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Biomedical subjects

S A Ward

Publications and source records attributed to S A Ward.

At least 19 recordsLinked to original sources
PubMed1992

Selective determination, in plasma, of artemether and its major metabolite, dihydroartemisinin, by high-performance liquid chromatography with ultraviolet detection.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of artemether and its major metabolite dihydroartemisinin in plasma has been developed. It involves extraction of plasma with dichloromethane, solid-phase separation of the two analytes and acid decomposition prior to chromatography on a C18 Spherisorb column with a mobile phase of acetonitrile-water (50:50, v/v). Run time is 30 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies.

Artemether↗
PubMed1992

Rapid chloroquine efflux phenotype in both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. A correlation of chloroquine sensitivity with energy-dependent drug accumulation.

Recent reports suggest that lower levels of chloroquine accumulation in chloroquine-resistant isolates of Plasmodium falciparum are achieved by energy-dependent chloroquine efflux from resistant parasites. In support of this argument, a rapid chloroquine efflux phenotype has been observed in some chloroquine-resistant isolates of P. falciparum. In this study, no relationship was found between chloroquine sensitivity and the rate of [3H]chloroquine efflux from four isolates of P. falciparum with a greater than 10-fold range in sensitivity to chloroquine. All the isolates tested displayed the rapid efflux phenotype, irrespective of sensitivity. However, chloroquine sensitivity of these isolates was correlated with energy-dependent rate of drug accumulation into these parasites. Verapamil and a variety of other compounds reverse chloroquine resistance. The reversal mechanism is assumed to result from competition between verapamil and chloroquine for efflux protein translocation sites, thus causing an increase in steady-state accumulation of chloroquine and hence a return to sensitivity. Verapamil accumulation at a steady-state is increased by chloroquine, possibly indicating competition for efflux of the two substrates. Increases in steady-state verapamil concentrations caused by chloroquine were identical in sensitive and resistant strains, suggesting that similar capacity efflux pumps may exist in these isolates. These data suggest that differences in steady-state chloroquine accumulation seen in these isolates can be attributed to changes in the chloroquine concentrating mechanism rather than the efflux pump. It seems likely that chloroquine resistance generally in P. falciparum, results at least in part from a change in the drug concentrating mechanism and that changes in efflux rates per se are insufficient to explain chloroquine resistance.

Animals↗
PubMed1992

Vacuolar acidification and chloroquine sensitivity in Plasmodium falciparum.

The antimalarial chloroquine concentrates in the acid vesicles of Plasmodium falciparum partially as a result of its properties as a weak base. Chloroquine-resistant parasites accumulate less drug than sensitive parasites. A simple hypothesis is that the intravacuolar pH of resistant strains is higher than that for sensitive strains, as a consequence of a weakened proton pump in the vacuoles of resistant strains, thereby explaining the resistance mechanism. We have attempted to test this hypothesis by the use of bafilomycin A1, a specific inhibitor of vacuolar proton pumping ATPase systems in plant cells, animal cells and microorganisms. Bafilomycin A1 significantly reduces uptake of [3H]chloroquine into both chloroquine-sensitive and -resistant strains of P. falciparum, at concentrations of inhibitor which have no antimalarial effect. Additionally, chloroquine-resistant strains of P. falciparum are more sensitive to bafilomycin A1 than chloroquine-sensitive strains. The use of bafilomycin A1 in combination with chloroquine in the standard in vitro sensitivity assay, produced an apparent reduction in sensitivity of both strains to chloroquine. The reported data support the hypothesis that chloroquine resistance in P. falciparum is associated with increased vacuolar pH, possibly due to a weakened vacuolar proton pumping ATPase.

Animals↗
PubMed1992

The effect of catecholamines and catecholamine antagonists on the third larval moult of Dirofilaria immitis in vitro.

