piperidines and Cerebrovascular-Disorders

Topics: Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Humans; Nicergoline; Piperidines; Pyridines; Vasodilator Agents

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.

Topics: Cerebrovascular Disorders; Cholinesterase Inhibitors; Clinical Trials as Topic; Dementia, Vascular; Diagnosis, Differential; Disease Progression; Donepezil; Humans; Indans; Nootropic Agents; Parasympathetic Nervous System; Piperidines

Although stroke is a major cause of morbidity and mortality, it is only relatively recently that a concerted effort has been made to develop acute treatments. Thrombolytics, such as recombinant tissue plasminogen activator (rt-PA), may benefit selected patients within 3 h of cerebral infarction. CUrrently, rt-PA is only licensed for use in the United States. Many potential strategies for neuroprotection exist and are currently under investigation. Because the mechanisms of neurotoxicity involve numerous interdependent processes, it may be that the interpretation of a single site in the cascade of events is insufficient to provide effective neuroprotection. Drugs acting at several sites in the neurotoxic cascade may be more effective, and the results of Phase III studies with the novel neoroprotectant lubeluzole are anticipated.

Topics: Cerebrovascular Disorders; Disease Models, Animal; Humans; Neuroprotective Agents; Piperidines; Plasminogen Activators; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Thiazoles; Thrombolytic Therapy; Tissue Plasminogen Activator

Cholinesterase inhibitors (ChE-Is) are among the drugs more largely used for the treatment of mild-to-moderate symptoms of Alzheimer's disease (AD), but beneficial long-term effects of these compounds on the cognitive, functional, and behavioural symptoms of the disease are small and not always apparent in practice. Preclinical investigations have suggested that association between ChE-Is and the cholinergic precursor choline alphoscerate enhances cholinergic neurotransmission more effectively than single compounds alone. The ongoing clinical trial on the "Effect of association between a ChE-I and choline alphoscerate on cognitive deficits in Alzheimer's disease associated with cerebrovascular injury" (ASCOMALVA) was designed to assess if association of the ChE-I donepezil with choline alphoscerate has a more favourable clinical profile than monotherapy with donepezil alone.. ASCOMALVA is a double-blind multicentre trial that has completed the first 12 months of observation of 91 patients of the 210 planned. Patients were aged between 56 and 91 years (mean 75 ± 10 years) and were included in the protocol with a MMSE score between 15 and 24. Patients with AD diagnosed according to the DSM IV criteria suffer from ischemic brain damage documented by neuroimaging (MRI and CT scan), with a score≥2 in at least one subfield of the New Rating Scale for Age-Related White Matter Changes (ARWMC). Patients were randomly allotted to an active treatment group (donepezil+choline alphoscerate) or to a reference treatment group (donepezil+placebo) and were examined after 3, 6, 9 and 12 months of treatment.. Cognitive functions, patient's daily activities and behavioural symptoms were assessed by the Mini-Mental State Evaluation (MMSE), Alzheimer's Disease Assessment Scale Cognitive subscale (ADAS-cog), Basic Activities of Daily Living (BADL), Instrumental Activities of Daily Living (IADL) and Neuropsychiatric Inventory (NPI), of severity and of caregiver distress measures (NPI-F and NPI-D). Patients of the reference group (donepezil+placebo) showed along the course of the 12months of observation, a slight time-dependent worsening of MMSE, ADAS-cog, IADL and NPI-D scores and no changes in the BADL and NPI-F scores. Donepezil plus choline alphoscerate improved compared to donepezil alone the different items analysed except the BADL.. The first results of the ASCOMALVA trial suggest that association of choline alphoscerate to the standard treatment with a ChE-I may represent an option to prolong beneficial effects of cholinergic therapies in AD with concomitant ischemic cerebrovascular injury.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Disorders; Donepezil; Double-Blind Method; Female; Follow-Up Studies; Glycerylphosphorylcholine; Humans; Indans; Male; Mental Status Schedule; Middle Aged; Nootropic Agents; Piperidines; Treatment Outcome

