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Inhalational Durg Abuse
Published in Jacob Loke, Pathophysiology and Treatment of Inhalation Injuries, 2020
Jacob Loke, Richard Rowley, Herbert D. Kleber, Peter Jatlow
Amyl nitrite has been used for the medical treatment of angina pectoris for more than 100 years. It has been abused as an intoxicant and as a sex stimulant (Sigell et al, 1978). The street names for amyl nitrite include snappers, poppers, and pearls. Butyl and isobutyl nitrites used as room odorizers are also inhaled for their “high” effect. The effects of the volatile nitrites are on the central nervous system, the cardiovascular, and hematologic systems (Newell et al., 1985; Haley, 1980). There is hypotension with peripheral vasodilatation and tachycardia. Toxic effects consist of flushing of the face, headache, eye orbital pain, increase in intraocular pressure (Pearlman and Adams, 1970), cyanosis, syncope, and cardiovascular collapse. There is also formation of methemoglobinemia with nitrites, which can be fatal (Shesser et al., 1982). Clues to the diagnosis of significant levels of methemoglobinemia include central and peripheral cyanosis, a dark blue color of the arterial blood gas sample, and the methemoglobin value. Volatile nitrites can be nitrosation reagents, which can lead to formation of N-nitrosamines and N-nitrosamides. These are mutogenic and carcinogenic compounds. The abuse of amyl nitrite among male homosexuals may be related to the current epidemic of the acquired immune deficiency syndrome and to Kaposi’s sarcoma (Newell et al., 1985; Jorgensen and Lawesson, 1982).
Experimental Colon Carcinogens and Their Mode of Action
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
John H. Weisburger, Emerich S. Fiala
It is not known whether N-nitrosoureido compounds play a role in human colon cancer. Mower et al.137 have described an enzyme capable of transferring a nitroso group from a nitrosamine to an amide, thus forming a direct-acting mutagen analogous to the model compounds MNNG or NMU. However, most of the simpler nitro-samines such as dimethylnitrosamine or nitrosopyrrolidine that have been demonstrated to occur at low levels in the human environment are not likely to be found in the luminal flow in the lower part of the intestinal tract. Direct nitrosation by any nitrite, that is potentially present,138–140 at a substrate such as methylurea with the production of a locally active carcinogen does not seem to occur to a sufficient extent to induce colon cancer.7 Under conditions of limited carcinogen administration, the surgical elimination of the luminal flow and, in consequence, the promoting effects due to bile acids, was found to reduce or abolish the occurrence of colon cancer.119,141,142 Recent results show that indomethacin could inhibit the development of colon cancer induced by NMU and related reactive carcinogens.143–146 On the other hand, vitamin A or retinoids generally have failed to affect colon carcinogenesis.4,147–149 Thus, these models have been most useful to study modifying elements in the promotional or developmental phase of colon cancer, with potential application to the clinical treatment of this important human disease.
Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
The proteostasis network includes cellular pathways that together maintain protein homeostasis by regulating protein synthesis, folding, trafficking, and degrading, and as such it is an attractive target for the development of therapeutic approaches (125). S-nitrosation (or S-nitrosylation) is a cellular post-translational modification by which nitric oxide (NO) is transferred to a protein thiol group and thereby regulates NO-mediated signaling pathways. The S-nitrosoglutathione reductase (GSNOR) alcohol dehydrogenase (ADH) enzyme is responsible for metabolizing S-nitrosoglutathione (GSNO), which is the main source of nitric oxide in cells, and as such regulates NO levels for protein S-nitrosation (126).
Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products
Published in Expert Opinion on Drug Safety, 2021
Nasr Eldin Hussein Nasr, Metwaly Gamel Metwaly, Eman Osama Ahmed, Ahmed Roshdy Fares, Aliaa Nabil ElMeshad
In 2020, ranitidine (H2 histamine receptor antagonist) was added to the list of drugs carrying this mutagenic impurity [15], leading to their market recall worldwide. FDA recently reported that NDMA levels in different ranitidine products may reach 860 ng/tablet [12]. Many studies had been conducted to pinpoint the possible conditions that led to NDMA formation in ranitidine products. Yong Dong Liu et al, suggested that the nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines [16]. The presence of NDMA results from the slow degradation of the ranitidine molecule. NDMA is formed solely from an intermolecular reaction of ranitidine hydrochloride without involvement of impurities. Factors that influence the rate of degradation include heat, humidity, and the crystal morphology of ranitidine hydrochloride with the material exhibiting a columnar habit showing a slower rate of degradation [17]. Yasuhiro Abe et al. studied the impact of temperature on NDMA formation during the storage of ranitidine products. They concluded that different factors including storage conditions (e.g. humidity, oxygen, and temperature), solid-state forms (e.g. crystal form) and components of drug formulations (e.g. impurities, excipients, residual water, tablet/powder form, and coatings) may affect NDMA formation [18]. As a result, pharmaceutical companies abided by FDA regulations, relying on the presence of safe alternative molecules to valsartan (azilsartan, olmesartan, and telmisartan) and ranitidine (cimetidine, esomeprazole, famotidine, lansoprazole, omeprazole).
The Association between the Preservative Agents in Foods and the Risk of Breast Cancer
Published in Nutrition and Cancer, 2019
Fardin Javanmardi, Jamal Rahmani, Fatemeh Ghiasi, Hadi Hashemi Gahruie, Amin Mousavi Khaneghah
Furthermore, the lethal dose for nitrite in adults was estimated to be between 2–9 g/day and 33–250 mg/kg body weight of NaNO2, whereas the lethal dose for nitrates was estimated as 20 g per day, or 330 mg/kg body weight nitrates (69). Animal products, particularly processed meats, are the main responsible sources for dietary intake of nitrate and nitrite, as well as amines and amides which are the precursors necessary for endogenous nitrosation (70). Therefore, the consumption of animal-based products leads to greater endogenous exposure to NOCs than plant-based products. A mixture of nitrite and sorbate was proposed for meat preservation by American agriculture ministry in 1978, but only a year later unfavorable properties of products that preserved by this mixture banned the use of this protocol (71,72).
Role of Heme Iron in the Association Between Red Meat Consumption and Colorectal Cancer
Published in Nutrition and Cancer, 2018
Arianna Sasso, Giovanni Latella
However, NOC are also formed endogenously in the colon through nitrosation, which involves the addition of a nitroso group to the amines and amides produced by bacterial decarboxylation of amino acids (29,30). Nitrosation occurs in presence of nitrosating agents, which are found in the nitrites used to preserve meat, but can also derive from nitrates. Nitrates are found in water and in a variety of foods and are reduced to nitrite via dissimilatory metabolism by the colonic bacterial flora through bacterial nitroreductase in presence of hypochlorhydria and gastric bacterial proliferation (31). Red meat ingestion results in high colonic levels of nitrogenous residues arising from protein metabolism and of nitrosating agents from dissimilatory metabolism of bacteria. A study conducted in Cambridge (UK) has hypothesized that the increase in nitrogenous residues in the colon could stimulate endogenous nitrosation, thus explaining the epidemiological association between red meat and CRC (32). The Cambridge researchers measured the levels of N-nitroso compounds in fecal samples from volunteers fed different amounts of red meat (60, 120, 240 and 420 g/day), mean levels of ATNC output are highly correlated with dose of meat: under controlled conditions and found that they were closely related to the amount of red meat consumed, whereas eating the same amount of white meat did not result in an increase in N-nitroso compounds.