Pharmacological features of an almitrine-raubasine combination. Activity at cerebral levels.

Treatment with the combination of almitrine-raubasine increases both arterial oxygen partial pressure and haemoglobin oxygen saturation, reflecting an actual increase in the oxygen content of arterial blood. Furthermore, at the trans-cerebral carotid artery/internal jugular vein level, the treatment increases cerebral arterio-venous oxygen and glucose differences, suggesting an actual increase both in oxygen and glucose availability and uptake in cerebral tissues. The increased glucose transfer to the brain is supported also by enhancement of the 3H-deoxyglucose uptake induced by drug pre-treatment both in normoxia and hypoxia. Both almitrine and raubasine act at cerebral mitochondrial levels by decreasing the 'loss' of the 'biological' free energy for phosphorylation supported by the age-related drop in the cerebral enzyme activities, such as phosphofructokinase, pyruvate dehydrogenase and citrate synthase. Furthermore, the components interfere with the alterations induced by peroxidative stress acting at the level of cytochrome c, cytochrome c oxidase and succinate dehydrogenase. Treatment with the combination almitrine-raubasine increases the concentration of noradrenaline metabolites, while alteration of the dopaminergic system is less important. The interference with the noradrenergic system is possibly linked to the electroencephalographic changes induced by drug treatment: increasing alpha-rhythm distribution and reactivity, and increases in beta-rhythm amplitude. Pharmacological effects of almitrine-raubasine, obtained in experimental conditions, correlate with clinical therapeutic efficacy, e.g., in the treatment of cognitive disorders associated with ageing and other cerebral and neurosensory impairments. It is difficult to summarise, in a few pages, the large number of papers related to the cerebral pharmacometabolic and pharmacodynamic activities of the almitrine-raubasine combination. Thus, this review presents in sequential steps some of the interrelated research in humans and laboratory animals which describes in a critical way preclinical to clinical results.