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Biomedical subjects

J A Clements

Publications and source records attributed to J A Clements.

At least 127 records · Page 7Linked to original sources
PubMed1981

Precursor-product relationship between rabbit type II cell lamellar bodies and alveolar surface-active material. Surfactant turnover time.

To estimate the turnover time of alveolar surfactant in New Zealand white rabbits, we injected [9,10-(3)H] palmitic acid and [2-(14)C] glycerol intravenously. From 1-48 h after injection, wer killed the animals, lavaged the lungs for alveolar surfactant with saline, and isolated the lamellar bodies by homogenization and sucrose density gradient centrifugation. Lamellar bodies and alveola surfactant had comparable phospholipid composition and surface activity. Lamellar bodies contained little DNA, no mitochondrial enzyme activity and less than 5% contaminating phospholipids from microsomal and Golgi-enriched fractions. We measured radioactivity of phosphatidylcholine, saturated phosphatidylcholine and phosphatidylglycerol for each isotope in lamellar bodies and surfactant at each time point. The plot of the integral with respect to time of the difference between lamellar body and surfactant specific activity against surfactant specific activity has a slope determined by the turnover time, and a shape which tests the precision of the precursor-product relationship. This analysis does not assume a pulse label and allows for possible recycling of tracer from surfactant to lamellar bodies. We obtained turnover times of 4-11 h. We detected an imprecise precursor-product relationship between lamellar bodies and alveolar surfactant, which is not due to experimental variability or to contamination of lamellar bodies by other subcellular fractions but may reflect imperfect mixing within surfactant compartments.

Animals↗
PubMed1981

Acute effects of pulmonary artery occlusion on the pool of alveolar surfactant.

Electron microscopic evidence has shown that the occlusion of one pulmonary artery acutely decreases the content of lamellar inclusion bodies in alveolar type II cells. We studied the effect of unilateral pulmonary artery occlusion (UPAO) on the estimated alveolar pool of saturated phosphatidylcholine (SPC). Under pentobarbital anesthesia 13 rabbits, spontaneously breathing, underwent UPAO for 1--7 hours by balloon catheter. Eight rabbits with balloon deflated in the pulmonary trunk served as controls. After sacrifice the lungs were excised and alveolar SPC was harvested by lavage. After UPAO the alveolar pool of SPC was significantly higher in the occluded lungs than in the unoccluded ones. The average difference was 33.7% after 1 hour and 14.5% after 2 hours. After 4 and 7 hours of occlusion the alveolar pools of SPC in occluded and unoccluded lungs were not significantly different. We suggest that the temporarily larger pool size in the occluded lungs was due to an increase in surfactant secretion, although we cannot rule out entirely a decrease in the rate of clearance.

Animals↗
PubMed1981

Acetaminophen absorption and metabolism in celiac disease and Crohn's disease.

To investigate further the conflicting results in reports of drug absorption in patients with small intestinal mucosal disease, gastric emptying and the disposition of acetaminophen were assessed simultaneously in 41 subjects (13 controls, 12 patients with Crohn's disease, and 16 with celiac disease). Acetaminophen absorption as judged by plasma concentrations and gastric emptying were slower in patients with celiac disease and Crohn's disease. Total drug absorption as indicated by urinary recovery did not differ, but plasma acetaminophen half-life was shorter and glucuronide conjugation was enhanced in the patients with Crohn's disease. Contrary to expectation, the mean rate constant for acetaminophen absorption from the small intestine was not decreased in Crohn's disease and celiac disease. The abnormally slow acetaminophen absorption in the patients with Crohn's or celiac disease could be explained by slower gastric emptying of the drug solution.

Acetaminophen↗
PubMed1981

Alveolar subphase pH in the lungs of anesthetized rabbits.

We measured the pH of the alveolar subphase fluid by puncturing the most superficial alveoli of the exposed lungs of anesthetized rabbits with H+-selective and nonselective KCl microelectrodes. In these experiments, we bathed the lung surface with paraffin oil or buffered Ringer's solutions that had a CO2 tension of 40 Torr (1 Torr = 133.3 Pa) and found an alveolar pH of 6.92 +/- 0.01 (mean +/- sEM). When the pH of the surface buffer was below 6.7 or above 7.5, alveolar pH varied with surface buffer pH. With the nonselective electrode, we did not find a significant electrical potential difference between the alveolar fluid and the pleural surface. These results are consistent with active transport of H+ (or HCO3(-) across alveolar epithelium.

