Is insulin resistance or diabetes mellitus
associated with stroke? An 18-year follow-up study.
Adachi H, Hirai Y, Tsuruta M, et al. Diabetes Res Clin Pract. 2001 Mar; 51(3):215-23. Insulin resistance and/or diabetes are risk factors for coronary artery disease. However, it is still controversial whether they are associated with the development of stroke. A total of 304 Japanese men and women, aged 20-69 years, were selected on the basis of casual high blood glucose concentrations from 2732 participants of a population-based health examination in 1980. They all underwent a 50 g oral glucose tolerance test in 1981. Homa IR (index of insulin resistance) and Homa beta-cells (index of beta-cell function) were calculated from their fasting insulin and glucose using the formulas for the homeostasis model. They were followed-up for 18 years. Incidence of stroke was investigated by computed tomography. During 18 years, 28 subjects had a stroke; 21 had ischemic and nine had hemorrhagic strokes (two had both). Baseline variables, which showed an independent association with the incidence of stroke in the Cox proportional hazard model, were blood pressure, use of anti-hypertensive medications, and Homa beta-cell index (inversely) after adjustments for age and sex. After further adjustment for blood pressure using a step-forward method, Homa beta-cell was significantly related to the incidence of stroke (Hazard ratio: 0.65, 95% confidence interval: 0.44-0.95). In addition to hypertension, diabetes but not insulin resistance, is a risk factor for stroke
Guidelines for Thrombolytic Therapy for Acute Stroke: a Supplement to the Guidelines for the Management of Patients with Acute Ischemic Stroke. A statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Adams HP, Jr., Brott TG, Furlan AJ, et al. Stroke. 1996 Sep; 27(9):1711-8.
Effect of intravenous nimodipine on blood pressure and outcome after acute stroke. Ahmed N, Nasman P, Wahlgren NG. Stroke. 2000 Jun; 31(6):1250-5. BACKGROUND AND PURPOSE: The Intravenous Nimodipine West European Stroke Trial (INWEST) found a correlation between nimodipine-induced reduction in blood pressure (BP) and an unfavorable outcome in acute stroke. We sought to confirm this correlation with and without adjustment for prognostic variables and to investigate outcome in subgroups with increasing levels of BP reduction. METHODS: Patients with a clinical diagnosis of ischemic stroke (within 24 hours) were consecutively allocated to receive placebo (n=100), 1 mg/h (low-dose) nimodipine (n=101), or 2 mg/h (high-dose) nimodipine (n=94). The correlation between average BP change during the first 2 days and the outcome at day 21 was analyzed. RESULTS: Two hundred sixty-five patients were included in this analysis (n=92, 93, and 80 for placebo, low dose, and high dose, respectively). Nimodipine treatment resulted in a statistically significant reduction in systolic BP (SBP) and diastolic BP (DBP) from baseline compared with placebo during the first few days. In multivariate analysis, a significant correlation between DBP reduction and worsening of the neurological score was found for the high-dose group (beta=0.49, P=0. 048). Patients with a DBP reduction of > or =20% in the high-dose group had a significantly increased adjusted OR for the compound outcome variable death or dependency (Barthel Index <60) (n/N="25/26," OR 10. 16, 95% CI 1.02 to 101.74) and death alone (n/N="9/26," OR 4.336, 95% CI 1.131 16.619) compared with all placebo patients (n/N="62/92" and 14/92, respectively). There was no correlation between SBP change and outcome. CONCLUSIONS: DBP, but not SBP, reduction was associated with neurological worsening after the intravenous administration of high-dose nimodipine after acute stroke. For low-dose nimodipine, the results were not conclusive. These results do not confirm or exclude a neuroprotective property of nimodipine
Antithrombotic agents in cerebral ischemia. Albers GW. Am J Cardiol. 1995 Feb 23; 75(6):34B-8B. The choice of antithrombotic agent in cerebral ischemia depends on the pathogenesis: thrombosis, embolism, or hemorrhage. Antiplatelet agents are considered most beneficial in thrombotic stroke, anticoagulants are most effective in cardioembolic stroke; antithrombotic agents are generally contraindicated in hemorrhagic stroke. A meta-analysis of 18 trials documented a 23% reduction in stroke risk with antiplatelet agents; aspirin is typically the antiplatelet agent of choice for stroke prevention. There are no definitive data regarding the optimal aspirin dose for stroke prevention and this issue remains controversial. Ticlopidine is the most effective antiplatelet agent, but its adverse effect profile restricts its use. Anticoagulants are highly effective for preventing cardioembolic stroke, but their effectiveness in non-cardioembolic stroke is uncertain because of lack of trial data. Results of the ongoing Warfarin/Aspirin Recurrent Stroke Study (warfarin [INR 1.8-2.8] vs aspirin [325 mg/day]) may clarify this issue. There is renewed interest in thrombolytics because recent data indicate that reperfusion within a few hours of stroke onset appears to be effective in preventing neuronal damage. In addition, when given within 6 hours of stroke onset, thrombolytics appear to be relatively safe. Several direct thrombin inhibitors are being evaluated. Experimentally, hirudin, hirulog, D-Phe-L-Pro-L-Arg-CH2Cl (PPACK), and argatroban are clearly more effective than heparin in inhibiting platelet deposition and thrombus formation, and also show promise in preventing reocclusion after thrombolysis for both experimental thrombotic and embolic stroke. However, the risk of hemorrhage in patients with cerebrovascular disease is unknown for these agents.(ABSTRACT TRUNCATED AT 250 WORDS)
