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1.
Front Immunol ; 13: 878029, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35833137

RESUMO

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.


Assuntos
Anti-Helmínticos , Esquistossomose , Animais , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Formação de Anticorpos , Citocinas/uso terapêutico , Feminino , Humanos , Mortalidade Materna , Mebendazol/uso terapêutico , Camundongos , Morbidade , Praziquantel/farmacologia , Praziquantel/uso terapêutico , Gravidez , Schistosoma , Esquistossomose/tratamento farmacológico
2.
J Chem Inf Model ; 62(15): 3604-3617, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35867562

RESUMO

Recent experimental evidence suggests that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibits acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity, and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five mebendazole tautomers using the MP2/aug-cc-pVTZ theory level resulted in 152 minima. Mebendazole-Hsp90 complex models were subsequently created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.


Assuntos
Mebendazol , Simulação de Dinâmica Molecular , Trifosfato de Adenosina , Proteínas de Choque Térmico HSP90/química , Humanos , Mebendazol/farmacologia , Conformação Molecular , Ligação Proteica , Conformação Proteica
3.
Sci Rep ; 12(1): 11582, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35804178

RESUMO

This article presents the binding interaction between mebendazole (MBZ) and bovine serum albumin. The interaction has been studied using different techniques, such as fluorescence quenching spectroscopy, UV-visible spectroscopy, synchronous fluorescence spectroscopy, fourier transform infrared, and fluorescence resonance energy transfer in addition to molecular docking. Results from Stern Volmer equation stated that the quenching for MBZ-BSA binding was static. The fluorescence quenching spectroscopic study was performed at three temperature settings. The binding constant (kq), the number of binding sites (n), thermodynamic parameters (ΔHο, ΔSο and ΔGο), and binding forces were determined. The results exhibited that the interaction was endothermic. It was revealed that intermolecular hydrophobic forces led to the stabilization of the drug-protein system. Using the site marker technique, the binding between MBZ and BSA was found to be located at subdomain IIA (site I). This was furtherly approved using the molecular docking technique with the most stable MBZ configuration. This research may aid in understanding the pharmacokinetics and toxicity of MBZ and give fundamental data for its safe usage to avoid its toxicity.


Assuntos
Mebendazol , Soroalbumina Bovina , Sítios de Ligação , Dicroísmo Circular , Simulação de Acoplamento Molecular , Ligação Proteica , Soroalbumina Bovina/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica
4.
Artigo em Inglês | MEDLINE | ID: mdl-35793340

RESUMO

Analytical methodology for quantification of 15 antiparasitic drugs and their respective metabolites in laying hen eggs was optimized and validated. The method uses acetonitrile as solvent extraction, sodium chloride for salting-out, low-temperature purification and analysis by LC-MS/MS. A total of 348 egg samples were collected in 11 states of Brazil and 50% of the total samples presented antiparasitic residues, which were albendazole, fipronil, fenbendazole, ivermectin, oxibendazole and mebendazole. A total of 12.4% of the samples were considered non-compliant, and residues quantified in these samples were albendazole, fipronil, and mebendazole. Albendazole was always identified as albendazole sulfone. Only one sample presented fipronil and fipronil sulfone; all others exclusively the sulfone metabolite. Fenbendazole was characterized by the presence of both metabolites: sulfone and sulfoxide. Maximum limits adopted are based on the Normative Instruction 51/2019 of the Brazilian Health Regulatory Agency (ANVISA), but albendazole, fipronil, oxibendazole, ivermectin, and mebendazole do not have their maximum residue level established. In addition, metabolites of albendazole, fipronil and fenbendazole in eggs are not considered in this Instruction.


