RESUMO
Rarer causes of acute pancreatitis may be considered in certain settings, such as parasitism in endemic regions. This report describes a pregnant female (second trimester) in her 20s who presented with 3-day steady epigastric pain radiating to the back and passage of worm from the mouth. She was diagnosed with mild acute pancreatitis, given a significantly elevated serum lipase and absence of organ failures. Fecalysis showed Ascaris lumbricoides ova; hence, she was treated with mebendazole. Plain MR cholangiopancreatography showed an 842 mL necrotic pancreatic fluid collection and tubular flow void foci within the gallbladder and duodenum consistent with helminthiasis. The patient was managed conservatively in the absence of indications for drainage. The abdominal pain remarkably improved, and she underwent eventual vacuum-assisted delivery to a healthy term baby 4 months after the bout of acute pancreatitis.
Assuntos
Ascaríase , Ascaris lumbricoides , Pancreatite Necrosante Aguda , Humanos , Feminino , Ascaríase/diagnóstico , Ascaríase/tratamento farmacológico , Ascaríase/complicações , Gravidez , Pancreatite Necrosante Aguda/diagnóstico , Pancreatite Necrosante Aguda/parasitologia , Animais , Ascaris lumbricoides/isolamento & purificação , Complicações Parasitárias na Gravidez/diagnóstico , Complicações Parasitárias na Gravidez/tratamento farmacológico , Adulto , Mebendazol/uso terapêutico , Dor Abdominal/etiologia , Dor Abdominal/parasitologia , Colangiopancreatografia por Ressonância MagnéticaRESUMO
BACKGROUND: Enterobius vermicularis (E. vermicularis), also referred to as pinworm, is a widespread human intestinal parasite which predominantly occurs in young children, making their caretakers a population at risk for the transmission of this helminth. It can occasionally affect extraintestinal organs and tissues, including the female genital tract. Infestation can be asymptomatic or manifest as different kinds of gynaecological disorders, such as pelvic inflammation mimicking tumours, abnormal uterine bleeding, or vaginitis. Diagnosis is made by identifying ova in the sample collected from the perineal skin using a transparent adhesive tape or microscopic examination of resected tissue. Mebendazole is the first-line medication and should also be administered to all household members. CASE PRESENTATION: We present a case of a patient who had undergone surgery for invasive cervical cancer with an accidental finding of E. vermicularis eggs in the cervix. CONCLUSIONS: Although not very common, infestation with E. vermicularis should be considered in differential diagnoses of various gynaecological disorders accompanied by histological findings of granulomatous inflammation.
Assuntos
Enterobíase , Enterobius , Neoplasias do Colo do Útero , Humanos , Feminino , Enterobíase/diagnóstico , Enterobíase/complicações , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/cirurgia , Enterobius/isolamento & purificação , Animais , Mebendazol/uso terapêutico , Colo do Útero/parasitologia , Colo do Útero/patologia , Diagnóstico Diferencial , Pessoa de Meia-Idade , AdultoRESUMO
Helminthiasis remains a public health issue in endemic areas. Various drugs have been proposed to improve efficacy against helminths. The study aimed to assess the safety and efficacy of three different anthelmintic combinations to treat Trichuris trichiura infections. We conducted a randomized assessors-blind clinical trial involving children aged 2-17 years with T. trichiura. Participants were randomly assigned to one of three treatment arms. On the first and third days, all participants got albendazole 400 mg, and on the second day, albendazole (arm A), mebendazole 500 mg (arm B), or pyrantel 125 mg/kg (arm C). We assessed treatment efficacy using the cure rate (CR) and egg reduction rate (ERR) at 3 and 6 weeks post-treatment. At 3 weeks post-treatment, ERR and CR were highest in study arm A [ERR = 94%, 95% confidence interval (CI): 92-95; CR = 71%; 95% CI: 58-81] compared to the B and C arms. Decrease in ERR was significant only for arm B versus arm A (P-value <0.001); decrease in ERR was significant for arms B and C (P-value <0.001). No statistical difference was observed in CR when comparing arms A and B (P-value =1.00) and C (P-value =0.27). At 6 weeks, a decrease in ERR was observed in three arms, significant only for arm C, 81% (95% CI: 78-83). A significant increase in egg counts was observed between 3 and 6 weeks post-treatment. All treatments were safe with mild adverse events. Albendazole 400 mg/day (arm A) showed the highest efficacy against trichuriasis. Nonetheless, this treatment regimen was able to cure half of the treated individuals highlighting concerns about controlling the transmission of T. trichiura.CLINICAL TRIALRegistered at ClinicalTrials.gov (NCT04326868).
