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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 -
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 -
Pathogens (Basel, Switzerland) Jun 2023This review presents the main cell characteristics altered after in vitro incubation of the parasite with commercial drugs used to treat the disease caused by . This... (Review)
Review
This review presents the main cell characteristics altered after in vitro incubation of the parasite with commercial drugs used to treat the disease caused by . This important intestinal parasite primarily causes diarrhea in children. Metronidazole and albendazole are the primary compounds used in therapy against . However, they provoke significant side effects, and some strains have developed resistance to metronidazole. Benzimidazole carbamates, such as albendazole and mebendazole, have shown the best activity against . Despite their in vitro efficacy, clinical treatment with benzimidazoles has yielded conflicting results, demonstrating lower cure rates. Recently, nitazoxanide has been suggested as an alternative to these drugs. Therefore, to enhance the quality of chemotherapy against this parasite, it is important to invest in developing other compounds that can interfere with key steps of metabolic pathways or cell structures and organelles. For example, exhibits a unique cell structure called the ventral disc, which is crucial for host adhesion and pathogenicity. Thus, drugs that can disrupt the adhesion process hold promise for future therapy against . Additionally, this review discusses new drugs and strategies that can be employed, as well as suggestions for developing novel drugs to control the infection caused by this parasite.
PubMed: 37375500
DOI: 10.3390/pathogens12060810 -
Blood Cancer Journal Feb 2024Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors...
Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
Topics: Humans; Animals; Mice; Core Binding Factor Alpha 2 Subunit; Leukemia, Myeloid, Acute; Homoharringtonine; Blood Platelets; Blood Platelet Disorders; Proto-Oncogene Proteins c-bcl-2
PubMed: 38316746
DOI: 10.1038/s41408-024-00981-4 -
Journal of Epidemiology and Global... May 2024Soil-transmitted helminthic (STH) infections are the leading cause of stunting among children. To lessen the burden, the World Health Organization (WHO) recommended a...
BACKGROUND
Soil-transmitted helminthic (STH) infections are the leading cause of stunting among children. To lessen the burden, the World Health Organization (WHO) recommended a periodic deworming program through the use of single-dose therapy in the endemic regions. Therefore, the purpose of this study was to synthesize evidence about the efficacy of anthelminthic drugs against STH infections among preschool and school-age children.
METHODS
The Preferred Reposting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria were followed in this study. Relevant electronic databases, including PubMed, Scopus, Embase, DOAJ, Science Direct, the WHO Clinical Trials.gov library, Google Scholar, and AJOL databases, were searched for relevant publications. Randomized controlled trials (RCTs) and non-randomized interventional studies focused on the efficacy of albendazole and mebendazole against STHs in children were included in the study. Review Manager was used to analyze the data. A random effects model was used to obtain the pooled estimated efficacy. To evaluate heterogeneity, the I test and Cochrane Q (χ) were employed. The risk of publication bias was investigated using Egger's test and the funnel plot. The protocol of this review was registered at the PROSPERO international prospective register of systematic reviews (CRD42023401196).
RESULTS
Of the 69 publications selected for the systematic review, 66 with complete data were included in the meta-analysis. Single doses of albendazole and mebendazole have shown satisfactory efficacy [egg reduction rate (ERR)] against Ascaris lumbricoides [95.54% (95% CI: 88.75-102.34%) and 98.69% (95% CI: 97.68-99.65%), respectively. The effectiveness of these two drugs against Trichuris trichiura and hookworms was comparatively low (< 80% ERR), except for albendazole, which showed high ERRs [93.44% (95%CI: 92.39-94.49%)] against hookworms. The cure rate (CR) of albendazole against T. trichiura, A. lumbricoides, and hookworms were 50.8%, 91.3%, and 78.32%, respectively. Likewise, mebendazole showed CRs of 48.15%, 92.8%, and 49.32% against T. trichiura, A. lumbricoides, and hookworms, respectively. Subgroups such as studies conducted after 2000, diagnostic type (McMaster), and longer follow-up weeks significantly reduced the efficacy of the two drugs against T. trichura. While the combination of albendazole or mebendazole with other drugs and RCT showed significantly improved efficacy against T. trichura. The count of eggs per gram of stool (EPG) was identified as one of the variables that negatively and significantly influenced the efficacy of albendazole or mebendazole against A. lumbricoides.
