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Biomedical subjects

B M Greene

Publications and source records attributed to B M Greene.

At least 55 records · Page 3Linked to original sources
PubMed1988

Ivermectin prophylaxis against experimental Onchocerca volvulus infection in chimpanzees.

Ivermectin was tested for possible prophylactic action against the third and fourth larval stages (L3 and L4) of Onchocerca volvulus inoculated into chimpanzees. The infective larvae (L3) were obtained from laboratory-raised black flies. Eighteen chimpanzees were inoculated, each with approximately 250 L3. Six were treated with ivermectin (200 micrograms/kg) on the day of inoculation, 6 were treated with ivermectin on day 28, and 6 were not treated. Monthly skin snips were taken for the next 30 months to detect patent infection. One of the chimpanzees treated with ivermectin on the day of infection developed a patent infection as did 4 of the 6 treated at day 28 and 4 of the 6 control animals. The results suggest that ivermectin may have a partial in vivo effect against the L3 of O. volvulus but has no effect against later larval stages of the parasite.

Animals↗
PubMed1988

Effects of high doses of diethylcarbamazine on adult Onchocerca volvulus examined by the collagenase technique and by histology.

Thirty adult male nodule carriers from a hyperendemic onchocerciasis area in the Liberian rain forest were treated with high doses of diethylcarbamazine (30 mg/kg/d) over one week. Another ten patients received placebo tablets and served as a control. All detectable nodules were removed from half of the patients at two months and from the remaining patients at ten months after chemotherapy. The adult worms in the nodules were examined for pathological alterations by the collagenase technique including embryogram, and by histology. No macrofilaricidal effect was observed at either time, and no significant reduction of microfilariae in the uteri of the female worms or in the tissue of the nodules was seen. Two months after the therapy there was a significant increase of degenerated stretched intrauterine microfilariae but this effect was no longer observed after ten months. No pathological effect was seen on the intrauterine coiled microfilariae. On the contrary, their number had significantly increased after ten months which could mean a stimulation of the embryogenesis. No effect on spermatogenesis was observed. Both techniques, the collagenase digestion and the histological examination of the nodules, provided similar results to demonstrate that there was no marked long lasting effect on O. volvulus after a treatment with high doses of diethylcarbamazine.

Animals↗
PubMed1988

Histological examination of onchocercomata after therapy with ivermectin.

During chemotherapy trials in hyperendemic onchocerciasis areas in West Africa 15 adult nodule carriers in Liberia and 24 patients in Mali received single doses of ivermectin (150 or 200 micrograms/kg). Nodules were extirpated two, six and ten months after therapy and examined histologically. No macrofilaricidal effect of ivermectin was observed. Two months after therapy, in 93% of all female worms with intrauterine stretched microfilariae nearly all microfilariae were degenerated. The percentage was lower after ten months but still significantly higher than in untreated control groups. Ivermectin did not cause degeneration of the intrauterine coiled microfilariae. But the percentage of the female worms with coiled microfilariae was significantly lower two and ten months after therapy than that in the placebo or untreated control groups. Correspondingly, the percentage of nodules with intact microfilariae in the nodule tissue was also significantly lower throughout the examination period than that of the untreated control groups. There was not observed any effect on the spermatogenesis and spermatozoa were found frequently in the uteri of female worms. Using the method of histology, the long lasting inhibitory effect of a single dose of ivermectin on the intrauterine production of microfilariae could clearly be demonstrated. This proves the value of histology for the assessment of drug effects on adult O. volvulus.

Animals↗
PubMed1988

Chemotherapy of onchocerciasis with high doses of diethylcarbamazine or a single dose of ivermectin: microfilaria levels and side effects.

Fifty adult male subjects with moderate to heavy onchocerciasis from the Liberian rain forest were selected for a double-blind placebo-controlled chemotherapy study. The effects of high doses of diethylcarbamazine (DEC) - 30 mg/kg/d - over one week preceded by a one week initial treatment with normal oral doses of DEC or DEC lotion were compared with a single dose of ivermectin (150 micrograms/kg) and placebo. During the initial treatment DEC tablets or lotion caused distinctly more frequent and severe reactions than did invermectin. The reactions to ivermectin did not differ from those of the placebo patients. High doses of DEC caused, in about half of the patients, headache, dizziness, nausea or vomiting. DEC markedly increased the number of corneal microfilariae and of corneal opacities compared to ivermectin. All changes resolved with a return to pretreatment findings two months after treatment. The three treatment groups showed no differences at the ten months follow-up. In all treated patients skin microfilaria counts fell almost to zero by the end of the two week therapy. In the ivermectin group microfilaria counts remained significantly lower than in the DEC patients at the two and ten months examinations. In summary, ivermectin was much better tolerated than DEC and had a longer lasting effect on the microfilariae in the skin. Since high doses of DEC were less effective and caused more frequent and severe side effects, this approach cannot be recommended for treatment of onchocerciasis.

