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Biomedical subjects

J E Patrick

Publications and source records attributed to J E Patrick.

72 records · Page 4Linked to original sources
PubMed1978

Comparative bioavailability of a lipophilic steroid.

17beta-Acetoxy-2alpha-chloro-3-(p-nitrophenoxy)imino-5alpha-androstane (I) is a lipophilic steroid with postimplantive antifertility activity in laboratory animals. The bioavailability of micronized I from solutions and suspensions was compared in four groups of adult female Wistar rats. Each group received varying concentrations of micronized 3H-I (specific activity of 0.38--8.94 muCi/mg) in sesame oil by oral gavage. Samples of whole blood and urine collected following drug administration were assayed for radioactive content. Calculation of the mean area under the blood radioactivity versus time curve, when corrected for the quantity of drug administered, indicated that a substantially larger fraction of the dose was absorbed in the two instances where I was present only in solution. A linear relationship between the amount of I absorbed based on whole blood radioactivity and urinary excretion and the administered dose was found primarily for groups receiving the drug in solution. Preliminary results in humans indicate that 3H-I was absorbed to a much greater extent following oral administration of the drug in sesame oil than when admixed with lactose.

Abortifacient Agents↗
PubMed1978

Disposition of norgestimate in the presence and absence of ethinyl estradiol after oral administration to humans.

The disposition of radioactivity following oral administration of 14C-norgestimate was compared to that following administration of the drug in combination with 3H-ethinyl estradiol in humans. Seven normal, healthy female subjects were each administered one capsule orally containing 14C-norgestimate either alone (74.4 muCi, 0.50 mg) or in combination (73.5 muCi, 0.49 mg) with 3H-ethinyl estradiol (103 muCi, 0.14 mg) in polyethylene glycol 400. Peak levels of radioactivity due to carbon-14 and tritium in plasma occurred within 2 hr after drug administration, followed by distribution and elimination phases. The mean apparent elimination half-life and mean cumulative elimination of radioactivity in the urine and feces following 14C-norgestimate administration were not significantly different than those following administration of the combination dose. Approximately 50% of the administered radioactivity due to carbon-14 was excreted in the urine following administration of 14C-norgestimate both in the presence and absence of coadministered 3H-ethinyl estradiol.

Administration, Oral↗
PubMed1978

Disposition of ORF 9326, a novel contragestational steroid, in animals.

The disposition of ORF 9326 [17BETA-acetoxy-2alpha-chloro-3(p-nitrophenoxy) imino-5-androstane], an O-aryl oxime of 2beta-chlorodihydrotestosterone acetate, was studied in rats, dogs, monkeys and rabbits. Intravenous administration of 3H-ORF 9326 dissolved in PEG-400 to rats, dogs and monkeys resulted in a rapid decline of radioactivity in blood followed by a terminal slope suggesting long retention of radioactivity. Apparent half lives of radioactivity in blood were calculated to be from 50--95 hours for the three species, which peak levels of radioactivity in whole blood occurring within 4--7 hours after administration of the compound. Tissue distribution studies in the rat and dog indicate that body fat is one of the major depot areas for the drug and/or its metabolites. The major route of excretion for ORF 9326 and/or its metabolites in dog and rat is biliary whereas in monkey and rabbit it appears to be renal. Greater than 90% of the radioactive compounds excreted in the urine of dogs and monkeys following intravenous administration of 3H-ORF 9326 appear to be in the form of conjugates.

Abortifacient Agents↗
PubMed1977

Diurnal, respiratory, and other rhythms of fetal heart rate in lambs.

In lambs during the last third of gestation fetal heart periods were measured to 0.2 msec. and the variation was calculated with a computer in real time. The rate was subject to low-frequency variations in association with breathing movements, with a 2 to 4 hour rhythm of large amplitude and unknown origin, with the time of day, and with increasing gestational age. The calculated standard deviation of heart period bore a semilogarithmic relation to increasing length of observational epoch. There were also multiple rhythms in heart rate variability. The immeidate effect of fetal hypoxia was to increase heart rate variability despite the arrest of fetal breathing movements. The analysis of heart rate variability is examined critically.

Animals↗
PubMed1977

Steroids in the amniotic fluid of the rhesus monkey (Macaca mulatta).

Representative C21, C19 and C18 steroids have been measured in the amniotic fluid and maternal femoral plasma of rhesus monkeys during the last 50 days of pregnancy. The concentrations of cortisol, progesterone, androstenedione, oestrone sulphate all increased in amniotic fluid before spontaneous parturition. In contrast, amniotic fluid oestradiol levels remained low and unchanged, and were always less than the concentrations in the maternal plasma. The changes in progesterone, cortisol and oestrone concentrations in amniotic fluid occurred independently of significant changes in the concentration of these steroids in the maternal plasma. Betamethasone administered to monkeys after day 150 of pregnancy suppressed amniotic fluid and maternal plasma cortisol. This treatment markedly suppressed the concentration of progesterone in amniotic fluid, but did not alter its concentration in maternal plasma. It is concluded that during late pregnancy in the rhesus monkey there is an increase in the concentration of some steroids in amniotic fluid independent of alterations in their concentrations in maternal plasma. These changes could reflect an increase in foetal adrenal steroid secretion.

