% of the administered dose. CONCLUSIONS: Distribution and elimination kinetics of bumetanide were similar in all patients. Elimination kinetics were first order over the dose range of 0.005 to 0.10 mg/kg. Pharmacokinetic parameter estimates (beta volume of distribution, volume of distribution at steady state, clearance, renal clearance, half-life, and mean residence time) were independent of the dose of bumetanide administered. Single doses of bumetanide up to 0.10 mg/kg appear to be well tolerated in acutely ill volume-overloaded infants aged 0 to 6 months.

Dose-ranging evaluation of bumetanide pharmacodynamics in critically ill infants.

OBJECTIVES: Determine the diuretic effects of single intravenous doses of bumetanide in volume-overloaded critically ill infants. METHODS: A prospective, open-label study was carried out in 56 infants aged 0 to 6 months who required diuretic therapy. Each patient received a single intravenous dose of bumetanide. Doses selected in sequential order ranged from 0.005 to 0.10 mg/kg. Determinations of urine volume, electrolytes, creatinine levels, and osmolality were performed before (collected from -2 to -4 hours to time 0) and at 1, 2, 3, 4, 6, and 12 hours after bumetanide dosing. Serum samples collected at time 0 and at 5, 15, 30, 60, 120, 180, 240, 360, and 480 minutes and urine aliquots collected at time 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, and 6 to 12 hours were analyzed for bumetanide concentration. Individual changes in urine flow rate and electrolyte excretion were plotted against corresponding bumetanide excretion rates, taken as the effective dose of the drug. RESULTS: Peak bumetanide excretion rates increased linearly with increasing doses of drug. Time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. Urine flow rate and electrolyte excretion increased linearly up to a bumetanide excretion rate of approximately 7 micrograms/kg/hr and either plateaued (urine flow rate) or declined at a bumetanide excretion rate of > 10 micrograms/kg/hr. Diuretic efficiency of bumetanide was maximal at doses of 0.005 to 0.010 mg/kg but decreased at higher doses. CONCLUSIONS: Maximal diuretic responses occurred at a bumetanide excretion rate of about 7 micrograms/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a proportionately higher bumetanide excretion rate but no increased diuretic effect. Lower doses of bumetanide had the greatest diuretic efficiency, suggesting that continuous infusion of low doses of bumetanide or intermittent low-dose boluses may produce optimal diuretic responses in critically ill infants.

The distribution of bovine pancreatic polypeptide/FMRFamide-like immunoreactivity in the ventral nervous system of the locust.

The distribution of bovine pancreatic polypeptide (BPP) FMRFamide-like immunoreactivity is described in the ganglia of the ventral nerve cord and in the peripheral median nervous system of the locust, Schistocerca gregaria. Immunoreactive cell bodies occur in three regions of the thoracic ganglia: 1) two pairs of cells lie in the anterior of the ganglion ventral to the root of nerve 1 and the anterior ventral association centre; 2) a group of cells lies in the ventral midline at the level at which nerves 3 and 4 leave the ganglion; 3) and two bilaterally symmetrical, posterior lateral groups lie between nerves 5 and 6 at the edge of the ganglion. Immunoreactive cell bodies in the suboesophageal and abdominal ganglia are confined to the midline and are distributed along the anterior-posterior axis both dorsally and ventrally. The processes of the posterior lateral groups have been traced into the neurohaemal organs of the median nerve and beyond. In the periphery such processes innervate the salivary glands and various muscles. The nature of the endogenous antigen contained in the immunoreactive cells has been investigated with the use of antisera against other peptides of the pancreatic polypeptide family, namely avian pancreatic polypeptide, neuropeptide Y, and peptide YY. In addition, BPP antisera not specific for the C terminal hexapeptide have been tested. Liquid preabsorption experiments with BPP and FMRFamide (the molluscan cardioacceleratory peptide) suggest that the endogenous peptide antigen contained in the stained neurones may belong to the pancreatic polypeptide family or to the FMRFamide family.

Ciprofloxacin monotherapy for acute pulmonary exacerbations of cystic fibrosis.

