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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A common and dose-limiting side effect is encephalopathy (brain dysfunction), which occurs in up to 50% of all patients treated. This may be mediated by chloroacetaldehyde, one of the breakdown products of ifosfamide that has similar pharmacological properties to acetaldehyde and chloral hydrate. The symptoms of ifosfamide encephalopathy can range from mild (e.g., difficulty concentrating, fatigue), to moderate (e.g., delirium, psychosis), to severe (e.g., nonconvulsive status epilepticus or coma). In children, this can interfere with neurological development. Apart from the brain, ifosfamide can also affect peripheral nerves, although in most cases this resolves spontaneously within 72 hours. If this problem develops during administration of the drug, then immediate discontinuation of treatment is advised. Interestingly, the most effective treatment for severe encephalopathy is an intravenous solution of methylene blue, the mechanism of action of which is unknown. In some cases, methylene blue is used as a prophylaxis treatment before further doses of ifosfamide are administered. Due to all of these potential problems, ifosfamide has limited use in the clinic, although it remains on the World Health Organization’s List of Essential Medicines.
Hepatotoxic and Hepatocarcinogenic Effects of Chlorinated Ethylenes*
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Jeffrey L. Larson, Richard J. Bull
It has been suggested that the epoxide intermediate is the active carcinogen derived from VC (Van Duuren, 1975). VC has been shown to introduce a 2-oxoethyl group into nucleophilic sites in DNA (Osterman-Golker et al., 1977). The 2-oxoethyl group was found at the N-7 position of guanine in DNA in mice treated with VC. According to their calculations, the alkylating species was the epoxide and not chloroacetaldehyde.
Nasal Cavity Carcinogens: Possible Routes of Metabolic Activation
Published in D. V. M. Gerd Reznik, Sherman F. Stinson, Nasal Tumors in Animals and Man, 2017
Stephen S. Hecht, Andre Castonguay, Dietrich Hoffmann
Vinyl chloride (1), (Figure 13), is metabolized by microsomal mixed-function oxidases to chloroethylene oxide (2) which rearranges to chloroacetaldehyde (3). The latter can be oxidized to chloroacetic acid (4). Chloroethylene oxide, chloroacetaldehyde, and chloroacetic acid react directly with glutathione or enzymatically via glutathione S-transferase to form S-formylmethyl glutathione (5) or S-carboxymethylglutathione (6), respectively. Urinary excretion products include N-acetyl-S-(2-hydroxyethyl)cysteine (10), S-(carboxyme-thyl)cysteine (9), and thiodiglycolic acid (H).200-203
Synthesis and therapeutic delivery approaches for praziquantel: a patent review (2010-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Tayo A. Adekiya, Pradeep Kumar, Pierre P.D. Kondiah, Viness Pillay, Yahya E. Choonara
In their patent, it was recorded that the condensation of β-phenylethylamine with chloroacetyl chloride in the presence of a solvent lead to the production of 2-chloro-N-phenethylacetamide as showed in formula V. Subsequently, compound VI (N-benzyl-2,2-dimethoxyethanamine) was reported to be generated by the condensation of benzylamine with chloroacetaldehyde dimethylacetal in the presence of water. Hence, both the products formed in compounds V and VI were condensed to form 2-[(2,2-dimethoxyethyl) benzylamino]-N-phenethylacetamide of compound IV in the presence of water. Thereafter, the reduction of compound IV (2-[2,2-dimethoxyethyl) benzylamino]-N-phenethylacetamide) with the help of reducing agent and a solvent in the presence of hydrogen produced 2-[(2,2-dimethoxyethyl) amino]-N-(2-phenylethyl) acetamide showed in compound III. It was stated that the cyclization of compound III (2-[(2,2-dimethoxyethyl) amino]-N-(2-phenylethyl) acetamide) produces compound II (4-oxo-1,2,3,6,7,11b-hexahydro-4 H-pyrazino[2,1-a] isoquinoline) using an acid in the presence of solvent. The end product, which is praziquantel (compound I), was produced through the acylation of compound II with cyclohexanoylchloride in the presence of base and solvent [22].
Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats
Published in Toxicology Mechanisms and Methods, 2020
Shereen M. Galal, Heba H. Mansour, Abeer A. Elkhoely
In the current investigation, CP induced a significant reduction in the activity of nNOS and NO level. These results are in consistent with the report of Sancho et al. (2014) who postulated that, the reduction in the nitrergic relaxation induced by the intermediate CYP concurrent with the reduction in the expression of nNOS in CP-treated group. Furthermore, the decrease in NO might be due to increased utilization, with possible endothelial dysfunction and vascular impairment. NO reacts with superoxide to form peroxynitrite. These free radicals impair intracellular proteins, cellular membranes, and DNA (Fujikawa 2015). Treatment of DAS prior to CP in the present study resulted in a significant decrease of GABA and NMDA, plus significant augmentation of nNOS activity and NO level. CP is bio transformed by CYP 2B6, 3A4 and 2C6 isoforms to active metabolites, like phosphoramide mustard and acrolein (Gedye et al. 2006). A minimal percentage of CP is metabolized by CYP 3A4 to the neurotoxic metabolite chloroacetaldehyde, which is increased in the presence of CYP 3A4 inducers and neurotoxicity is increased probably due to central nervous system glutathione reduction (Gedye et al. 2006). CP-induced posterior reversible encephalopathy syndrome was occurred secondary to the renal failure, fluid overload and hypertension, which could contribute to endothelial dysfunction (Pan et al. 2017). DAS can obstruct numerous families of CYP450, such as CYP 2C9, 3A4 and 2C19 and may interfere with remedies metabolized by these enzymes (Collado-Borrell et al. 2016).
The safety of current pharmacotherapeutic strategies for osteosarcoma
Published in Expert Opinion on Drug Safety, 2021
Mariella Spalato, Antoine Italiano
IFO shares with its parent compound, cyclophosphamide, a toxic profile characterized by myelosuppression and urotoxicity. It can also give rise to adverse neurological effects. Acute central nervous system (CNS) toxicity represents the dose-limiting toxicity of IFO when preventive measures are taken to reduce nephrotoxicity, affecting more than 50% of orally treated patients and a smaller percentage of patients treated with intravenous regimens, as in osteosarcoma chemotherapy schedules[53]. Peripheral nervous system toxicity with IFO is far less frequent; painful peripheral neuropathy has been reported, either as the exacerbation of a preexisting neuropathy or as sporadic cases [54,55]. IFO-induced encephalopathy represents a severe adverse effect of unknown origin[56]. The most widely accepted hypothesis is that encephalopathy is produced by the IFO metabolites, particularly chloroacetaldehyde, through at least one of the following three mechanisms: (1) a direct neurotoxic effect, (2) depletion of glutathione in the CNS, or (3) inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism. The other potential responsible metabolite is S-carboxymethylcysteine, which can be implicated in neurotoxicity through cellular acidification and the activation of the alpha-amino-3 carboxy-5-methyl-4 isoxazoleprionic acid/kainite receptor, which can affect normal brain function[57]. Normally, the onset of IFO-related encephalopathy appears most often during, or shortly after, the start of infusion (between 12 and 146 hours after) and spontaneously reverses within 48–72 hours after IFO discontinuation [55,58–60], even in cases of progressing encephalopathy leading to coma and death [61–64].