Assuntos
Albendazol , Espectrometria de Massas em Tandem , Albendazol/análise , Animais , Antiparasitários , Brasil , Galinhas/metabolismo , Cromatografia Líquida/métodos , Ovos/análise , Feminino , Fenbendazol , Ivermectina , Mebendazol , Sulfonas , Espectrometria de Massas em Tandem/métodos
5.
PLoS Negl Trop Dis ; 16(6): e0010477, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35759453

RESUMO

Soil-transmitted helminth (STH) infections cause significant morbidity in children and women of reproductive age. The World Health Organization (WHO) recommends preventive chemotherapy (PC) of at-risk populations with anthelminthics to control these infections. Historically, STH are very intensively transmitted in Pemba Island (Zanzibar). A survey conducted in 1994 in 12 schools estimated a STH prevalence near to 100%. This extremely high prevalence induced the introduction of PC in the island; initially, however, PC was not regularly administered because of difficulties linked to drug procurement. A second STH survey, conducted in 2011, in 24 schools estimated a prevalence of STH of 89%; after this survey, PC was regularly administered until 2018. We conducted a survey in 2021 using the same method as that used in 2011. The prevalence of STH was evaluated at 80% (95% CI 78.1-81.5) and most of the STH cases were due to Trichuris trichiura. More than 32% (95% CI 30.3-34.0) of the children investigated had infections of moderate or heavy intensity. PC has been conducted for over 25 years in Pemba Island. However, despite its beneficial impact, both the prevalence and the intensity of STH infections remain high, and the intervention has been insufficient in controlling STH morbidity. This is probably due to a combination of irregular PC, climatic conditions favourable to STH transmission, the low sensitivity of T. trichiura to benzimidazoles, high population density and poor sanitation. Improvement of sanitation coverage remains a key measure to permanently reduce the prevalence and intensity of STH. Possible changes to the present PC approaches to better control STH in Pemba would be (i) to assure high coverage in all schools, (ii) to use mebendazole instead of albendazole given its better activity on T. trichiura and (iii) to use a combination of ivermectin and mebendazole to further increase anthelminthic efficacy on T. trichiura.


Assuntos
Anti-Helmínticos , Helmintíase , Animais , Anti-Helmínticos/uso terapêutico , Criança , Fezes , Feminino , Helmintíase/tratamento farmacológico , Helmintíase/epidemiologia , Helmintíase/prevenção & controle , Humanos , Mebendazol/uso terapêutico , Prevalência , Solo , Tanzânia/epidemiologia , Trichuris
6.
Sci Rep ; 12(1): 10249, 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35715495

RESUMO

Mebendazole (MBZ) is an efficacious anthelmintic with known anti-inflammatory and fibrinolytic properties. In this study, we aimed to explore the protective effects of this FDA-approved drug against DSS-induced colitis in a murine model either alone or in combination with Sulfasalazine (SSZ), a standard therapy for ulcerative colitis. We found that MBZ significantly improved colitis disease activity index as assessed by changes in body weight, degree of stool consistency, rectal bleeding, and prolapse. We also found that MBZ ameliorated the colon histopathological score by attenuating crypt loss, mucosal damage, and inflammation score in colitis tissues. Similarly, DSS-induced colon shortening, colon weight loss, and increase in spleen weight were all abrogated in the presence of MBZ. Moreover, MBZ decreased inflammation, possibly by reducing oxidative stress markers, suppressing inflammatory cell infiltration, and down-regulation of inflammatory genes in colon tissues. Furthermore, MBZ potently reduced fibrosis by decreasing collagen deposition and down-regulating pro-fibrotic genes including Col 1a1 and Col 1a2 in colitis tissue homogenates. In conclusion, our study showed that this broad-spectrum anthelminthic could be repurposed as a novel therapy for ulcerative colitis without any observed side effects, however, regarding the concerns about the potential toxicity of MBZ in UC patients, future experiments on MBZ therapy in other models of UC is needed to completely address the toxicity concerns.


