RESUMO
INTRODUCTION: Four species of the Mansonella genus infect millions of people across sub-Saharan Africa and Central and South America. Most infections are asymptomatic, but mansonellosis can be associated with nonspecific clinical manifestations such as fever, headache, arthralgia, and ocular lesions (M. ozzardi); pruritus, arthralgia, abdominal pain, angioedema, skin rash, and fatigue (M. perstans and perhaps Mansonella sp. 'DEUX'); and pruritic dermatitis and chronic lymphadenitis (M. perstans). AREAS COVERED: We searched the PubMed and SciELO databases for publications on mansonelliasis in English, Spanish, Portuguese, or French that appeared until 1 May 2023. Literature data show that anthelmintics - single-dose ivermectin for M. ozzardi, repeated doses of mebendazole alone or in combination with diethylcarbamazine (DEC) for M. perstans, and DEC alone for M. streptocerca - are effective against microfilariae. Antibiotics that target Wolbachia endosymbionts, such as doxycycline, are likely to kill adult worms of most, if not all, Mansonella species, but the currently recommended 6-week regimen is relatively impractical. New anthelmintics and shorter antibiotic regimens (e.g. with rifampin) have shown promise in experimental filarial infections and may proceed to clinical trials. EXPERT OPINION: We recommend that human infections with Mansonella species be treated, regardless of any apparent clinical manifestations. We argue that mansonellosis, despite being widely considered a benign infection, may represent a direct or indirect cause of significant morbidity that remains poorly characterized at present.
Assuntos
Anti-Helmínticos , Mansonelose , Adulto , Animais , Humanos , Mansonelose/complicações , Mansonelose/tratamento farmacológico , Mansonella , Ivermectina/uso terapêutico , Antibacterianos/uso terapêutico , Anti-Helmínticos/uso terapêutico , Artralgia/complicações , Artralgia/tratamento farmacológicoRESUMO
Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life.
RESUMO
Soil-transmitted helminthiasis (STH) is among the most common of parasitic infections, affecting vulnerable populations in tropical/subtropical areas globally. In endemic countries, children, a high-risk population, require treatment and preventive interventions. Mebendazole, a WHO-recommended medicine, originally formulated as a tablet that was often crushed for administration to young children unable to swallow it, was reformulated as a chewable tablet. Acceptability is a key aspect for treatment effectiveness in pediatrics. Herein, we used a validated data-driven approach to investigate the acceptability of the 500-mg mebendazole chewable tablet in children aged 2 to 4 years in Peru. Observer-reported outcomes were collected for 182 medicine intakes. Acceptability was scored using the acceptability reference framework: a three-dimensional map juxtaposing "positively accepted" and "negatively accepted" profiles. Results found that the 500-mg mebendazole chewable tablet was classified as "positively accepted" in children aged 2 to 4 years. Acceptability increased with age and some acceptability issue remain for the younger children. Nevertheless, this formulation was considerably better accepted than the conventional tablets regardless of treatment in young children. This chewable formulation appears to be an appropriate alternative to the hard tablet of mebendazole for treatment of STH and preventive interventions in children aged 2 to 4 years.
RESUMO
Although mebendazole (MBZ) has demonstrated antitumor activity in glioblastoma models, the drug has low aqueous solubility and therefore is poorly absorbed. Considering that other strategies are needed to improve its bioavailability, the current study was aimed to develop and evaluate novel microemulsions of MBZ (MBZ-NaH ME) for intranasal administration. MBZ raw materials were characterized by FTIR, DSC, and XDP. Subsequently, the raw material that contained mainly polymorph C was selected to prepare microemulsions. Two different oleic acid (OA) systems were selected. Formulation A was composed of OA and docosahexaenoic acid (3:1% w/w), while formulation B was composed of OA and Labrafil M2125 (1:1% w/w). Sodium hyaluronate (NaH) at 0.1% was selected as a mucoadhesive agent. MBZ MEs showed a particle size of 209 nm and 145 nm, respectively, and the pH was suitable for nasal formulations (4.5-6.5). Formulation B, which showed the best solubility and rheological behavior, was selected for intranasal evaluation. The nasal toxicity study revealed no damage in the epithelium. Furthermore, formulation B improved significantly the median survival time in the orthotopic C6 rat model compared to the control group. Moreover, NIRF signal intensity revealed a decrease in tumor growth in the treated group with MBZ-MaH ME, which was confirmed by histologic examinations. Results suggest that the intranasal administration of mebendazole-loaded microemulsion might be appropriated for glioblastoma treatment. Graphical abstract.