The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury.

Nitric oxide (NO) is an important regulator of vascular and myocardial function. Cardiac ischemia/reperfusion injury is reduced in mice overexpressing endothelial NO synthase (eNOS) suggesting cardioprotection by eNOS. Novel pharmacological substances, so called eNOS enhancers, upregulate eNOS expression and thereby increase NO production. We tested the effects of the eNOS enhancer AVE 9488 on cardiac ischemia/reperfusion injury in vivo in mice. After treatment with the eNOS enhancer AVE 9488 (30 mg/kg/day) or placebo for one week mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in mice treated with the eNOS enhancer when compared to placebo treated mice (infarct/area at risk 65.4 +/- 4.1 vs. 36.9 +/- 4.0%, placebo vs. eNOS enhancer, P = 0.0002). The protective effect was blunted in eNOS knockout mice treated with the eNOS enhancer (infarct/area at risk 64.1 +/- 6.2%, eNOS knockout + eNOS enhancer vs. WT + eNOS enhancer, P = ns). Reactive oxygen species were significantly reduced in mice treated with the eNOS enhancer as indicated by significantly lower malondialdehyde-thiobarbituric acid levels (placebo vs. eNOS enhancer, 3.2 +/- 0.5 vs. 0.8 +/- 0.07 micromol/l, P = 0.0003). Thus pharmacological interventions addressed to increase eNOS-derived NO production constitute a promising therapeutic approach to prevent myocardial ischemia/reperfusion injury.

B cell depletion therapy for 19 patients with refractory systemic lupus erythematosus.

OBJECTIVE: B cell dysregulation is involved in the development of childhood-onset systemic lupus erythematosus (SLE). The safety and efficacy of B cell depletion therapy is evaluated in the the largest series of children to be presented in the literature. METHODS: 19 children (89% female) with SLE, aged 6-16 (median 14) years, treated with rituximab in a single centre were retrospectively reviewed. The British Isles Lupus Assessment Group (BILAG) index and biochemical, haematological and immunological parameters were evaluated before and after treatment, with the primary outcome assessed as normal results. Rituximab therapy was used for acute life- or organ-threatening symptoms or symptoms that had not responded to standard treatment. The range of symptoms included lupus nephritis, cerebral lupus and severe general symptoms. Rituximab 750 mg/m(2) was given intravenously twice, usually within a 2-week period. Patients were followed up for 6-38 (median 20) months. RESULTS: Rapid reduction of SLE disease activity was observed within the first month, represented by a reduction of BILAG scores (14 to 6, p<0.005) and an improvement in renal function (estimated glomerular filtration rate of 54 to 68 ml/min/1.73 m(2), p = 0.07), immunological (complement C3: 0.46 to 0.83 g/l, p = 0.02) and haematological (haemoglobin: 9.7 to 10.3 g/dl, p = 0.04) parameters. No serious side effects were observed, except for herpes zoster in five cases. CONCLUSION: In our cohort of children, rituximab was safe and effective when used in combination with standard immunosuppressive agents. Randomised controlled studies are needed to further evaluate the safety and efficacy of rituximab therapy.