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J L Bennett

Publications and source records attributed to J L Bennett.

At least 109 records · Page 6Linked to original sources
PubMed1987

Detecting in vitro anthelmintic effects with a micromotility meter.

An in vitro target parasite anthelmintic assay utilizing a micromotility meter has been developed and validated. Haemonchus contortus, an economically important ruminant helminth with worldwide distribution, was the parasite used in the model. Four commercially available ruminant anthelmintics (albendazole, ivermectin, levamisole hydrochloride and coumaphos) were initially evaluated at concentrations of 200, 150, 100 and 50 micrograms ml-1. All four significantly affected helminth motor activity and were active at 200 and 150 micrograms ml-1, and three of the four were active at 100 and 50 micrograms ml-1. An Upjohn compound (p-toluoyl chloride phenylhydrazone) was also assayed and was significantly active at all four levels. In a subsequent titration study, albendazole, levamisole hydrochloride, ivermectin and the hydrazone were significantly active at 100 and 10 micrograms ml-1; only levamisole hydrochloride and the hydrazone were active at 1.0 microgram ml-1. None of the drugs were active at 0.1 microgram ml-1. The data indicate that the in vitro H. contortus assay utilizing the micromotility meter is sensitive, accurate, rapid, repeatable, and inexpensive. With additional effort, this model can be extended to incorporate other target helminth parasites and stages of development. This in vitro assay system should be a valuable addition to the battery of tests used to identify anthelmintic candidates, monitor drug resistance, and define the kinetics and mode of action of drugs.

Albendazole↗
PubMed1987

L-glutamine: an amino acid required for maintenance of the tegumental membrane potential of Schistosoma mansoni.

The tegumental membrane potential (-63 +/- 2.9 mV) of adult male Schistosoma mansoni in RPMI-1640 is significantly depolarized (-26 +/- 7.3 mV) when the parasite is incubated in inorganic media (Hank's Balanced Saline or RPMI-1640 without organic constituents). Of 9 amino acids (L-glutamine, D-glutamine, L-arginine, L-proline, L-aspartate, L-glutamate, L-asparagine, L-isoleucine and L-methionine) L-glutamine alone is sufficient to repolarize the membrane potential to a value (-56 +/- 4.5 mV) not significantly different from that found in RPMI-1640. Repolarization by glutamine is dose-dependent, with significant effects obtained as low as 0.10 mM. The concentration of phosphate in the medium also significantly alters the membrane potential. Physiological levels of phosphate (5.6 mM) are necessary in conjunction with L-glutamine to obtain the full repolarization of the membrane potential. In the absence of organic constituents, the membrane potential is strongly dependent on the external medium pH. When L-glutamine is present in the medium, the membrane potential becomes virtually independent of the external pH.

Amino Acids↗
PubMed1986

Micromotility meter: an instrument designed to evaluate the action of drugs on motility of larval and adult nematodes.

An instrument for measuring the motility of larval and adult nematodes is described along with an analysis of its use as a tool to analyse drug action on these parasites. Motility was detected from larval parasites of Nippostrongylus brasiliensis and Ascaris suum in the absence and presence of various anti-nematodal drugs. These agents produced, within 48 h, a significant decrease in larval parasite motility. The instrument was also capable of detecting the motility of Caenorhabditis elegans, adult female Brugia pahangi and their response to anti-nematodal drugs. The design of the instrument allows us to accurately measure motility in a single sample within 60 sec.

Animals↗
PubMed1986

Calmodulin: biochemical, physiological, and morphological effects on Schistosoma mansoni.