An analysis of time of presentation after stroke. Alberts MJ, Bertels C, Dawson DV. JAMA. 1990 Jan 5; 263(1):65-8. The recent development of potential therapies for acute stroke has focused attention on the time delay between stroke onset and presentation. We used the Duke/Veterans Administration stroke registry to collect data about this delay. Results were analyzed using Fisher's Exact Test and ridit analysis. Data from 457 patients at two hospitals were used. Only 42% (192/457) of patients presented within 24 hours of stroke onset, while 25% (116/457) presented within 48 hours and 33% (149/457) presented after 48 hours. Presentation time varied significantly with stroke type. A majority of patients with infarcts (64% [176/276]), stroke-in-evolution (54% [44/81]), and subarachnoid hemorrhage (54% [25/46]) did not present within 24 hours of stroke onset. Most patients with intracerebral hemorrhage (63% [34 of 54]) did present within 24 hours. Reasons for this delay may include patients' lack of awareness about the symptoms of stroke and lack of recognition of early signs by medical personnel. Because of this delay in presentation, a majority of patients may not be candidates for some therapies for acute stroke
tPA in acute ischemic stroke: United States experience and issues for the future. Alberts MJ. Neurology. 1998 Sep; 51(3 Suppl 3):S53-S55. The approval of tissue plasminogen activator (tPA) for treatment of patients with ischemic stroke in the United States marked the first therapy proven to reverse or limit the effects of an acute stroke. Despite this approval and the lack of an alternative therapy, the use of tPA in stroke has been quite low. Several explanations for this underutilization have been identified, including lack of patient awareness, potential complications, infrastructure deficiencies, and physician concerns. This article explores these issues and suggests strategies for improving the use of tPA as an acute therapy in stroke
Role of magnesium and calcium in alcohol-induced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR, spectroscopy and a unique magnesium ion-selective electrode. Altura BM, Altura BT. Alcohol Clin Exp Res. 1994 Oct; 18(5):1057-68. It is not known why alcohol ingestion poses a risk for development of hypertension, stroke and sudden death. Of all drugs, which result in body depletion of magnesium (Mg), alcohol is now known to be the most notorious cause of Mg-wasting. Recent data obtained through the use of biophysical (and noninvasive) technology suggest that alcohol may induce hypertension, stroke, and sudden death via its effects on intracellular free Mg2+ ([Mg2+]i), which in turn alter cellular and subcellular bioenergetics and promote calcium ion (Ca2+) overload. Evidence is reviewed that demonstrates that the dietary intake of Mg modulates the hypertensive actions of alcohol. Experiments with intact rats indicates that chronic ethanol ingestion results in both structural and hemodynamic alterations in the microcirculation, which, in themselves, could account for increased vascular resistance. Chronic ethanol increases the reactivity of intact microvessels to vasoconstrictors and results in decreased reactivity to vasodilators. Chronic ethanol ingestion clearly results in vascular smooth muscle cells that exhibit a progressive increase in exchangeable and cellular Ca2+ concomitant with a progressive reduction in Mg content. Use of 31P-NMR spectroscopy coupled with optical-backscatter reflectance spectroscopy revealed that acute ethanol administration to rats results in dose-dependent deficits in phosphocreatine (PCr), the [PCr]/[ATP] ratio, intracellular pH (pHi), oxyhemoglobin, and the mitochondrial level of oxidized cytochrome oxidase aa3 concomitant with a rise in brain-blood volume and inorganic phosphate. Temporal studies performed in vivo, on the intact brain, indicate that [Mg2+]i is depleted before any of the bioenergetic changes. Pretreatment of animals with Mg2+ prevents ethanol from inducing stroke and prevents all of the adverse bioenergetic changes from taking place. Use of quantitative digital imaging microscopy, and mag-fura-2, on single-cultured canine cerebral vascular smooth muscle, human endothelial, and rat astrocyte cells reveals that alcohol induces rapid concentration-dependent depletion of [Mg2+]i. These cellular deficits in [Mg2+]i seem to precipitate cellular and subcellular disturbances in cytoplasmic and mitochondrial bioenergetic pathways leading to Ca2+ overload and ischemia. A role for ethanol-induced alterations in [Mg2+]i should also be considered in the well-known behavioral actions of alcohol
Association of alcohol in brain injury, headaches, and stroke with brain-tissue and serum levels of ionized magnesium: a review of recent findings and mechanisms of action. Altura BM, Altura BT. Alcohol. 1999 Oct; 19(2):119-30. Although there is general agreement that chronic ingestion of alcohol poses great risks for normal cardiovascular functions and peripheral-vascular homeostasis, a direct cause and effect between the real phenomena of alcohol-induced headache and risk of brain injury and stroke is not appreciated. "Binge drinking" of alcohol is associated with an ever-growing number of strokes and sudden death. It is becoming clear that alcohol ingestion can result in profoundly different actions on the cerebral circulation (e.g., vasodilation, vasoconstriction-spasm, vessel rupture), depending upon dose and physiologic state of host. Using rats, it has been demonstrated that acute, high doses of ethanol can result in stroke-like events concomitant with alterations in brain bioenergetics. We review recent in vivo findings obtained with 31P-NMR spectroscopy, optical reflectance spectroscopy, and direct in vivo microcirculatory studies on the intact brain. Alcohol-induced hemorrhagic stroke is preceded by a rapid fall in brain intracellular free magnesium ions ([Mg2+]i) followed by cerebrovasospasm and reductions in phosphocreatine (PCr)/ATP ratio, intracellular pH, and the cytosolic phosphorylation potential (CPP) with concomitant rises in deoxyhemoglobin (DH), mitochondrial reduced cytochrome oxidase aa3 (rCOaa3), blood volume, and intracellular inorganic phosphate (Pi). Using osmotic mini-pumps implanted in the third cerebral ventricle, containing 30% ethanol, it was found that brain [Mg2+]i is reduced 30% after 14 days; brain PCr fell 15%, whereas the CPP fell 40%. Such animals became susceptible to stroke from nonlethal doses of ethanol. Human subjects with mild head injury have been found to exhibit early deficits in serum ionized Mg (IMg2+); the greater the degree of early head injury (30 min-8 h), the greater and more profound the deficit in serum IMg2+ and the greater the ionized Ca (ICa2+) to IMg2+ ratio. Patients with histories of alcohol abuse or