Biomedical subjects
Publications and source records attributed to J A Knowles.
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Explore the source record for details and available documents.
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One hundred-ninety-two children, ages 2 to 16 years, selected from the outpatient department medical clinic without regard to presenting complaint were examined by conventional cellulose tape specimens obtained at home. Twenty-four per cent of the patients were found to have pinworm ova present. The physicians seeing the last 84 patients were asked to estimate the likelihood of enterobiasis in these children. By various means from history, physical examination or blood cell differential counts, estimates were slightly better than by chance. Treatment of 185 patients in a random fashion with placebo, thiabendazole and pyrvinium pamoate resulted in negative tests three weeks after therapy, in 15, 92 and 95 per cent of patients, respectively. Transient side effects consisting of anorexia and vomiting were noted in all three groups, but were most pronounced in adults receiving thiabendazole.
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Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.
Fifteen healthy male volunteers received long-term daily treatment with oral lorazepam at doses as high as 10 mg per day for a period of 26 weeks. Steady-state plasma concentrations of lorazepam and its glucuronide metabolite were measured in all subjects at least every two weeks. At daily doses of 6 mg per day, the mean steady-state lorazepam level was 88 ng/ml and that of lorazepam glucuronide was 170 ng/ml. Mean levels among seven subjects who received 10 mg per day were 164 and 266 ng/ml, respectively. Lorazepam concentrations fluctuated from week to week despite constant dosage, but there was no evidence of systematic variation. Mean steady-state lorazepam levels were highly correlated with daily dose in mg/kg, but were not related to age. Lorazepam was not detected in any plasma samples drawn one week after discontinuation of treatment.
Twelve healthy volunteers received single 1200-mg oral doses of oxaprozin while fasting and immediately after a standard breakfast in a two-period crossover design with three weeks between administrations. Oxaprozin plasma concentrations were monitored during a 10-day period after each dose. No statistically significant differences were noted between kinetic parameters obtained in the fasting and post-prandial states for mean peak plasma concentrations (Cmax, 103 vs. 109 micrograms/ml), absorption rate constants (ka, 1.1 vs. 0.8 h-1), or total AUC (7042 vs. 7066 micrograms/ml X hr). Compared with doses administered during fasting, postprandial doses led to a delay in the onset of absorption in the gastrointestinal tract (lag time t0, 24 vs. 9 min), but not in the peak time (tmax approximately 5 hours). Oxaprozin's mean residence time t was slightly shorter for subjects in the postprandial state (72 hours) than for those in fasting state (73 hours), probably because of the intrasubject variability in half-life (48 vs. 50 hours). The results of this study indicate that the ingestion of food has no effect on the bioavailability of oxaprozin.
Following intragastric doses of 14C-oxaprozin to beagle dogs and rhesus monkeys, oxaprozin was rapidly absorbed and was essentially the only drug-related substance in the plasma for at least 24 hr. Recovery of radioactivity in the excreta was 87% in both species, with the fecal route accounting for almost all of the excretion by the dog, and the urinary route predominating in the monkey. The drug was slowly eliminated by both species. The concentrations in tissues of monkeys were generally less than those in plasma, and their decline with time paralleled that in plasma. High concentrations of 14C were found in the bile and urine. Qualitative and quantitative metabolite patterns of both fluids were similar. About 90% of the 14C in both bile and urine was recovered as identified compounds in the free, ester conjugate, and ether conjugate fractions. The ester conjugate fraction, mainly consisting of oxaprozin glucuronide, was quantitatively the most important in both fluids. Two phenolic metabolites were characterized by mass spectrometry and co-chromatography. They were present in free form and as ester and ether glucuronides.
Oxazepam glucuronide isolated from swine urine by previously published methods was separated into its diastereoisomers by ion-exchange chromatography on a preparative scale. Quantitative high-performance liquid chromatography was used to monitor the separation. The two isomers were obtained in analytically pure form and then characterized by elemental analysis, oxazepam content, mass spectrometry, ultraviolet spectroscopy, optical rotation and optical rotatory dispersion-circular dichroism. The latter permitted the assignment of the dextrorotatory and the levorotatory isomers to the (S)- and (R)- configurations, respectively. Rates of enzymic hydrolysis depend on the configuration of the substrate as well as on the enzyme preparation used. Rate of cleavage was highest with the (S)-(+)-glucuronide and beta-glucuronidase from Escherichia coli. This enzyme possesses the highest degree of stereoselectivity; it hydrolyzes the (S)-(+)-isomer more than 400 times faster than the (R)-(-)-form. Bovine liver glucuronidase is less stereoselective, whereas glucuronidase preparations of molluscan origin exhibit little stereoselectivity. The ready hydrolysis of one of the glucuronides by an enzyme from an intestinal microorganism may play a role in the enterohepatic circulation of oxazepam.