Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.271
Filtrar
1.
BMJ Case Rep ; 17(6)2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862191

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 Magnética
2.
Eur J Pharm Biopharm ; 200: 114333, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38768766

RESUMO

Developing co-amorphous systems is an attractive strategy to improve the dissolution rate of poorly water-soluble drugs. Various co-formers have been investigated. However, previous studies revealed that it is a challenge to develop satisfied acidic co-formers, e.g., acidic amino acids showed much poorer co-former properties than neutral and basic amino acids. Only a few acidic co-formers have been reported, such as aspartic acid, glutamic acid, and some other organic acids. Thus, this study aims to explore the possibility of adenosine monophosphate and adenosine diphosphate used as acidic co-formers. Mebendazole, celecoxib and tadalafil were used as the model drugs. The drug-co-former co-amorphous systems were prepared via ball milling and confirmed using XRPD. The dissolution study suggested that the solubility and dissolution rate of the drug-co-formers systems were increased significantly compared to the corresponding crystalline and amorphous drugs. The stability study revealed that using the two nucleotides as co-formers enhanced the physical stability of pure amorphous drugs. Molecular interactions were observed in MEB-co-former and TAD-co-former systems and positively affected the pharmaceutical performance of the investigated co-amorphous systems. In conclusion, the two nucleotides could be promising potential acidic co-formers for co-amorphous systems.


Assuntos
Celecoxib , Estabilidade de Medicamentos , Nucleotídeos , Solubilidade , Água , Água/química , Nucleotídeos/química , Celecoxib/química , Tadalafila/química , Química Farmacêutica/métodos , Mebendazol/química , Liberação Controlada de Fármacos
3.
Anal Chem ; 96(21): 8317-8324, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38739544

RESUMO

Nuclear magnetic resonance (NMR) longitudinal rotating frame relaxation time (T1ρ), rarely used in low-field NMR, can be more effective than conventional T1 and T2 relaxation times to differentiate polymorphic forms of solid pharmaceuticals. This could be attributed to T1ρ sensibility to structural and molecular dynamics that can be enhanced by changing the strength of the oscillating magnetic field (B1) of spinlock pulses. Here, we compared the capacity of T1, T2, and T1ρ to differentiate inactive (A) and active (C) crystalline forms of the World Health Organization essential drug Mebendazole. The results showed that T1 and T2 values of both forms were statistically identical at 0.47 T. Conversely, T1ρ of both forms measured with weak spinlock B1 fields, ranging from 0.08 to 0.80 mT were statistically different in the same spectrometer. The T1ρ also has the limit of detection to detect the presence of at least 10% of inactive A form in the active C form. Therefore, T1ρ, measured with weak spinlock B1 fields can be an effective, streamlined, and complementary approach for characterizing not only solid active pharmaceutical ingredients but other solid-state materials as well.


Assuntos
Espectroscopia de Ressonância Magnética , Espectroscopia de Ressonância Magnética/métodos , Mebendazol/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/análise , Campos Magnéticos , Estudo de Prova de Conceito , Princípios Ativos
4.
J Neurooncol ; 168(1): 125-138, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38563850

RESUMO

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 fármacos
5.
Antimicrob Agents Chemother ; 68(5): e0121123, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563751

RESUMO

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 Parasitas
6.
Nanomedicine (Lond) ; 19(12): 1087-1101, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38661720

RESUMO

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 Nus
7.
Parasitol Res ; 123(4): 186, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38634933

RESUMO

Onchocerciasis is a devastating skin and eye disease that afflicts about 21 million people, most of whom live in sub-Saharan Africa. Its control with the microfilaricidal drug ivermectin is limited, thus necessitating the development of preclinical animal models to aid in the discovery of a macrofilaricide. Previously, we found that Onchocerca ochengi (the closest relative of the human O. volvulus) worm masses survive better in hamsters than in gerbils. The aim of this study was to compare the survival of O. ochengi adult male worms and their susceptibility to flubendazole (FBZ, a macrofilaricide) in gerbils and hamsters. The animals were intraperitoneally implanted with O. ochengi male worms, treated with FBZ, and sacrificed 35 days post-implantation. Unlike gerbils which had some worms moving freely in the peritoneum and some in newly formed nodules (neo-nodules), all the worms in the hamsters were found in neo-nodules. FBZ significantly decreased worm burden, motility, and viability in gerbils whereas it had no significant effect in hamsters. These results highlight a major difference in how O. ochengi adult male worms are sustained and affected by FBZ in gerbils compared to hamsters. Understanding the difference between these two models is important in the development of effective macrofilaricides for onchocerciasis.


