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Journal of Pharmaceutical Sciences Jun 2023N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine...
N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.
Topics: Nitrites; Nitrosamines; Excipients; Chemistry, Pharmaceutical; Amines; Risk Assessment
PubMed: 35500671
DOI: 10.1016/j.xphs.2022.04.016 -
Journal of Pharmaceutical Sciences May 2023This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures,...
This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions and the challenges to determine compound-specific AIs based on data available or read-across approaches for these nitrosamines and their acceptance by health authorities. Our data indicate that the presence of nitrosamines in pharmaceuticals is likely more prevalent than originally expected. In total, 40.4 % of the analyzed APIs and 29.6 % of the API impurities are potential nitrosamine precursors. Most structures identified through our workflow could form complex API-related nitrosamines, so-called nitrosamine drug substance related impurities (NDSRIs), although we also found structures that could release the well-known small and potent nitrosamines NDMA, NDEA, and others. Due to common structural motifs including secondary or tertiary amine moieties, whole essential drug classes such as beta blockers and ACE inhibitors are at risk. To avoid the risk of drug shortages or even the complete loss of therapeutic options, it will be essential that the well-established ICH M7 principles remain applicable for nitrosamines and that that the industry and regulatory authorities keep an open communication not only about the science but also to make sure there is a good balance between risk and benefit to patients.
Topics: Humans; Nitrosamines; Amines; Pharmaceutical Preparations
PubMed: 36402198
DOI: 10.1016/j.xphs.2022.11.013 -
Acta Medica Indonesiana Jan 2010Human beings are often being exposed to carcinogenic factors during their life, some of which are the nutritional factors. From the mechanistic view, nutritional factors... (Review)
Review
Human beings are often being exposed to carcinogenic factors during their life, some of which are the nutritional factors. From the mechanistic view, nutritional factors are classified into genotoxic and non-genotoxic agents. Genotoxic agent begins their action at the DNA level, causing DNA damage through several mechanisms, e.g. gene point mutations, deletions and insertions, recombinations, rearrangements and amplifications, as well as chromosomal aberrations. Most genotoxic agents are micro components of nutrition, i.e. polycyclic aromatic hydrocarbon (PAH) or heterocyclic amines (HCAs), aflatoxin, and N-nitrosamine. Non-genotoxic agents are less defined in their modes of action, but they are presumed to indirectly affect the cell through tumor promoters. These agents are generally macro components, e.g. high fat. Moreover, epigenetic factors, including changes in the DNA methylation pattern, and peroxidation process resulting reactive oxygen species (ROS), are also known to cause cancer. On the other hand, it is also well recognized that diet and nutrition contain components that can reduce the risk of cancer, in some cases by decreasing the effects of food mutagens, or through carcinogen detoxification, or protection of DNA from electrophilic carcinogen. Thus nutritionally related cancer ultimately develops from an imbalance of carcinogenesis and anti-carcinogenesis process.
Topics: Aflatoxin B1; Carcinogens, Environmental; Chromosome Aberrations; Diet; Ethanol; Heterocyclic Compounds; Humans; Mutagens; Neoplasms; Nitrosamines; Polycyclic Aromatic Hydrocarbons; Risk Factors
PubMed: 20305331
DOI: No ID Found -
World Journal of Gastroenterology Jul 2006To study the association between nitrite and nitrosamine intake and gastric cancer (GC), between meat and processed meat intake, GC and oesophageal cancer (OC), and... (Review)
Review
AIM
To study the association between nitrite and nitrosamine intake and gastric cancer (GC), between meat and processed meat intake, GC and oesophageal cancer (OC), and between preserved fish, vegetable and smoked food intake and GC.
METHODS
In this article we reviewed all the published cohort and case-control studies from 1985-2005, and analyzed the relationship between nitrosamine and nitrite intake and the most important related food intake (meat and processed meat, preserved vegetables and fish, smoked foods and beer drinking) and GC or OC risk. Sixty-one studies, 11 cohorts and 50 case-control studies were included.
