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Journal of Chemical Information and... Nov 2023Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis...
Carbendazim derivatives, commonly used as antiparasitic drugs, have shown potential as anticancer agents due to their ability to induce cell cycle arrest and apoptosis in human cancer cells by inhibiting tubulin polymerization. Crystallographic structures of α/β-tubulin multimers complexed with nocodazole and mebendazole, two carbendazim derivatives with potent anticancer activity, highlighted the possibility of designing compounds that occupy both benzimidazole- and colchicine-binding sites. In addition, previous studies have demonstrated that the incorporation of a phenoxy group at position 5/6 of carbendazim increases the antiproliferative activity in cancer cell lines. Despite the significant progress made in identifying new tubulin-targeting anticancer compounds, further modifications are needed to enhance their potency and safety. In this study, we explored the impact of modifying the phenoxy substitution pattern on antiproliferative activity. Alchemical free energy calculations were used to predict the binding free energy difference upon ligand modification and define the most viable path for structure optimization. Based on these calculations, seven compounds were synthesized and evaluated against lung and colon cancer cell lines. Our results showed that compound , which incorporates an α-naphthyloxy substitution, exhibits the highest antiproliferative activity against both cancer lines (SK-LU-1 and SW620, IC < 100 nM) and induces morphological changes in the cells associated with mitotic arrest and mitotic catastrophe. Nevertheless, the tubulin polymerization assay showed that has a lower inhibitory potency than nocodazole. Molecular dynamics simulations suggested that this low antitubulin activity could be associated with the loss of the key H-bond interaction with V236. This study provides insights into the design of novel carbendazim derivatives with anticancer activity.
Topics: Humans; Tubulin Modulators; Molecular Structure; Structure-Activity Relationship; Nocodazole; Tubulin; Cell Proliferation; Molecular Docking Simulation; Antineoplastic Agents; Polymerization; Drug Screening Assays, Antitumor
PubMed: 37947759
DOI: 10.1021/acs.jcim.3c01379 -
International Journal of Environmental... Oct 2023Toxocariasis remains an important neglected parasitic infection representing one of the most common zoonotic infections caused by the parasite or, less frequently, by .... (Review)
Review
Toxocariasis remains an important neglected parasitic infection representing one of the most common zoonotic infections caused by the parasite or, less frequently, by . The epidemiology of the disease is complex due to its transmission route by accidental ingestion of embryonated eggs or larvae from tissues from domestic or wild paratenic hosts. Even though the World Health Organization and Centers for Disease Control classified toxocariasis amongst the top six parasitic infections of priority to public health, global epidemiological data regarding the relationship between seropositivity and toxocariasis is limited. Although the vast majority of the infected individuals remain asymptomatic or experience a mild disease, the infection is associated with important health and socioeconomic consequences, particularly in underprivileged, tropical, and subtropical areas. Toxocariasis is a disease with multiple clinical presentations, which are classified into five distinct forms: the classical visceral larva migrans, ocular toxocariasis, common toxocariasis, covert toxocariasis, and cerebral toxocariasis or neurotoxocariasis. Anthelmintic agents, for example, or , are the recommended treatment, whereas a combination with topical or systemic corticosteroids for specific forms is suggested. Prevention strategies include educational programs, behavioral and hygienic changes, enhancement of the role of veterinarians, and anthelmintic regimens to control active infections.
Topics: Animals; Humans; Toxocariasis; Zoonoses; Albendazole; Public Health; Anthelmintics
PubMed: 37947530
DOI: 10.3390/ijerph20216972 -
The Science of the Total Environment Jan 2024The distribution and fate of 19 anthelmintic drugs (ADs) were investigated in two wastewater treatment plants (WWTPs) using different wastewater treatment technologies,...
The distribution and fate of 19 anthelmintic drugs (ADs) were investigated in two wastewater treatment plants (WWTPs) using different wastewater treatment technologies, including anaerobic-anoxic-aerobic (A/O) biological process and cyclic activated sludge system (CASS) process. All the 19 ADs were found in the two WWTPs, with concentrations ranging from N.D. to 324.6 ng/L in the influent and from N.D. to 1579.2 ng/L in the effluent. Benzimidazoles were the primary pollutants in the wastewater and suspended particulate matter, accounting for more than half of the total concentration. The concentrations of macrocyclic lactones in the sludge were significantly higher than that of other two media. The ADs removal efficiency of A/O ranged from -330 % (albendazole sulfoxide) to 100 % (fenbendazole, mebendazole and pyrantel). While the ADs removal efficiency of CASS process ranged from -425 % (albendazole sulfoxide) to 100 % (abamectin, moxidectin and ivermectin). There was no significant difference in the average removal efficiency of the ADs between the two processes (64 % and 63 %, except albendazole sulfoxide). The removal efficiencies of the ADs in the biodegradation stage were better than them in the sedimentation stage. The load per capita of the 19 ADs in two WWTPs ranged from 0 (moxidectin) to 36 μg.d.p (albendazole), and the emission in the effluent ranged from 0 (moxidectin) to 163 μg.d.p (albendazole sulfoxide). This study provided the first comprehensive data on the occurrence and fate of the 19 ADs and evaluated the removal efficiencies of the 19 ADs in two WWTPs using AO process and CASS process in the city.
