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1.
Neurology ; 77(12): 1182-90, 2011 Sep 20.
Article in English | MEDLINE | ID: mdl-21900638

ABSTRACT

OBJECTIVE: Data on long-term use of secondary prevention medications following stroke are limited. The Adherence eValuation After Ischemic stroke-Longitudinal (AVAIL) Registry assessed patient, provider, and system-level factors influencing continuation of prevention medications for 1 year following stroke hospitalization discharge. METHODS: Patients with ischemic stroke or TIA discharged from 106 hospitals participating in the American Heart Association Get With The Guidelines-Stroke program were surveyed to determine their use of warfarin, antiplatelet, antihypertensive, lipid-lowering, and diabetes medications from discharge to 12 months. Reasons for stopping medications were ascertained. Persistence was defined as continuation of all secondary preventive medications prescribed at hospital discharge, and adherence as continuation of prescribed medications except those stopped according to health care provider instructions. RESULTS: Of the 2,880 patients enrolled in AVAIL, 88.4% (2,457 patients) completed 1-year interviews. Of these, 65.9% were regimen persistent and 86.6% were regimen adherent. Independent predictors of 1-year medication persistence included fewer medications prescribed at discharge, having an adequate income, having an appointment with a primary care provider, and greater understanding of why medications were prescribed and their side effects. Independent predictors of adherence were similar to those for persistence. CONCLUSIONS: Although up to one-third of stroke patients discontinued one or more secondary prevention medications within 1 year of hospital discharge, self-discontinuation of these medications is uncommon. Several potentially modifiable patient, provider, and system-level factors associated with persistence and adherence may be targets for future interventions.


Subject(s)
Medication Adherence , Secondary Prevention/trends , Stroke/epidemiology , Stroke/prevention & control , Aged , Cohort Studies , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Registries , Stroke/drug therapy
2.
Neurology ; 67(1): 20-7, 2006 Jul 11.
Article in English | MEDLINE | ID: mdl-16832072

ABSTRACT

BACKGROUND: Riluzole is currently the only Food and Drug Administration-approved treatment for ALS, but its effect on survival is modest. OBJECTIVE: To identify potential neuroprotective agents for testing in phase III clinical trials and to outline which data need to be collected for each drug. METHODS: The authors identified 113 compounds by inviting input from academic clinicians and researchers and via literature review to identify agents that have been tested in ALS animal models and in patients with ALS. The list was initially narrowed to 24 agents based on an evaluation of scientific rationale, toxicity, and efficacy in previous animal and human studies. These 24 drugs underwent more detailed pharmacologic evaluation. RESULTS: Twenty drugs were selected as suitable for further development as treatments for patients with ALS. Talampanel and tamoxifen have completed early phase II trials and have demonstrated preliminary efficacy. Other agents (ceftriaxone, minocycline, ONO-2506, and IGF-1 polypeptide) are already in phase III trials involving large numbers of patients with ALS. Remaining agents (AEOL 10150, arimoclomol, celastrol, coenzyme Q10, copaxone, IGF-1-viral delivery, memantine, NAALADase inhibitors, nimesulide, scriptaid, sodium phenylbutyrate, thalidomide, trehalose) require additional preclinical animal data, human toxicity and pharmacokinetic data including CNS penetration prior to proceeding to large scale phase III human testing. Further development of riluzole analogues should be considered. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in ALS.


Subject(s)
Amyotrophic Lateral Sclerosis/drug therapy , Clinical Trials as Topic/methods , Neuroprotective Agents/therapeutic use , Outcome Assessment, Health Care , Evaluation Studies as Topic , Humans
3.
Neurology ; 60(8): 1234-40, 2003 Apr 22.
Article in English | MEDLINE | ID: mdl-12707423

ABSTRACT

BACKGROUND: Current therapies for PD ameliorate symptoms in the early phases of disease but become less effective over time, as the underlying disease progresses. Therapies that slow the progression of PD are needed. However, there have been relatively few clinical trials aimed at demonstrating neuroprotection. The authors sought to identify potential neuroprotective agents for testing in clinical trials. METHODS: First a broad array of compounds were identified by working with clinicians and researchers in academics and industry. Specific criteria were drafted for drug evaluation, including scientific rationale, blood-brain barrier penetration, safety and tolerability, and evidence of efficacy in animal models or humans. Agents were prioritized based on these criteria. RESULTS: The authors identified 59 potential neuroprotective compounds, proposed by 42 clinicians and scientists from 13 countries. After systematic reviews using the specified criteria they found 12 compounds to be attractive candidates for further clinical trials in PD. CONCLUSIONS: Several potential neuroprotective compounds, representing a wide range of mechanisms, are available and merit further investigation in PD.


