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Biomedical subjects

R E Howells

Publications and source records attributed to R E Howells.

At least 37 records · Page 2Linked to original sources
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

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↗
PubMed1989

The efficacy of 22,23-dihydroavermectin B1 (Ivermectin) acting singly or in combination with a benzodiazepine on microfilariae of Onchocerca species and Brugia pahangi (an in vitro study).

An in vitro study of the antinematodal action of two groups of compounds which act on the receptor complex of the inhibitory neurotransmitter, Gamma-aminobutyric acid (GABA) in mammalian systems is described. The compounds, Ivermectin and two benzodiazepines, Diazepam and a water soluble Midazolam were tested singly or in combination against two microfilarial parasites Onchocerca lienalis (closely related to Onchocerca volvulus) and Brugia pahangi. The combination of ivermectin and diazepam at a concentration of 0.1 microgram/ml and 33 micrograms/ml respectively achieved the same effect on microfilarial motility as when ivermectin was given at 1 microgram/ml alone or diazepam at 66 micrograms/ml alone. Similarly when the combination of ivermectin at 0.1 microgram/ml and midazolam at 10 micrograms/ml was used it achieved the same effect as ivermectin at 1 microgram/ml alone or midazolam at 33 micrograms/ml alone. This showed that both benzodiazepines had a synergistic effect on the activity of ivermectin. The microfilariae of B. pahangi were insensitive to both groups of compounds at all concentrations used.

Animals↗
PubMed1989

Effects of potential inhibitors on Brugia pahangi in vitro: macrofilaricidal action and inhibition of microfilarial production.

A series of compounds that apparently disrupt hormonally regulated processes in insects have been examined for effects on the viability and microfilarial production of adult Brugia pahangi cultured in vitro. The azasteroids, 25-azacoprostane and 25-azacholestane, inhibited the production of microfilariae at 5 ppm, the former also exhibiting macrofilaricidal activity at this concentration. The brassinosteroids examined inhibited microfilarial production at 5 ppm but did not affect worm viability. Azadirachtin also proved to be a significant inhibitor of microfilarial release without effect on worm motility or viability. Of all the compounds tested, the non-steroidal amines appeared to be the most promising as potential filaricides, several of them proving to be macrofilaricidal at 1 ppm and affecting microfilarial production at even lower concentrations.

Amines↗
PubMed1989

Egg production in Brugia pahangi (Nematoda: Filarioidea).

Oogenesis in Brugia pahangi has been studied by means of the aceto-orcein chromosomal squash technique and light-microscope autoradiography. The use of colchicine has demonstrated a 2-3 mm terminal germinative zone within the ovary, in which continuous and rapid mitotic division of germ cells occurs. In 80% of the gonads, oocytes within a 1-2 mm length of the ovary proximal to the germinative zone were at the prophase of meiosis I. Primary oocytes with markedly less condensed chromatin, apparently interphase cells, were observed in the corresponding region of the ovary in the remaining 20% of material examined. A cyclical or phased development of primary oocytes is suggested. Autoradiographic studies, concerned with the incorporation of [5-3H]uridine into germ cells of B. pahangi in vitro, further suggest that the onset of meiotic prophase is associated with the initiation of high RNA synthetic activity. Following meiotic prophase, oocytes complete meiosis I before entering a period of growth during which the chromatin material is decondensed. Recondensation of chromosomes prior to meiosis II is only observed after fertilization within the seminal receptacle. On completion of meiosis II, with the extrusion of a polar body, the haploid chromosome complement of the female unites with that of the male, re-establishing the diploid number of the zygote (2n = 10).

Animals↗
PubMed1989

Neurosecretory-like material in 3rd- and 4th-stage Dirofilaria immitis larvae (Nematoda: Filarioidea).

