*Inactivation of encysted muscle larvae of Trichinella spiralis in pigs using Mebendazole.

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.

Flubendazole carbonyl reduction in drug-susceptible and drug-resistant strains of the parasitic nematode Haemonchus contortus: changes during the life cycle and possible inhibition.

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.

Mebendazole targets essential proteins in glucose metabolism leading gastric cancer cells to death.

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.

Histopathological Study to Evaluate the Effect of Aqueous Extract of Portunuspelagicus and Mebendazole on Hydatid Cysts in Mice.

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.

Flubendazole exhibits anti-glioblastoma effect by inhibiting STAT3 and promoting cell cycle arrest.

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.

Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers.

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.

Mebendazole prevents distant organ metastases in part by decreasing ITGß4 expression and cancer stemness.

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.

Mebendazole Increases Anticancer Activity of Radiotherapy in Radiotherapy-Resistant Triple-Negative Breast Cancer Cells by Enhancing Natural Killer Cell-Mediated Cytotoxicity.

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.

Modeling the effect of different drugs and treatment regimen for hookworm on cure and egg reduction rates taking into account diagnostic error.

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.

Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy.

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.

Egg excretion indicators for the measurement of soil-transmitted helminth response to treatment.

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.

Early-Life Mebendazole Exposure Increases the Risk of Adult-Onset Ulcerative Colitis: A Population-Based Cohort Study.

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.

Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.

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.

Impact of preventive chemotherapy on transmission of soil-transmitted helminth infections in Pemba Island, United Republic of Tanzania, 1994-2021.

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.

Mebendazole, an anti-helminth drug, suppresses inflammation, oxidative stress and injury in a mouse model of ulcerative colitis.

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.

High infection rates for onchocerciasis and soil-transmitted helminthiasis in children under five not receiving preventive chemotherapy: a bottleneck to elimination.

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.

A large case series of travel-related Mansonella perstans (vector-borne filarial nematode): a TropNet study in Europe.

BACKGROUND: Infection with Mansonella perstans is a neglected filariasis, widely distributed in sub-Saharan Africa, characterized by an elusive clinical picture; treatment for mansonellosis is not standardized. This retrospective study aimed to describe the clinical features, treatment schemes and evolution, of a large cohort of imported cases of M. perstans infection seen in four European centres for tropical diseases. METHODS: Mansonella perstans infections, diagnosed by identification of blood microfilariae in migrants, expatriates and travellers, collected between 1994 and 2018, were retrospectively analysed. Data concerning demographics, clinical history and laboratory examinations at diagnosis and at follow-up time points were retrieved. RESULTS: A total of 392 patients were included in the study. Of the 281 patients for whom information on symptoms could be retrieved, 150 (53.4%) reported symptoms, abdominal pain and itching being the most frequent. Positive serology and eosinophilia were present in 84.4% and 66.1%, respectively, of those patients for whom these data were available. Concomitant parasitic infections were reported in 23.5% of patients. Treatment, administered to 325 patients (82.9%), was extremely heterogeneous between and within centres; the most commonly used regimen was mebendazole 100 mg twice a day for 1 month. A total of 256 (65.3%) patients attended a first follow-up, median 3 months (interquartile range 2-12) after the first visit; 83.1% of patients having received treatment based on mebendazole and/or doxycycline, targeting Wolbachia, became amicrofilaremic, 41.1-78.4% of whom within 12 months from single treatment. CONCLUSIONS: Lack of specific symptoms, together with the inconstant positivity of parasitological and antibody-based assays in the infected population, makes the clinical suspicion and screening for mansonellosis particularly difficult. Prospective studies evaluating prevalence of infection in migrants from endemic areas, infection-specific morbidity, presence of Wolbachia endosymbionts in M. perstans populations from different geographical areas and efficacy of treatment regimens are absolutely needed to optimize the clinical management of infection.

Mebendazole; from an anti-parasitic drug to a promising candidate for drug repurposing in colorectal cancer.

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.