Ciprofloxacin has potent in vitro activity against Pseudomonas aeruginosa and Pseudomonas cepacia strains isolated from cystic fibrosis patients. Our previous single-dose pharmacokinetic and pharmacodynamic studies identified important differences between cystic fibrosis patients and age- and sex-matched controls. Based on these data, 30 acutely ill cystic fibrosis patients (aged 18 to 44 years) received 750 mg of ciprofloxacin orally every eight hours for 21 days. Multiple timed serum, urine, and sputum samples for pharmacokinetic analysis were obtained on Days 3, 12, 14, and 21 of the study. Estimates of steady-state pharmacokinetic parameters averaged (+/- SD): t1/2 beta, 3.8 (1) hours; Vd/F, 4.4 (2) liters/kg; Cl/F, 772.9 (301) ml/minute/1.73 m2; Fe, 46 percent; peak, 5.4 (2) mg/liter; and trough, 1.8 (0.8) mg/liter. Serum ciprofloxacin concentrations and pharmacokinetic estimates remained unchanged throughout the study. Sputum ciprofloxacin concentrations exceeded those observed in serum. Sputum cultures revealed 43 P. aeruginosa (MIC90 = 2 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml) strains. Sputum ciprofloxacin concentrations exceeded the MIC90 for P. aeruginosa approximately fivefold, yet only eight isolates were fully suppressed. Posttreatment sputum cultures revealed 35 P. aeruginosa (MIC90 = 16 micrograms/ml) and 15 P. cepacia (MIC90 = 16 micrograms/ml). All patients showed clinical improvement based upon the results of pulmonary function tests and an acute clinical efficacy score (median pre 49/post 60). No patients experienced drug-related toxicity. Ciprofloxacin monotherapy is effective for the acute treatment of cystic fibrosis patients. The development of pathogen resistance during oral therapy may limit its utility in ambulatory patients.

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.

Dermoids of the eustachian tube: CT and MR findings with histologic correlation.

Two patients with congenital dermoids of the eustachian tube presented with recurrent otitis media and chronic otorrhea resistant to antimicrobial therapy. CT demonstrated fat density, homogeneous lesions, filling and expanding the eustachian tube. On MR, signal from the lesions was consistent with fat, and the relationship with the internal carotid artery was better delineated than by CT. Microscopically, the masses consisted of a conglomeration of ectodermal and mesodermal elements.

The dexamethasone suppression test in mania.

The results of the overnight 2 mg Dexamethasone Suppression Test administered to 50 manic patients are reported. Twenty-three (46%) cases showed an absence of normal suppression, results which are similar to those seen in endogenous depression and which differ to those of others who have all reported normal suppression in mania. Suppressors and non-suppressors were not shown to differ in the factors of age, weight, polarity or the rated severity of mood.

Single-dose pharmacokinetics of aztreonam in children with cystic fibrosis.

The single-dose pharmacokinetics of aztreonam was evaluated in 10 clinically stable subjects with cystic fibrosis. Each child received 30 mg aztreonam/kg intravenously over 2 to 3 minutes. Multiple timed blood samples were obtained over 8 hours for determination of aztreonam elimination kinetics; all urine excreted for 24 hours was collected in timed aliquots for the determination of aztreonam and its microbiologically inactive metabolite, SQ 26,992. Aztreonam pharmacokinetic parameters were determined by model-independent methods. Mean t1/2, steady-state volume distribution, and body clearance were 1.3 hr, 0.25 L/kg, and 127.2 ml/min/1.73m2, respectively. In 9 of the 10 subjects, two-compartment pharmacokinetic analysis was possible and compared favorably with model-independent parameter estimates. Twenty-four-hour urinary recovery of aztreonam was 76.3% of the administered dose; 2.6% was recovered as the metabolite SQ 26,992. The renal clearance of aztreonam averaged 92.5 ml/min/1.73m2. When these data are combined with in vitro susceptibility data for aztreonam against Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis, a dose of 200 mg aztreonam/kg/day divided six hourly would be predicted to maintain serum concentrations above the minimum inhibitory concentration (MIC) for these organisms for the majority of the dosing interval.

Therapeutic evaluation of piperacillin for acute pulmonary exacerbations in cystic fibrosis.

The efficacy and pharmacokinetics of piperacillin monotherapy were studied in 46 patients with cystic fibrosis. Two patients were dropped from the study within 24 hr of enrollment because of drug-associated nausea and vomiting. Initially fourteen older patients (greater than 12 years) receiving piperacillin 450 mg/kg/day underwent a preliminary evaluation. Based on the results, 30 younger patients (less than or equal to 12 years) randomized in a double-blind fashion received either 600 or 900 mg/kg/day of piperacillin in six divided doses. Pharmacokinetic parameter estimates for t1/2 Vdss, and Cl were similar for first dose and steady-state evaluations. In 27 patients, approximately 43% of the administered dose was recovered in the urine after 4 hr. Piperacillin CiR averaged 49% of the total Cl. No difference in overall clinical efficacy could be identified between 600 and 900 mg/kg/day of piperacillin using two different objective scoring systems. Although a reduction in sputum Pseudomonas colony counts was greater following the 900 mg/kg/day regimen, this appeared to be independent of clinical effect. In 14 patients (32%), a distinct adverse serum-sicknesslike reaction was observed. The incidence of this reaction appeared to increase as the dose of piperacillin increased. All signs and symptoms of this reaction resolved within 36 hr of discontinuing piperacillin administration but recurred immediately on rechallenge in four patients. All patients with the adverse reaction were subsequently treated with beta-lactam antibodies without ill effect. Overall, clinical improvement appeared to be independent of the piperacillin dose. Our data support the use of total daily piperacillin dosages not exceeding 600 mg/kg.