Results of radioimmunoassays for the Ca2+-binding protein, calmodulin, revealed that this receptor constitutes 0.53 +/- 0.12% of the total protein in adult male Schistosoma mansoni. Schistosome calmodulin purified by Ca2+-dependent hydrophobic interaction chromatography showed an apparent molecular weight of 19 kDa, and its mobility on sodium dodecyl sulfate polyacrylamide gels was influenced by the presence of Ca2+ but not the antischistosomal drug praziquantel. Calmodulin from the parasite effected a four-fold stimulation of bovine heart adenosine 3',5'-cyclic monophosphate phosphodiesterase; this process was inhibited by removal of Ca2+ with ethyleneglycol-bis(B-aminoethylether)-N,N'-tetraacetic acid but not by praziquantel. Inhibition of calmodulin-activated processes with antipsychotic compounds in vitro resulted in a number of time- and concentration-dependent changes, including inhibition of schistosome calmodulin stimulation of bovine heart phosphodiesterase, disruption and depolarization of the parasite's tegument, and positive inotropic effects on longitudinal musculature. Results of this study indicate that calmodulin is a functional component of schistosomes and suggest that the role it serves is analogous to that obtained in other eukaryotes; i.e., it is an important component of numerous processes regulated, in part, by Ca2+.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Field trials with Oltipraz against Schistosoma mansoni in the Gezira Irrigated Area, Sudan.

Oltipraz, a new antischistosomal drug, has been field tested in Sudan for acceptability, tolerance and efficacy against Schistosoma mansoni. One hundred and fifty-one school children aged 7 to 12 years were selected for treatment with 20 mg/kg Oltipraz, 78 with a single dose and 73 with a split dose, on the same day. The drug was well tolerated except that 20 children in one school complained of fingertip pain. Parasitological follow-up after 5 weeks, 3 and 6 months produced cure rates (i.e., 2 negative stools) of 41 to 72% with the single dose and 53 to 75% with the split dose. The overall egg output reduction was over 95% from a pretreatment geometric mean egg count of 840 eggs/g. These results indicate that a 20-mg/kg dose of Oltipraz can effectively reduce egg counts but that a larger dose will be required to produce higher cure rates.

Child↗
PubMed1984

Schistosoma mansoni: differences in acetylcholine, dopamine, and serotonin control of circular and longitudinal parasite muscles.

The physiological and pharmacological properties of circular and longitudinal somatic musculature in adult male Schistosoma mansoni were compared using cut muscle sections. Carbachol reduced tone in both circular and longitudinal muscle, but was without effect on circular muscle bathed in high Mg2+, indicating that cholinergic receptors were not associated with circular muscle membrane. 5-Hydroxytryptamine (5-HT) induced rhythmic contractile activity in both sets of muscle. It decreased muscle tone in circular muscle but increased the tone of longitudinal muscle. Metergoline blocked 5-HT effects on both sets of muscle. 5-HT continued to be effective on both sets of muscle bathed in high-Mg2+ medium, indicating that serotonergic receptors were present on both circular and longitudinal muscle membranes. Dopamine decreased both circular and longitudinal muscle tone. Its effects on circular muscle were still present after exposure to high Mg2+, but its effects on the longitudinal muscle were significantly reduced, leading to the conclusion that dopaminergic sites were probably associated with circular muscle membrane but not that of longitudinal muscle. Also, spiroperidol blocked stimulus responsiveness of the circular muscle but not that of the longitudinal muscle. From these studies it appears that there are significant physiological and pharmacological differences between circular and longitudinal muscles in the adult male schistosome.

Acetylcholine↗
PubMed1984

Changes in glucose metabolism and cyanide sensitivity in Schistosoma mansoni during development.

