Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is increasing evidence to suggest that patients with vascular dementia (VaD) exhibit a cholinergic deficit. These patients may therefore benefit from treatment with cholinesterase (ChE) inhibitors such as donepezil. However, there are difficulties in accurately defining patients with VaD. Clinical trials to assess the efficacy and tolerability of donepezil in patients with VaD have been completed. National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria were used to establish inclusion and exclusion criteria: evidence of dementia (impaired memory and two other cognitive domains), and evidence of cerebrovascular disease (CVD) from neuroimaging and physical examination and a possible or probable relationship between dementia and CVD were required for enrollment. Patients with a diagnosis of Alzheimer's disease (AD) or dementia caused by other conditions not associated with the cardiovascular system (e.g., MS, chronic infections, hypothyroidism) were excluded. These criteria ensured that only patients with probable or possible VaD were enrolled. Enrolled patients had a mean Hachinski score of 9.7, with memory impairment the most prominent feature of their dementia. Sixty percent of patients had a history of at least one stroke and 18% of patients had a history of transient ischemic attack (TIA) pre-dementia. Cortical and subcortical infarcts were among the lesions observed on computer-assisted tomography and magnetic resonance imaging scans with significant white matter lesions also present in some patients. Placebo-treated patients demonstrated stable cognitive and global function over the 24 weeks of the study. These observations suggest that the patients enrolled in these trials have a broad range of CVD, and are different from those enrolled in AD trials.
 ...
PMID:Patient populations in clinical trials of the efficacy and tolerability of donepezil in patients with vascular dementia. 1241 58

Vascular dementia (VaD) is the second-most-common cause of dementia in the elderly, after Alzheimer's disease (AD). VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology. Diagnosis requires the following criteria: cognitive loss, often predominantly subcortical; vascular brain lesions demonstrated by imaging; a temporal link between stroke and dementia; and exclusion of other causes of dementia. Poststroke VaD may be caused by large-vessel disease with multiple strokes (multiinfarct dementia) or by a single stroke (strategic stroke VaD). A common form is subcortical ischemic VaD caused by small-vessel occlusions with multiple lacunas and by hypoperfusive lesions resulting from stenosis of medullary arterioles, as in Binswanger's disease. Unlike with AD, in VaD, executive dysfunction is commonly seen, but memory impairment is mild or may not even be present. The cholinesterase inhibitors used for AD are also useful in VaD. Prevention strategies should focus on reduction of stroke and cardiovascular disease, with attention to control of risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, and hyperhomocysteinemia.
 ...
PMID:Vascular dementia: distinguishing characteristics, treatment, and prevention. 1280 86

The diagnosis and treatment of vascular dementia (VaD) are particularly challenging because of its multiple causal lesions and the variety of its clinical presentations. Even poststroke dementia cases may be due to preexisting Alzheimer's disease. Diagnostic criteria for clinical trials have been implemented quite recently. Of the vasodilator agents, only the ergoloid mesylates have shown mild benefit. The calcium channel blocker nimodipine appears to be useful in subcortical VaD. Of the nootropic agents, memantine appears to be promising. Pentoxifylline produced significant improvement in multi-infarct VaD. Aspirin, triflusal and Ginkgo biloba extract were associated with some stabilization of dementia progression, perhaps due to their antiplatelet effects. Acetyl-cholinesterase inhibitors appear to be useful in improving memory and activities of daily living in VaD. Results of a large trial of donepezil in VaD should be available soon. Hyperbaric oxygen has been reported to be effective in Binswanger's disease. From the public health perspective, stroke prevention, particularly in atrial fibrillation, and the early and adequate treatment of arterial hypertension clearly decrease the incidence of VaD.
 ...
PMID:Perspectives in the treatment of vascular dementia. 1284 69

The present study evaluated the effect of galanthamine, a selective competitive cholinesterase inhibitor, on histological and functional outcome after experimental stroke in rats. Cholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people, including those who may sustain ischemic attacks. Young adult (5 months) and aged (24 months) rats were treated with saline or galanthamine at a dose of 2.5 mg/kg (i.p., once a day). Drug treatment started 4 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 21 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze over a 3-week follow-up period. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. Infarct volumes in the cortex were similar in ischemic controls and ischemic rats treated with galanthamine. In the beam-walking test, there was a transient impairment forelimb function and a permanent impairment in hindlimb after cortical infarct both in young adult and aged rats. Galanthamine treatment did not affect the sensorimotor recovery rate. Analysis of water-maze data did not reveal significant differences in length of path, escape latency, or swim speed between sham-operated, ischemic controls and ischemic rats treated with galanthamine. In conclusion, present findings suggest that the aging brain has considerable plastic capacity to maintain functioning after focal cerebral insults restricted to the motor cortex. Galanthamine is not beneficial with respect to the histological or functional outcome in rats subjected to cortical photothrombosis.
 ...
PMID:Effect of cholinergic medication, before and after focal photothrombotic ischemic cortical injury, on histological and functional outcome in aged and young adult rats. 1547 53

Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
 ...
PMID:Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. 1551 30

Coagulation factor XIII is a transglutaminase catalysing the crosslinking of fibrin chains as well as the formation of covalent links between several extracellular matrix proteins such as fibronectin, vitronectin and collagen. By mediating the incorporation of alpha2 antiplasmin into the fibrin network, this factor also interferes with fibrinolysis. Increased plasma factor XIII activity was reported by our laboratory 30 years ago in hypertriglyceridemic subjects who also displayed increased activity of serum cholinesterase, a marker of hepatic protein synthesis, and a delayed diluted, blood clot lysis time. Recent data in the literature emphasize a relationship between insulin resistance (metabolic syndrome) and increased plasma levels of factor XIII, confirming our results. It was also reported that a faster activation of this factor related to the Val 34 leu polymorphism provides protective effect against myocardial infarction and stroke, this effect being however negated in patients with insulin resistance and high plasma levels of plasminogen activator inhibitor-1. The pathogenic role of factor XIII in atherothrombosis seems to be bivalent. On the one side, an increased activity would favor the persistence of fibrin depositions and increase plaque burden, while on the other side it would reduce plaque vulnerability and the risk of downstream embolization.
 ...
PMID:Coagulation factor XIII and atherothrombosis. A mini-review. 1552 18

Significant progress in the field of VaD resulted from publication of the NINIDS-AIREN Diagnostic Criteria for VaD (G.C. Roman, T.K. Tatemichi, T. Erkinjuntti, et al., Vascular dementia (VaD): diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 43 (1993) 250-260). Epidemiological studies confirmed the importance of VaD as the second most common cause of dementia in the elderly, representing 15-20% of all cases of dementia. In Europe and North America, Alzheimer's disease (AD) predominates over VaD in a 2:1 ratio; in contrast, in Japan and China VaD accounts for almost 50% of all dementias. Case-control studies have identified risk factors for VaD including ageing, hypertension, diabetes mellitus, hyperlipidemia, recurrent stroke, cardiac disease, smoking, sleep apnea, and more recently, hyperhomocysteinemia, among others. Hypertension treatment may prevent VaD and AD. This finding has enormous importance from the Public Health viewpoint to decrease the future number of patients with dementia in the elderly. Along with advances in the field of VaD came a number of controversies and damaging misconceptions and myths. Myth no. 1--Vascular dementia is a non-entity: The false idea that VaD does not exist is particularly destructive because it creates the perspective that VaD is unworthy of study or research. A condition that either does not exist or represents only a minute proportion of all cases of dementia in the elderly, lacks public health relevance and becomes a low priority for research by funding agencies and industry. In fact, vascular brain lesions are the commonest and most important component of dementia in the elderly. Myth no. 2--Vascular dementia is so difficult to diagnose that only experts can recognize and identify it accurately: VaD does exist and the diagnosis of post-stroke VaD, in particular is straightforward. Most cases fulfill NINDS-AIREN criteria for probable VaD; i.e., (1) there is acute onset of dementia demonstrated by impairment of memory and two other cognitive domains, such as orientation, praxis or executive dysfunction; (2) relevant cerebrovascular lesions are demonstrated by neuroimaging; and (3) a temporal relation between stroke and cognitive loss is evident. In the donepezil trials on VaD, post-stroke dementia represented about 75% of the >1,200 patients enrolled. Myth no. 3--Improvement in clinical trials of cholinergics in VaD is due to underlying AD, not to the vascular lesions. Experimental, clinical and pathological evidence has demonstrated cholinesterase deficits in VaD (independently of any concomitant AD pathology), including low acetylcholine in cerebrospinal fluid, and reduced choline acetyltransferase (ChAT) in the brain.
 ...
PMID:Facts, myths, and controversies in vascular dementia. 1553 19

