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Biomedical subjects

J L Bennett

Publications and source records attributed to J L Bennett.

At least 91 records · Page 5Linked to original sources
PubMed1989

Efficacy of a new Hoffmann-La Roche compound (Ro 15-5458) against Schistosoma mansoni (Gezira strain, Sudan) in vervet monkeys (Cercopithecus aethiops).

Some compounds of the class 9-acridanone-hydrazones have recently been developed by Hoffmann-La Roche (Basel-Switzerland) and were shown to have antischistosomal effects. One of these compounds (RO 15-5458/000) was administered at two dose levels (25 mg and 15 mg/kg body-weight) to S. mansoni (Gezira strain-Sudan) infected vervet monkeys. The faecal egg-output was terminated, worm-burden killed and tissue egg-counts were greatly reduced as compared with the untreated control monkey. Severe necrotic changes were seen around dead worms in sections from treated animals' livers. The efficacy of this compound as an antischistosomal is encouraging and deserves further studying.

Acridines↗
PubMed1989

Anti-filarial effects of nine quinoline-containing drugs on adult filariae in vitro.

The potencies and efficacies of 9 quinoline-containing anti-malarials including chloroquine, (bis)desethylchloroquine, SN6911, SN12108, amodiaquine, CN-2999-2K, primaquine, quinacrine, and quinine were examined in vitro against adult female Brugia pahangi. Parasite motility and lactate excretion were measured as indicators of drug effects. All of the agents tested showed time-dependent increases in potency over a 24-72-hr incubation period. SN12108 was the most potent at 72 hr, reducing motility by greater than or equal to 50% (IC50) at 1.0 x 10(-7) M. Chloroquine (IC50 2.3 x 10(-6) M), desethylchloroquine (IC50 7.0 x 10(-6) M), quinacrine (IC50 1.9 x 10(-6) M), and quinine (IC50 1.5 x 10(-5) M) were the least potent. All of the drugs caused time-dependent decreases in lactate excretion, except quinine; decreases were found to be dose dependent. A high correlation (r greater than 0.85) was seen between time-dependent effects on motility and lactate excretion. The effects of chloroquine (10 microM) on motility were also examined in female Acanthocheilonema viteae, Dirofilaria immitis, Onchocerca volvulus, and male Onchocerca gutturosa. Dirofilaria immitis was less sensitive to chloroquine than B. pahangi; A. viteae was equally sensitive. Species of Onchocerca were the most sensitive parasites studied. Adult O. gutturosa and O. volvulus were affected by 10 microM chloroquine within 4-6 hr; motility was reduced by 80% within 24 hr. Although the mechanism of anti-filarial activity of the quinoline-containing drugs is not known, their in vitro activity against a variety of adult filariae at clinically relevant concentrations, as well as differential sensitivity seen between the different filariae examined, warrants further study of these compounds.

Animals↗
PubMed1989

Effect of closantel on intrategumental pH in Schistosoma mansoni and Fasciola hepatica.

It has been proposed that the anthelmintic activity of the flukicide, closantel, is due to the drug's ability to interfere with the proton gradient in the parasite's mitochondria that in turn inhibits the generation of ATP by the parasite. Recent results using 31P-NMR suggest that this is not the primary target of the drug. We measured the effects of closantel on fluke intrategumental pH and observed a significant decrease (6.8 to 6.5). This decrease occurred within 10 min and at concentrations that were lower than those that produced significant changes in parasite ATP concentration. We also noted that this drug-induced change in intrategumental pH was associated with a marked reduction in fluke motility. Our results, when coupled to previous reports, would suggest that closantel is a membrane-active molecule that is capable of affecting a number of helminth biochemical and physiological processes.

Animals↗
PubMed1988

Effect of antischistosomal chemotherapy on prevalence of Symmers' periportal fibrosis in Sudanese villages.

Almost all mortality caused by Schistosoma mansoni is secondary to Symmers' periportal fibrosis of the liver which can now be diagnosed by ultrasonography. This study assessed the usefulness of ultrasonography in measuring the effect of chemotherapy on the prevalence of Symmers' periportal fibrosis in Sudanese villagers. The prevalence of Symmers' fibrosis in 318 randomly selected patients from two villages not receiving systemic antischistosomal chemotherapy was compared with that in 168 patients from a village where antischistosomal chemotherapy had been systematically applied since 1979. The prevalence of Symmers' fibrosis was two to three times lower among treated villagers, with an eight-fold difference for villagers aged 10-20 years.