Antibody prevalence of St. Louis encephalitis virus in avian hosts in Los Angeles, California, 1986.

A study was conducted to determine the pattern of St. Louis encephalitis (SLE) virus activity in the avian populations of the Los Angeles metropolitan area in 1986. In total, 679 birds of 42 species were captured at 7 study sites. The overall prevalence of SLE neutralizing (N) antibody of 3% indicated enzootic transmission. Antibody prevalences were higher in birds sampled in the central part of the metropolitan area, which was consistent with other epidemiologic data. The use of specific avian species as sentinels for future surveillance of SLE virus activity was suggested.

An overview of plague in the United States and a report of investigations of two human cases in Kern county, California, 1995.

Plague was confirmed in the United States from nine western states during 1995. Evidence of Yersinia pestis infection was identified in 28 species of wild or domestic mammals. Thirteen of the plague positive species were wild rodents; 15 were predators/carnivores. Yersinia pestis was isolated from eight species of fleas. Seven confirmed cases of human plague were reported in 1995 (New Mexico 3; California 2; Arizona and Oregon 1 each). Five of the seven cases were bubonic; one was septicemic and one a fatal pneumonic case. Months of onset ranged from March through August. In California, during 1995, plague was recorded from 15 of the 58 counties. Over 1,500 animals were tested, of which 208 were plague positive. These included 144 rodents and 64 predators/carnivores. Two confirmed human cases (one bubonic and one fatal pneumonic) occurred, both in Kern County. Case No. 1 was reported from the town of Tehachapi. The patient, a 23 year-old male resident, died following a diagnosis of plague pneumonia. The patient's source of plague infection could not be determined precisely. Field investigations revealed an extensive plague epizootic surrounding Tehachapi, an area of approximately 500-600 square miles (800-970 square kilometers). Case No. 2 was a 57 year-old female diagnosed with bubonic plague; she was placed on an antibiotic regimen and subsequently recovered. The patient lives approximately 20 miles (32 km) north of Tehachapi. Field investigations revealed evidence of a plague epizootic in the vicinity of the victim's residence and adjacent areas. Overall results of the joint field investigations throughout the entire Kern county area revealed a high rate of plague positive animals. Of the numerous samples submitted, 48 non-human samples were plague positive.

An FMRFamide antiserum differentiates between populations of antigens in the brain and retrocerebral complex of the locust, Schistocerca gregaria.

The distribution of FMRFamide-irmunoreactive cell bodies in the brain and retrocerebral complex of the locust, Schistocerca gregaria, is described. Most of the immunoreactive cell bodies are found in the pars intercerebralis and in the optic lobes. Many, but not all, of the cell bodies also react with an antiserum raised against bovine pancreatic polypeptide, but this antiserum also reveals another population of cells that stain selectively with this antiserum. In addition to the cell bodies, numerous immunoreactive processes are revealed by both antisera in neuropilar regions of the brain. The results of blocking experiments suggest that a differential distribution of three locust antigens can be determined from the examination of alternate serial sections stained with the two antisera used.

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.

Determination of imipenem and cilastatin in serum by high-pressure liquid chromatography.

Imipenem and cilastatin concentrations in serum were determined by using reverse-phase high-pressure liquid chromatography. Serum samples were stabilized with 0.5 M morpholineethanesulfonic acid buffer (pH 6.0) and subjected to ultrafiltration before chromatography. The elution solvent consisted of water or potassium phosphate buffered to pH 2.5 and methanol. The imipenem and cilastatin peaks were detected at 300 and 220 nm, respectively. Recovery from serum was 99% for both imipenem and cilastatin, and the limits of detectability for the two compounds were 0.3 and 0.5 microgram/ml, respectively. The assay may be readily applied to pharmacokinetic analysis of imipenem and cilastatin biodisposition in patients.

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.

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

Cefsulodin is a third-generation cephalosporin with a unique specificity for Pseudomonas aeruginosa. To study the pharmacokinetics of this agent in children, a rapid and sensitive high-performance liquid chromatographic micromethod was developed for plasma and urine. Protein was precipitated from plasma with one volume of cold methanol, and 20 microliter of the resulting supernatant solution was injected into a Zorbax C-8 reversed-phase column. The mobile phase was composed of 4.5 parts acetonitrile and 95.5 parts of 0.035 M ammonium acetate buffer (pH 5.2). Flow rate was 1.0 ml/min and peaks were detected at 265 nm. A flow gradient from 0.3 to 2.0 ml/min over 34 min was employed for urine. The analysis had a limit of detectability of 1 microgram/ml and a between-day coefficient of variation of 4.4 and 5.0 for 100 and 10 micrograms/ml samples, respectively.