As clinicians we talk about "the best interests of our patients". How can a treatment which doubles the rate of cognitive decline, triples the rate of stroke, doubles mortality, substantially increases falls and fractures and reduces quality of life be beneficial, especially, as in real life, once neuroleptics are started they are rarely discontinued with cumulative adverse effects? As there is clearly no rational reason for prescribing, we need to consider other explanations. We would suggest the following: Therapeutic impotence: Doctors, especially specialists feel they need to do something, and prescribing a familiar drug is the easiest option. Ignorance: Doctors are either unaware of the substantial evidence of harm with neuroleptics or are swayed by slick marketing information, portraying atypical neuroleptics in an "over-safe" light that does not reflect the actual data. Placebo effect: If neuroleptics are prescribed, the majority of patients experience an improvement in BPSD symptoms. This reinforces the apparent value of this practice, as we like to take the credit for any improvements that occur. The reality is that the majority of people would have experienced a comparable improvement with monitoring. Bowing to pressure: Sometimes the pressure to respond can be great, and a prescription is an easy way to relieve the pressure. This is understandable, and reflects a similar phenomenon to that of general practioners prescribing antibiotics for sore throats. In neither situation does it represent good practice. Lack of skills to implement non-pharmacological alternatives: The main evidence for alternative treatment options are for therapies that by and large are not a core part of the physician or psychiatrist's skill-base, such as psychological interventions. Doctors therefore feel uncomfortable pursuing these options. Why for example is so little time spent on the nonpharmacological interventions that everyone agrees should be the first line of treatment for BPSD in people with dementia? It is largely assumed that the "enlightened clinician has already appropriately assessed and diagnosed the patient and exhausted all the possible environmental and behavioral interventions before resorting to the prescription pad." Accumulating evidence clearly indicates that the need for psychotropic medication is substantially reduced by proactive services or interventions which can provide training and promote psychological, social and environmental and sensory interventions. The prescription but is an easy but not an acceptable alternative. Over-adherence to prescribing guidance: There are pharmacological alternatives to neuroleptics if a prescription is needed. Although the evidence for the more promising alternatives needs to be developed much further, drugs such as cholinesterase inhibitors may offer a much less harmful alternative. The reluctance of clinicians to use cholinesterase inhibitors in this way is puzzling, and presumably is because of the culture of "guidance-prescribing" that has evolved around these agents. If the treatment of BPSD is to move forward, we need to challenge the way we have always done things, examine the evidence and move forward with new and flexible multi-disciplinary approaches if we are truly to look after the "best interests of our patients".
 ...
PMID:Drugs used to relieve behavioral symptoms in people with dementia or an unacceptable chemical cosh? Argument. 1594 89

Patients with vascular dementia (VaD) and Alzheimer's disease with cerebrovascular disease (AD + CVD) have dementia associated with underlying CVD. Although diagnosis of VaD is challenging, VaD is typically characterized by a stepwise progression of dementia that is closely associated with stroke and focal neurological findings, and a symptom profile that often includes executive dysfunction leading to decreased ability to perform instrumental activities of daily living (IADL). In contrast, AD + CVD patients typically present with progressive deterioration of cognition/memory that may also be influenced by concurrent cerebrovascular events. Early diagnosis and intervention are desirable to prevent further decline due to subsequent vascular events. Management of CVD can limit deterioration of cognitive symptoms in VaD patients, and treatment benefits with cholinesterase inhibitors may be realized as improvement above baseline levels in dementia symptoms. Results from a combined analysis of two 24-week, placebo-controlled clinical trials show that donepezil-treated VaD patients improve in cognition, global function, and performance of IADL. In contrast, AD + CVD patients may continue to decline despite management of CVD, and treatment benefits should be recognized as initial improvements followed by stabilization or slowed decline of dementia symptoms over time. In post-marketing studies, donepezil-treated AD and AD + CVD patients show similar benefits in cognition, global function, and quality of life. The results of these studies support the use of donepezil in treatment of patients with VaD or AD + CVD.
 ...
PMID:Dementia with cerebrovascular disease: the benefits of early treatment. 1614 33

Accompanying the gradual rise in the average age of the population of most industrialized countries is a regrettable progressive rise in the number of individuals afflicted with age-related neurodegenerative disorders, epitomized by Alzheimer's disease (AD) but, additionally, including Parkinson's disease (PD) and stroke. The primary therapeutic strategy, to date, involves the use of cholinesterases inhibitors (ChEIs) to amplify residual cholinergic activity. The enzyme, acetylcholinesterase (AChE), along with other elements of the cholinergic system is depleted in the AD brain. In contrast, however, its sister enzyme, butyrylcholinesterase (BuChE), that likewise cleaves acetylcholine (ACh), is elevated and both AChE and BuChE co-localize in high amounts with the classical pathological hallmarks of AD. The mismatch between increased brain BuChE and depleted levels of both ACh and AChE, particularly late in the disease, has supported the design and development of new ChEIs with a preference for BuChE; exemplified by the novel agent, cymserine, whose binding kinetics are characterized for the first time. Specifically, as assessed by the Ellman method, cymserine demonstrated potent concentration-dependent binding with human BuChE. The IC50 was determined as 63 to 100 nM at the substrate concentration range of 25 to 800 microM BuSCh. In addition, the following new binding constants were investigated for human BuChE inhibition by cymserine: T(FPnubeta), K(nubeta), K(Bs), K(MIBA), M(IC50), D(Sc), R(f), (O)K(m), OIC100, K(sl), theta(max) and R(i). These new kinetic constants may open new avenues for the kinetic study of the inhibition of a broad array of other enzymes by a wide variety of inhibitors. In synopsis, cymserine proved to be a potent inhibitor of human BuChE in comparison to its structural analogue, phenserine.
 ...
PMID:Kinetic analysis of the inhibition of human butyrylcholinesterase with cymserine. 1630 45


<< Previous 1 2 3 4 5 Next >>