Corticosteroids structure

Other groups also made attempts to separate local and systemic effects by integrating moieties susceptible to rapid, nonhepatic metabolism within the corticosteroid structure. One of the more successful attempts explored 17a-(alkoxycarbonyl)alkanoate analogs (35) of clobetasol propionate (144). Again, this can be considered as a hypothetical inactive metabolite—based approach, and a corresponding metabolite (35)(n. = 2, R = H) has indeed been shown to be inactive. Esters that were susceptible to rapid hydrolysis exhibited good separation of topical anti-inflammatory to systemic activity. The study also indicated the existence of an optimal volume for the 17a side chain. For example, the methyl succinate derivative (35) (/i = 2, R = methyl) showed as potent topical anti-inflammatory activity as clobetasol propionate, but a dramatically reduced thymolytic activity. Therefore, the cor-... 

This structure encoding method has been applied both for the classification of a data set comprising 31 corticosteroids, for which affinity data were available in the literature, binding to the corticosteroid-binding globulin (CBG) receptor, and for the simulation of infrared spectra [28, 29). 

Antihistamines are drags used to counteract the effects of histamine on body organs and structures. Examples of antihistamines include diphenhydramine (Benadryl), loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec). A new antihistamine, deslorata-dine (Clarinex), is die active metabolite of loratadine and is intended to eventually replace loratadine (Claritin). Topical corticosteroid nasal sprays such as fluticasone propionate (Flonase) or triamcinolone ace-tonide (Nasacort AQ) are also used for nasal allergy symptoms. See Chapter 56 for more information on die topical corticosteroids. 

This section of the chapter discusses the hormones produced by the adrenal cortex or the adrenocortical hormones, which are the glucocorticoids and mineralocorticoids. These hormones are essential to life and influence many organs and structures of the body. The glucocorticoids and mineralocorticoids are collectively called corticosteroids. 

Mager DE and Jusko WJ. Quantitative structure-pharmacokinetic/pharmacody-namic relationships of corticosteroids in man. J Pharm Sci 2002 91 2441-51. 

Clearly the physicochemical properties of a drug are a decisive factor in its overall activity. Where possible, molecular structures should be optimized to obtain best clinical performance. Rarely does an oral drug have physicochemical features suitable for topical or transdermal therapy, and it can take a great deal of systematic research to identify where the best balance of activity and permeability lies. Experience with corticosteroids suggests that as much as a 100-fold improvement in clinical activity may be attainable through molecular design, for today s most potent topical corticosteroids are more active than hydrocortisone by a factor at least this large. 

H15. Hammond, G. L., Smith, C. L., and Underhill, D. A., Molecular studies of corticosteroid binding globulin structure, biosynthesis, and function. J. Steroid Biochem. Mol. Biol. 40, 755-767 (1991). 

Many of these compounds have been shown to be effective in the treatment of arthritis. Since they apparently work by a mechanism different from that of the corticosteroids and are structurally unrelated, they have no corresponding endocrine effects. 

Transamination of barbiturate derivatives with semicarbazide Hydrolysis and acyl migration of corticosteroid esters Rate enhancement by CTABr depends on substrate structure Substrate micellization inhibits hydrolysis and acyl migration Reddy and Katiyar, 1981 Anderson el ai, 1983... 

The impacts of contaminants on the structure of the immune system can be assessed by examining white blood cell (WBC) numbers and the mass and cellularity of immune organs, although these indicators are usually not as sensitive as measures of immune function. Avian immunotoxicity studies frequently assess total and (or) differential WBC counts [79], and immunosuppression can be indicated by reduced numbers of WBCs or elevated WBC numbers caused by recurrent infections. An elevated heterophil to lymphocyte ratio can indicate altered immune status in response to corticosteroid stress hormones or other factors [78,7 9], Exposure to lead shot or lead acetate has been shown to alter total and (or) differential WBC numbers in Japanese quail (Coturnix coturnix) and mallards [81-83], In western grebes (Aechmophorus occidentalis) from California, concentrations of mercury in the kidney were positively correlated with heterophil... 

Fig. 5 Chemical structure of the hapten conjugated to BSA used as immunogen by Roberts et al. [158] and Meyer et al. [154] to raise antibodies against dexamethasone. Structures of other corticosteroids subsequently tested by Creaser et al. [180] in order to evaluate the selectivity of the ELISA obtained are also shown...

Some of these environmental aspects are obvious, such as anthropogenic sources of chemicals that disrupt the structure of delicate epithelia involved in solute transport, or directly inhibit the solute transporting proteins (e.g. Cu inhibition of Na+K+ ATPase [82]). The general effects of environmental stress are also well known, since many of the hormones released into the blood during stressful situations will alter the activity of ion transporters (e.g. corticosteroids, catecholamine [14]). 

The connection between chemical structure and biological action of corticosteroids is extremely complex. However, it is possible to make a number of generalizations. 

Figure 1.7. Structure of some of the major corticosteroids that have found routine therapeutic application...

The structures of some corticosteroids listed in order of their elution from an ODS column eluted with a methanol/water (75 25) mobile phase and below the chromatogram produced by the mixture. 

Excellent separations of corticosteroids can be achieved on an ODS column with a suitable ratio of methanol/water as an eluent. In this assay hydrocortisone is quantified using betamethasone as an internal standard. The structure of betamethasone is close to that of hydrocortisone but since it is more lipophilic it elutes from the ODS column after hydrocortisone (Fig. 12.12). The assay is a modification of the BP assay for hydrocortisone cream. In the assay described here the internal standard is added at the first extraction step rather than after extraction has been carried out in order to ensure that any losses in the course of sample preparation are fully compensated for. Extraction is necessary in the case of a cream because the large amount of oily excipients in the basis of the cream would soon clog up the column if no attempt was made to remove them. The corticosteroids are sufficiently polar to remain in the methanol/water layer as they have a low solubility in hexane, while the oily excipients are removed by extraction into hexane. The sodium chloride (NaCl) is included in the sample extraction solution to prevent the formation of an emulsion when the extract is shaken with hexane. Solution 2, where the internal standard is omitted, is prepared in order to check that there are no excipients in the sample which would interfere with the peak due to the internal standard. 

B. Indications and nse Remicade is indicated for the reduction of the symptoms of moderate to severe Crohn s disease in patients who have not responded well to traditional treatments, including corticosteroids and other immunosuppressants, and antibiotics, and to close enterocuta-neous fistulas. Remicade, with concomitant methotrexate, is indicated for the reduction in signs and symptoms, and inhibiting the progression of structural damage due to RA in patients who have had an inadequate response to methotrexate alone. 

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