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S A Ward

Publications and source records attributed to S A Ward.

At least 163 records · Page 9Linked to original sources
PubMed1988

Carbaryl metabolism is inhibited by cimetidine in the isolated perfused rat liver and in man.

The potential for cimetidine to alter the metabolism of carbaryl has been investigated in the isolated perfused rat liver and in man. In the isolated perfused rat liver, carbaryl was removed by a high intrinsic clearance process, which was inhibited in a dose dependent fashion by cimetidine in the concentration range of 60-240 micrograms/ml. The pharmacokinetic profile in one subject for orally administered carbaryl was altered following administration of cimetidine (200 mg every eight hours for three days). The peak carbaryl level occurred 25 minutes later and was increased by twofold, due to a 46% reduction in apparent oral clearance. The observations indicate that cimetidine can inhibit the metabolism of carbaryl in both rat and man. These data suggest that administration of cimetidine to individuals exposed to carbaryl could result in enhanced toxicity.

Adult↗
PubMed1988

Control of blood-gas and acid-base status during isometric exercise in humans.

1. At a given level of pulmonary gas exchange, ventilation (VE) is appreciably higher during isometric exercise than during isotonic exercise. It is presently not clear whether the resultant hypocapnia represents a compensatory hyperventilation for an arterial metabolic acidaemia or whether it might reflect a primary respiratory alkalaemia. 2. To resolve this issue, five subjects performed isometric leg exercise designed to induce exhaustion in ca. 5 min and, on a separate occasion, ca. 8 min. VE, CO2 output (VCO2), O2 uptake (VO2) and end-tidal gas tensions (PET,CO2, PET,O2) were measured breath-by-breath during exercise and recovery; arterialized venous blood (drawn from the dorsum of the heated hand) was sampled frequently and analysed for PCO2, PO2, pH, bicarbonate and lactate. These response profiles were compared with those resulting from exhausting bouts of isotonic leg exercise (cycle ergometry) of similar duration. 3. The isotonic exercise induced a metabolic (lactic) acidaemia with partial respiratory compensation. In contrast, isometric exercise consistently resulted in a respiratory alkalaemia, with little or no increase of blood [lactate]. At the end of the isometric exercise, VE fell abruptly and then rose again after a short interval (20 s, on average). This secondary stimulation presumably reflected the acid-base consequences of the increased blood [lactate] (3-5 mM, on average) which occurred in the recovery phase. 4. We therefore conclude that a primary respiratory alkalaemia occurs during isometric exercise, and that this results from ventilatory stimulation at a time when the 'exercise' metabolites are trapped within the contracting muscles as a consequence of impeded blood flow. The initial rapid reduction of ventilation which occurred at the cessation of the isometric exercise is consistent with a washing-out of 'hyperpnoea-inducing' metabolites from the muscles. Allowing for transit to the central circulation, the reduced ventilation is subsequently supplemented by a powerful humoral drive to breathe which results in a further hyperpnoea and secondary hypocapnia. Because of its latency, we hypothesize that this secondary hypocapnia is of peripheral chemoreceptor origin. 5. The ventilatory response profile for isometric exercise, and the subsequent recovery phase, supports the contention that both the exercising muscles and the peripheral chemoreceptors can be important sites for inducing hyperpnoea in humans.

Acid-Base Equilibrium↗
PubMed1987

The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite.

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.

Animals↗
PubMed1987

S-mephenytoin 4-hydroxylase is inherited as an autosomal-recessive trait in Japanese families.

The 4-hydroxylation of S-mephenytoin exhibits polymorphism in both whites and Japanese such that the populations can be divided into extensive and poor metabolizers. To determine whether genetic constitution is a primary determinant in the expression of such metabolism, four extended Japanese families containing 13 sets of parent/offspring relationships were phenotyped for their mephenytoin 4-hydroxylation activity using the 8-hour urinary ratio of unchanged R- and S-mephenytoin as the trait measurement. The incidence of the poor metabolizer phenotype in these families was 2.2 times greater than that in an unrelated Japanese population. In three families in which both parents were poor metabolizers of mephenytoin, all six children also exhibited the poor metabolizer trait. The phenotype distribution for each family studied was consistent with the hypothesis that mephenytoin 4-hydroxylation activity is under diallelic, monogenic control, with the poor metabolizer phenotype being the autosomal recessive homozygous genotype and the extensive metabolizer phenotype including both the autosomal dominant and heterozygous genotypes.