Donepezil has not been evaluated in Korean patients with Alzheimer's disease (AD) for up to 1 year. The objectives of this study were to evaluate the differential efficacy of donepezil in Korean AD patients with and without concomitant cerebrovascular lesions (CVL).. This study was a 48-week open-label trial of donepezil in patients with probable AD of mild to moderate severity. CVL were evaluated through magnetic resonance imaging (MRI) findings within 3 months. Efficacy analyses were performed for cognitive, behavioral and functional outcome measures.. Concomitant CVL were documented in 35 (30.7%) of the patients on MRI. Seventy-nine (69.3%) of the patients were considered not to have concomitant CVL. The mean Mini-Mental State Examination scores of both patients with and without CVL showed improvement at each evaluation. However, there was no statistical difference in improvement between the groups.. The presence of CVL should not deter clinicians from treating AD with donepezil.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebrovascular Disorders; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Indans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Retrospective Studies; Time Factors; Treatment Outcome

This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.. Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.. Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Aspirin; Benzodiazepines; Cerebrovascular Disorders; Coronary Disease; Creatinine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Proportional Hazards Models; Risk Assessment; Treatment Outcome

Donepezil, a selective acetylcholinesterase inhibitor, is approved for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). In a post-marketing surveillance (PMS) study in Germany, patients under routine treatment conditions were observed while treatment was switched from other antidementia drugs (i.e., nootropics) to donepezil. A total of 913 patients were enrolled (60.1% female, mean+/-S.D. age 73.4+/-8.6 years, mean Mini-Mental Status Examination [MMSE] 18.0+/-5.3), and were treated with donepezil (5 or 10 mg/day according to recommended dosing). 709/913 (77.1%) of patients had been pretreated with other antidementive drugs (piracetam, memantine, ginkgo, and others). In 29.6% of patients, investigators documented concomitant cerebrovascular disease (CVD+) according to their clinical judgment. Observation period was 3 months for the individual patient. Efficacy parameters were changes in MMSE, global clinical (investigators) judgment of efficacy, and a clinical judgment about the patients' quality of life (QoL). Adverse events were also analyzed. The objective of the present investigation was to compare-in a "real-life" setting-the differential efficacy and tolerability of donepezil in AD patients with and without concomitant cerebrovascular disease. After 3 months, patients had improved by a mean MMSE change from baseline of 2.2 points (CVD+: 2.4 pts, CVD-: 2.1 pts). QoL was judged "improved" in 70.0% of patients (CVD+: 72.5%, CVD-: 69.6%). Adverse events were reported in 85/913 (9.3%) of patients (CVD+: 11.2%, CVD-: 7.9%). Reported adverse events were substantially less than reported previously in controlled clinical trials. This suggests that donepezil therapy is effective and well tolerated in AD patients, both with and without concomitant cerebrovascular disease.

Topics: Adult; Aged; Aged, 80 and over; Alzheimer Disease; Cerebrovascular Disorders; Donepezil; Female; Germany; Humans; Indans; Male; Middle Aged; Neuropsychological Tests; Nootropic Agents; Piperidines; Quality of Life

Pharmacokinetics of NS-105, a novel agent for cerebrovascular disease, in elderly subjects were compared with those in younger subjects. Fourteen healthy male volunteers (7 elderly subjects aged 68-79 years and 7 young subjects aged 20-32 years) were included in the study. In a parallel group design, a tablet containing 100 mg NS-105 was administered orally after breakfast. One young subject was excluded from the pharmacokinetic analyses owing to an insufficient urine collection. The maximum plasma concentration (Cmax) was higher in the elderly (3.06 +/- 0.69 vs. 2.13 +/- 0.34 micrograms/ml, the elderly vs. the young, mean +/- SD, p = 0.0117) and area under the plasma concentration curve (AUC) was also higher in the elderly (24.6 +/- 4.4 vs. 14.4 +/- 3.1 micrograms.hr/ml, p = 0.0006). There is a tendency that time to reach Cmax was longer in the elderly (2.1 +/- 1.1 vs. 1.3 +/- 0.5 hr, p = 0.1199), and a tendency of prolongation of elimination half-life. Urinary recovery of NS-105 was less in the elderly up to 8 h after administration, while total recovery of the dose was not different in the two groups. Total clearance was reduced in the elderly (0.076 +/- 0.013 vs. 0.121 +/- 0.025l/kg/hr, p = 0.0013) and the decrease seemed to be mainly due to a decrement in renal clearance of the drug in the elderly. A significant correlation was found between renal clearance of NS-105 and creatinine clearance of each subject (r = 0.583, p = 0.0364). These observations indicate that the plasma concentration of NS-105 will increase in elderly subjects mainly due to a decrement in renal clearance of the drug. Careful observation is needed when prescribing the drug to an elderly patient.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Area Under Curve; Cerebrovascular Disorders; Chromatography, High Pressure Liquid; Humans; Kidney; Least-Squares Analysis; Linear Models; Male; Metabolic Clearance Rate; Nootropic Agents; Piperidines; Proline