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Emulsões/química , Glioblastoma/tratamento farmacológico , Mebendazol/administração & dosagem , Administração Intranasal , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Disponibilidade Biológica , Masculino , Mebendazol/farmacocinética , Mebendazol/uso terapêutico , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Água/químicaRESUMO
OBJECTIVE: To evaluate the effectiveness and tolerability of secnidazole combined with high-dose mebendazole for treatment of 5-nitroimidazole-resistant giardiasis. METHOD: Adults with microscopically verified Giardia intestinalis monoinfection attending a secondary level hospital in Matanzas City, Cuba were prospectively included in a cohort. A recently introduced treatment ladder consisting of metronidazole as first-line treatment, followed by secnidazole, tinidazole, secnidazole plus mebendazole and quinacrine as second-to fifth-line treatments, respectively, was used. Adverse events and treatment success were determined by questioning and microscopy on concentrated stool samples, respectively on days 3, 5 and 7 after the end of treatment. If G. intestinalis was detected on day 3, 5 or 7, then the infection was classified as refractory and no further microscopy was performed. RESULTS: A total of 456 individuals were included. Metronidazole, 500 mg three times daily for 5 days, cured 248/456 (54%) patients. A single 2-g secnidazole dose as second-line treatment cured 50/208 (24%) patients. A single 2-g tinidazole dose as third-line treatment cured 43/158 (27%) patients. Three rounds of 5-nitroimidazole therapy therefore cured 341/456 (75%) patients. Secnidazole plus mebendazole (200 mg every 8 hours for 3 days) cured 100/115 (87%) of nitroimidazole refractory infections. Quinacrine cured the remaining 15 patients. All treatments were well tolerated. CONCLUSIONS: 5-Nitroimidazole refractory giardiasis was common, indicating that an alternative first-line treatment may be needed. Retreatment of metronidazole refractory giardiasis with an alternative 5-nitroimidazole was suboptimal, indicating cross-resistance. Mebendazole plus secnidazole were well tolerated and effective for the treatment of 5-nitroimidazole refractory G. intestinalis infection in this setting.
Assuntos
Antiprotozoários/administração & dosagem , Giardíase/tratamento farmacológico , Mebendazol/administração & dosagem , Metronidazol/análogos & derivados , Quinacrina/administração & dosagem , Adulto , Idoso , Antiprotozoários/farmacologia , Cuba , Esquema de Medicação , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Fezes/parasitologia , Feminino , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/isolamento & purificação , Humanos , Masculino , Mebendazol/farmacologia , Metronidazol/administração & dosagem , Metronidazol/farmacologia , Pessoa de Meia-Idade , Nitroimidazóis/uso terapêutico , Estudos Prospectivos , Quinacrina/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
The objective of study was to examine the role of MBZ on malignant ascites cells and the involvement of C-MYC. Comet assay was used to assess the genotoxic effects of MBZ in AGP01 cells and human lymphocytes; differential staining by ethidium bromide and acridine orange, caspase 3/7 and flow cytometry assay was done to access the mechanisms of apoptosis and cell cycle analysis of MBZ in AGP01 cells. C-MYC amplification, C-MYC mRNA and C-MYC protein expression were evaluated by FISH, RT-qPCR and Western blotting, respectively. In addition, cytotoxicity of MBZ was evaluated in AGP01 and AGP01 shRNA MYC by MTT. MBZ significantly increased the damage index and no produced in human lymphocytes. MBZ caused remarkable cell cycle arrest in G0/G1 and G2/M phases at 0.5µM and 1.0⯵M, respectively and induced significantly apoptosis in higher concentrations. Additionally, MBZ (0.5⯵M and 1.0⯵M) increased caspase 3 and 7 activities. MBZ decreased signals, C-MYC mRNA and C-MYC protein expression in AGP01 cells. MBZ induced lower cell viability in AGP01 cells compared AGP01 shRNA MYC in the same concentration. Therefore, our results show the evidence of C-MYC gene as one of the pathways by which MBZ induces cell death in gastric cancer cells.