Assuntos
Colite Ulcerativa , Colite , Animais , Colite/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Fibrose , Humanos , Inflamação/patologia , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Camundongos , Estresse Oxidativo
8.
Exp Parasitol ; 238: 108265, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35525309

RESUMO

Taenia crassiceps is often used as experimental model for T. solium cysticercosis studies. Currently cysticercosis antiparasitic treatment is based on albendazole and praziquantel which may present side effects and parasitic resistance. The search for other antiparasitic drugs is necessary. Nitazoxanide (NTZ) and flubendazole (FLB) are broad spectrum antiparasitic drugs that present anti-cysticercosis effect. Metabolic analyses help to determine the impact of these drugs on parasites. The aim of this study was to determine the impact on the production and excretion of organic metabolites in T. crassiceps cysticerci after in vitro exposure to NTZ and FLB, isolated or in combination. T. crassiceps cysticerci were culture in RPMI medium and exposed to 10 µg/mL of NTZ, 10 µg/mL of FLB or 10 µg/mL of NTZ +10 µg/mL of FLB. 24 h after exposure, the parasites were chromatographic analyzed to determine the impact of these drugs on glycolysis, homolactic fermentation, tricarboxylic acid cycle, fatty acids oxidation and proteins catabolism. It was possible to determine that the drugs combination induced greater metabolic impact on cysticerci in comparison to the isolated drugs exposure. The drugs combination induced gluconeogenesis, metabolic acidosis, increase in tricarboxylic acid cycle and in proteins catabolism. While the NTZ isolated exposure induced metabolic acidosis and protein catabolism and the FLB isolate exposure induced gluconeogenesis and protein catabolism. These results show that the combination of drugs with different modes of action increase the antiparasitic effect and may be indicated as alternative cysticercosis treatments.


Assuntos
Cisticercose , Taenia , Animais , Antiparasitários/farmacologia , Antiparasitários/uso terapêutico , Cisticercose/tratamento farmacológico , Cysticercus , Mebendazol/análogos & derivados , Camundongos , Camundongos Endogâmicos BALB C , Nitrocompostos , Estresse Fisiológico , Tiazóis
9.
Int J Mol Sci ; 23(8)2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35457043

RESUMO

Mebendazole (MBZ) is a synthetic benzimidazole known for its antiparasitic properties. In recent years, growing evidence showed that MBZ was also used as an anti-tumor agent. However, whether (and to what extent) this drug treatment affected the male reproductive system was not well-understood. In this study, male C57BL/6 mice were injected with 40 mg/kg/day of MBZ. The treatment was for 3 and 7 days. Our results showed that the injected mice exhibited an abnormal spermatogenic phase with a significant decrease in sperm. We further detected microtubule disruption and transient functional destruction of the blood-testes barrier (BTB) in the MBZ-injected mice testes (BTB). Our data confirmed that MBZ suppressed the expression of the BTB junction-associated proteins and disrupted the Sertoli cells' function in vivo. Moreover, MBZ-treated mice demonstrated an aberrant caspase-3 signalling pathway, which resulted in the apoptosis of the germ cells. Here, we present our data, indicating that MBZ impairs BTB by reducing the expression of the microtubules' and BTB junction-associated proteins. The last leads to activating the caspase-3 pathway, which triggers extensive germ cell apoptosis.


Assuntos
Barreira Hematotesticular , Mebendazol , Animais , Apoptose , Barreira Hematotesticular/metabolismo , Caspase 3/metabolismo , Masculino , Mebendazol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos , Células de Sertoli/metabolismo , Testículo
10.
Cell Death Dis ; 13(4): 375, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440104

RESUMO

Breast cancer is still one of the most common malignancies worldwide and remains a major clinical challenge. We previously reported that the anthelmintic drug flubendazole induced autophagy and apoptosis via upregulation of eva-1 homolog A (EVA1A) in triple-negative breast cancer (TNBC) and was repurposed as a novel anti-tumor agent. However, the detailed underlying mechanisms remain unclear and need further investigation. Here, we found that flubendazole impairs the permeability of the mitochondrial outer membrane and mitochondrial function in breast cancer. Meanwhile, flubendazole increased dynamin-related protein (DRP1) expression, leading to the accumulation of PTEN induced putative kinase 1 (PINK1) and subsequent mitochondrial translocation of Parkin, thereby promoting excessive mitophagy. The resultant excessive mitophagy contributed to mitochondrial damage and dysfunction induced by flubendazole, thus inhibiting breast cancer cells proliferation and migration. Moreover, we demonstrated that excessive DRP1-mediated mitophagy played a critical role in response to the anti-tumor effects of EVA1A in breast cancer. Taken together, our results provide new insights into the molecular mechanisms in relation to the anti-tumor activities of flubendazole, and may be conducive to its rational use in potential clinical applications.


