Deflazacort

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Abstract
Deflazacort is an oxazoline derivative of prednisolone with anti-inflammatory and immunosuppressive activity. Both short (4 to 6 weeks) and longer term (13 to 52 weeks) studies have shown deflazacort to be as effective as prednisone or methylprednisolone in patients with rheumatoid arthritis. The drug was at least as effective as prednisone in children with juvenile chronic arthritis. Insufficient data are available to draw firm conclusions regarding the efficacy of deflazacort as treatment for patients with severe asthma, but the drug has demonstrated some efficacy as treatment for nephrotic syndrome and other applications such as Duchenne dystrophy, systemic lupus erythematosus, uveitis and transplantation. The overall incidence of adverse events in deflazacort recipients (16.5%) is lower than that recorded in patients treated with prednisone (20.5%) or methylprednisolone (32.7%) and similar to that in betamethasone recipients (15.3%). Gastrointestinal symptoms are the most frequently reported adverse events in deflazacort recipients; other adverse events associated with the drug include metabolic and nutritional disorders, central and peripheral nervous system disturbances and psychiatric disorders. In general, deflazacort appears to have less effect than prednisone on parameters which may be associated with the development of corticosteroid-induced osteoporosis. Further, the drug appears have less negative impact on growth rate in children with diseases requiring corticosteroid therapy. In a study of 2 months’ duration in patients with conditions requiring corticosteroid treatment, moderate dosages of deflazacort produced no clinically relevant diabetogenic effects. Thus, deflazacort may be associated with less serious metabolic sequelae than prednisone but further well designed long term trials are required to confirm this. In the meantime, in adults, deflazacort should be reserved for use in those predisposed to, or who develop, intolerable metabolic sequelae during treatment with corticosteroids. In children, however, even though available efficacy data are minimal, deflazacort should be considered as an initial option in those requiring corticosteroid therapy since the adverse effects caused by this drug class are particularly debilitating in this patient group. Deflazacort has been shown to significantly inhibit proliferation of human peripheral blood mononuclear cells in vitro and to inhibit the release of certain cytokines by these cells. Marked depletion of CD4+ lymphocytes coupled with a relative increase in the CD8+ subset has been observed after exposure to the drug (15mg administered prior to cell harvest). In the same experiment, prednisone (12.5mg administered prior to cell harvest) produced similar, albeit less sustained, effects. A reduction in CD4+ clones and a reversal of the ratio of CD3+CD4+ to CD3+CD8+ clones was seen in lymphocytes cloned from cells taken from the synovial fluid of patients with rheumatoid arthritis given deflazacort prior to sampling. The drug also inhibited chemotaxis, Superoxide anion generation and chemiluminescence in human polymorphonuclear leucocytes in vitro. Deflazacort 36mg administered 12 and 2 hours before oral glucose tolerance testing in volunteers with familial history of non insulin-dependent diabetes mellitus had less impact on glucose metabolism than prednisone 30mg similarly administered. In a longer term (2 month) crossover study in patients with conditions requiring corticosteroid therapy, moderate dosages of deflazacort (vs 17.1 after 12 months) than in prednisone recipients (15 at baseline vs 15 after 12 months). Few studies have evaluated the efficacy of deflazacort as treatment for asthma and those that are available were designed primarily to assess the dosage equivalence of deflazacort and prednisone; clinical efficacy was a secondary end-point. The larger of 2 studies comparing deflazacort and prednisone in patients with asthma was conducted in 3 stages. During the final stage (12 weeks) parameters of pulmonary function worsened in deflazacort recipients but improved in prednisone recipients. In addition, 1 trial has compared the efficacy of deflazacort with that of prednisone as short term treatment for acute exacerbation of chronic asthma. Both drugs were administered at a high initial dose (deflazacort 30 or 60mg; prednisone 30 or 50mg) which was then progressively decreased over 15 to 18 days. Parameters of pulmonary function significantly increased with both treatments. Results from 2 short preliminary studies showed that deflazacort reduced airways obstruction in patients with chronic obstructive pulmonary disease. In 3 comparisons with prednisone, deflazacort demonstrated some efficacy as treatment for adults and children with nephrotic syndrome. Trials have also been conducted in many other less prevalent conditions including: breast cancer; essential mixed cryoglobulinaemia; Duchenne dystrophy; protection of residual islet cell function in patients with recent onset insulin-dependent diabetes mellitus; myasthenia gravis; systemic lupus erythematosus; sarcoidosis; thrombocytopenic purpura; after organ transplantation; and uveitis. Deflazacort was generally as effective as the comparative drug, and more effective than placebo, in controlled trials. Pooled tolerability data from 46 comparative or noncomparative clinical trials revealed a 16.5% overall incidence of adverse events in deflazacort recipients (n = 1064) compared with 20.5, 32.7 and 15.3% in prednisone (n = 605), methylprednisolone (n = 88) and betamethasone (n = 26) recipients, respectively. Gastrointestinal disorders were the most common adverse events in deflazacort recipients but the incidence of these symptoms was lower than that in patients treated with prednisone or methylprednisolone. Other adverse events reported in deflazacort recipients included metabolic and nutritional disorders, central and peripheral nervous system disturbances and psychiatric disorders. Studies have reported that symptoms of Cushing’s syndrome are less severe in deflazacort than in prednisone recipients and that deflazacort has the ability to reverse prednisone-induced Cushing’s syndrome. In general deflazacort appears to have less effect than prednisone on urinary calcium excretion, serum osteocalcin levels and serum parathyroid hormone levels; parameters implicated in the pathogenesis of corticosteroid-induced osteoporosis. In 3 studies conducted to evaluate its effects on bone mass/density, deflazacort therapy was associated with a smaller loss of bone mass/density than prednisone. Results from several studies suggest that deflazacort has a less deleterious effect on growth rate than prednisone in children (most with juvenile chronic arthritis). Similar results were reported in a single study comparing deflazacort with methylprednisolone in children who had undergone renal transplantation. The recommended dosage range of the reference glucocorticoid prednisone is 5 to 60 mg/day. Deflazacort is less potent than prednisone and is usually administered in proportionally higher dosages. In general, studies designed to determine the dosage equivalence of deflazacort and prednisone found deflazacort to be 25% less potent than prednisone, a dosage ratio of 1:1.3.
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