ANTI-INFLAMMATORY AGENTS in .NET

Make QR Code ISO/IEC18004 in .NET ANTI-INFLAMMATORY AGENTS

CHAPTER 35 ANTI-INFLAMMATORY AGENTS
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ANTI-INFLAMMATORY AGENTS FOR THE TREATMENT OF INFLAMMATORY SKIN DISEASES
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Topical Immune Modulators
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Topical calcineurin inhibitors tacrolimus and pimecrolimus have been investigated in the past decade as treatment options for inflammatory skin disorders These relatively new immunosuppressive drugs act by inhibiting the protein calcineurin, subsequently preventing T cell dephosphorylation of transcription factors As a result of this inhibition, the signal transduction pathways in such cells are blocked, and inflammatory cytokine production is suppressed50 Between December 2000 and December 2001, topical tacrolimus
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Topical Corticosteroids
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Not so long ago, dermatologic therapy was completely revolutionized with the introduction of corticosteroids in the early 1950s Spies and Stone, two dermatologists from Alabama, were the first to use topical hydrocortisone to successfully treat a patient with chronic hand dermatitis35,36 After this therapeutic success, many dermatologists seri-
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Cutaneous In ammation
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The skin is the primary barrier between our bodies and the environment and therefore the spectrum of insults to
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ointment and topical pimecrolimus cream received approval by the Food and Drug Administration (FDA) for the treatment of atopic dermatitis51 Furthermore, topical tacrolimus has been proven to inhibit other inflammatory skin conditions such as nickelinduced ACD52,53 as measured by a reduction in erythema, pruritus, vesiculation, induration,53 and histopathologic pattern54 Its inhibitory action has even been found by some researchers to be stronger than the steroid aclometasone dipropionate55 Even though these medicaments are structurally very similar, pimecrolimus has a higher lipophilicity index than tacrolimus (20-fold more lipophilic) Although a higher lipophilicity index has been correlated with a higher affinity for the skin,43 pimecrolimus is threefold less potent an inhibitor of calcineurin than tacrolimus56 In February 2005, just a few years after these drugs were approved by the FDA, the pediatric advisory committee of the Center for Drug Evaluation and Research of the FDA required that the labeling of tacrolimus and pimecrolimus include the placement of a black box warning about the potential cancer risks associated with the systemic administration of these medications57 However, although there is a theoretical concern, there has been no evidence to suggest an increased risk of cutaneous or visceral cancer associated with the use of these drugs in their topical form58
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Cyclooxygenase Inhibitors
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An increasing number of anti-inflammatory agents specifically target bioactive lipids generated from AA, namely, nonsteroidal anti-inflammatory drugs (NSAIDs) Although this group of medicaments is one of the most studied and used throughout medicine, their application for cutaneous disease is somewhat limited59 Ibuprofen, however, has been shown to be effective for the treatment of acne, since inflammatory acne lesions are infiltrated with neutrophils and ibuprofen is known to inhibit leukocyte chemotaxis60 More than two decades ago, Wong et al conducted a double-blind study of 60 male and female patients 15 to 35 years old with acne vulgaris61 Patients were randomly assigned to one of four groups: (1) oral ibuprofen (600 mg) plus tetracycline (250 mg) 4 times daily (qid); (2) ibuprofen (600 mg) plus placebo qid; (3) tetracycline (250 mg) plus placebo qid; and (4) two placebos qid Only the com-
bination therapy had an effect statistically better than the placebo in the improvement of total lesion count The administration of ibuprofen alone yielded beneficial results comparable to the ones of tetracycline alone but with fewer side effects As a follow-up to this study, 1 year later, Funt treated 22 male and female patients aged 14 to 25 years with nodulocystic acne with a combination of minocycline (50 mg) plus oral ibuprofen (400 mg) 3 times daily After 1 month, all patients apparently responded to the combination therapy with improvement ranging from 75% to 90% Notably, all 22 patients had a history of unsuccessful oral antibiotic treatment (3-month course of minocycline, 50 mg 3 times daily)62 NSAIDs are also applied in dermatology in the treatment of sunburn Hughes et al studied the ability to modify skin injury induced by UVB radiation by nonsteroidal drugs (ie, oral ibuprofen or indomethacin) plus topical betamethasone dipropionate in 24 subjects63 Skin responses to UVB (erythema and increased skin blood flow [SBF]) were measured serially and showed a synergistic effect of oral NSAIDs in combination with topical corticosteroids in the reduction of UVBinduced skin injury In another study, ibuprofen and placebo were compared in a randomized double-blind cross-over study of 19 psoriatic patients receiving UVB phototherapy Signs and symptoms of UVB-induced inflammation were then assessed Although a statistical difference was noted for only one variable (ie, technician s assessment of erythema), results suggest that ibuprofen was more effective than placebo for the symptomatic relief of UVB-induced inflammation after high doses of UVBphototherapy for psoriasis The postulated biochemical basis for this result derives from the observation that dermal PGs are elevated after UVB irradiation64 Therefore, an NSAID agent that interferes with PG synthesis may reduce UVB-induced inflammation
expressions They suppress the expression of proinflammatory genes by inhibiting the DNA-binding activities of transcription activators such as NF- B, activation protein-1 (AP-1) and CCAAT/enhancer-binding protein (C/EBP )65 Salicylic acid is known to decrease the frequency and severity of acne eruptions by reducing acne-associated inflammation in addition to imparting an exfoliating action over the pores It has therefore become a popular ingredient in over-the-counter acne products (see 20) Salicylic acid is also used to treat rosacea and other superficial inflammatory disorders In addition, it is found in products intended to treat photoaged skin Topical salicylic acid in concentrations of up to 30% has been shown to fade age-related pigmented spots, decrease surface roughness, and reduce fine lines66 If used in high concentrations or too frequently, salicylic acid may lead to redness, pruritus, scaling, increased skin sensitivity, and even epidermolysis
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