Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although FDA-approved Alzheimer's disease (AD) treatment strategies (cholinesterase inhibitors and memantine) offer proven benefits, providers recognize unmet needs beyond what is currently available. Consequently there is a significant use of anecdotal yet unproven combinations for treating AD in practice. Based on the best evidence, combination drug therapy is the standard of care for treating other medical conditions such as malignancies, human immunodeficiency virus (HIV), and hypertension. We review recent combination drug therapy studies in AD. To date, the best evidence-based combination strategy is for moderate-to-severe AD, in which the addition of memantine to stable donepezil therapy was found to benefit cognition, behavior, and function. In milder stages of AD, the benefit of combination drug therapy has not been demonstrated. This review highlights the urgent need to systematically test additional rational drug combinations and the need for future trials to enroll adequate sample sizes and utilize relevant and sensitive outcome measures.
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PMID:Combination drug therapy for Alzheimer's disease: what is evidence-based, and what is not? 1594 60

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins in rats and that activities of these AHA neurons are enhanced in spontaneously hypertensive rats (SHR). In addition, we have demonstrated that cholinergic mechanisms in the posterior hypothalamic nucleus (PHN) are involved in the activation of AHA angiotensin-II-sensitive neurons. It has been suggested that cholinergic function in the posterior hypothalamus is enhanced in SHR and that this hyperactivity plays a role in hypertension in SHR. In the present study, we examined whether the PHN cholinergic stimulation-induced activation of AHA angiotensin-II-sensitive neurons is altered in SHR. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY) were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjection of the cholinoceptor agonist carbachol, the cholinesterase inhibitor physostigmine and the excitatory amino acid glutamate into the PHN caused increases in firing rate of AHA angiotensin-II-sensitive neurons in anesthetized WKY and SHR. The increase in firing rate of AHA neurons induced by these drugs was enhanced in SHR as compared to WKY. The enhancement of the physostigmine-induced activation of AHA neurons in SHR was similar to that of the carbachol-induced activation of AHA neurons in SHR. The enhancement of the glutamate-induced activation of AHA neurons in SHR was similar to that of the carbachol-induced activation of AHA neurons in SHR. Microinjection of scopolamine, a cholinoceptor antagonist, into the PHN caused a small but significant decrease of firing rate of AHA angiotensin-II-sensitive neurons in SHR but not in WKY. These findings indicate that the PHN cholinergic stimulation-induced activation of AHA angiotensin-II-sensitive neurons is enhanced in SHR and that PHN cholinergic mechanisms are involved in tonic activation of angiotensin-II-sensitive neurons in the AHA of SHR. It appears that the enhancement of the PHN cholinergic stimulation-induced activation of AHA neurons in SHR results mainly from the enhanced neural reactivity to angiotensins in AHA neurons of SHR.
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PMID:Posterior hypothalamus cholinergic stimulation-induced activation of anterior hypothalamic area neurons is enhanced in spontaneously hypertensive rats. 1621 27

Alzheimer's disease (AD) and vascular dementia (VaD) are widely accepted as the most common forms of dementia. Cerebrovascular lesions frequently coexist with AD, creating an overlap in the clinical and pathological features of VaD and AD. This review assembles evidence for a role for cholinergic mechanisms in the pathogenesis of VaD, as has been established for AD. We first consider the anatomy and vascularization of the basal forebrain cholinergic neuronal system, emphasizing its susceptibility to the effects of arterial hypertension, sustained hypoperfusion, and ischemic cerebrovascular disease. The impact of aging and consequences of disruption of the cholinergic system in cognition and in control of cerebral blood flow are further discussed. We also summarize preclinical and clinical evidence supporting cholinergic deficits and the use of cholinesterase inhibitors in patients with VaD. We postulate that vascular pathology likely plays a common role in initiating cholinergic neuronal abnormalities in VaD and AD.
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PMID:Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. 1630 Aug 56

The authors used 2 national Veterans Health Administration databases to identify outpatient medications and all 30 Elixhauser comorbidities for 2579 unique patients, age 65+ years, hospitalized for syncope in fiscal year 2004. For comparison, we identified other elderly patients hospitalized with acute myocardial infarction (N = 4491), fracture (N = 2797), or pneumonia (N = 9473). The categories of medications included drugs that affect the cardiovascular, central nervous, or the muscular skeletal system. The most notable differences between syncope compared to acute myocardial infarction patients occurred in central nervous system drugs in anticonvulsants/barbiturates, antidepressants, antihistamine/antinauseants, antipsychotics, and cholinesterase inhibitors (P < .0018). Comparing syncope patients with fracture patients, the central nervous medication profile was similar, but the cardiovascular medication profile differed (P < .0018); their hypertension comorbidities also differed (60.45% vs 46.34%); (P < .0016). These findings indicate significant potential associations that warrant further study. Studies linking national outpatient medications to hospitalizations for specific conditions can foster the development of more proactive pharmacovigilance systems.
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PMID:National Veterans Health Administration hospitalizations for syncope compared to acute myocardial infarction, fracture, or pneumonia in community-dwelling elders: outpatient medication and comorbidity profiles. 1670 7

