pyrantel-pamoate and Disease-Models--Animal

It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations.. We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo.. We calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI) = 2.53). Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively). A highly synergistic effect (CI = 0.15) was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg) lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo.. Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be launched.

Topics: Ancylostoma; Ancylostomiasis; Animals; Anthelmintics; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Mice; Mice, Inbred C57BL; Necator americanus; Necatoriasis; Parasitic Sensitivity Tests; Pyrantel Pamoate; Treatment Outcome; Trichuriasis; Trichuris

Laboratory golden hamsters (Mesocricetus auratus) were infected with Necator americanus under several different parasite and host conditions to optimize the model for testing anthelminthic drugs. The results confirmed that male hamsters were more susceptible to infection than females. Host age in the range of 5-15 weeks was not a factor that impacted on adult worm burden, and similar worm burdens were achieved using doses of 150, 250 or 500 N. americanus L3 (NaL3). The largest numbers of adult hookworms were recovered on days 21-28 post-infection, with a significant decrease at days 40-50 post-infection. Therefore adult worm recovery is maximal approximately 11-18 days prior to patency and host blood loss. From these studies a drug evaluation protocol was developed using 150 NaL3 as the infectious dose and then evaluating the anthelminthic effects of the drugs albendazole, tribendimidine, and pyrantel pamoate on days 21-28 post-infection. The model confirms the anthelminthic activity of albendazole, tribendimidine, and pyrantel pamoate and has the potential as a laboratory animal model to detect emerging drug resistance.

Topics: Age Factors; Albendazole; Animals; Anthelmintics; Cricetinae; Disease Models, Animal; Erythrocyte Count; Female; Male; Mesocricetus; Necator americanus; Necatoriasis; Phenylenediamines; Pyrantel Pamoate; Sex Factors

Third-stage larvae of the major human and canine Ancylostoma hookworm species have the capacity to undergo developmental arrest in the somatic tissues of an infected host. Arrested larvae reactivate at opportune periods such as pregnancy, which results in the transmammary transmission of infection to the nursing neonates. Using murine paratenic hosts to focus specifically on tissue-arrested stages of Ancylostoma caninum, the present study found that neither recommended nor elevated doses of commonly used anthelmintics were effective in eliminating latent infections at the accepted standard of greater than 90% reduction in parasite burden. Of the drugs tested, i.e., pyrantel, fenbendazole, ivermectin, and milbemycin, ivermectin was the most effective and engendered an 80% reduction in the burden of tissue-arrested A. caninum larvae but only if administered repeatedly or at elevated doses. Studies in 2 inbred mouse strains, BALB/c (H-2b) and C57BL/6 (H-2d), that typically display divergent immune responses to various infections showed no significant differences in the efficacies of the drugs tested. The results of this study indicate that there is still a need for effective strategies of eradicating latent infections with tissue-arrested hookworm larvae.

Topics: Ancylostomiasis; Animals; Anti-Bacterial Agents; Antinematodal Agents; Disease Models, Animal; Dogs; Female; Fenbendazole; Humans; Ivermectin; Macrolides; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pyrantel Pamoate; Random Allocation

A laboratory model of acquired immunity to human hookworm is described. Significant resistance to challenge infection with Ancylostoma ceylanicum was elicited in mature DSN hamsters. The serum and mucosal antibody responses were investigated in both quantitative and qualitative terms and changes associated with immunity were identified. Marked differences in numbers of mast and goblet cells in the small intestine were also recorded and related to the immune status of the host.

Topics: Ancylostoma; Ancylostomiasis; Animals; Antibodies, Helminth; Blotting, Western; Body Weight; Cell Count; Cricetinae; Disease Models, Animal; Immunity; Immunization; Intestinal Mucosa; Intestine, Small; Male; Mast Cells; Parasite Egg Count; Pyrantel Pamoate

Adult Necator americanus infection in laboratory hamsters (the hamster-hookworm model) was examined as an anthelminthic screening system. Three reference anthelminthics--pyrantel (PYTL), mebendazole (MBZ) and ivermectin (IVRN)--were used to assess the sensitivity of adult N. americanus and also to investigate the value of the hamster-hookworm model for predicting clinical results. Serial drug dosages were used, and the ED50 was determined from the resulting cure rates. In addition, percentage worm reductions were calculated by reference to the worm burdens in control groups. The results showed that the hamster-hookworm model was able to differentiate anthelminthics on their efficacy. Absolute activity (100% worm reduction) followed treatment with 8 mg kg-1 MBZ, 38-40 mg kg-1 PYTL and 18 mg kg-1 IVRN. Based on ED50 data of PYTL and MBZ, adult N. americanus appeared to be two to five times more sensitive than pre-adult stages. However, with IVRN the reverse appeared true. MBZ appeared to be most active and PYTL least active in terms of curing infected animals, but there were no obvious differences between the rates of worm reductions following single or multiple doses of anthelminthics. It is considered that the hamster-hookworm model will prove of value in identifying and characterizing possible new anthelminthics.

Topics: Animals; Cricetinae; Disease Models, Animal; Humans; Ivermectin; Mebendazole; Mesocricetus; Necator; Necatoriasis; Pyrantel; Pyrantel Pamoate; Random Allocation