Subject(s)
Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Clinical Trials as Topic/standards , Drug Evaluation, Preclinical , Humans , Neuroprotective Agents/classification , Neuroprotective Agents/pharmacokinetics
4.
Pharmacoeconomics ; 19(9): 927-36, 2001.
Article in English | MEDLINE | ID: mdl-11700779

ABSTRACT

BACKGROUND: There are over 40000 ischaemic strokes annually in Canada, which result in significant morbidity, mortality and burden to the healthcare system. A recent, large clinical trial has evaluated tissue plasminogen activator (t-PA) intravenously for the treatment of acute ischaemic stroke with promising outcomes but with an increased risk of symptomatic intracranial haemorrhage. OBJECTIVE: To compare clinical and economic outcomes of intravenous t-PA therapy (0.9 mg/kg, to a maximum of 90 mg, initiated within 3 hours of stroke onset) versus no t-PA for acute ischaemic stroke based on the outcomes achieved in the National Institute of Neurological Disorders and Stroke (NINDS) trial. DESIGN: A Markov model depicting the natural lifetime course after an initial acute ischaemic stroke. On the basis of this model, a simulated trial compared no t-PA with t-PA. PATIENTS: A hypothetical cohort of 1000 patients with acute ischaemic stroke. STUDY PERSPECTIVE: Canadian healthcare system. OUTCOME MEASURES: Total acute stroke and post-stroke treatment costs and cumulative quality-adjusted life-years (QALYs). RESULTS: For a hypothetical cohort of 1000 patients, the estimated lifetime stroke costs were 103100000 Canadian dollars (SCan) [1999 values) in the t-PA arm ($Can103100 per patient) compared with SCan106900000 in the no t-PA arm ($Can106900 per patient), yielding a lifetime cost difference of $Can3800000 in favour of t-PA versus no t-PA (SCan3800 per patient). In the hypothetical cohort, t-PA treatment resulted in 13 130 QALYs versus 9670 QALYs with no t-PA treatment. This translated into a net benefit of 3460 additional QALYs per 1000 patients (3.46 QALYs per patient). No treatment, outcome or economic variables influenced the model outcome. CONCLUSION: From the standpoint of cost effectiveness, treatment of acute ischaemic stroke with intravenous t-PA is an economically attractive strategy.


Subject(s)
Cost-Benefit Analysis , Fibrinolytic Agents/therapeutic use , Myocardial Ischemia/drug therapy , Myocardial Ischemia/economics , Quality-Adjusted Life Years , Tissue Plasminogen Activator/therapeutic use , Canada/epidemiology , Decision Support Techniques , Fibrinolytic Agents/economics , Hospitalization/economics , Humans , Markov Chains , Myocardial Ischemia/epidemiology , Tissue Plasminogen Activator/economics
5.
Ann Neurol ; 49(6): 736-44, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11409425

ABSTRACT

We used stored plasma samples from 409 patients in the National Institute of Neurological Diseases and Stroke (NINDS) tissue plasminogen activator (t-PA) Stroke Trial to examine the relationship between an apolipoprotein (Apo) E2 or an Apo E4 phenotype and a favorable outcome 3 months after stroke, the risk of intracerebral hemorrhage, and the response to intravenous t-PA therapy. For the 27 patients with an Apo E2 phenotype who were treated with t-PA, the odds ratio (OR) of a favorable outcome at 3 months was 6.4 [95% confidence interval (CI) 2.7-15.3%] compared to the 161 patients without an Apo E2 phenotype who were treated with placebo. The 190 patients treated with t-PA who did not have an Apo E2 phenotype also had a greater, though less pronounced, likelihood of a favorable outcome (OR 2.0, 95% CI 1.2-3.2%) than patients without an Apo E2 phenotype treated with placebo. For the 31 patients with an Apo E2 phenotype treated with placebo, the OR of a favorable 3 month outcome was 0.8 (95% CI 0.4-1.7%) compared to the 161 patients without an Apo E2 phenotype treated with placebo. This interaction between treatment and Apo E2 status persisted after adjustment for baseline variables previously associated with 3 month outcome, for differences in the baseline variables in the two treatment groups and in the Apo E2-positive and -negative groups, and for a previously reported time-to-treatment x treatment interaction (p = 0.03). Apo E4 phenotype, present in 111 (27%) of the 409 patients, was not related to a favorable 3 month outcome, response to t-PA, 3 month mortality, or risk of intracerebral hemorrhage. We conclude that the efficacy of intravenous t-PA in patients with acute ischemic stroke may be enhanced in patients who have an Apo E2 phenotype, whereas the Apo E2 phenotype alone is not associated with a detectable benefit on stroke outcome at 3 months in patients not given t-PA. In contrast to prior studies of head injury and stroke, we could not detect a relationship between Apo E4 phenotype and clinical outcome.


