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Regulatory Toxicology and Pharmacology... Apr 2019A range of generic valsartan products have been found to be contaminated with nitrosamines (principally N-nitrosodimethylamine; NDMA). We present information and discuss... (Review)
Review
A range of generic valsartan products have been found to be contaminated with nitrosamines (principally N-nitrosodimethylamine; NDMA). We present information and discuss various elements of this phenomenon including: actions taken by regulatory agencies, source of the nitrosamine impurities, range of possible risk assessments based mainly on ICH M7 criteria, epidemiological assessment and analytical aspects.
Topics: Dimethylnitrosamine; Drug Contamination; Humans; Molecular Structure; Risk Assessment; Valsartan
PubMed: 30629969
DOI: 10.1016/j.yrtph.2019.01.007 -
Cell Death & Disease Jan 2019Hepatic fibrosis is marked by excessive synthesis and deposition of connective tissue proteins, especially interstitial collagens in the extracellular matrix of the... (Review)
Review
Hepatic fibrosis is marked by excessive synthesis and deposition of connective tissue proteins, especially interstitial collagens in the extracellular matrix of the liver. It is a result of an abnormal wound healing in response to chronic liver injury from various causes such as ethanol, viruses, toxins, drugs, or cholestasis. The chronic stimuli involved in the initiation of fibrosis leads to oxidative stress and generation of reactive oxygen species that serve as mediators of molecular events involved in the pathogenesis of hepatic fibrosis. These processes lead to cellular injury and initiate inflammatory responses releasing a variety of cytokines and growth factors that trigger activation and transformation of resting hepatic stellate cells into myofibroblast like cells, which in turn start excessive synthesis of connective tissue proteins, especially collagens. Uncontrolled and extensive fibrosis results in distortion of lobular architecture of the liver leading to nodular formation and cirrhosis. The perpetual injury and regeneration process could also results in genomic aberrations and mutations that lead to the development of hepatocellular carcinoma. This review covers most aspects of the molecular mechanisms involved in the pathogenesis of hepatic fibrosis with special emphasize on N-Nitrosodimethylamine (NDMA; Dimethylnitorsmaine, DMN) as the inducing agent.
Topics: Actins; Animals; Antioxidants; Collagen; Cytokines; Dimethylnitrosamine; Extracellular Matrix; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Oxidative Stress; Reactive Oxygen Species; Wound Healing
PubMed: 30622238
DOI: 10.1038/s41419-018-1272-8 -
Carcinogenesis 1981The urinary excretion of dimethylnitrosamine (DMN) was studied in male Sprague-Dawley rats. Animals were given DMN (3, 5, 10, 20, 30 and 50 mg/kg body weight, i.p.) or...
The urinary excretion of dimethylnitrosamine (DMN) was studied in male Sprague-Dawley rats. Animals were given DMN (3, 5, 10, 20, 30 and 50 mg/kg body weight, i.p.) or [3H]DMN (0.1, 1 and 3 mg; 8.7, 1.5 and 0.28 mCi/kg body weight, respectively, i.p.) diluted with sterile 0.9% NaCl. Urine was collected for 24 h after dosing. DMN was quantitated by gas chromatography using a Thermal Energy Analyzer as detector and [3H]DMN by liquid scintillation counting after purification by high pressure liquid chromatography. Multiple regression analysis programs were used to evaluate the fit of the data to a variety of models relating excretion to dose. All models which gave an acceptable fit including a term for dose squared. The models are discussed in terms of the relationship between urinary excretion and blood clearance of DMN.
Topics: Animals; Dimethylnitrosamine; Dose-Response Relationship, Drug; Male; Rats; Rats, Inbred Strains
PubMed: 7273340
DOI: 10.1093/carcin/2.7.609 -
Mutation Research Apr 1979
Topics: Animals; Carcinogens; Dimethylnitrosamine; Mice; Microsomes, Liver; Mutagens; Mutation; Nitrosamines; Rats; Salmonella typhimurium
PubMed: 377068
DOI: 10.1016/0165-1161(79)90004-9 -
IARC Scientific Publications 1980NDMA and NDEA are metabolized by a microsomal enzyme system that requires NADPH and oxygen. This metabolism leads to an unstable product which decomposes to yield a... (Review)
Review
NDMA and NDEA are metabolized by a microsomal enzyme system that requires NADPH and oxygen. This metabolism leads to an unstable product which decomposes to yield a reactive alkylating species. This species is too reactive chemically to influence significantly organs other than those in which it was generated. Alkylation of cellular components, particularly DNA, is a critical event in the initiation of tumours by these carcinogens. The greatest capacity to metabolize these nitrosamines to alkylating agents is found in the liver, but other organs, including the oesophagus, lung and kidney, are also capable of activation. These organs may be more susceptible to alkylation than the liver because they have a lesser ability to catalyse the removal of 06-alkylguanine from their DNA. However, orally administered doses of NDMA and the NDMA formed by nitrosation reactions within the gastrointestinal tract are rapidly absorbed from the upper part of the small intestine and carried to the liver in the portal blood supply. When small doses are given in this way, the capacity of the liver to metabolize the carcinogen is sufficient that the nitrosamine is effectively cleared in a 'first-pass' effect, leaving very little to interact with other organs. This has two important consequences: firstly, levels of NDMA found in peripheral blood may be significantly lower than those expected on the basis of total dietary exposure because of the rapid metabolism and effective clearance of the carcinogen by the liver; secondly, physiological factors leading to reduction of the metabolic activation in the liver may result in more of the carcinogen being metabolized other tissues and in a greater risk of cancer developing in those tissues.
