**6. Conclusions**

16 Rheumatoid Arthritis – Treatment

neutrophils (Miossec et al., 2009). There is increasing evidence to suggest they play a role in

The earliest reports of TH-17 cell involvement in GC resistance emerged from the asthma research community. McKinley et al. showed in a mouse model of asthma that naive T cells which were polarized to the TH-17 phenotype during differentiation (by adding IL-23, IL-6 and TGF-β in vitro) were less sensitive to dexamethasone compared to cells which differentiated to the TH-2 phenotype (McKinley et al., 2008). Subsequent work has shown an expanded TH-17 subset within PBMC cultures of patients with UC and uveitis (Lee et al., 2009; Lee et al., 2007). The data from the uveitis and UC studies seems to suggest that the TH-17 phenotype is inherently GC resistant when tested using in-vitro stimulation assays. It

Fig. 9. The proposed model for GC resistance. Monocyte derived macrophages influence T helper cell phenotype differentiation through various cytokines. The balance of proinflammatory TH-17 cells and induced regulatory iTRegs alters the balance of IL-17, which increases GCR-β expression and hence reduces response to GC, and IL-10, which increases GCR-α expression and hence increases responsiveness to GC. The balance between these

Increases

Increases

cytokines determines the balance between GC resistance and GC responsiveness.

seems that their number is expanded in patients with clinical GC resistance.

GC resistance in a variety of inflammatory diseases.

Glucocorticoids have become an even more important therapeutic intervention in rheumatoid arthritis both for the control of acute disease flares and for the long term prevention of joint erosions. A better understanding of their mechanisms of action has

The Clinical Role of Glucocorticoids in the Management of Rheumatoid Arthritis 19

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begun to address the two key challenges which limit their use: developing better targeted GCs which achieve clinical benefit while minimising adverse effects, and reversing GC resistance. There is likely to be progress on both fronts over the next few years.

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**2** 

*Turkey* 

**Novel Formulation Approaches for** 

Alper Okyar1, Yldz Özsoy2 and Sevgi Güngör2  *1Istanbul University Faculty of Pharmacy Department of* 

*2Istanbul University Faculty of Pharmacy Department of* 

*Pharmaceutical Technology, Beyazt- Istanbul,* 

*Pharmacology, Beyazt- Istanbul* 

**Dermal and Transdermal Delivery of** 

 **Non-Steroidal Anti-Inflammatory Drugs** 

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drug groups. These drugs are used dermally or systemically in treatment of various rheumatic diseases, including rheumatoid arthritis (RA), as well as for osteoarthritis, low back pain and some joint diseases. The mechanism of action of NSAIDs is reversible inhibition of the cyclooxygenase enzyme (COX) and decreasing the synthesis of prostaglandins (Lionberger 2010; Massey 2010). However, these drugs lead to unfavorable effects specifically on the stomach as a result of inhibition of prostaglandins (PGs), which play a role in protection of the gastric mucosa, in systemic administration. The severity of these unfavorable side effects may range from a simple ailment like dyspepsia to peptic ulcer and gastrointestinal hemorrhage. Furthermore, the acidic character of NSAIDs may lead to local irritation and lesions on the gastrointestinal mucosa. Therefore, some NSAIDs are administered percutaneously and transdermally to achieve local or systemic effect as an alternative to oral and parenteral administration (Heyneman et al., 2000; Hooper et al., 2004). In dermal administration, the drug substances have to pass the *stratum corneum (SC)*  layer to reach lower layers of the skin and/or to enter systemic circulation. In this context, formulation of the product may play a key role for penetration and absorption of the active ingredient (Lee & Maibach, 2006). Several formulation approaches for cutaneous administration of NSAIDs have been employed. The conventional pharmaceutical forms particularly used for dermal administration to achieve local effect are gels, creams and ointments (Williams, 2003). Furthermore, studies on novel drug delivery systems are available for transdermal administration of NSAIDs. These new approaches include liquid crystals, nano/micro emulsions, liposomes, solid lipid particles and patches. These systems are used to enhance cutaneous passage of drugs into systemic circulation and to target different layers of the skin (Guy, 2010; Santos et al., 2008; El Maghraby et al., 2008; Ceve, 2004). Different approaches have been performed to enhance cutaneous passage of drugs with the objective of overcoming the low skin permeability (Guy, 2010; Tromer & Neubert,

**1. Introduction** 

