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S A Ward

Publications and source records attributed to S A Ward.

At least 109 records · Page 6Linked to original sources
PubMed1994

Clinical pharmacokinetics in the treatment of tropical diseases. Some applications and limitations.

In recent years major advances have been made in the clinical pharmacology of many drugs used for the treatment of tropical diseases, particularly in the design and development of dosage regimens for the treatment of severe malaria. For example, by careful manipulation of its rate of administration, chloroquine has been shown to be well tolerated when used for treatment of severe disease caused by susceptible parasites. Similarly, important advances have been made in the rational design of quinine dosage regimens for patients in South East Asia and Africa. Investigation of the pharmacokinetics of mefloquine has drawn attention to the problems associated with its administration as combination therapy with pyrimethamine and sulfadoxine in Thailand. Similarly, evaluation of the pharmacokinetic properties of halofantrine has led to the demonstration that poor and erratic absorption could be just as likely to explain therapeutic failure as resistance of the parasite to effects of this drug. Disposition of the antimalarial biguanides has highlighted the role of host-related effects in the determination of drug response. For example, a small percentage of individuals are unable to convert proguanil (chloroguanide) to its active triazine metabolite, cycloguanil. Finally, agents that reverse chloroquine resistance are currently under development for the treatment of malaria. The importance of assessing the clinical pharmacokinetic properties of potential resistance reversers must be recognised. While limited success has been achieved in antifilarial chemotherapy, other parasitic diseases have been largely neglected with advances in the laboratory still awaiting full recognition of their clinical application. For example, clinical pharmacokinetic concepts may be used to improve the therapy of human hydatid disease. We believe that clinical management of tropical diseases can be improved by the application of clinical pharmacokinetic principles. However, this may not be universally advantageous. For example, the artemisinin (qinghaosu) derivatives are among the most recently developed antimalarials that have great therapeutic promise. Recent evidence suggests that pharmacokinetic data would be of limited value in the design and optimisation of dosage regimens because of its chemical reactivity and the unusual mechanism by which these drugs kill parasites. Similar limitations may apply to the microfilaricidal drug, ivermectin.

Chloroquine↗
PubMed1994

Assessment of peripheral chemoreflex contributions to exercise hyperpnea in humans.

The inaccessibility of the peripheral chemoreceptors (carotid bodies) precludes their direct investigation in exercising humans. As a result, a range of indirect techniques has been developed to assess the carotid body contribution to ventilatory control in exercise. The considerable controversy surrounding their involvement in this control process is a reflection, in part, of the limitations associated with current estimators of their reflex responsiveness. Most estimators of carotid chemosensitivity rely on the premise that, as the carotid bodies appear to be the sole mediators of the ventilatory response to hypoxia in humans, the entire ventilatory response to an hypoxic challenge necessarily should be ascribed to carotid chemoreceptor activation. Other estimators rely on the assumption, in humans, inhalation of 100% oxygen effectively "silences" the carotid chemoreflex. This article will review these estimators, and present a critical evaluation of their relative merits and limitations.

Carotid Body↗
PubMed1993

Malaria chemotherapy: resistance to quinoline containing drugs in Plasmodium falciparum.

Resistance to quinoline containing drugs, particularly chloroquine (CQ), is a major impediment to the successful chemotherapy and prophylaxis of malaria. CQ-resistant parasites fail to accumulate as much drug as their sensitive counterparts and two major hypotheses have been proposed to account for this phenomenon. CQ-resistant parasites are thought to maintain lower intracellular drug levels by means of an active efflux system, similar to that found in multi-drug resistant cancer cells, despite major differences in both the genetic and biochemical manifestations of drug resistance in the two cell types. Alternatively, CQ-resistance could be linked to a defective CQ uptake mechanism, possibly an impaired acidification process in the food vacuole of the resistant parasite. These two theories are discussed in detail in the following review. The potential of pharmacological intervention to override these resistance mechanisms is also discussed.