Subject(s)
Apolipoproteins E/genetics , Cerebral Hemorrhage/genetics , Stroke/drug therapy , Stroke/genetics , Tissue Plasminogen Activator/therapeutic use , Aged , Aged, 80 and over , Apolipoprotein E2 , Apolipoprotein E4 , Apolipoproteins E/blood , Cerebral Hemorrhage/blood , Cerebral Hemorrhage/drug therapy , Cerebral Hemorrhage/pathology , Chi-Square Distribution , Double-Blind Method , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Multicenter Studies as Topic , Odds Ratio , Phenotype , Placebos , Randomized Controlled Trials as Topic , Retrospective Studies , Stroke/blood , Stroke/pathology , Survival Rate , Time Factors , Tissue Plasminogen Activator/blood , Tomography, X-Ray Computed , Treatment Outcome
6.
Expert Opin Pharmacother ; 2(1): 153-63, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11336576

ABSTRACT

Simvastatin (Zocortrade mark, Merck) is a safe and effective 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Simvastatin potently lowers total and low density lipoprotein (LDL) cholesterol. Simvastatin was the first cholesterol-lowering agent that reduced total mortality in a randomised clinical trial. Simvastatin is effective at reducing total mortality, myocardial infarction, coronary mortality and the incidence of stroke or transient ischemic attack in patients with coronary heart disease and hypercholesterolemia. Simvastatin, like other statins, also has non-lipid mechanisms of action. These include anti-inflammatory effects, antiproliferative effects on smooth muscle cells and an upregulation of endothelial nitric oxide synthase. Overall, simvastatin has an excellent safety profile. Simvastatin, along with other statins, has made a significant impact on the morbidity and mortality from coronary heart disease.


Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Simvastatin/pharmacology , Simvastatin/therapeutic use , Aged , Arteriosclerosis/drug therapy , Arteriosclerosis/etiology , Cholesterol, LDL/blood , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Coronary Disease/prevention & control , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hypercholesterolemia/blood , Hypercholesterolemia/complications , Simvastatin/adverse effects , Treatment Outcome
7.
Stroke ; 32(3): 661-8, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11239184

ABSTRACT

BACKGROUND AND PURPOSE: Little is known in regard to cerebral arterial reocclusion after successful thrombolysis. In the absence of arteriographic information, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial investigators prospectively identified clinical deterioration following improvement (DFI) as a possible surrogate marker of cerebral arterial reocclusion after rt-PA-induced recanalization. Also, we identified any significant clinical deterioration (CD) even if not preceded by improvement. This observational analysis was designed to determine the incidence of DFI and CD in each treatment group, to identify baseline or posttreatment variables predictive of DFI or CD, and to determine any relationship between DFI, CD, and clinical outcome. METHODS: DFI was defined as any 2-point deterioration on the NIH Stroke Scale after an initial 2-point improvement after treatment. CD was defined as any 4-point worsening after treatment compared with baseline. All data were collected prospectively by investigators blinded to treatment allocation. A noncontrast brain CT was mandated when a 2-point deterioration occurred. All cases were validated by a central review committee. RESULTS: DFI was identified in 81 of the 624 patients (13%); 44 were treated with rt-PA and 37 were treated with placebo (P:=0.48). DFI occurred more often in patients with a higher baseline NIH Stroke Scale score. CD within the first 24 hours occurred in 98 patients (16% of all patients); 43 were given rt-PA and 55 were given placebo (P:=0.19). Baseline variables associated with CD included a less frequent use of prestroke aspirin and a higher incidence of early CT changes of edema or mass effect or dense middle cerebral artery sign. Patients with CD had higher rates of increased serum glucose and fibrin degradation products, and they also had higher rates of symptomatic intracranial hemorrhage and death. Patients who experienced either DFI or CD were less likely to have a 3-month favorable outcome. CONCLUSIONS: We found no association between DFI, CD, and rt-PA treatment, and no clinical evidence to suggest reocclusion. Deterioration was strongly associated with stroke severity and poor outcome and was less frequent in patients whose stroke occurred while they were on aspirin.