Assuntos
Albendazol , Anti-Helmínticos , Mebendazol , Pirantel , Tricuríase , Trichuris , Humanos , Albendazol/uso terapêutico , Albendazol/efeitos adversos , Albendazol/administração & dosagem , Criança , Mebendazol/uso terapêutico , Tricuríase/tratamento farmacológico , Masculino , Feminino , Trichuris/efeitos dos fármacos , Animais , Pré-Escolar , Anti-Helmínticos/uso terapêutico , Anti-Helmínticos/efeitos adversos , Anti-Helmínticos/administração & dosagem , Adolescente , Pirantel/uso terapêutico , Quimioterapia Combinada , Resultado do Tratamento , Contagem de Ovos de ParasitasRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.
Assuntos
Movimento Celular , Reposicionamento de Medicamentos , Mebendazol , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Animais , Humanos , Feminino , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Camundongos , Movimento Celular/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Proliferação de Células/efeitos dos fármacosRESUMO
Aim: To investigate the therapeutic potential of mebendazole (MBZ)-loaded nanostructured lipid carriers (NLCs). Methodology: NLC-MBZ was prepared and characterized to evaluate the in vitro and in vivo anticancer effects and the inhibitory effect on RanGTP and its potential as an antimetastatic treatment in vivo. Results: NLC-MBZ exhibited a size and charge of 155 ± 20 nm and -27 ± 0.5 mV, respectively, with 90.7% encapsulation. Free MBZ and NLC-MBZ had a 50% inhibitory concentration of 610 and 305 nM, respectively, against MDA-MB-231 cell lines. NLC-MBZ decreased tumor size, suppressed tumor lung metastases, and lowered the expression of CDC25A, SKP2, RbX1 and Cullin1 while boosting the Rb proteins. Conclusion: NLC-MBZ displayed antiangiogenic potential and resulted in a reduced rate of lung metastasis in vivo.
[Box: see text].
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Mebendazol , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Humanos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Linhagem Celular Tumoral , Camundongos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Portadores de Fármacos/química , Lipídeos/química , Camundongos Endogâmicos BALB C , Antineoplásicos/farmacologia , Antineoplásicos/química , Camundongos NusRESUMO
We evaluated the effect of 4 anthelmintic treatments on the viability of Trichinella spiralis encysted muscle larvae (ML) 55 days post infection (PI) in experimentally infected pigs. Muscle larvae were isolated from pig muscle by artificial digestion after oral treatment of pigs with Levamisole (8 mg/kg, daily for 5 days) and Mebendazole (50 mg/kg, daily for 5 days); Doramectin (0.3 mg/kg, single IM injection), and Moxidectin (0.5 mg/kg, single pour on). Isolated larvae from treated pigs were orally inoculated into mice to assess viability of ML from each treatment. Only Mebendazole treatment of pigs significantly reduced ML viability in mice. The effect of timing of the effective Mebendazole treatment on ML from a longer term infection was then examined in a second experiment. Analysis revealed that Mebendazole treatment of pigs with 250 mg/kg over 3 days (83 mg/kg/day) or 5 days (50 mg/kg/day) reduced numbers of ML recovered from pig tissues compared to untreated, infected controls, and rendered ML non-infective to mice; Mebendazole treatment of pigs with 250 mg/kg in a single dose was not effective in reducing ML numbers recovered from pigs or in impacting ML infectivity to mice. An examination of the lowest effective dose of Mebendazole on encysted ML was determined in a third experiment. Mebendazole of pigs with 5, 50, or 100 mg/kg over 3 days demonstrated that 5 or 50 mg/kg over 3 days insufficient to reduce infectivity in recovered ML, while 100 mg/kg (and 83 g from experiment 2) over 3 days significantly reduces infectivity of ML. This procedure provides a means to evaluate the efficacy of various anthelmintic treatments on the viability of Trichinella spiralis ML in pig tissues, and identified Mebendazole, at 83-100 mg/kg administered over a 3-5 day period as an anthelmintic which renders encysted Trichinella spiralis ML from pig tissues non-infective. As risk from Trichinella significantly impacts acceptance of pork from pasture-raised pigs, these data provide a method, especially for producers of these high-risk pigs, to eliminate the potential of Trichinella transmission from infected pork.