Alleles↗
PubMed1987

Influence of inspiratory assistance on ventilatory control during moderate exercise.

In five healthy subjects, we studied the effects of controlled mechanical unloading of the respiratory system on ventilatory control during moderate exercise, utilizing a modified positive-pressure ventilator (IEEE Trans. Biomed. Eng. BME-33: 361-365, 1986). We were especially interested in whether isocapnia was maintained when a portion of the normal ventilatory response to constant-load cycling was subserved by the ventilator. The mechanical unloading was achieved by "assisting" airflow throughout inspiration in a constant proportion to instantaneous flow. Two modest degrees of assistance (A1 = 1.5 and A2 = 3.0 cmH2O X l-1 X s) were imposed. The assistance caused minute ventilation (VE) to increase immediately (inspiratory time shortening and tidal volume rising) and end-tidal PCO2 (PETCO2) to fall. Some 10-15 s later, inspiratory occlusion pressure (P100) decreased, and in the new steady-state VE and PETCO2 were virtually restored to their control exercise levels. The modest residual hyperventilation [delta PETCO2 = -0.9 Torr (A1) and -1.6 Torr (A2)], which was not significant statistically, contrasted markedly with the much larger increase predicted for VE had there been no compensatory reduction in ventilatory drive (as evidenced by the fall in P100). Consistent with earlier studies utilizing resistive loading (J. Appl. Physiol. 35: 361-366, 1973 and Acta Physiol. Scand. 120: 557-565, 1984), these observations suggest that ventilatory drive during moderate exercise is controlled to compensate for modest changes in respiratory-mechanical load, so that VE is preserved at a level appropriate to metabolic rate or nearly so.

Adult↗
PubMed1987

Effect of interbreath fluctuations on characterizing exercise gas exchange kinetics.

Breathing has inherent irregularities that produce breath-to-breath fluctuations ("noise") in pulmonary gas exchange. These impair the precision of characterizing nonsteady-state gas exchange kinetics during exercise. We quantified the effects of this noise on the confidence of estimating kinetic parameters of the underlying physiological responses and hence of model discrimination. Five subjects each performed eight transitions from 0 to 100 W on a cycle ergometer. Ventilation, CO2 output, and O2 uptake were computed breath by breath. The eight responses were interpolated uniformly, time aligned, and averaged for each subject; and the kinetic parameters of a first-order model (i.e., the time constant and time delay) were then estimated using three methods: linear least squares, nonlinear least squares, and maximum likelihood. The breath-by-breath noise approximated an uncorrelated Gaussian stochastic process, with a standard deviation that was largely independent of metabolic rate. An expression has therefore been derived for the number of square-wave repetitions required for a specified parameter confidence using methods b and c; method a being less appropriate for parameter estimation of noisy gas exchange kinetics.

Adult↗
PubMed1987

Chemoreflex modulation of ventilatory dynamics during exercise in humans.

The precision of arterial blood gas homeostasis following a change of work rate depends on the response kinetics of ventilation. The carotid bodies (CB's) have been proposed as modulators of these kinetics. The present investigation was undertaken to determine whether the effect is specific to CB activation or whether other factors that augment the exercise hyperpnea would produce a similar response. We therefore established the effects of increased CB and central (C) chemoreflex activation on the inspired ventilatory (VI) dynamics for moderate-intensity cycling. Work tests were separately performed with air, 12% O2 to increase CB activity, 100% O2 to "abolish" CB activity, and CO2 in O2 to increase C activity. The time constant of the VI response was substantially shortened by hypoxia (40 s) compared with air breathing (58 s) and increased by 100% O2 (92 s) and, even more so, by CO2 in O2 (101 s). We conclude that increased carotid (but not central) chemoreflex responsiveness speeds the kinetics of the exercise hyperpnea by a process that is not merely the consequence of increased ventilatory drive.

Adult↗
PubMed1986

Naloxone and the ventilatory response to exercise in man.

Endogenous opiate peptides are known to exert a depressant action on ventilation (VE), and their plasma levels have been shown to be elevated during a variety of exercise protocols. We investigated whether they might modulate the control of the hyperpnea of short-term constant-load (CLE) and incremental (IE) cycle-ergometer exercise. Four healthy subjects performed CLE tests at ca. 80% of the anaerobic threshold (theta an) for 5 min following a period of unloaded pedaling, and IE tests (10 or 20 W min-1) to the limit of tolerance. Normal saline (3 ml) or the opiate antagonist naloxone (1.2 mg in 3 ml) were administered intravenously prior to each test. Naloxone elicited no discernible effect on VE, alveolar gas tensions, or heart rate throughout the entire range of work rates; neither were theta an nor the maximum work rate affected. It is concluded that, for short-term exercise ranging in intensity from moderate to severe, the role played by endogenous opiate peptides in the control of the exercise hyperpnea appears to be negligible in man.