Cerebrovascular disease (CVD) is an important cause of psychiatric disability in the elderly. Much of this disability can be attributed to dementia and lesser degrees of cognitive impairment, which result from strokes and other forms of cerebrovascular pathology. While vascular dementia is common, estimates of its frequency vary due to its clinical and pathologic heterogeneity, the challenges involved in its measurement and its frequent co-occurrence with Alzheimer's disease. Nevertheless the clinical features and natural histories of vascular dementia can be described, and risk factors have been identified and include hypertension, diabetes mellitus, hyperlipidaemia, other conditions that promote atherosclerosis, and rare genetic mutations. While vascular dementia is not curable, treatments are available. For example, a few recent clinical trials suggest that cholinesterase inhibitors have some efficacy. Our knowledge of the risk factors has also provided opportunities for the primary and secondary prevention of vascular dementia, and indicates promising avenues for research.
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PMID:Cerebrovascular disease and dementia. 1708 61

Vascular dementia is a term used to describe a constellation of cognitive and functional impairment that can be viewed as a subset of the larger syndrome of vascular cognitive impairment associated with cerebrovascular brain injury. Vascular dementia is a common disorder among the elderly, although it can also occur in younger persons. Comprising 20% of all cases of dementia in the United States, vascular dementia is the second most common form of dementia after Alzheimer's disease. Patients with vascular dementia often exhibit mood and behavioral changes and may have focal neurological signs on neurological examination. Primary treatment is through primary or secondary modification of cerebrovascular risk factors such as hypertension, although symptomatic treatments with cholinesterase inhibitors have shown modest symptomatic benefit.
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PMID:Vascular dementia: emerging trends. 1722 43

Ischemic stroke is a leading cause of mortality and disability particularly in the elderly. Hypertension is the most important risk factor in strokes, representing roughly 70% of all cases. Oxidative stress is believed to be one of the mechanisms taking part in neuronal damage in stroke. It is well documented that cholinergic system plays a key role in normal brain functions and in memory disturbances of several pathological processes, such as in cerebral blood flow regulation. This study investigated the oxidative status and acetylcholinesterase (AChE) activity in whole blood in patients diagnosed with acute and chronic stages of ischemia, as well as with hypertension. Malondialdehyde (MDA) levels and protein carbonylation content showed increased levels both in the acute ischemic groups and in the hypertensive group, when compared to the control. Catalase activity and reduced glutathione (GSH) levels in the acute group were also higher than in the hypertensive, chronic ischemic and control groups (p<0.05). The activity of AChE in acute ischemic patients was significantly higher than that presented by the control, hypertensive and chronic ischemic patients (p<0.05). The hypertensive group presented AChE activity significantly lower than control and chronic groups. In spite of having a defined location the ischemic event results in a systemic disorder that induces changes, which can be detected by measuring the peripheral markers of oxidative stress and AChE activity in erythrocytes.
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PMID:Oxidative stress and erythrocyte acetylcholinesterase (AChE) in hypertensive and ischemic patients of both acute and chronic stages. 1803 75

Plasma levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and lipid peroxides are high whereas those of endothelial nitric oxide are low in insulin resistance, obesity, type 2 diabetes mellitus, hypertension, hyperlipidemias, metabolic syndrome X, and Alzheimer's disease suggesting that these diseases are characterized by low-grade systemic inflammation. Recent studies showed that the plasma and tissue activities of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in patients with Alzheimer's disease, and diabetes mellitus, hypertension, insulin resistance, and hyperlipidemia. As a result of this increase in the activities of enzymes acetylcholinesterase and butyrylcholinesterase, the plasma and tissue levels of acetylcholine (ACh) will be low. The "cholinergic anti-inflammatory pathway" mediated by acetylcholine acts by inhibiting the production of tumor necrosis factor, interleukin-1, macrophage migration inhibitory factor, and high mobility group box-1 and suppresses the activation of nuclear factor-kappa B expression. ACh is a neurotransmitter and regulates the levels and activities of serotonin, dopamine and other neuropeptides and thus, modulates both immune response and neurotransmission. Hence, both acetylcholinesterase and butyrylcholinesterase by inactivating acetylcholine may enhance inflammation. This suggests that increased plasma and tissue activities of acetylcholinesterase and butyrylcholinesterase seen in various clinical conditions could serve as a marker of low-grade systemic inflammation.
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PMID:Acetylcholinesterase and butyrylcholinesterase as possible markers of low-grade systemic inflammation. 1804 45

Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic (alpha 3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacologic enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function. Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurologic disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. The patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents. Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10-15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.
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PMID:Invited Article: Autonomic ganglia: target and novel therapeutic tool. 1847 49

We review the main therapeutic targets in Alzheimer's disease. Current treatments include cholinesterase inhibitors and the glutamate-modulating drug memantin. Other neurotransmitters such as serotonin, histamine and noradrenaline may also be targeted. Although useful, however, these symptomatic treatments do not prevent neuronal degeneration and death. Epidemiological studies suggest that treatments given for other reasons, such as antiinflammatory agents (including NSAIDs), cholesterol-lowering drugs, hormone replacement therapy and antioxidants, may prevent or improve Alzheimer-type dementia, but this is not always borne out in controlled clinical trials. Prevention of hypertension significantly reduces the incidence of vascular dementia and of Alzheimer-type dementia, albeit through an unknown mechanism. Alzheimer's disease is characterized by two main lesions: amyloid plaques and neurofibrillary tangles composed of aggregated A Beta peptides and hyperphosphorylated tau. Active and passive immunization against A beta has given promising results. Other exciting approaches include modulation of A beta processing by inhibiting BACE1 or gamma-secretase or upregulating alpha-secretase; A beta peptide catabolism; inhibition of beta fibrillization; and reducing tau phosphorylation or inhibiting tau aggregation. More remote possibilities include gene therapy and the use of growth factors to increase neurogenesis.
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PMID:[Alzheimer's disease: from brain lesions to new drugs]. 1881 89


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