Lubeluzole is a novel benzothiazole compound that has shown neuroprotective activity in preclinical models of ischemic stroke. The present multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of lubeluzole in the treatment of ischemic stroke.. Seven hundred twenty-one patients with clinical symptoms of acute ischemic stroke were randomized to receive either lubeluzole (7.5 mg over 1 hour, followed by a continuous daily infusion of 10 mg for up to 5 days) or placebo. Treatment was initiated within 6 hours of symptom onset. Mortality at 12 weeks was the primary efficacy end point. Secondary efficacy end points included neurological recovery (based on the National Institutes of Health Stroke Scale [NIHSS]), functional status (based on the Barthel Index), and level of disability (based on the Rankin Scale). Safety assessments included standard and continuous electrocardiographic monitoring, physical examination, measurements of vital signs, clinical laboratory evaluation, and adverse events reports.. The overall mortality rate at 12 weeks for lubeluzole-treated patients was 20.7% compared to 25.2% for placebo-treated patients (NS). Controlling for relevant covariates, the degree of neurological recovery (NIHSS) at week 12 significantly favored lubeluzole over placebo (P = .033). Lubeluzole treatment similarly resulted in significantly greater improvements in functional status (Barthel Index) (P = .038) and overall disability (Rankin Scale) (P = .034) after 12 weeks. A global test statistic confirmed that lubeluzole-treated patients had a more favorable clinical outcome at 12 weeks (P = .041). The safety profile of lubeluzole resembled that of placebo.. Treatment with lubeluzole within 6 hours of the onset of ischemic stroke had a nonsignificant effect on mortality and resulted in improved clinical outcome compared with placebo, with no safety concerns.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cerebrovascular Disorders; Double-Blind Method; Female; Heart Diseases; Humans; Male; Middle Aged; Mortality; Neuroprotective Agents; Piperidines; Survival Analysis; Thiazoles; Treatment Outcome

We aimed to assess the safety and efficacy of lubeluzole in patients with a clinical diagnosis of acute (< 6 hours) ischemic stroke in the carotid artery territory.. A randomized, double-blind, placebo-controlled multicenter trial was conducted in 232 patients. Because treatment was administered within 6 hours and a CT scan was not mandatory before the start of treatment, 39 patients with either an intracerebral hemorrhage or ischemic stroke in the vertebrobasilar circulation were excluded from the primary efficacy analysis as prespecified in the protocol. Of the 193 patients with acute ischemic stroke in the carotid artery territory (target population), 61 received placebo, 66 lubeluzole 7.5 mg over 1 hour followed by 10 mg/d for 5 days, and 66 lubeluzole 15 mg over 1 hour followed by 20 mg/d for 5 days.. The trial, initially aimed at a patient inclusion of 270, was terminated prematurely according to the advice of the Safety Committee because of an imbalance in mortality between the treatment groups. Mortality rates at the final follow-up of 28 days for placebo, lubeluzole 10 mg/d, and lubeluzole 20 mg/d were, respectively, 18%, 6%, and 35% in the target population, results that were confirmed in the intent-to-treat population. Multivariate logistic regression analysis showed that the lower mortality in the lubeluzole 10 mg/d group was significantly in favor of the 10 mg/d treatment (P = .019). The higher mortality rate in the 20 mg/d group could be explained, at least in part, by an imbalance at randomization that led to a higher number of patients in that group with severe ischemic stroke. A total of 26 of 66 patients (39%) who received lubeluzole 10 mg/d had a score on the Barthel Index of > 70 at day 28, indicating no or mild disability, compared with 21 of 61 (34%) in the placebo group and 19 of 66 (29%) in the lubeluzole 20 mg/d group (P = NS).. In patients with acute ischemic stroke, the dosage regimen of 7.5 mg over 1 hour followed by 10 mg/d of intravenous lubeluzole is safe and statistically significantly reduced mortality. Further clinical trials in a larger number of patients are ongoing to confirm efficacy.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Cardiovascular Agents; Carotid Artery Diseases; Cerebrovascular Disorders; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Intravenous; Logistic Models; Male; Middle Aged; Multivariate Analysis; Piperidines; Placebos; Safety; Thiazoles