Assuntos
Ascite/tratamento farmacológico , Mebendazol/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Apoptose/efeitos dos fármacos , Ascite/genética , Ascite/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Humanos , Linfócitos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
Mebendazole (MBZ), designated as a WHO essential drug, can exist in diverse solid forms and presents low absorption at the gastrointestinal level. Considering the potential of cyclodextrins to enhance the solubility and permeability of drugs, inclusion complexes of polymorphs A and C of MBZ with ßcyclodextrin were obtained. The characterization of the complexes in solid state was performed by using a combination of experimental techniques including Fourier transform infrared spectroscopy, powder X-ray diffractometry and solid state nuclear magnetic resonance. Moreover, the effect of the binary complexes on their physical stability was evaluated. In addition, for a complete characterization of polymorphs A and C, one dimensional spectra and correlation nuclear magnetic resonance experiments were employed. Our physical studies showed that the inclusion complexes were new crystalline forms that induced shifts and broadening in the infrared and nuclear spectra. A molecular modelling analysis performed on the inclusion modes, demonstrated that the most favourable structure for the complex was the head down orientation. Moreover, the intermolecular interactions calculated for the complex with the atoms in molecules theory are in good agreement with the spectroscopic results. The inclusion complexes exhibited an increment of solubility in simulated physiological media. Furthermore, it was demonstrated that the complex formation did not affect the physical stability of the polymorphs.
Assuntos
Anti-Helmínticos/química , Mebendazol/química , beta-Ciclodextrinas/química , Cristalização , Modelos MolecularesRESUMO
BACKGROUND: Giardia duodenalis is the most common intestinal pathogenic protozoan infection reported in humans. Both in vitro studies and 4 separate, sequential, comparative clinical trials conducted by our group in Cuba demonstrated mebendazole activity against G. duodenalis infection in both children and adults. OBJECTIVE: The 2 additional, prospective, open-label, Phase IV follow-up studies reported here were performed to further assess the effectiveness and safety profile of mebendazole in the outpatient treatment of G. duodenalis infection. METHODS: Assenting children (nâ¯=â¯522) whose guardians gave permission and consenting adults (nâ¯=â¯423) diagnosed with G. duodenalis infection were given mebendazole (200 mg 3 times daily for 3 days). Medical histories and stool samples were obtained and physical/laboratory examinations were performed pretreatment then repeated on days 3, 5, and 7 after treatment completion. The evaluation of efficacy (ie, cure) was based on parasitologic response to therapy. Participants were considered cured, if no Giardia trophozoites or cysts were found in any of the 3 posttreatment fecal specimens evaluated by direct wet mounts and/or after Ritchie concentration techniques. RESULTS: No participant refused to be enrolled and all returned for follow-up examinations. At the end of the treatment, stool samples were negative in 450 out of 522 children (86.2%) and 392 of 423 adults (92.7%). Treatment was well tolerated. In adults, the only adverse effect reported was abdominal pain (6.2%). Side effects reported in children included abdominal pain (5.6%), nausea (2.9%), and vomiting (2.3%). Reported side effects were all mild, transient, and self-limited and did not require discontinuation of treatment or additional medication. CONCLUSIONS: Mebendazole may be an effective alternative treatment of G. duodenalis infections in both children and adults.
RESUMO
Glioblastoma (GBM) is a very aggressive tumor that has not had substantial therapeutic improvement since the introduction of temozolomide (TMZ) in combination with radiotherapy. Combining TMZ with other chemotherapeutic agents is a strategy that could be further explored for GBM. To search for molecular predictors of TMZ resistance, the TCGA (The Cancer Genome Atlas) database was utilized to assess the impact of specific genes on TMZ response. Patients whose tumors expressed low levels of FGFR3 and AKT2 responded poorly to TMZ. Combination treatment of vinblastine (VBL) plus mebendazole (MBZ) with TMZ was more effective in reducing cell number in most cultures when compared to TMZ alone, especially in cells with low expression levels of FGFR3 and AKT2. Cell cycle distribution and nuclear morphometric analysis indicated that the triple combination of TMZ, VBL and MBZ (TVM) was able to induce polyploidy and senescence, in addition to increasing the Notch3 RNA level in patient-derived gliomas. Thus, this set of data suggests that the triple combination of TMZ, VBL and MBZ may be a considerable therapeutic alternative for the TMZ-tolerant gliomas that harbor low expression of FGFR3/AKT2.
