Studies on anthelmintics. XXXIV. Synthetic studies on stereoisomers of artemisin.
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Thiabendazole incorporated in the diet at a rate of 0.1%, fed to all animals over a period of 3 months, successfully eliminated the parasite from the colony. Samples taken 12 months after treatment were still negative for the parasite. During the period between the discovery of the organism and the preparation of the diet a course of piperazine citrate was administered at a rate of 2 g/litre in the drinking water in order to limit the spread of the infection.
An oral combination of piperazine and ivermectin was used over a 6-week period for treating three different colonies of mice or rats infested with Syphacia obvelata, Syphacia muris or Aspiculuris tetraptera. No acute toxic effect was found in transgenic lines of mice or rats with these products in a preliminary trial. The colonies were treated with piperazine, 2.1 mg/ml in tap water for 2 weeks, then with ivermectin, 0.007 mg/ml, in tap water for the third and fourth weeks, and finally with piperazine for two further weeks. Hygiene measures such as a complete cage change, thorough disinfection and cleaning of the rooms were associated with the treatment. All examinations subsequent to completion of treatment have proved negative for further parasites.
The nematocidal effect of doramectin was assessed by subcutaneous injection of 200 micrograms/kg (single dosage) in cattle with naturally acquired gastrointestinal nematode infection in Japan. This study consisted of two experiments. In experiment 1, animals were randomly divided into a doramectin group (n = 21) and a non-treated control group (n = 21) by fecal egg count. In experiment 2, another group of ivermectin treatment (n = 12) was prepared in addition to doramectin (n = 23) and control (n = 10) groups, by random assignment as in study 1. After doramectin or ivermectin treatment, the egg count/5 g of feces was measured by the sucrose centrifugal flotation method at intervals of 7 days until Day 21 in experiment 1 and at Days 7, 14, 21, 35, 42, 49 and 63 in experiment 2. Coproculture was also carried out using some of the fecal samples. In the 2 doramectin-treated groups, 96.1%-100% egg reduction rates were obtained for Haemonchus, Cooperia, Mecistocirrus, Trichostrongylus, Ostertagia, Bunostomum, Strongyloides and Trichuris from the 7th day until the 49th day after treatment. Thus doramectin was confirmed to be highly effective against those species of adult nematoda. The effect against Mecistocirrus has not been previously determined. The nematocidal effect against Nematodirus was lower (egg reduction rate approximately 50%) than other species. No adverse reactions to treatment were seen in any animal during either study.
The antiparasitic activity of racemic albendazole-sulphoxide (Ricobendazole = racRBZ) and its (+) and (-) enantiomers was tested in an ex vivo murine model for Trichinella spiralis infection. Larvae were isolated from the muscle of infected mice and exposed to concentrations between 0.01 and 1 microg/ml of the racemic mixture or to each of its enantiomers. The activity of each compound was then assayed by measuring the ability of the treated larvae to infect naive mice (larval viability). At a concentration of 0.5 microg/ml, all 3 compounds were highly effective in reducing the viability of the larvae, achieving reductions of 91.26% (racRBZ), 96.7% (+), and 89.2% (-), when compared with untreated controls. At lower concentrations (0.1 microg/ml), only treatment with (+)RBZ rendered a significant reduction in larval viability in comparison with controls (84.3%; P < 0.01), whereas at 0.01 microg/ml, none of the compounds altered larval viability (P > 0.05).
The effect of chronic intestinal trematode infection on malaria was examined in a murine model of co-infection using Echinostoma caproni and Plasmodium yoelii. BALB/c mice (n = 32) infected with a low dose of E. caproni (approximately 10 cysts) 25-35 days before malaria infection displayed significantly increased malaria parasitemia (P = 0.01), extended patency of malaria (P = 0.03), and increased fatality (47%; P < 0.001) compared to mice infected only with P. yoelii (17X nonlethal strain) (n = 18). Further analysis revealed that differences in malaria parasitemia between fatal co-infections and infections with P. yoelii only were highly significant (P < 0.0001), whereas nonfatal co-infections were not statistically different. Exacerbation of malaria was demonstrated to be reversible through clearance of E. caproni worms by praziquantel treatment administered 10 days before malaria infection. No deaths were observed during malaria infection in mice cleared of their E. caproni infection (n = 10), and parasitemia was significantly reduced from that of untreated co-infected mice (P = 0.03) and was not different from that of mice infected with P. yoelii only. Further studies examining parasite-parasite interactions and host immune response in the echinostome model are warranted to understand the mechanisms affecting the course and outcome of malaria infection during concomitant helminth infection.