Schistosoma mansoni was studied by biochemical and electrophysiological techniques to follow the physiological changes occurring during transformation in the mammalian host. Volume conducted electrical potentials and measurement of CO2 evolution indicate that 3 h post-transformational schistosomula are highly sensitive to cyanide. By 24 h after transformation, evolution of CO2 under control conditions is reduced by 77% from 3 h levels, while lactate excretion rises by 84%. Cyanide does not affect the frequency or magnitude of endogenous electrical transients, but does eliminate 83% of the already reduced levels of CO2 evolved in 24 schistosomula. Electrophysiological analyses indicate that the timecourse of metabolic changes in skin- and mechanically transformed schistosomula are similar, and incubation of schistosomula in 200 micrograms ml-1 puromycin does not alter the onset of cyanide insensitivity. The adult parasite evolves a low level of CO2 which is reduced by 88% in the presence of 1 mM cyanide. No significant Pasteur effect is detected, however, and endogenous electrical activity as well as mechanical responses of the adult musculature are unaffected by cyanide exposure. Our results indicate that schistosomula continue to rely on cyanide-sensitive respiratory components for at least 3 h after transformation; by 24 h, however, the parasites are metabolically similar to the adult stage, i.e., they depend on lactate fermentation for most of their energy requirements.

Aerobiosis↗
PubMed1984

Schistosoma mansoni: a comparative study of schistosomula transformed mechanically and by skin penetration. Electrophysiological responses to a wide range of substances.

Volume conducted potentials were recorded from schistosomula of Schistosoma mansoni transformed mechanically (MS) and by skin penetration (SS). The spontaneous electrical activity recorded consisted of bi- and triphasic transients ranging from 20 to 200 microV in amplitude and 10 to 300 msec in duration. Low amplitude potentials occurred at a much greater frequency than large amplitude potentials, which appeared to correlate with peristaltic-like contractions of the schistosomulum's musculature. Electrical activity in the schistosomulum was highly sensitive to a number of agents believed to affect metabolic pathways, the neuromuscular system or the host/parasite interface of adult schistosomes. Among the most reactive substances were potassium antimony tartrate, eserine, poly-L-arginine and potassium cyanide. Over a wide range of experimental treatments, electrophysiological responses in schistosomula transformed from cercariae by mechanical decaudation and skin penetration were remarkably similar, supporting the notion that MS are suitable material for in vitro immunochemical, biochemical and physiological study. Some treatments, however, were more or less effective in altering electrophysiological activity and motility in the schistosomulum than in adult S. mansoni. This suggests that significant physiological alterations may occur during development from skin stage to adult parasites concomitant with immunochemical and morphological changes already known to occur.

Animals↗
PubMed1984

Diet-controlled blood levels of oltipraz in healthy male subjects.

The bioavailability of the new antischistosomal agent, oltipraz, was examined under three different dietary conditions in seven healthy males. Oltipraz tablets (500 mg) were administered in single doses (25 mg/kg) under fasting conditions, with a low fat meal (less than 5% fat) and a high fat meal (24% fat). The extent and rate of oltipraz bioavailability were significantly increased by concurrent administration of the drug with food, as demonstrated by the increase in the plasma peak concentration, the area under the plasma concentration vs. time curve and the absorption rate constant. The plasma peak concentration was also reached earlier. Oltipraz plasma concentrations, following its administration under fasting conditions, were almost negligible. The likely mechanisms underlining oltipraz-food interaction are discussed.

Adult↗
PubMed1984

Effect of cysteine on oltipraz blood levels in green monkeys (Cercopithecus aethiops).

Oral coadministration of oltipraz, an antischistosomal compound, with cysteine to green monkeys (Cercopithecus aethiops) led to a marked increase in both the extent and rate of oltipraz bioavailability. The drug blood levels were monitored using a single extraction gas-liquid chromatographic assay. When 6 healthy adult animals were given oltipraz together with cysteine in a crossover study, peak serum concentrations, areas under the curve and absorption rate constants of oltipraz were on average 7 times greater than when the drug was administered alone. Oltipraz peak serum concentrations were reached 1 h earlier as a result of cysteine administration (2 h after dosing). At present, the mechanisms responsible for the effect(s) of cysteine on oltipraz bioavailability have not been identified. The marked increase in oltipraz bioavailability produced by coadministration of cysteine, irrespective of the exact mechanisms involved, may have significant clinical implications with regard to the treatment of schistosomiasis. Our results also indicate that oltipraz blood levels seem to be influenced by some sex-related factors. Male monkeys had higher oltipraz blood levels than females. These sex-induced differences were more evident in oltipraz-cysteine-treated monkeys.