Phase-interference microscopic examination of the infective, post-infective 3rd-stage and 4th-stage larvae of Dirofilaria immitis has identified a single cell body in each of the paired lateral amphidial nerves which undergoes characteristic morphological change during the development from 3rd- to 4th-stage larvae. Acetaldehyde-fuchsin staining of worm sections revealed fuchsinophilic material in the precise location of the amphidial nerve-cell bodies observed by phase-interference microscopy. This material was found in 70% of infective larvae recovered from mosquitoes and in 100% of larvae recovered from micropore chambers 24 h after implantation into BALB/C mice. In pre-moult larvae recovered at 42 h (Experiment 1) and at 48 h (Experiment 2) fuchsinophilic material was demonstrable, but no staining was observed in those larvae in which separation of the 3rd- and 4th-stage cuticles had occurred. No such material was observed in 4th-stage larvae recovered from chambers after 74 h, and in these larvae the amphidial nerve-cell bodies were not discernible. These cytological observations are consistent with a cycle of elaboration and release of neurosecretion associated with moulting in D. immitis.

Animals↗
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

Studies on the biosynthesis and fate of ecdysteroids in filarial nematodes.

Experiments were performed to investigate whether adult Dirofilaria immitis and Brugia pahangi were capable of synthesising ecdysteroids from cholesterol or various intermediates from the biosynthetic pathway functioning in insects. Metabolites of radioactively-labelled cholesterol and 5 beta-ketodiol (2,22,25-trideoxy-ecdysone) were detected in the filarial nematodes, but there was no radioactivity corresponding to ecdysteroid. Uptake of tritiated 2-deoxyecdysone was poor and metabolism was not observed. [3H]Ecdysone was absorbed sparingly by adult D. immitis, but was metabolised efficiently to several less polar products. There was no evidence of C-20 hydroxylation capability.

Animals↗
PubMed1989

Analysis of ecdysteroids in Onchocerca gibsoni, O. volvulus and nodule tissues.

Free ecdysteroids were detected in Onchocerca gibsoni, in tissues constituting O. volvulus and O. gibsoni nodules and in unrelated bovine tissues. Ecdysone and 20-hydroxyecdysone were identified by HPLC-RIA and GC/MS(SIM). The concentration of free ecdysteroids in the nodule tissue immediately surrounding the parasites was at least an order of magnitude higher than that detected in the worms themselves, or in adjacent nodular tissues or other bovine tissues.

Abattoirs↗
PubMed1988

Chlorproguanil/dapsone for the treatment of non-severe Plasmodium falciparum malaria in Kenya: a pilot study.

Chlorocycloguanil, the active metabolite of chlorproguanil, was synergistic in vitro with dapsone against 2 culture-adapted Plasmodium falciparum isolates from Kenya; maximal synergy occurred at lower concentrations that it did with pyrimethamine and sulfadoxine. 48 children with asymptomatic P. falciparum infections were treated with chlorproguanil (at a target dose of 1.2 mg/kg) and dapsone (target dose of 1.2 or 2.4 mg/kg); all were free of parasitaemia by day 7. The following numbers had recurrences on days 14, 21, and 28, respectively: 1 of 48, 7 of 47, and 7 of 40. All 39 children treated with pyrimethamine (target dose 1.2 mg/kg) and sulfadoxine (target dose 24 mg/kg) were cleared of infection, while the following had recurrences on days 14, 21, and 28: 1 of 39, 2 of 38, and 2 of 36. The rate of decrease in parasitaemia was the same in the 2 groups, and there was no change in haematocrit or haemoglobin during the follow-up. The rate of recurrence in the children receiving chlorporguanil/dapsone was higher, probably because these drugs have a much shorter clearance time than pyrimethamine/sulfadoxine. Chlorproguanil/dapsone is an effective combination for treating P. falciparum malaria and deserves further study.

Animals↗
PubMed1988

The changing response of Plasmodium falciparum to antimalarial drugs in east Africa.

For the past 20 years, chloroquine chemotherapy has been the single most effective malaria control measure in East Africa. The advent of chloroquine-resistant Plasmodium falciparum has reduced the clinical effectiveness of chloroquine and this trend is likely to continue. Combinations of antifol drugs are at present effective inhibitors of most P. falciparum infections in the region, in spite of widespread resistance to pyrimethamine. The development of (i) sensitive methods for monitoring changes in sensitivity to antifol combinations, (ii) more effective and less costly alternatives to commercially available combinations, and (iii) investigation of host and parasite factors leading to drug treatment failure in P. falciparum infections has been the primary goal of the Wellcome Trust Research Laboratories in Kenya (directed by Dr W.M. Watkins) within the malaria programme of the Kenya Medical Research Institute, and collaborating laboratories at the School of Tropical Medicine and the University of Liverpool.