Various catecholamines and catecholamine antagonists have been examined for their effects on the third larval moult of the parasitic nematode. Dirofilaria immitis, cultured in vitro. The non-selective alpha and beta agonist, noradrenaline, and the beta agonist, isoprenaline, had no effect on the timing of the third stage moult when used at a concentration of 10(-5) M. The alpha-adrenergic antagonist, phentolamine, resulted in worm mortality at 10(-5) M. At 10(-7) M, both phentolamine and the beta-antagonist, propranolol caused a significant reduction in the numbers of larvae capable of completing the third stage moult. Idazoxan, an alpha 2-antagonist, at 10(-5) M did not affect worm mortality but did completely prevent ecdysis. The potential of these compounds as possible filaricides is discussed.

Animals↗
PubMed1992

Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects.

1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.

Child↗
PubMed1992

The binding of the antimalarial arteether to human plasma proteins in-vitro.

The binding of the novel antimalarial drug, arteether, to human plasma, pure albumin and alpha 1-acid glycoprotein has been investigated by ultrafiltration, using [14C]arteether. The protein binding in plasma obtained from 11 healthy male subjects ranged from 73.4 to 81.8% bound, with a mean of 78.7 +/- 2.1%. The binding of drug in plasma was mainly accounted for by binding to albumin and alpha 1-acid glycoprotein. Scatchard analysis of the binding data revealed that the binding affinity of arteether to alpha 1-acid glycoprotein is much greater (20-fold) than that to albumin. This suggests that alpha 1-acid glycoprotein is the more important binding protein in plasma. This may have clinical importance due to alterations in plasma protein binding in patients with malaria, as the concentration of alpha 1-acid glycoprotein is markedly increased during malarial infection.

Adult↗
PubMed1992

Physiologic changes following bilateral carotid-body resection in patients with chronic obstructive pulmonary disease.

In an attempt to establish the characteristic pattern of change in (1) indices of pulmonary function, (2) arterial blood gas, and (3) arterial acid-base status which result from bilateral carotid body resection (BCBR), we analyzed the results of 146 consecutive patients with severe chronic obstructive pulmonary disease who had undergone BCBR at a single hospital site. In addition, we analyzed the results of incremental exercise testing in 21 similar patients, performed at a separate hospital. On average, TLC, FRC, and RV all decreased after surgery, whereas FEV1 increased. Although the data were highly variable, PaO2 decreased on average in proportion to the increase in PaCO2. The smaller group exercised to a higher metabolic rate after surgery; maximum ventilation, however, was unchanged. This led to a further fall in PaO2 and increase in PaCO2. We conclude that individual patient responses to BCBR are highly variable, but the procedure typically results in a small further hypoxemia and hypercapnia with no further impairment to pulmonary function.

Adult↗
PubMed1992

Pulmonary gas exchange dynamics and the tolerance to muscular exercise: effects of fitness and training.

Oxygen uptake (VO2) kinetics are generally agreed to be first-order for moderate work rates with a time constant (tau VO2) that is thought to reflect the kinetics of intramuscular creatine phosphate depletion. However, when there is a concomitant lactic acidosis, tau VO2 is appreciably longer, reflecting an additional, delayed and slowed component that leads to VO2S greater than the aerobic equivalent of that work rate and which therefore invalidates current techniques for O2 deficit estimation. This "excess" VO2 is no more than approximately 250-300 ml/min at work rates for which [lactate] and [H+]a can be stabilized. At higher work rates which demand sustained and progressive increases in [lactate] and [H+]a, however, VO2 also continues to increase progressively, yielding excess VO2S greater than 11/min at exhaustion. The trajectory of excess VO2 therefore is to the maximum VO2: the resulting exercise limitation becomes progressively more pronounced the higher the work rate, which accounts for the hyperbolic character of the power-duration curve. Factors which speed VO2 kinetics in this domain reduce the excess VO2 mechanism and lead to improved exercise performance. We have demonstrated that, in addition to appropriately-designed training regimens, induction of a metabolic acidosis prior to exercise speeds VO2 kinetics at high work rates, reducing the increase in both [lactate] and [H+]a and reducing the CO2 load to ventilation during the transient phase of the work. The optimum procedure for inducing these improved pulmonary gas-exchange kinetics, however, remains to be determined.

