Nitrosamine Contamination in Pharmaceuticals: Threat, Impact, and Control

Tuesuwan, Bodin; Vongsutilers, Vorasit

doi:10.1016/j.xphs.2021.04.021

Cited by 73 publications

(57 citation statements)

References 38 publications

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“…Cancer classifications of some nitrosamines found in pharmaceutical drugs and structurally related Nnitrosomethylalkylamines (NMAs). Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

Section: Nitrosaminementioning

confidence: 99%

“…While there no carcinogenicity data are available for N-nitroso-varenicline, N-nitroso compounds as a group have been identified as a "cohort of concern" in internationally harmonized guidance on impurities in pharmaceuticals, based on their mutagenic properties and carcinogenic potencies [13]. Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

Section: Nitrosaminementioning

confidence: 99%

“…Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions. Additional sources of Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

Section: Nitrosaminementioning

confidence: 99%

“…These conditions have resulted in unacceptable levels of NDMA in the drug ranitidine and have led to the market withdrawal of all prescription and OTC ranitidine-containing products in the US [20]. While some aspects of this problem, such as source of contamination and mechanisms of formation as well as some risk estimates have been discussed elsewhere [16][17][18]21], we calculated cancer risk estimates using chemical-specific cancer potencies developed by different agencies [8,9,22,23]. We further illustrate the significant carcinogenic potential of additional N-nitrosomethyl-n-alkylamines (NMAs) besides NDMA; these NMAs are closely related to several other contaminants identified to-date and if present in medications, would raise additional concerns.…”

Section: Nitrosaminementioning

confidence: 99%

“…Using the cancer potency estimate of 16 (mg/kg/day) −1 , the extra cancer risk accrued as a result of exposure for 6 years to one daily 320 mg tablet of valsartan, where each tablet contains 20.19 µg NDMA is:16 (mg/kg/day) −1 × 0.000288 mg/kg/day × Extra Cancer Risk Calculation for NDEA The cancer potency for NDEA is estimated as 36 (mg/kg/day) −1 by California's Proposition65 program …”

mentioning

confidence: 99%

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Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications

Ricker

Tsai

et al. 2021

IJERPH

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Many nitrosamines are potent carcinogens, with more than 30 listed under California’s Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl-n-alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California’s Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.

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Section: Nitrosaminementioning

confidence: 99%

Section: Nitrosaminementioning

confidence: 99%

Section: Nitrosaminementioning

confidence: 99%

Section: Nitrosaminementioning

confidence: 99%

mentioning

confidence: 99%

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Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications

Ricker

Tsai

et al. 2021

IJERPH

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Safety Considerations

2023

Destruction of Hazardous Chemicals in the Laboratory

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Nitric Oxide Delivering Surfaces: An Overview of Functionalization Strategies and Efficiency Progress

Beurton

Boudier

Seabra

et al. 2022

Adv Healthcare Materials

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An overview on the design of nitric oxide (NO) delivering surfaces for biomedical purposes is provided, with a focus on the advances of the past 5 years. A localized supply of NO is of a particular interest due to the pleiotropic biological effects of this diatomic compound. Depending on the generated NO flux, the surface can mimic a physiological release profile to provide an activity on the vascular endothelium or an antibacterial activity. Three requirements are considered to describe the various strategies leading to a surface delivering NO. Firstly, the coating must be selected in accordance with the properties of the substrate (nature, shape, dimensions…). Secondly, the releasing and/or generating kinetics of NO should match the targeted biological application. Currently, the most promising structures are developed to provide an adaptable NO supply driven by pathophysiological needs. Finally, the biocompatibility and the stability of the surface must also be considered regarding the expected residence time of the device. A critical point of view is proposed to help readers in the design of the NO delivering surface according to its expected requirement and therapeutic purpose.

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Nitrosamine Contamination in Pharmaceuticals: Threat, Impact, and Control

Cited by 73 publications

References 38 publications

Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications

Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications

Safety Considerations

Nitric Oxide Delivering Surfaces: An Overview of Functionalization Strategies and Efficiency Progress

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