Adult↗
PubMed1987

Clq enhancement of IgG-dependent eosinophil-mediated killing of schistosomula in vitro.

Antibody-dependent eosinophil-mediated cytotoxicity plays a role in host protection against metazoan parasite invasion. We examined a possible role for Clq in eosinophil-mediated cytotoxicity by using a Schistosoma mansoni schistosomula killing system in vitro. The addition of monomeric purified human Clq enhanced IgG-dependent human eosinophil-mediated killing from 1.4-fold to 2.3-fold (mean percent killing 12% +/- 4 vs 21% +/- 4, p less than 0.005) when the immune IgG concentration was low. In contrast, there was no significant enhancement of neutrophil-mediated killing. When the IgG concentration was increased fourfold Clq did not cause enhancement of eosinophil-mediated killing (35% +/- 9 vs 37% +/- 5). Preincubation of eosinophils with type 1 collagen abrogated Clq enhancement of killing, raising the possibility of a receptor-mediated process, which depends upon cellular binding of Clq via the collagenous portion of the molecule. Eosinophils and neutrophils were examined for the presence of Clq receptors by using 125I labeled Clq. Clq binding to both cell types was saturable, reversible, and specific, indicating that binding is through specific receptors. Type 1 collagen inhibited binding of Clq to cells, suggesting that Clq binding is via the collagenous stalk of Clq. The number of receptors was approximately twice as high for eosinophils as compared with neutrophils (1.9 X 10(7) vs 1.1 X 10(7), p less than 0.025). Affinity constants for the two cell types were similar (1.5 X 10(7) vs 1.3 X 10(7). These findings suggest that Clq and receptors for Clq on eosinophils may be important for eosinophil-mediated schistosomula killing.

Animals↗
PubMed1987

Primate model for onchocerciasis research.

A major impediment to progress in research in onchocerciasis has been the lack of a suitable animal model. However, chimpanzees can be reliably infected by injection of living third-stage larvae of Onchocerca volvulus, and develop a pattern of infection that closely resembles that seen in humans. This includes the formation of nodules by adult worms, the subcutaneous distribution of microfilariae and the apparent lack of development of resistance to infection after repeated larval challenge. Ocular lesions resembling those in humans have not been observed in animals studied so far, but this may reflect in part the low intensity of infection and the limited time of observation. We infected 18 chimpanzees by subcutaneous injection of 250 third-stage larvae of O. volvulus. Six received ivermectin on day 1, another six received ivermectin on day 28 after infection, and six received no drug. Four control animals received no infective larvae and no drug. During the first year after infection, all three infected groups, but not control animals, have shown a clear increase in their lymphocyte blastogenic response to crude O. volvulus antigen in vitro. Antibody responses have also been increasing with time. Further assessment of the cellular and antibody responses in the infected chimpanzees is under way, as is evaluation of the effects of ivermectin on the course of infection.

Animals↗
PubMed1987

Controlled trial and dose-finding study of ivermectin for treatment of onchocerciasis.

Ivermectin, given as a single oral dose, has shown considerable promise as a new treatment for onchocerciasis. We assessed the safety and efficacy of ivermectin and tried to determine the optimal dose. Two hundred Liberians received 100, 150, or 200 micrograms of ivermectin/kg or placebo and were followed up for 12 months. Therapy was associated with only minimal systemic and ocular side effects. A 200-micrograms/kg dose was associated with greater systemic reaction than was a 100-micrograms/kg dose. Each treatment group had significant reduction in skin microfilaria counts by day 3 and a decrease of approximately 95% at three months. At three months the proportion of persons with no microfilariae in a specimen of skin was significantly less in the 100-micrograms/kg group than in the 150-micrograms/kg or 200-micrograms/kg groups. At 12 months, the level of microfilariae in skin was still reduced approximately 80%. Significant reduction in ocular involvement was seen in all groups. These results confirm that single-dose ivermectin is effective and well-tolerated and suggest that 150 micrograms of ivermectin/kg may be the optimal dose for initial therapy.

