Aims/hypothesis Fidarestat, an aldose reductase inhibitor (ARI), has been reported to improve clinical symptoms and nerve conduction deficits in human diabetic neuropathy. We evaluated the dose-dependency and some of the mechanisms of the drug action in experimental diabetic neuropathy (EDN). Methods Control rats and rats with EDN were fed on normal pellets or pellets containing 0.00066% (1 mg/kg) or 0.00263% (4 mg/kg) fidarestat for 10 weeks. We evaluated the effect of fidarestat on nerve blood flow (NBF), electrophysiology, and sorbitol and fructose content in sciatic nerve in control and diabetic rats. For detection of oxidative stress in peripheral nerve, we measured sciatic nerve reduced glutathione (GSH) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunolabelling of dorsal root ganglion (DRG) neurons. Results NBF, compound muscle action potential and amplitude of C-potential were significantly improved in diabetic rats fed on the diet supplemented with fidarestat. Fidarestat suppressed the increase in sorbitol and fructose, normalised GSH in sciatic nerve, and reduced the number of 8-OHdG-positive cells in DRG. Conclusions/interpretation Fidarestat improves neuropathy, presumably via an improvement in oxidative stress. This study supports a role for fidarestat in the treatment of diabetic neuropathy.

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The current study was conducted to examine the effects of cilnidipine, a dual L/N-type calcium channel blocker, on blood pressure, pulse rate, and autonomic functions in patients with mild-to-moderate hypertension. Sixteen patients with mild-to-moderate hypertension (8 males and 8 females; 44-72 years of age) were treated with cilnidipine (10 mg/day) for 3 months. Before and after the treatment, the following measurements were conducted; beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver, the Valsalva ratio, heart rate response to deep breathing, systolic and diastolic blood pressure, and pulse rate. The head-up tilt test was also performed before and after the treatment. Cilnidipine significantly decreased either the systolic or diastolic blood pressure from 151 +/- 15 mmHg to 129 +/- 14 mmHg or 84 +/- 11 mmHg to 71 +/- 9 mmHg, respectively. For pulse rate, there were no significant changes during therapy. Beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver indicated significant improvements in both figures. The heart rate response to deep breathing and the Valsalva ratio indicated no significant differences during therapy. Before and after the treatment, no orthostatic hypotension was observed during the head-up tilt test. The current study revealed that cilnidipine significantly decreases blood pressure with improving autonomic functions while having no adverse effects on heart rate response and pulse rate.

F i g. 1 MR I o b t a i n e d o n t h e d a y o f a d mi s s i o n (a a n d b) , t h e 1 0 t h d a y (c a n d d) , a n d t h e 4 2 n d d a y (e a n d f). (a) Ax i a l T2-we i g h t e d MR I s h o ws h i g h i n t e n s i t y a r e a s i n b i l a t e r a l f r o n t a l a n d t e mp o r a l l o b e s. (b) Ax i a l p o s t-g a d o l i n i u m T1-we i g h t e d MR I d o e s n o t s h o w a r e a s o f e n h a n c e me n t. (c) Ax i a l T2-we i g h t e d MR I s h o ws t h a t h i g h-i n t e n s i t y l e s i o n s a r e e n l a r g e d c o mp a r e d wi t h t h o s e i n t h e MR I o b t a i n e d o n t h e d a y o f a d mi s s i o n .

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