Assuntos
Anti-Helmínticos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Glioma/tratamento farmacológico , Mebendazol/uso terapêutico , Temozolomida/uso terapêutico , Vimblastina/uso terapêutico , Anti-Helmínticos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioma/genética , Humanos , Mebendazol/farmacologia , Fenótipo , Poliploidia , Temozolomida/farmacologia , Vimblastina/farmacologiaRESUMO
Este trabalho teve por finalidade desenvolver um método para a caracterização do perfil de dissolução de suspensões de mebendazol (MBZ), discriminatório para as formas polimórficas do fármaco. Pertencendo a classe II do Sistema de Classificação Biofarmacêutica (SCB), além da baixa solubilidade, o MBZ é bastante crítico por apresentar-se comercialmente disponível em duas formas polimórficas (A e C) e misturas destas. Além disso, pouca informação é encontrada acerca de métodos de dissolução de suspensões. O material apresentado está dividido em três capítulos, sendo o primeiro deles uma revisão da literatura sobre a dissolução de suspensões de fármacos que apresentam polimorfismo. Neste capítulo é feita uma abordagem sobre questões relacionadas ao desenvolvimento de métodos, como inserção das amostras na cuba de dissolução, agitação, uso de tensoativos no meio e a quantificação do fármaco. No segundo capítulo é apresentado o desenvolvimento do método de dissolução, com ênfase no estudo da solubilidade das formas polimórficas A e C de MBZ e sua interação com tensoativos. Foram realizados ensaios de solubilidade pelo método do equilíbrio, cálculo de concentração micelar crítica para os tensoativos lauril sulfato de sódio e polissorbato 80, sendo ao final realizado delineamento experimental (DOE) para o desenvolvimento do método. Pela avaliação do DOE, o local de inserção da amostra não influencia a dissolução de MBZ, por outro lado, a presença de tensoativo, assim como a forma polimórfica empregada, exercem efeito nos resultados apresentados. A partir destas informações, o método indicado para avaliação das suspensões de MBZ com potencial discriminatório de suas formas polimórficas foi definido pela utilização do aparato 2 (pá) a 75 rpm, com 2 litros de HCl 0,1 M sem tensoativo, como meio de dissolução. No último capítulo, o método desenvolvido foi utilizado na avaliação de especialidades farmacêuticas adquiridas no Brasil e em alguns países da América Latina, sendo os respectivos perfis de dissolução, comparados por meio de uma análise multivariada de componentes principais, com formulações contendo o MBZ em diferentes proporções de polimorfos. A partir dos resultados, foi possível observar que grande parte das formulações comercializadas não apresentaram perfil de dissolução satisfatório, isso pode estar relacionado com a presença considerável de polimorfo A nas matérias-primas utilizadas, comprometendo assim a sua solubilidade
The aim of this work was to develop a method for characterization of the dissolution profile of mebendazole (MBZ) suspensions, being discriminatory for the polymorphic forms of the drug. MBZ belongs to class II of the Biopharmaceutics Classification System (BCS), besides its low solubility, it is very critic, being commercially available in two polymorphic forms (A and C) and their mixtures. Moreover, there is low information about dissolution methods for suspensions. The text presented herein is divided into three chapters, the first chapter is a literature review about dissolution of suspensions containing drugs that present polymorphism. In this chapter is made a discussion about the variables of the method, as sample insertion in the dissolution vessel, rotation speed, use of surfactants in the dissolution medium and drug quantification. The development of the dissolution method, focused on the solubility study of MBZ polymorphic forms A and C and their interaction with surfactants is presented in the chapter 2. Some tests were performed: solubility using shake flask method, calculation of micellar critical concentration for the surfactants sodium lauryl sulphate and polysorbate 80, and an experimental design (DOE) was done for developing the method. By DOE evaluation, the sample insertion site does not influence on MBZ dissolution, but the presence of surfactant and the polymorphic form used, show effect on the results. Based on these information, the method indicated for evaluation of MBZ suspensions, with discriminatory power for its polymorphic forms was defined by using apparatus 2 (paddle) at 75 rpm and 2 L of 0.1M HCl without surfactant as dissolution medium. In chapter 3, the method developed was used to evaluate pharmaceutical suspensions from Brazil and from some countries of Latin America. The respective dissolution profiles were compared by means of multivariate analysis of principal components with formulations containing MBZ in different polymorphs ratios. From the results, it was possible to observe that a great part of the commercially available formulations do not presented a satisfactory dissolution profile, and this fact can be related to a considerable amount of the crystalline form A in the raw material, which compromises its solubility
Assuntos
Suspensões , Dissolução/métodos , Mebendazol/análiseRESUMO
The present study aimed to investigate whether MBZ down-regulates drug transporter expression (ABCB1, ABCC1, SLC47A1). mRNA expression level of ABCB1, ABCC1 and SLC47A1 was evaluated by qPCR and protein expression levels MDR-1 was performed by western blotting in malignant ascites cells (AGP-01) treated with MBZ for 24h. The mRNA expression level of ABCB1 and ABCC1 significantly decreased at a 1.0µM of MBZ compared to negative control, while SLC47A1 extremely decreased at all tested concentrations of MBZ. Protein expression levels MDR-1 significantly decreased at a 1.0µM of MBZ compared to negative control. Therefore, our results showed MBZ may play an important role in inhibiting MDR gene expression in malignant ascites cells.
