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On-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we conducted chemical screens and identified the antihelmintic flubendazole. Flubendazole induced cell death in leukemia and myeloma cell lines and primary patient samples at nanomolar concentrations. Moreover, it delayed tumor growth in leukemia and myeloma xenografts without evidence of toxicity. Mechanistically, flubendazole inhibited tubulin polymerization by binding tubulin at a site distinct from vinblastine. In addition, cells resistant to vinblastine because of overexpression of P-glycoprotein remained fully sensitive to flubendazole, indicating that flubendazole can overcome some forms of vinblastine resistance. Given the different mechanisms of action, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. Flubendazole synergized with vinblastine to reduce the viability of OCI-AML2 cells. In addition, combinations of flubendazole with vinblastine or vincristine in a leukemia xenograft model delayed tumor growth more than either drug alone. Therefore, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma.
The therapeutic activity of parenteral nocodazole was studied on four larval alveococcosis models: golden hamsters (Mesocricetus auratus), Djungarian hamsters (Phodopus sungorus campbelli Thomas), albino rats (Rattus rattus albus), and cotton rats (Sigmodon hispidus) at the late stage of E. multilocularis invasion. The agent (aqueous suspension) was intraperitoneally, intramuscularly, and subcutaneously injected in daily doses of 0.125-0.5 g/kg as 1-8 injections. Mebendazole was the drug of comparison. In the golden hamsters, one intraperitoneal nocodazole injection in daily doses of 0.25 and 0.5 g/kg caused death of all alveococcosis larvocysts whereas mebendazole 0.5 g/kg proved to be ineffective. In the Djungarian hamsters, one intraperitoneal nocodazole injection in a dose of 0.25 g/kg was fatal to alveococcosis larvocysts in 3 (75%) of the 4 animals. In the albino rats, nocodazole once administered intraperitoneally in a dose of 0.125 g/kg caused no death of all parasitic larvocysts, but inhibited their growth by 94.4%. The found alveococcus larvocysts were dead in all the cotton rats receiving nocodazole intramuscularly and subcutaneously 8 times in daily doses of 0.125 and 0.2 g/kg, respectively. Larvocystic death induced by nocodazole in animals with intensive invasion was accompanied by the high rate of collapse in larvocysts.
A rare case of ischemic stroke related to Herpes zoster infection of the eye and documented arteritis in an HIV-positive patient is analyzed. The woman, aged 32, who was born in Angola and lived in Zaire, was diagnoses at the Hospital Universitario de Santa Maria, Lisbon. She presented with a 5-month history of sudden hemiplegia, 4 months after onset of herpes zoster ophthalmicus. Among extensive diagnosis tests, she was positive for HIV by ELISA and Western blot, hepatomegaly, and generalized lymphadenopathy. She has left Herpes zoster ophthalmicus with ptosis bulbi and mottled discoloration of the skin over the distribution of the 1st division of the left trigeminal nerve, and right spastic hemiparesis. Her helper T-cell count was 952/cubic mm, and her T-cell ratio was 0.9. She had anemia, hypoalbuminemia, positive serology for cytomegalovirus, Herpes simplex, Epstein Barr virus, and hepatitis B. She had no bacterial infections, but her stool contained Trichuris trichiura eggs and giardia lamblia cysts. Her cardiovascular system and cerebrovascular fluid were negative. Computed tomography of the head showed an old left capsular infarct. Cerebral angiography showed arteritis of the left choroidal artery with occlusion. She was treated with metronidazole and mebendazole, and had surgery for removal of the left eye with a prosthetic replacement. Strokes are common in AIDS patients, resulting from fungal infections, endocarditis, infectious or non-infectious emboli, or arteritis from herpes zoster infections. This is the 1st published case of hemiplegia and Herpes zoster in a European or African patient with HIV-1.