Topics: Animals; Biotransformation; Carcinogens; DNA; Dimethylnitrosamine; Humans; Intestinal Absorption; Kidney; Kidney Neoplasms; Kinetics; Liver; Liver Neoplasms; Methylation; Methyltransferases; Oxygen Consumption; RNA
PubMed: 6160100
DOI: No ID Found -
Cancer Letters Sep 1975Three groups of Chinese hamsters (20 males, 20 females/group) received weekly subcutaneous injections for life of dimethylnitrosamine (DMN) at dose levels 0.20, 0.10 and...
Three groups of Chinese hamsters (20 males, 20 females/group) received weekly subcutaneous injections for life of dimethylnitrosamine (DMN) at dose levels 0.20, 0.10 and 0.05 of the LD50. Eighty-two to 100% of the animals developed tumors of vascular origin. The neoplasms were primarily hepatic hemangioendotheliomas and their incidence was unrelated to dose or sex. Although animals in the low dose group received a total dose which was one-third that of the highest dose group, their survival times were only slightly longer.
Topics: Animals; Carcinogens; Cricetinae; Dimethylnitrosamine; Dose-Response Relationship, Drug; Female; Hemangioendothelioma; Injections, Subcutaneous; Liver Neoplasms; Male; Mesocricetus; Mice; Neoplasms, Experimental; Nitrosamines; Species Specificity
PubMed: 1235055
DOI: 10.1016/s0304-3835(75)94759-x -
Journal of the National Cancer Institute Mar 1977Pretreatment of rats with pyrazole or 3-amino-1,2,4-triazole (3-AT) known inhibitors of alcohol metabolism, profoundly inhibited the metabolism of dimethylnitrosamine...
Pretreatment of rats with pyrazole or 3-amino-1,2,4-triazole (3-AT) known inhibitors of alcohol metabolism, profoundly inhibited the metabolism of dimethylnitrosamine (DMN), both in terms of [14C]CO2 excretion and of the decline in the blood concentration. Additionally, 4-methylpyrazole, tetraethylthiuram disulfide (disulfiram), methanol, and ethanol inhibited the metabolism of DMN in the whole animal. In parallel experiments with [14C]aminopyrine, no substantial inhibitory effect was found with pyrazole, 3-AT, or disulfiram pretreatment. Investigations into the effects of pyrazole and 3-AT pretreatment on the acute toxicity and hepatotoxicity of DMN showed that pyrazole significantly increased the median lethal dose (LD50) of DMN and provided substantial protection against the hepatotoxicity of DMN, in that centriblobular necrosis was not seen at dose levels of DMN up to 25 mg/kg and early histochemical changes indicative of liver injury were not observed at a dose level of 15 mg DMN/kg. In contrast, 3-AT pretreatment did not affect the LD50 of DMN or provide any protection against the hepatotoxicity of DMN. Further, although both inhibitors delayed the incorporation of radioactivity from [14C]DMN into hepatic subcellular organelles, pyrazole was significantly more effective than was 3-AT.
Topics: Amitrole; Animals; Dimethylnitrosamine; Female; Lethal Dose 50; Liver; Male; Mixed Function Oxygenases; Nitrosamines; Oxidoreductases, N-Demethylating; Pyrazoles; Rats; Triazoles
PubMed: 839558
DOI: 10.1093/jnci/58.3.629 -
The AAPS Journal Apr 2022Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day.... (Review)
Review
Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.
Topics: Dimethylnitrosamine; Humans; Metformin; Nitrosamines
PubMed: 35449372
DOI: 10.1208/s12248-022-00702-4 -
Postepy Higieny I Medycyny... 2001In this paper we have presented data on an environmental exposure to N-nitrosodimethylamine (NDMA) and factors which favour endogenous biosynthesis of this compound. The... (Review)
Review
In this paper we have presented data on an environmental exposure to N-nitrosodimethylamine (NDMA) and factors which favour endogenous biosynthesis of this compound. The factors influencing metabolism and toxicity as well as health effect of exposure have been reported.
Topics: Animals; Dimethylnitrosamine; Environmental Pollutants; Humans; Lethal Dose 50
PubMed: 11468977
DOI: No ID Found -
Report on Carcinogens : Carcinogen... 2004
Topics: Animals; Animals, Newborn; Animals, Suckling; Carcinogenicity Tests; Carcinogens; Cricetinae; Dimethylnitrosamine; Ducks; Environmental Exposure; Fishes; Government Regulation; Guidelines as Topic; Guinea Pigs; Humans; Mice; Models, Biological; Murinae; Rabbits; Rats; Salamandridae; Solvents; United States
PubMed: 21089929
DOI: No ID Found