Assuntos
Anti-Helmínticos , Doenças dos Roedores , Trichinella spiralis , Trichinella , Triquinelose , Suínos , Camundongos , Animais , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Triquinelose/tratamento farmacológico , Triquinelose/veterinária , Triquinelose/diagnóstico , Larva , Músculos , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Doenças dos Roedores/tratamento farmacológicoRESUMO
Carbonyl-reducing enzymes (CREs) catalyse the reduction of carbonyl groups in many eobiotic and xenobiotic compounds in all organisms, including helminths. Previous studies have shown the important roles of CREs in the deactivation of several anthelmintic drugs (e.g., flubendazole and mebendazole) in adults infected with the parasitic nematode Haemonchus contortus, in which the activity of a CRE is increased in drug-resistant strains. The aim of the present study was to compare the abilities of nematodes of both a drug-susceptible strain (ISE) and a drug-resistant strain (IRE) to reduce the carbonyl group of flubendazole (FLU) in different developmental stages (eggs, L1/2 larvae, L3 larvae, and adults). In addition, the effects of selected CRE inhibitors (e.g., glycyrrhetinic acid, naringenin, silybin, luteolin, glyceraldehyde, and menadione) on the reduction of FLU were evaluated in vitro and ex vivo in H. contortus adults. The results showed that FLU was reduced by H. contortus in all developmental stages, with adult IRE females being the most metabolically active. Larvae (L1/2 and L3) and adult females of the IRE strain reduced FLU more effectively than those of the ISE strain. Data from the in vitro inhibition study (performed with cytosolic-like fractions of H. contortus adult homogenate) revealed that glycyrrhetinic acid, naringenin, mebendazole and menadione are effective inhibitors of FLU reduction. Ex vivo study data showed that menadione inhibited FLU reduction and also decreased the viability of H. contortus adults to a similar extent. Naringenin and mebendazole were not toxic at the concentrations tested, but they did not inhibit the reduction of FLU in adult worms ex vivo.
Assuntos
Anti-Helmínticos , Ácido Glicirretínico , Haemonchus , Feminino , Animais , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Vitamina K 3/farmacologia , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Larva , Ácido Glicirretínico/farmacologiaRESUMO
Colon cancer is one of the most common cancers and one of the main causes of death worldwide. Therefore, new treatment methods with better efficiency and fewer risks are very necessary. Mebendazole (MBZ), a drug commonly used for helminthic infections, has recently received attention as a suitable candidate for the treatment of various cancers. This study aimed to investigate, in vitro and in vivo, anticancer activity and selectivity Index of MBZ on colon cancer. HT-29 (human colorectal adenocarcinoma) and MCF-10 (non-tumorigenic epithelial) cell lines were treated with MBZ and Doxorubicin (DOX; positive control drug). IC50 values were estimated using methyl thiazole diphenyl-tetrazolium bromide (MTT) assay. We employed flow cytometry using annexin V-FITC and propidium iodide dyes. For the animal study, colon cancer was subcutaneously induced by CT26 cells (mouse colon cancer) in Bulb/C mice. The mice were treated with 0.05 of LD50, intraperitoneal, every other day for 35 days. Finally, the survival rate, tumor volume, and tumor weight were calculated. Our results demonstrated that IC50 values after 72 h for HT29 and MCF-10 cell lines were 0.29 ± 0.04 µM and 0.80 ± 0.02 µM, respectively. MBZ was more selective than DOX in inhibiting the proliferation of cancer cells compared to normal cells (2. 75 vs. 2.45). Annexin V/PI staining demonstrated that MBZ treatment at IC50 concentrations induced (78 ± 12%) apoptosis in the HT29 cancer cell line after 48 h (P ≤ 0.0001). Also, in mice bearing colon cancer, MBZ significantly reduced the tumor volume (1177 ± 1109 mm3; P ≤ 0.001) and tumor weight (2.30 ± 1.97 g; P ≤ 0.0001) compared to the negative control group (weight 12.45 ± 2.0 g; volume 7346 ± 1077). Also, MBZ increases mean survival time (MST) and increase life span (ILS) percentage in the animal study (51.2 ± 37% vs 93%, respectively). This study suggests that mebendazole strongly and selectively inhibits proliferation and induces apoptosis in colon cancer cells. It may be, accordingly, a promising drug for clinical research and application.