Assuntos
Mebendazol/análogos & derivados , Onchocerca , Oncocercose , Adulto , Animais , Cricetinae , Humanos , Masculino , Gerbillinae
8.
BMC Womens Health ; 24(1): 265, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38678281

RESUMO

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 , Adulto
9.
Chem Biol Drug Des ; 103(3): e14503, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38480495

RESUMO

Flubendazole, an FDA-approved anthelmintic, has been predicted to show strong VEGFR2 inhibitory activity in silico screening combined with in vitro experimental validation, and it has shown anti-cancer effects on some human cancer cell lines, but little is known about the anti-angiogenesis effects and anti-prostate cancer effects. In this study, we analyzed the binding modes and kinetic analysis of flubendazole with VEGFR2 and first demonstrated that flubendazole suppressed VEGF-stimulated cell proliferation, wound-healing migration, cell invasion and tube formation of HUVEC cells, and decreased the phosphorylation of extracellular signal-regulated kinase and serine/threonine kinase Akt, which are the downstream proteins of VEGFR2 that are important for cell growth. What's more, our results showed that flubendazole decreased PC-3 cell viability and proliferation ability, and suppressed PC-3 cell wound healing migration and invasion across a Matrigel-coated Transwell membrane in a concentration-dependent manner. The antiproliferative effects of flubendazole were due to induction of G2-M phase cell cycle arrest in PC-3 cells with decreasing expression of the Cyclin D1 and induction of cell apoptosis with the number of apoptotic cells increased after flubendazole treatment. These results indicated that flubendazole could exert anti-angiogenic and anticancer effects by inhibiting cell cycle and inducing cell apoptosis.


Assuntos
Angiogênese , Mebendazol/análogos & derivados , Fator A de Crescimento do Endotélio Vascular , Humanos , Células PC-3 , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cinética , Movimento Celular , Proliferação de Células , Inibidores da Angiogênese/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
10.
Biomed Pharmacother ; 174: 116434, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38513592

RESUMO

The cilium is a microtubule-based organelle that plays a pivotal role in embryonic development and maintenance of physiological functions in the human body. In addition to their function as sensors that transduce diverse extracellular signals, including growth factors, fluid flow, and physical forces, cilia are intricately involved in cell cycle regulation and preservation of DNA integrity, as their formation and resorption dynamics are tightly linked to cell cycle progression. Recently, several studies have linked defects in specific ciliary proteins to the DNA damage response. However, it remains unclear whether and how primary cilia contribute to cancer development. Mebendazole (MBZ) is an anthelmintic drug with anticancer properties in some cancer cells. MBZ is continuously being tested for clinical studies, but the precise mechanism of its anticancer activities remains unknown. Here, using Xenopus laevis embryos as a model system, we discovered that MBZ significantly hinders cilia formation and induces DNA damage. Remarkably, primary cilium-bearing cancer cells exhibited heightened vulnerability to combined treatment with MBZ and conventional anticancer drugs. Our findings shed light on the specific influence of MBZ on cilia, rather than cytosolic microtubules, in triggering DNA damage, elucidating a previously unidentified mechanism underlying potential MBZ-mediated cancer therapy.


Assuntos
Cílios , Dano ao DNA , Mebendazol , Xenopus laevis , Cílios/efeitos dos fármacos , Cílios/metabolismo , Dano ao DNA/efeitos dos fármacos , Animais , Mebendazol/farmacologia , Humanos , Antineoplásicos/farmacologia , Sinergismo Farmacológico , Linhagem Celular Tumoral , Embrião não Mamífero/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo
11.
Cell Rep ; 43(2): 113763, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38358890

RESUMO

The lateral root angle or gravitropic set-point angle (GSA) is an important trait for root system architecture (RSA) that determines the radial expansion of the root system. The GSA therefore plays a crucial role for the ability of plants to access nutrients and water in the soil. Only a few regulatory pathways and mechanisms that determine GSA are known. These mostly relate to auxin and cytokinin pathways. Here, we report the identification of a small molecule, mebendazole (MBZ), that modulates GSA in Arabidopsis thaliana roots and acts via the activation of ethylene signaling. MBZ directly acts on the serine/threonine protein kinase CTR1, which is a negative regulator of ethylene signaling. Our study not only shows that the ethylene signaling pathway is essential for GSA regulation but also identifies a small molecular modulator of RSA that acts downstream of ethylene receptors and that directly activates ethylene signaling.