Subject(s)
Fibrinolytic Agents/therapeutic use , Recombinant Proteins/therapeutic use , Stroke/drug therapy , Tissue Plasminogen Activator/therapeutic use , Disease Progression , Female , Humans , Logistic Models , Male , Multivariate Analysis , National Institutes of Health (U.S.) , Odds Ratio , Prospective Studies , Recurrence , Severity of Illness Index , Stroke/diagnosis , Treatment Outcome , United States
8.
Ann Pharmacother ; 34(1): 39-43, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10669185

ABSTRACT

OBJECTIVE: To describe the use of intravenous verapamil in a migraine patient with hemiplegia to reverse the symptomatology and hemodynamics of the middle cerebral artery as determined by transcranial Doppler. CASE SUMMARY: A 31-year-old white woman was admitted with an acute exacerbation of migraine with hemiplegia. A transcranial Doppler showed an increased flow velocity through the middle cerebral artery consistent with a migrainous process. The patient was treated with verapamil 5 mg iv and the hemiplegia gradually resolved. A transcranial Doppler indicated that the flow velocity through the middle cerebral artery was decreased after verapamil administration, indicating reversal of the vasospasm. DISCUSSION: Transcranial Doppler has not been previously used to determine the effect of intravenous verapamil on the migrainous process. Intravenous verapamil reversed the altered hemodynamics of the middle cerebral artery as determined by transcranial Doppler. This finding correlated with the gradual resolution of hemiplegia. Whether both subjective and objective findings in this patient can be attributed to the reversal of the cerebral artery hemodynamics is not known. CONCLUSIONS: Intravenous verapamil appears to reverse the vasospasm that may be associated with a migrainous process. Whether this effect is solely responsible for clinical improvement is not known. Verapamil may be a consideration for the treatment of intractable migraine, especially when there is evidence of spasm of the major cerebral arteries.


Subject(s)
Calcium Channel Blockers/therapeutic use , Cerebrovascular Circulation/drug effects , Hemiplegia/drug therapy , Migraine Disorders/drug therapy , Verapamil/therapeutic use , Adult , Calcium Channel Blockers/administration & dosage , Female , Hemiplegia/complications , Hemodynamics/drug effects , Humans , Injections, Intravenous , Middle Cerebral Artery/drug effects , Middle Cerebral Artery/physiology , Migraine Disorders/complications , Time Factors , Ultrasonography, Doppler, Transcranial , Verapamil/administration & dosage
9.
Pharmacotherapy ; 19(2): 139-42, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10030763

ABSTRACT

We used an adaptation of a well-established rat model of middle cerebral artery occlusion (MCAO) that is both minimally invasive and reproducible to determine the effects of time to reperfusion and administration of tissue plasminogen activator (t-PA) on the development of hemorrhagic transformation (HT) in a rat model of acute stroke. Animals were randomized to receive either t-PA 10 mg/kg (29 rats) or an equal volume of saline (29 rats) over 20 minutes, beginning 5 minutes before reperfusion. Time to artery reopening varied between 1 and 24 hours after MCAO in both groups. At 18-24 hours after ischemia, the animals were sacrificed and their brains were preserved for analysis of HT. Logistic regression was used to determine the influence of time on HT risk and calculate the time at which 50% of animals developed HT (HT50%). At 24 hours, HT was present in 17 of 29 animals in each group and was significantly influenced by the time of artery reopening: 3 (15%) of 20 animals reperfused less than 3 hours after onset of ischemia and 32 (84%) of 38 reperfused 3 or more hours after the onset of ischemia (p<0.001). There was no difference in HT50% between groups. Time to artery reopening is an important determinant of HT risk in this model of cerebral ischemia. This model may have utility in developing strategies to reduce HT formation after thrombolytic therapy in patients with acute stroke.