Topics: Aged; Carotid Artery Diseases; Cerebrovascular Disorders; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Piperidines; Quinolines; Vasodilator Agents; Vinyl Compounds

Carotid endarterectomy is the most effective treatment for reducing the risk of stroke in patients with significant carotid stenosis. Few studies have focused on the failure rate of regional anesthesia.. Data of all patients undergoing carotid endarterectomy (June 2009 to December 2014) in a single center were collected. Combined deep and superficial cervical plexus block or superficial plexus block alone was used according to the attending anesthesiologist's choice and the patient's characteristics (eg, dual antiplatelet or anticoagulation therapy). Intraoperative remifentanil (0.025-0.05 μg/kg/min) was administered to maintain an adequate level of comfort, responsiveness, and cooperation. General anesthesia was planned only in the case of major contraindications or the patient's refusal of locoregional anesthesia. The primary end point of our study was the incidence of intraoperative conversion from locoregional to general anesthesia.. A total of 2463 carotid endarterectomies were included in the analysis. Regional anesthesia was initially chosen in 2439 patients, whereas 24 patients received planned general anesthesia. In seven cases, regional anesthesia was converted to general anesthesia because of severe agitation of the patient (before clamping in four cases, after carotid clamping in two cases, and after declamping in one case). A shunt was used in 302 patients (12.3%) because of neurologic deterioration at the carotid clamping test. Intraoperative complications were emergent repeated surgical procedures in 13 cases (0.53%) because of acute neurologic deterioration, 1 intraoperative acute myocardial infarction (0.04%), and 3 cases (0.04%) of hemodynamically relevant supraventricular tachyarrhythmia. No intraoperative death occurred. In-hospital mortality was 0.12% (three patients). Major stroke occurred in 23 patients (0.93%); minor stroke occurred in 16 patients (0.65%). The combined stroke and death rate was 1.62% (40 patients).. In our practice, carotid endarterectomy under regional anesthesia is safe and associated with a very low rate of conversion to general anesthesia.

Topics: Analgesics, Opioid; Anesthesia, General; Carotid Stenosis; Cerebrovascular Disorders; Cervical Plexus Block; Endarterectomy, Carotid; Hospital Mortality; Humans; Hypnotics and Sedatives; Italy; Myocardial Infarction; Piperidines; Remifentanil; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Tachycardia, Supraventricular; Time Factors; Treatment Outcome

We previously demonstrated a positive correlation with nursing home (NH) replacement and donepezil (DNP) administration on lifetime expectancy after the onset of Alzheimer's disease (AD). However, the correlation with quality-adjusted life-year (QALY) remains to be elucidated, along with the additional impact of concomitant cerebrovascular disease (CVD). Based upon our recently reported health state utility values, we retrospectively analyzed the correlation with NH replacement and/or DNP administration on QALY and life expectancy in 'pure' AD (without CVD) and AD with CVD patients.. All outpatients at the Tajiri Clinic from 1999-2012 with available medical records and death certificates were included. The entry criteria were a dementia diagnosis (DSM-IV) and diagnoses of pure AD or AD with CVD (NINCDS-ADRDA), medical treatment for more than 3 months, and follow up to less than 1 year before death. The main outcomes were lifetime expectancy (months between the onset of dementia and death) and QALY.. We identified 390 subjects, of whom 275 had the diagnosis of dementia that met the entry criteria, including 67 pure AD, 33 AD with CVD, and 110 VaD patients. For the AD patients, 52 had taken DNP and 48 had not received the drug due to treatment prior to the introduction of DNP in 1999 in Japan. For the pure AD group, there were positive correlation between NH and DNP and QALY, as well as lifetime expectancy. As for the AD with CVD group, only a correlation between DNP and lifetime expectancy was noted, with no correlation with QALY.. We found positive correlations between DNP administration and NH replacement and lifetime expectancy and QALY after the onset of AD. However, concomitant CVD negated such a positive correlation with QALY. The findings suggest that QALY in AD is affected by CVD; thus, indicating the importance of CVD prevention.