Humans↗
PubMed1992

Use of enzyme immunoassays to compare the effect and assess the dosage regimens of three Brazilian Bothrops antivenoms. The Butantan Institute Antivenom Study Group (BIASG).

The effect of the three main Brazilian polyspecific antivenoms on venom clearance was assessed in 118 moderately envenomed victims of bites by Bothrops species (mainly B. jararaca) in Sao Paulo State, Brazil. Serum samples taken from patients at intervals during their stay in the hospital and at followup approximately four weeks later were tested by enzyme immunoassay for the presence of whole venom and therapeutic antivenom. Results indicated that in patients treated with the standard regimen of either four (40 ml) or eight (80 ml) ampules of each antivenom, venom was cleared from the circulation within four days of antivenom administration. However, high concentrations of antivenom persisted for approximately 10 days and remained detectable until 30-50 days after administration. This suggests that patients may be being treated with excessive amounts of antivenom in Brazil. This practice increases the national cost of antivenom therapy and may contribute to the high frequency of antivenom reactions. Clinically, there was no obvious difference in the efficacy between the three antivenoms.

Adolescent↗
PubMed1992

Characterisation of ramified microglial cells: detailed morphology, morphological plasticity and proliferative capability.

Several cellular properties of brain microglia in the rat were investigated using both whole tissue and cultures of dissociated cerebral cortical cells. As revealed by thiamine pyrophosphatase histochemistry, tissue microglia possessed a highly distinctive cellular morphology. Stained microglia showed similar overall features of morphology and distribution in both preparations; however, the cells in culture displayed some slight differences from those of the tissue, including larger somata and less developed processes. Through studying living ramified cells in culture, both morphological plasticity as evidenced by patterned variations in soma size and mitotic activity were directly confirmed. It was concluded that ramified microglia definitely possess proliferative capability, and this may reduce the need for blood cell recruitment in brain immune responses. In addition, cultured microglia exist in a somewhat more activated state than those in normal tissue, and in some instances undergo further activation as macrophages. This cortical tissue culture system should provide an amenable preparation for investigating the regulation of microglial function.

Animals↗
PubMed1991

Measurement of quinine in filter paper-absorbed blood by high-performance liquid chromatography.

An adaptation of an existing high-performance liquid chromatographic assay is described for the measurement of quinine, within the therapeutic concentration range, in whole blood. This method, in particular the use of small blood samples which have been dried onto filter paper strips, has advantages for clinical and pharmacokinetic studies in the tropics on children with malaria.

Chromatography, High Pressure Liquid↗
PubMed1991

The effect of malaria infection on paracetamol disposition in the rat.

The effect of Plasmodium berghei infection, a rodent malarial model, on the disposition of paracetamol (50 mg/kg, i.v.) was investigated in rats. Malaria infection (MI) resulted in a significant decrease in clearance (control: 21.6 +/- 5.5 vs test: 11.8 +/- 2.9 mL/min/kg, P less than 0.005) with no change in volume of distribution and a significant prolongation of the elimination half-life (control: 30.7 +/- 6.3 vs 53.3 +/- 12.1 min, P less than 0.005) of paracetamol in malaria infected rats. These changes were not related to the severity of MI. Malaria infection also decreased biliary clearance of paracetamol (64%) but not its glucuronide and sulphate conjugates in the bile compared with controls. In addition, glutathione conjugates were not detected in bile samples of malaria infected rats. These data suggest that important pathways of drug detoxification may be compromised by MI in a relatively selective fashion and the relevance of these findings to the clinical use of drugs eliminated by these pathways merits further study.

Acetaminophen↗
PubMed1991

Rapid and sensitive method for the determination of albendazole and albendazole sulphoxide in biological fluids.

A sensitive and selective reversed-phase high-performance liquid chromatographic method for the determination of albendazole and its active metabolite albendazole sulphoxide in plasma has been developed. It involves single-step extraction of plasma with dichloromethane, evaporation of the solvent and chromatography on a muBondapak phenyl column with a mobile phase of water containing 1% (v/v) triethylamine-methanol-acetonitrile (70:10:20, v/v) at pH 3.1. Run time is 12 min. The assay satisfies all of the criteria required for use in clinical pharmacokinetic studies and possesses important advantages, notably speed and expense, over current methods.