Subject(s)
Cerebral Hemorrhage/etiology , Cerebral Hemorrhage/prevention & control , Fibrinolytic Agents/therapeutic use , Ischemic Attack, Transient/complications , Tissue Plasminogen Activator/therapeutic use , Animals , Arterial Occlusive Diseases/etiology , Disease Models, Animal , Male , Random Allocation , Rats , Rats, Wistar , Regression Analysis , Reperfusion/methods , Time Factors
10.
J Stroke Cerebrovasc Dis ; 8(6): 359-67, 1999.
Article in English | MEDLINE | ID: mdl-17895189

ABSTRACT

BACKGROUND: With the implementation of thrombolysis, a large number of distinct pharmacological agents are now under consideration for the treatment of acute ischemic stroke, with disappoiting early results. Because the processes that ultimately lead to ischemic cell death involve a variety of pathophysiologic pathways, it is likely that combinations of agents may be necessary to positively affect neurological outcome. We review the general strategies under consideration for reduction of ischemic injury in the central nervous system, the types of possible interactions between compounds, and the experimental evidence showing effective combination therapies. SUMMARY OF REVIEW: Reduction of ischemic injury has been attempted by the following pharmacologic mechanisms: thrombolysis, neuroprotection, and perfusion/reperfusion enhancers. There is experimental evidence that the combination of thrombolytic therapy with a neuroprotective agent is additive in some ischemic models, as is the combination of a thrombolytic with an agent that facilitates reperfusion (thromboxane A(2) receptor antagonist and neutrophil adhesion/activation inhibition). Combinations of neuroprotective agents such as glutamate antagonists and calcium channel antagonists may be additive, and other combinations of neuroprotective agents, such as a glutamate antagonist with a gamma-aminobutyric acid (GABA) agonist, have even shown synergism in a rat stroke model. It has also been suggested that lower doses of toxic drugs may be used together to yield a positive neurologic outcome. Successful demonstration of additive or synergistic effects of pharmacologic agents in ischemia will depend on (1) the model used (well below a maximal "ceiling effect"); (2) the timing of drug administration; (3) the doses of the drugs used; and (4) the primary neurologic endpoint used. (Infarction size requires prolonged survival.) CONCLUSIONS: It appears from preclinical studies that some combinations of pharmacotherapeutic agents may be beneficial in cerebral ischemia, but rigorous evaluation is needed before initiating clinical trials.

11.
Neurotoxicol Teratol ; 20(6): 617-26, 1998.
Article in English | MEDLINE | ID: mdl-9831123

ABSTRACT

Animal studies show FC-23 to be a promising magnetic resonance imaging indicator of regional cerebral blood flow. In a Phase 1, dose ranging (investigative new drug) study, neuropsychological (NP) tests, subjective ratings, and intensive physiological monitoring were used to determine the maximum tolerated concentration of FC-23 for human application. Five normal healthy male volunteers were exposed to concentrations of FC-23 between 10% and 60% [randomly interleaved with exposures to both room air and 40% nitrous oxide (N2O)] in a within-subjects, double-blind design. Analyses of individual cases and ranked group data showed that individuals tolerated the 30% concentration of FC-23 according to established criteria. Planned comparisons indicated that inhalation of FC-23 produced smaller NP changes and fewer negative symptoms than 40% N2O but poorer NP performance and more negative symptoms than room air. This study indicated that FC-23 is not inert and that humans do not tolerate concentrations suitable for current MRI technology. NP and subjective data assisted in characterizing the sedative effect of FC-23.


