Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment

BACKGROUND: Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel. METHODS: We performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis. RESULTS: Mebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival. CONCLUSIONS: Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation

Low Dose Daily Iron Supplementation Improves Iron Status and Appetite but not Anemia, Whereas Quarterly Anthelminthic Treatment Improves Growth, Appetite and Anemia in Zanzibari Preschool Children.

Iron deficiency and helminth infections are two common conditions of children in developing countries. The consequences of helminth infection in young children are not well described, and the efficacy of low dose iron supplementation is not well documented in malaria-endemic settings. A 12-mo randomized, placebo controlled, double-blind trial of 10 mg daily iron and/or mebendazole (500 mg) every 3 mo was conducted in a community-based sample of 459 Zanzibari children age 6-71 mo with hemoglobin > 70 g/L at baseline. The trial was designed to examine treatment effects on growth, anemia and appetite in two age subgroups. Iron did not affect growth retardation, hemoglobin concentration or mild or moderate anemia (hemoglobin < 110 g/L or < 90 g/L, respectively), but iron significantly improved serum ferritin and erythrocyte protoporphyrin. Mebendazole significantly reduced wasting malnutrition. but only in children <30 mo old. The adjusted odds ratios (AORs) for mebendazole in this age group were 0.38 (95% CI: 0.16, 0.90) for weight-for-height less than -1 Z-score and 0.29 (0.09, 0.91) for small arm circumference. In children <24 mo old, mebendazole also reduced moderate anemia (AOR: 0.41, 0.18, 0.94). Both iron and mebendazole improved children's appetite, according to mothers' report. In this study, iron's effect on anemia was limited, likely constrained by infection, inflammation and perhaps other nutrient deficiencies. Mebendazole treatment caused unexpected and significant reductions in wasting malnutrition and anemia in very young children with light infections. We hypothesize that incident helminth infections may stimulate inflammatory immune responses in young children, with deleterious effects on protein metabolism and erythropoiesis

Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms : revival of an old drug

BACKGROUND: 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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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. CONCLUSIONSIGNIFICANCE: 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 launche

Mebendazole spectrophotometric determination: theorical and experimental study of the interaction with sodium hydroxide

USP, EP, and Argentinian Pharmacopoeia proposed HPLC-UV for quantitative quality control of mebendazole (MBZ) tablets. In this work, a spectrophotometric method is proposed. A mebendazole solution was prepared by dissolving the active ingredient in an ethanolic solution of HCl (1: 100) and adding NaOH 3N. It was allowed to stand 10 minutes. Absorbance spectrum was scanned between 350 and 700 nm. Maximum was found at 400 nm. A calibration curve in the range of 0.05 to 0.25 mg / mL, responded to A = (2.2746 ± 0.0224) C + (0.0012 ± 0.0068) with R2 = 0.9999. The RSD% was 0.961 indicating good repeatability for the analytical procedure. Accuracy in recovery experience was found to be 99.2 - 100.6%. Statistical comparison using t -test and F ?test indicate that there are no significant differences between HPLC and the spectrophometric methods, whith a 95% confidence level. Specificity and intermediate precision assays were satisfactory. Quantum theoretical chemistry was applied to elucidate the interaction that gives origin to the color, using static approximation and density functional theory, B3LYP and base 6-311G (d, p). Excitation energies B3LYP for MBZ and MBZ product of the interaction with sodium atom, were coincidental with experimental results.Fil: Delfino, Mario Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; ArgentinaFil: Monzón, Celina María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; ArgentinaFil: Jorge, Nelly Lidia. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Departamento de Química; ArgentinaFil: Sarno, María del Carmen Teresa. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Departamento de Química; Argentin

Development of an in vitro drug sensitivity assay for Trichuris muris first-stage larvae

