Blood levels and electroencephalographic effects of diazepam and bromazepam.

Blood levels and electroencephalographic (EEG) data were collected for 2 hr after single oral doses of bromazepam (9 mg), diazepam (10 mg), and placebo in 13 male adult volunteers. Both drugs caused an increase in beta activity (above 13 Hz) and a decrease in alpha activity (9 to 11 Hz) in the EEG. Blood levels of 100 ng/ml of diazepam or 50 ng/ml of bromazepam were associated with significant changes in EEG beta activity. Temporal changes in the EEG after administration of diazepam or bromazepam paralleled development of plasma levels of these drugs. Although a weakly significant correlation was found between measurable diazepam blood levels and amount of increased EEG beta activity, the relationship between measurable bromazepam blood levels and the degree of EEG changes was not significant. Quantitative EEG is a sensitive continuous response measure, useful in defining cerebral activity, response latency, and relative potency of psychoactive benzodiazepines.

Simultaneous automated determination of free and total sulfisoxazole and sulfamethoxazole in plasma and urine.

A fully automated method for the determination of sulfisoxazole, N4-acetylsulfisoxazole, sulfamethoxazole, and N4-acetylsulfamethoxazole in human plasma and urine was developed. Untreated plasma is analyzed by automation of dialysis, hydrolysis, color development, and quantitation. The method has a sensitivyt limit of 2 microgram/ml of plasma and has been used successfully to determine sulfonamide levels following administration of sulfoxazole and a combination drug product containing sulfamethoxazole and trimethoprim in humans. Samples are processed at the rate of 40 per hour, with a minimum of sample handling, data reduction, and materials.

GLC determination of l-2-hydroxy-N-cyclopropylmethylmorphinan in plasma and urine.

A specific method was developed for the determination of l-2-hydroxy-N-cyclopropylmethylmorphinan in plasma and urine by GLC, using flame-ionization detection. The method involves the extraction of the compound into ether from plasma or urine at pH 7.4, followed by back-extraction into 1 N HCl. The acid phase is ether washed and made alkaline, and the compound is reextracted into ether. The ether is evaporated to dryness, the residue is dissolved in methanol, and an aliquot is analyzed by GLC. The same method is applicalble to plasma and urine samples following deconjugation of the compound with glucuronidase-sulfatase. The overall recovery is 93.1 +/- 9.4% SD) in the concentration range of 0.020-2.0 microgram/ml. The method was successfully applied to plasma and urine specimens obtained after administering single 25-mg oral doses to humans.

Bumetanide: radioimmunoassay and pharmacokinetic profile in humans.

A simple, specific, and sensitive radioimmunoassay was developed for the determination of the diuretic bumetanide in plasma and urine. Antiserum to bumetanide was obtained from rabbits immunized with an immunogen prepared by covalently coupling the glycine conjugate of bumetanide to bovine serum albumin. Following extraction of the sample at pH 5.5 with ether, radioimmunoassay of the residue from the ether extract allows for the determination of bumetanide with a limit of sensitivity of about 1 ng/ml using 0.1 ml of plasma or urine. The specificity of the radioimmunoassay was established by comparison with specific radiometric and spectrofluorometric techniques. The pharmacokinetic profile of bumetanide in eight human subjects receiving single 2-mg oral doses of the drug was elucidated using the radioimmunoassay. The peak plasma levels ranged from 39 to 50 ng/ml at 1-4 hr after administration and declined with a mean apparent half-life of 1.17 hr. The mean plasma clearance rate was calculated to be 255 ml/min. During the first 24 hr, a mean of 43% of the bumetanide dose was excreted in the urine as intact drug.

Determination of the major urinary metabolite of flurazepam in man by high-performance liquid chromatography.