Adolescent↗
PubMed1988

Schistosoma mansoni: evidence for protein kinase-C-like modulation of muscle activity.

The phorbol esters, phorbol-12,13-dibutyrate, phorbol-12-myristate-13-acetate, phorbol-12,13-didecanoate, and phorbol-12,13-diacetate, as well as mezerin at concentrations as low as 10 nM produce a spastic paralysis of the schistosome musculature. The action of these protein kinase-C activators is dependent on the sites of esterification and is stereo-specific since phorbol-13,20-diacetate, phorbol-12,13,20-triacetate, 20-oxo, 20-deoxy-beta-phorbol-12,13-dibutyrate, alpha-phorbol-12,13-didecanoate, and alpha-phorbol are inactive. A phospholipid and phorbol ester-dependent protein kinase is identified. This kinase is stimulated by all of the phorbol esters that increase muscle tone but is not stimulated by phorbol esters that do not affect muscle tone. A high affinity, stereo-specific phorbol ester receptor is identified. Dose-response curves of phorbol-12,13-dibutyrate-induced muscle tension and -stimulated kinase activity and receptor binding indicate that these responses are mediated by the same system. These results indicate that protein kinase-C-like enzyme may play an important role in modulating activity of the schistosome musculature.

Animals↗
PubMed1988

Hydrophilic polyphosphazenes as hydrogels: radiation cross-linking and hydrogel characteristics of poly[bis(methoxyethoxyethoxy)phosphazene].

The water-soluble polyphosphazene, [NP(OCH2CH2OCH2CH2OCH3)2]n, cross-links when exposed to gamma rays to form hydrophilic, water-swellable membranes and hydrogels. The degree of cross-linking increases with irradiation dose in a manner that can be utilized to change the properties. gamma irradiation studies of the small molecule model compound, [NP(OCH2CH2OCH2CH2OCH3)2]4, were also carried out to probe the relationship between irradiation dose and cross-link density.

Chemical Phenomena↗
PubMed1988

Pharmacology of ivermectin.

Ivermectin is a semi-synthetic macrocyclic lactone (Fig. I) active in single low doses against many parasites - particularly nematodes and arthropods. It has been registered for animal health use since early 1985, and was earlier this year approved for human use by the French Directorate o f Pharmacy and Drugs. Of particular interest is ivermectin's potential as a micro filaricide for treatment o f onchocerciasis. Clinical trials leave little doubt about the potential o f ivermectin as a therapeutic tool for symptomatic relief from the effects o f infection with Onchocerca volvulus, and the drug is also recognized to have potential in reducing transmission o f the parasite. The manufacturers (Merck, Sharp and Dohme) recently arranged to provide the drug free o f charge to the WHO for mass trials against onchocerciasis in 12 African and Central American countries. In this article we focus on the pharmacological properties o f ivermectin, with a brief consideration of its absorption, fate, excretion and side-effects, and a discussion o f its micro filaricidal action.

Journal Article↗
PubMed1988

Efficacy and tolerance of praziquantel in patients with Schistosoma mansoni infection and Symmers' fibrosis: a field study in the Sudan.

Ultrasonography was used in a village in the Gezira-Managil scheme in the Sudan to identify patients with Symmers' fibrosis. In a random sample from patients with active Schistosoma mansoni infection, 238 patients were found to have no liver involvement while 59 had Symmers' periportal fibrosis. Patients were treated with a single dose of 40 mg/kg body weight of praziquantel. Six months after dosing, 51% and 58% were cured of the infection with 81% and 84% reduction in egg burden in the Symmers' and non-Symmers' patients, respectively. The drug was equally well tolerated by the two groups. It is concluded that patients with Symmers' fibrosis respond to praziquantel and tolerate the drug in a similar manner to patients without Symmers'.

Drug Tolerance↗
PubMed1988

Diagnosis of pathologically confirmed Symmers' periportal fibrosis by ultrasonography: a prospective blinded study.