Assuntos
Antiparasitários/farmacologia , Mebendazol/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Proteínas de Membrana Transportadoras/genética , RNA Mensageiro/metabolismoRESUMO
Cryptococcus neoformans is the most lethal pathogen of the central nervous system. The gold standard treatment of cryptococcosis, a combination of amphotericin B with 5-fluorocytosine, involves broad toxicity, high costs, low efficacy, and limited worldwide availability. Although the need for new antifungals is clear, drug research and development (R&D) is costly and time-consuming. Thus, drug repurposing is an alternative to R&D and to the currently available tools for treating fungal diseases. Here we screened a collection of compounds approved for use in humans seeking for those with anti-cryptococcal activity. We found that benzimidazoles consist of a broad class of chemicals inhibiting C. neoformans growth. Mebendazole and fenbendazole were the most efficient antifungals showing in vitro fungicidal activity. Since previous studies showed that mebendazole reaches the brain in biologically active concentrations, this compound was selected for further studies. Mebendazole showed antifungal activity against phagocytized C. neoformans, affected cryptococcal biofilms profoundly and caused marked morphological alterations in C. neoformans, including reduction of capsular dimensions. Amphotericin B and mebendazole had additive anti-cryptococcal effects. Mebendazole was also active against the C. neoformans sibling species, C. gattii. To further characterize the effects of the drug a random C. gattii mutant library was screened and indicated that the antifungal activity of mebendazole requires previously unknown cryptococcal targets. Our results indicate that mebendazole is as a promising prototype for the future development of anti-cryptococcal drugs.
RESUMO
Structural polymorphism of active pharmaceutical ingredients (API) is a relevant concern for the modern pharmaceutical industry, since different polymorphic forms may display dissimilar properties, critically affecting the performance of the corresponding drug products. Mebendazole (MEB) is a widely used broad spectrum anthelmintic drug of the benzimidazole class, which exhibits structural polymorphism (Forms A-C). Form C, which displays the best pharmaceutical profile, is the recommended one for clinical use. The polymorphs of MEB were prepared and characterized by spectroscopic, calorimetric and microscopic means. The polymorphs were employed to develop a suitable chemometrics-assisted sample display model based on the first two principal components of their ATR-FTIR spectra in the 4000-600 cm(-1) region. The model was internally and externally validated employing the leave-one-out procedure and an external validation set, respectively. Its suitability for revealing the polymorphic identity of MEB in tablets was successfully assessed analyzing commercial tablets under different physical forms (whole, powdered, dried, sieved and aged). It was concluded that the ATR-FTIR/PCA (principal component analysis) association is a fast, efficient and non-destructive technique for assigning the solid-state forms of MEB in its drug products, with minimum sample pre-treatment.
Assuntos
Mebendazol/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Comprimidos/química , Química Farmacêutica/métodos , Cristalização/métodos , Pós/química , Análise de Componente Principal/métodosRESUMO
This work evaluates the feasibility of using NIR spectroscopy for quantification of three polymorphs of mebendazole (MBZ) in pharmaceutical raw materials. Thirty ternary mixtures of polymorphic forms of MBZ were prepared, varying the content of forms A and C from 0 to 100% (w/w), and for form B from 0 to 30% (w/w). Reflectance NIR spectra were used to develop partial least square (PLS) regression models using all spectral variables and the variables with significant regression coefficients selected by the Jack-Knife algorithm (PLS/JK). MBZ polymorphs were quantified with RMSEP values of 2.37% w/w, 1.23% w/w and 1.48% w/w for polymorphs A, B and C, respectively. This is an easy, fast and feasible method for monitoring the quality of raw pharmaceutical materials of MBZ according to polymorph purity.
Assuntos
Anti-Helmínticos/análise , Contaminação de Medicamentos , Mebendazol/análise , Espectroscopia de Luz Próxima ao Infravermelho , Tecnologia Farmacêutica/métodos , Química Farmacêutica , Estudos de Viabilidade , Análise dos Mínimos QuadradosRESUMO
The present study aimed to investigate the effects of MBZ on a human malignant ascites cell line derived from a primary gastric cancer tumor. Our data reveal that MBZ showed high cytotoxicity in vitro, displaying an IC50 of 0.39 µM and 1.25 µM in ACP-02 and ACP-03, respectively. The association between MBZ and 5-FU increased slightly the cytotoxicity when compared to MBZ and 5-FU alone. Furthermore, MBZ disrupted the microtubule structure of AGP-01 cells and inhibited significantly the invasion and migration of these cells. Activity of active MMP-2 significantly decreased at all tested concentration of MBZ compared to negative control. These results support the indication of MBZ in combination with chemotherapeutic agents as a possible adjuvant therapy for the management/treatment of patients with advanced gastric cancer since MBZ is a drug of low cost with acceptable safety profile and reduced toxicity to normal cells. However, clinical trials must be performed in o to evaluate its efficacy in gastric cancer patients.