Adult↗
PubMed1991

The effect of malaria infection on antipyrine metabolite formation in the rat.

We have shown that malaria infection can impair selectively the formation of antipyrine metabolites in the rat. During malaria, a significant increased urinary levels of unchanged antipyrine was observed (control: 1.7 +/- 0.4 vs test: 8.1 +/- 1.1% of dose, P less than 0.001). This was associated with significantly decreased excretion of 3-hydroxymethylantipyrine (control: 24.5 +/- 1.2 vs test: 21.4 +/- 0.7%, P less than 0.001) and 4-hydroxyantipyrine (control: 20.1 +/- 0.9 vs test: 15.5 +/- 1.3%, P less than 0.001) but not norantipyrine compared to control. Following treatment of the malaria infection with halofantrine, only the formation of 3-hydroxymethylantipyrine (control: 25.2 +/- 0.9 vs test: 24.1 +/- 0.6%, P less than 0.05) is impaired. The implications of these findings in relation to metabolism of other antimalarial drugs during malaria remains to be elucidated. Further work is needed to determine the changes in the pharmacokinetics of AP and its metabolites before, during and after MI in the rat in order to give a better insight into the effect of MI on hepatic drug metabolism.

Animals↗
PubMed1991

Characterization of ramified microglia in tissue culture: pinocytosis and motility.

Functional properties of ramified microglia were investigated in primary cultures of rat cerebral cortical cells. These microglia could be readily identified in both fixed and living cultures through previously established features. Based on their destruction by 5 mM L-leucine methyl ester, a high level of intrinsic endocytotic activity was established. When cultures were incubated with fluorescent latex beads to assess phagocytosis, little or no such activity was exhibited by ramified cells. However, when cultures were incubated with dyes or other soluble tracer compounds, these cells always exhibited labeling. This labeling was selective for ramified microglia in the cultures and was demonstrated using a variety of compounds, including trypan blue, lucifer yellow, horseradish peroxidase (HRP), and India ink. Intracellular label could be observed in vesicular structures; this localization corresponded to an active cellular process. Also, cellular labeling was inhibited by the presence of colchicine. These features supported the inference that the labeling was attributable to pinocytosis, and this process appeared to account for the vast majority of endocytotic activity in the ramified microglia. Possible physiological significance of this pinocytotic activity was indicated by the accumulation of various neurotransmitters/modulators: gamma-aminobutyric acid and vasoactive intestinal polypeptide (VIP). Ramified cells in these cultures have been previously noted to exhibit a constant and rapid pattern of motility, which was consistently observed here through time-lapse video recording; pinocytosis and rapid motility were shown to concur in individual cells. Based on their high intrinsic pinocytotic activity and pattern of cellular motility, the ramified microglia specifically are suggested to serve a constitutive function of fluid cleansing within the interstitial spaces of brain tissue.

Animals↗
PubMed1991

Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1-acid glycoprotein and the binding of quinine in Malawian children.

1. We have measured plasma concentrations of alpha 1-acid glycoprotein (AGP) in 18 healthy children and 85 children with falciparum malaria in Malawi. In addition, we determined the degree of protein binding of quinine (QN) in the plasma of 52 of the patients and each of the healthy controls. 2. The mean plasma AGP concentration was higher in patients than in controls (P less than 0.0001) and remained elevated 3 weeks after complete resolution of malaria infection. 3. The mean unbound QN fraction was significantly less (P less than 0.00001) in patients with malaria (0.128 +/- 0.037) than in controls (0.193 +/- 0.051) and significantly higher (P = 0.02) in convalescence (0.153 +/- 0.067) than during acute illness. 4. There were highly significant negative correlations between plasma AGP concentration and the free QN fraction in spiked plasma samples (r = -0.534, P less than 0.0001, n = 93) and in clinical samples (r = -0.484, P less than 0.00001, n = 225). There was a significant positive correlation between plasma concentrations of AGP and another acute phase reactant, C reactive protein (P less than 0.001).

Animals↗