Topically active

In 1973 D-homo corticosteroids (109—112), eg, D-homo-9a- uoroprednisolone acetate (111) were reported to have antiinflammatory activity (107). Compounds such as 21-acetoxy-liP- uoto-9a-chloto-17aa-hydtoxy-D-homo-ptegn-4-en-3,20-dione (110) had especially strong topical activity with weak systemic activity (108). Other preparations of D-homocorticoids included... 

Lidocaine hydrochloride [73-78-9] (Xylocaine), is the most versatile local anesthetic agent because of its moderate potency and duration of action, rapid onset, topical activity, and low toxicity. Its main indications are for infiltration, peripheral nerve blocks, extradural anesthesia, and in spinal anesthesia where a duration of 30 to 60 min is desirable. Because of its vasodilator activity, addition of the vasoconstrictor, epinephrine, increases the duration of action of Hdocaine markedly. It is also available in ointment or aerosol preparations for a variety of topical appHcations. 

Mepivacaine hydrochloride [1722-62-9] similar in profile to Hdocaine, is used for infiltration, peripheral nerve blocks, and extradural anesthesia. It appears to be less toxic than Hdocaine in adults but more toxic in newborns. The duration of action is longer than that of Hdocaine because of its lower vasodilator activity. Mepivacaine has Htde topical activity. 

Giclopiroxolamine. This ethanolamine salt, C24H24N2O2, of ciclopinox (9) is a topically active antimycotic, available as a cream and powder... 

ATC D01AE15 D01BA02 J02AX Use orally and topically active antifungal... 

Viader MP, McKeever BM, Navia MA. Thienothiopyran-2-sulfonamides novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma. J Med Chem 1989 32 2510-13. 

Patients should be taught how to administer topical therapy. With a forefinger pulling down the lower eyelid to form a pocket, the patient should place the dropper over the eye, look at the tip of the bottle, and then look up and place a single drop in the eye. To maximize topical activity and minimize systemic absorption, the patient should close the lid for 1 to 3 minutes after instillation and place the index finger over the nasolacrimal drainage system in the inner corner of the eye. 

Apart from the primitive Deinopsini and Gymnusini, adult Aleocharinae show impaired tergal glands situated between tergites 6 and 7 [ 127]. Up to now, chemical data of the topically active defensive secretions are available from... 

Aryl esters of retinoids have also received some interest. The 4-(acet-amido)phenyl ester of (all- )-retinoic acid, for example, showed topical activity in various animal models but was ineffective for the local treatment of acne in patients [86]. This difference is probably due to the prodrug being readily hydrolyzed in mice skin homogenates but not in human skin preparations. 

Merck s L-651,896 (54) was the lead compound from a series of dihydro-benzofuranols [158]. L-651,896 inhibited cRBL (1 //M) as well as platelet 12-LO (5.9 /zM). In zymosan-stimulated mouse macrophages, both LTC4 and PGE2 release were inhibited (0.1 //M and 1.1 //M, respectively) similar potency was seen in rat and human ISN. Potent topical activity in AAE was seen, with LT production and oedema both inhibited at 20-30 nM/ear. LT levels were also reduced in mouse oxazolone contact sensitivity, but in this... 

The unsubstituted 1-naphthyl compound Wy-47,288 (144) was inactive orally, but showed topical activity in several models (AAE, phorbol ester ear oedema, oxazolone-induced contact sensitivity, and UV erythema) [351]. In rat neutrophils, Wy-47,288 showed selectivity for 5-LO over CO (0.4 and 6.3 /iM, respectively), and was even more selective in mouse macrophages. 

It was clear, from even a qualitative inspection of the data, that the presence of a methyl or fluoro group in the meta position had the effect of not only increasing activity versus the design insect, the southern armyworm, but also lead to dramatic increases in level of topical activity against other species. 

Fluconazole and itraconazole are newer, orally effective triazole derivatives. The topically active allylamine naftidine and the morpholine amorolfine also inhibit ergosterol synthesis, albeit at another step. 

Topically active sulfonamides are useful in preventing infections in burn patients. Mafenide acetate... 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are available and reduce intraocular pressure without producing detectable plasma levels. Thus, diuretic and systemic metabolic effects are eliminated for the topical agents. 

Topical administration to the nose The safety of nasal glucocorticoids in the treatment of allergic rhinitis has been reviewed (434,435). The local application of glucocorticoids for seasonal or perennial rhinitis often results in systemic adverse effects. The use of nasal sprays containing a glucocorticoid that has specific topical activity (such as beclomethasone dipropionate or flunisolide) seems to reduce the systemic adverse effects, but they can nevertheless occur, even to the extent of suppression of basal adrenal function in children (436). Local adverse effects include Candida infection, nasal stinging, epistaxis, throat irritation (437), and, exceptionally, anosmia (438). 

The thieno[2,3-6]furan-2-sulfonamides (11), thieno[2,3-6]thiophene-2-sulfonamides, and thieno-[3,2-6]thiophene-2-sulfonamides were prepared and found to be a new class of topically active ocular hypotensive carbonic anhydrase inhibitors (91JMC1805,92JMC3027). 

Miconazole [my KON a zole], clotrimazole [kloe TRIM a zole], and econazole [e KON a zole] are topically active drugs and are only rarely administered parenterally because of their severe toxicity. Their mechanism of action, antifungal spectrum, distribution, and type of metabolism are the same as ketoconazole. 

Since 1952, about 40 new topically active anti-inflammatory corticosteroids have been introduced into therapy. 

In order to avoid even the minimal systemic side effects seen with currently available corticosteroids, scientists at Glaxo synthesized a series of androstane 17/ -car-boxylates and carbothiolates. It was found that halomethyl carbothiolates showed the highest topical activity as assessed by the inhibition of croton oil-induced ear inflammation in mice. The highest activity was found in the fluoromethyl car-bo thiolate-17-propionate (fluticasone propionate) synthesized from flumethasone [49-51],... 

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. 

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