The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells.
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Microtubules have a critical role in cell division, and consequently various microtubule inhibitors have been developed as anticancer drugs. In this study, we assess mebendazole (MZ), a microtubule-disrupting anthelmintic that exhibits a potent antitumor property both in vitro and in vivo. Treatment of lung cancer cell lines with MZ caused mitotic arrest, followed by apoptotic cell death with the feature of caspase activation and cytochrome c release. MZ induces abnormal spindle formation in mitotic cancer cells and enhances the depolymerization of tubulin, but the efficacy of depolymerization by MZ is lower than that by nocodazole. Oral administration of MZ in mice elicited a strong antitumor effect in a s.c. model and reduced lung colonies in experimentally induced lung metastasis without any toxicity when compared with paclitaxel-treated mice. We speculate that tumor cells may be defective in one mitotic checkpoint function and sensitive to the spindle inhibitor MZ. Abnormal spindle formation may be the key factor determining whether a cell undergoes apoptosis, whereas strong microtubule inhibitors elicit toxicity even in normal cells. (+info)
Bacillus thuringiensis crystal proteins that target nematodes.
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Bacillus thuringiensis (Bt) crystal proteins are pore-forming toxins used as insecticides around the world. Previously, the extent to which these proteins might also target the invertebrate phylum Nematoda has been mostly ignored. We have expressed seven different crystal toxin proteins from two largely unstudied Bt crystal protein subfamilies. By assaying their toxicity on diverse free-living nematode species, we demonstrate that four of these crystal proteins are active against multiple nematode species and that each nematode species tested is susceptible to at least one toxin. We also demonstrate that a rat intestinal nematode is susceptible to some of the nematicidal crystal proteins, indicating these may hold promise in controlling vertebrate-parasitic nematodes. Toxicity in nematodes correlates with damage to the intestine, consistent with the mechanism of crystal toxin action in insects. Structure-function analyses indicate that one novel nematicidal crystal protein can be engineered to a small 43-kDa active core. These data demonstrate that at least two Bt crystal protein subfamilies contain nematicidal toxins. (+info)
Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan.
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OBJECTIVES: This study sought to identify the risk factors associated with an outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) among Filipino laborers in Taiwan. METHODS: Forty-six SJS/TEN patients were matched to 92 controls according to month of arrival in Taiwan, sex, and age. RESULTS: The odds ratio for development of SJS/TEN was 9.5 (95% confidence interval [CI] = 3.9, 23.9) among workers who had used both metronidazole and mebendazole sometime in the preceding 6 weeks. In addition, a gradient increase in the occurrence of SJS/TEN was found with an increasing level of exposure to metronidazole. CONCLUSIONS: This outbreak highlights the risk of SJS/TEN resulting from the use of both metronidazole and mebendazole and the need for control measures. (+info)
Betagamma-dehydrocurvularin and related compounds as nematicides of Pratylenchus penetrans from the fungus Aspergillus sp.
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The new nematicidal compound, betagamma-dehydrocurvularin (1), together with three known compounds, alphabeta-dehydrocurvularin (2), 8-beta-hydroxy-7-oxocurvularin (3) and 7-oxocurvularin (4), were isolated from the culture filtrate and mycelial mats of Aspergillus sp. The structures of 1-4 were established by spectroscopic methods including 2D NMR. The biological activities of 1-4 were examined by bioassays with root-lesion nematodes, and lettuce and rice seedlings. (+info)
Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar.
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OBJECTIVE: To evaluate the efficacy of and resistance to mebendazole (500 mg) and levamisole (40 or 80 mg), alone or in combination, for the treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections on Pemba Island - an area exposed to periodic school-based mebendazole treatment since 1994. METHODS: A randomized, placebo-controlled trial was carried out in 914 children enrolled from the first and fifth grades of primary schools. Stool samples collected at baseline and 21 days after treatment were examined by the Kato-Katz technique to assess the prevalence and intensity of helminth infection. FINDINGS: Efficacies of mebendazole and levamisole as single treatments against intestinal nematode infections were comparable with those in previous trials, but mebendazole treatment of hookworm infections gave significantly lower cure (7.6%) and egg reduction (52.1%) rates than reported in a study undertaken before the beginning of periodic chemotherapy (cure rate, 22.4%; egg reduction rate, 82.4%). Combined treatment with mebendazole and levamisole had a significantly higher efficacy against hookworm infections (cure rate, 26.1%; egg reduction rate, 88.7%) than either drug given alone. No difference in mebendazole efficacy was found in children who had been treated repeatedly compared with those who had not been treated previously. CONCLUSION: The overall efficacy of mebendazole against hookworm infections after periodic chemotherapy is reduced. The efficacy of benzimidazoles in chemotherapy-based control programmes should be monitored closely. Combined treatment with mebendazole and levamisole may be useful as a tool to delay the development of benzimidazole resistance. (+info)
Modulation of the multidrug resistance (MDR) system in the nematode Haemonchus contortus by changing cholesterol content: effects on resistance to anthelmintics.
