Psoriasis Clinical Trials Research Articles

Differential Modulation of Pro- and Anti-inflammatory Cytokine Receptors by N-(4-Trifluoromethylphenyl)-2-Cyano-3-Hydroxy-Crotonic Acid Amide (A77 1726), the Physiologically Active Metabolite of the Novel Immunomodulator Leflunomide

N-(trifluoromethylphenyl)-2-cyano-3-hydroxy-crotonic acid amide (A77 1726), the physiologically active metabolite of leflunomide, has been described to exert antiproliferative effects in vitro and anti-inflammatory actions in several animal models. Currently, its use is being evaluated in clinical trials in psoriasis, which is characterized by epidermal hyperproliferation and infiltration of inflammatory cells. We studied the effects of A77 1726 on growth and gene expression in cultured epidermal cells by 5-bromo-2′-deoxy-uridine (BrdU) incorporation, reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot hybridizations and flow cytometry. A77 1726 inhibited epidermal proliferation at concentrations above 5 μM after 24 hr. However, the cells were still fully viable at a concentration of 100 μM. The drug caused a dose-dependent reduction in the mRNA level of the type A receptor for the proinflammatory cytokine interleukin-8 (IL-8-RA) and, in contrast, induced gene expression of the receptor for the anti-inflammatory cytokine IL-10 (IL-10R) at the mRNA and protein levels. In addition, the mRNA and protein levels of the p53 gene, which is a negative cell cycle regulator, were up-regulated by A77 1726. These data suggest that A77 1726 exerts its anti-inflammatory action via the modulation of epidermal gene expression.

The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930.

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-3,4- dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a selective, orally active, LTB4 receptor antagonist currently in clinical trials for psoriasis and ulcerative colitis. Exhaustive SAR studies found a potential backup compound, SC-50605, which was 7-16 times more potent than SC-41930 in LTB4 receptor binding, chemotaxis and degranulation assays. SC-50605 also inhibited LTB4-induced intradermal chemotaxis in cavine skin at an oral dose of 0.10 mg/kg and displayed good activity in animal models of colitis and epidermal inflammation both orally and topically.

Development of anthralin short-contact therapy in psoriasis: survey of published clinical trials.

In a survey of clinical trials concerning the efficacy of short-contact therapy with anthralin in psoriasis vulgaris, focusing principally on methodologic issues, twenty-four papers published between January 1982 and December 1989, in English, French, and Italian, were selected. Nine of 24 papers reported on more than one trial, giving a total of 37 clinical trials to be evaluated. A great heterogeneity was evident in many aspects of the design and conduct of these trials, making pooling of results impossible. Most trials suffered from flaws in general methodologic aspects such as randomization and blinding. Limitations in general applicability of results were discussed with reference to the popular use of self-control design and selection of composite indexes (e.g., PASI) as an outcome variable. Published trials are not a reliable guide to clinical decisions concerning short-contact therapy, and some methodologic observations we made could be of general interest in designing clinical trials of psoriasis.

Selection of patients for psoriasis clinical trials: a survey of the recent dermatological literature

Reports of 62 psoriasis clinical trials listed in the Cumulated Index Medicos for the years 1988 and 1989 and published only in leading dermatological journals were evaluated for different elements of research methodology concerned with the recruitment of subjects. The evaluation included items such as eligibility criteria, the sampling process, ethical considerations and sample size calculation. Major weaknesses in the description of all aspects of the recruitment procedure were demonstrated. For example, a quantitative disease activity criterion at entry was mentioned in 15% of the studies, consecutive patients were included in 5% of the trials, sufficient information on ethical approval was given in 16% of the studies, and a pre-study sample size calculation was not mentioned in any of the trials.