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Biomedical subjects

J E Patrick

Publications and source records attributed to J E Patrick.

At least 37 records · Page 2Linked to original sources
PubMed1988

Secretion of dilevalol in breast milk.

The pharmacokinetics of unchanged and total (unchanged plus Glusulase [Biotechnology Systems, Boston, MA]) released dilevalol and secretion into human breast milk was studied in six healthy breast-feeding female volunteers administered a single 400-mg dilevalol hydrochloride capsule. In plasma, the mean Cmax for unchanged dilevalol, 485 ng/mL was reached at 0.8 hour (tmax) and the AUC(48 hours) was 1435 hr X ng/mL. Pharmacokinetic analysis of unchanged dilevalol in plasma showed that dilevalol was distributed and eliminated with half-lives of 0.9 and 8.2 hours, respectively. Breast milk concentrations of unchanged dilevalol as a function of time, paralleled those of plasma but were consistently lower. The milk Cmax, 149 ng/mL, occurred during the 0 to 2 hour collection interval; the AUC(42 hours) for unchanged dilevalol in milk was 663 hr X ng/mL. The mean milk to plasma concentration ratio was 0.46. The unchanged dilevalol plasma concentrations were 12 to 18% those of total drug suggesting that the drug is extensively conjugated. By contrast, the concentrations of unchanged dilevalol in breast milk, based on Cmax and AUC data were 63 to 94% those of total drug, indicating that very little conjugated drug is secreted into breast milk. Through 48 hours, a mean of only 27 micrograms dilevalol or 0.007% of the administered dose was secreted into breast milk, which is much less than that reported for other beta blockers.

Administration, Oral↗
PubMed1988

Perinatal pulmonary hyperplasia due to laryngeal atresia.

A premature newborn boy, who died at birth because of cartilaginous laryngeal atresia, showed lung development that was far more advanced than normal for gestational age. The lungs, which were histologically normal, were three times the expected weight and showed a degree of alveolarization appropriate for 3 months' postnatal age. The lungs crowded the chest cavity so that the diaphragm was flattened and immobilized; the massive ascites, documented by ultrasound 5 weeks prior to delivery, appeared to be due to obstructed venous return. Thus, the pulmonary hyperplasia, a new finding in perinatal pathology, caused severe fetal ascites. Subsequently, the hyperplasia led to acute polyhydramnios that, ultrasonographically, was observed to develop 2 weeks prior to delivery. The observation that fetal lungs may be hyperplastic has a bearing on the known relationship between fetal lung growth and retention of lung fluid.

Ascites↗
PubMed1987

High-performance liquid chromatographic assay for azatadine in human urine.

A high-performance liquid chromatographic assay for the quantitative determination of azatadine and a base (1 M sodium hydroxide) hydrolyzable conjugate of azatadine in human urine has been developed. Reversed-phase separation of azatadine and the internal standard, 8-chloroazatadine, was accomplished on a 300 X 3.9 mm I.D. mu Bondapak CN column. Following liquid-liquid extraction from urine, azatadine was quantitatively determined by UV detection at 214 nm. No interferences were observed in the extracts obtained from drug-free urine. Detector response (peak area ratio) was linear from 10 to 2500 ng/ml. This method has been shown to provide accurate and precise determinations of the unchanged and hydrolyzed drug in human urine, following the twice daily oral administration (1-2 mg) of azatadine maleate.

Chromatography, High Pressure Liquid↗
PubMed1986

High-performance liquid chromatographic assay for hydrochlorothiazide in human urine.

A high-performance liquid chromatographic assay was developed for the quantitative determination of hydrochlorothiazide (HCT) in human urine. Reversed-phase separation of HCT and the internal standard, trichloromethiazide (TCMT), was accomplished on a 300 X 3.9 mm mu Bondapak Phenyl column. Following solvent extraction, concentrations of HCT as low as 0.25 micrograms/ml in urine were quantified by UV detection at 280 nm. Detector response (peak-area ratio of HCT to TCMT) was linear to 50 micrograms/ml. No interferences were observed in the extracts obtained from drug-free urine nor from several antihypertensive agents which are commonly co-administered with HCT. This method has been routinely employed in bio-availability studies evaluating a variety of formulations as well as characterizing the pharmacokinetics of this drug from urinary excretion data.

