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Scientific Reports Dec 2023Parasitic roundworms cause significant sickness and mortality in animals and humans. In livestock, these nematodes have severe economic impact and result in losses in...
Parasitic roundworms cause significant sickness and mortality in animals and humans. In livestock, these nematodes have severe economic impact and result in losses in food production on a global scale. None of the currently available drugs ideally suit all treatment circumstances, and the development of drug-resistant nematode strains has become a challenge to control the infection. There is an urgent need to develop novel anthelmintic compounds. According to our previous report, N-methylbenzo[d]oxazol-2-amine (1) showed anthelmintic activity and lowest cytotoxicity. In this study, in vivo anthelmintic properties were evaluated using Trichinella spiralis infected mice. Toxicity was evaluated using the rats and mode of action using molecular docking and metabolomics approaches. The in vivo results demonstrate that a dose of 250 mg/kg reduced the T. spiralis abundance in the digestive tract by 49%. The 250 mg/kg Albendazole was served as control. The relatively low acute toxicity was categorized into chemical category 5, with an LD greater than 2000 mg/kg body. Molecular docking analysis showed the T. spiralis tubulin beta chain and glutamate-gated channels might not be the main targets of compound 1. Metabolomics analysis was used to explain the effects of compound 1 on the T. spiralis adult worm. The results demonstrated that compound 1 significantly up-regulated the metabolism of purine, pyrimidine and down-regulated sphingolipid metabolism. In conclusion, compound 1 could be a potential molecule for anthelmintic development. The bioavailability, pharmacokinetics, and absorption of this compound should be studied further to provide information for its future efficacy improvement.
Topics: Humans; Mice; Rats; Animals; Molecular Docking Simulation; Anthelmintics; Albendazole; Nematoda; Trichinella spiralis
PubMed: 38129499
DOI: 10.1038/s41598-023-50305-y -
PloS One 2023Drug repurposing is the finding new activity of the existing drug. Recently, Albendazole's well-known antihelmintic has got the attention of an anticancer drug....
Drug repurposing is the finding new activity of the existing drug. Recently, Albendazole's well-known antihelmintic has got the attention of an anticancer drug. Plausible evidence of the interaction of Albendazole with one of the types of tyrosine kinase protein receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) is still not well understood. Inhibition of the VEGFR-2 receptor can prevent tumor growth. The current study investigated the interaction of Albendazole with VEGFR-2.It was found that the said interaction exhibited potent binding energy ΔG = -7.12 kcal/mol, inhibitory concentration (Ki) = 6.04 μM, and as positive control comparison with standard drug (42Q1170A) showed ΔG = -12.35 kcal/mol and Ki = 881 μM. The key residue Asp1046 was formed involved hydrogen bonding with Albendazole. The molecular dynamics simulation study revealed the stable trajectory of the VEGFR-2 receptor with Albendazole bound complex having significant high free energy of binding as calculated from Molecular Mechanics Generalized Born and Surface Area study ΔG = -42.07±2.4 kcal/mol. The binding energy is significantly high for greater stability of the complex. Principal component analysis of molecular docking trajectories exhibited ordered motion at higher modes, implying a high degree of VEGFR-2 and Albendazole complex stability as seen with the standard drug 42Q. Therefore, the current work suggests the role of Albendazole as a potent angiogenesis inhibitor as ascertained by its potential interaction with VEGFR-2. The findings of research will aid in the future development of Albendazole in anticancer therapy.
Topics: Structure-Activity Relationship; Albendazole; Vascular Endothelial Growth Factor Receptor-2; Molecular Docking Simulation; Drug Repositioning; Vascular Endothelial Growth Factor A; Protein Kinase Inhibitors; Antineoplastic Agents
PubMed: 37585409
DOI: 10.1371/journal.pone.0287198 -
Memorias Do Instituto Oswaldo Cruz 2020It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB...