RESULTS
Evidence from case-control studies supported an association between nitrite and nitrosamine intake with GC but evidence was insufficient in relation to OC. A high proportion of case-control studies found a positive association with meat intake for both tumours (11 of 16 studies on GC and 11 of 18 studies on OC). A relatively large number of case-control studies showed quite consistent results supporting a positive association between processed meat intake and GC and OC risk (10 of 14 studies on GC and 8 of 9 studies on OC). Almost all the case-control studies found a positive and significant association between preserved fish, vegetable and smoked food intake and GC. The evidence regarding OC was more limited. Overall the evidence from cohort studies was insufficient or more inconsistent than that from case-control studies.
CONCLUSION
The available evidence supports a positive association between nitrite and nitrosamine intake and GC, between meat and processed meat intake and GC and OC, and between preserved fish, vegetable and smoked food intake and GC, but is not conclusive.
Topics: Case-Control Studies; Cohort Studies; Esophageal Neoplasms; Fish Products; Food Preservation; Humans; Meat Products; Nitrates; Nitrosamines; Risk Factors; Stomach Neoplasms; Vegetables
PubMed: 16865769
DOI: 10.3748/wjg.v12.i27.4296 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2021In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received... (Review)
Review
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: -nitrosodimethylamine (NDMA) and -nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.
Topics: Carcinogens; Diethylnitrosamine; Dimethylnitrosamine; Drug Contamination; Humans; Nitrosamines
PubMed: 33787187
DOI: 10.2478/aiht-2021-72-3491 -
Water Research Jan 2019As potable reuse guidelines and regulations continue to develop, the presence of N-nitrosamines is a primary concern because of their associated health concerns. In this...
As potable reuse guidelines and regulations continue to develop, the presence of N-nitrosamines is a primary concern because of their associated health concerns. In this study, bench-, pilot-, and full-scale tests were conducted to focus on the occurrence and treatment of N-nitrosomorpholine (NMOR) in United States (U.S.) potable reuse systems. Out of twelve U.S. wastewater effluents collected, ambient NMOR was detected in eleven (average = 20 ± 18 ng/L); in contrast, only two of the thirteen surface water and stormwater samples had NMOR. Across all of these samples maximum formation potential by chloramination produced an average increase of 3.6 ± 1.8 ng/L. This result underscores the need to understand the sources of NMOR as it is not likely a disinfection byproduct and it is not known to be commercially produced within the U.S. At the pilot-scale, three potable reuse systems were evaluated for ambient NMOR with oxidation (i.e., chlorination and ozonation), biofiltration, and granular activated carbon (GAC). Both pre-oxidation and biofiltration were ineffective at mitigating NMOR during long-term pilot plant operation (at least eight-months). GAC adsorbers were the only pilot-scale treatment to remove NMOR; however, complete breakthrough occurred rapidly from <2000 to 10,000 bed volumes. For comparison, a full-scale reverse osmosis (RO) potable reuse system was monitored for a year and confirmed that RO effectively removes NMOR. Systematic bench-scale UV-advanced oxidation experiments were undertaken to assess the mitigation potential for NMOR. At a fluence dose of 325 ± 10 mJ/cm UV alone degraded 90% of the NMOR present. The addition of 5 mg/L hydrogen peroxide did not significantly decrease the UV dose required for one-log removal. These data illustrate that efficient NMOR removal from potable reuse systems is limited to RO or UV treatment.
Topics: Filtration; Nitrosamines; Wastewater; Water Purification
PubMed: 30390511
DOI: 10.1016/j.watres.2018.10.010 -
International Journal of Molecular... May 2022The tobacco-specific -nitrosamines 4-(-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and '-nitrosonornicotine (NNN) always occur together and exclusively in tobacco... (Review)
Review
The tobacco-specific -nitrosamines 4-(-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and '-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as "carcinogenic to humans" by the International Agency for Research on Cancer. In 1998, we published a review of the biochemistry, biology and carcinogenicity of tobacco-specific nitrosamines. Over the past 20 years, considerable progress has been made in our understanding of the mechanisms of metabolism and DNA adduct formation by these two important carcinogens, along with progress on their carcinogenicity and mutagenicity. In this review, we aim to provide an update on the carcinogenicity and mechanisms of the metabolism and DNA interactions of NNK and NNN.