Chromatography, High Pressure Liquid↗
PubMed1986

Rising multiple-dose pharmacokinetics of labetalol in hypertensive patients.

Labetalol, a drug possessing both alpha- and beta-adrenergic blocking activities, is used in the treatment of hypertension. The current study was undertaken to elucidate the steady-state pharmacokinetics of labetalol following a rising oral multiple-dosage regimen. Twelve patients received oral labetalol every 12 hours for 18 days. An initial dose of 100 mg was increased at three-day intervals to 200, 300, 400, and 600 mg q12h. Selected blood samples were taken at various times following drug administration at each dose level and analyzed for labetalol levels by a specific high-performance liquid chromography assay. The pharmacokinetics of labetalol are best described by a two-compartment open model with first-order absorption. The half-lives of the absorption, distribution, and elimination phases are 0.6, 1.3, and 8.3 hours, respectively. The steady-state plasma drug concentrations are predictable from the pharmacokinetic data and are in good agreement with the observed values. Steady-state levels are reached by the third day at each dose level studied and increase proportionally with dose.

Adult↗
PubMed1986

Plasma adrenocorticotropic hormone and cortisol and adrenal blood flow during sustained hypoxemia in fetal sheep.

We examined the effect of sustained hypoxemia with progressive acidemia on pituitary-adrenal endocrine function (adrenocorticotropic hormone, cortisol) and on adrenal blood flow in fetal sheep. Hypoxemia was induced by the maternal sheep breathing a gas mixture containing 9% oxygen, with 3% carbon dioxide added. Induced hypoxemia resulted in a progressive fetal metabolic acidosis but with little change in maternal pH. During induced hypoxemia there was little change in maternal plasma adrenocorticotropic hormone or cortisol level. Fetal adrenocorticotropic hormone and cortisol increased to peak values within 2.8 hours of induced hypoxia but by 7.2 hours had begun to fall to values that were not significantly different from those at 1.4 hours. Fetal adrenal blood flow (microsphere technique) also increased significantly and remained elevated throughout the duration (7.2 hours) of hypoxemia. The maximum fetal adrenal blood flow achieved during hypoxemia was significantly correlated with the basal (prehypoxemia) flow to the adrenals. We conclude that the changes in fetal adrenocorticotropic hormone, cortisol, and adrenal blood flow seen in short-term hypoxemia are reproduced during sustained hypoxemia with acidemia. Furthermore, the noted rise in the fetal adrenocorticotropic hormone level may be an important factor contributing to the increase in adrenal blood flow during hypoxemia.

Adrenal Glands↗
PubMed1985

Cerebral oxidative metabolism in the fetal lamb: relationship to electrocortical state.

Cerebral oxidative metabolism and blood flow were measured in 14 chronically prepared fetal lambs with changes in fetal electrocortical activity. Myocardial blood flow was also measured with changes in fetal state in order to determine whether metabolic changes observed were organ specific. Samples of preductal arterial and sagittal vein blood were analyzed for oxygen content, blood gases, and pH. Blood flow was measured with a radioactive microsphere technique. Cerebral oxidative metabolism increased significantly from 126 +/- 7 mumol/100 gm/min during the high-voltage electrocortical state to 152 +/- 7 mumol/100 gm-1/min-1 (p less than 0.05) during the low-voltage electrocortical state. The increase in cerebral oxidative metabolism was sustained by an increase in blood flow, 148 +/- 7 ml/100 gm/min to 173 +/- 10 ml/100 gm/min (p less than 0.01), whereas the arterial venous oxygen difference remained unchanged. Changes in myocardial blood flow were in the opposite direction, with a decrease noted during the low-voltage electrocortical state, and were correlated with changes in fetal heart rate. We conclude that cerebral oxidative metabolism is increased during the fetal low-voltage electrocortical state and suggests an important role for the increased incidence of this state during the accelerated growth and development of the brain during the perinatal period.

