Nonsteroidal anti-inflammatory compounds

CYP2C9 is the major CYP2C enzyme expressed in human liver [35] and plays a major role in the metabolism of numerous therapeutics including many weak acidic drugs such as the nonsteroidal anti-inflammatory compounds (e.g. flurbiprofen) [36] and antidiabetics (e.g. tolbutamide) [37]. In addition, CYP2C9 also metabolizes (S)-warfarin [38], lornoxicam [39] and phenytoin [37]. 

You may have noticed that the reaction occurred only at the 2-position on pyrrole. Though all positions react with reagents like bromine, more selective reagents usually go for the 2- (or 5-) position and attack the 3- (or 4-) position only if the 2- and 5-positions are blocked. A good example is the Mannich reaction (Chapter 27). In these two examples N-methylpyrrole reacts cleanly at the 2-position while the other pyrrole with both 2- and 5-positions blocked by methyl groups reacts cleanly at the 3-position. These reactions are used in the manufacture of the nonsteroidal anti-inflammatory compounds, lolmetin and clopirac. 

Thus, despite the curious tissue and species specificity of the action of nonsteroidal anti-inflammatory compounds on bradykinin action, it is impossible to dismiss the connection as being fortuitous. 

This test can be useful when gastrointestinal bleeding is suspected but blood cannot be seen macroscopically in the feces (e.g., with some nonsteroidal anti-inflammatory compounds). The sampling procedures and their timing are important, particularly when the bleeding may be intermittent. 

Ceserani, R., Ferrari, M., Goldaniga, G., Moro, E., Buttinoni, A., 1977 Role of protein binding and pharmacokinetics in the lack of correlation between in vitro inhibition of PG-synthetase and in vivo anti-inflammatory activity of a homologous series of nonsteroidal anti-inflammatory compounds. Life Sci. 21, 223-230. 

Class I compounds have both good solubility and permeability and generally offer no problems with regard to having a good absorption profile (e.g., acetaminophen, disopyramide, ketoprofen, metoprolol, nonsteroidal anti-inflammatory agents, valproic acid, verapamil). In general, one would not expect the presence of food to influence the absorption of this class... 

Nonsteroidal anti-inflammatory agents are used extensively as nonprescription drugs, and residues of these compounds have been detected ubiquitously in WWTP effluents at the pg L 1 levels, and they also frequently occur at the ng L 1 level in the aquatic environment (see [2], this volume). As a result, many researchers have focused on the degradation of these pharmaceuticals, which are one of the most studied groups of therapeutic agents in terms of fungal transformation. 

Mefenamic is a nonsteroidal anti-inflammatory drug used to treat pain, including menstrual pain. Hata et al. [11] treated that drug with P. sordida, and obtained a 90% reduction in mefenamic acid concentration (initial concentration 24 mg L ) after 6 days. The system produced four metabolites, identified as 3 -hydroxymethyl-mefenamic acid, 3 -hydroxymethyl-5-hydroxymefenamic acid, 3 -hydroxmethyl-6 -hydroxymefenamic acid, and 3 -carboxymefenamic acid. Moreover, the authors confirmed that the fungus almost completely removed the acute lethal toxicity of mefenamic towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment, suggesting that the metabolites are less toxic than the parental compound. 

A number of compounds activate TRPA1 without any apparent ability to form covalent adducts, including nonelectrophilic fenamate nonsteroidal anti-inflammatory drugs (NSAIDs), such as flufenamic acid (17, FFA), niflumic acid (18, NFA), and mefenamic acid (19, MFA) [13]. Phenols such as thymol (20) and 2-ferf-butyl-5-methylphenol (21) have been shown to activate human TRPA1 with micromolar EC50 values in stably transfected HEK293 cells [14]. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medicines. Although these compounds represent a very effective class of drugs, their use is associ-... 

Primary hepatocyte cultures have been used as a tool to predict the hepatotoxicity of many compounds such as nonsteroidal anti-inflammatory drugs (Castell et ah, 1988), psychotropic drugs (Boelsterli et ah, 1987), immunosuppressant drugs (Boelsterli et ah, 1988), and salicylates (Tolman et ah, 1978). Rat primary hepatocyte cultures have also been shown to be a good model for examining the mechanisms of metallothionein-induced tolerance to cadmium toxicity (Liu et ah,... 

The compound 5-[5-(4-chlorophenyl)furan-2-yl]-2,3,4,5-tetrahydrofuran-2-one (F-1044, 7.85) is a nonsteroidal anti-inflammatory agent possibly acting via a ring-opened hydroxybutyric acid metabolite. To examine this hypothesis, F-1044 was submitted to extensive in vivo testing, which revealed potent activities and a unique pharmacological profile markedly different from that of acidic nonsteroidal anti-inflammatory drugs [169], These results have been interpreted to mean that part or most of the observed effects of F-... 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Lelievre and Gareil (31) studied chiral separations of nonsteroidal anti-inflammatory drugs (carprofen, flurbiprofen, indoprofen, ketoprofen, naproxen, propafenone, and suprofen) and determined the acidity and inclusion complex formation constants of these chiral compounds with different neutral CDs (/3-CD, HP-/3-CD, DM-/3-CD, TM-/3-CD, and HP-y-CD). In... 

Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acids. Aspirin (8.69) (acetylsalicylic acid, ASA) has been used since the turn of the last century to reduce pain and fever, but the parent compound, salicylic acid, has been known and used since antiquity, owing to its common occurrence as a glycoside in willow bark. Acetylation merely decreases its irritating effect. Among the numerous other salicylates known and used, flufenisal (8.70) has a longer duration of activity and fewer side effects than aspirin. Mefenamic acid (8.71) and flufenamic acid (8.72) are derivatives of anthranilic acid, while ibuprofen (8.73) and naproxen (8.74) are derivatives of phenylacetic and naphthylacetic acids, respectively. 

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