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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
The organic solvents are present in many workplaces and households. Methylene chloride is used for stripping paint and trichloroethane for cleaning upholstery. Toluene (methyl benzene) is present in glue, paint, and lacquers, and degreasing agents or cleaning fluids contain carbon tetrachloride or trichloroethylene. The abuse of these organic solvents is mainly for their hallucinogenic and intoxicating effects (Crites and Schuckit, 1979). However, the toxic effects with inhalation are not on the pulmonary system but on the renal, hepatic, hematologic, and neurologic systems (Hayden, et al., 1976).
Preclinical Antidepressant-Like Effects of Terpenes, Polyphenolics, and Other Non-Flavonoid Phytochemicals
Published in Scott Mendelson, Herbal Treatment of Major Depression, 2019
Orcinol, with the chemical name, 5-methylbenzene-1,3-diol, is a phenolic compound found in various species of lichen.141 Orcinol glucoside can be extracted from the rhizomes of Curculigo orchioides, a common traditional Chinese medicinal herb with diverse pharmacological activities, including immunomodulatory activity and antioxidant effects. That herb is also considered an adaptogen with neuroprotective effects.142 Of note, Curculigo orchioides is considered an endangered plant.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Iloperidone is an atypical antipsychotic with a low propensity to produce extrapyramidal side effects (Albers et al. 2008). It is a dopamine-D2/5-HT2 antagonist (Szewczak et al. 1995). Iloperidone is extensively metabolized via O-dealkylation, N-dealkylation, reduction, and hydroxylation in humans (Figure 3.24) (Mutlib et al. 1995). Iloperidone is O-dealkylated to form 6-fluoro-3-[1-(3-hydroxypropyl)-4-piperidinyl]-1,2-benzisoxazole and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone (M2). Oxidative N-dealkylation results in 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazol and a secondary metabolite, 3-[(4-ace-tyl-2-methoxy)phenoxy]propionic acid (Mutlib et al. 1995). Iloperidone is reduced to 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-α-methylbenzene methanol (M3), which is the major circulating metabolite in humans and rats (Mutlib et al. 1995). Hydroxylation of iloperidone yields 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl]-1-piperidinyl]-3-methoxyphenyl]-2-hydroxyethanone (M4) (Mutlib et al. 1995). M4 is further oxidized to 4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl)-piperidin1-yl]propoxy]-3-methoxyphenol (M5). In human liver microsomes, the formation of M4 is mediated by CYP2D6, while M2 is formed by CYP3A (Mutlib and Klein 1998). M3 is postulated to be produced mainly by a cytosolic enzyme, but CYP3A, 1A2, and 2E1 are involved in its formation as well (Mutlib and Klein 1998).
Biofilm and Quorum Sensing inhibitors: the road so far
Published in Expert Opinion on Therapeutic Patents, 2020
Simone Carradori, Noemi Di Giacomo, Martina Lobefalo, Grazia Luisi, Cristina Campestre, Francesca Sisto
2,4-Dimethoxy-6-methylbenzene-1,3-diol (DMD) is a benzenoid (Figure 6) usually isolated from Antrodia camphorate. In a patent from Taiwan it was synthesized and characterized by NMR spectroscopy before biological evaluation as growth and biofilm formation inhibitor of S. aureus at MBEC values comparable to MBC [24].
Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
A new set of derivatives having 5-cyano-6-phenyl pyrimidine structure was assessed for their inhibitory activity against ABC transporters. Among these derivatives, one molecule having an acylurea group exhibited the strongest activity in inverting resistance to PTX in colon adenocarcinoma cell line (SW620/AD300). Additional tests showed that the aforementioned compound increased intracellular concentration of PTX, disturbed ABCB1-facilitated Rh123 accretion and outflow, and particularly had no impact on CYP3A4 activity, which evades drug–drug interactions and substantial adverse effects. Furthermore, this compound meaningfully improved the cytotoxic activity of PTX against xenografted SW620/AD300 cells to mice without noticeable adverse events when given orally [114]. In another study, the common phenethyl tetrahydroisoquinoline group in the structure of third-generation chemosensitizers of P-gp and common active groups of BCRP modulators were connected by carboxamide linker. Also, the common pyrimidine aminobenzene group in TKIs was combined with the third-generation inhibitors chemical scaffold in order to get another series of compounds. Reversal potency of furan ring is stronger than that observed with thiophene ring. This kind of activity in methylbenzene groups is improved in benzene rings substituted with other groups, against either P-gp or BCRP. Molecular docking tests demonstrated a compound with pyrimidine ring interacting with P-gp in two separate hydrophobic parts and with BCRP in one hydrophobic region and also via a strong hydrogen bond. This compound raised the accretion of adriamycin (ADM) and mitoxantrone (MX) inside human leukemic K562/A02 cell line, signifying repressive impact on the activity of P-gp and BCRP transporters. More interestingly, coadministration of this compound considerably raised the intestinal absorption of PTX [115]. Using imatinib in combination with DOX in a pH-responsive liposome reversed resistance of MCF-7/ADR cells against DOX. Imatinib reverses MDR via reducing production of p-gp and BCRP transporters. This leads to higher levels of chemotherapeutic drug inside tumor cells [116].
Dynamic thiol/disulphide homeostasis as indicator of oxidative stress in automotive workers
Published in Biomarkers, 2020
Murat Büyükşekerci, Meşide Gündüzöz, Osman Gökhan Özakıncı, Mevlüt Karataş, Almila Şenat, Salim Neşelioğlu, Özcan Erel
Volatile organic compounds found in automotive paints are emitted to the workplace during automotive painting. Most of these emissions come from spraying operations via the use of solvent-based paints, as the spray booth air picks up gaseous solvent compounds and overspray paint materials. The volatile organic compounds consist of aromatic and aliphatic hydrocarbons, esters, alcohols, ketones and glycol ethers (Kim et al. 2011). Toluene (methylbenzene) is used in in numerous commercial products such as paints, glues, ink, cosmetics, coatings, and cleaning products. The workers in industries like painting, printing, shoemaking and automotive are under risk of exposure to high concentrations of toluene (Moro et al. 2012). Personal protective equipment (PPE) including respirators, goggles, and gloves can reduce a automotive painters exposure to organic solvents and when utilised at workplace minimises exposure to a variety of hazards. Toluene accumulates in tissues with high lipid content such as brain and liver (Angerer and Krämer 1996). Occupational exposure to toluene may cause significant neurologic disturbances hence it crosses the blood-brain barrier after inhalation. The effects of toluene on central nervous system is similar with those of sedative-hypnotics that is tendency to sleep, frequent headaches, memory impairment, eye irritation, cerebellar dysfunction, deficit in memory and spatial learning (Gericke et al. 2001, Win-Shwe and Fujimaki 2010). Toluene has been shown to act on lipid barrier of cell membrane resulting in dysfunctional membrane proteins (Martínez et al. 2011). Oxidative stress, an imbalance between the rate of free radical production and the effect of protective antioxidants, has also been implicated as one of the molecular mechanisms toluene toxicity (Bayil et al. 2008). Previous reports have shown the alterations in enzymatic oxidative markers e.g. glutathione peroxidase, superoxide dismutase (Halifeoglu et al. 2000, Dundaroz et al. 2003, Verma et al. 2017), catalase (Moro et al. 2010, Cassini et al. 2011), total antioxidant capacity (Bayil et al. 2008, Verma et al. 2017) and non-enzymatic markers e.g. malondialdehyde, 8-hydroxydeoxyguanine (Halifeoglu et al. 2000, Dundaroz et al. 2003, Yoon et al. 2010, Kim et al. 2011, Moro et al. 2012) in toluene exposure.