Topics: Alzheimer Disease; Cerebrovascular Disorders; Cholinesterase Inhibitors; Comorbidity; Donepezil; Humans; Indans; Japan; Life Expectancy; Nursing Homes; Piperidines; Quality-Adjusted Life Years; Retrospective Studies

The use of locoregional anesthesia versus general anesthesia (GE) in carotid endarterectomy (CEA) has been a debatable issue in clinical studies for the past several years. In our study, GE with wake-up tests (WUTs) during carotid cross-clamping was used instead of stump pressure (SP) to directly assess the neurological status of the patient to determine whether shunting was needed. Our study assessed the percentage of patients under light sedation and mechanically ventilated needing shunting based on WUT compared to a systolic stump pressure (SPs) cutoff value of

Topics: Aged; Aged, 80 and over; Anesthesia, General; Anesthetics, Intravenous; Blood Pressure; Blood Pressure Determination; Carotid Stenosis; Cerebrovascular Circulation; Cerebrovascular Disorders; Endarterectomy, Carotid; Female; Humans; Logistic Models; Male; Middle Aged; Monitoring, Intraoperative; Neurologic Examination; Piperidines; Predictive Value of Tests; Propofol; Remifentanil; Reproducibility of Results; Respiration, Artificial; Retrospective Studies; Risk Assessment; Wakefulness

Topics: Aged; Aged, 80 and over; Antipsychotic Agents; Cerebrovascular Disorders; Cholinesterase Inhibitors; Dementia, Vascular; Donepezil; Female; Galantamine; Humans; Indans; Male; Piperidines; Risperidone

Cerebrovascular disease (CVD) and ischemic brain injury secondary to cardiovascular disease are common causes of dementia and cognitive decline in the elderly. CVD also contributes to cognitive loss in Alzheimer disease (AD).. Progress in understanding vascular cognitive impairment (VCI) and vascular dementia (VaD) has resulted in promising symptomatic and preventive treatments. Cholinergic deficits in VaD due to ischemia of basal forebrain nuclei and cholinergic pathways can be treated with cholinesterase inhibitors used in AD. Controlled clinical trials with donepezil and galantamine in patients with VaD, as well as in patients with AD plus CVD, have demonstrated improvement in cognition, behavior, and activities of daily living. The N-methyl-D-aspartate receptor antagonist memantine stabilized progression of VaD compared with placebo. Primary and secondary stroke prevention, in particular with control of hypertension and hyperlipidemia, can decrease VaD incidence.. From a public health viewpoint, recognition of VCI before the development of dementia and correction of vascular burden on the brain may lead to a global decrease of incident dementia.

Topics: Carbamates; Cardiovascular Diseases; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Controlled Clinical Trials as Topic; Dementia, Vascular; Donepezil; Galantamine; Humans; Indans; Phenylcarbamates; Piperidines; Risk Factors; Rivastigmine; Stroke; Terminology as Topic

Topics: Alzheimer Disease; Cerebrovascular Disorders; Cholinesterase Inhibitors; Cognition Disorders; Dementia, Vascular; Diagnosis, Differential; Donepezil; Galantamine; Humans; Indans; Neuropsychological Tests; Nootropic Agents; Piperidines; Severity of Illness Index; Terminology as Topic; Treatment Outcome

Topics: Adult; Breast Neoplasms; Cerebrovascular Disorders; Drug Costs; Endometrial Neoplasms; Estrogen Antagonists; Estrogens; Female; Fractures, Bone; Humans; Middle Aged; Myocardial Infarction; Osteoporosis, Postmenopausal; Piperidines; Placebos; Pulmonary Embolism; Raloxifene Hydrochloride; Randomized Controlled Trials as Topic; Tamoxifen; Thrombophlebitis