Assuntos
Arabidopsis , Mebendazol , Citocininas , Etilenos , Ácidos Indolacéticos
12.
Vet Parasitol ; 327: 110140, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38330532

RESUMO

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 farmacológico
13.
Pediatr Blood Cancer ; 71(4): e30874, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38234020

RESUMO

BACKGROUND: High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG. OBJECTIVE: To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group. DESIGN/METHOD: Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of mebendazole in combination with bevacizumab (10 mg/kg/dose) and irinotecan (150 mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles. RESULTS: Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50 mg/kg/day (n = 3), 100 mg/kg/day (n = 4), and 200 mg/kg/day (n = 3). One subject assigned to 100 mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n = 3) and lymphopenia (n = 4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10 months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4 months, respectively. CONCLUSION: Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200 mg/kg/day. Further studies are needed to determine the efficacy of this treatment.


Assuntos
Glioma , Mebendazol , Criança , Adulto Jovem , Humanos , Bevacizumab , Irinotecano/efeitos adversos , Mebendazol/efeitos adversos , Camptotecina/efeitos adversos , Glioma/tratamento farmacológico
14.
Poult Sci ; 103(3): 103405, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38183880

RESUMO

Ascaridia galli is the most common nematode in chickens. Ascaridia galli is highly prevalent in chickens reared in scavenging or semiscavenging systems. Here, we studied the epidemiology, pathology, genetic diversity, ex vivo culture protocol and anthelmintic sensitivity of A. galli prevalent in indigenous chickens in Bangladesh. Through morphological study and molecular analyses, the isolated worms were confirmed as A. galli. Of the chickens examined, 45.6% (178 out of 390) were found infected. The male and young chickens were significantly (P < 0.05) more prone to A. galli infection. Prevalence of the infection was significantly (P < 0.05) lower in the summer season. In heavy infections, A. galli blocked the small intestine. Marked inflammation, increased mucus production and petechial hemorrhages were evident in the small intestine, particularly in the duodenum. Also, there were desquamation and adhesion of the mucosal villi; degeneration, necrosis of the epithelial cells and goblet cell hyperplasia. The mucosal layer was infiltrated mainly with eosinophils and heterophils. We developed a hen egg white-based long-term ex vivo culture protocol which supported the survival and reproduction of A. galli for more than a week. Levamisole (LEV) and ivermectin (IVM) efficiently killed A. galli. However, albendazole (ABZ), mebendazole (MBZ), and piperazine (PPZ) did not kill the worms even at 120 µg/mL and 1mg/mL concentrations, respectively. Taken together, our results suggest that A. galli is highly prevalent in semiscavenging chickens in Bangladesh. Ascaridia galli can be easily maintained ex vivo in egg white supplemented M199 medium. LEV and IVM, but not ABZ, MBZ and PPZ, can be used for treating and controlling A. galli infections in chickens.


Assuntos
Anti-Helmínticos , Anti-Infecciosos , Animais , Masculino , Ascaridia , Galinhas , Bangladesh/epidemiologia , Epidemiologia Molecular , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Albendazol , Levamisol , Mebendazol , Ivermectina
15.
Vet Res ; 55(1): 7, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225645

RESUMO

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/farmacologia
16.
Naunyn Schmiedebergs Arch Pharmacol ; 397(4): 2379-2388, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-37837472

RESUMO

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 farmacológico
17.
Int J Pharm ; 650: 123721, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38110011