ingestion of alcohol prior to head injury exhibited greater deficits in IMg2+ (and higher ICa2+/IMg2+ ratios) and, unlike the subjects without alcohol, did not leave the hospital for at least several days. Women, for some unknown reason, exhibit a much higher incidence of morbidity and mortality from subarachnoid hemorrhage (SAH) than men. Data on 105 men and women with different types of stroke indicate that, on the average, a 20% deficit in serum IMg2+ is seen; total Mg (TMg) or blood pH is usually near normal. Women with SAH, however, exhibit much lower IMg2+ and higher ICa2+/IMg2+ ratios; the presence of ethanol in the blood is associated with even more depression in IMg2+ in SAH in women. It is possible that prior alcohol ingestion is, in large measure, responsible for a great deal of this unexplained higher incidence of SAH in women. It has recently been reported that the cyclical changes in estrogenic hormones appear to control the serum IMg2+ level in young women. A surge in estrogenic levels prior to SAH could thus precipitate, in part, the SAH. In other human studies, it has been shown that migraines and headache, dizziness, and hangover, which accompany ethanol ingestion, are associated with rapid deficits in serum IMg2+ but not in TMg. The former, and the alcohol-associated headache, can be ameliorated with IV administration of MgSO4. Premenstrual tension-headache (PTH) and its exacerbation by alcohol in women is also accompanied by deficits in IMg2+, and elevation in serum ICa2+/IMg2+; IV MgSO4 corrects the PTH and the serum deficit in IMg2+. Animal experiments show that IV Mg2+ can prevent alcohol-induced hemorrhagic stroke and the subsequent fall in brain [Mg2+]i, [PCr], pHi, and CPP. Other recent data indicate that alcohol-induced cellular loss of [Mg2+]i is associated with cellular Ca2+ overload and generation of oxygen-derived free radicals; chronic pretreatment with vitamin E prevents alcohol-induced vascular injury and pathology in the brain. (ABSTRACT TRUNCATED)
Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Amin-Hanjani S, Stagliano NE, Yamada M, et al. Stroke. 2001 Apr; 32(4):980-6. BACKGROUND AND PURPOSE: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) lower serum cholesterol and decrease the incidence of stroke and cardiovascular disease. There is growing evidence that statins exert some of their beneficial effects independent of cholesterol lowering. Indeed, we have previously demonstrated that chronic simvastatin administration upregulates endothelial nitric oxide synthase (eNOS), resulting in more functional protein, augmentation of cerebral blood flow, and neuroprotection in a murine model of cerebral ischemia. In this report we examined whether another member of the statin family shared these effects and whether eNOS upregulation is sustained with longer treatment. METHODS: Mevastatin (2 mg/kg or 20 mg/kg per day) was administered to 18- to 22-g male mice for 7, 14, or 28 days before 2-hour middle cerebral artery occlusion with the use of the filament model (n=9 to 12). Neurological deficits and cerebral infarct volumes were assessed at 24 hours. Arterial blood pressure and gases, relative cerebral blood flow, and blood cholesterol levels were monitored in a subset of animals (n=5). Absolute cerebral blood flow was measured by the [(14)C]iodoamphetamine indicator fractionation technique (n=6). eNOS mRNA and protein levels were determined. RESULTS: Mevastatin increased levels of eNOS mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. Greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced only after 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment. CONCLUSIONS: Chronic prophylactic treatment with mevastatin upregulated eNOS and augmented cerebral blood flow. These changes occurred in the absence of changes in serum cholesterol levels, were sustained for up to 1 month of treatment, and resulted in neuroprotection after middle cerebral artery occlusion
Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Andersen M, Overgaard K, Meden P, et al. Stroke. 1999 Jul; 30(7):1464-71. BACKGROUND AND PURPOSE: We sought to evaluate the effects of the combination of cytidine-5'-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model. METHODS: Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg, (5) rtPA 5 mg/kg plus citicoline 250 mg/kg, and (6) rtPA 5 mg/kg plus citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily. RESULTS: The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared with 22% (5% to 52%; P=NS) in group 2, 11% (5% to 34%; P=NS) in group 3, 24% (12% to 31%; P=NS) in group 4, 11% (3% to 22%; P=0.02) in the combined group 5, and 19% (9% to 51%; P=NS) in group 6. The infarct size was significantly reduced in the combined citicoline+rtPA-treated groups to a median of 13% (5% to 30%; P<0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery. CONCLUSIONS: These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model
Citicoline for treatment of experimental focal ischemia: histologic and behavioral outcome. Aronowski J, Strong R, Grotta JC. Neurol Res. 1996 Dec; 18(6):570-4. We evaluated the effect of chronic administration of CDP-choline, an intermediate of phospholipid synthesis, on outcome from middle cerebral artery occlusion, ranging from 30 to 120 min in duration in spontaneously hypertensive rats. Rats were randomly assigned to either CDP-choline 500 mg kg-1 or saline. CDP-choline treatment was initiated by intraperitoneal injection 15 min after the onset of ischemia and continued once a day for 14 days. Morphologic damage and behavioral dysfunction (motor and sensorimotor performance) were evaluated, and the maximal morphologic damage (Volmax), maximal behavioral dysfunction (BDmax) as well as the duration of ischemia producing half-maximal morphologic damage (T50) or behavioral dysfunction (BD50) were calculated using a curve-fitting program (ALLFIT). Ischemia in control animals produced a Volmax of 103.3 +/- 13.6 mm3. CDP-choline did not affect this value (Volmax of 101.6 +/- 11.4 mm3). However, CDP-choline significantly extended the T50 from 38.3 +/- 5.9 to 60.5 +/- 4.3 min (p < 0.05). Similar to the morphologic outcome, CDP-choline had no effect on BDmax but significantly extended BD50 from 41.9 +/- 4.6 to 72.9 +/- 24.5 min (p < 0.05). Our results suggest that the effectiveness of CDP-choline is greater in animals demonstrating submaximal ischemic injury which in this model is produced by 30-75 min of ischemia (effect on T50 and BD50), than in animals suffering maximal ischemic injury produced by ischemia longer than 75 min (no effect on Volmax and BDmax). These results may reflect a threshold of biological membrane damage within which CDP-choline is able to restore phospholipid content/arrangement and retain membrane integrity