Animals↗
PubMed1983

The relationship between tegumental disruption and muscle contraction in Schistosoma mansoni exposed to various compounds.

The antischistosomal drugs praziquantel and Ro 11-3128, which cause a tetanic contraction of Schistosoma musculature, concurrently produce a disruption of the parasite's tegument. Both phenomena are attenuated by preincubation of the parasites in high Mg2+ containing media before addition of the drugs, and the therapeutically inactive stereoisomers of these drugs cause neither effect. Other antischistosomal drugs tested cause neither muscle contraction nor tegumental disruption. Some unrelated agents which cause muscle contraction (but have no antischistosomal effect) alter the parasite's tegument, while others do not. Cytochalasin B, but not colchicine, causes tegumental disruption without affecting muscle tension. Thus, there is no simple correlation between a drug's antischistosomal activity or ability to contract the parasite's muscle and its ability to damage the parasite's tegument.

Animals↗
PubMed1983

Neurophysiology of adult male Schistosoma mansoni.

From the studies on the neurophysiology of schistosomes it appears that in spite of the unique hexilaminar arrangement of the tegument's outer membrane, it has biophysical properties not markedly different from those of a variety of other multi-dimensional syncytia. The close electrical coupling of the muscle and tegument must be taken into account when one attempts to define sites and modes of action of drugs which affect motor activity. Agents which disrupt muscle function in the schistosome may exert their action indirectly by way of an effect on the tegumental membrane. The syncytial nature of the musculature and the possibility that longitudinal contraction waves are myogenic suggests that neurotransmitters may simply function as modulators of muscle activity as is the case for many vertebrate visceral muscles. External recordings indicate the presence of a variety of electrically active tissues within the schistosomes. There is no clear correlation of this activity with longitudinal muscle activity or with active membrane responses in this muscle. From this it would appear the bulk of this activity may have its origins in tissues other than the longitudinal muscle such as other muscle groups, nerve trunks, or the peripheral nerve net.

Animals↗
PubMed1983

Schistosoma mansoni: a comparison of male and female muscle physiology.

Surface electrical activity and membrane potentials recorded from male and female Schistosoma mansoni are similar. Surface electrical activity and responses to electrical stimulation are slightly higher in females. Contractures induced by praziquantel, 60 mM K+, ouabain or 5 degrees C are slightly less in females but responses to putative neurotransmitters (5-HT, dopamine and carbachol) are the same in both sexes. Females are more susceptible to the removal of Ca2+ and to the increase of Mg2+ in the medium. These differences may be due to anatomical differences in the sexes or to the recording methods used.

Animals↗
PubMed1983

Tegumental disruption with Triton X-100 and its effects on longitudinal muscle function in male Schistosoma mansoni.

Longitudinal muscles in adult male Schistosoma mansoni appear to remain in almost all respects functional after tegumental disruption by Triton X-100. Responses to high K+, ouabain, low temperature, praziquantel and neurotransmitters are still present. Muscle membrane potentials remain near those of control animals and lanthanum nitrate is still excluded from the muscle after the Triton treatment. Although muscle contractility remains after tegumental disruption, sodium and calcium levels, as measured by plasma emission spectroscopy, increase by 20-30% while potassium and magnesium levels decrease by 15%. 45Ca2+ accumulation is double that of control animals. Upon exposure to a bathing medium lacking Ca2+, Triton-treated animals lose responsiveness to high K+, ouabain, low temperature and praziquantel more rapidly than do control animals. D-600, which effectively blocks the high K+ response in control animals, has no measurable effect on the high K+ response in Triton-treated animals, suggesting that voltage-dependent Ca2+ channels are present in the tegument.

Animals↗