Animals↗
PubMed1985

Comparative bioavailability and pharmacokinetics of three formulations of albuterol.

Albuterol sulfate, alpha'[[1,1-dimethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol sulfate, is a relatively selective beta-2-adrenergic bronchodilator used for the relief of bronchospasm. The bioavailability of two 4-mg tablet formulations, differing in their inactive excipients, and a syrup formulation, was evaluated. The three dosage forms were orally administered to 12 normal male volunteers in a randomized three-way crossover study. Plasma samples were collected at frequent time points through 12 h and analyzed for albuterol content by a specific GC-MS method. The drug was rapidly absorbed from all three formulations. Maximum drug concentrations were comparable for the three formulations and were obtained between 1.8-2.0 h. The areas under the plasma concentration-time curves were 68-78 h X ng/mL. The drug elimination phase half-live (t1/2 beta) ranged from 4.8 to 5.5 h. Analysis of the data showed that the bioavailability of albuterol from a tablet formulation is equivalent to that from a solution.

Administration, Oral↗
PubMed1985

Cerebral metabolism in fetal lamb after maternal infusion of ethanol.

Cerebral uptake of glucose and O2 (VCO2) was measured in 10 chronically catheterized fetal lambs during a control period, after a 1-h maternal infusion of ethanol (1.0 g X kg-1 X h-1) and 1-h postethanol infusion, to determine if alterations in cerebral metabolism might occur. Brachiocephalic artery and sagittal vein blood samples were analyzed for glucose, O2 content, blood gases, pH, and ethanol. Cerebral blood flow (Qc) was measured with a radioactive microsphere technique. VCO2 decreased significantly, from 140 +/- 13 mumol X 100 g-1 X min-1 during the control period to 91 +/- 8 (P less than 0.05) with the ethanol infusion, with a related fall in Qc, 177 +/- 12 to 104 +/- 9 ml X 100 g-1 X min-1 (P less than 0.001), the cerebral arteriovenous O2 difference being little changed. Cerebral glucose uptake, although decreased, was not significantly changed with the ethanol infusion, because the cerebral arteriovenous difference for glucose increased with the related fall in Qc. We conclude that maternal infusion of ethanol results in a decreased fetal VCO2 with a related fall in Qc. If prolonged, this decrease in cerebral oxidative metabolism might well affect cerebral development and provide a mechanism whereby chronic alcohol intake contributes to central nervous system growth anomalies and dysfunction of infants exposed to alcohol in utero.

Animals↗
PubMed1984

Biotransformation of norgestimate in women.

The metabolism of norgestimate (ORF-10131; 14C-d-13-ethyl-17-acetoxy-18,19-dinor-17 alpha-pregn-4-en-20- yn -3-oxime) was studied in humans. Compound labeled with carbon-14 in the 17 alpha-ethynyl group was administered to four female subjects. An average of 46.8 percent of the administered radioactivity was excreted in the urine and 36.8 percent in the feces over a two-week collection period. About 12 percent of the urinary radioactivity represented freely extractable metabolites and another 57 percent consisted of extractable material released by enzyme hydrolysis. The ethynylated metabolites of norgestimate were separated from endogenous compounds and non- ethynylated metabolites by silver- sulfoethyl cellulose column chromatography. Metabolites were subsequently isolated by high performance liquid chromatography and thin layer chromatography. The identification of five urinary metabolites was accomplished by combined gas-liquid chromatography/mass spectrometry. These metabolites include norgestrel, 16 beta- hydroxynorgestrel , 2 alpha- hydroxynorgestrel , 3 alpha, 5 beta- tetrahydronorgestrel , and a fifth trihydroxylated metabolite of undetermined stereochemical configuration; 3,16-dihydroxy-5- tetrahydronorgestrel .

Biotransformation↗
PubMed1984

Effects of naloxone on the breathing, electrocortical, heart rate, glucose and cortisol responses to hypoxia in the sheep fetus.

