Topical anti-inflammatory activity

In 1985, workers at Syntex described RS-43179 (lonapalene) (60) as a selective 5-LO inhibitor with topical anti-inflammatory activity [166,167]. The release of 5-LO products from human ISN was inhibited (20 /zM), as was the cRBL system (0.5 /zM). AAE was effectively inhibited (1 mg/ear), and... 

Manoalide (164), a marine natural product which inhibits the release of arachidonic acid from phospholipids by phospholipase A2 [397,398], showed topical anti-inflammatory activity in mouse ear models [399]. Activity in ISN and cRBL (< 1 M) have also been reported [400]. A series of analogues consisting of the furanone ring of manoalide bearing simple unsaturated 16-20 carbon chains showed similar activity in rabbit neutrophils and isolated guinea-pig neutrophil 5-LO [401] interestingly, however, topical anti-inflammatory activity was seen in phorbol ester ear oedema but not in AAE [399]. The importance of 5-LO inhibition to the anti-inflammatory activity of manoalide is unknown effects on phospholipase C and calcium channels have also been shown [402, 403]. 

Beclometasone (as dipropionate) is a pro-drug with weak glucocorticoid receptor-binding activity. It is hydrolysed via esterase enzymes to the active metabolite beclometasone-17-monopropionate (B-17-MP), which has high topical anti-inflammatory activity. 

In the croton oil topical inflammation test in mice, 20 pi of a 3% solution of croton oil is applied topically to the anterior and posterior surfaces of one ear and 20 pi of the test drug is applied to the same ear 30 min later. Inhibition of ear swelling by more than 50% relative to vehicle-treated controls measured 2h after croton oil application indicates acute topical anti-inflammatory activity. 

Pimecrolimus is a non-steroidal ascomycin derivative with topical anti-inflammatory activity. In a 1% cream it is effective and safe in atopic dermatitis in infants, children, and adults (1-3), although its efficacy has been questioned (4). 

The ethylene ketal derivative of prostaglandin E2 (dinopros-tone) possesses much improved solid-state stability (see Chapter 41). Functionalized spirothiazolidines of hydrocortisone and hydrocortisone 21-acetate (Figure 36.6), prepared with cysteine esters or related 3-aminothiols, have improved topical anti-inflammatory activity. It is specnlated... 

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-... 

The relative potency is based on the drug concentration, type of vehicle used, and the vasoconstrictor assay as a measure of topical anti-inflammatory activity. 

Gomez, M.A. et ah. Study of the topical anti-inflammatory activity of Achillea ageratum on chronic and acute inflammation models, Z. Naturforsch. [C], 54, 937, 1999. 

Reaction of the side chain hydroxyacetone in flumethasone (27-4) with periodic acid leads to cleavage of that function to give carboxylic acid (29-1) with the loss of the carbon atom at C-21. Further reaction of the very hindered acid group requires prior activation. Thus, acylation with diphenyl chlorophosphate leads to the mixed anhydride (29-2) this is not isolated, but treated immediately with methyl mercaptan. The product, tibecasone (29-3), is a quite effective topical anti-inflammatory agent [24]. Cleavage of the ester side chain would lead back to the inactive starting acid (29-1). 

Among five triterpenoids isolated from Calendula officinalis flowers, P-amyrin (119), faradiol (232), i /-taraxasterol (238), taraxasterol (239), and lupeol (238), the diol 232 was the most active. It showed a dose-dependent effect with a potency that equals that of indomethacin (5) in the topical anti-inflammatory assay with croton oil [33]. Esterification at C-3 of 232 with a fatty acid reduced the activity by more than 50% [33] consistent with our observation in the TPA-induced assay described above. The anti-inflammatory properties, as determined by croton oil-induced edema of mouse ear, of faradiol-3-O-myristate (233) and its 3-O-palmitate (234), the main components of lipophilic extracts of C. officinalis flowers, were shown to be contribute significantly to the pronounced antiphlogistic activity of the lipophilic extracts of C. officinalis flowers [34]. 

Caribbean coral Pseudopterogorgia elisabethae discovered by Fenical et al. [47], Pseudopterosin E, Fig. (3) is the one with the best pharmacological profile, combining low toxicity and potent antiinflammatory activity. In human neutrophils, pseudopterosin E inhibits degranulation and formation of Ieukotrienes [2], In 1991, phase I clinical trials were initiated with pseudopterosin E as a topical anti-inflammatory agent. Recently, novel anti-inflammatory natural products have been isolated from this Caribbean soft coral [48,49], Japanese researchers reported the isolation of a group of compounds designated helioporins A-E, which are related to the pseudopterosins [1],... 