Assuntos
Neoplasias do Colo , Mebendazol , Humanos , Animais , Camundongos , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Linhagem Celular Tumoral , Reposicionamento de Medicamentos , Células HT29 , Neoplasias do Colo/tratamento farmacológicoRESUMO
Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy.
Assuntos
Antineoplásicos , Neoplasias Gástricas , Humanos , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , GlucoseRESUMO
Hydatid disease is a parasitic infestation by a tapeworm of the genus Echinococcus sp., which has a global distribution. The current study was conducted to evaluate the effectiveness of the crustacean aqueous extract of Portunuspelagicus for 2 weeks of treatment compared to mebendazole on hydatid cyst in laboratory mice male Balb / C strain. Mice were infected intraperitoneally with 2000 protoscolices. After 12 weeks of infection, each mouse was treated with mebendazole (50mg/kg) and the hot aqueous extract of p. pelagicus (8, 16 g/kg). Samples of infected organs (liver, spleen, and lungs) were examined under a microscope to evaluate the morphological and histopathological changes of hydatid cysts and tissues. The study confirmed macroscopically that there were a number of hydatid cysts of different sizes in the liver, spleen, and lungs, splenomegaly, and congestion of the lungs of the positive control group. The histological changes in the organs of the group treated with the crustacean extract were represented by the vacuolation of hepatocytes in the centrilobular area of the liver. At the same time, the lungs show intensive peri-bronchiolar inflammation, pulmonary vascular congestion, and in the spleen, the deposition of amyloid-like material in the white pulp, extramedullary hematopoiesis, While the histopathological changes in the organs of mice treated with mebendazole, were represented by the presence in the mild liver vacuolation of the centrilobular area. In contrast, the lungs show mild pulmonary vascular congestion and emphysema, and the spleen shows normal white pulp, the normal red pulp of mice. The aqueous extract Portunuspelagicus and mebendazole are effective in controlling the contamination in the intermediate hosts.
Assuntos
Equinococose , Echinococcus , Masculino , Animais , Camundongos , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Equinococose/tratamento farmacológico , Equinococose/veterinária , Fígado , Inflamação/veterináriaRESUMO
Glioblastoma multiforme (GBM) belongs to most aggressive and invasive primary brain tumor in adults whose prognosis and survival remains poor. Potential new treatment modalities include targeting the cytoskeleton. In our study, we demonstrated that repurposed drug flubendazole (FLU) significantly inhibits proliferation and survival of GBM cells. FLU exerted its effect by affecting microtubule structure and our results also suggest that FLU influences tubulins expression to a certain degree. Moreover, FLU effects decreased activation of STAT3 and also partially inhibited its expression, leading to upregulation of p53 signaling pathway and subsequent cell cycle arrest at G2/M phase as well as caspase-dependent cell death in GBM cells. These results suggest FLU as a promising agent to be used in GBM treatment and prompting further testing of its effects on GBM.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/patologia , Linhagem Celular Tumoral , Pontos de Checagem do Ciclo Celular , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Proliferação de Células , Neoplasias Encefálicas/patologia , Apoptose , Ciclo Celular , Fator de Transcrição STAT3/metabolismoRESUMO
Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.
Assuntos
Anti-Infecciosos , Antineoplásicos , Neoplasias Encefálicas , Glioma , Neoplasias de Cabeça e Pescoço , Masculino , Animais , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Antiparasitários , Linhagem Celular Tumoral , Proteínas Hedgehog , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Glioma/tratamento farmacológicoRESUMO
Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC50) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin ß4 (ITGß4) expression and cancer stem cell properties. ITGß4 has previously been implicated in promoting "cancer stemness," which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.
Assuntos
Mebendazol , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Integrina beta4 , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular TumoralRESUMO
Breast cancer is the most commonly diagnosed cancer worldwide and ranks first in terms of both prevalence and cancer-related mortality in women. In this study, we aimed to evaluate the anticancer effect of mebendazole (MBZ) and radiotherapy (RT) concomitant use in triple-negative breast cancer (TNBC) cells and elucidate the underlying mechanisms of action. Breast cancer mouse models and several types of breast cancer cells, including TNBC-derived RT-resistant (RT-R) MDA-MB-231 cells, were treated with MBZ and/or RT. In mice, changes in body weight, renal and liver toxicity, tumor volume, and number of lung metastases were determined. In cells, cell viability, colony formation, scratch wound healing, Matrigel invasion, and protein expression using western blotting were determined. Our findings showed that MBZ and RT combined treatment increased the anticancer effect of RT without additional toxicity. In addition, we noted that cyclin B1, PH2AX, and natural killer (NK) cell-mediated cytotoxicity increased following MBZ + RT treatment compared to unaided RT. Our results suggest that MBZ + RT have an enhanced anticancer effect in TNBC which acquires radiation resistance through blocking cell cycle progression, initiating DNA double-strand breaks, and promoting NK cell-mediated cytotoxicity.