Amniotic Fluid↗
PubMed1976

Breathing patterns before death in fetal lambs.

Continuous observations in 16 fetal lambs over many days before death in utero from hypoxia, asphyxia, infection, and other causes have shown that death is preceded by variable changes in breathing movements. There was always a prolonged period of apnea succeeded by continuous abnormal breathing in six lambs and by gasping or brief episodes of abnormal breathing in the remainder. These abnormal patterns are described as a warning of what may be encountered in the human fetus.

Animals↗
PubMed1976

Prostaglandins in the plasma and amniotic fluid of rhesus monkeys during pregnancy and after intra-uterine foetal death.

Prostaglandin F (PGF) was measured in amniotic fluid, and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) was measured in maternal peripheral venous plasma and amniotic fluid of rhesus monkeys during late pregnancy. 13,14-Dihydro-15-keto-PGF2 alpha was determined in the maternal peripheral venous plasma of two animals following intra-uterine foetal death. The mean concentration of PGF and PGFM in amniotic fluid increased fourfold during the last 5 days of pregnancy. This increase was associated with an increase in the oestrone concentration in amniotic fluid and in maternal plasma. In normal pregnancy there was no increase in PGFM levels in the maternal peripheral vein, up to 1-2 days pre partum. After intra-uterine death, progesterone concentration in the maternal peripheral vein was unaltered, but oestrone and oestradiol declined. In plasma samples taken within 12 h of delivery, the concentration of PGFM was raised. It is concluded that an increase in prostaglandin production accompanies delivery at normal term, and at delivery past term following intra-uterine foetal death.

Amniotic Fluid↗
PubMedDate not supplied

Comparative steady state bioavailability of conventional and controlled-release formulations of albuterol.

A new controlled-release (CR) dosage formulation of albuterol has been developed which is suitable for twice-a-day dosing. The present study was conducted in twelve healthy adult male volunteers to compare the steady state plasma levels obtained following repeated administration of a 4 mg CR tablet (q12h) compared to a 2 mg conventional table (q6h) for 5 consecutive days. The mean steady state plasma level-time curves for both the CR and conventional tablet treatments were comparable over time and reproducible. There were no significant differences in the AUC or Cmax values between the two treatments. The mean 48-h AUC values were 240.7 and 231.3 h X ng ml-1 for the conventional and CR tablets, respectively, while the corresponding Cmax values ranged from 5.3 to 6.8 ng ml-1 and 5.4 to 6.5 ng ml-1. There were no significant differences in Cmin values except for one 12-h (day 4) value. Cmin values ranged from 3.8 to 4.3 ng ml-1 and 3.0 to 4.8 ng ml-1 for the conventional and CR tablets, respectively. The data show that the 4 mg albuterol CR tablet (q12h) is bioequivalent to a 2 mg conventional albuterol tablet (q6h). The CR tablet formulation will offer the advantage of increased patient compliance; additionally, the CR formulation may prove to be especially beneficial in the treatment of nocturnal asthma.

Adult↗
PubMedDate not supplied

Multiple-dose albuterol kinetics.

Albuterol, a beta-adrenergic agonist bronchodilator, was studied in 12 healthy male volunteers to evaluate the steady-state pharmacokinetics following oral administration of 4-mg tablets, given every six hours for five days. The kinetics of albuterol were best described by a two-compartment open model with first-order absorption kinetics. Steady-state plasma levels were predictable from the kinetic data and were reached by the third day of dosing (ninth and tenth dose). Small accumulation ratios of approximately two were seen based on area under the plasma concentration-time curve and maximal and minimal concentration data. The elimination phase half-life was determined to be 6.5 hours, which is similar to the values reported following single-dose administration.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics of isosorbide-5-mononitrate after oral administration of an extended-release mononitrate formulation versus a standard dinitrate formulation.

The steady-state pharmacokinetic profile of isosorbide-5-mononitrate (5-ISMN) after oral administration of an extended-release tablet formulation of 5-ISMN 60 mg or 120 mg once a day was compared with that after administration of isosorbide dinitrate (ISDN) 40 mg every 6 hours, in a randomized, open-label, three-way crossover trial in 24 healthy men. After oral administration of extended-release 5-ISMN 60 mg or 120 mg once daily, 5-ISMN was slowly absorbed, reaching mean peak plasma concentrations of 557 and 1151 ng/mL, respectively, in approximately 3 hours. Plasma concentrations of 5-ISMN were dose proportional between 60 mg and 120 mg. After oral administration of ISDN 40 mg every 6 hours, a mean peak plasma 5-ISMN concentration of 806 ng/mL was achieved in less than 2 hours (mean time to reach the maximum plasma concentration was 1.5 hours). The mean plasma apparent elimination half-life of 5-ISMN was 6.2 hours after extended-release 5-ISMN administration and 7.1 hours after ISDN. Although the maximum plasma concentration was higher and the minimum plasma concentration was lower after administration of extended-release 5-ISMN 120 mg once daily compared with ISDN 40 mg every 6 hours, there was no significant difference (P > 0.05) in the "bioavailability" of 5-ISMN between these two treatments. The most commonly reported adverse events in these "nitrate-naive" subjects were headache, dizziness, nausea, and vomiting; these were dose related and their incidence decreased with repeated exposure.