Topics: Sewage; Waste Disposal, Fluid; Environmental Monitoring; Water Pollutants, Chemical; Anthelmintics; Water Purification
PubMed: 37914119
DOI: 10.1016/j.scitotenv.2023.168240 -
Parasites & Vectors Oct 2023In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical... (Review)
Review
In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.
Topics: Humans; Ivermectin; Rifampin; Doxycycline; Fluconazole; Off-Label Use; Anti-Infective Agents; Drug Combinations; Neglected Diseases
PubMed: 37907954
DOI: 10.1186/s13071-023-05909-8 -
Naunyn-Schmiedeberg's Archives of... Apr 2024Colon 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...
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 mm; 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.
Topics: Humans; Animals; Mice; Mebendazole; Cell Line, Tumor; Drug Repositioning; HT29 Cells; Colonic Neoplasms
PubMed: 37837472
DOI: 10.1007/s00210-023-02722-z -
Annals of Medicine and Surgery (2012) Oct 2023Worm infestations are a common occurrence in low-income countries. Anemia due to iron deficiency can be brought on by human intestinal worms. The authors report a case...
INTRODUCTION
Worm infestations are a common occurrence in low-income countries. Anemia due to iron deficiency can be brought on by human intestinal worms. The authors report a case of an 86-year-old frail older adult with upper gastrointestinal (GI) bleeding caused by a worm infestation most likely to be hookworm.
CASE PRESENTATION
An 86-year-old male, presented to the Emergency Department with complaints of bilateral lower limb swelling and shortness of breath for 4 days associated with melena for 2 months. The authors made a provisional diagnosis of heart failure precipitated by anemia. Upper GI endoscopy revealed multiple whitish exudates, which are resistant to water jets. Multiple worms were noted in the second part of the duodenum. Based on clinical evaluation and endoscopy, the diagnosis of oesophagial candidiasis and iron deficiency anemia secondary to upper GI bleeding due to Hookworm infestation was made.
CLINICAL DISCUSSION
In low-income countries, especially those involving the tropical area, worm infestation should be considered as an important cause of obscure acute GI bleeding and severe anemia. Usually, malignancy is suspected in an older adult with severe anemia but hookworm infestation is a treatable disease with a good prognosis and complete recovery. The most commonly used drugs for treatment are mebendazole and albendazole. In a low-income country with a high burden of worm infestations, empirical treatment of iron deficiency anemia with single dose albendazole has been recommended.
CONCLUSION
Usually, severe anemia in an older adult is mostly attributed to an underlying malignancy. Our case serves as a good example of how a treatable condition can improve the quality of life in a frail older adult. Normally, there is a tendency to defer UGI endoscopy in frail elderly due to ageism. However, the diagnosis of a treatable cause of upper GI bleeding can be made by a simple upper GI endoscopy. Severe anemia due to hookworm infestation is treated effectively and quickly with albendazole and iron therapy.
PubMed: 37811116
DOI: 10.1097/MS9.0000000000001171 -
Journal of Biomolecular Structure &... Sep 2023Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the...
Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations. The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, fenbendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under and studies.Communicated by Ramaswamy H. Sarma.
PubMed: 37740654
DOI: 10.1080/07391102.2023.2258419 -
Biomedicine & Pharmacotherapy =... Nov 2023We examined whether combinig diclofenac and metformin in doses equivalent to human doses would synergize their anticancer activity on fibrosarcoma inoculated to hamsters...