Africa, Eastern↗
PubMed1987

Inadequacy of chlorproguanil 20 mg per week as chemoprophylaxis for falciparum malaria in Kenya.

After treatment with chloroquine and pyrimethamine/sulfadoxine, 118 school children aged 6 to 10 years living near the Kenyan coast were enrolled in a malaria chemoprophylaxis study and followed up for 20 weeks. Children were randomly assigned to receive either chlorproguanil 20 mg weekly (n = 78) or placebo (n = 37). The attack rate of Plasmodium falciparum infection was 42% in chlorproguanil recipients (39.8 episodes per 1000 person-weeks of prophylaxis) and 73% in placebo recipients (69.2 episodes per 1000 person-weeks, p less than 0.02). Sensitivity tests on 36 isolates successfully cultured in vitro showed that all 21 isolates from chloroproguanil recipients were resistant to dihydrofolate-reductase inhibitors, whereas only 3 of 15 isolates from the placebo group were resistant (p less than 10(-6)). Chlorproguanil in a weekly adult dose of 40 mg does not provide adequate prophylaxis against P falciparum in Kenya, probably because drug levels between doses fall below those required to suppress parasites resistant to dihydrofolate-reductase inhibitors.

Adolescent↗
PubMed1987

Dynamics of the filarial surface.

The surface of the filarial worm consists of an extracellular cuticle which overlies the outer plasma membrane of the hypodermis. The cuticle is permeable to a wide range of molecules of low molecular weight, and L-amino acid and D-glucose uptake occurs transcuticularly by active transport and diffusion in physiologically significant amounts. Transport mechanisms are associated with the plasma membrane of the hypodermis, and the cuticle may be considered an 'unstirred layer' distal to the transport loci. The outermost layer of the cuticle, or epicuticle, consists of a lipid bilayer which differs from a typical plasma membrane. There is no conclusive evidence for turnover of the epicuticular materials between the larval moults and in the adult stage. It is proposed that the filarial surface does not show the dynamic properties associated with the surface membranes of parasitic cestodes and trematodes.

Animals↗
PubMed1987

Identity and tissue localization of free and conjugated ecdysteroids in adults of Dirofilaria immitis and Ascaris suum.

Adult males and females of the dog heartworm, Dirofilaria immitis, and of the swine parasite, Ascaris suum, were extracted, the free and polar conjugated ecdysteroid fractions separated and the latter hydrolysed enzymically. The ecdysteroids released by hydrolysis of the conjugates and the free hormones were analysed by radioimmunoassay, high-performance liquid chromatography on reversed phase and adsorption columns monitoring fractions by radioimmunoassay, and by gas-liquid chromatography/mass spectrometry (selected ion monitoring). In both species, males and females contained free and polar conjugated ecdysteroids, with evidence for the presence primarily of ecdysone and 20-hydroxyecdysone together with smaller amounts of 20,26-dihydroxyecdysone. Males and females of both species were then dissected into body fluid, reproductive system, gut and remaining body wall compartments, the ecdysteroids extracted, fractionated and analysed by radioimmunoassay and high-performance liquid chromatography monitoring fractions by radioimmunoassay. The results for both sexes in the two species were similar and indicated that ecdysteroids were not detectable in body fluids and that free ecdysteroids occurred in the reproductive system and the body wall, whereas polar conjugated ecdysteroids were detected in the reproductive system and the gut; a minor portion of the free ecdysteroids in A. suum was also apparently present in the gut. Further localization of the ecdysteroids in the body wall of A. suum females suggested that negligible immunoreactivity was associated with the circumpharyngeal nerve ring. The possible significance of the results is discussed.

Animals↗