Additives mechanisms of actions

Mozaffarian N, Berman JW, Casadevall A. Enhancement of nitric oxide synthesis by macrophages represents an additional mechanism of action for amphotericin B. Antimicrob Agents Chemother 1997 41 1825. 

The major action of sulfonylureas is to increase insulin release from the pancreas (Table 41-5). Two additional mechanisms of action have been proposed—a reduction of serum glucagon levels and closure of potassium channels in extra pancreatic tissue (which are of unknown but probably minimal significance). 

The remarkable efficacy of topical corticosteroids in the treatment of inflammatory dermatoses was noted soon after the introduction of hydrocortisone in 1952. Numerous analogs are now available that offer extensive choices of potencies, concentrations, and vehicles. The therapeutic effectiveness of topical corticosteroids is based primarily on their antiinflammatory activity. Definitive explanations of the effects of corticosteroids on endogenous mediators of inflammation await further experimental clarification. The antimitotic effects of corticosteroids on human epidermis may account for an additional mechanism of action in psoriasis and other dermatologic diseases associated with increased cell turnover. The general pharmacology of these endocrine agents is discussed in Chapter 39. 

Ibutilide slows cardiac repolarization by blockade of the rapid component of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action. After intravenous administration, ibutilide is rapidly cleared from the plasma by hepatic metabolism. The metabolites are excreted by the kidney. The elimination half-life averages 6 hours. 

Of these active metabolites, endoxifen is suggested to be the primary active metabolite responsible for the majority of tamoxifen clinical efficacy, as endoxifen plasma concentrations are about five to tenfold higher than those of 4-hydroxy-tamoxifen [11, 165], Endoxifen may have additional mechanisms of action than 4-hydroxy-tamoxifen by targeting Era for degradation by proteasome [166] and through the promotion of ERa/ERf) heterodimerization, blocking ERa transcriptional activity [167],... 

The complex rocaglate silvestrol (461) was isolated from the plant Aglaia foveolata by Kinghorn et al. (398-400). Silvestrol (461) shows very potent cytotoxic activity against human lung cancer cells (ED q =1.2 nM), comparable to the activity of the prominent anticancer agent Taxol. In addition, mechanism of action studies indicate that cytotoxicity induced by 461 for human prostate cancer (LNCaP) cells is associated mainly with a block in the cell cycle at the G2/M checkpoint (400, 401). 

Overall, the combination of the results presented above suggests that several mechanisms are responsible for the cytotoxicity observed for 31. The inhibition of the COX enzymes is most likely one of them, but both the NSAID as well as the organometallic moiety could have additional activities. The cytotoxicity of celecoxib, a COX-2-specific NSAID, in cancer cell lines that lack COX [113], as well as the cytotoxicity of Co2(CO)6-modified peptides that clearly do not interact with COX [130], underline that additional mechanisms of action are likely. 

Additional mechanisms of action of indomethacin suggested are the inhibition of leukocyte migration and antagonism of capillary constriction.- Like other ajrti-inflammatory agents it possesses moderate auitil3miphocytic properties in vitro, but no adverse effect on the host-resistance of experimental animals. 9... 

Diesel fuels, like gasoline, are formulated with additives that affect the process of combustion, in this case to improve the cetane number. Diesel fuels also contain detergents for irijection systems as well as compounds for improving the fuel s low tempierature rheology. Finally, decreasing particulate emissions is a problem of increasing concern, but the mechanism of action to promote this effect is not clearly understood. 

NitrofuraZone. 2-[5-Nitro-2-furanyl)methylene]hydrazinecarboximide, the first nitrofiiran to be employed clinically, is prepared from 5-nitro-2-furancarboxaldehyde and semicarbazide (19). This product has seen clinical use topically as an antibacterial, for systemic appHcation for bacterial infections in poultry and swine, and also has been employed as a food additive. In rats, nitrofurazone is hydroxylated at the 4 position of the furan moiety (27). The involvement of nitrenium ions has also been postulated in the mechanism of action of nitrofurazone (38). 

Fig. 19. Generic addition fragmentation CT stmcture and the mechanism of action, where F = functional group.

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

Another limitation with the HI approach is that Uie assumption of dose additivity is most properly applied to compounds iliat induce die same effect by die same mechanism of action. Consequendy, application of die liazard index equation to a number of compounds diat are not expected to induce die same t) pc of effects or that do not act by the same ineclianism could overestimate die potential for effects, aldiough such an approach is appropriate at a screening lc cl. This possibility is generally not of concern if only one or two substances are responsible for driving the HI above unity. 

The procedure for recalculating the HI by effect and by mechanism of action is briefly described later. If one of the effect-specific luizard indices exceeds unity, consideration of tlic mechanism of action might be warranted. A strong case is required, however, to indicate that two compounds which produce adverse effects on the same organ system (c.g., liver), altliough by different mechanisms, should not be treated as dose additive. Any such determination should be reviewed. 

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

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