Assuntos
Mebendazol , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Camundongos , Animais , Mebendazol/farmacologia , Mebendazol/uso terapêutico , Linhagem Celular Tumoral , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Neoplasias de Mama Triplo Negativas/patologia , Apoptose , Células Matadoras Naturais , Proliferação de CélulasRESUMO
BACKGROUND: Hookworm infections, caused by Ancylostoma duodenale and Necator americanus, are of considerable public health importance. The World Health Organization recommends preventive chemotherapy as the key strategy for morbidity control. Meta-analyses have been conducted to estimate treatment efficacy of available drugs and drug combinations. However, in most studies, the relation between the diagnostic error and infection intensity have not been considered, resulting in an overestimation of cure rates (CRs). METHODOLOGY: A Bayesian model was developed to compare the 'true' CR and egg reduction rate of different treatment regimens for hookworm infections taking into account the error of the recommended Kato-Katz thick smear diagnostic technique. It was fitted to the observed egg count data which was linked to the distribution of worms, considered the day-to-day variation of hookworm egg excretion and estimated the infection intensity-dependent sensitivity. The CR was obtained by defining the prevalence of infection at follow-up as the probability of having at least one fertilized female worm. The model was applied to individual-level egg count data available from 17 treatments and six clinical trials. PRINCIPAL FINDINGS: Taking the diagnostic error into account resulted in considerably lower CRs than previously reported. Overall, of all treatments analyzed, mebendazole administered in six dosages of 100 mg each was the most efficacious treatment with a CR of 88% (95% Bayesian credible interval: 79-95%). Furthermore, diagnostic sensitivity varied with the infection intensity and sampling effort. For an infection intensity of 50 eggs per gram of stool, the sensitivity is close to 60%; for two Kato-Katz thick smears it increased to approximately 76%. CONCLUSIONS/SIGNIFICANCE: Our model-based estimates provide the true efficacy of different treatment regimens against hookworm infection taking into account the diagnostic error of the Kato-Katz method. Estimates of the diagnostic sensitivity for different number of stool samples and thick smears are obtained. To accurately assess efficacy in clinical trials with the Kato-Katz method, at least two stool samples on consecutive days should be collected.
Assuntos
Ancylostomatoidea , Infecções por Uncinaria , Animais , Feminino , Humanos , Contagem de Ovos de Parasitas/métodos , Mebendazol/uso terapêutico , Teorema de Bayes , Infecções por Uncinaria/diagnóstico , Infecções por Uncinaria/tratamento farmacológico , Fezes , Erros de Diagnóstico , Sensibilidade e EspecificidadeRESUMO
Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.
Assuntos
Anti-Helmínticos , Antimaláricos , Antineoplásicos , Neoplasias da Mama , Diabetes Mellitus Tipo 2 , Inibidores de Hidroximetilglutaril-CoA Redutases , Metformina , Monofosfato de Adenosina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Helmínticos/uso terapêutico , Antibacterianos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antimaláricos/uso terapêutico , Antineoplásicos/uso terapêutico , Atorvastatina/uso terapêutico , Neoplasias da Mama/patologia , Colesterol , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Masculino , Mebendazol/uso terapêutico , Metformina/uso terapêutico , Ácido Mevalônico/uso terapêutico , Propranolol/uso terapêutico , Proteínas Quinases/metabolismo , Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf , Receptores Adrenérgicos beta 2/uso terapêutico , TirosinaRESUMO
INTRODUCTION: According to the hygiene hypothesis, exposure to parasites may protect against inflammatory bowel disease (IBD). Our aim was to examine the risk of IBD with childhood exposure to mebendazole, a broad-spectrum antihelminthic agent. METHODS: We conducted a population-based cohort study using prospectively collected historical data of all individuals born in Denmark between 1995 and 2018. We identified mebendazole exposure at age younger than 18 years and during early life (younger than 5 years). We performed adjusted Cox proportional hazards regression analysis to determine the risk of IBD, ulcerative colitis (UC), and Crohn's disease with mebendazole exposure after adjusting for potential confounders. RESULTS: Of 1,520,290 individuals in the cohort, 615,794 had childhood or adolescence mebendazole exposure. One thousand five hundred fifty-five and 1,499 individuals were subsequently diagnosed with pediatric-onset and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at age younger than 18 years did not affect pediatric-onset or adult-onset IBD risk (adjusted hazard ratio [aHR] 0.97, 95% confidence interval [CI] 0.87, 1.07, and 1.08, 95% CI 0.97, 1.19, respectively). On limiting mebendazole exposure to age younger than 5 years while there was no association with pediatric-onset IBD (aHR 0.98, 95% CI 0.87, 1.11), adult-onset IBD risk was increased (aHR 1.17, 95% CI 1.04, 1.31). This increase in risk was driven by UC (aHR 1.32, 95% CI 1.12, 1.55), but not Crohn's disease (1.03, 95% CI 0.87, 1.22). DISCUSSION: Early-life mebendazole exposure is associated with an increase in the risk of adult-onset UC. These findings suggest the importance of early-life exposures in shaping the risk of IBD later in life.