Topics: Acute Disease; Brain Ischemia; Cardiovascular Agents; Cerebrovascular Disorders; Humans; Piperidines; Thiazoles

Topics: Cerebrovascular Disorders; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Neuroprotective Agents; Piperidines; Randomized Controlled Trials as Topic; Research Design; Thiazoles; Thrombolytic Therapy; Time Factors; Treatment Outcome

In the present study, we have assessed the efficacy of eliprodil, a neuroprotective agent which blocks both the modulatory polyamine site of the NMDA receptor and neuronal voltage-sensitive calcium channels, alone or in combination with the thrombolytic agent, rt-PA, in a rat embolic stroke model using a neurological score and the volume of the infarct as endpoints. Embolization was induced by intracarotid injection of an arterial blood clot. Eliprodil, administered at the dose of 1 mg/kg, iv. 10 min and 2 h 30 after embolization, reduced the neurological deficit by 54% (P < 0.01) and the total volume of the brain lesion by 49%. Thrombolysis with rt-PA (2.5 mg/kg, as a 30 min iv infusion beginning 1 h after embolization) decreased the neurological deficit by 48% (P < 0.05) and the size of the total infarct by 55% (P < 0.05). Combined therapy greatly improved the degree of neuroprotection as assessed by neurological and histological outcomes (70% (P < 0.001) and 89% (P < 0.01) neuroprotection, respectively). These results demonstrate that the administration of a neuroprotective drug (eliprodil) or a thrombolytic agent (rt-PA) similarly reduce the volume of brain damage and the neurological deficit in a rat embolic stroke model. Combined cytoprotective therapy and thrombolysis markedly improved the degree of neuroprotection and may, thus, represent a valuable approach for the treatment of stroke in humans.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Cerebrovascular Disorders; Disease Models, Animal; Fibrinolytic Agents; Hemostasis; Male; Neurologic Examination; Neuroprotective Agents; Partial Thromboplastin Time; Piperidines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tissue Plasminogen Activator

In search of a better treatment for acute ischemic stroke, we evaluated the use of lubeluzole and hemodilution with diaspirin cross-linked hemoglobin (DCLHb) therapy to test whether treatment with two complementary acting compounds provides more potent protection than either treatment alone.. We used unilateral reversible middle cerebral artery (MCA) and common carotid artery (CCA) occlusion of various durations in Long-Evans rats to produce ischemic cortical lesions. We calculated the average maximal lesion volume (Volmax) and the time required to produce half maximal lesion size (T50) in control animals (n = 31) and evaluated the effects on cerebral perfusion and infarct size of treatment with lubeluzole (n = 23), hemodilution (to 30% hematocrit) with albumin (n = 17) or DCLHb (n = 23), and combined lubeluzole + DCLHb therapy initiated 15 minutes after MCA/CCA occlusion.. The Volmax produced by MCA/CCA occlusion in control animals was 138.5 +/- 7.7 mm3, and T50 was 98.5 +/- 10.2 minutes. Lubeluzole alone reduced Volmax by 53% with no significant effect on T50. In contrast to lubeluzole, DCLHb hemodilution prolonged T50 by 68% with no significant effect on Volmax. Prolongation of T50 by DCLHb was not due to hemodilution itself, since a similar degree of hemodilution with albumin had no effect. Finally, combined lubeluzole+DCLHb rescued 72% of the tissue and augmented the effect of lubeluzole alone by 40% (Volmax, 66.3 +/- 13.0 versus 39.4 +/- 12.2 mm3) while prolonging T50 by 31%.. Combination therapy for acute stroke using compounds with complementary action can result in more complete attenuation of neuronal damage and demonstrates the possible clinical utility of combined neuroprotective and reperfusion therapies.

