Corticoids anti-inflammatory effects

The glucocorticoids have been found not only to increase apoptosis, but also to modulate the expression of apoptosis-related markers in both unstimulated and IL-2-stimulated T lymphocytes. In one study, this class of drugs induced apoptosis while reducing Bcl-2, Fas, and CD25 expression. Only negligible effects were detected on Bax expression, a fact which points towards a potential mechanism by which some corticoids exert their anti-inflammatory effects [59]. 

Triterpenes are widely distributed in plants, and in many cases are the principles responsible for their anti-inflammatory effects. Many of these compounds are active in different in vivo experimental models such as hind paw edema induced by carrageenan, serotonin and phospholipase A2 ear edema induced by phorbol and daphnane esters, ethylphenylpropiolate, arachidonic acid and capsaicin adjuvant arthritis and experimental models of allergy. Other effects have been studied in vitro, and some triterpenes are active against inflammatory enzymes like 5-lipoxygenase, elastase and phospholipase A2. Others inhibit histamine, collagenase and interleukin release, lipid peroxidation and free radical-mediated processes, metabolism of endogenous corticoids, and complement and protein-kinase activities. 

The vasoconstrictive property of corticoids may contribute to their anti-inflammatory effects. The mechanisms by which topical corticoids cause vasoconstriction remains unclear but is thought to be related to their inhibition of natural vasodilators, histamine, bradykinins, and prostaglandins [2, 46]. Some have suggested that corticosteroids potentiate norepinephrine [34], while others suggest that corticoids cause the release of norepinephrine [81]. Corticoids are thought to also have a direct effect on vascular endothelial cells. 

A iD-Corticoids have been important intermediates since it was shown ° that substitution at C-9 enhances anti-inflammatory activity. These olefins are usually obtained from 11a- or 11)5-alcohols, and consequently several refined methods have been devised for effecting this dehydration. It is desirable that such methods be compatible with the presence of A" -3-ketone and 17-hydroxy functions. The first direct procedure for which high yields were claimed was described in a patent issued to Upjohn. According to this method, the alcohol (11a or )5) is treated first with A-bromoacetamide in pyridine, then with sulfur dioxide. Recently it has been claimed " that the A-haloamide/sulfur dioxide method gives results superior to other methods, although the methanesulfonyl chloride/sulfur dioxide procedure (see below) apparently was not compared (see also ref. 94). 

Corticosteroids do not heal illnesses, but they are widely used in various conditions when it is necessary to utilize their anti-inflammatory, immunosuppressant, and mineralo-corticoid properties. In addition, they are used in replacement therapy for patients who have adrenal insufficiency. Corticosteroids can be used in vital situations for asthma, severe allergic reactions, and transplant rejections. They are effective in noninfectious granulomatous diseases such as sarcoidosis, collagen vascular disease, rheumatoid arthritis, and leukemia. Steroids are used as lotions, ointments, etc. in treating a number of dermatological and ophthalmologic diseases. 

The introduction of a 16a-hydroxy group into 6a,9-difluoro-prednisolone led to a compound (fluocinolone) with the anticipated favorable biological spectrum, namely high anti-inflammatory activity (35-fold that of hydrocortisone, seven-fold that of triamcinolone) and - in contrast to the C-16 unsubstituted compound - no retention of sodium. The corresponding 16,17-acetonide (fluocinolone acetonide) exhibited 100-fold the anti-inflammatory activity of hydrocortisone, with no sodium retention. In clinical trials, 6a,9-difluoro-16a-hydroxyprednisolone was found to be a potent suppressor of inflammatory conditions such as rheumatoid arthritis, as well as allergic conditions such as asthma, whilst its acetonide proved to be highly effective as topical corticoid. 

The effect on the potency of steroids of adding the extra double in ring A has resulted in the incorporation of this structural feamre in the majority of anti-inflammatory and anti-allergic corticoids. This observation also holds true for inclusion of halogen atoms and most frequently fluorine in the structure. Fluorine at C9 and/or Cg is thus found in the majority of corticoids. The very versatile sequence for introducing fluorine discussed in Chapter 5 (Scheme 5.31) was most likely first developed and subsequently applied in the corticoid series. 

A number of the potent anti-inflammatory steroids have proven very useful for treating topical manifestation of allergies such as rashes, rhinitis and asthma. Even topical application of the drugs carry the possibility that some would be absorbed and find its way into the circulation, where it could cause the typical corticoid side-effects. Several compounds in both this and other unrelated therapeutic areas include functional groups that will be destroyed by serum enzymes, thus inactivating that portion of the topically applied compound that may have entered the circulation. 

The very small amount of steroid that reaches the bloodstream from a topically administered drug can at least in theory cause some of the typical corticoid side-effects. This has occasioned research on corticoids that contain weak links that will lead to deactivation of the steroid by serum enzymes. The drug fluticasone (32-6) acts as a typical anti-inflammatory and antiallergic corticoid even though the side chain on ring D consists of a thioamide instead of a 2-hydroxyacetyl function. That thioamide provides the weak link that causes the drug to be destroyed by serum enzymes. As a result, fluticasone powder is used extensively in inhalers for treating asthma. 

Of the more recently introduced antirheumatics, indomethacin is equally active in anti-inflammatory test in intact and adrenalectomized rats , and there is no evidence of adrenal/dependence or corticoid hormone effects for flufenamic acid at non-toxic [Pg.123]

These are corticoids that are active in protidic and glucidic metabolism. The natural glucocorticoids are cortisone and hydrocortisone (or cortisol). The latter responds to stress by raising the level of sugar in the blood. Cortisone is used as an anti-inflammatory. Synthetic glucocorticoids have enhanced activity to permit more effective anti-inflammatory behavior and their mineralocorticoid effects are reduced. 

Corticoids being lipophilic in nature permeate the skin by passive diffusion, the rate of which is directly related to the extracellular concentration. The extracellular concentration is determined by many factors, which include the concentration of the applied steroid, percutaneous penetration, metabolic inactivation, and removal into the systemic circulation. Even though the precise sequence of cellular and subcellular events leading to the observed effects of topical steroids are still unclear these compounds are known to act in four ways anti-inflammatory, immunosupprossive, antimitotic and vasoconstrictive. 

The adrenocortical hormones have been highly effective drugs in many diseases (arthritis, skin disorders, inflammations). Modification of the chemical structure, particularly by introduction of fluoro or methyl groups, has provided substances with different action spectra and with much greater effectiveness than the natural hormones. From the multitude of such compounds we present the following two formulas. Both substances have strong anti-inflammatory properties, but relatively low mineral-corticoid effects. 

---