Symmers' periportal fibrosis of the liver is the major cause of morbidity and mortality in Schistosoma mansoni infection. The diagnosis is best established definitively by a wedge biopsy of the liver. The ability of abdominal ultrasonography to diagnose this condition was prospectively compared with two independent pathological examinations of wedge biopsies of the liver. Both pathologists and the ultrasonographer were unaware of the clinical diagnosis and each other's findings. Twenty-eight of 41 patients had Symmers' fibrosis by pathological examination and all were diagnosed correctly by ultrasonography prior to surgery. Symmers' fibrosis was not diagnosed by ultrasound in any of 10 patients without Symmers' fibrosis on biopsy. In 3 patients the diagnosis of Symmers' fibrosis was uncertain because the pathologists disagreed as to its presence. These results confirm the findings of previous studies and establish that ultrasonography is at least as sensitive as wedge biopsy in diagnosing Symmers' fibrosis.

Double-Blind Method↗
PubMed1988

Morbidity associated with Schistosoma mansoni infection as determined by ultrasound: a study in Gezira, Sudan.

Previous studies demonstrated the usefulness of ultrasonography in diagnosing Symmers' periportal fibrosis. The prevalence and grade of Symmers' fibrosis was determined using ultrasonography in two villages in the Gezira region of Sudan and compared to standard clinical criteria. In El Dar 18% and Abu Jin 13% of the population had Symmers' fibrosis by ultrasonography. In contrast, only 6.3% in El Dar and 5.2% in Abu Jin with Symmers' fibrosis had splenomegaly, thus most of the population with Symmers' fibrosis would not have been diagnosed clinically. The degree of involvement was estimated by a set of previously defined criteria which ranged from mild (grade 1) to severe (grade 3). Involvement was greatest between 20-30 years and followed the age peak egg excretion rate by 5 years. The prevalence and degree of splenomegaly as well as the portal and splenic vein diameters increased with grade. The presence of hepatomegaly did not correlate with increasing grade. Ultrasonography is a much more sensitive technique than clinical evaluation in estimating the degree of Symmers' fibrosis in this population. A more accurate assessment of involvement will allow a more rational approach to the study of the pathophysiology of this complication and its eventual control.

Adult↗
PubMed1988

Development of a novel in vitro equine anthelmintic assay.

An in vitro assay involving the use of a horse strongyle (Strongylus edentatus) and the micromotility meter has been developed to test for equine anthelmintic activity. Three commercially available equine anthelmintics (dichlorvos, ivermectin, and pyrantel pamoate) and an investigational drug (p-toluoyl chloride phenylhydrazone) were evaluated in this assay at four concentrations. After a 24-h incubation, greater than or equal to 10 micrograms/ml of all four drug treatments significantly (P less than or equal to 0.05) reduced the motility of ensheathed L-3 S. edentatus larvae, thereby indicating anthelmintic activity. Pyrantel pamoate also reduced motility at 1 microgram/ml, while the hydrazone significantly increased movement at this level. At 0.1 microgram/ml, none of the treatments significantly reduced motility; one treatment (dichlorvos) significantly increased larval motility. Incubation for 48 h resulted in significant activity (reduction in motility) at greater than or equal to 1 microgram/ml with two drugs (ivermectin, pyrantel pamoate); dichlorvos and the hydrazone reduced motility at greater than or equal to 10 micrograms/ml. None of the treatments significantly reduced motility at the lowest concentration (0.1 microgram/ml); however, at 48 h, two treatments (dichlorvos, hydrazone) significantly increased motility at the lowest concentration (0.1 microgram/ml). The in vitro S. edentatus motility assay proved to be sensitive, accurate and rapid. This assay system should be a valuable addition to tests used to identify potential equine anthelmintics, monitor helminth resistance to drugs, and perhaps define the kinetics and mode of action for drugs.

Animals↗
PubMed1988

In vitro response of Haemonchus contortus larvae harvested during different times of the patent period to anthelmintics.

Three commercially available ruminant anthelmintics and an investigational drug were evaluated for effects on the motor function/motility of third stage (ensheathed) Haemonchus contortus. Helminth ova were collected at one, five, nine and 13 weeks during the patent period, cultured to the third larval stage and assayed for sensitivity to four different drugs. All four drugs (100 and 10 micrograms ml-1) significantly affected the motility of third stage H contortus larvae cultured from eggs passed at each of the times examined. However, the investigational drug (p-toluoyl chloride phenylhydrazone, 10 micrograms ml-1) had a significantly greater effect on the motility of larvae harvested at 13 weeks than those cultured at nine weeks (32 per cent difference). No other significant differences in the motility response during the patent period were observed.