A high performance liquid chromatographic method for the determination of N-1-hydroxyethylflurazepam, the major urinary metabolite of flurazepam, in human urine is described. Urine specimens were incubated enzymatically to deconjugate N-1-hydroxyethylflurazepam glucuronide (metabolite) and were then extracted at pH 9.0 to extract the metabolite. The extracts were chromatographed on a microparticulate silica gel column using automatic sample injection, isocratic elution at ambient temperature and UV monitoring at 254 nm. The internal standard was 7 chloro-5(2'-chlorophenyl) 1,3-dihydro-1-2-dimethylaminoethyl-2H-1,4-benzodiazepine-2-one. The recovery from urine, in the 0.5-25.0 microgram/ml range, was 96.5 +/- 11.5% (S.D.), and the sensitivity limit was 0.5 microgram/ml. The method was found to be specific for N-1-hydroxyethylflurazepam in the presence of intact flurazepam and other possible urinary metabolites of flurazepam. The method was successfully applied to urine specimens collected from human subjects following the administration of 30-mg single oral doses of flurazepam dihydrochloride.

Determination of trimethoprim in biological fluids by high-performance liquid chromatography.

A rapid, sensitive, and specific high-performance liquid chromatographic assay was developed for the determination of trimethoprim in blood, plasma, and urine using normalphase (adsorption) chromatography on a microparticulate silica column and UV monitoring at 280 nm. Trimethoprim is selectively extracted from the biological sample matrix at alkaline pH with chloroform, providng nearly quantitative extraction (greater than 95%) and a sensitivity limit of 0.01 to 0.02 microgram/ml blood or plasma, without interference from sulfonamides.

Clinical pharmacology of ceftriaxone in patients with neoplastic disease.

Pharmacological studies of ceftriaxone, a new semisynthetic cephalosporin, were conducted in 35 cancer patients. This antibiotic was administered in a variety of doses and schedules with no observed toxicity. Intramuscular administration of 500 mg of ceftriaxone to seven patients produced mean peak serum concentrations of 32.9 mug/ml 2.0 h after administration. The terminal serum half-life was 10.9 h. Intravenous infusion of 500 mg of ceftriaxone over 5 min to the same group of seven patients produced a mean peak concentration of the drug in serum of 83 mug/ml at the end of administration which decreased to 16.8 mug/ml at 8 h. A dose of 1 g of ceftriaxone given in identical fashion to the same group of seven patients produced mean peak concentrations in serum of 130 mug/ml at the end of administration and 17.3 mug/ml at 12 h. The mean percentages of drug recovered in urine 12 h after single intravenous doses of 500 mg and 1 g were 30 and 20%, respectively. A 1-g dose of ceftriaxone was administered every 8 h to 10 patients, and a 2-g dose was administered every 12 hours to 9 patients. Drug concentrations in serum were measured for each patient after drug administration on day 1, day 3 or 4, and day 7 or 8. The 1-g dose produced an observed mean peak concentration of 154 mug/ml and a mean terminal-phase half-life of 5.6 h on day 3 or 4. The 2-g dose produced a mean peak concentration in serum of 262 mug/ml and a terminal-phase serum half-life of 6.3 h on day 3 or 4. Continuous infusion studies were performed in nine neutropenic patients for up to 8 days by using a loading dose of 1 g over 30 min, followed by 2 g every 8 h. Mean concentrations in serum were maintained at about 135 mug/ml during the infusion period.

Single-dose ceftriaxone pharmacokinetics in pediatric patients with central nervous system infections.

Ceftriaxone has greater in vitro and in vivo efficacy against many common bacteria than other third-generation cephalosporins. Single-dose ceftriaxone pharmacokinetics were studied in 17 patients, aged 0.6 to 52 months, with infections of the central nervous system. Patients received a randomized dose of 50 or 75 mg/kg ceftriaxone intravenously over 5 minutes on the second to fifth day of illness. Serial blood samples were collected over 24 hours in all patients, and cerebrospinal fluid (CSF) was obtained 1 to 4.5 hours after injection. Ceftriaxone mean peak plasma concentrations, determined by high-power liquid chromatography, were 267 and 184 microgram/ml for the 75 and 50 mg/kg dosage groups, respectively. The harmonic mean elimination half-life was 4.2 hours, and the mean percent drug penetrance into CSF was 4.8 +/- 3.5%. Of CSF studies evaluated, the glucose concentration was correlated most closely (inversely) with CSF penetration of ceftriaxone. Individual CSF concentrations of ceftriaxone exceeded the minimal inhibitory concentrations of the respective bacteria causing infection by 480 to 5,600 times. Ceftriaxone may be useful in the treatment of serious pediatric infections, including meningitis.