Animals↗
PubMed1993

Effect of malaria infection and endotoxin-induced fever on phenacetin O-deethylation by rat liver microsomes.

We have investigated the effect of malaria infection with the rodent parasite Plasmodium berghei and fever induced by Escherichia coli endotoxin on the metabolism of phenacetin to paracetamol by rat liver microsomes from young (4 weeks old) male Wistar rats (N = 5 in control and fever groups; N = 10 in malaria-infected group). Following determination of % parasitaemia, the malaria-infected group was divided into a low parasitaemia subgroup (N = 5; mean % parasitaemia = 9.87 +/- 2.6) and a high parasitaemia subgroup (N = 5; mean % parasitaemia = 36.6 +/- 8.1). The control group received normal saline. Total microsomal protein was not significantly affected by fever or malaria infection while cytochrome P450 levels were reduced by approximately 50% in the high parasitaemia subgroup, 20% in the low parasitaemia subgroup and 20% in the endotoxin-treated group. Phenacetin-O-deethylation kinetics were biphasic in both control and malaria-infected rats, but monophasic in endotoxin-treated rats. Total apparent intrinsic clearance (CL(int),total; calculated as Vmax/Km; Vmax is maximum velocity, Km is Michaelis constant) of phenacetin was reduced approximately 6-fold in low parasitaemia, 30-fold in high parasitaemia and 35-fold in fever. There was a poor correlation between CL(int),total and % parasitaemia (r = -0.6). However, log CL(int),total correlated inversely with % parasitaemia (r = -0.9), suggesting that Cl(int),total decreased exponentially with an increase in % parasitaemia. Phenacetin O-deethylation is a marker for cytochrome P4501A2 activity and the results of the present study suggest that both malaria infection and fever might specifically reduce P4501A2 activity in the rat.

Acetaminophen↗
PubMed1993

Effect of malaria infection and endotoxin-induced fever on the metabolism of antipyrine and metronidazole in the rat.

Antipyrine and metronidazole were administered as a cocktail to young (4 weeks old) male Wistar rats (N = 12 for each treatment) to investigate the effect of malaria infection due to the rodent parasite Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of the two compounds in vivo. Control rats received normal saline. Antipyrine and metronidazole clearances were estimated from a single saliva sample while the formation clearances of their metabolites (in malaria-infected and control rats) were estimated from the product of clearance of parent drug and the fraction of the administered dose excreted as metabolites in urine in 24 hr. Rats treated with endotoxin produced no urine during this period. Malaria infection had no effect on clearance of antipyrine or on formation clearance of any of its metabolites. However, the clearance of metronidazole was reduced by approximately 20% compared with controls as a result of decreased formation of hydroxymetronidazole. Fever decreased clearance of both antipyrine and metronidazole by approximately 36% and 23%, respectively. These results demonstrate that both malaria infection and fever can influence P450-dependent drug metabolism and the effects seen appear to be isozyme-selective.

Animals↗
PubMed1993

The multiple dose pharmacokinetics of proguanil.

Proguanil, a prophylactic antimalarial agent, is metabolised by the polymorphic isoenzyme CYP2Cmep in man. In this study the multiple dose pharmacokinetics of proguanil were investigated in subjects who were phenotyped previously as extensive (n = 6) or poor (n = 2) metabolisers of the drug. Steady-state plasma concentrations of proguanil were achieved within 48 h in extensive metaboliser subjects and chronic administration of the drug did not appear to alter the disposition of proguanil or that of its active metabolite, cycloguanil. The currently recommended dosage regimen appears to be appropriate for extensive metabolisers of proguanil. Poor metabolisers of proguanil had significantly lower plasma concentrations of the active metabolite cycloguanil compared with extensive metabolisers. Thus, even on multiple dose administration these subjects may not achieve adequate plasma concentrations of cycloguanil. Deficient metabolism of proguanil to cycloguanil leads to an increased appearance of the N-dealkylated metabolite p-chlorphenylbiguanide in the urine of poor metabolisers.