CONCLUSION
Despite the wide range of ERRs and CR reported in the different articles included in this review, the pooled estimated efficacy of albendazole and mebendazole against STHs falls in the satisfactory category of WHO recommendations. Further evaluation of the combination of anthelminthic drugs as a preventive chemotherapy option and routine drug efficacy testing are necessary to prevent the emergence and widespread use of drug-resistant STHs.
PubMed: 38696109
DOI: 10.1007/s44197-024-00231-7 -
Parasites & Vectors Jul 2023Helminth infections are an important public health problem in humans and have an even greater impact on domestic animal and livestock welfare. Current readouts for...
BACKGROUND
Helminth infections are an important public health problem in humans and have an even greater impact on domestic animal and livestock welfare. Current readouts for anthelmintic drug screening assays are stage development, migration, or motility that can be subjective, laborious, and low in throughput. The aim of this study was to apply and optimize a fluorometric technique using resazurin for evaluating changes in the metabolic activity of Ascaris suum third-stage larvae (L3), a parasite of high economic relevance in swine.
METHODS
Ascaris suum L3 were mechanically hatched from 6- to 8-week embryonated and sucrose-gradient-enriched eggs. Resazurin dye and A. suum L3 were titrated in 96-well microtiter plates, and resazurin reduction activity was assessed by fluorometry after 24 h of incubation. Fluorescence microscopy was used to localize the resazurin reduction site within the larvae. Finally, we exposed A. suum L3 to various stress conditions including heat, methanol, and anthelmintics, and investigated their impact on larval metabolism through resazurin reduction activity.
RESULTS
We show that the non-fluorescent dye resazurin is reduced inside vital A. suum L3 to fluorescent resorufin and released into the culture media. Optimal assay parameters are 100-1000 L3 per well, a resazurin concentration of 7.5 µg/ml, and incubation at 37 °C/5% CO for 24 h. An intact L2 sheath around the L3 of A. suum completely prevents the uptake of resazurin, while in unsheathed L3, the most intense fluorescence signal is observed along the larval midgut. L3 exposed to methanol or heat show a gradually decreased resazurin reduction activity. In addition, 24 h exposure to ivermectin at 0.625 µM, mebendazole at 5 µM, and thiabendazole from 10 to 100 µM significantly decreased larval metabolic activity by 55%, 73%, and 70% to 89%, respectively.
CONCLUSIONS
Together, our results show that both metabolic stressors and anthelmintic drugs significantly and reproducibly reduce the resazurin reduction activity of A. suum L3, making the proposed assay a sensitive and easy-to-use method to evaluate metabolic activity of A. suum L3 in vitro.
Topics: Humans; Animals; Swine; Ascaris suum; Methanol; Anthelmintics; Xanthenes; Ascariasis; Larva
PubMed: 37468906
DOI: 10.1186/s13071-023-05871-5 -
Biomedicine & Pharmacotherapy =... Aug 2023In recent years, microtubule-targeting agents (MTAs) have gained considerable interest in developing novel small-molecule anticancer drugs. MTAs demonstrate anticancer...