Ceftriaxone pharmacokinetics following multiple intramuscular dosing.

The steady-state pharmacokinetics and tolerance of ceftriaxone after multiple i.m. doses of 0.5 and 1 g q12 h for 3.5 days were investigated in 12 healthy, adult volunteers. Ceftriaxone was rapidly absorbed after i.m. administration with mean peak times ranging from 1.3 to 1.9 h. Steady-state plasma concentrations were apparent after the third dose of both dosage regimens, with trough plasma concentrations of 24 +/- 6 and 39 +/- 8 micrograms/ml (mean +/- SD) after the 0.5 and 1 g q12 h regimens, respectively. Multiple i.m. administrations of ceftriaxone did not alter its elimination half-life; however, small increases were observed in the plasma clearance and volume of distribution at the 1-g regimen. These increases were attributed to the non-linear binding of ceftriaxone to human plasma proteins, and are therapeutically unimportant. Ceftriaxone was well tolerated and serious or lasting adverse reactions were not encountered in the study.

Pharmacokinetics and tolerance of ceftriaxone in humans after single-dose intramuscular administration in water and lidocaine diluents.

The effects of 1% lidocaine as a diluent on the pharmacokinetics and tolerance of ceftriaxone administered intramuscularly were investigated in 12 adult volunteers. Each subject received two 0.5-g doses of ceftriaxone (one in water and the other in 1% lidocaine) at least 1 week apart in a randomized crossover fashion. Plasma and urine samples were collected serially and assayed for ceftriaxone content by high-performance liquid chromatography. The mean peak plasma concentration, time to attain the peak, area under the plasma curve from time zero to infinity, and elimination half-life were 45 micrograms/ml, 2.5 h, 578 micrograms . h/ml, and 7.1 h, respectively, after intramuscular administration of ceftriaxone in water diluent. The corresponding mean values in 1% lidocaine diluent were 42 micrograms/ml, 3 h, 577 micrograms . h/ml, and 7.0 h. The pharmacokinetic data suggested that 1% lidocaine does not alter either the elimination parameters or the bioavailability of intramuscularly administered ceftriaxone. The intensity and frequency of pain at the injection site were reduced considerably by the coadministered lidocaine.

Determination of clorazepate and its major metabolites in blood and urine by electron capture gas-liquid chromatography.

A sensitive and specific blood level method employing differential extraction was developed for the determination of clorazepate and its N-desmethyldiazepam metabolite by electron capture gas-liquid chromatography (GLC-ECD). The assay requires the initial extraction of N-desmethyldiazepam, the major metabolite, into benzene-methylene chloride (90:10) from the biological sample made alkaline with 0.1 N NaOH. The samples is then acidified with 2 N HCl to decarboxylate clorazepate to N-desmethyldiazepam, which is then extracted into benzene-methylene chloride (90:10) after adjusting the pH to 12.8 with NaOH. The two extracts are evaporated and the residues are dissolved in benzene which contains griseofulvin as the reference standard. These solutions are assayed by GLC-ECD. The overall recovery and sensitivity limit of the assay for clorazepate is 60+/-5% (S.D.) and 4.0 ng/ml blood, respectively, while that for N-desmethyldiazepam is 95+/-5% (S.D.) and 4.0 ng/ml blood, respectively. The urinary excretion of clorazepate was determined by the measurement of the levels of N-desmethyldiazepam and oxazepam, the major urinary metabolites of clorazepate, both prior to and after enzymatic deconjugation. These methods were applied to the measurement of clorazepate and its metabolites in blood and urine following a single 15-mg dose of clorazepate dipotassium.