Assuntos
Adenocarcinoma/tratamento farmacológico , Mebendazol/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Invasividade NeoplásicaRESUMO
SUMMARYThe efficacy of nitazoxanide (NTZ) against toxocariasis was investigated in an experimental murine model and results were compared to those obtained using mebendazole. Sixty male BALB/c mice, aged six to eight weeks-old, were divided into groups of 10 each; fifty were orally infected with 300 larvaed eggs of T. canisand grouped as follows, G I: infected untreated mice; G II: infected mice treated with MBZ (15 mg/kg/day) 10 days postinfection (dpi); G III: infected mice treated with NTZ (20 mg/kg/day) 10 dpi; G IV: infected mice treated with MBZ 60 dpi; G V: infected mice treated with NTZ 60 dpi; GVI: control group comprising uninfected mice. Mice were bled via retro-orbital plexus on four occasions between 30 and 120 dpi. Sera were processed using the ELISA technique to detect IgG anti- Toxocaraantibodies. At 120 dpi, mice were sacrificed for larval recovery in the CNS, liver, lungs, kidneys, eyes and carcass. Results showed similar levels of anti- ToxocaraIgG antibodies among mice infected but not submitted to treatment and groups treated with MBZ or NTZ, 10 and 60 dpi. Larval recovery showed similar values in groups treated with NTZ and MBZ 10 dpi. MBZ showed better efficacy 60 dpi, with a 72.6% reduction in the parasite load compared with NTZ, which showed only 46.5% reduction. We conclude that administration of these anthelmintics did not modify the humoral response in experimental infection by T. canis. No parasitological cure was observed with either drug; however, a greater reduction in parasite load was achieved following treatment with MBZ.
RESUMOFoi investigada a eficácia da nitazoxanida (NTZ) na toxocaríase murina experimental e os resultados comparados com os obtidos usando mebendazol (MBZ). Sessenta camundongos BALB/c machos, com idade entre seis e oito semanas foram divididos em grupos de 10 cada, 50 foram infectados oralmente com 300 ovos larvados de T. canise agrupados a seguir: GI: camundongos infectados não tratados; GII: camundongos infectados tratados com MBZ (15 mg/kg/dia) 10 dias pós-infecção (dpi); GIII: camundongos infectados tratados com NTZ (20 mg/kg/dia) 10 dpi, GIV: camundongos infectados tratados com MBZ 60 dpi; GV: camundongos infectados tratados com NTZ 60 dpi; GVI: controle não infectado. Os camundongos foram sangrados via plexo retro orbitário em quatro ocasiões entre o 30º e 120º dpi. Os soros foram processados pela técnica de ELISA para detecção de anticorpos IgG anti- Toxocara.Aos 120 dpi, os animais foram sacrificados para a recuperação larvária do SNC, fígado, pulmões, rins, olhos e carcaça. Os resultados mostraram níveis similares de anticorpos IgG anti- Toxocaraentre os camundongos infectados mas não submetidos a tratamento e os grupos infectados e tratados com MBZ ou NTZ, aos 10 e 60 dpi. Os valores da recuperação larval foram similares nos grupos tratados com NTZ e MBZ 10 dpi. MBZ mostrou melhor eficácia aos 60 dpi, com redução de 72,6% da carga parasitária comparada com NTZ, que mostrou redução somente de 46,5%. Concluímos que a administração destes anti-helmínticos não modificou a resposta humoral na infecção experimental por T. canis. Não foi observada cura parasitológica com nenhuma das drogas; porém maior redução na carga parasitária foi obtida após o tratamento com MBZ.