Assuntos
Mitofagia , Neoplasias de Mama Triplo Negativas , Dinaminas/metabolismo , Humanos , Mebendazol/análogos & derivados , Mitocôndrias/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
11.
Infect Dis Poverty ; 11(1): 47, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35484570

RESUMO

BACKGROUND: The current mainstay for control/elimination of onchocerciasis and soil-transmitted helminthiasis (STH) relies on ivermectin- and mebendazole/albendazole-based preventive chemotherapies. However, children under five years of age have been excluded in both research activities and control programs, because they were believed to have insignificant infection rates. There is therefore a need for up-to-date knowledge on the prevalence and intensity of STH and onchocerciasis infections in this age group. This study aimed at assessing the rates and intensities of onchocerciasis and STH infections in children under five years of age who are excluded from ivermectin- or mebendazole/albendazole-based preventive chemotherapies. METHODS: A series of cross-sectional surveys was conducted in four Health Districts in the Centre and Littoral Regions of Cameroon between 2018 and 2019. All subjects aged 2 to 4 years, were screened for prevalence (or infection rate) and intensity [number of eggs per gram of stool (epg) or number of microfilariae per skin snip (mf/ss)] of STH and onchocerciasis infections respectively using the Kato-Katz and skin snip methodologies. Chi-square and the non-parametric tests (Mann Whitney and Kruskal Wallis) were used to compare infection rates and intensities of infections between Health Districts and genders, respectively. RESULTS: A total of 421 children were enrolled in this study. The overall prevalence of onchocerciasis was 6.6% [95% confidence interval (CI): 4.3‒9.9], ranging from 3.6% (in the Ntui Health District) to 12.2% (in the Bafia Health District). The intensity of infection ranged from 0.5 to 46 microfilariae per skin snip [median: 5; interquartile range (IQR): 2.25‒8.5]. The overall prevalence of STH was 9.6% (95% CI: 6.5‒13.9), with a high infection rate (29.6%) in the Akonolinga Health District. Two STH species (Ascaris lumbricoides and Trichuris trichiura) were found among infected individuals. The median intensities of STH infections were 1,992 epg (IQR: 210‒28,704) and 96 epg (IQR: 48‒168) for A. lumbricoides and T. trichiura, respectively. CONCLUSIONS: This study reveals that children < 5 years of age are highly infected with STH and onchocerciasis, and could contribute to the spread of these diseases, perpetuating a vicious circle of transmission and hampering elimination efforts. These findings reveal the urgent need to provide (or scale) treatments (likely pediatric formulations) to these preschool-aged children, especially in areas of high transmission, to accelerate efforts to reach WHO 2030 target.


Assuntos
Helmintíase , Oncocercose , Albendazol/uso terapêutico , Animais , Criança , Pré-Escolar , Estudos Transversais , Feminino , Helmintíase/tratamento farmacológico , Helmintíase/epidemiologia , Helmintíase/prevenção & controle , Humanos , Ivermectina/uso terapêutico , Masculino , Mebendazol/uso terapêutico , Oncocercose/tratamento farmacológico , Oncocercose/epidemiologia , Oncocercose/prevenção & controle , Solo
12.
Immunity ; 55(4): 623-638.e5, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35385697

RESUMO

The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.


Assuntos
Alarminas , Mucosa Intestinal , Acilação , Alarminas/imunologia , Anti-Helmínticos/imunologia , Biomarcadores Tumorais , Citocinas , Proteínas de Ligação a DNA , Helmintíase/imunologia , Humanos , Hiperplasia , Inflamação , Interleucina-33 , Mucosa Intestinal/imunologia , Mebendazol , N-Acetilglucosaminiltransferases/imunologia , Proteínas Citotóxicas Formadoras de Poros , Fator de Transcrição STAT6/imunologia
13.
Leukemia ; 36(6): 1541-1549, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35368048

RESUMO

A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, we demonstrate that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines throughout the world indicates that it represents a promising candidate for repurposing into AML therapy.


Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-myb , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mebendazol , Oncogenes , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , Fatores de Transcrição/genética
14.
Acta Parasitol ; 67(2): 970-975, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35426620

RESUMO

PURPOSE: Diplectanum is a life-threatening metazoan infecting the gills of Sea bass Dicentrarchus labrax causing a wide-ranging extensive economic loss in the aquaculture sector. This study has focused on verifying the most effective non-toxic dose of the Neem (Azadirachta indica) and (flubendazole) bath treatment on infested D. labrax fingerlings. METHODS: In the first phase of the experiment, a total of 180 apparently healthy fingerlings were subdivided into six groups for each treatment. The tested concentrations were 0, 50, 100, 150, 200, and 250 mg L-1 for A. indica and 0, 10, 20, 30, 40, and 50 mg L-1 for flubendazole. The second phase was conducted for one week in five groups for each treatment. The first group was untreated healthy. The remaining groups were infested and received different concentrations of 0, 50, 100, and 150 mg L-1 & 0, 10, 20, and 30 mg L-1 for A. indica and flubendazole, respectively. RESULTS: The most toxic dose exhibited high mortality rates at 200 & 250 and 40 & 50 mg L-1 for A. indica and flubendazole, respectively. In the second phase of the experiment, the most effective dose was 150 and 30 mg L-1; for A. indica and flubendazole, respectively. They demonstrated the lowest mortality rates 20.00 & 20.00 %, prevalence rates 43.33 & 23.33%, and mean parasitic intensities were 2.35 & 2.00 accompanied by the highest therapeutic efficacy value 67.85 & 74.6% for both treatments; respectively. CONCLUSION: The most effective anthelmintic efficacy has been assigned for flubendazole and A. indica at 30 and 150 mg L-1.


Assuntos
Azadirachta , Bass , Trematódeos , Animais , Bass/parasitologia , Mebendazol/análogos & derivados , Folhas de Planta
15.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35408808

RESUMO

Microtubule targeting agents (MTAs) have been exploited mainly as anti-cancer drugs because of their impact on cellular division and angiogenesis. Additionally, microtubules (MTs) are key structures for intracellular transport, which is frequently hijacked during viral infection. We have analyzed the antiviral activity of clinically used MTAs in the infection of DNA and RNA viruses, including SARS-CoV-2, to find that MT destabilizer agents show a higher impact than stabilizers in the viral infections tested, and FDA-approved anti-helminthic benzimidazoles were among the most active compounds. In order to understand the reasons for the observed antiviral activity, we studied the impact of these compounds in motor proteins-mediated intracellular transport. To do so, we used labeled peptide tools, finding that clinically available MTAs impaired the movement linked to MT motors in living cells. However, their effect on viral infection lacked a clear correlation to their effect in motor-mediated transport, denoting the complex use of the cytoskeleton by viruses. Finally, we further delved into the molecular mechanism of action of Mebendazole by combining biochemical and structural studies to obtain crystallographic high-resolution information of the Mebendazole-tubulin complex, which provided insights into the mechanisms of differential toxicity between helminths and mammalians.


Assuntos
COVID-19 , Mebendazol , Animais , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Mamíferos , Mebendazol/farmacologia , Microtúbulos , SARS-CoV-2 , Tubulina (Proteína)
16.
Life Sci ; 299: 120536, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35385794