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OBJECTIVES: The efficiency of the anthelmintics used to treat small domestic ruminants infected with nematodes is compromised by the emergence of resistant parasites. Both specific and non-specific mechanisms of resistance exist. The non-specific mechanisms involve multiple resistance phenomena and are dependent on the multidrug resistance (MDR) system, which is also responsible for the development of chemotherapy-resistant tumour cells. We showed previously that the system also exists in nematodes. Membrane 'pumps', known as P-glycoproteins (Pgp), are activated in the MDR system. The nature of the membrane, in particular the lipids, appears to condition the activity of the pumps. Thus, we studied the effects of cholesterol on drug transport activity in the nematode Haemonchus contortus. MATERIALS AND METHODS: We used methyl-beta-cyclodextrin to carry out cholesterol depletion and cholesterol loading experiments. The resulting changes in resistance were estimated by measuring changes in drug transport (a) by means of in vitro egg hatch assays in the presence of a benzimidazole anthelmintic, thiabendazole and (b) by measuring the transport of rhodamine 123 (R123), a specific substrate of Pgp. We used biochemical assays to estimate the cholesterol concentration in the parasites. RESULTS: Changes in the cholesterol content induced changes in anthelmintic resistance; cholesterol depletion gave increased resistance and cholesterol loading gave decreased resistance. These changes also altered the transport of R123. CONCLUSION: Cholesterol depletion or cholesterol loading allow modulation of xenobiotic resistance in nematode eggs as they do in tumour cells. The effect appears to be correlated with changes in the function of membrane P-glycoproteins. The lipid environment thus influences the nematode Pgp activity. (+info)
Case report: Rectal adminstration of ivermectin to a patient with Strongyloides hyperinfection syndrome.
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Strongyloides hyperinfection syndrome may be complicated by paralytic ileus that interferes with the absorption of oral anti-helminthics. We report on the administration of ivermectin as a rectal enema preparation to a renal transplant recipient with Strongyloides hyperinfection syndrome and progressive ileus. Attempts at treatment using nasogastric albendazole and ivermectin were unsuccessful despite clamping the nasogastric tube after drug administration. Ivermectin tablets were ground to a powder, resuspended in a commercially available suspending agent, and administered per rectum. The suspending agent was chosen for its near-physiologic osmolality to allow longer retention, in contrast to many enema preparations that have a laxative effect. The patient improved markedly within 72 hours of initiation of the therapy per rectum and recovered fully. Ivermectin administered as an enema may be beneficial in patients with severe strongyloidiasis who are unable to absorb or tolerate oral therapy. (+info)
Percutaneous sonographically guided treatment of hydatid cysts in sheep: direct injection of mebendazole and albendazole.
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OBJECTIVE: The purpose of this study was to investigate the scolicidal effect of intracystic injection of benzimidazolic solutions in naturally infected sheep with hydatid disease. METHODS: Twenty-four sheep with 37 hydatid cysts were included in this study for percutaneous treatment with benzimidazolic solutions. The animals were divided into 3 groups: group I, treatment group with mebendazole; group II, treatment group with albendazole; and group III, control group with distilled water. All solutions were given percutaneously under sonographic guidance. Cyst contents were aspirated with a needle, and then scolicidal solutions were injected into the cysts; reaspiration was not done. Routine follow-up sonographic images were taken on the 15th day after treatment, then once per month for 3 months, and then at 3-month intervals thereafter. At the 1-month follow-up, the percutaneous aspirate yielded orange juice-like material containing necrotic debris without living scolices. RESULTS: Sonography showed a reduction in cyst size in the benzimidazolic groups (groups I and II) and progressive changes in echo patterns. An anaphylactic reaction was observed during the procedure in 1 animal. After 12 months of sonographic follow-up, the animals in all groups were killed, and macroscopic and microscopic changes in tissue samples were evaluated. At autopsy, no cysts with living scolices were found in the benzimidazolic groups, and the appearance of the treated cysts was different from that of those in the control group. Microscopic examination showed the degeneration, necrosis, and thickening of the cyst walls in the treatment groups. CONCLUSIONS: Intracystic injection of benzimidazolic solutions as scolicidal agents may be used for percutaneous treatment of hepatic hydatid cysts in sheep. (+info)