Assuntos
Animais , Masculino , Camundongos , Anti-Helmínticos/administração & dosagem , Anticorpos Anti-Helmínticos/sangue , Mebendazol/administração & dosagem , Tiazóis/administração & dosagem , Toxocara canis/efeitos dos fármacos , Toxocaríase/tratamento farmacológico , Modelos Animais de Doenças , Imunidade Humoral , Larva/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Contagem de Ovos de Parasitas , Toxocaríase/imunologiaRESUMO
Para avaliar a atividade anti-helmíntica conduziu-se um estudo controlado. Dezoito éguas, com peso entre 300 kg e 600 kg, naturalmente infectados foram distribuídas após randomização em três grupos homogêneos com seis animais cada. O grupo controle solução fisiológica (Grupo I), grupo Gil tratado com Platelmin Pasta equino~ (mebendazol 10 mg/kg), grupo Gil tratado com Ivermectina Pasta equlno" (ivermectina 200 pg/kg). Contagens de ovos por gramas de fezes (OPG), foram realizadas nos dias -2, -1, O (dia do tratamento), 3, 7, 14, 21 e 28 pós-tratamento. Os dados coletados foram transformados em log (x + 1) e analisados em um delineamento inteiramente casualizado. A contagem de OPG do grupo controle permaneceu entre 378 a 766 durante todo o período experimental. De acordo com as quantificações, foram observadas eficácias de 100% no grupo tratado com Ivermectina e 88% no grupo tratado com mebendazol. Ambos os medicamentos mostram-se eficazes na redução de OPG. (AU)
To evaluate the anthelmintic activity was conducted a controlled study. Eighteen mares, weighing between 300 kg and 600 kg, naturally infected were distributed after randomization into three homogeneousgroups of six animais each. The control group treated with saline (Group I), Gil group treated with PlatelminPasta equíno" (mebendazole 10 mg / kg), Gil group treated with Ivermectina Paste equino~ (ivermectin 200mcg/kg). EPG (eggs per gram ofteces) counts were performed on days -2, -1, O (day oftreatment), 3, 7,14,21 and 28 post-treatment. The collected data were transformed into log (x + 1) and analyzed in a completely randomized designo The EPG control group remained between 378 and 766 during ali experimental period.According to the measurements, 100% of efficacy were observed in the group treated with Ivermectin and88% in the group treated with mebendazole. Both drugs are effective in the reduction of eggs per gram offeces. (AU)
Para evaluar la actividad antihelmíntica fue realizado un estudio controlado. Dieciocho yeguas,con peso entre 300 kg Y 600 kg, naturalmente infectadas, fueron distribuidas aleatoriamente en tres grupos homogéneos con seis animales cada uno. EI Grupo I no tratado - solución fisiológica, grupo Gil tratado conPlatelmin Pasta equino~ (mebendazol1 O mg/kg), grupo GIII tratado con Ivermectina Pasta equino~ (ivermectina 200pg/kg). EI recuento de huevos por gramo de heces (HPG), fueron realizados en los días-2, -1, O (día del tratamiento), 3, 7,14,21 Y 28 post-tratamiento. Los datos colectados fueron transformados en log(x + 1) Yanalizados en un delineamiento enteramente ai acaso. EI recuento de HPG dei grupo control permaneció entre 378 a 766 durante todo el periodo experimental. De acuerdo con Ias cuantificaciones, fueron observadas eficacias de 100% en el grupo tratado con ivermectina y 88% en el grupo tratado con mebendazol. Ambos medicamentos fueron eficaces en Ia reducción de HPG. (AU)
Assuntos
Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/análise , Anti-Helmínticos/uso terapêutico , Cavalos/parasitologia , Ivermectina/análise , Ivermectina/uso terapêutico , Mebendazol/análise , Mebendazol/uso terapêutico , Parasitologia/estatística & dados numéricos , Resultado do TratamentoRESUMO
Para avaliar a atividade anti-helmíntica conduziu-se um estudo controlado. Dezoito éguas, com peso entre 300 kg e 600 kg, naturalmente infectados foram distribuídas após randomização em três grupos homogêneos com seis animais cada. O grupo controle solução fisiológica (Grupo I), grupo Gil tratado com Platelmin Pasta equino~ (mebendazol 10 mg/kg), grupo Gil tratado com Ivermectina Pasta equlno" (ivermectina 200 pg/kg). Contagens de ovos por gramas de fezes (OPG), foram realizadas nos dias -2, -1, O (dia do tratamento), 3, 7, 14, 21 e 28 pós-tratamento. Os dados coletados foram transformados em log (x + 1) e analisados em um delineamento inteiramente casualizado. A contagem de OPG do grupo controle permaneceu entre 378 a 766 durante todo o período experimental. De acordo com as quantificações, foram observadas eficácias de 100% no grupo tratado com Ivermectina e 88% no grupo tratado com mebendazol. Ambos os medicamentos mostram-se eficazes na redução de OPG.