Characterisation of the in vitro activity of a Nitazoxanide-N-methyl-1H-benzimidazole hybrid molecule against albendazole and nitazoxanide susceptible and resistant strains of Giardia intestinalis and its in vivo giardicidal activity.
BACKGROUND
It was previously demonstrated that CMC-20, a nitazoxanide and N-methyl-1H-benzimidazole hybrid molecule, had higher in vitro activity against Giardia intestinalis WB strain than metronidazole and albendazole and similar to nitazoxanide.
OBJETIVES
To evaluate the in vitro activity of CMC-20 against G. intestinalis strains with different susceptibility/resistance to albendazole and nitazoxanide and evaluate its effect on the distribution of parasite cytoskeletal proteins and its in vivo giardicidal activity.
METHODS
CMC-20 activity was tested against two isolates from patients with chronic and acute giardiasis, an experimentally induced albendazole resistant strain and a nitazoxanide resistant clinical isolate. CMC-20 effect on the distribution of parasite cytoskeletal proteins was analysed by indirect immunofluorescence and its activity was evaluated in a murine model of giardiasis.
FINDINGS CMC-20
showed broad activity against susceptible and resistant strains to albendazole and nitaxozanide. It affected the parasite microtubule reservoir and triggered the parasite encystation. In this process, alpha-7.2 giardin co-localised with CWP-1 protein. CMC-20 reduced the infection time and cyst load in feces of G. muris infected mice similar to albendazole.
MAIN CONCLUSIONS
The in vitro and in vivo giardicidal activity of CMC-20 suggests its potential use in the treatment of giardiasis.
Topics: Albendazole; Animals; Antiprotozoal Agents; Cytoskeletal Proteins; Fluorescent Antibody Technique, Indirect; Giardia lamblia; Humans; Mice; Nitro Compounds; Parasitic Sensitivity Tests; Thiazoles; Time Factors
PubMed: 32049098
DOI: 10.1590/0074-02760190348 -
BMC Infectious Diseases Jun 2022Deworming programs aimed at reducing morbidity and mortality from geohelminth infections are common in many countries where these infections are endemic, but data...
BACKGROUND
Deworming programs aimed at reducing morbidity and mortality from geohelminth infections are common in many countries where these infections are endemic, but data demonstrating increasing levels of resistance to albendazole and mebendazole are causes for concern. Studies to evaluate the clinical efficacy of deworming programs are critical to maintain high infection control goals.
METHODS
We propose to assess the clinical efficacy of Peruvian national guidelines for deworming programs in a prospective observational study conducted in the Amazon River basin area near Iquitos, Peru. Major outcomes to be evaluated include (1) albendazole resistance of intestinal helminths (trichuriasis, ascariasis, hookworm), and (2) frequency of reinfection with intestinal helminths 4 months after treatment with albendazole. Children ages 2-11 years from the Belén District of Iquitos will be identified based on a community census. Following parental informed consent, demographic data, weight, and height will be recorded and a stool specimen for parasitological exam by direct observation and Kato-Katz concentration method, and helminthic egg counts will be collected prior to administration of albendazole, following Peruvian national guidelines. Follow-up stool specimens examined in the same manner will be collected at 20 days, 90 days, and 100 days following initial administration of albendazole, and based on parasites found repeat treatment will be administered in accordance with national guidelines. Real-time multiplex qPCR will be performed on helminth positive samples collected prior to initial deworming and on helminth-positive specimens detected on day 15-20. A total sample size of 380 participants was calculated based on total population in the target group and prevalence estimates of helminth infections and clinical resistance based on recent data.
DISCUSSION
Data from observational clinical efficacy studies are important to guide geohelminth infection control programs. Trial registration https://www.researchregistry.com/ . Identification number: researchregistry7736; Registered retrospectively March 13, 2022; https://www.researchregistry.com/browse-the-registry#home/registrationdetails/622e024cf06132001e3327bf/.