Adult↗
PubMed1985

The disposition of pyrimethamine in the isolated perfused rat liver.

We have investigated the disposition of pyrimethamine base in the isolated perfused rat liver (IPRL) preparation after the administration of pyrimethamine (0.5 mg, 5 microCi). In the first half hour of the study, pyrimethamine underwent marked hepatic uptake, thereafter perfusate plasma drug levels declined monoexponentially with a half life (t 1/2) of 3.0 +/- 1.0 hr. Area under the perfusate plasma concentration/time curve (AUC)0----infinity was 6.9 +/- 1.9 microgram/hr/ml. Pyrimethamine was found to be a low clearance compound (78.4 +/- 25.3 ml/hr identical to 8.6% of liver perfusate flow) with a large volume of distribution (267.5 +/- 55.3 ml) in the IPRL. The combined AUCS(0----5hr) for pyrimethamine (AUC 4.8 +/- 0.5 microgram/hr/ml) and pyrimethamine 3-N-oxide (AUC0----5hr 0.9 +/- 0.6 microgram/hr/ml) accounted for 57% of the total AUC0----5hr of [14C] radioactivity (10.0 +/- 2.6 micrograms/hr/ml). This indicates the presence of metabolites of pyrimethamine as yet unidentified in the perfusate. Biliary excretion of [14C] during the course of the IPRL preparations was extensive (29.0 +/- 10.3%) though only a small proportion was due to pyrimethamine and the 3-N-oxide metabolite. The majority of radioactivity in the bile was attributable to highly polar, but unidentified metabolites of pyrimethamine. At the conclusion of each experiment (5 hr), a significant proportion of [14C] radioactivity was recovered from the livers (22.9 +/- 5.3%). Subsequent HPLC analysis of the liver tissue indicated this to be unchanged pyrimethamine, with trace levels of the 3-N-oxide metabolite. Sub-cellular fractionation of the homogenized livers revealed the most pronounced localisation of pyrimethamine to be in the lipid rich 10,000 g pellet (13.0 +/- 2.6%), the remainder being distributed equally between the 105,000 g pellet and supernatant. Neither pyrimethamine, [14C] radioactivity, nor pyrimethamine 3-N-oxide were extensively taken up by red cells throughout the study. Therefore, the large volume of distribution (267.5 +/- 55.3 ml) underlines the extent of pyrimethamine localisation in the liver.

Animals↗
PubMed1985

The effects of primaquine stereoisomers and metabolites on drug metabolism in the isolated perfused rat liver and in vitro rat liver microsomes.

The effect of the antimalarial drug primaquine, its stereoisomers and its proposed metabolites, on the metabolism of substrates for mixed function oxidase, has been studied in isolated perfused rat livers (IPRL) and/or in vitro microsomal suspension. Following acute administration to an IPRL preparation, racemic primaquine produced a dose related reduction in the hepatic clearance of antipyrine which at the highest dose of primaquine (5.0 mg) represented a decrease to 46% of control values. Antipyrine clearance was reduced to a comparable extent by the (+) and (-) isomers and the racemic mixture (each at a dose of 2.5 mg) with mean reductions of 45, 49 and 47%, respectively. These changes in clearance were reflected by significant increases in half-life relative to control. The apparent volume of distribution of antipyrine was unchanged in all experiments. Racemic primaquine and its (+) and (-) isomers were equipotent in inhibiting aminopyrine N-demethylase activity, producing reductions of 56, 59 and 55%, respectively, relative to control values. These three compounds also produced corresponding reductions of 73, 58 and 73% in ethoxyresorufin O-deethylase activity. The N-acetyl and 5-hydroxy derivative of primaquine produced inhibitory effects comparable to that seen for the parent drug. In contrast the carboxylic acid metabolite of primaquine, 6-desmethylprimaquine and 5-hydroxy-6-desmethyl primaquine did not influence aminopyrine N-demethylase activity. These results indicate that the propensity to inhibit drug metabolism by these primaquine related substances, is influenced by functional group substitution rather than the optical activity of the parent drug.

Animals↗