Trichuriasis represents a major public health problem in the developing world and is regarded as a neglected disease. Albendazole and mebendazole, the two drugs of choice against trichuriasis display only moderate cure rates, hence alternative drugs are needed. To identify candidate compounds, in vitro drug sensitivity testing currently relies on the adult Trichuris muris motility assay. The objective of the present study was to develop a simple and cost-effective drug sensitivity assay using Trichuris muris first-stage larvae (L1).; Several potential triggers that induce hatching of T. muris were studied, including gastrointestinal enzymes, acidic environment and intestinal microflora. Next, optimal culture conditions for T. muris L1 were determined assessing a wide range of culture media. T. muris L1 were incubated in the presence of mebendazole, ivermectin, nitazoxanide, levamisole or oxantel pamoate at 37°C. The viability of the parasites was evaluated microscopically after 24 hours. The usefulness of fluorescent markers (resazurin, calcein AM, ethidium homodimer-1 or fluorescein-conjugated albumin) in drug sensitivity testing was also assessed.; The established L1 motility assay provided accurate and reproducible drug effect data in vitro. IC50 values for oxantel pamoate, levamisole and nitazoxanide were 0.05, 1.75 and 4.43 μg/mL, respectively. Mebendazole and ivermectin failed to show any trichuricidal effect on L1. No correlation was found between data from the four fluorescent markers and the comparative motility assay.; The motility assay based on L1 was found suitable for drug sensitivity screening. It is rather simple, cost-effective, time-saving and sustains medium-throughput testing. Furthermore, it greatly reduces the need for the animal host and is therefore more ethical. None of the viability markers assessed in this study were found to be satisfactory

Use of Micellar Liquid Chromatography to Determine Mebendazole in Dairy Products and Breeding Waste from Bovine Animals

Mebendazole is an anthelmintic drug used in cattle production. However, residues may occur in produced food and in excretions, jeopardizing population health. A method based on micellar liquid chromatography (MLC) was developed to determine mebendazole in dairy products (milk, cheese, butter, and curd) and nitrogenous waste (urine and dung) from bovine animals. Sample treatment was expedited to simple dilution or solid-to-liquid extraction, followed by filtration and direct injection of the obtained solution. The analyte was resolved from matrix compounds in less than 8 min, using a C18 column and a mobile phase made up of 0.15 M sodium dodecyl sulfate (SDS)–6% 1-pentanol phosphate buffered at pH 7, and running at 1 mL/min under isocratic mode. Detection was performed by absorbance at 292 nm. The procedure was validated according to the guidelines of the EU Commission Decision 2002/657/EC in terms of: specificity, method calibration range (from the limit of quantification to 25–50 ppm), sensitivity (limit of detection 0.1–0.2 ppm; limit of quantification, 0.3–0.6 ppm), trueness (92.5–102.3%), precision (<7.5%, expressed at RSD), robustness, and stability. The method is reliable, sensitive, easy-to-handle, eco-friendly, safe, inexpensive, and provides a high sample-throughput. Therefore, it is useful for routine analysis as a screening or quantification method in a laboratory for drug-residue control

School-Based Deworming Program Yields Small Improvement in Growth of Zanzibari School Children After one Year.

Efficacy trials of antihelminthic therapies conducted in Africa have reported improvements in children's growth, but nutritional evaluations of large-scale deworming programs are lacking. We evaluated the first-year effect on growth of a school-based deworming program in Zanzibar, where growth retardation occurs in school children. Children in four primary schools were given thrice-yearly mebendazole (500 mg) and compared with children in four schools that received twice-yearly mebendazole and children in four non-program schools. Evaluation schools were randomly selected and allocated to control, twice-yearly or thrice-yearly deworming. Approximately 1000 children in each program group completed the 1-y follow-up. Children <10 y old gained 0.27 kg more weight (P < 0.05) and 0.13 cm more height (P = 0.20) in the twice-yearly group, and 0. 20 kg more weight (P = 0.07) and 0.30 cm more height (P < 0.01) in the thrice-yearly group, compared with the control group. Children <10 y old with higher heights-for-age at baseline had higher weight and height gains in response to deworming. In children >/=10 y old, overall program effects on height or weight gains were not significant. But in this age range, younger boys had significant improvements in height gain with thrice-yearly deworming, and children with higher heights-for-age had greater improvements in weight gain with deworming. We conclude that the deworming program improved the growth of school children, especially children who were younger and less stunted, but the improvements were small. More effective antihelminthic regimens or additional dietary or disease control interventions may be needed to substantially improve the growth of school children in areas such as Zanzibar

Soil-transmitted helminth infections

More than a quarter of the world's population is at risk of infection with the soil-transmitted helminths Ascaris lumbricoides, hookworm (Ancylostoma duodenale and Necator americanus), Trichuris trichiura, and Strongyloides stercoralis. Infected children and adults present with a range of medical and surgical conditions, and clinicians should consider the possibility of infection in individuals living in, or returning from, endemic regions. Although safe and effective drugs are donated free to endemic countries, only half of at-risk children received treatment in 2016. This Seminar describes the epidemiology, lifecycles, pathophysiology, clinical diagnosis, management, and public health control of soil-transmitted helminths. Previous work has questioned the effect of population-level deworming; however, it remains beyond doubt that treatment reduces the severe consequences of soil-transmitted helminthiasis. We highlight the need for refined diagnostic tools and effective control options to scale up public health interventions and improve clinical detection and management of these infections

Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma.

Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib's target profile holds promise for the treatment of Hh-dependent cancers

Provision of medical supply kits to improve quality of antenatal care in Mozambique: a stepped-wedge cluster randomised trial

Background High levels of maternal and newborn mortality and morbidity remain a daunting reality in many low-income countries. Several interventions delivered during antenatal care have been shown to improve maternal and newborn outcomes, but stockouts of medical supplies at point of care can prevent implementation of these services. We aimed to evaluate whether a supply chain strategy based on the provision of kits could improve quality of care. Methods We did a pragmatic, stepped-wedge, cluster-randomised controlled trial at ten antenatal care clinics in Mozambique. Clinics were eligible if they were not already implementing the proposed antenatal care package; they served at least 200 new pregnant women per year; they had Maternal and Child Health (MCH) nurses; and they were willing to participate. All women attending antenatal care visits at the participating clinics were included in the trial. Participating clinics were randomly assigned to shift from control to intervention on prespecified start dates. The intervention involved four components (kits with medical supplies, a cupboard to store these supplies, a tracking sheet to monitor stocks, and a one-day training session). The primary outcomes were the proportion of women screened for anaemia and proteinuria, and the proportion of women who received mebendazole in the first antenatal care visit. The intervention was delivered under routine care conditions, and analyses were done according to the intention-to-treat principle. This trial is registered with the Pan African Clinical Trial Registry, number PACTR201306000550192. Findings Between March, 2014, and January, 2016, 218 277 antenatal care visits were registered, with 68 598 first and 149 679 follow-up visits. We found significant improvements in all three primary outcomes. In first visits, 5519 (14·6%) of 37 826 women were screened for anaemia in the control period, compared with 30 057 (97·7%) of 30 772 in the intervention period (adjusted odds ratio 832·40; 99% CI 666·81–1039·11; p<0·0001); 3739 (9·9%) of 37 826 women were screened for proteinuria in the control period, compared with 29 874 (97·1%) of 30 772 in the intervention period (1875·18; 1447·56–2429·11; p<0·0001); and 17 926 (51·4%) of 34 842 received mebendazole in the control period, compared with 24 960 (88·2%) of 28 294 in the intervention period (1·88; 1·70–2·09; p<0·0001). The effect was immediate and sustained over time, with negligible heterogeneity between sites. Interpretation A supply chain strategy that resolves stockouts at point of care can result in a vast improvement in quality during antenatal care visits, when compared with the routine national process for procurement and distribution of supplies. Funding Government of Flanders and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.Fil: Betrán, Ana Pilar. Organizacion Mundial de la Salud; ArgentinaFil: Bergel, Eduardo. World Health Organization; Suiza. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Griffin, Sally. International Centre For Reproductive Health; MozambiqueFil: Melo, Armando. Mozambique Ministry Of Health; MozambiqueFil: Nguyen, My Huong. World Health Organization; SuizaFil: Carbonell, Alicia. World Health Organization; SuizaFil: Mondlane, Santos. Consultório de Estatística E Serviço de Soluções; MozambiqueFil: Merialdi, Mario. World Health Organization; SuizaFil: Temmerman, Marleen. World Health Organization; SuizaFil: Gülmezoglu, A Metin. World Health Organization; SuizaFil: Aleman, Alicia. World Health Organization; SuizaFil: Althabe, Fernando. World Health Organization; Suiza. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Biza, Adriano. World Health Organization; SuizaFil: Crahay, Beatrice. World Health Organization; SuizaFil: Chavane, Leonardo. World Health Organization; SuizaFil: Colomar, Mercedes. World Health Organization; SuizaFil: Delvaux, Therese. World Health Organization; SuizaFil: Dique Ali, Ussumane. World Health Organization; SuizaFil: Fersurela, Lucio. World Health Organization; SuizaFil: Geelhoed, Diederike. World Health Organization; SuizaFil: Jille-Taas, Ingeborg. World Health Organization; SuizaFil: Malapende, Celsa Regina. World Health Organization; SuizaFil: Langa, Célio. World Health Organization; SuizaFil: Osman, Nafissa Bique. World Health Organization; SuizaFil: Requejo, Jennifer. World Health Organization; SuizaFil: Timbe, Geraldo. World Health Organization; Suiz