Topics: Albendazole; Animals; Anthelmintics; Child; Child, Preschool; Feces; Helminthiasis; Helminths; Humans; Intestinal Diseases, Parasitic; Observational Studies as Topic; Peru; Reinfection; Retrospective Studies; Soil; Trematode Infections
PubMed: 35672751
DOI: 10.1186/s12879-022-07494-0 -
Molecules (Basel, Switzerland) Jun 2020Soil-transmitted nematodes (STN) infect 1-2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many...
Soil-transmitted nematodes (STN) infect 1-2 billion of the poorest people worldwide. Only benzimidazoles are currently used in mass drug administration, with many instances of reduced activity. Terpenes are a class of compounds with anthelmintic activity. Thymol, a natural monoterpene phenol, was used to help eradicate hookworms in the U.S. South circa 1910. However, the use of terpenes as anthelmintics was discontinued because of adverse side effects associated with high doses and premature stomach absorption. Furthermore, the dose-response activity of specific terpenes against STNs has been understudied. Here we used hollow, porous yeast particles (YPs) to efficiently encapsulate (>95%) high levels of terpenes (52% ) and evaluated their anthelmintic activity on hookworms (, a rodent parasite (), and whipworm (. We identified YP-terpenes that were effective against all three parasites. Further, YP-terpenes overcame albendazole-resistant . These results demonstrate that terpenes are broad-acting anthelmintics. Terpenes are predicted to be extremely difficult for parasites to resist, and YP encapsulation provides water-suspendable terpene materials without surfactants and sustained terpene release that could lead to the development of formulations for oral delivery that overcome fast absorption in the stomach, thus reducing dosage and toxic side effects.
Topics: Albendazole; Ancylostoma; Ancylostomatoidea; Animals; Anthelmintics; Benzimidazoles; Humans; Nematoda; Nematode Infections; Saccharomyces cerevisiae; Terpenes
PubMed: 32605043
DOI: 10.3390/molecules25132958 -
PLoS Neglected Tropical Diseases Feb 2021Better drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed... (Randomized Controlled Trial)
Randomized Controlled Trial
An open label, block randomized, community study of the safety and efficacy of co-administered ivermectin, diethylcarbamazine plus albendazole vs. diethylcarbamazine plus albendazole for lymphatic filariasis in India.
BACKGROUND
Better drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed to compare the safety and efficacy of MDA with IDA (ivermectin, diethylcarbamazine and albendazole) or DA (diethylcarbamazine and albendazole) in India.
METHODOLOGY/PRINCIPAL FINDINGS
This two-armed, open-labelled, block randomised, community study was conducted in LF endemic villages in Yadgir district, Karnataka, India. Consenting participants ≥5 years of age were tested for circulating filarial antigenemia (CFA) and microfilaremia (Mf) before treatment with a single oral dose of IDA or DA. Adverse events (AEs) were monitored actively for two days and passively for five more days. Persons with positive CFA or Mf tests at baseline were retested 12-months post-treatment to assess treatment efficacy. Baseline CFA and Mf-rates were 26.4% and 6.9% in IDA and 24.5% and 6.4% in DA villages respectively. 4758 and 4160 participants received IDA and DA. Most AEs were mild after both treatments; fewer than 0.1% of participants experienced AEs with severity > grade 1. No serious AEs were observed. Fever, headache and dizziness were the most common AEs. AE rates were slightly higher after IDA than DA (8.3% vs. 6.4%, P<0.01). AEs were more frequent in females and Mf-positives after either treatment, but significantly more frequent after IDA (40.5% vs 20.2%, P < 0.001). IDA was more effective for clearing Mf than DA (84% vs. 61.8%, P < 0.001). Geometric mean Mf counts per 60μl in retested Mf-positives decreased by 96.4% from 11.8 after IDA and by 90.0% from 9.5 after DA. Neither treatment was effective for clearing CFA.
CONCLUSIONS/SIGNIFICANCE
IDA had an acceptable safety profile and was more effective for clearing Mf than DA. With adequate compliance and medical support to manage AEs, IDA has the potential to accelerate LF elimination in India.