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An analytical method is presented for liquid chromatographic (LC) determination of mebendazole (MBZ), hydroxymebendazole (MBZ-OH), and aminomebendazole (MBZ-NH2) in eel muscle tissue. Muscle tissue is extracted with ethyl acetate at pH 7.5. After addition of n-hexane, the extract is cleaned up and concentrated on an aminopropyl solid-phase extraction column. The test solutions are analyzed isocratically on a ChromSpher B LC column with acetonitrile-phosphate buffer, pH 6.2, as mobile phase. Limits of detection and quantitation were 0.7 and 1.1 micrograms/kg, respectively, for MBZ-OH; 1.4 and 2.3 micrograms/kg, respectively, for MBZ; and 1.5 and 2.1 micrograms/kg, respectively, for MBZ-NH2- Interand intraday coefficients of variation were 3.5 and 3.4%, respectively, for MBZ-OH; 2.5 and 3.1%, respectively, for MBZ; and 5.8 and 4.8%, respectively, for MBZ-NH2. Mean recoveries were 90% for MBZ, 74% for MBZ-NH2, and 92% for MBZ-OH. A linear range of applicability of at least 10-1000 micrograms/kg was found for each analyte. Incurred MBZ-NH2 (181.3 micrograms/kg) was identified in eel muscle tissue apart from MBZ (23.7 micrograms/kg) after 48 h exposure in a treatment bath containing MBZ at 1 mg/L.
Neglected parasitic infections, including Chagas disease, toxocariasis, cysticercosis, and toxoplasmosis, affect millions of persons in the United States. Relatively few resources have been devoted to surveillance, prevention, and treatment of these diseases. Chagas disease primarily affects Latin American immigrants and can cause heart failure and death if not treated. Immediate antiparasitic treatment is indicated for most patients with acute Chagas disease. Treatment is recommended for patients younger than 18 years who have chronic Chagas disease and is generally recommended for adults younger than 50 years who do not have advanced cardiomyopathy; treatment decisions for other patients should be made on an individual basis. Toxocariasis primarily affects children and can cause gastrointestinal, respiratory, and ophthalmologic disease. Treatment options include albendazole and mebendazole. Patients with ocular infection require referral to an ophthalmologist. Neurocysticercosis, a form of cysticercosis, is the most common infectious cause of seizures in some parts of the United States. Initial treatment should focus on symptom control. Humans generally acquire toxoplasmosis by eating undercooked contaminated meat or ingesting things that have been contaminated with cat feces. Congenital infection can result in miscarriage or adverse fetal effects. Treatment is recommended for immunosuppressed persons, pregnant women, and immunocompetent persons with severe symptoms.
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The effect of a combination of albendazole and mebendazole was evaluated by stool examination in 7 patients with Ascaris lumbricoides eggs, 7 patients with Trichuris trichiura eggs and 9 patients with hookworm eggs. Albendazole and mebendazole were given at 300 mg and 375 mg, respectively. Both drugs were divided into 3 parts, one part b. id., and given in 1.5 days. The fecal eggs turned negative in all the patients with Ascaris infection in 3 days, while the fecal eggs were negative in all patients with Trichuris or hookworm infection in 5 days. The development rates of the eggs were remarkably lower post-treatment than pre-treatment. It was found that the ovicidal rates in human ascariasis, trichuriasis and ancylostomiasis were 98.8%, 100% and 100%, respectively on the second day following the initiation of treatment. The results showed that the worm-repelling and ovicidal effect of the combined chemotherapy was more evident.
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In this study, we investigated the anthelmintic activity of -gingerol, -shogaol, -gingerol, -shogaol and hexahydrocurcumin, a constituent isolate from the roots of ginger (Zingiber officinale), for the parasite Angiostrongylus cantonensis. This study found that the above constituents killed A. cantonensis larvae or reduced their spontaneous movements in a time- and dose-dependent manner. The larvicidal effect or ability to halt spontaneous parasite movement of -shogaol, -gingerol, -gingerol, -shogaol and hexahydrocurcumin at various concentrations was reached from 24 to 72 h, respectively. Further investigation to determine minimal effective doses of -gingerol and hexahydrocurcumin revealed -gingerol to have a greater maximum larvicidal effect and loss of spontaneous movements than hexahydrocurcumin, mebendazole and albendazole. These constituents of ginger showed effects against DPPH and peroxyl radical under larvicidal effect. Together, these findings suggest that these constituents of ginger might be used as larvicidal agents against A. cantonensis.
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.