Subject(s)
Affect/drug effects , Chlorofluorocarbons, Methane/pharmacology , Cognition/drug effects , Nitrous Oxide/pharmacology , Psychomotor Performance/drug effects , Adult , Contrast Media/pharmacology , Double-Blind Method , Humans , Magnetic Resonance Imaging/methods , Male , Neuropsychological Tests
12.
Stroke ; 29(8): 1504-9, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9707184

ABSTRACT

BACKGROUND AND PURPOSE: We examined the frequency, course, and treatment of hypertension in the NINDS rt-PA Stroke Trial. METHODS: Blood pressure (BP) was measured at the time of admission, at randomization, and then 36 times during the first 24 hours after randomization. Patients with a systolic BP of >185 mm Hg and a diastolic BP of >110 mm Hg at admission were defined as hypertensive before randomization, and those with a systolic BP of >180 mm Hg or a diastolic BP of >105 mm Hg within the first 24 hours after randomization were defined as hypertensive after randomization. Standardized clinical assessments were conducted at 24 hours and at 3 months. Post hoc analyses were conducted to evaluate the association of antihypertensive therapy with clinical outcomes. RESULTS: Of the 624 patients, 121(19%) had hypertension on admission and 372 (60%) had hypertension in the 24 hours after randomization. The use of antihypertensive therapy before randomization (tPA 9%, placebo 9%) and after randomization (tPA 24%, placebo 29%) was similar between placebo- and tPA-treated patients. No adverse effects of prerandomization antihypertensive therapy on 3-month favorable outcome were detected for either the placebo- or tPA-treated groups. For placebo patients with hypertension in the 24 hours after randomization, clinical outcome measures were similar for those patients who did and did not receive antihypertensive therapy after randomization (P > or = 0.26); antihypertensive therapy was not associated with declines in BP (P = 0.44) or with abrupt declines (P = 0.14). Those tPA patients who were hypertensive after randomization and received antihypertensive therapy were less likely to have a favorable outcome at 3 months (P < 0.01) than those who were hypertensive and did not receive antihypertensive therapy. CONCLUSIONS: The frequency of hypertension and the use of antihypertensive therapy were similar between the tPA and placebo groups in the NINDS rt-PA Stroke Trial. In the placebo group, antihypertensive therapy was not associated with less favorable outcomes at 3 months; postrandomization antihypertensive therapy was associated with less favorable outcomes for the tPA patients who were hypertensive. However, because of the nonrandomized use of antihypertensive therapy and the many post hoc comparisons leading to type 1 errors, the significance of this observation is unclear. Careful attention to BP and gentle management remain warranted for stroke patients treated with tPA.


Subject(s)
Antihypertensive Agents/administration & dosage , Cerebrovascular Disorders/drug therapy , Hypertension/drug therapy , Tissue Plasminogen Activator/administration & dosage , Blood Pressure , Cerebrovascular Disorders/complications , Humans , Hypertension/complications , Recombinant Proteins/administration & dosage
13.
Neurology ; 50(4): 883-90, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9566367

ABSTRACT

Tissue plasminogen activator (tPA) has been shown to improve 3-month outcome in stroke patients treated within 3 hours of symptom onset. The costs associated with this new treatment will be a factor in determining the extent of its utilization. Data from the NINDS rt-PA Stroke Trial and the medical literature were used to estimate the health and economic outcomes associated with using tPA in acute stroke patients. A Markov model was developed to estimate the costs per 1,000 patients eligible for treatment with tPA compared with the costs per 1,000 untreated patients. One-way and multiway sensitivity analyses (using Monte Carlo simulation) were performed to estimate the overall uncertainty of the model results. In the NINDS rt-PA Stroke Trial, the average length of stay was significantly shorter in tPA-treated patients than in placebo-treated patients (10.9 versus 12.4 days; p = 0.02) and more tPA patients were discharged to home than to inpatient rehabilitation or a nursing home (48% versus 36%; p = 0.002). The Markov model estimated an increase in hospitalization costs of $1.7 million and a decrease in rehabilitation costs of $1.4 million and nursing home cost of $4.8 million per 1,000 eligible treated patients for a health care system that includes acute through long-term care facilities. Multiway sensitivity analysis revealed a greater than 90% probability of cost savings. The estimated impact on long-term health outcomes was 564 (3 to 850) quality-adjusted life-years saved over 30 years of the model per 1,000 patients. Treating acute ischemic stroke patients with tPA within 3 hours of symptom onset improves functional outcome at 3 months and is likely to result in a net cost savings to the health care system.