Administration, Oral↗
PubMedDate not supplied

Disposition of 14C-eptifibatide after intravenous administration to healthy men.

Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of 14C-eptifibatide in man after a single intravenous (i.v.) bolus dose. 14C-Eptifibatide (approximately 50 microCi) was administered to eight healthy men as a single 135-microgram/kg i.v. bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following 14C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).

Adult↗
PubMedDate not supplied

Comparative biotransformation of triflubazam in rats, dogs, and monkeys.

The biotransformation of 14C-triflubazam (ORF 8063; 1-methyl-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepin-2-4-[3H,5H]-dione) was investigated in rats, dogs, and monkeys. Urinary metabolites, representing 65, 74, and 87%, respectively, of the total urinary radioactivity excreted by these three species, were isolated by preparative layer chromatography and characterized by various spectral techniques including gas chromatography/mass spectrometry, solid probe mass spectrometry, polarimetry, and infrared and nuclear magnetic resonance spectrometry. No parent drug was found in the urine of any species. Four metabolites were isolated from the rat including the 4'-hydroxyphenyl, dihydrodiol, and 3'-methoxy-4'hydroxy derivatives. N-demethylated metabolites were not isolated from rat urine. Five metabolites were isolated from dog urine, including 4-hydroxyphenyl, dihydrodiol, and catechol derivatives of triflubazam. Unlike the case of the rat, a catechol-O-methyl ether was not detected in dog urine. Six metabolites were isolated from monkey urine. The only major difference in metabolism in the monkey was the existence of both the dihydrodiol and N-desmethyldihydrodiol metabolites. No catechol-0-methyl ether was detected in monkey urine. Biotransformation through a common arene oxide intermediate can be proposed for these three animal species.

Animals↗
PubMedDate not supplied

Biotransformation of a 1,5-benzodiazepine, triflubazam, by man.

The biotransformation of triblubazam (ORF 8063; 1-methyl-5-phenyl-7-trifluoromethyl-1H-1,5-benzodiazepin-2,4-[3H,5H]-dione) was studied in man. Seven male subjects received a chronic regimen of orally administered triblubazam for 19 consecutive days and their urine was collected for 29 days. Seven urinary metabolites were isolated by application of Sephadex LH-20 column chromatography and preparative thin-layer chromatography. Six of the purified compounds were subsequently characterized by utilizing thin-layer and gas-liquid chromatography and infrared, nuclear magnetic resonance, and mass spectrometry. The structure of a seventh metabolite was established by the use of an enzymatic assay involving catechol O-methyl-transferase. These compounds included unchanged triflubazam, the N-desmethyl catechol derivative, the 4'-hydroxyphenyl derivative, N-desmethyltriflubazam, the N-desmethyl dihydrodiol derivative, the N-desmethyl-4'-hydroxy compound, and the N-desmethyl-3'-methoxy-4'-hydroxy derivative. Unlike the situation in the metabolism of 1,4-benzodiazepines by man, no C3-hydroxylated derivatives of triflubazam were isolated. The metabolism of triblubazam by man is characterized by extensive N-demethylation, aromatic hydroxylation, aromatic O-methylation, and dihydrodiol formation.

Anti-Anxiety Agents↗
PubMedDate not supplied

Biotransformation of bromperidol in rat, dog, and man.

The metabolic fate of 14C-bromperidol after po administration was studied in rat, dog, and man. When 14C-bromperidol was given to female Wistar rats, 23-29% of the dose was excreted in the urine and 38-45% in the feces over a 7-day period. In dogs, 39-74% of the administered dose was excreted in the urine and 26-43% in the feces over the same period. In both rats and dogs, bromperidol was extensively metabolized; most of the urinary radioactivity associated with metabolites arose from cleavage of the bromperidol molecule via oxidative N-dealkylation. After administration of 14C-bromperidol to human volunteers, 28-50% of the dose was eliminated in the urine while 18-46% was eliminated in the feces over a 13-day period. Although bromperidol appeared to be extensively metabolized in man, the major portion of the urinary radioactivity (70-75%) was associated with the O-glucuronide conjugate of intact drug. Thus, oxidative N-dealkylation does not appear to be the major urinary metabolic pathway of the drug in man.

Adult↗