Continuous infusions of naloxone HC1 (0.5 mg/kg or 3.8 mg/kg) or saline were given intravenously to fetal sheep at 119 to 137 days of gestation during a one hour period of air administration and a one hour period of hypoxia induced by having ewes breathe 9% O2, 3% CO2 and 88% N2. Fetal carotid PaO2 fell to 13.0 +/- 0.5 mmHg during hypoxia with no change in pH. During hypoxia, plasma cortisol concentration increased significantly more in naloxone-infused fetuses than controls. Ewes, whose fetuses received naloxone, showed a significant increase in cortisol during hypoxia whereas no increase was observed in controls. There were no significant differences between saline and naloxone-infused fetuses during hypoxia in fetal breathing incidence, amplitude, frequency, number of deep inspiratory efforts per hour, heart rate, electrocortical activity or in the rise in plasma glucose caused by hypoxia. Results suggest that endogenous opiates may have a role in modulating cortisol production in the ewe and fetus during hypoxia but do not have a role in mediating the decrease in incidence of breathing activity or rise in plasma glucose. During air administration, naloxone significantly increased fetal breath amplitude, fetal and maternal plasma glucose, fetal heart rate, and the number of electrocortical changes per hour. This suggests endogenous opiates may have a more important role in the normoxic pregnant ewe and fetus.

Animals↗
PubMed1983

Ultrasonic measurement of rate and depth of human fetal breathing: effect of glucose.

A recently developed ultrasonic tracking device was used to determine the effect of maternal intravenous glucose infusion on amplitude and frequency of breathing movements in six healthy human fetuses at 38 to 40 weeks' gestation. Following a 2-hour observation period, an intravenous injection of either 25 gm of a 50% glucose solution or an equal volume of saline was given to the mother. Observations were continued for a further 4 hours. Fetal rib cage and abdominal diameters were measured continuously with the ultrasonic tracking device and the information was recorded on a strip chart recorder for later analysis. Breath interval and incidence measurements were highly correlated with data obtained by an independent technique (r greater than or equal to 0.90). During the first 80 minutes after glucose injection, total fetal trunk movement recorded during breathing movements increased from 1.5 +/- 0.2 to 2.9 +/- 0.4 mm (P less than 0.05). There was no significant change in the frequency or variability of fetal breathing movements after glucose infusion.

Blood Glucose↗
PubMed1983

The autonomic nervous system and fetal heart rate variability.

Although it is often assumed that fetal heart rate variability reflects simple "push-pull" interactions between the parasympathetic and beta-sympathetic limbs of the autonomic nervous system, there has been little direct experimental evidence to support this view. We used autonomic blocking agents to investigate heart rate variability in chronically catheterized fetal lambs, and an on-line computer to make measurements of heart rate and of the higher and lower frequency components of its variability. beta-sympathetic blockade alone had no effect on variability. Parasympathetic blockade alone reduced it, but did not abolish it. Even after double blockade, some 35% to 40% of variability remained, thus implying that there is a major nonneural component to heart rate variability. There was evidence that the fetus, unlike the adult, is subject to a resting cardioacceleratory drive.

Animals↗
PubMed1983

Quantitative analysis of albuterol in human plasma by combined gas chromatography chemical ionization mass spectrometry.

A highly sensitive and specific quantitative assay for the determination of albuterol in human plasma, based on selected ion monitoring gas chromatography chemical ionization mass spectrometry, has been developed. The [MH]+ ions from the tri-TMS derivatives of albuterol (m/z 456) and the internal standard (2H3)albuterol (m/z 459), were assayed simultaneously by selected ion monitoring. The lower limit of quantitation is 0.25 ng ml-1 and the average assay precision (CV) for albuterol concentrations ranging from 0.25 ng ml-1 to 25 ng ml-1 is approximately 4%. This method is currently being employed for the routine quantitation of albuterol in plasma following the administration of doses therapeutically effective to man.

Albuterol↗
PubMed1983

Changes in the diurnal rhythms of plasma cortisol in women during the third trimester of pregnancy.