Anesthesia, General↗
PubMed1981

Pharmacokinetics and analgesic effect of ketamine in man.

The pharmacokinetics and analgesic effect of i.v. ketamine in doses of 125 microgram kg-1 and 250 microgram kg-1 were determined in five healthy volunteers. Analgesia was measured with the submaximal effort tourniquet test. Both doses of ketamine prolonged the period of pain-free ischaemic exercise while the plasma ketamine concentration was greater than 100 ng ml-1. Ketamine was distributed rapidly (T 1/2 alpha = 17 min). The elimination half-life was 186 min.

Adult↗
PubMed1981

Lack of effect of ketamine analgesia on gastric emptying in man.

The effect of ketamine analgesia on gastric emptying was assessed in five healthy volunteers. Gastric emptying, estimated indirectly by the absorption of orally administered paracetamol, was not significantly delayed following administration of i.m. ketamine when compared with placebo.

Acetaminophen↗
PubMed1981

Pharmacokinetics and analgesic effects of i.m. and oral ketamine.

The pharmacokinetics and analgesic effects of i.m. and oral ketamine in a dose of 0.5 mg kg-1 were determined in six healthy volunteers. Analgesia was measured by the submaximal effort tourniquet test. Following both routes of administration, ketamine prolonged the period of pain-free ischaemic exercise. Pain thresholds were increased at 15 min and 30 min after i.m. injection and at 30 min after oral ketamine. The plasma ketamine concentration associated with analgesia was 150 ng ml-1 following the i.m. dose, but only 40 ng ml-1 after the oral dose. Oral administration was, however, associated with much greater concentrations of the metabolite norketamine, which may have contributed to the analgesic effect.

Administration, Oral↗
PubMed1981

Prepartum maturation of the lung in fetal sheep: relation to cortisol.

We studied the relationship of certain fetal and maternal hormones to indicators of lung maturation in 12 fetal lambs delivered at gestational ages (GA) of 123-149 days. Maternal estrogen, maternal progesterone, and fetal prolactin did not correlate with GA or the indicators of fetal lung maturation. Fetal cortisol (range 4-165 ng X ml-1) increased with advancing GA (r = 0.747, P less than 0.01). All of the following showed a wide range of late gestation and showed a significant positive correlation with fetal cortisol: lung volumes at 40 cmH2O and 10 cmH2O on the deflation during air pressure-volume studies; saturated phosphatidylcholine (SPC) in lung tissue and in lavage fluid expressed both as mg X g-1 of wet lung and as percent of total phospholipids (%PL); total SPC (lung tissue plus lavage fluid): and SPC in lavage fluid as percent of total SPC. Lung DNA correlated inversely with GA and cortisol. All variables (except lavage fluid SPC as %PL) correlated more closely with cortisol than GA. Morphological development of lung was also related more closely to cortisol than GA. These results suggest that functional lung maturity is attained late in gestation and that endogenous cortisol is an important physiological factor in control of fetal lung maturation.

Animals↗
PubMed1981

Surfactant release in excised rat lung is stimulated by air inflation.

Because increased ventilation has been associated with an acceleration of lung surfactant turnover, we investigated the effect of fluid and air inflations on the release of surfactant into the air spaces. We found that excised rat lungs, initially lavaged three times at 23 degrees C, release approximately 40-90 micrograms of phospholipid/g wet lung wt into the air spaces in response to a further infusion of fluid into the airway equal to total lung capacity. A single air inflation to the same volume, followed by degassing and lavage, contributes approximately 230 micrograms to the yield of phospholipid. We estimated basal release of phospholipid as 112 micrograms wet lung wt-1 . h-1, which is far less than the 2,050 micrograms -1 . h-1 retrieved during a series of air and fluid inflations. The above findings are consistent with the hypothesis that air inflation to total lung capacity is a major physiological stimulus to release of lung surfactant into the alveolar space. The lung lavage process itself also causes the release of surfactant.