Clinical Trials as Topic↗
PubMed1987

Inhibition of the activation of Hageman factor (factor XII) by complement subcomponent C1q.

Hageman factor (HF, Factor XII) is activated by glass, collagen, and ellagic acid, and initiates blood coagulation via the intrinsic pathway. C1q inhibits collagen-induced platelet aggregation and adherence of platelets to glass, effects attributable to the collagen-like region of C1q. We examined the actions of C1q on HF activation. Incubation of C1q with HF before addition of HF-deficient plasma extended the activated partial thromboplastin time. Similarly, when glass tubes were coated with C1q before testing, the partial thromboplastin time of normal plasma was increased. C1q reduced the activation of HF by ellagic acid, as measured by the release of p-nitroaniline from the synthetic substrate H-D-prolyl-L-phenylalanyl-L-arginine-p-nitroanilide dihydrochloride, an effect inhibited by monoclonal anti-human C1q murine IgG and by digestion of C1q by collagenase. Thus, C1q inhibits activation of HF in vitro in clot-promoting and amidolytic assays and suggests a regulatory mechanism for the inhibition of coagulation.

Amides↗
PubMed1987

Ivermectin effect on microfilariae of Onchocerca volvulus after a single oral dose in humans.

Ivermectin is a broad spectrum anti-helminthic agent which is currently being tested for use in human onchocerciasis. Its activity is believed to result from its effect on GABA-mediated neurotransmission. We examined the effects of ivermectin on motility of microfilariae of O. volvulus following administration to humans. When ivermectin was given in dosages of 100, 150 and 200 mcg/kg on day 1 there was a clear reduction in motility of microfilariae obtained on day 3 when compared to microfilariae from the placebo group. The mean motility scores in microfilariae from ivermectin recipients were 3.1, 2.3, and 2.2 at 0, 12, and 24 hours of incubation compared to 3.3, 2.9, and 2.5, respectively, in microfilariae from placebo recipients (p less than 0.003, p less than 0.005, and p less than 0.012, respectively). Examination of the effect according to dose suggested a dose-response relationship. Microfilariae in the anterior chamber of the eye 2 days after a single oral dose of ivermectin showed abnormal and reduced winding and coiling. Microfilariae in 50% of ivermectin recipients showed abnormal motility compared to no such effects in subjects examined concurrently who received oral DEC, DEC lotion or placebo. These observations indicate that ivermectin has an effect on motility of microfilariae of O. volvulus following administration to humans.

Animals↗
PubMed1987

Sensitivity of skin snips in the diagnosis of onchocerciasis.

To find the optimum number and combination of skin snips for the diagnosis of onchocerciasis, data of six skin snips (two shoulder, two hip, two calf) taken from 776 Liberians aged 12 to 60 years were examined. From these data, proportions of positive skin snips from the hip, or hip and calf areas, for different levels of skin microfilaria density were calculated. These proportions were used in a mathematical model that examined 20 hypothetical populations with different levels of endemicity and skin microfilaria densities. The sensitivity of using two or four snips was then estimated. If only two snips were taken, two hip snips had the highest sensitivity (ranging from 80.7% to 100% according to the population). When the microfilaria density was high, the addition of two extra snips from the calf did not significantly improve the sensitivity. However, when the microfilaria density was low, the combination of two hip and two calf snips substantially improved the sensitivity (ranging from 80.7% to 94%). If fewer than six skin snips are desired for a particular field study, the choice of how many skin snips to be taken should be based on the expected precision required for that study. This in turn can be determined by skin microfilaria density. If such information is lacking, an estimate can be made from the findings of six snips from a small sample.

Adolescent↗
PubMed1986

The effects of ivermectin on transmission of Onchocerca volvulus.

Ivermectin, given to onchocerciasis patients as a single oral dose of 200 micrograms per kilogram of body weight, substantially reduced the uptake of Onchocerca volvulus microfilariae by Simulium yahense, an efficient black fly vector of the parasite in the tropical rain forests of West Africa. Three months after treatment, patients given ivermectin infected flies at a significantly lower rate than those who had received diethylcarbamazine or placebo, thereby reducing the number of developing larvae in the vector population. This diminished rate of infectiousness was also evident 6 months after treatment. These results strongly suggest that ivermectin could be effective in interrupting transmission of Onchocerca volvulus for epidemiologically important periods of time.

Humans↗
PubMed1986

Treatment of onchocerciasis. The ocular effects of ivermectin and diethylcarbamazine.