Comparative study of policosanol, aspirin and the combination therapy policosanol-aspirin on platelet aggregation in healthy volunteers. Arruzazabala ML, Valdes S, Mas R, et al. Pharmacol Res. 1997 Oct; 36(4):293-7. A randomized, double-blind, placebo-controlled study was conducted in 43 healthy volunteers to compare the effects of policosanol (20 mg day-1), aspirin (ASA) (100 mg day-1) and combination therapy (policosanol 20 mg day-1 plus ASA 100 mg day-1) on platelet aggregation. The healthy volunteers were randomly treated for 7 days. Both, platelet aggregation and coagulation time were measured at baseline and after therapy. When policosanol was administered platelet aggregation induced by ADP (37.3%), epinephrine (32.6%) and collagen (40.5%) were significantly reduced. Meanwhile, aspirin significantly reduced platelet aggregation induced by collagen (61.4%) and epinephrine (21.9%) but not ADP-induced aggregation. Combined therapy significantly inhibited aggregation induced by all the agonists reaching the highest reductions of platelet aggregation induced by collagen (71.3%) and epinephrine (57.5%). Coagulation time did not change significantly in any group. No subject withdrew from the trial. Four volunteers reported mild adverse experiences during the study: three ASA-treated cases referred headache, epigastralgia and nose bleeding, meanwhile one patient receiving combination therapy reported gum bleeding. The present results demonstrate that policosanol (20 mg day-1) is as effective as ASA (100 mg day-1). Moreover, combination therapy shows some advantages compared with the respective monotherapies
Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Ascherio A, Rimm EB, Hernan MA, et al. Circulation. 1998 Sep 22; 98(12):1198-204. BACKGROUND: Animal experiments and epidemiological studies have suggested that high potassium intake may reduce the risk of stroke, but the evidence is inconclusive, and the role of other nutrients in potassium-rich foods remains unknown. METHODS AND RESULTS: We examined the association of potassium and related nutrients with risk of stroke among 43 738 US men, 40 to 75 years old, without diagnosed cardiovascular diseases or diabetes, who completed a semiquantitative food frequency questionnaire in 1986. During 8 years of follow-up, 328 strokes (210 ischemic, 70 hemorrhagic, 48 unspecified) were documented. The multivariate relative risk of stroke of any type for men in the top fifth of potassium intake (median intake, 4.3 g/d) versus those in the bottom (median, 2.4 g/d) was 0.62 (95% CI, 0.43, 0.88; P for trend=0.007). Results for ischemic stroke alone were similar. Intakes of cereal fiber and magnesium, but not of calcium, were also inversely associated with risk of total stroke. These inverse associations were all stronger in hypertensive than normotensive men and were not materially altered by adjustment for blood pressure levels. Use of potassium supplements was also inversely related to risk of stroke, particularly among men taking diuretics (relative risk, 0.36; 95% CI, 0.18, 0.72). CONCLUSIONS: Although these data do not prove a causal relationship, they are consistent with the hypothesis that diets rich in potassium, magnesium, and cereal fiber reduce the risk of stroke, particularly among hypertensive men. Potassium supplements may also be beneficial, but because of potential risks, use should be carefully monitored and restricted to men taking potassium-losing diuretics
Low concentrations of ethanol deplete type-2 astrocytes of intracellular free magnesium. Babu AN, Cheng TP, Zhang A, et al. Brain Res Bull. 1999 Sep 1; 50(1):59-62. The acute effects of low concentrations of ethanol on intracellular free magnesium ions ([Mg2+]i) in cultured type-2 astrocytes were studied by digital imaging microscopy using the Mg2+ fluorescent probe, mag-fura-2. In 0-mM ethanol, the basal level of [Mg+]i was 124.7+/-2.56 microM with a heterogeneous distribution within the cells. Treatment of the cells with 10 and 25 mM ethanol (10 min) resulted in rapid concentration-dependent reduction in [Mg2+]i; the greater the concentration of alcohol, the greater the depletion of [Mg2+]i. Exposure of cells to 10 and 25 mM resulted in approximately 27 and 50% reductions in [Mg2+]i, respectively. Reincubation in normal Mg2+-physiological buffer solution restored [Mg2+]i levels. These observations may suggest that acute "binge drinking" of ethanol, which often results in cerebral ischemia and stroke, may do so as a result of depletion of astrocytic [Mg2+]i, possibly producing disruption of the blood-brain barrier
A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction. Balestreri R, Fontana L, Astengo F. J Am Geriatr Soc. 1987 May; 35(5):425-30. In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg vinpocetine three times a day (tid) for 30 days, then 5 mg tid for 60 days. Matching placebo tablets were given to another 42 patients for the 90 day trial period. Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug
Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study. Barrett-Connor E, Von Muhlen DG, Kritz-Silverstein D. J Clin Endocrinol Metab. 1999 Feb; 84(2):573-7. A cross-sectional population-based study examined the association between endogenous sex hormones and depressed mood in community-dwelling older men. Participants included 856 men, ages 50-89 yr, who attended a clinic visit between 1984-87. Total and bioavailable testosterone, total and bioavailable estradiol, and dihydrotestosterone levels were measured by radioimmunoassay in an endocrinology research laboratory. Depressed mood was assessed with the Beck Depression Inventory (BDI). Levels of bioavailable testosterone and bioavailable estradiol decreased with age, but total testosterone, dihydrotestosterone, and total estradiol did not. BDI scores increased with age. Low bioavailable testosterone levels and high BDI scores were associated with weight loss and lack of physical activity, but not with cigarette smoking or alcohol intake. By linear regression or quartile analysis the BDI score was significantly and inversely associated with bioavailable testosterone (both Ps = 0.007), independent of age, weight change, and physical activity; similar associations were seen for dihydrotestosterone (P = 0.048 and P = 0.09, respectively). Bioavailable testosterone levels were 17% lower for the 25 men with categorically defined depression than levels observed in all other men (P = 0.01). Neither total nor bioavailable estradiol was associated with depressed mood. These results suggest that testosterone treatment might improve depressed mood in older men who have low levels of bioavailable testosterone. A clinical trial is necessary to test this hypothesis
The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke. Bath PM, Pathansali R, Iddenden R, et al. Cerebrovasc Dis. 2001; 11(3):265-72. BACKGROUND AND PURPOSE: Hypertension is a common medical complication in acute stroke and is associated with a poor outcome. However, no large trials have assessed the effect of lowering blood pressure (BP) on outcome, and it remains unclear how BP should be managed in acute stroke. We assessed, in a double-blind randomised controlled trial, whether the nitric oxide (NO) donor glyceryl trinitrate (GTN, a known systemic and cerebral vasodilator), would lower BP and alter platelet function. METHODS: Thirty-seven patients with recent (< 5 days) ischaemic or haemorrhagic stroke were randomised by minimisation to 12 days of daily treatment with transdermal GTN or matching placebo patches. Twenty-four-hour ambulatory BP was measured before and during GTN treatment at days 0, 1 and 8. Platelet aggregation and expression of adhesion molecules were assessed at the same time points. Functional outcome (Rankin scale) and case fatality were assessed at 3 months. Analysis was by intention-to-treat. RESULTS: GTN significantly lowered BP by 13.0/5.2 mm Hg at day 1 and 9.3/5.0 mm Hg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to GTN was developing. Non-significant falls of 0.9/0.6 and 3.8/0.0 mm Hg occurred at days 1 and 8, respectively, in the placebo group. GTN had no effect on heart rate, or platelet aggregation or expression of platelet adhesion molecules, including glycoproteins Ia, Ib, IIIa and P-selectin. Additionally, GTN did not alter case fatality or dependency, although the study was not powered for these outcomes. CONCLUSIONS: Transdermal GTN, an NO donor, lowered BP by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke. However, GTN had no effect on platelet aggregation or expression of adhesion molecules. Since NO donors increase cerebral blood flow in patients with acute ischaemic stroke, GTN may be an appropriate drug for testing the effect of lowering BP on functional outcome
Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow-up study. Bazzano LA, He J, Ogden LG, et al. Stroke. 2001 Jul; 32(7):1473-80. BACKGROUND AND PURPOSE: The few prospective studies that have explored the association between dietary intake of potassium and risk of stroke have reported inconsistent findings. This study examines the relationship between dietary potassium intake and the risk of stroke in a representative sample of the US general population. METHODS: Study participants included 9805 US men and women who participated in the first National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-Up Study. Dietary potassium and total energy intake were estimated at baseline by using a 24-hour dietary recall. Incidence data for stroke and coronary heart disease were obtained from medical records and death certificates. RESULTS: Over an average of 19 years of follow up, 927 stroke events and 1847 coronary heart disease events were documented. Overall, stroke hazard was significantly different among quartiles of potassium intake (likelihood ratio P=0.03); however, a test of linear trend across quartiles did not reach a customary level of statistical significance (P=0.14). Participants consuming a low potassium diet at baseline (<34.6 mmol potassium per day) experienced a 28% higher hazard of stroke (hazard ratio 1.28, 95% CI 1.11 to 1.47; P<0.001) than other participants, after adjustment for established cardiovascular disease risk factors. CONCLUSIONS: These findings suggest that low dietary potassium intake is associated with an increased risk of stroke. However, the possibility that the association is due to residual confounding cannot be entirely ruled out in this observational study
Persistent inflammatory response in stroke survivors. Beamer NB, Coull BM, Clark WM, et al. Neurology. 1998 Jun; 50(6):1722-8. OBJECTIVE: Goals were to determine how long acute-phase markers remain elevated after ischemic stroke and how marker levels relate to stroke risk factors, stroke mechanism, and subsequent vascular events. METHODS: Fibrinogen (FIB), C-reactive protein (CRP), leukocytes (WBC), neutrophils (PMN), interleukin-6, and interleukin-1 receptor antagonist were measured at stroke onset and at 6 weeks, 6 months, and 1 year after enrollment, or until a vascular event occurred in 136 acute ischemic stroke patients, 76 patients with comparable risk factors for stroke, and 48 age-balanced healthy subjects. RESULTS: Multivariate logistic analysis showed that prior stroke and FIB level predicted new events in stroke patients (p < 0.04 for both), whereas congestive heart failure (p < 0.02) and creatinine level (p < 0.006) were predictive in at-risk patients. After controlling for infection, FIB, CRP, and PMN levels at baseline were higher in at-risk but not in stroke patients with recurrent events (p < 0.05 for all). At 1 year, FIB levels remained elevated in event-free stroke survivors compared with levels in the risk and control groups (p < 0.001 for both). FIB also remained higher in stroke survivors who had atheroembolism (AE) compared with non-AE stroke survivors (381+/-72 versus 342+/-78 mg/dL, p < 0.02). Peripheral vascular disease was an independent predictor (p < 0.0001) of longitudinal FIB in stroke survivors. Of note, both WBC and PMN levels were chronically elevated in patients with stroke risk factors and in stroke survivors (p < 0.0001 for both) compared with healthy elderly subjects. CONCLUSIONS: Most acute-phase markers decline gradually after stroke, but FIB remains significantly elevated and is associated with increased risk for recurrent vascular events