We have examined whether there are changes in the day-night variation in plasma cortisol in normal women during the third trimester of pregnancy. Maximum cortisol values at 07.30-10.30 h were similar at 30-31, 34-35 and 38-39 weeks of pregnancy. The daily increment in plasma cortisol (fold change) was greater, and the trough values lower at 30-31 than at 38-39 weeks. The time taken for plasma cortisol to fall to 50% of the morning maximum values was longer at 38-39 weeks than at 30-31 weeks of pregnancy. These changes in cortisol rhythms may have implications with respect to alterations in circadian patterns of maternal steroid concentrations as well as fetal biophysical functions.

Circadian Rhythm↗
PubMed1983

Relation between diurnal changes in peripheral plasma progesterone, cortisol, and estriol in normal women at 30-31, 34-35, and 38-39 weeks of gestation.

To determine the relation of diurnal changes in plasma progesterone to those in cortisol and estriol we measured the concentrations of progesterone, cortisol and estriol in samples of plasma taken at 30- to 60-min intervals throughout 24 h from women at 30-31, 34-35, and 38-39 weeks of gestation. Plasma progesterone showed a significant diurnal rhythm at 30-31 and at 34-35 weeks of pregnancy, with troughs at 04.30-10.00 h. Major peaks occurred between 15.30 and 02.30 h. There was no diurnal rhythm in progesterone at 38-39 weeks. Plasma progesterone showed a significant negative correlation with plasma cortisol at 30-31 and 34-35 but not at 38-39 weeks. Plasma progesterone showed a significant positive correlation with estriol at 34-35 and at 38-39 weeks. We suggest that daily fluctuations in plasma progesterone may be related to the concentration of plasma cortisol, either directly by competition for binding sites on transcortin, or indirectly after modulation of fetal pituitary-adrenal function by maternally derived glucocorticoid.

Circadian Rhythm↗
PubMed1982

Activation of adrenal function in fetal sheep by the infusion of adrenocorticotropin to the fetus in utero.

We determined whether ACTH1-24, infused into fetal lambs at a rate that is known to cause premature labor, elicits changes in the responsiveness of the fetal adrenal glands, and alters the pattern of corticosteroid output. Plasma cortisol (F), corticosterone (B) and progesterone (P4) were measured during 72 h of infusion of saline or ACTH (10 micrograms/h) beginning on Day 127 of pregnancy. Adrenals were then dispersed into isolated cells, and the output of F, B and P4 after exogenous ACTH determined in vitro. Plasma concentrations of F and B were higher in ACTH-treated fetuses. The increment in F (5-to 7-fold) was greater than that in B (2-fold) such that the F:B ratio in plasma of ACTH-treated fetuses on Days 2 and 3 of infusion was 2.5 times higher than in controls. After 72 h of infusion, the adrenal weights in ACTH-treated fetuses (741 +/- 38 mg, +/- SEM; n = 4) were greater than in the control animals (349 +/- 11 mg). There was a significant effect of ACTH pretreatment in vivo on F output by isolated adrenal cells in vitro. Mean increments in F output after addition of ACTH1-24 (5000 pg/ml) in vitro rose from 368 +/- 235 pg/50,000 cells in controls, to 64,639 +/- 19,875 pg/50,000 cells after ACTH in vivo. There was no significant effect of ACTH in vivo on B output in vitro; the ratio of F:B output, either in the absence or presence of ACTH in vitro, was significantly higher in cells from ACTH-pretreated fetuses. There was a significant effect of in vivo ACTH on in vitro P4 output. After ACTH treatment in vivo there was an increase in the vitro output ratio of F:P4, but no change in the output ratio of B:P4. We conclude that ACTH treatment of the fetal lamb in vivo results in activation of fetal adrenal function, increased fetal adrenal responsiveness to ACTH, and directed corticosteroid biosynthesis towards cortisol. Our results are consistent with an increase in fetal adrenal 17 alpha-hydroxylase activity after ACTH treatment.

Adrenal Glands↗