We examined whether combinig diclofenac and metformin in doses equivalent to human doses would synergize their anticancer activity on fibrosarcoma inoculated to hamsters and in vitro. Rescue experiment was performed to examine whether the prosurvival NF-κB stimulation by mebendazole can reverse anticancer effects of the treatment. BHK-21/C13 cell culture was subcutaneously inoculated to Syrian golden hamsters randomly divided into groups (6 animals per group): 1) untreated control; treated daily with 2) diclofenac; 3) metformin; 4) combinations of diclofenac and metformin at various doses; 5) combination of diclofenac, metformin and mebendazole; 6) mebendazole. Dose response curves were made for diclofenac and metformin combination. Tumor growth kinetics, biophysical, pathological, histological and immunohistochemical characteristics of excised tumors and hamster organs as well as biochemical and hematological blood tests were compared among the groups. Single treatments had no anticancer effects. Diclofenac (60 mg/kg/day) exhibited significant (P < 0.05) synergistic inhibitory effect with metformin (500 mg/kg/day) on all tumor growth parameters, without toxicity and influence on biochemical and hematological blood tests. The same results were obtained with double doses of diclofenac and metformin combination. The addition of mebendazole to the diclofenac and metformin combination rescued tumor expansion. Furthermore, diclofenac with metformin demonstrated antiproliferative effects in hamster fibrosarcoma BHK-21/C13, human lung carcinoma A549 (CCL-185), colon carcinoma HT-29 (HTB-38) and cervical carcinoma HeLa (CCL-2) cell cultures, with markedly lower cytotoxicity in the normal fetal lung MRC-5 cells. In conclusion, diclofenac and metformin combination may be recommended for potential use in oncology, due to synergistic anticancer effect in doses achievable in humans.
PubMed: 37738800
DOI: 10.1016/j.biopha.2023.115528 -
Frontiers in Veterinary Science 2023Novel therapies are needed for treatment of gliomas. Mebendazole previously demonstrated anti-neoplastic effects on canine glioma cell lines at mean inhibitory...
Novel therapies are needed for treatment of gliomas. Mebendazole previously demonstrated anti-neoplastic effects on canine glioma cell lines at mean inhibitory concentrations (IC) of 10 ng/mL. Our study aimed to titrate the oral dose of mebendazole necessary to achieve concentrations ≥10 ng/mL in cerebrospinal fluid (CSF) of healthy dogs. We hypothesized that an oral dose up to 200 mg/kg would be necessary. Phase one was a dose titration study using a total of 6 mixed breed dogs that described dose vs. plasma concentrations for 72 h after single oral dosing of either 50 mg/kg ( = 2), 100 mg/kg ( = 2), or 200 mg/kg ( = 2). Based on phase one, phase two dogs (total of 9) received 100 mg/kg ( = 4) or 200 mg/kg ( = 5) orally and blood samples were collected intermittently for 60 h with CSF samples collected intermittently for 24 h. Mebendazole was quantitated in plasma and CSF using high performance liquid chromatography. Median peak plasma concentrations (Cmax) were reached at 7 ± 2 h (100 mg/kg) of 220 ng/mL (81, 283) and at 15 ± 4 h (200 mg/kg) of 147 ng/ml (112, 298). The respective area under the curve (AUC: ng/ml/h) reported as a median was 2,119 (1,876, 3,288) vs. 3,115 (1,559, 4,972). Median plasma concentrations (ng/ml) for 100 vs. 200 mg/kg were 47 (32, 52) vs. 65 (35, 104), respectively. For CSF, the median value for Cmax (at 100 mg/kg vs. 200 mg/kg) was 8 (2, 28) vs. 21 (12, 27) and AUC was 87 (22, 157) vs. 345 (92, 372), respectively. Relative bioavailability in CSF vs. plasma was 4 to 10%. Although several animals demonstrated clinical signs indicative of gastrointestinal upset [i.e., vomiting ( = 2), diarrhea ( = 2), or both ( = 1)], these events were not considered serious. The IC for gliomas can be reached in CSF at 100 mg/kg ( = 1), however a 200 mg/kg dose yielded more consistent concentrations.
PubMed: 37701529
DOI: 10.3389/fvets.2023.1231769 -
Animals : An Open Access Journal From... Aug 2023This study aims to report the clinical signs, therapeutic strategy, necropsy results, and histopathological findings of airsacculitis caused by enterobacteria and the...
This study aims to report the clinical signs, therapeutic strategy, necropsy results, and histopathological findings of airsacculitis caused by enterobacteria and the occurrence of eggs from the superfamily Diplotriaenoidea in the feces of in the Amazon biome. A tropical screech owl nestling was rescued and admitted for hand-rearing. The animal was kept hospitalized for five months. It was fed a diet based on larvae and thawed chicken breast meat with vitamin and mineral supplements. On the 37th day of hacking training for release, the owl showed weakness, lack of appetite, regurgitation, cachexia, dyspnea, ruffled feathers, dry droppings in the vent and pericloaca, and diarrhea. The parasitological examination showed eggs of the Diplotriaenoidea superfamily in the feces. The therapy employed included oxytetracycline, sulfamethoxazole, mebendazole, Potenay, sodium chloride 0.9%, and Mercepton. However, five days after starting the treatment, the bird died. Upon necropsy, prominence of the keel, pieces of undigested food in the oral cavity and proventriculus, intestinal gas, and thickened and turbid air sacs were found. The microbiological analysis of air sacs identified , , and . Histopathological examination showed heterophilic bacterial airsacculitis.
PubMed: 37685014
DOI: 10.3390/ani13172750