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Biomedical subjects

S A Ward

Publications and source records attributed to S A Ward.

At least 145 records · Page 8Linked to original sources
PubMed1990

The effects of training on the metabolic and respiratory profile of high-intensity cycle ergometer exercise.

The tolerable work duration (t) for high-intensity cycling is well described as a hyperbolic function of power (W): W = (W'.t-1) + Wa, where Wa is the upper limit for sustainable power (lying between maximum W and the threshold for sustained blood [lactate] increase, theta lac), and W' is a constant which defines the amount of work which can be performed greater than Wa. As training increases the tolerable duration of high-intensity cycling, we explored whether this reflected an alteration of Wa, W' or both. Before and after a 7-week regimen of intense interval cycle-training by healthy males, we estimated ( ) theta lac and determined maximum O2 uptake (mu VO2); Wa; W'; and the temporal profiles of pulmonary gas exchange, blood gas, acid-base and metabolic response to constant-load cycling at and above Wa. Although training increased theta lac (24%), mu VO2 (15%) and Wa (15%), W' was unaffected. For exercise at Wa, a steady state was attained for VO2, [lactate] and pH both pre- and post-training, despite blood [norepinephrine] and [epinephrine] ([NE], [E]) and rectal temperature continuing to rise. For exercise greater than Wa, there was a progressive increase in VO2 (resulting in mu VO2 at fatigue), [lactate], [NE], [E] and rectal temperature, and a progressive decrease for pH. We conclude that the increased endurance capacity for high-intensity exercise following training reflects an increased W asymptote of the W-t relationship with no effect on its curvature; consequently, there is no appreciable change in the amount of work which can be performed above Wa.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Cytochrome P-450 activity in malarial parasites and its possible relationship to chloroquine resistance.

Cytochrome P-450-dependent enzyme activities have been determined in malarial parasites. Both Plasmodium berghei and Plasmodium falciparum parasites exhibited activity and these activities were greater in chloroquine resistant parasites than in sensitive strains. This enzyme activity could be induced by phenobarbitone and inhibited by specific inhibitors of the cytochrome P-450 family of enzymes. The significance of these observations in parasite drug resistance is discussed.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

A review of prehospital care litigation in a large metropolitan EMS system.

A retrospective review of all claims brought against a large, metropolitan emergency medical services (EMS) system related to paramedic-patient encounters during the 12-year period from 1976 through 1987 was undertaken to review and describe the incidence and types of malpractice claims. During this period, EMS units responded to approximately 2 million calls and transported more than 1 million patients. Sixty claims occurred during the incidence study period (1976 through 1985). The overall litigation rate was one lawsuit per 27,371 paramedic-patient encounters and one lawsuit per 17,995 patient transports. While the total number of runs and transports did not change significantly during the study period, the data indicate a trend of increasing claims filed against the prehospital care provider. To date, 26 cases (38%) have been settled with the majority involving either no monetary awards or nominal out-of-court settlements.

Adolescent↗
PubMed1990

In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme.

The metabolic activation of the arylbiguanide antimalarials proguanil (PG) and chlorproguanil (CPG) has been investigated in liver microsomes from three human livers. All three microsomal preparations activated the biguanides. The kinetic parameters for PG metabolism to cycloguanil (CG) were Km 21.8, 29.6 and 26.4 microM and Vmax 1.5, 5.9, and 8.2 pmol min-1 mg-1. The values for CPG conversion to chlorcycloguanil (CCG) were Km 12.9, 19.7 and 26.1 microM and Vmax 5.7, 4.8 and 3.6 pmol min-1 mg-1. The metabolic activation of both biguanides was competitively inhibited by the anticonvulsant mephenytoin. Sparteine and tolbutamide had no effect on biguanide metabolism. These data suggest an involvement of the mephenytoin hydroxylase enzyme, which exhibits a genetic polymorphism in man, in the metabolic activation of the biguanide antimalarials.

Antimalarials↗
PubMed1990

The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min-1) compared with the rest of the population (858 +/- 482 ml min-1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml-1) compared with the rest of the population (141 +/- 45.2 ng ml-1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.

Biotransformation↗
PubMed1990

The effect of malaria infection on the disposition of quinine and quinidine in the rat isolated perfused liver preparation.