Adult↗
PubMed1993

Interactions among primaquine, malaria infection and other antimalarials in Thai subjects.

1. The pharmacokinetics of rac-primaquine (45 mg base) and its principal plasma metabolite, carboxyprimaquine have been investigated in healthy Thai adults prior to and following a single oral dose of mefloquine (10 mg kg-1). 2. Primaquine was rapidly absorbed, attaining peak plasma concentrations (median and range) of 167 (113-532) micrograms l-1 in 2 (1-4) h. Thereafter, concentrations declined rapidly with an apparent terminal half-life of 6.1 (1.7-16.1) h and an oral clearance (CLpo) of 33.1 (17.6-49.3) l h-1. Administration of mefloquine had no effect on the values of any of these parameters at the 5% level of significance [Cmax 229 (114-503) micrograms l-1; tmax 3 (2-4) h; t1/2,z 3.9 (1.7-13.5) h; CLpo 34.0 (21.7-49.0) l h-1]. 3. The carboxylic acid metabolite of primaquine achieved maximum concentrations (median and range) of 890 (553-3634) micrograms l-1 at 6 (3-16) h. Thereafter, plasma concentrations of carboxyprimaquine declined to 346 (99-918) micrograms l-1 at 24 h. AUC (0,24 h) was 12737 (6837-27388) micrograms l-1 h. Administration of mefloquine had no effect on the plasma concentrations of this metabolite [Cmax 1035 (174-3015) micrograms l-1; tmax 8 (2-24) h; AUC(0,24) 13471 (2132-17863) micrograms l-1 h]. 4. The effect of falciparum malaria and treatment with quinine (10 mg salt kg-1 p.o.) on the pharmacokinetics of primaquine (45 mg base p.o.) has been investigated in adult Thai patients during and after infection with falciparum malaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Development of halofantrine resistance and determination of cross-resistance patterns in Plasmodium falciparum.

Intermittent exposure to halofantrine (HF) of both chloroquine-susceptible (T9.96) and chloroquine-resistant (K1) isolates of Plasmodium falciparum in vitro resulted in a rapid reduction in susceptibility to HF. After 6 months, the 50% inhibitory concentration (IC50) of HF, determined with [G-3H]hypoxanthine incorporation as a marker, increased ninefold for the chloroquine-resistant (K1) isolate and threefold for the cloned chloroquine-susceptible (T9.96) isolate, the derived isolates being termed the K1HF3 and T9.96HF4 isolates, respectively. By microscopic examination of cultured erythrocytes, we determined that there was a fivefold increase in the IC50 for isolate T9.96HF4. The responses of the parental isolates and the HF-resistant isolates to chloroquine, mefloquine, quinine, amodiaquine, qinghaosu, and pyrimethamine were determined. In comparison with the parental K1 isolate, HF-resistant isolate K1HF3 was significantly more susceptible to the action of chloroquine and exhibited a significantly reduced susceptibility to quinine and mefloquine. The other HF-resistant isolate, T9.96HF4, showed no alteration in susceptibility to amodiaquine or chloroquine but a significantly decreased susceptibility to mefloquine. Resistance was stable in the two isolates, both in the absence of drug pressure or when kept frozen in liquid nitrogen. In contrast, continuous exposure to HF had no effect on the susceptibility of the parasites to this drug above HF concentrations of 3.2 x 10(-9) M.

Animals↗
PubMed1993

Enhancement of drug susceptibility in Plasmodium falciparum in vitro and Plasmodium berghei in vivo by mixed-function oxidase inhibitors.

