Temic side-effects and skin atrophyPharmaceutics 2013,that is commonly associated with other

Temic side-effects and skin atrophyPharmaceutics 2013,that is commonly associated with other topical treatments such as steroids. Its precise mode of action is unknown but various cellular targets and pathways have been proposed, including: DNA replication and repair mechanisms [8], the mitochondrial membrane and mitochondrial function (by inhibition of cellular respiration) [9], induction of epidermal growth factor receptor (EGFR) phosphorylation in keratinocytes [10] and modulation of several key cytosolic enzymes associated with cell proliferation and inflammation [11]. Despite its efficacy, dithranol is limited by undesirable pro-inflammatory effects on the skin, as well as severe staining of skin and clothing. Topical application of dithranol has been shown to increase the production of reactive oxygen species (ROS) in the skin [12,13]. In addition, dithranol is chemically unstable, especially when exposed to sunlight or air (or in the presence of a strong base). The skin staining effect of dithranol has been ascribed to a number of its degradation products, most notably danthron (2) and a dithranol dimer (3) as outlined in Figure 2. These properties of dithranol limit patient acceptability and ultimately its usefulness as a topical agent. Figure 2. Dithranol (1) and its common degradation products.In co-drug design, the selection of therapeutic moieties is restricted to those with complementary functional groups which can form a biologically labile bond [7].Omeprazole sodium Several dithranol derivatives have been prepared and studied, mostly involving modification at the C-10 methylene group with the aim of diminishing oxygen-radical formation, reducing staining or irritation, and/or improving anti-proliferative properties [12,146].Alpidem Given the clinical efficacy of dithranol and potential for derivatization with biologically labile ester functional groups at the C-1 and C-8 hydroxyl groups, carboxylic acid containing drugs with clinical applications in psoriasis that could be formulated as a dithranol ester co-drug were investigated.PMID:23341580 In many cases, linking two active species together increasesPharmaceutics 2013,the molecular weight of the co-drug beyond the topical delivery optimum of 500; similarly the logP of the co-drug may deviate from the ideal range of approximately 1.5. These parameters were taken into account when considering appropriate candidates for a topical co-drug [7,179]. To evaluate the potential of a novel small molecule approach to psoriasis, a series of co-drugs based on dithranol were synthesized and the evaluation of in vitro bioactivation of the most promising candidate molecule was also studied herein. Non-steroidal anti-inflammatory drugs (NSAIDs) are often part of the first-line treatment for psoriasis and psoriatic arthritis [6]. NSAIDs owe their anti-inflammatory actions to the inhibition of cyclooxygenase enzymes, which are up-regulated in inflammatory disorders. Topical NSAID therapy can deliver therapeutic concentrations of the drug to the site of action and is potentially safer and more effective than oral delivery, particularly by reducing gastrointestinal side effects [20,21]. Ketoprofen (4) and (S)-naproxen (5) (Figure 3), both potent NSAIDs widely prescribed for inflammatory skin conditions, were identified as dithranol co-drug candidates with complementary functional groups for co-drug synthesis [22,23]. Figure 3. Chemical structures of ketoprofen (4), (S)-naproxen (5).2. Materials and Methods Dithranol was purch.