TRIAL REGISTRATION
Clinical Trial Registry of India (CTRI No/2016/10/007399).
Topics: Adolescent; Adult; Albendazole; Animals; Child; Diethylcarbamazine; Drug-Related Side Effects and Adverse Reactions; Elephantiasis, Filarial; Female; Filaricides; Humans; India; Ivermectin; Male; Mass Drug Administration; Wuchereria bancrofti
PubMed: 33591979
DOI: 10.1371/journal.pntd.0009069 -
BioMed Research International 2019Drug repurposing and/or repositioning is an alternative method to develop new treatment for certain diseases. Albendazole was originally developed as an anthelmintic...
Drug repurposing and/or repositioning is an alternative method to develop new treatment for certain diseases. Albendazole was originally developed as an anthelmintic medication, and it has been used to treat a variety of parasitic infestations. In this study, we investigated the antitumor effect of albendazole and putative action mechanism. Results showed that albendazole dramatically decreased the cell viability of SCC cell lines (SCC12 and SCC13 cells). Albendazole increased apoptosis-related signals, including cleaved caspase-3 and PARP-1 in a dose-dependent fashion. The mechanistic study showed that albendazole induced endoplasmic reticulum (ER) stress, evidenced by increase of CHOP, ATF-4, caspase-4, and caspase-12. Pretreatment with ER stress inhibitor 4-PBA attenuated albendazole-induced apoptosis of SCC cells. In addition, albendazole decreased the colony-forming ability of SCC cells, together with inhibition of Wnt/-catenin signaling. These results indicate that albendazole shows an antitumor effect via regulation of ER stress and cancer stemness, suggesting that albendazole could be repositioned for cutaneous SCC treatment.
Topics: Albendazole; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Endoplasmic Reticulum Stress; Humans; Keratinocytes; Neoplastic Stem Cells; Skin Neoplasms; Tunicamycin
PubMed: 31281836
DOI: 10.1155/2019/3689517 -
Infection and Immunity Jul 2023Parasitic diseases are a major public health problem worldwide. Plant-derived products appear to be ideal candidates from a biotechnological perspective, being...
Parasitic diseases are a major public health problem worldwide. Plant-derived products appear to be ideal candidates from a biotechnological perspective, being sustainable and environmentally friendly. The antiparasitic properties of have been attributed to some of its components, including papain and other compounds that are concentrated in the latex and seeds. This study demonstrated a high and insignificantly different cysticidal activity of soluble extract that was obtained after the disruption of nontransformed wild-type (WT) cells as well as transformed papaya calluses (PC-9, PC-12, and PC-23) and papaya cell suspensions (CS-9, CS-12, and CS-23). , cell suspensions of CS-WT and CS-23 that had been previously lyophilized were tested with respect to their cysticidal effects, compared with those of three commercial antiparasitic drugs. CS-WT and CS-23 together reduced the number of cysticerci, the number of buds, and the percentage of calcified cysticerci in a similar extent to albendazole and niclosamide, whereas ivermectin was less effective. Mice were then orally immunized with CS-23 that expressed the anti-cysticercal KETc7 antigen (10 μg/mouse), CS-WT (10 mg/mouse), or both together to evaluate their preventive properties. CS-23 and CS-WT significantly reduced the expected parasite and increased the percentage of calcified cysticerci as well as recovery, being more effective when employed together. The results reported in this study support the feasibility of the development of an anti-cysticercosis vaccine from cells of in cultures, as they are a source of an anthelmintic, natural, and reproducible product.
Topics: Mice; Animals; Carica; Suspensions; Albendazole; Plant Extracts; Seeds
PubMed: 37341599
DOI: 10.1128/iai.00517-22 -
PLoS Neglected Tropical Diseases Jan 2022Echinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to...