RESUMO

AIMS: Metastatic colorectal cancer (mCRC) predominantly contributes to cancer-related mortalities secondary to distant metastasis. This study aimed at investigating anti-tumor activity and safety of mebendazole in patients with mCRC. MATERIALS AND METHODS: This prospective, randomized double blind placebo-controlled study enrolled 40 mCRC patients who were randomized into two groups; the control group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus placebo tablets BID and mebendazole group (n = 20) which received 6 cycles of bevacizumab with FOLFOX4 plus mebendazole 500 mg orally BID for 12 weeks. Computed tomography scanning and serum levels of carcinoembryonic antigen (CEA), vascular endothelial growth factor (VEGF), liver and renal parameters were assessed at baseline and after 12 weeks. One-year overall survival and progression free survival (PFS) were also determined. Data were analyzed using paired, independent sample-t-tests, Mann-Whitney U, Chi-Square and Kaplan-Meier tests and p < 0.05 was considered statistically significant. KEY FINDINGS: Mebendazole was well tolerated and its addition to bevacizumab and FOLFOX4 enhanced tumor response to treatment which was translated by significant improvement of overall response rate 12 weeks after intervention [10 % (2) versus 65% (13) for control and mebendazole groups, respectively; p = 0.000] and significant elevation of PFS (median: 3 and 9.25 months for control and mebendazole groups, respectively; p = 0.000). Furthermore, mebendazole produced significant decline in VEGF level (p = 0.006) with non-significant variation in CEA level (p = 0.063). SIGNIFICANCE: Mebendazole may represent an attractive candidate for drug repositioning against mCRC secondary to its safety and efficacy in enhancing tumor response to chemotherapy. GOV ID: NCT03925662, retrospectively.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Antígeno Carcinoembrionário , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Reposicionamento de Medicamentos , Fluoruracila , Humanos , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular
17.
Artigo em Inglês | MEDLINE | ID: mdl-35442868

RESUMO

As a typical and broad-spectrum benzimidazole, mebendazole (MBZ) has long been used in human and veterinary medicine to treat parasitic infestations, and is widely employed in the aquaculture of Japanese pufferfish (Takifugu rubripes). However, there have been no studies examining the pharmacokinetic characteristics of MBZ in Japanese pufferfish. Furthermore, the presence of MBZ and its metabolites in animal-derived raw food represents a notable safety concern. Here, we investigated the metabolism of MBZ using a UPLC-Q-TOF system. Additionally, we evaluated the pharmacokinetics of MBZ and two metabolites, 2-amino-5(6)-benzoylbenzimidazole (MBZ-NH2) and 5-hydroxymebendazole (MBZ-OH), in Japanese pufferfish following intramuscular injection of 20 mg/kg MBZ. We detected three metabolites of MBZ (M1-M3), among which, 2-amino-5(6)-(a-hydroxybenzyl) benzimidazole (M3) was detected in an aquatic animal for the first time. The plasma dispositions of MBZ, MBZ-NH2, and MBZ-OH were characterized by low plasma clearance, medium distribution volume, and long terminal half-life. Moreover, these compounds were widely distributed in the muscle, from which they were rapidly cleared. The pharmacokinetics and metabolism of mebendazole in Japanese pufferfish are described for the first time in this study. Our findings provide a basis for the rational application of MBZ in Japanese pufferfish farming and contribute to our understanding of the metabolism of MBZ in cultured fish.


Assuntos
Mebendazol , Takifugu , Animais , Benzimidazóis/metabolismo , Mebendazol/metabolismo , Músculos/metabolismo , Takifugu/metabolismo
19.
Int J Mol Sci ; 23(1)2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-35008943

RESUMO

Flubendazole, belonging to benzimidazole, is a broad-spectrum insect repellent and has been repurposed as a promising anticancer drug. In recent years, many studies have shown that flubendazole plays an anti-tumor role in different types of cancers, including breast cancer, melanoma, prostate cancer, colorectal cancer, and lung cancer. Although the anti-tumor mechanism of flubendazole has been studied, it has not been fully understood. In this review, we summarized the recent studies regarding the anti-tumor effects of flubendazole in different types of cancers and analyzed the related mechanisms, in order to provide the theoretical reference for further studies in the future.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mebendazol/análogos & derivados , Animais , Antineoplásicos/química , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estudos Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mebendazol/química , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade de Órgãos/efeitos dos fármacos , Transdução de Sinais , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Int J Pharm ; 614: 121456, 2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35017024

RESUMO

The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug-rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole:copovidone amorphous dispersions.


Assuntos
Química Farmacêutica , Excipientes , Varredura Diferencial de Calorimetria , Portadores de Fármacos , Composição de Medicamentos , Temperatura Alta , Mebendazol/análogos & derivados , Pirrolidinas , Solubilidade , Compostos de Vinila
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