Both avarol and avarone inhibit replication of the ethiological agent of acquired immuno-deficiency syndrome (AIDS) [77], Additionally, avarol and avarone effectively control acute inflammation in experimental models after either oral or topical administration. Their anti-inflammatory activity may result from inhibition of eicosanoid release and depression of superoxide generation in leukocytes [78], Several studies reviewed the structures and bioactivity of compounds related to avarone as an antihuman immuno-deficiency virus (HIV), antitopoisomerase II activity and as proteinkinase C (PKC) inhibitors [3, 79],... 

Substituted-l-naphthols are synthetic phenolic compounds with dual inhibitory activities. The most active compound, 2-allyl-l-naphthol, is a very potent 5-LOX inhibitor with an IC50 value in nanomolar range and also has moderate COX enzyme inhibition activity. The compound also possesses excellent topical anti-inflammatory potency in the mouse ear edema model... 

Claeson, P., Pongprayoon, U., Sematong, T., Tuchinda, P., Reutrakul, V. and Soontornsaratune, P. (1996) Non-phenolic linear diarylheptanoids from Curcuma xanthorrhiza a novel type of topical anti-inflammatory agents structure activity relationship. Planta Medica 62, 236-240. 

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 introduction of a 16a-hydroxy-group into 9a-fluoro-prednisolone leads to a compound which is devoid of sodium retention but has anti-inflammatory activity considerably lower than that of the parent compound. The 16a- and 16/7-rnelhyl-9a-fluoro-prednisolones, on the other hand, are more potent than the parent compound yet free of sodium retention. Peculiarly, the conversion of 16a-hydroxy-9a-fluoro-prednisolone to the 16a, 17-acetonide markedly increases topical activity, without significantly affecting oral anti-inflammatory activity. 

A new class of corticosteroids consists of heterocyclic ester derivatives of the 17a-hydroxy function. The most potent topical anti-inflammatory compounds were 17a-heterocydic esters in the 16a-methyl series, where the 21-substituent was either chloro or fluoro. Exceptional safety through the effective separation of topical from systemic activity has been demonstrated in studies. 

In addition to variables in clinical signs and symptoms and the ability to penetrate the ocular structures, the derivative of a steroid base also seems to influence its anti-inflammatory efficacy. Using a rabbit corneal model, it was demonstrated that acetate and alcohol derivatives are more effective than the phosphate derivative in suppressing corneal inflammation both in the presence and absence of corneal epithelium (see Table 12-1). The mechanism by which a derivative affects the anti-inflammatory activity of a steroid base applied topically to the eye is not known, but some data seem to indicate that receptor binding or metabolism plays a role in the observed antiinflammatory and ocular hypertensive effects. 

After topical application to the eye, fluorometholone alcohol penetrates and is rapidly metabolized within the aqueous humor. Comparative anti-inflammatory studies indicate that the efficacy of fluorometholone alcohol is somewhat less than dexamethasone alcohol and prednisolone acetate (see Table 12-1). Increasing the concentration of fluorometholone alcohol from 0.1% to 0.25% does not significantly increase its anti-inflammatory activity but does enhance its tendency to raise lOP. The 17-acetate derivative of fluorometholone has demonstrated greater anti-inflammatory activity in the experimental rabbit keratitis model than has fluorometholone alcohol. However, studies with fluorometholone acetate show that it is metabolized slowly as compared with the alcohol derivative (Figure 12-1). Thus it is possible that the 17-acetate substitution to the fluorometholone base not only enhances its anti-inflammatory effects, but also impedes its metabolism. 

The anti-inflammatory effects of corticosteroids reduce CME, vitreous inflammation, and retinal vasculitis. Use of corticosteroids is especially important if the macular area is threatened. Because they are immunosuppressive, they should never be used without concurrent antimicrobial agents. Oral prednisone 40 to 60 mg is given daily for 2 to 6 weeks depending on clinical response. Topical corticosteroids are used for the secondary anterior chamber reaction but have no impact on retinal inflammation, and periocular injections should be used cautiously, if at all, because of their intense anti-inflammatory activity. 

Recently, we have reported the in vivo and in vitro anti-inflammatory activity of two saikosaponins isolated from B. rigidum, budlejasaponin IV and sandrosaponin I, in order to establish the possible real value of these kinds of compounds as anti-inflammatory agents [44]. We showed that saikosaponins inhibited the mouse ear edema induced by topical administration of phorbol myristate acetate (PMA). Saikosaponins, at a dose of 1 mg/ear, significantly inhibited swelling and were as potent as the reference drug indomethacin at 3 mg/ear. These findings were supported by vascular permeability analysis [Table 10 and Fig. (4)]. 

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