Topics: Animals; Aspirin; Cardiovascular Agents; Cerebral Infarction; Cerebrovascular Disorders; Drug Therapy, Combination; Hemodilution; Hemoglobins; Male; Neuroprotective Agents; Piperidines; Rats; Rats, Inbred Strains; Reperfusion; Thiazoles

A method for measuring the organic infarct focus induced by arachidonate infusion into rat brain was devised, and the statistical relationship between the measured values and stroke signs in the rat was studied. By the infusion of arachidonate, a high incidence of cerebral infarction was found in the live rats with uniformly necrotized foci. The size of these foci (infarction rate) were measured by transcripting them to a graduated brain sheet. The relationship between the independent parameter of the infarction rate and the dependent parameter of stroke signs was fully analyzed by multidimensional quantification. Many animals showed no stroke signs despite having lesions (false negative). By contract, no animal without any lesion showed stroke signs (false positive). When each parameter of these signs were quantified and normalized, the stumbling and abnormal posture signs showed a wide range of values, relatively accurately reflecting the infarction degree. Moreover, the highest partial correlation ratio between the various parameters was found to be that between the stumbling and abnormal posture stroke signs. Thus, it may be said that the stumbling and the abnormal posture stroke signs can be considered relatively good parameters for evaluating the degree of an infarction. These parameters should be useful for the testing of anti-infarction drugs.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Brain; Cerebral Infarction; Cerebrovascular Disorders; Drug Evaluation; gamma-Aminobutyric Acid; Male; Pantothenic Acid; Piperidines; Rats; Rats, Inbred Strains

Recently, it has been proposed that the combined administration of ifenprodil tartrate and calcium hopantenate might produce a beneficial synergistic effect in the treatment of cerebrovascular diseases. To further examine this clinical phenomena, the blood flow in the internal carotid arteries of the rat and the isometric tension of canine internal carotid arteries were measured with a transit-time ultrasonic volume flowmeter and a force transducer, respectively. Ifenprodil tartrate produced a sustained increase in the internal carotid arterial blood flow of rats, while calcium hopantenate had no effect. However, the increase in the internal carotid arterial blood flow induced by ifenprodil tartrate was significantly enhanced by calcium hopantenate. Ifenprodil tartrate caused a dose-related relaxation of K+-induced contractions in the isolated canine internal carotid arteries, while calcium hopantenate had no effect. The dose-response curve of ifenprodil tartrate was shifted to the left by pre-incubation in calcium hopantenate. Ifenprodil tartrate inhibited the K+-induced Ca2+ uptake in the canine internal carotid arteries, and the inhibition induced by ifenprodil tartrate was significantly enhanced by calcium hopantenate. These results suggest that the observed enhancement by calcium hopantenate of the ifenprodil tartrate effect on the internal carotid arterial blood flow was due to increased vascular myorelaxation resulting from the influence of calcium hopantenate on the Ca2+ movement.

Topics: Animals; Blood Flow Velocity; Calcium; Carotid Artery, Internal; Cerebrovascular Disorders; Dogs; Drug Synergism; Drug Therapy, Combination; gamma-Aminobutyric Acid; In Vitro Techniques; Muscle Relaxation; Muscle, Smooth, Vascular; Pantothenic Acid; Piperidines; Rats; Rats, Inbred Strains; Vascular Resistance

Topics: Acetylcholine; Animals; Cats; Cerebral Arteries; Cerebrovascular Disorders; Female; Humans; Male; Norepinephrine; Papaverine; Phentolamine; Pia Mater; Piperidines; Potassium; Serotonin; Vasodilator Agents; Vincamine; Xanthines

Topics: Adrenergic alpha-Antagonists; Amino Alcohols; Cerebrovascular Disorders; Humans; Piperidines; Vasodilator Agents

Topics: Adolescent; Adult; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Brain Diseases; Cerebrovascular Disorders; Child; Epilepsy; Humans; Hypertension; Hypnotics and Sedatives; Intracranial Arteriosclerosis; Middle Aged; Phenothiazines; Piperidines; Schizophrenia; Seizures

Topics: Aged; Blood Circulation Time; Cerebrovascular Circulation; Cerebrovascular Disorders; Computers; Female; Humans; Intracranial Arteriosclerosis; Male; Middle Aged; Oxygen Consumption; Piperidines; Quinolines; Scintillation Counting; Technetium; Technology, Radiologic; Vasodilator Agents; Vinyl Compounds