Albendazole↗
PubMed1988

Comparative effects of anthelmintics on motility in vitro of Onchocerca gutturosa, Brugia pahangi and Acanthocheilonema viteae.

The effects of standard anthelmintics on the motor activity in vitro of adult Onchocerca gutturosa, Brugia pahangi and Acanthocheilonema viteae were determined using a micromotility meter. Fresh adult males dissected from bovine tissues were the best source for observations on O. gutturosa. Parasites liber-ated by collagenase digestion showed poor viability and motility. Only segments of O. gutturosa females were obtainable by dissection and these were not able to sustain motility in vitro. Adult males and females of O. volvulus were active after collagenase digestion of human nodular tissue, but behaved so irregularly that satisfactory monitoring of their movements with the meter was not possible on a regular enough basis to permit quantitation of drug-induced changes. Inhibitory effects on motility of O. gutturosa, B. pahangi and A. viteae were produced by anthelmintics which showed macrofilaricidal effects in vivo in a laboratory rodent model, with the exception of the benzimidazoles. O. gutturosa was, however, much more sensitive than B. pahangi or A. viteae to the temporary paralyzing effects of levamisole and pyrantel. The utility of in vitro screening against O. gutturosa and B. pahangi was evaluated by determining the discriminatory capacity of the tests in detecting novel compounds with reproducible in vivo activity in the jird-B. pahangi/A. viteae model. The results suggested that this would be a valuable selective screening procedure. Although false positives were detected at the rate of 15-17% of the novel anthelmintic chemical series tested, no false negatives were allowed through the screen provided both O. gutturosa and B. pahangi were included.2=

Animals↗
PubMed1987

Fasciola hepatica: action in vitro of triclabendazole on immature and adult stages.

Under in vitro conditions in a balanced salt solution, triclabendazole was found to accumulate in significant amounts in both immature (3 week old) and adult Fasciola hepatica. A viable parasite was needed to concentrate the drug, but a high percentage of the compound was also bound by the dead worm. The drug could penetrate into liver flukes even when the oral route had been closed off by ligation, indicating that the drug can be taken up by transtegumentary absorption. A 24 hr exposure to triclabendazole, at 10-25 microM concentrations, was found to result in a strong inhibition of the parasite's motility. This effect was paralleled by dramatic changes in the worm's resting tegumental membrane potential. The onset of these actions was found to develop very slowly, and high drug levels had to accumulate within the parasite to initiate its immobilization. In addition to drug concentration and incubation time, physiological alterations observed were also dependent on other culture conditions, such as the presence or absence of serum albumin and the drug tissue/medium ratio. Biochemical examinations showed that triclabendazole significantly stimulated glucose derived acetate and propionate formation by adult liver flukes. Adenosine triphosphate levels were not changed even in the presence of high triclabendazole concentrations (25 microM). Likewise, the activities of various membrane associated adenosine triphosphatases were not altered by the drug. However, the ability of the drug to inhibit colchicine binding to microtubular protein purified from adult liver flukes suggested an interference of the drug with microtubular structure and function.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed1987

Schistosoma mansoni: measurement of Na+ ion activity in the tegument and the extracellular spaces using ion-selective microelectrodes.

Ion-selective microelectrodes were used to measure sodium ion activity (aNa) in the tegument and interstitial spaces in adult male Schistosoma mansoni. In RPMI 1640, aNa averaged 31 +/- 13 mM in the tegument, a value significantly less than that in the bathing medium. In the interstitial spaces, it averaged 72 +/- 17 mM, a value nearly the same as that in the bathing medium. In hypo- or hyperosmotic media, aNa in the interstitial spaces varied by a value commensurate with change in aNa in the medium, but aNa in the tegument was changed by only a small amount. Monensin (10 microM), low temperature (20 C), and ouabain (0.3 to 10 microM) all caused significant increases in aNa in the tegument. Hypo- and hyperosmotic media produced initial weight changes followed by gradual recovery back toward original weights. It is concluded that the schistosome is a volume regulating osmoconformer with osmolality of the extracellular fluid approximating that of the bathing medium, but that within the tegument of the parasite, Na+ concentration is controlled by active transport processes.

Animals↗