Lipoprotein(a) in the arterial wall. Beisiegel U, Niendorf A, Wolf K, et al. Eur Heart J. 1990 Aug; 11 Suppl E:174-83. We compared CHD patients with healthy blood donors to confirm the role of Lp(a) as an independent risk factor. More important, we performed biochemical and immunohistochemical studies to evaluate the potential mechanism by which Lp(a) causes CHD. We measured the Lp(a) concentration in comparison with other lipoprotein parameters in fresh human arterial wall biopsies and, in autopsy tissue, we localized apo (a) and apo B, as well as fibrin, with immunohistochemical methods in different vessel areas. Density gradient ultracentrifugation was used to analyse lipoprotein fractions isolated from human arterial wall. Lp(a) accumulates in the intima, preferentially in plaque areas, dependent on the serum Lp(a) level. Most of the Lp(a) can be located extracellularly, but apo(a) can also be detected in foam cells. A strong co-localization has been observed for apo(a) and apo B; only a few areas containing only apo B were detected. Moreover, a striking co-localization for apo(a) and fibrin was found. The possibilities for the pathways by which Lp(a) enters the arterial wall and accumulates extracellularly are discussed on the basis of the present data and recent data published by other groups
The white blood cell and plasma fibrinogen in thrombotic stroke. A significant correlation. Belch J, McLaren M, Hanslip J, et al. Int Angiol. 1998 Jun; 17(2):120-4. OBJECTIVES: Thrombotic stroke is a common disorder with considerable mortality and morbidity. Risk factors for stroke include cigarette smoking, hypertension and hyperlipidaemia and these have been linked to abnormalities of haemorrheology and coagulation such as increased fibrinogen. Other haemorrheological abnormalities have also been documented. These include an elevation in the white blood cell (WBC) count. The aim of our study was to evaluate plasma fibrinogen, WBC aggregation and the release of free radicals in thrombotic stroke. EXPERIMENTAL DESIGN: Thirty-four patients with thrombotic stroke were enrolled in the study. The data were compared to 58 matched controls. SETTING: This study was carried out in Ninewells Hospital, Dundee on patients previously admitted to the medical wards with acute stroke. MEASURES: Plasma fibrinogen, WBC aggregation and plasma malondialdehyde (MDA) were measured in this study. RESULTS: As expected, the stroke patients have a significantly higher fibrinogen level (4.3+/-1.2 g/dl versus 3.1+/-0.6, p<0.001). WBC aggregation is also increased in the patient group (47.5+/-10.4% versus 42.7+/-10.6, p="0.036)," as is plasma MDA (8.6+/-2.0 micromol/l versus 7.1+/-1.07, p<0.001). The factor VIII von Willebrand factor antigen measured as a marker as vascular damage was also significantly higher in the patient group (251+/-87% versus 182+/-64, p<0.001). There was also a statistically significant correlation between fibrinogen level and WBC aggregation, and fibrinogen and MDA. These are both statistically significant p="0.012" and p<0.001 respectively. CONCLUSIONS: We believe our study suggests that enhanced WBC aggregation/adhesion with release of free radicals may be another mechanism whereby fibrinogen exerts its known detrimental effect in stroke development. This may allow planning of therapeutic strategies as yet undeveloped
S-adenosylmethionine treatment of depression: a controlled clinical trial. Bell KM, Plon L, Bunney WE, Jr., et al. Am J Psychiatry. 1988 Sep; 145(9):1110-4. The antidepressant properties of S-adenosylmethionine, an endogenous methyl donor, were studied in inpatients who met the DSM-III criteria for major depression. Nine patients given intravenous S-adenosylmethionine and nine given low oral doses of imipramine were compared in a double-blind design for 14 days. The S-adenosylmethionine produced superior results by the end of the first week of treatment. By the end of the second week, 66% of the S-adenosylmethionine patients had a clinically significant improvement in depressive symptoms, compared to 22% of the imipramine patients. Side effects appeared to be fewer with S-adenosylmethionine than with imipramine during the last 5 days of the study
Cations of cisternal cerebrospinal fluid in humans and the effect of different doses of nimodipine on CSF calcium after stroke. Bereczki D, Fekete I, Loof I, et al. Clin Neuropharmacol. 2000 Nov; 23(6):318-23. Cisternal samples of cerebrospinal fluid (CSF) were analyzed for protein, albumin, sodium (Na), potassium (K), and calcium (Ca) content in 21 control subjects and 64 patients who had experienced acute stroke. A second cisternal CSF sample was taken in 37 of the stroke patients after 2-3 weeks treatment with the calcium antagonist nimodipine. Increased permeability of the blood-brain barrier was reflected by the significantly higher CSF/serum ratio of albumin in stroke patients than in control subjects (0.0046 vs. 0.0028,p = 0.0012). Serum and CSF concentrations of Na, K, and Ca did not differ between control subjects and stroke patients. In control subjects and in stroke patients, concentration of calcium in cisternal CSF ([Ca]) was smaller than values reported by others in lumbar samples. In stroke patients, the pH of CSF was lower than that of simultaneously taken blood (7.38 vs. 7.44, p < 0.001). No differences between stroke patients and control subjects were found for the cisternal CSF/serum ratios of Na (1.0 and 0.99), K (0.61 and 0.63), and Ca (0.25 and 0.24). When patients and controls were pooled together, CSF total [Ca] correlated weakly with serum total [Ca] (Spearman r = "0.28," p = "0.014)" and with serum ionized [Ca] (Spearman r = "0.27," p = "0.016)." After 2-3 weeks of nimodipine treatment, CSF [Ca] was significantly lower in the subgroup treated with 60 mg nimodipine four times daily (240 mg/d) than with 30 mg four times daily. A nimodipine dosage of 30 mg four times daily (120 mg/d) did not affect CSF [Ca]. A 240 mg daily dosage, but not a 120 mg daily dosage, of nimodipine may affect the Ca transport system in humans at the choroid plexus