A number of compounds, as exemplified by verapamil and desipramine, have been shown to enhance the susceptibility of resistant malaria parasites to chloroquine. The mechanism by which these agents reverse resistance is still controversial but is though to involve alterations in drug transport causing an increase in steady-state drug concentrations. We have proposed that an alternative resistance mechanism may involve the metabolic deactivation of the drug in some resistant parasites via cytochrome P-450 mixed-function oxidases. If the hypothesis is true, it should be possible to alter drug susceptibility in malaria parasites by the use of agents known to inhibit or induce cytochrome P-450 activities. We have assessed the ability of known inhibitors of cytochrome P-450 enzymes (cimetidine, metyrapone, and alpha-naphthoflavone) to enhance chloroquine susceptibility in Plasmodium falciparum culture-adapted and wild-type isolates in vitro and P. berghei in vivo. In all three systems, the inhibitor cimetidine enhanced parasite susceptibility to chloroquine, and this increase in susceptibility was unrelated to changes in chloroquine steady-state concentrations in vitro or to alterations in host pharmacokinetics in vivo. Additionally, the cytochrome P-450 inducer phenobarbital produced slight decreases in P. falciparum drug susceptibility in vitro. We have compared the ability of the cytochrome P-450 inhibitors cimetidine and metyrapone to enhance drug susceptibility with that of verapamil by using wild-type malaria isolates obtained from Cameroon. Verapamil completely reversed resistance, i.e., to below the cutoff point of 70 nM, in all the resistant isolates. Cimetidine enhanced chloroquine susceptibility in 60% of the isolates and reduced 50% inhibitory concentrations by at least 43% in all the resistant isolates. The compounds tested had little or no effect on the 50% inhibitory concentrations for the susceptible isolates. The data support a possible role for detoxification in chloroquine resistance, and even in the absence of such a process we have observed apparent chemosensitization by agents whose common biological feature is the inhibition of cytochrome P-450 enzymes. Additionally, sensitization has been observed in wild-type isolates of P. falciparum obtained form immune residents of an area of endemicity as well as culture-adapted parasites.

Adolescent↗
PubMed1993

Transient regional osteoporosis presenting as a septic arthritis.

A 52 year old man developed a painful swollen left knee. Clinically there was an effusion and radiographs showed local osteoporosis. Sepsis was suspected but tests proved negative and the symptoms gradually settled. During the course of the following year he developed similar pain migrating from the left foot to the right knee then to the right foot. Investigations showed a right knee effusion and 'punctate' radiographic lucencies in the patellae thought to be erosions. A bone scan demonstrated increased uptake at all four sites and sepsis was once again suspected. Biopsies and culture proved negative and a computed tomographic scan confirmed that the lucencies were due to focal osteoporosis rather than erosions. This case of transient regional osteoporosis illustrates two unusual features of this condition which resulted in diagnostic difficulty with respect to sepsis.

Arthritis, Infectious↗
PubMed1993

Metabolism of caffeine and theophylline in rats with malaria and endotoxin-induced fever.

1. The effects of malaria infection due to Plasmodium berghei and Escherichia coli endotoxin-induced fever on the metabolism of orally-administered caffeine (CA: 10 mg/kg) to its primary metabolites (theobromine (TB), paraxanthine (PX) and theophylline (TH)) were studied in 5-week-old male Wistar rats (n = 5 for each treatment). In separate experiments, the effects of malaria and endotoxin-induced fever on the clearance of i.v.-administered theophylline (TH; 15 mg/kg) were studied in another group of rats. 2. The ratios of CA to the three primary metabolites (TB/CA, PX/CA, PH/CA) determined in a single plasma sample obtained 3 h after CA administration were significantly reduced (p < 0.05) both by malaria and fever compared with control (saline) treatment. The clearance of TH determined from the concentration of TH in a single plasma sample obtained 6 h after TH administration was significantly reduced (p < 0.05) by fever but not malaria (4.0 +/- 0.7 ml/min/kg in controls; 4.2 +/- 0.5 in malaria; 2.4 +/- 0.4 in fever). 3. These results suggest that malaria and fever have different effects on CA and TH metabolism in vivo, probably as a result of different effects on the hepatic isozymes involved.

Administration, Oral↗
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↗