Air↗
PubMed1981

Inhibitors of prostaglandin synthesis, tracheal fluid, and surfactant in fetal lambs.

To study their effects on tracheal fluid (TF) production and surfactant flux, we gave 12-h infusions of prostaglandin synthetase inhibitors (PGSI) on 16 occasions to 10 fetal lambs at gestational ages (GA) of 125--141 days. Results were similar with both sodium meclofenamate (13.9 +/- 3.4 mg.kg-1, 12 studies) and indomethacin (33.6 +/- 8.0 mg.kg-1, 4 studies). All studies were done at least 6 days after surgery and 4 days before spontaneous birth. During infusions of PGSI, there were no changes in fetal arterial blood pressure, pH, PaO2, PaCO2, TF production or its concentration of sodium, potassium, and chloride; calcium concentration in TF increased slightly. We expressed tracheal surfactant flux as micrograms.kg-1.h-1 of saturated phosphatidylcholine (SPC). If control SPC flux was less than 5 micrograms.kg-1.h-1 (10 studies at GA of 125--141 days), it did not change during infusion of PGSI; however, if control was greater than 5 micrograms.kg-1.h-1 (6 studies at GA 132--140 days), SPC flux decreased during the infusions in all studies. The results suggest that prostaglandins do not strongly influence TF production up to 4 days before birth and that prostaglandins are involved in the increased flux of surfactant which occurs in late gestation.

Animals↗
PubMed1981

Naloxone, adrenalectomy, and steroid replacement: evidence against a role for circulating beta-endorphin in food intake.

Naloxone has a dose-dependent, significant anorectic effect when administered to normal rats, consistent with an antagonism of central or peripheral enkephalinergic or endorphinergic mechanisms. Mean levels of circulating immunoreactive beta-endorphin were similar in intact rats (0.5 ng/ml) and dexamethasone-treated adrenalectomized rats (0.5 ng/ml). In contrast, plasma levels were high in adrenalectomized rats with no replacement steroid (1.3 ng/ml) and in adrenalectomized rats given the mineralocorticoid deoxycorticosterone (0.9 ng/ml). In sharp distinction to the clear changes in circulating immunoreactive beta-endorphin produced by adrenalectomy and selective steroid replacement, no differences were seen in baseline food intake or anorectic response to naloxone. We conclude that a physiological role for circulating beta-endorphin in the regulation of food intake appears unlikely.

Adrenal Cortex Hormones↗
PubMed1981

Pulmonary maturation in the hypophysectomised ovine fetus. Differential responses to adrenocorticotrophin and cortisol.

Pulmonary maturation in six ovine fetuses hypophysectomised by a cryosurgical method at 0.7-0.8 of pregnancy and delivered by hysterotomy at 152.2 +/- 2.9 (SD) days was compared with that in seven control fetuses delivered at 144.5 +/- 3.5 days. Both the wet and the dry weight of the lungs was less in the hypophysectomised fetuses but total DNA did not differ. Lung volumes at 40 cm of H2O and at 5 cm of H2O on deflation in hypophysectomised fetuses were less than one-third that of controls. Saturated phosphatidylcholine, as an estimate of surfactant, was lower in both lung tissue and lavage fluid. A further group of hypophysectomised fetuses was infused intravenously either with cortisol at 1 mg/h for 72 h (n = 6), or with ACTH1-24 at 5 microgram/h for 84 h (n = 6) before delivery at 155.0 +/- 2.1 days and 154.2 +/- 3.9 days respectively. None of the indices of pulmonary maturation in the cortisol-treated fetuses differed from those in untreated hypophysectomised fetuses whereas values for lung volumes at 40 and 5 cm of H2O in ACTH-treated fetuses were more than twice those of untreated hypophysectomised fetuses and did not differ significantly from controls. In addition, the amount of saturated phosphatidylcholine in lavage fluid was greater in ACTH-treated fetuses (0.13 +/- 0.10 mg/g) than in untreated hypophysectomised fetuses (0.04 +/- 0.48 mg/g). Lung volume at 40 cm of H2O in four fetuses that were thyroidectomised at the time of hypophysectomy responded to ACTH as in hypophysectomised fetuses with intact thyroids but other indices were unaffected. We conclude that hypophysectomy retards pulmonary maturation in fetal sheep. Since ACTH restores distensibility and increases alveolar surfactant in the absence of other pituitary hormones it is likely that ACTH has a major role in lung maturation. The lack of response to cortisol suggests that the effect of ACTH is not mediated only by circulating cortisol.