Antiinflammatory activities of procyanidin-containing extracts from Pinus pinaster Ait. after oral and cutaneous application. Blazso G, Gabor M, Rohdewald P. Pharmazie. 1997 May; 52(5):380-2. Orally in liquid diet administered procyanidin-containing extracts from Pinus pinaster Ait. decreased the croton oil-induced ear edema in mice or the compound 48/80-induced hind paw edema in rats to a statistically significant extent. Most effective were the extracts containing mainly oligomeric procyanidins with chain lengths greater then 4 units (extracts A or B). Further, the different extracts incorporated in various concentrations (1.0, 3.0 or 0.1%) in 5% hydroxyethylcellulose gel and applied topically on the shaved back of rats, inhibited significantly the ultraviolet radiation-induced increased capillary permeability. In these experiments, normalisation of capillary permeability was not correlated with the content of the extracts on higher oligomeric procyanidins
Lifestyle factors and stroke risk: exercise, alcohol, diet, obesity, smoking, drug use, and stress. Boden-Albala B, Sacco RL. Curr Atheroscler Rep. 2000 Mar; 2(2):160-6. Various lifestyle factors have been associated with increasing the risk of stroke. These include lack of exercise, alcohol, diet, obesity, smoking, drug use, and stress. Guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health recommend that Americans should exercise for at least 30 minutes of moderately intense physical activity on most, and preferably all, days of the week. Recent epidemiologic studies have shown a U-shaped curve for alcohol consumption and coronary heart disease mortality, with low-to-moderate alcohol consumption associated with lower overall mortality. High daily dietary intake of fat is associated with obesity and may act as an independent risk factor or may affect other stroke risk factors such as hypertension, diabetes, hyperlipidemia, and cardiac disease. Homocysteine is another important dietary component associated with stroke risk, while other dietary stroke risk factors are thought to be mediated through the daily intake of several vitamins and antioxidants. Smoking, especially current smoking, is a crucial and extremely modifiable independent determinant of stroke. Despite the obstacles to the modification of lifestyle factors, health professionals should be encouraged to continue to identify such factors and help improve our ability to prevent stroke
The effect of vitamin C on blood lipids, fibrinolytic activity and platelet adhesiveness in patients with coronary artery disease. Bordia AK. Atherosclerosis. 1980 Feb; 35(2):181-7. Forty patients with past history myocardial infarction were divided into three groups. Group I served as controls, while Groups II and III were given respectively, 1 g and 2 g vitamin C daily, divided in two doses. Samples were collected initially, and then every 2 months during the 6-month period of vitamin C administration and finally 2 months after stopping vitamin C. Vitamin C, 0.5 g twice daily (Group II), increased serum ascorbic acid by about 22% (P less than 0.05). However, no significant changes were observed in fibrinolytic activity or blood lipids. When the dose of vitamin C was doubled, serum ascorbic acid increased by about 96% and fibrinolytic activity increased by 45% (P less than 0.01), while the platelet adhesive index decreased by 27% (P less than 0.01). The serum cholesterol level dropped by 12% (P less than 0.05) and a significant decrease in serum beta lipoproteins and an increase in the alpha fraction was also seen. A further 40 patients with acute myocardial infarction were divided into two groups; one received 2 g vitamin C daily for the first 20 days and the other received a placebo. Blood samples were collected every 10th day during the 40-day follow up. Vitamin C administration increased fibrinolytic activity by 62.5%, while serum ascorbic acid rose by 94%
Therapeutic conduct in light of a cerebral vascular accident and the use of CDP-choline. Boudouresques AB. 1980;
The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Broderick J, Brott T, Kothari R, et al. Stroke. 1998 Feb; 29(2):415-21. BACKGROUND AND PURPOSE: The Greater Cincinnati/Northern Kentucky Stroke Study was designed to be the first large, population-based metropolitan study of temporal trends in stroke incidence rates and outcome within a biracial population. METHODS: We are identifying all hospitalized and autopsied cases of stroke and transient ischemic attack (TIA) among the 1.3 million inhabitants of a five-county region of Greater Cincinnati/Northern Kentucky for the period 7/1/93-6/30/94. We have already prospectively monitored for out-of-hospital stroke and TIAs for this same time period at 128 screening sites, including a random sample of all primary care physicians and nursing homes in the region. We have already identified all hospitalized and autopsied cases of stroke and TIA among blacks for 1/1/93-6/30/93 and report preliminary incidence rates for this 6-month period. RESULTS: The overall incidence rate for all first-ever hospitalized or autopsied stroke (excluding TIAs) among blacks in the Greater Cincinnati region was 288 per 100000 (95% CI, 250 to 325, age- and sex-adjusted to 1990 US population). The overall incidence rate for first-ever and recurrent stroke (excluding TIAs) was 411 per 100000 (95% CI, 366 to 456). By comparison, the overall incidence rate of first-ever stroke among whites in Rochester, Minn, during the period 1985-1989 was 179 per 100000 (95% CI, 164 to 194, age- and-sex adjusted to 1990 US population). The incidence rates among blacks in Greater Cincinnati were substantially greater than the rates among whites in Rochester, Minn, for all age categories except ages 75 and older, for which the rates were similar. CONCLUSIONS: We conservatively estimate that 731100 first-ever or recurrent strokes occurred in the United States during 1996. Studies of first-ever as well as total stroke among biracial and representative populations are critical for understanding temporal trends in the incidence rate and the burden of stroke in the US population
Guidelines for the management of spontaneous intracerebral hemorrhage. Broderick JPAHPBW. Stroke. 1997;(28):1-5.