Topics: Carcinogens; DNA Adducts; Humans; Nitrosamines; Nicotiana; Tobacco Products
PubMed: 35563500
DOI: 10.3390/ijms23095109 -
Journal of Physiology and Biochemistry Mar 2016The link between tobacco abuse and cancer is well-established. However, emerging data indicate that toxins in tobacco smoke cause cellular injury due to enhanced... (Review)
Review
The link between tobacco abuse and cancer is well-established. However, emerging data indicate that toxins in tobacco smoke cause cellular injury due to enhanced toxic/metabolic effects of metabolites, disruption of intracellular signaling mechanisms, and formation of DNA, protein, and lipid adducts that impair function and promote oxidative stress and inflammation. These effects of smoking, which are largely non-carcinogenic, can be produced by tobacco-specific nitrosamines and their metabolites. These factors could account for the increased rates of neurodegeneration and insulin resistance diseases among smokers. Herein, we review nicotine and tobacco-specific nitrosamine metabolism, mechanisms of adduct formation, DNA damage, mutagenesis, and potential mechanisms of disease.
Topics: Humans; Nitrosamines; Nicotiana
PubMed: 26767836
DOI: 10.1007/s13105-016-0465-9 -
Journal of Food Science Oct 2022Due to the growing consumer demand for safe and naturally processed meats, the meat industry is seeking novel methods to produce safe-to-consume meat products without... (Review)
Review
Due to the growing consumer demand for safe and naturally processed meats, the meat industry is seeking novel methods to produce safe-to-consume meat products without affecting their sensory appeal. The green technologies can maintain the sensory and nutritive characteristics and ensure the microbial safety of processed meats and, therefore, can help to reduce the use of chemical preservatives in meat products. The use of chemical additives, especially nitrites in processed meat products, has become controversial because they may form carcinogenic N-nitrosamines, a few of which are suspected as cancer precursors. Thus, the objective of reducing or eliminating nitrite is of great interest to meat researchers and industries. This review, for the first time, discusses the influence of processing technologies such as microwave, irradiation, high-pressure thermal processing (HPTP) and multitarget preservation technology on the quality characteristics of processed meats, with a focus on their sensory quality. These emerging technologies can help in the alleviation of ingoing nitrite or formed nitrosamine contents in meat products. The multitarget preservation technology is an innovative way to enhance the shelf life of meat products through the combined use of different technologies/natural additives. The challenges and opportunities associated with the use of these technologies for processing meat are also reviewed.
Topics: Nitrites; Meat; Meat Products; Nitrosamines; Technology
PubMed: 36120824
DOI: 10.1111/1750-3841.16329 -
Cancer Epidemiology, Biomarkers &... Oct 2017Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and...
Few studies have examined differences in product consumption patterns and nicotine and tobacco-specific nitrosamines (TSNA) exposure between single versus dual- and poly-tobacco users. We applied the Tobacco Product Use Patterns (T-PUPs) model to fill this gap in the literature. Data from adults (age ≥18 years) who used any tobacco products during the 5 days prior to participating in the 1999-2012 National Health and Nutrition Examination Survey (NHANES) were analyzed. Participants were classified into seven T-PUPs: (1) cigarettes only, (2) noncigarette combustibles only, (3) noncombustibles only, (4) dual noncigarette combustibles and noncombustibles, (5) dual cigarettes and noncombustibles, (6) dual cigarettes and noncigarette combustibles, and (7) poly-tobacco use. Weighted regression models were used to compare product consumption, serum cotinine, and urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL) levels between single-, dual-, and poly-tobacco T-PUPs. Dual- and poly-tobacco T-PUPs were associated with lower product consumption compared with single-product T-PUPs only in some cases (e.g., dual cigarette and noncombustible users smoked cigarettes on 0.6 fewer days in the past 5 days compared with cigarette-only users; < 0.05). Dual- and poly-tobacco T-PUPs had either nondistinguishable or higher levels of serum cotinine and urinary total NNAL than corresponding single-product T-PUPs. Product consumption, and nicotine and TSNAs exposure of dual- and poly-tobacco product category users somewhat differ from those of single-product category users as defined by the T-TUPs model. Higher levels of cotinine and NNAL among dual- and poly-tobacco T-TUPs users compared with the single-product T-TUPs users may indicate health concerns. .
Topics: Adolescent; Adult; Aged; Female; History, 20th Century; History, 21st Century; Humans; Male; Middle Aged; Nicotine; Nitrosamines; Tobacco Use; Young Adult
PubMed: 28710077
DOI: 10.1158/1055-9965.EPI-17-0338