A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Different therapy options protecting microvasculature after experimental cerebral ischaemia and reperfusion.

Recombinant tissue plasminogen activator (rt-PA) is successfully used in human stroke, but often shows serious drawbacks. To find an alternative, we hypothesised that the novel thrombolytic microplasmin would have fewer adverse effects on haemoglobin extravasation and microvascular damage compared with the effects of rt-PA and tenecteplase (TNK). A constant period of ischaemia (3 hours) was induced in a rat suture model followed by reperfusion (24 hours). Mikroplasmin (10 mg/kg), TNK (5 mg/kg), rt-PA (9 mg/kg) and saline (control), were administered. The volume of the ischaemic lesion was calculated, the loss of collagen type IV and the extravasation of haemoglobin were quantified by Western blotting. The matrix-metalloproteinases 2 and 9 (MMP-2/-9) were quantified by zymography and their endogenous tissue inhibitors (TIMPs) were analysed by reverse zymography. Microplasmin treatment caused the lowest volume of the ischaemic lesion (51.0 +/- 22.6 mm(3)) compared with control (167.3 +/- 13.1 mm(3); p<0.05). The content of collagen type IV was significantly increased and haemoglobin extravasation reduced (154 +/- 24%; p<0.05) compared with control (442 +/- 124%); MMP-2/-9 and the corresponding TIMPs remained unchanged. In comparison, TNK did not significantly reduce basal lamina damage and caused the highest extravasation. MMP-2/-9 were severely increased after TNK treatment (p<0.05). Thus, the balance between MMPs and TIMPs was shifted toward the inhibitory side with TNK. Microplasmin had a protective effect on the microvascular basal lamina and blood-brain barrier, whereas TNK was significantly disadvantageous from the viewpoint of ischaemic damage. Microplasmin also appears to be safer than other PAs in terms of damage to the microvasculature associated with thrombolytic therapy of ischaemic stroke.