RESUMO

Mebendazole (MBZ) is a broad-spectrum active pharmaceutical ingredient (API) indicated for treating parasitosis, and it has three solid-state forms, A, B, and C. These solid forms exhibit significant differences in dissolution properties, which cause considerable changes in the therapeutic effect. When at least 30 % of Form A is present in the formulation, it has a similar effect to the placebo. The aim of this study was to develop a reliable quantitative method for MBZ (Forms A and C) suspensions that allowed to study the solid-state stability and the kinetics of the solid-state transformation of MBZ suspensions under the recommended pharmaceutical industry conditions. One method was developed to carry out the drying process and the other one to quantify Forms A and C of MBZ suspensions; both were evaluated. For the stability study, samples were prepared with different starting reference concentrations of Form A and stored from 1 to 24 months under long-term stability conditions (30 ± 2 °C and 75 ± 5 % RH) and from 1 to 6 months under accelerated stability conditions (40 ± 2 °C and 75 ± 5 % RH). Data collection was performed by powder X-ray diffraction (PXRD). The Rietveld method (RM) and Topas's program were used to solid form quantification. Avrami's equation was used to determine the kinetic parameters. The results showed that the combination of the drying process and solid form quantification developed method for suspension was a very accurate methodology for solid-state stability studies. Furthermore, in long-term and accelerated solid-state conditions, suspension with an initial value of 1 % of Form A were sufficient to cause a solid-state transformation (Form C to A) greater than 30 % in the first and second months, with a complete transformation in nine and six months respectively. These results demonstrate that suspensions show complete solid-state transformation (Form C to A) in a shorter time than the product's shelf life (∼2 years). In this work, a reliable methodology was developed to quantify MBZ (Forms A and C) suspensions. This methodology could be used to control the different solid forms for MBZ and other APIs to avoid solid-state transformation problems.


Assuntos
Mebendazol , Difração de Raios X , Pós , Solubilidade , Cristalização , Suspensões
18.
Curr Opin Infect Dis ; 36(5): 303-307, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37593991

RESUMO

PURPOSE OF REVIEW: Cystic echinococcosis is a neglected zoonosis for which humans are dead end hosts. It is not only widely distributed in sheep rearing areas of low-income and middle-income countries but also has a significant presence in wealthy countries, for example, in Europe. It results in considerable morbidity, and its current management is far from optimal. Medical management is with a benzimidazole, with the addition of praziquantel under some circumstances. RECENT FINDINGS: Interest in mebendazole as an anticancer drug has stimulated research into new drug formulations to improve bioavailability and possibly reduce inter-individual variability in in-vivo drug levels, which may help its activity against cystic echinococcosis. Further evidence to support administration of albendazole with a fatty meal has been provided. GlaxoSmithKilne (GSK) has agreed to extend its albendazole donation programme to include echinococcosis. The search for new drugs has focussed on natural products, such as essential oils and on repurposing of existing drugs licensed for human use against other conditions. SUMMARY: The medical treatment of cystic echinococcosis remains sorely neglected, with no new drugs for almost 40 years. We need a better understanding of how to use the drugs we do have, whilst seeking new ones. Drug repurposing may be the best pathway.


Assuntos
Albendazol , Equinococose , Humanos , Animais , Ovinos , Albendazol/uso terapêutico , Equinococose/tratamento farmacológico , Zoonoses , Europa (Continente) , Mebendazol
19.
Toxicol Appl Pharmacol ; 475: 116630, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37473966

RESUMO

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 , Glucose
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 300: 122938, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37269657

RESUMO

UV-vis, fluorescence, circular dichroism (CD) and 1H NMR spectroscopic techniques have been employed to explore the mode of binding of Mebendazole (MBZ) drug with calf thymus DNA (CT-DNA). UV-vis and fluorescence spectral studies suggested a complex formation between the drug and nucleic acid. The fluorescence of MBZ was found to enhance upon binding with CT-DNA through a ground state complex formation with Kb in the order of 104 M-1. The thermodynamic aspects indicated that the complex formation is a spontaneous process and an entropy-driven one. ΔH0 > 0 and ΔS0 > 0 revealed that hydrophobic interaction plays a dominant role in the stabilization of the complex. Competitive dye displacement assays with ethidium bromide (EB) and Hoechst 33258 dyes and viscosity measurements pointed out that MBZ binds with CT-DNA via intercalation mode, which is confirmed by CD and 1H NMR spectral studies as well as denaturation studies. Molecular docking analysis could not match well with the experimental results. However, molecular simulation studies and the resultant free energy surface (FES) analysis clearly showed that the benzimidazole ring of MBZ intercalated between the base pairs of the nucleic acid, which is in excellent agreement with the results of the various biophysical experiments.


Assuntos
DNA , Mebendazol , Simulação de Acoplamento Molecular , Espectrofotometria Ultravioleta , DNA/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...