In recent years, microtubule-targeting agents (MTAs) have gained considerable interest in developing novel small-molecule anticancer drugs. MTAs demonstrate anticancer activity either as microtubule-stabilizing agents (paclitaxel) or microtubule-destabilizing agents (nocodazole). FDA-approved drugs containing a benzimidazole ring (nocodazole, albendazole, mebendazole, etc.) are well-known microtubule-destabilizing agents. Thus, most recent research on benzimidazole scaffold-based MTAs focuses on developing microtubule-destabilizing agents. However, there is no report on the benzimidazole scaffold-based microtubule-stabilizing agent. Here, we present the benzimidazole derivatives NI-11 and NI-18 that showed a profound anticancer activity as microtubule-stabilization agents. About twenty benzimidazole analogues were synthesized with excellent yield (80.0% ∼ 98.0%) and tested for their anticancer activity using two cancer cell lines (A549, MCF-7) and one normal cell line (MRC-5). NI-11 showed IC values of 2.90, 7.17, and 16.9 µM in A549, MCF-7, and MRC-5 cell lines. NI-18 showed IC values of 2.33, 6.10, and 12.1 µM in A549, MCF-7, and MRC-5 cell lines. Thus, NI-11 and NI-18 demonstrated selectivity indexes of 5.81 and 5.20, respectively, which are much higher than the currently available anticancer agents. NI-11 and NI-18 inhibited the cancer cell motility and migration, induced the early phase apoptosis. Both of these comounds were found to show an upregulation of DeY-α-tubulin and downregulation of Ac-α-tubulin expressions in cancer cells. Eventhough the reported benzimidazole scaffold-based commercially available drugs are known to be microtubule-destabilizing agents, the analogues NI-11 and NI-18 were found to have microtubule-stabilizing activity. The in vitro tubulin polymerization assay and the immunofluorescence assay results indicate that the NI-11 and NI-18 exhibit anticancer activity by stabilizing the microtubule network.
Topics: Humans; Tubulin; Nocodazole; Microtubules; Antineoplastic Agents; Neoplasms; Benzimidazoles; Cell Proliferation; Cell Line, Tumor; Structure-Activity Relationship; Drug Screening Assays, Antitumor
PubMed: 37271075
DOI: 10.1016/j.biopha.2023.114977 -
Diagnostics (Basel, Switzerland) Jun 2023Acute interstitial nephritis (AIN) due to helminths is a rare cause of acute kidney injury (AKI). Helminthiases often progresses insidiously, making diagnosis difficult....
Acute interstitial nephritis (AIN) due to helminths is a rare cause of acute kidney injury (AKI). Helminthiases often progresses insidiously, making diagnosis difficult. This was the case of a 72-year-old man, who presented with renal failure, itching and diarrhoea. Urinalysis revealed leukocyturia, microhaematuria and mild proteinuria. A full blood count revealed leucocytosis with eosinophilia. A stool parasitological examination revealed fertilised eggs of Tubulointerstitial nephropathy secondary to infection was suspected. A percutaneous renal biopsy was not performed since the patient refused the anti-platelet therapy discontinuation. Mebendazole, albendazole and prednisone therapy was administered. After worm eradiation and discharge, recovery from the parasitosis, absence of pruritus and eosinophilia, and progressive improvement of renal function were observed, strongly suggesting a causal relationship between infection and AIN. Parasite infection should be considered in the differential diagnosis of unexplained renal failure because early diagnosis and treatment are necessary to avoid irreversible complications.
PubMed: 37370949
DOI: 10.3390/diagnostics13122054 -
Antimicrobial Agents and Chemotherapy May 2024Helminthiasis remains a public health issue in endemic areas. Various drugs have been proposed to improve efficacy against helminths. The study aimed to assess the... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized assessors-blind clinical trial to evaluate the safety and the efficacy of albendazole alone and in combination with mebendazole or pyrantel for the treatment of infection in school-aged children in Lambaréné and surroundings.
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 infections. We conducted a randomized assessors-blind clinical trial involving children aged 2-17 years with . 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 (-value <0.001); decrease in ERR was significant for arms B and C (-value <0.001). No statistical difference was observed in CR when comparing arms A and B (-value =1.00) and C (-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 .CLINICAL TRIALRegistered at ClinicalTrials.gov (NCT04326868).
Topics: Humans; Albendazole; Child; Mebendazole; Trichuriasis; Male; Female; Trichuris; Animals; Child, Preschool; Anthelmintics; Adolescent; Pyrantel; Drug Therapy, Combination; Treatment Outcome; Parasite Egg Count
PubMed: 38563751
DOI: 10.1128/aac.01211-23