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Biomedical subjects

S A Ward

Publications and source records attributed to S A Ward.

At least 127 records · Page 7Linked to original sources
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

Inter-individual variation in the metabolic activation of the antimalarial biguanides.

The aryl-biguanides proguanil and chlorproguanil were developed as part of a collaborative programme between ICI and the Liverpool School of Tropical Medicine during the 1940s. The compounds were characterized by their absence of host toxicity. However, the rapid development of parasite resistance to the actions of these drugs and the development of the 4-aminoquinoline, chloroquine, severely limited their use. The subsequent widespread development of parasite resistance to chloroquine, together with the observations that the magnitude of dihydrofolate reductase inhibitor resistance (the site of action of the biguanides) developed to pyrimethamine is not directly correlated with biguanide resistance(1,2). has resulted in renewed interest in these drugs. In particular, proguanil is now the drug of choice for malaria prophylaxis, in combination with chloroquine; used in combination with a suitable sulphonamide, it may be of value in malaria therapy.

Journal Article↗
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↗
PubMed1991

Pharmacokinetics of halofantrine in Thai patients with acute uncomplicated falciparum malaria.

Twelve patients with acute uncomplicated falciparum malaria were admitted to the Hospital for Tropical Diseases for 42 days. The patients were treated with halofantrine 500 mg 6 hourly for three doses and halofantrine and its desbutyl metabolite were analysed in plasma by h.p.l.c. Cmax values of halofantrine and desbutylhalofantrine (n = 12) were 1192 +/- 410 (mean +/- s.d.) and 397 +/- 160 ng ml-1 with tmax values of 16 +/- 2 and 55 +/- 26 h, respectively. AUC was 60.6 +/- 23.9 and 48.5 +/- 22.2 mg l-1 h, respectively, for halofantrine and its metabolite. Halofantrine cured 83% of the patients but in two patients a reduction only in asexual parasitaemia was seen and no overall parasite clearance occurred. One of these, however had relatively low plasma concentrations of both halofantrine and its desbutyl metabolite and it appeared to be a case of inadequate treatment rather than true resistance. We suggest that the large intersubject variability in plasma drug concentrations may relate in part to its poor and inconsistent bioavailability and this rather than true resistance might be responsible for some of the treatment failures.

Acute Disease↗
PubMed1991

The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study.

The activation of the antimalarial drug proguanil (PG) to the active metabolite cycloguanil (CG) has been evaluated in a panel of 18 subjects. These subjects had previously been screened and classified as mephenytoin poor (PMm) or extensive metabolisers (EMm) and sparteine poor (PMs) or extensive metabolisers (EMs). Five subjects had the phenotype PMm/EMs, one was PMm/PMs, six subjects were EMm/PMs and six were EMm/EMs. The PG/CG ratio in urine (8 h) was significantly higher in PMm than in EMm (P = 0.0013). This study shows that the P450-isozyme involved in the polymorphic oxidation of mephenytoin is of critical importance in the activation of PG to CG and this may explain the large intersubject variability in CG concentrations in man. PMm make up about 3% of Caucasians, but up to about 20% of Orientals. From the present study, it may be anticipated that the antimalarial effect of PG is absent or impaired in this phenotype. The sparteine polymorphism appeared not to influence the activation of PG to CG significantly.

Adult↗
PubMed1991

The effect of fever on quinine and quinidine disposition in the rat.

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.

Animals↗
PubMed1991

The influence of alpha 1-acid glycoprotein on quinine and quinidine disposition in the rat isolated perfused liver preparation.

We have studied the effect of 0.5 and 2.0 g L-1 of alpha 1-acid glycoprotein (AAG) on the disposition of quinine and quinidine in the rat isolated perfused liver preparation. The higher concentration of AAG (2.0 g L-1) resulted in a significant decrease in clearance [quinine study (control: 9.6 +/- 2.9 vs test: 3.1 +/- 1.2 mL min-1); quinidine study (control: 9.8 +/- 2.4 vs test: 3.5 +/- 1.1 mL min-1]) and volume of distribution [quinine study (control: 1198 +/- 416 vs test: 466 +/- 95 mL); quinidine study (control: 1352 +/- 459 vs test: 317 +/- 24 mL]) but not the elimination half-life compared with control. At the lower concentration (0.5 g L-1) of AAG there was no significant difference in clearance, volume of distribution and elimination half-life for either drug compared with control. By increasing the concentration of AAG from 0.5 to 2.0 g L-1 both the hepatic extraction ratio and the fraction of drug unbound when compared with controls significantly decreased by about 66 and 60% for quinine, and by 65 and 58% for its diastereoisomer quinidine, respectively. The consequence of these changes is a substantial increase in the total quinine (or quinidine) concentrations without any change in the free quinine (or quinidine) concentrations. However, at 0.5 g L-1 AAG compared with control, no significant difference was observed in fraction of drug unbound, extraction ratio, total drug concentration or free drug concentration for either drug. In summary, changing concentrations of AAG, an important binding protein for quinine and quinidine, can affect the hepatic disposition of both drugs.

Animals↗
PubMed1990

Lack of effect of halofantrine on hepatic drug metabolism in the rat in vivo and in vitro.

The effect of the antimalarial drug halofantrine (Hf) on hepatic drug metabolism in the rat has been studied in vivo and in vitro using different model drug substrates. Hf in vitro produced no significant effect on the values of Km and Vmax for aminopyrine N-demethylation or 7-ethoxycoumarin O-dealkylation in microsomes incubated with Hf (0.01-0.1 mM) or on the rate of N-demethylation of aminopyrine or O-dealkylation of Ec in microsomes produced from rats dosed chronically with Hf (200 mg/kg) for 4 days. The disposition of antipyrine (Ap) was investigated in the isolated perfused rat liver preparation (IPRL). Following the administration of bolus doses of Hf (0.5, 2.5 and 5.0 mg) no significant changes were observed in the half-life (t1/2), clearance (Cl) or apparent volume of distribution (Vd) for Ap compared with controls. Pentobarbitone induced sleeping time was also assessed in mice. No significant difference was determined in time to recovery of the righting reflex for mice receiving Hf as single oral doses or chronically over 4 days when compared with appropriate controls. The potential for selective isoenzyme effects was studied in vivo. The three principal urinary metabolites of Ap, norantipyrine (Np), 3-OH and 4-OH Ap were measured in rat urine, with no significant change in urinary recovery of Ap or any of the metabolites in the presence of Hf (1.25 mg/kg i.p.) compared with controls. These results suggest that Hf is not, in contrast to many commonly used quinoline antimalarials, a potent or specific inhibitor of drug metabolism in vitro or in vivo.

Animals↗