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This article describes the drugs used in helminthic infections and their therapeutic indications, mode of action, toxicity and other details of each of the recommended drugs, and discusses the nature and treatment of infection by helminths important in human medicine. Infestation due to the roundworms Enterobius vermicularis, Ascaris lumbricoides and the hookworms, Ancylostoma duodenale and Necator americanus can all be treated effectively with pyrantel pamoate. For Enterobius vermicularis, however, a newer drug, mebendazole, is equally as effective. The advantage of these drugs in the indicated circumstances is that they can be administered in a single dose. Unfortunately, pyrantel pamoate is not a panacea and in the case of Necator it is not as effective as in the other roundworms. In that situation the use of tetrachlorethylene is preferable. For treatment of Strongyloides stercoralis, and important human parasite, because it can become disseminated and lead to fatal infections in immunoincompetent hosts, the only effective drug is thiabendazole. In treatment of Trichuris trichiura infection, mebendazole, administered over a period of 3 days, is the most effective available drug. For the roundworms inhabiting tissues--either as aberrant infections of man or as the normal part of their life cycle in man--therapy tends to be largely non-specific. For example, in visceral larva migrans, caused by the dog roundworm Toxocara canis, only palliative therapy with systemic anti-inflammatory agents and corticosteroids may be helpful. Cutaneous larva migrans, caused by the dog hookworms Ancylostoma brasiliensis and Ancylostoma caninum, is also treated primarily with symptomatic measures, but there is a suggestion that thiabendazole may kill the larvae and thus be effective. Trichinella spiralis may cause severe, even fatal infections in man, but only symptomatic therapy can be offered. Therapy for filarial infections is regrettably complicated and not completely effective. Diethylcarbamazine remains the best available drug, but in some of these infections local surgical excision may also be used. It is important to bear in mind that release of antigens from dying or dead worms may cause systemic inflammatory and allergic reactions that may require therapy with corticosteroids. Therapy for Cestodes is achieved most effectively with niclosamide, but the antimicrobial agent paromomycin has also been effective. For the aberrant cestode infections of man, such as echinococcal cysts or Taenia solium cycticerci, treatment is surgical if the affected areas are accessible. Treatment of schistosomal infections is quite toxic and, therefore, it is mandatory to determine viability of the worms before recommending therapy. If therapy is required, then Schistosoma mansoni infections are treated with stibophen and S. japonicum with antimony potassium tartrate, taking care in both of these instances to watch for the early signs of antimony toxicity; therapy of S. haematobium infections is based on administration of niridazole...
Three distinct chemical classes for the control of gastrointestinal nematodes are available: benzimidazoles, imidazothiazoles, and macrocyclic lactones. The relentless development of drug resistance has severely limited the usefulness of such drugs and the search for a new class of compounds preferably with a different mode of action is an important endeavor. Marcfortine A (1), a metabolite of Penicillium roqueforti, is structurally related to paraherquamide A (2), originally isolated from Penicillium paraherquei. Chemically the two compounds differ only in one ring; in marcfortine A, ring G is six-membered and carries no substituents, while in paraherquamide A, ring G is five-membered with methyl and hydroxyl substituents at C14. Paraherquamide A (2) is superior to marcfortine A as a nematocide. 2-Desoxoparaherquamide A (PNU-141962, 53) has excellent nematocidal activity, a superior safely profile, and is the first semi-synthetic member of this totally new class of nematocides that is a legitimate candidate for development. This review describes the chemistry, efficacy and mode of action of PNU-141962.