Subject(s)
Brain Ischemia/drug therapy , Cerebrovascular Disorders/drug therapy , Outcome Assessment, Health Care/economics , Plasminogen Activators/economics , Tissue Plasminogen Activator/economics , Acute Disease , Aged , Brain Ischemia/complications , Brain Ischemia/economics , Cerebrovascular Disorders/economics , Cerebrovascular Disorders/etiology , Cost-Benefit Analysis , Humans , Models, Economic , Outcome Assessment, Health Care/statistics & numerical data , Plasminogen Activators/therapeutic use , Quality-Adjusted Life Years , Tissue Plasminogen Activator/therapeutic use
14.
Exp Neurol ; 150(1): 153-8, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9514832

ABSTRACT

We examined the relationship between acute hypertension following cerebral embolization and subsequent hemorrhagic transformation (HT) in a rabbit embolic stroke model. We have shown previously that the likelihood and severity of hemorrhage were significantly correlated with the magnitude of an acute hypertensive response to embolization. It was not clear, however, whether hypertension actually caused hemorrhage or was merely a marker of more severe stroke. In the current studies, we attempted to clarify the relationship between acute hypertension and HT by either pharmacologically inducing or attenuating the brief hypertensive response to embolization in rabbits. Under halothane anesthesia, two catheters were implanted in the right carotid arteries of male New Zealand white rabbits, one oriented toward the heart and one toward the brain. The animals were allowed to awaken and were embolized using blood clot emboli injected into the middle cerebral artery. Blood pressure was monitored via the second carotid catheter. In the first experiment, hypertension was induced with angiotensin II, administered at the time of embolization or 1 h later. In the second experiment, we attempted to attenuate the hypertensive response using intravenous labetalol. The animals were sacrificed 18 h after embolization and the brains evaluated for hemorrhage. In the first experiment, administration of angiotensin II immediately after embolization did not increase the hypertensive response to embolization further than that spontaneously occurring, and no angiotensin II-related HT was observed. In contrast, an additional angiotensin-II-induced hypertensive episode 1 h after embolization significantly increased the number of 5-mm serial brain sections displaying HT, from 3.0 +/- .3 (mean +/- SE) in Controls to 5.4 +/- .8 in treated animals. In the second experiment, administration of labetalol (15 mg/kg) significantly reduced the number of brain sections with visible HT, from 3.2 +/- .5 in controls to 1.6 +/- .4 in treated animals. Acute hypertension during the first hour after cerebral embolization promotes HT in this rabbit embolic stroke model. Labetalol prevents blood pressure elevation and reduces the extent of HT in the same model.


Subject(s)
Antihypertensive Agents/therapeutic use , Cerebral Hemorrhage/etiology , Hypertension/complications , Intracranial Embolism and Thrombosis/complications , Labetalol/therapeutic use , Acute Disease , Angiotensin II/toxicity , Animals , Cerebral Hemorrhage/pathology , Cerebral Infarction/etiology , Cerebral Infarction/pathology , Hypertension/chemically induced , Male , Rabbits
15.
Stroke ; 29(1): 144-51, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9445344

ABSTRACT

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) of ischemic brain tissue may occur in stroke patients either spontaneously or after thrombolysis. A method to assess the risk of HT in ischemic tissue after stroke would improve the safety of thrombolytic therapy. As a means of predicting HT, we investigated the role of contrast-enhanced MRI at acute time points in a rat middle cerebral artery occlusion model with reperfusion. METHODS: Intraluminal suture occlusion of the middle cerebral artery was used to produce transient ischemia in male Wistar rats (n=11). Reperfusion was performed by withdrawal of the occluding filament after 2 (n=4), 3 (n=6), or 4 (n=1) hours. MRI studies were performed before and after reperfusion with the use of conventional T1-weighted imaging, with and without gadolinium (Gd-DTPA) contrast agent, and T2-weighted imaging. Follow-up MRI and histological studies were obtained at 24 hours. RESULTS: Petechial hemorrhage occurred by 24 hours in 9 of 11 animals. All animals showed brain swelling and cellular death throughout the ischemic region at 24 hours. A hyperintense region in the preoptic area became visible after Gd-DTPA injection within minutes after reperfusion in animals with subsequent HT. All animals showing acute Gd-DTPA enhancement subsequently developed petechial hemorrhage (or died) by 24 hours. In these animals, statistically significant differences in signal intensity (P=.0005) between the ipsilateral enhancing region and a homologous contralateral region were detected on post-Gd-DTPA T1-weighted imaging. There was also a statistically significant correlation (P=.01) between the rate of Gd-DTPA uptake and the size of the enhancing area. Two animals did not enhance with Gd-DTPA and did not exhibit hemorrhage on histological examination or MRI at 24 hours. No abnormalities were seen on precontrast T1-weighted images before and shortly after reperfusion or postcontrast T1-weighted images before reperfusion. CONCLUSIONS: The primary finding of this study was the detection of early Gd-DTPA parenchymal enhancement in 82% of the animals after reperfusion. Enhancement was seen before any detectable hemorrhage, suggesting that early endothelial ischemic damage occurs before gross brain infarction and hemorrhage. Thus, we suggest that acute Gd-DTPA enhancement may provide an early prediction of petechial hemorrhage.


