Main Degradation Products of Dabigatran Etexilate Evaluated by LC-UV and LC-ESI-MS, Degradation Kinetics and<i>in vitro</i>Cytotoxicity Studies

Bernardi, Raquel Martini; D'Avila, Felipe Bianchini; Todeschini, Vítor; Andrade, Juliana M. M.; Fröehlich, Pedro Eduardo; Bergold, Ana María

doi:10.5935/0103-5053.20150023

Cited by 3 publications

(4 citation statements)

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“…According to the MTT analysis, dabigatran showed toxic effects in all dilutions with the highest cytotoxicity. In a cytotoxicity study, although the study design and test concentrations of dabigatran were different from our study, no cytotoxic effect was shown with dabigatran and degradation products (24). In a real-life setting and clinical practice, mid-esophageal ulcer was reported in some of the patients using dabigatran, suggesting that dabigatran has a direct caustic effect on capsular formation (25,26).…”

Section: Assessment Of Cell Viabilitycontrasting

confidence: 67%

A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside

Kubat¹,

Gürpınar²,

Karasoy³

et al. 2018

BLL

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OBJECTIVE: Warfarin and nonvitamin-K oral anticoagulants including dabigatran, rivaroxaban, and apixaban are commonly used in the prophylaxis and treatment of systemic embolism and deep vein thrombosis. In this study, we aimed to compare the cytotoxic effects of warfarin and new oral anticoagulants and to show a possible correlation between cell cytotoxicity and gastrointestinal side effects in the real-life setting. METHODS: L929 cells were incubated with test materials. At 24 and 48 hours, morphological changes and cell viability were evaluated. RESULTS: At 24 and 48 hours, dabigatran resulted in altered cell morphology in all dilutions, while rivaroxaban, apixaban, and warfarin showed similar morphology with the control group, except for dilution I. Dabigatran and warfarin at 24 hours and at 48 hours had a statistically signifi cantly lower cell viability in all dilutions, compared to the control group. CONCLUSION: Gastrointestinal side effect profi les of these four agents in a real-life setting is consistent with the results obtained from the present study. There is no sole factor with the potential of explaining the entire gastrointestinal side effect profi les of anticoagulant agents. However, direct cytotoxic effects of anticoagulants should be considered primarily for gastrointestinal side effects in accordance with the results of present headto-head cytotoxicity study (Tab.

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Section: Assessment Of Cell Viabilitycontrasting

confidence: 67%

A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside

Kubat¹,

Gürpınar²,

Karasoy³

et al. 2018

BLL

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“…Sitagliptin phosphate reference standard (99.5%), vildagliptin reference standard (99.5%), and 3-(trifluoromethyl)-5,6,7,8-tetrahydro -[1, 2, 4] triazolo [4,3-a]pyrazine-HCl (99.3%) (impurity S1) were supplied by Sequoia Research Products (Oxford, UK). O-benzylhydroxylamine hydrochloride (99.0%) (impurity S2), 2-pyrrolidinecarboxamide (98.0%) (impurity V1) and 3-amino-1-adamantanol (96.0%) (impurity V2) were supplied by Sigma-Aldrich (Brazil).…”

Section: Methodsmentioning

confidence: 99%

“…Drug toxicity is one of the main challenges for the pharmaceutical industry and it also contributes to late-stage failures, increased cost, and market withdrawals [1]. Nowadays, besides the toxicity of compounds present in drug formulations, attention is being paid to the presence of impurities [2–6].…”

Section: Introductionmentioning

confidence: 99%

In vitro toxic evaluation of two gliptins and their main impurities of synthesis

Giordani

Campanharo

Wingert

et al. 2019

BMC Pharmacol Toxicol

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BackgroundThe presence of impurities in some drugs may compromise the safety and efficacy of the patient’s treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively).MethodsMTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated.ResultsCytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 μM of sitagliptin and 10 μM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations.ConclusionsThis study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

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“…The precision of the method was good as indicated by %RSD values less than 1.0. The proposed method forced degradation study was also carried out, but characterisation of all the DPs and the degradation pathway were not attempted [11].…”

Section: Introductionmentioning

confidence: 99%

Liquid Chromatographic Method Development for Forced Degradation Products of Dabigatran Etexilate: Characterisation and In Silico Toxicity Evaluation

et al. 2015

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Main Degradation Products of Dabigatran Etexilate Evaluated by LC-UV and LC-ESI-MS, Degradation Kinetics andin vitroCytotoxicity Studies

Cited by 3 publications

References 1 publication

A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside

A link between cytotoxicity in cell culture and gastrointestinal side effects of oral anticoagulants: bench-to-bedside

In vitro toxic evaluation of two gliptins and their main impurities of synthesis

Liquid Chromatographic Method Development for Forced Degradation Products of Dabigatran Etexilate: Characterisation and In Silico Toxicity Evaluation

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