Heifers treated with ivermectin at weaning have been reported to reach puberty at a younger age and lighter weight than untreated heifers. We tested the hypothesis that heifers administered ivermectin would respond with earlier follicular development and a greater LH response to a 1-mg estradiol-17beta challenge (E2C) than untreated heifers. Fall-born Angus heifers (n = 32) were randomly assigned on 284 +/- 9 d of age (215.5 +/- 20.8 kg) to receive ivermectin (IVR) or albendazole (ALB), IVR + ALB, or to remain as untreated controls (CONT). Each group (n = 8) was housed separately in adjacent pens throughout the trial and managed to gain .8 kg/heifer on a ration containing 13.2% CP, 58.8% TDN, and 49.9% DM. The CONT heifers received an additional 2.27 kg/heifer of corn silage and 1.59 kg/heifer of corn daily to maintain ADG at comparable levels. Individual body weight was recorded weekly, and nematode eggs per gram (EPG) of feces were measured every 21 d. Ultrasonography was performed on alternate days starting 2 wk prior to E2C to characterize follicular wave patterns. Follicles were separated into classes (C1 [3 to 5 mm], C2 [6 to 9 mm], and C3 [10 mm]) and sizes (largest [LF], second [SLF], third [TLF], and fourth largest follicles [FLF]). The sizes of the regressing dominant follicle 1 (DF1) and the progressing dominant follicle 2 (DF2) were also determined. Serum concentrations of LH were determined from hourly jugular blood samples collected 8 to 24 h after injection of E2C. The IVR + ALB treatment group had more C3 follicles than ALB and CONT (P < .07). The IVR-treated heifers had larger TLF than ALB and CONT (P < .04). The IVR- and IVR + ALB-treated heifers had larger FLF and DF2 than ALB and CONT (P < .1). Least squares means for DF2 were 9.5 +/- .5, 8.0 +/- .4, 9.5 +/- .3 and 8.3 +/- .3 mm, for IVR, ALB, IVR + ALB and CONT, respectively (P = .02 for treatment effect). The E2C-induced serum LH concentration did not differ with respect to treatment. We conclude that heifers administered IVR display increased follicular development, supporting our earlier investigations regarding reduced age at puberty in heifers treated with IVR near weaning.
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1. Clioxanide and related compounds were deacetylated by the cestode Moniezia expansa, the nematode Ascaris suum, by enzymes prepared from these species and by mouse- and sheep-liver homogenates. Deacetylase activity was found in the cytosol of cestode proglottids throughout the strobila, and in the cytosol of nematode intestinal cells and reproductive tract. 2. The O-deacetylases from both helminths showed similar pH optima of about 7.0. Activity was enhanced by Ca2+ and low molecular weight thiols. Cu2+, Cd2+, Hg2+, Zn2+, and La2+ inhibited the deacetylation of clioxanide. 3. Resorantel and clioxanide were not hydrolysed at the amide bond by helminth or mammalian enzymes. 4. Resorantel was hydroxylated by mammalian microsomal enzymes, but helminths did not modify the molecule.
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The halogenated salicylanilides are a large group of compounds developed mainly for their antiparasitic activity in animals. Several halogenated salicylanilides with potent antiparasitic activity have been synthesised of which only closantel, niclosamide, oxyclozanide, rafoxanide and resorantel are commercially available. Closantel and rafoxanide, which represent the most important drugs in the group, are used extensively for the control of Haemonchus spp. and Fasciola spp. infestations in sheep and cattle and Oestrus ovis in sheep in many parts of the world. Niclosamide is used extensively for its anticestodal activity in a wide range of animals. Antiparasitic activity of the halogenated salicylanilides has also been demonstrated against a large number of other internal parasites, in particular haematophagous helminths, and external parasites including ticks and mites, in a variety of animal species. Several cases of toxicity and mortality have been reported for closantel and rafoxanide in sheep and goats. Their unique pharmacokinetic behaviour appears to play an important role in the efficacy and safety of these compounds. The chemical and physical characteristics, mode of action, pharmacokinetics, antiparasitic activity and toxicity of the halogenated salicylanilides in animals are reviewed.