BACKGROUND
Echinococcus multilocularis causes alveolar echinococcosis (AE), a rising zoonotic disease in the northern hemisphere. Treatment of this fatal disease is limited to chemotherapy using benzimidazoles and surgical intervention, with frequent disease recurrence in cases without radical surgery. Elucidating the molecular mechanisms underlying E. multilocularis infections and host-parasite interactions ultimately aids developing novel therapeutic options. This study explored an involvement of unfolded protein response (UPR) and endoplasmic reticulum-stress (ERS) during E. multilocularis infection in mice.
METHODS
E. multilocularis- and mock-infected C57BL/6 mice were subdivided into vehicle, albendazole (ABZ) and anti-programmed death ligand 1 (αPD-L1) treated groups. To mimic a chronic infection, treatments of mice started six weeks post i.p. infection and continued for another eight weeks. Liver tissue was then collected to examine inflammatory cytokines and the expression of UPR- and ERS-related genes.
RESULTS
E. multilocularis infection led to an upregulation of UPR- and ERS-related proteins in the liver, including ATF6, CHOP, GRP78, ERp72, H6PD and calreticulin, whilst PERK and its target eIF2α were not affected, and IRE1α and ATF4 were downregulated. ABZ treatment in E. multilocularis infected mice reversed, or at least tended to reverse, these protein expression changes to levels seen in mock-infected mice. Furthermore, ABZ treatment reversed the elevated levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ in the liver of infected mice. Similar to ABZ, αPD-L1 immune-treatment tended to reverse the increased CHOP and decreased ATF4 and IRE1α expression levels.
CONCLUSIONS AND SIGNIFICANCE
AE caused chronic inflammation, UPR activation and ERS in mice. The E. multilocularis-induced inflammation and consecutive ERS was ameliorated by ABZ and αPD-L1 treatment, indicating their effectiveness to inhibit parasite proliferation and downregulate its activity status. Neither ABZ nor αPD-L1 themselves affected UPR in control mice. Further research is needed to elucidate the link between inflammation, UPR and ERS, and if these pathways offer potential for improved therapies of patients with AE.
Topics: Albendazole; Animals; Anticestodal Agents; Chronic Disease; Echinococcosis, Hepatic; Echinococcus multilocularis; Endoplasmic Reticulum Stress; Mice; Mice, Inbred C57BL
PubMed: 35030165
DOI: 10.1371/journal.pntd.0009192 -
Comparative Medicine Oct 2023( ), the causative agent of the most commonly reported disease of zebrafish, is a microsporidian parasite that confounds research by inducing behavioral and...
( ), the causative agent of the most commonly reported disease of zebrafish, is a microsporidian parasite that confounds research by inducing behavioral and physiologic changes in zebrafish. Although a treatment for has not been documented in zebrafish, albendazole (ALB) and fumagillin (FUM) have been used to treat microsporidian infections of other fish species. To investigate the efficacy of oral ALB and FUM in the treatment of we performed a pilot study that demonstrated the safety and palatability of novel gel-based diets containing FUM or ALB in adult AB zebrafish. In a subsequent study, approximately 250 adult AB zebrafish (previously infected with ) were treated with these medicated diets for 4 wk. At 4 different time points (weeks 0, 5, 10, and 16 of the study), fish were euthanized and whole-body qPCR was performed to assess prevalence across treatment and control groups. There was no statistically significant association between treatment group and prevalence at any time point, although potential biologically relevant reductions in prevalence occurred in the combination therapy group at weeks 5 and 16 and in the ALB group at week 5. Based on high-performance liquid chromatography analyses, the medicated diets contained less ALB and more FUM than expected, highlighting the importance of validating medicated feed concentrations to ensure safety, efficacy, and consistency. While remains challenging to eradicate and control, results of this study warrant further investigation into the utility of ALB and FUM as potential treatments for this pathogen.
Topics: Animals; Zebrafish; Albendazole; Pilot Projects; Microsporidia
PubMed: 38087410
DOI: 10.30802/AALAS-CM-23-000035