Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.
Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.
Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.
Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.
Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs. 相似文献
The effects of caffeine ingestion and exposure to bright light, both separately and in combination, on salivary melatonin and tympanic temperature were assessed in humans. Four treatments during a 45.5 h sleep deprivation period were compared: Dim Light-Placebo, Dim Light-Caffeine, Bright Light-Placebo and Bright-Light Caffeine. The Dim Light-Caffeine condition (200 mg twice each night) relative to the Dim Light-Placebo condition suppressed nighttime melatonin levels and attenuated the normal decrease in temperature. Combining caffeine ingestion with bright light exposure (≥2000 lux) suppressed melatonin and attenuated the normal nighttime drop in temperature to a larger degree than either condition alone; i.e. effects were additive. Circadian effects were also observed in that the amplitude and phase of the temperature rhythm were altered during treatment. These findings establish that the human melatonin system is responsive to caffeine. Other evidence suggests that caffeine may influence melatonin and temperature levels through antagonism of the neuromodulator adenosine. 相似文献