Subject(s)
Brain Ischemia/complications , Cerebral Hemorrhage/etiology , Magnetic Resonance Imaging/methods , Animals , Brain Edema/etiology , Brain Edema/pathology , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Cause of Death , Cell Death , Cerebral Arterial Diseases/complications , Cerebral Hemorrhage/pathology , Cerebral Infarction/etiology , Cerebral Infarction/pathology , Cerebrovascular Disorders/complications , Cerebrovascular Disorders/drug therapy , Cerebrovascular Disorders/pathology , Contrast Media , Disease Models, Animal , Endothelium, Vascular/pathology , Follow-Up Studies , Forecasting , Gadolinium DTPA , Image Enhancement/methods , Ischemic Attack, Transient/etiology , Ischemic Attack, Transient/pathology , Male , Purpura/etiology , Purpura/pathology , Rats , Rats, Wistar , Reperfusion , Risk Assessment , Safety , Thrombolytic Therapy/adverse effects , Time Factors
16.
J Stroke Cerebrovasc Dis ; 7(3): i-ii, 1998.
Article in English | MEDLINE | ID: mdl-17895075
19.
Ann Pharmacother ; 31(3): 290-3, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9066933

ABSTRACT

OBJECTIVE: To assess the relative antiaggregatory ability of aspirin on platelets of smoking and nonsmoking healthy volunteers. DESIGN: Prospective, randomized, crossover study. SETTING: Tertiary-care teaching institution. SUBJECTS: Eighteen healthy smoking and nonsmoking male volunteers. INTERVENTIONS: Each subject received aspirin 325 mg or ticlopidine 250 mg bid as an active control for 7 days in a crossover manner separated by a 1-month washout period. Whole blood platelet aggregation was measured on four occasions, twice at baseline and once after each drug treatment. OUTCOME MEASUREMENT: Whole blood ex vivo platelet aggregation in terms of impedance (omega) and adenosine triphosphate (ATP) release (nmol), as assessed using Lumi-aggregometry. RESULTS: Aspirin was associated with significantly less ATP release in both smokers (p = 0.01) and nonsmokers (p = 0.003). No significant differences in platelet aggregation were found between smokers and nonsmokers at baseline or with any treatment phases. Sixty-seven percent and 17% of volunteers receiving ticlopidine and aspirin, respectively, reported adverse effects. CONCLUSIONS: Twice-daily administration of aspirin for 7 days to healthy volunteers was well tolerated and also reduced platelet aggregation significantly regardless of smoking status.


Subject(s)
Aspirin/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Smoking/blood , Adenosine Triphosphate/metabolism , Adult , Cross-Over Studies , Electric Impedance , Humans , Male , Middle Aged , Prospective Studies , Ticlopidine/pharmacology
20.
Ann Pharmacother ; 30(12): 1446-51, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8968458

ABSTRACT

Disorders of the central nervous system provide innumerable challenges to the clinician. Often the underlying pathophysiology is not completely understood, thus preventing the design of treatment strategies aimed at correcting the underlying process. In this decade of the brain, basic science research combined with difficult but necessary clinical trials may answer some of these seemingly over-whelming questions for these devastating illnesses.


Subject(s)
Alzheimer Disease/drug therapy , Cerebrovascular Disorders/drug therapy , Parkinson Disease/drug therapy , Anticoagulants/therapeutic use , Apomorphine/pharmacology , Aspirin/therapeutic use , Cerebrovascular Disorders/prevention & control , Cholinergic Agents/therapeutic use , Dopamine Agonists/pharmacology , Humans , Monoamine Oxidase Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Tacrine/therapeutic use
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