Adrenocorticotropic Hormone↗
PubMed1980

Paracetamol pharmacokinetics in thyroid disease.

The absorption, distribution and elimination of oral paracetamol have been studied in patients before and after treatment of thyrotoxicosis (n = 7) and hypothyroidism (n = 4). Absorption was faster in patients with untreated thyrotoxicosis than when subsequently euthyroid. The peak paracetamol concentration, however, was lower in thyrotoxic patients due to an apparent increase in the total body clearance and a shorter plasma half-life. Both absorption and elimination rates were reduced in hypothyroid patients, but were not significantly different from the euthyroid results. When estimated using a two compartment model the total volume of distribution and the hybrid distribution rate constants were unrelated to thyroid status, but the apparent volume of the central compartment was significantly greater in the thyrotoxic group. These changes in drug disposition may contribute to differences in drug response seen in thyroid disease.

Acetaminophen↗
PubMed1980

Ventilation enhances pulmonary alveolar clearance of radioactive dipalmitoyl phosphatidylcholine in liposomes.

We examined the clearance from lungs of dipalmitoyl phosphatidylcholine (DPPC), the main component of pulmonary surfactant, after instillation in the form of radioactively labeled liposomes (small unilamellar vesicles) in anesthetized rabbits breathing spontaneously. There were 2 protocols: normal ventilation in control animals, and ventilation increased 100% by augmentation of the dead space in experimental animals. Liposomes containing 20% phosphatidylglycerol were also tested in animals breathing normally. We examined the stereospecificity of clearance with levo 14C-DPPC and dextro 3H-DPPC isomers. We measured phospholipid content and plotted curves of radioactivity versus time (0 to 5 h) for alveolar material obtained by lavage and for the whole lung. In the control animals (n = 15), alveolar clearance of 14C-L-DPPC was 7.8%/h, and with increased ventilation (n =13) it was 13.3%/h (p less than 0.025). With phosphatidylglycerol (n = 9) alveolar clearance during normal breathing was 13.9%/h(p less than 0.001). Alveolar clearance rates of 14C-L-DPPC and 3H-D-DPPC were not significantly different. Clearance from the whole lung did not differ between control and experimental animals or between isomers, and it averaged 3.1%/h.

Animals↗
PubMed1979

Antenatal prediction of graduated risk of hyaline membrane disease by amniotic fluid foam test for surfactant.

We measured amniotic fluid surfactant by the semiquantitative foam stability test within 24 hours before delivery of 410 infants, 64 of whom developed HMD diagnosed by standard criteria. When surfactant titers were ranked in eight categories, they predicted graded risks of HMD. On this basis we defined five "risk groups" with significantly different incidences of HMD (I = 0.5%; II = 10%; III = 25%; IV = 41%; V = 79%). Infants in Groups I and II were heavier and more mature than those in Groups III to V. However, among infants of equivalent GA or birth weight, the incidence of HMD still correlated significantly with the foam test results. Within each risk group the incidence of HMD was equal among infants delivered by vagina and by cesarean section, slightly greater among males than females, and inversely proportional to GA. In Group V the incidence of HMD was 100% among infants at less than 33 weeks' GA. We used this relationship to devise a system that improved prediction of HMD by combining the foam test results with GA.

Amniocentesis↗
PubMed1979

The disposition of intravenous doxapram in man.

The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg . kg-1) and by intravenous infusion (6.5 mg . kg-1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances 5.9 and 5.6 ml . min-1 . kg-1) following i.v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 microgram . ml-1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 microgram . ml-1 from 15--25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.

Adult↗