The effect of malaria on the disposition of quinine and quinidine was studied in livers isolated from young rats infected with merozoites of Plasmodium berghei, a rodent malaria model, and non-infected controls. Following bolus administration of quinine (1 mg) or quinidine (1 mg) to the 100 mL recycling perfusion circuit, perfusate was sampled (0-4 h) and plasma assayed for quinine and quinidine by HPLC. Higher quinine (AUC:6470 +/- 1101 vs 3822 +/- 347 ng h mL-1, P less than 0.001) and quinidine (AUC: 6642 +/- 1304 vs 4808 +/- 872 ng h mL-1, P less than 0.05) concentrations were observed during malaria infection (MI). MI resulted in decreased quinine clearance (CL) (0.33 +/- 0.08 vs 0.64 +/- 0.09 mL min-1 g-1, P less than 0.001) and volume of distribution (Vd) (53.0 +/- 13.3 vs 81.2 +/- 23.7 mL g-1, P less than 0.05) but no significant change in elimination half-life (t1/2) (1.93 +/- 0.6 vs 1.37 +/- 0.25 h, P greater than 0.05). With quinidine, however, MI resulted in decreased CL (0.38 +/- 0.16 vs 0.64 +/- 0.09, P less than 0.05) with no change in Vd and a significant increase in t1/2 (1.62 +/- 0.42 vs 0.88 +/- 0.22, P less than 0.01). In summary, the hepatic disposition of quinine and quinidine is altered in the malaria-infected rat.

Animals↗
PubMed1990

Ventilatory requirements during general anesthesia: the determinants of an "appropriate" response.

This review addresses the ventilatory requirements for regulating arterial PCO2 in the pre-, intra-, and postoperative phases of general anesthesia with respect both to the spontaneously breathing patient and the ventilated patient. These requirements are discussed in the context of (i) the rate of pulmonary CO2 elimination (VCO2) which, in the steady state, equals the rate of metabolic CO2 production and is therefore dictated by the metabolic rate and the respiratory quotient; (ii) the "set point" at which arterial PCO2 is regulated by the ventilatory control system which, for a given VCO2, determines the level of alveolar ventilation; and (iii) the dead space fraction of the breath (ie, the ratio of the total dead space to the tidal volume) which determines the total ventilation.

Anesthesia, General↗
PubMed1990

Physiological determinants of pulmonary gas exchange kinetics during exercise.

We consider how the optimal selection of the profile of imposed work rate, coupled with rigorous, statistically justified analysis of the pattern of the pulmonary gas exchange response, makes it possible to assemble a control model incorporating the proportional role of the muscle, circulation, and gas stores. Gains, time constants, and delays may be assigned to the components of the response and its linearity assessed. These techniques also allow the investigator to examine the features of poorly understood and even unexpected response patterns. Recent interest in the analysis of the non-steady state of exercise-in normal subjects and in patients with gas exchange defects-has led to an improved understanding of the sub-threshold dynamics. At work rates above the lactate threshold, the more complex kinetics are to date poorly described, and hence poorly understood, remaining a fertile area for the application of control-systems techniques to exercise.

Exercise↗
PubMed1989

Determination of artelinic acid in blood plasma by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatographic method is described for the analysis of the new antimalarial drug artelinic acid in blood plasma. The influence of mobile phase composition, pH and type of mobile phase modifier on the retention of artelinic acid on the reversed-phase column is reported. Linear calibration curves were obtained in the range 0-500 ng/ml artelinic acid. Intra-assay and inter-assay variability in the analysis of plasma samples spiked with the drug were less than or equal to 15%. Plasma samples of the drug were found to be unstable when stored at -20 degrees C, the concentration of the drug decreasing by over 50% within three days. Plasma samples stored at -70 degrees C remained stable for at least two weeks. Initial pharmacokinetic studies in the rat showed that following intravenous administration, plasma concentrations of artelinic acid declined mono-exponentially. The relatively short elimination half-life (17 +/- 5 min) of artelinic acid is consistent with what is known for qinghaosu and its derivatives.

Animals↗
PubMed1989

Determination of arteether in blood plasma by high-performance liquid chromatography with ultraviolet detection after hydrolysis acid.

