dihydropyridines and Dementia

Our review of cohort studies and clinical trials evaluating antihypertensive drugs in the prevention of cognition decline and all dementia in patients with hypertension indicates that two antihypertensive drug classes have greater protective effects, independent of blood pressure decrease: dihydropyridine calcium-channel blockers as shown in the Syst-Eur trial and angiotensin-AT1 receptor blockers as found in the MOSES and ONTARGET trials. By contrast, diuretics and angiotensin-converting enzyme-inhibitors (ACEIs) prevent dementia only in patients with a stroke history, provided they are combined, and prevent stroke recurrence. A Japanese cohort study and a small trial in patients already suffering from Alzheimer's disease (AD) suggest, however, that the BBB-penetrating ACEI may slow down cognitive decline. Only cohort studies support the hypothesis that diuretics, (especially potassium-sparing diuretics), may decrease the risk of AD. beta-blockers worsen cognition decline, or are neutral, according to whether or not they cross the BBB. Centrally-acting sympatholytic agent have a negative impact on cognition as BBB-penetrating beta-blockers, probably by blunting the adrenergic pathways. The AD protective effect of DHP appears related to the blockade of neuronal calcium channels. The ambiguous effect of ACEI on cognitive decline and dementia prevention may be explained by the fact that brain ACE is not specific for angiotensin-I. Brain ACE also catabolizes cognition-enhancing brain peptides, amyloid peptides and converts toxic Abeta(42) into less toxic Abeta(40). Therefore, ACEIs may have short-term cognition-enhancing properties and may increase in the long term Abeta(42) brain burden and cognitive decline. The clinical relevance of this scenario, mainly observed in animals, cannot be excluded in man, since the ACE gene has been associated with AD via the human whole genome analysis. To support the hypothesized deleterious effect of ACEI on human AD, confirmation that the ACE gene polymorphism DD is associated with protection against AD is necessary, since this polymorphism increases ACE activity. Independently of their preventive impact on beta-amyloid degenerative neuropathological process by overexpressing insulin degrading enzyme which catabolyses amyloid, the angiotensin AT1-receptor-blockers may have greater cognition protective effects than ACEI (observed in the ONTARGET trial), as they share with ACEI cognition-enhancing effects directly linked wi

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dementia; Dihydropyridines; Humans; Thiazides

Cognitive deterioration and its sequelae of vascular or Alzheimer's dementia is rapidly increasing all over the world. This is primarily caused by the worldwide increase of the ageing population. Additional causes may be sought in factors such as genetics and a habitually unhealthy life style. The significance of high blood pressure in the process leading to cognitive deterioration is relatively unknown. However, timely detection and treatment of hypertension seems to contribute to the preservation of cognition. Experience has shown that this applies in particular to dihydropyridine calcium antagonists. Medical care tends to make insufficient use of the existing possibilities for treating hypertension.

Topics: Aged; Aging; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cognition; Dementia; Dihydropyridines; Humans; Hypertension

Topics: Aging; Alzheimer Disease; Animals; Brain; Calcium; Calcium Channels; Dementia; Dihydropyridines; Glucocorticoids; Hippocampus; In Vitro Techniques; Ion Channel Gating; Membrane Potentials; Neuronal Plasticity; Rats; Synapses

Use of angiotensin II (ATII)-stimulating antihypertensive medication (AHM), including angiotensin receptor blockers (ARBs) and dihydropyridine calcium channel blockers (CCBs), has been associated with lower dementia risk. Previous studies had relatively short follow-up periods. The aim of this study is to investigate if these effects are sustained over longer periods.. This post hoc observational analysis was based on data from a dementia prevention trial (preDIVA and its observational extension), among Dutch community-dwelling older adults without prior diagnosis of dementia. Differential associations between AHM classes and incident dementia were studied after 7.0 and 10.4 years, based on the median follow-up durations of dementia cases and all participants.. After 7 years, use of ATII-stimulating antihypertensives [hazard ratio = 0.68, 95% confidence interval (CI) = 0.47-1.00], ARBs (hazard ratio = 0.54, 95% CI = 0.31-0.94) and dihydropyridine CCBs (hazard ratio = 0.52, 95% CI = 0.30-0.91) was associated with lower dementia risk. After 10.4 years, associations for ATII-stimulating antihypertensives, ARBs and dihydropyridine CCBs attenuated (hazard ratio = 0.80, 95% CI = 0.61-1.04; hazard ratio = 0.75, 95% CI = 0.53-1.07; hazard ratio = 0.73, 95% CI = 0.51-1.04 respectively), but still suggested lower dementia risk when compared with use of other AHM classes. Results could not be explained by competing risk of mortality.. Our results suggest that use of ARBs, dihydropyridine CCBs and ATII-stimulating antihypertensives is associated with lower dementia risk over a decade, although associations attenuate over time. Apart from methodological aspects, differential effects of antihypertensive medication classes on incident dementia may in part be temporary, or decrease with ageing.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Dementia; Dihydropyridines; Follow-Up Studies; Humans; Hypertension

To test the interrater reliability of the Clinical Dementia Rating (CDR) in a multicenter clinical trial.. Observational study.. Training session for a multicenter trial of milameline, a direct muscarinic agonist, in the treatment of Alzheimer's disease.. Twenty-four raters (physicians and nurses) familiar with drug trials and expert in the care of patients with Alzheimer's disease.. Independent scoring of the CDR using four videotaped CDR interviews.. Interrater reliability, as tested by the Kappa statistic. The overall interrater reliability was 0.62. Within the CDR domains, the global kappas ranged from 0.33 +/- 0.06 to 0.88 +/- 0.06.. The data support moderate to high overall interrater reliability but show important difficulties in the reliable assessment of early dementia.

Topics: Dementia; Dihydropyridines; Humans; Multicenter Studies as Topic; Muscarinic Agonists; Observer Variation; Oximes; Reproducibility of Results

In an attempt to provide a derivative of 3'-azido-3'-deoxythymidine (AZT) which might be sequestered in the central nervous system and release AZT, the dihydropyridine ester 5'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-3'-deoxythymidine, was synthesized in a three step sequence. This material showed potent anti-HIV-1 activity in MT-4 cells most probably by hydrolysis to the parent nucleoside, AZT. This dihydropyridine derivative of AZT could be easily oxidized to a positively charged pyridinium derivative of AZT in rat brain cytosol. In turn the pyridinium form could be hydrolyzed, non-enzymatically, to AZT.

Topics: Acquired Immunodeficiency Syndrome; Animals; Brain; Cell Line; Chemical Phenomena; Chemistry; Dementia; Dihydropyridines; HIV; Humans; Male; Mice; Moloney murine sarcoma virus; Pharmaceutical Preparations; Prodrugs; Rats; Rats, Inbred Strains; Thymidine; Virus Replication; Zidovudine