To evaluate the anthelmintic activity was conducted a controlled study. Eighteen mares, weighing between 300 kg and 600 kg, naturally infected were distributed after randomization into three homogeneousgroups of six animais each. The control group treated with saline (Group I), Gil group treated with PlatelminPasta equíno" (mebendazole 10 mg / kg), Gil group treated with Ivermectina Paste equino~ (ivermectin 200mcg/kg). EPG (eggs per gram ofteces) counts were performed on days -2, -1, O (day oftreatment), 3, 7,14,21 and 28 post-treatment. The collected data were transformed into log (x + 1) and analyzed in a completely randomized designo The EPG control group remained between 378 and 766 during ali experimental period.According to the measurements, 100% of efficacy were observed in the group treated with Ivermectin and88% in the group treated with mebendazole. Both drugs are effective in the reduction of eggs per gram offeces.
Para evaluar la actividad antihelmíntica fue realizado un estudio controlado. Dieciocho yeguas,con peso entre 300 kg Y 600 kg, naturalmente infectadas, fueron distribuidas aleatoriamente en tres grupos homogéneos con seis animales cada uno. EI Grupo I no tratado - solución fisiológica, grupo Gil tratado conPlatelmin Pasta equino~ (mebendazol1 O mg/kg), grupo GIII tratado con Ivermectina Pasta equino~ (ivermectina 200pg/kg). EI recuento de huevos por gramo de heces (HPG), fueron realizados en los días-2, -1, O (día del tratamiento), 3, 7,14,21 Y 28 post-tratamiento. Los datos colectados fueron transformados en log(x + 1) Yanalizados en un delineamiento enteramente ai acaso. EI recuento de HPG dei grupo control permaneció entre 378 a 766 durante todo el periodo experimental. De acuerdo con Ias cuantificaciones, fueron observadas eficacias de 100% en el grupo tratado con ivermectina y 88% en el grupo tratado con mebendazol. Ambos medicamentos fueron eficaces en Ia reducción de HPG.
Assuntos
Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/análise , Anti-Helmínticos/uso terapêutico , Cavalos/parasitologia , Ivermectina/análise , Ivermectina/uso terapêutico , Mebendazol/análise , Mebendazol/uso terapêutico , Parasitologia/estatística & dados numéricos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the impact of periodic selective treatment with 500 mg mebendazole on soil-transmitted helminth (STH) infections in Cuban schoolchildren. METHODS: We followed up a cohort of 268 STH-positive schoolchildren, aged 5-14 years at baseline, at six-month intervals for two years and a final follow-up after three years. Kato-Katz stool examination was used to detect infections with Ascaris lumbricoides, Trichuris trichiura and hookworm. Common risk factors related to STHs were assessed by parental questionnaire. RESULTS: A significant reduction in the number of STH infections was obtained after three years with the highest reduction for T. trichiura (87.8%) and the lowest for hookworm (57.9%). After six months, cure rates (CRs) were 76.9% for A. lumbricoides, 67.4% for T. trichiura and 44.4% for hookworm. After two treatment rounds, more than 75% of all STH-positive children at baseline were cured, but with important differences between STH species (95.2% for A. lumbricoides, 80.5% for T. trichiura and 76.5% for hookworm). At the end of the study, these cumulative CRs were almost 100% for all three STHs. Risk factors for STHs were sex, sanitary disposal and habit of playing in the soil. CONCLUSIONS: Our results indicate that periodic selective treatment with 500 mg mebendazole is effective in reducing the number of STH infections in Cuban schoolchildren. Although important differences were found between helminth species, two rounds of treatment appeared sufficient to obtain substantial reductions.
RESUMO
Mebendazole mesylate monohydrate, a new stable salt of mebendazole (MBZ), has been synthesized and fully characterized. It was obtained from recrystallization of MBZ forms A, B, or C in diverse solvents with the addition of methyl sulfonic acid solution. The crystal packing is first organized as a two-dimensional array consisting of rows of alternating MBZ molecules linked to columns of mesylate ions by hydrogen bonds. The three-dimensional structure is further developed by classical intermolecular interactions involving water molecules. In addition, nonclassical contacts are also found. The vibrational behavior is consistent with the crystal structure, the most important functional groups showing shifts to lower or higher frequencies in relation to the MBZ polymorphs. Thermal analysis indicates that the compound is stable up to 50°C. Decomposition occurs in five steps. Solubility studies show that the title compound presents a significant higher performance than polymorph C. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3528-3538, 2013.