The ocular changes that occur with diethylcarbamazine treatment of onchocerciasis seriously restrict its usefulness. Ivermectin, a newly developed antifilarial drug, was compared with diethylcarbamazine for treatment of onchocerciasis in a double-masked, placebo-controlled trial. Thirty men with moderate to severe infection and ocular involvement were randomly assigned to receive ivermectin as a single oral dose (200 micrograms/kg), diethylcarbamazine (administered for eight days), or placebo. Detailed ocular examinations were performed serially over a 12-month period. Diethylcarbamazine treatment caused a marked increase in living and dead microfilariae in the cornea, punctate opacities, and limbitis during the first week of therapy. Ivermectin had no such effect. However, ivermectin therapy resulted in a long-term reduction in intraocular microfilariae comparable to that seen with diethylcarbamazine. Ivermectin appears to have few ocular complications and be a better-tolerated and more effective microfilaricidal agent than diethylcarbamazine for the treatment of onchocerciasis.

Adult↗
PubMed1986

Delayed isotype switching in Dirofilaria immitis infection.

The anti-microfilarial immunoglobulin response in Dirofilaria immitis infection was investigated serially in a naturally infected dog. Spontaneous clearance of microfilariae was associated with IgM opsonizing antibodies which promoted in vitro killing of microfilariae by granulocytes. Over a 6- to 11-month period, there was a shift to a predominantly IgG response. The addition of fresh non-immune serum markedly enhanced killing mediated by both IgM and IgG. The findings document conversion from IgM to IgG isotype with chronic infection, and suggest that isotype switching in canine D. immitis infection is delayed relative to that seen in bacterial or viral infections.

Animals↗
PubMed1985

Comparison of ivermectin and diethylcarbamazine in the treatment of onchocerciasis.

We compared ivermectin with diethylcarbamazine for the treatment of onchocerciasis in a double-blind, placebo-controlled trial. Thirty men with moderate to heavy infection and ocular involvement were randomly assigned to receive ivermectin in a single oral dose (200 micrograms per kilogram of body weight), diethylcarbamazine daily for eight days, or placebo. Diethylcarbamazine caused a significantly more severe systemic reaction than ivermectin (P less than 0.001), whereas the reaction to ivermectin did not differ from the reaction to placebo. Diethylcarbamazine markedly increased the number of punctate opacities in the eye (P less than 0.001), as well as the number of dead and living microfilariae in the cornea over the first week of therapy. Ivermectin had no such effect. Both ivermectin and diethylcarbamazine promptly reduced skin microfilaria counts, but only in the ivermectin group did counts remain significantly lower (P less than 0.005) than in the placebo group at the end of six months of observation. Analysis of adult worms isolated from nodules obtained two months after the start of therapy showed no effect of either drug on viability. Ivermectin appears to be a better tolerated, safer, and more effective microfilaricidal agent than diethylcarbamazine for the treatment of onchocerciasis.

Adult↗
PubMed1984

The effects of diethylcarbamazine, mebendazole and levamisole on Onchocerca volvulus in vivo and in vitro.

The effects of mebendazole, levamisole, diethylcarbamazine citrate (DEC-C), and the combination of mebendazole and levamisole, on adult Onchocerca volvulus and on the in utero development of microfilariae was studied in nodules excised from patients in Southern Mexico. Adult worms isolated from patients treated with mebendazole showed a reduction in mobility and contained 40 times fewer developing microfilarial forms than did worms from untreated patients. Most of the developmental forms found in adult worms from mebendazole-treated patients were either oocytes or early morulae, with more mature forms being scarce or morphologically abnormal. Treatment with levamisole had a similar effect on embryogenesis, however it was much less marked. The number and distribution of developing forms in worms from patients treated with DEC-C was similar to that found in the control groups. The effect of the same three drugs on microfilariae in vitro was also tested. DEC-C at concentrations of 0.5 microgram - 2000 micrograms/ml did not have any obvious effect on motility or morphology of the worms provided the pH was maintained at physiological levels; levamisole also had no effect in vitro. Mebendazole induced the death of microfilariae when used at concentrations greater than 100 micrograms/ml, however these levels are greater than those found in the blood of patients under treatment. The optimal conditions for short-term maintenance of O. volvulus microfilariae in culture, are discussed. It is apparent from these studies that mebendazole has an effect on the maturation of microfilariae in utero and may also, at high concentrations, have a direct effect on mature microfilariae.

Animals↗