Assuntos
Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adulto , Criança , Adolescente , Humanos , Pré-Escolar , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/diagnóstico , Estudos de Coortes , Mebendazol/uso terapêutico , Doença de Crohn/diagnóstico , Fatores de RiscoRESUMO
BACKGROUND: Periodic administration of anthelmintic drugs is a cost-effective intervention for morbidity control of soil-transmitted helminth (STH) infections. However, with programs expanding, drug pressure potentially selecting for drug-resistant parasites increases. While monitoring anthelmintic drug efficacy is crucial to inform country control program strategies, different factors must be taken into consideration that influence drug efficacy and make it difficult to standardize treatment outcome measures. We aimed to identify suitable approaches to assess and compare the efficacy of different anthelmintic treatments. METHODOLOGY: We built an individual participant-level database from 11 randomized controlled trials and two observational studies in which subjects received single-agent or combination therapy, or placebo. Eggs per gram of stool were calculated from egg counts at baseline and post-treatment. Egg reduction rates (ERR; based on mean group egg counts) and individual-patient ERR (iERR) were utilized to express drug efficacy and analyzed after log-transformation with a linear mixed effect model. The analyses were separated by follow-up duration (14-21 and 22-45 days) after drug administration. PRINCIPAL FINDINGS: The 13 studies enrolled 5,759 STH stool-positive individuals; 5,688 received active medication or placebo contributing a total of 11,103 STH infections (65% had two or three concurrent infections), of whom 3,904 (8,503 infections) and 1,784 (2,550 infections) had efficacy assessed at 14-21 days and 22-45 days post-treatment, respectively. Neither the number of helminth co-infections nor duration of follow-up affected ERR for any helminth species. The number of participants treated with single-dose albendazole was 689 (18%), with single-dose mebendazole 658 (17%), and with albendazole-based co-administrations 775 (23%). The overall mean ERR assessed by day 14-21 for albendazole and mebendazole was 94.5% and 87.4%, respectively on Ascaris lumbricoides, 86.8% and 40.8% on hookworm, and 44.9% and 23.8% on Trichuris trichiura. The World Health Organization (WHO) recommended criteria for efficacy were met in 50%, 62%, and 33% studies of albendazole for A. lumbricoides, T. trichiura, and hookworm, respectively and 25% of mebendazole studies. iERR analyses showed similar results, with cure achieved in 92% of A. lumbricoides-infected subjects treated with albendazole and 93% with mebendazole; corresponding figures for hookworm were 70% and 17%, and for T. trichiura 22% and 20%. CONCLUSIONS/SIGNIFICANCE: Combining the traditional efficacy assessment using group averages with individual responses provides a more complete picture of how anthelmintic treatments perform. Most treatments analyzed fail to meet the WHO minimal criteria for efficacy based on group means. Drug combinations (i.e., albendazole-ivermectin and albendazole-oxantel pamoate) are promising treatments for STH infections.
Assuntos
Anti-Helmínticos , Helmintíase , Helmintos , Infecções por Uncinaria , Tricuríase , Albendazol/uso terapêutico , Ancylostomatoidea , Animais , Anti-Helmínticos/uso terapêutico , Helmintíase/tratamento farmacológico , Infecções por Uncinaria/tratamento farmacológico , Humanos , Mebendazol/uso terapêutico , Solo/parasitologia , Tricuríase/tratamento farmacológico , TrichurisRESUMO
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.