A reversed-phase high-performance liquid chromatographic method is described for determination of the antimalarial agent arteether in blood plasma based on its decomposition in acidic medium and measurement of the major decomposition product, which has been identified as an alpha,beta-unsaturated decalone. Linear calibration curves were obtained in the range 0-250 ng/ml arteether and the recovery of the drug from plasma was found to be quantitative. There is no interference from desoxyarteether, the putative major metabolite of arteether. The method has been applied to the measurement of arteether in the plasma of rats given 110 mg/kg by intramuscular injection of the drug as a solution in sunflower oil.

Animals↗
PubMed1989

Breathing-valve encumbrance and arterial blood gas and acid-base status in exercise in man.

It has been suggested that the mouth-piece-breathing valve assemblies commonly used in laboratory investigations of ventilatory control may influence regulation of arterial blood gas and acid-base status during exercise. To examine this hypothesis, 10 healthy males each underwent two incremental cycle-ergometer tests (15 W min-1) to the limit of tolerance: one was conducted free of breathing apparatus; the other utilized a mouth-piece (with noseclip) connected to a low-resistance turbine volume sensor. The order was randomly assigned and tests were separated by a 2 h recovery. Blood sampled from an indwelling brachial artery catheter at rest and every 30 W during exercise was analyzed for PCO2, PO2, pH and HCO-3. Maximum power was not different between the two tests. Furthermore, no systematic effect of the assembly could be discerned on PaCO2, PaO2 or pHa over the entire range of power. We therefore conclude that although ventilation and its pattern may be affected by laboratory breathing apparatus, such encumbrance (if of low resistance and dead space) does not influence blood gas and acid-base regulation during exercise.

Acid-Base Equilibrium↗
PubMed1989

Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities.

The relative contributions of the debrisoquin and mephenytoin isozymes of hepatic cytochrome P-450 to the stereoselective metabolism of propranolol have been studied in a panel of volunteers of known oxidative phenotypes. Six subjects were extensive metabolizers of both debrisoquin and mephenytoin (EM). Four subjects were poor metabolizers of debrisoquin but rapid for mephenytoin (PMD). Five subjects were poor metabolizers of mephenytoin but rapid for debrisoquin (PMM), and one individual had a deficiency for both test compounds (PMD/M). Partial metabolic clearances of each propranolol enantiomer to 4-hydroxypropranolol (4-OH-P), the sulfate, and glucuronide conjugates of 4-OH-P, naphthoxylactic acid (NLA) and propranolol glucuronide, were estimated after a single oral dose of racemic propranolol (80 mg). The partial metabolic clearance of both enantiomers to total 4-OH-P in the PMD group was 75% less than in the EM and PMM groups, indicating the contribution of the debrisoquin isozyme to this route of metabolism. The R/S ratios for the clearance to 4-OH-P were similar between EM and PMD (2.5 +/- 0.5 vs 2.5 +/- 0.4, respectively), implying that the different enzymes involved in ring hydroxylation (i.e., the debrisoquin isozyme and other hydroxylases) have similar stereoselective preferences. The partial metabolic clearance to NLA was 55% less in the PMM group than in the EM and PMD groups, indicating that S-mephenytoin 4-hydroxylase contributes to the metabolic conversion of propranolol to NLA. The R/S ratios for the clearance to NLA were close to unity in all groups. The partial metabolic clearance to propranolol glucuronide also did not exhibit stereoselectivity and was similar in all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aryl Hydrocarbon Hydroxylases↗
PubMed1989

Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man.

1. The metabolism of proguanil to the active metabolite cycloguanil has been evaluated in 135 British Troops and 26 Kenyan schoolchildren. 2. Large inter-subject variability was observed in both plasma and urinary concentrations of proguanil and cycloguanil after standard doses of drug. 3. Based on the ratio of proguanil to cycloguanil (P/C) in urine the British troops formed a non-normal distribution. 90% of the population formed a discrete distribution with P/C ranging from 0.5 to 9.0 while the remaining 10% were scattered throughout the distribution to an extreme value of 39. A similar pattern of variability was observed using P/C from a 6 h plasma sample. 4. This variability was due to differences in the ability of individuals to metabolise proguanil to cycloguanil. 5. Thirteen schoolchildren who had experienced malaria during prophylaxis with proguanil and thirteen matched controls each received proguanil (100 mg). We could not discriminate between the two groups based on P/C ratio in either a 6 h plasma or 0-6 h urine sample.

Adolescent↗
PubMed1989

Pharmacokinetics of halofantrine in man: effects of food and dose size.

1. Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2. Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3. AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250-500 mg. This increase was non-proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250-500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was non-proportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half-life of Hf remained unchanged across the dosage range. 4. Following a fatty meal, Cmax for Hf was increased from 184 +/- 115 micrograms l-1 (fasting) to 1218 +/- 464 micrograms l-1 (fed). AUC for Hf was increased from 3.9 +/- 2.6 mg l-1 h (fasting) to 11.3 +/- 3.5 mg l-1 h following a fatty meal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of peripheral and central chemoreflex activation on the isopnoeic rating of breathing in exercising humans.

1. Respiratory sensation during exercise is generally considered to be related to respiratory mechanical factors which may be manifest as an abnormal relationship between the force applied to the lungs and chest wall and the resulting motion (if any); that is, a 'length-tension' inappropriateness (Campbell & Howell, 1963). This suggests that there should be a direct correlation between ventilation (VE) and the associated intensity of the perceived sensation, such that the sensation associated with a particular level of VE should remain essentially constant regardless of the source of respiratory stimulation. 2. In order to establish whether certain respiratory stimuli might be 'dyspnoeagenic' (i.e. capable of evoking an intensity of respiratory sensation out of proportion to their influence on VE), we investigated the influence of both peripheral chemoreflex activation (induced by isocapnic hypoxia) and central chemoreflex activation (induced by hypercapnic hyperoxia) on the intensity of respiratory sensation in seven healthy adults during moderate cycle ergometer exercise (i.e. below the lactate threshold, theta 1ac). 3. In each test, an 'isopnoea' was established for which a particular level of VE was sustained over a prolonged period (approximately 30 min) while the proportional contributions to the ventilatory drive from either exercise and the peripheral chemoreflex or from exercise and the central chemoreflex were slowly altered to new stable levels, without the subject's knowledge, VE, tidal volume, inspiratory and expiratory durations, mean inspiratory flow, and end-tidal PCO2 and PO2 (PET,CO2, PET,O2) were monitored breath-by-breath. The intensity of respiratory sensation was rated with a visual analogue scale. 4. Isopnoeic ratings of respiratory sensation were systematically greater for peripheral chemoreflex activation by isocapnic hypoxia during exercise at 50% theta 1ac (for which the degree of peripheral chemoreflex activation, estimated by hyperoxic transition or 'Dejours' testing, averaged approximately 23% of the total VE), compared to 90% theta 1ac during isocapnic hyperoxia. Ratings during exercise at 50% theta 1ac for central chemoreflex activation by hypercapnic hyperoxia were not systematically different from 90% theta 1ac during isocapnic hyperoxia, however. 5. As VE was stable throughout each isopnoea and the MVV (maximum voluntary ventilation) was uninfluenced by the test condition, the dyspnoea index (VE x 100/MVV) was not affected. Breathing pattern was also unaffected. 6. We conclude that in normal subjects exercising moderately, activation of the peripheral chemoreceptors by isocapnic hypoxia evokes an intensity of respiratory sensation which is out of proportion to that evoked by an isopnoeic stimulation of the central chemoreceptors with hypercapnic hyperoxia at the same level of exercise.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1989

Model implications of gas exchange dynamics on blood gases in incremental exercise.

In humans, arterial PCO2 (PaCO2) has been demonstrated to be regulated at or near resting levels in the steady state of moderate exercise (i.e., for work rates not associated with a sustained lactic acidosis). To determine how PaCO2 might be expected to behave under the nonsteady-state conditions of incremental exercise testing, the influence of the dynamic characteristics of the primary variables that determine PaCO2 was explored by means of computer modeling. We constructed a dynamic model that utilized previously reported experimental estimates for the kinetic response parameters of ventilation (VE) and CO2 output (VCO2). In response to incremental work rate forcings, the model yielded an increase in PaCO2, which reflected the disparity between the VE and VCO2 time constants; this hypercapnic condition was maintained despite VE and VCO2 both increasing linearly with respect to the input work rate profile. The degree of hypercapnia increased with the rate of the incremental forcing, reaching 9 Torr for a 50-W/min forcing. In conclusion, therefore, sustained increases in PaCO2 during nonsteady-state incremental exercise should be interpreted with caution, because this is the predicted response even in subjects with normal ventilatory control and lung function.

Carbon Dioxide↗