Early hemorrhage growth in patients with intracerebral hemorrhage. Brott T, Broderick J, Kothari R, et al. Stroke. 1997 Jan; 28(1):1-5. BACKGROUND AND PURPOSE: The goal of the present study was to prospectively determine how frequently early growth of intracerebral hemorrhage occurs and whether this early growth is related to early neurological deterioration. METHODS: We performed a prospective observational study of patients with intracerebral hemorrhage within 3 hours of onset. Patients had a neurological evaluation and CT scan performed at baseline, 1 hour after baseline, and 20 hours after baseline. RESULTS: Substantial growth in the volume of parenchymal hemorrhage occurred in 26% of the 103 study patients between the baseline and 1-hour CT scans. An additional 12% of patients had substantial growth between the 1- and 20-hour CT scans. Hemorrhage growth between the baseline and 1-hour CT scans was significantly associated with clinical deterioration, as measured by the change between the baseline and 1-hour Glasgow Coma Scale and National Institutes of Health Stroke Scale scores. No baseline clinical or CT prediction of hemorrhage growth was identified. CONCLUSIONS: Substantial early hemorrhage growth in patients with intracerebral hemorrhage is common and is associated with neurological deterioration. Randomized treatment trials are needed to determine whether this early natural history of ongoing bleeding and frequent neurological deterioration can be improved
Prospects of the clinical utilization of melatonin. Bubenik GA, Blask DE, Brown GM, et al. Biol Signals Recept. 1998 Jul; 7(4):195-219. This review summarizes the present knowledge on melatonin in several areas on physiology and discusses various prospects of its clinical utilization. Ever increasing evidence indicates that melatonin has an immuno-hematopoietic role. In animal studies, melatonin provided protection against gram-negative septic shock, prevented stress-induced immunodepression, and restored immune function after a hemorrhagic shock. In human studies, melatonin amplified the antitumoral activity of interleukin-2. Melatonin has been proven as a powerful cytostatic drug in vitro as well as in vivo. In the human clinical field, melatonin appears to be a promising agent either as a diagnostic or prognostic marker of neoplastic diseases or as a compound used either alone or in combination with the standard cancer treatment. Utilization of melatonin for treatment of rhythm disorders, such as those manifested in jet lag, shift work or blindness, is one of the oldest and the most successful clinical application of this chemical. Low doses of melatonin applied in controlled-release preparation were very effective in improving the sleep latency, increasing the sleep efficiency and rising sleep quality scores in elderly, melatonin-deficient insomniacs. In the cardiovascular system, melatonin seems to regulate the tone of cerebral arteries; melatonin receptors in vascular beds appear to participate in the regulation of body temperature. Heat loss may be the principal mechanism in the initiation of sleepiness caused by melatonin. The role of melatonin in the development of migraine headaches is at present uncertain but more research could result in new ways of treatment. Melatonin is the major messenger of light-dependent periodicity, implicated in the seasonal reproduction of animals and pubertal development in humans. Multiple receptor sites detected in brain and gonadal tissues of birds and mammals of both sexes indicate that melatonin exerts a direct effect on the vertebrate reproductive organs. In a clinical study, melatonin has been used successfully as an effective female contraceptive with little side effects. Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity and hyperbaric oxygen exposure. In the digestive tract, melatonin reduced the incidence and severity of gastric ulcers and prevented severe symptoms of colitis, such as mucosal lesions and diarrhea
Effect of policosanol on experimental thrombosis models. Carbajal D, Arruzazabala ML, Mas R, et al. Prostaglandins Leukot Essent Fatty Acids. 1994 May; 50(5):249-51. Policosanol is a natural product, obtained from sugar cane wax (Saccharum officinarum L.) with which cholesterol-lowering effects have been demonstrated in experimental models, healthy volunteers and hypercholesterolemic patients. The effects of policosanol on experimental venous and arterial thrombosis in rats were investigated. Policosanol (25 mg/kg) significantly decreased the thrombus weight, in the venous thrombosis models, the protective effect persisting until 4 h after its oral administration. Policosanol (25 mg/kg single dose) was able to reduce rectal temperature variation induced by arterial thrombosis. Also at the same dose policosanol increased 6-keto-PGF1 alpha serum levels in rats
Effect of policosanol on platelet aggregation and serum levels of arachidonic acid metabolites in healthy volunteers. Carbajal D, Arruzazabala ML, Valdes S, et al. Prostaglandins Leukot Essent Fatty Acids. 1998 Jan; 58(1):61-4. Policosanol is a cholesterol-lowering drug with hypocholesterolemic effects demonstrated in experimental models, healthy volunteers and patients with type II hypercholesterolemia. In addition, antiplatelet effects of policosanol have been shown in experimental models and healthy volunteers. This study reports the results of a 2-week, randomized, double-blind, placebo-controlled trial investigating the effects of policosanol on platelet aggregation and thromboxane B2 and prostacyclin (6 keto PGF1alpha) production after stimulation with collagen in healthy volunteers. The volunteers were on a placebo-baseline period for 7 days and thereafter they received randomly, under double-blind conditions, placebo or policosanol (10 mg/day) for 15 days. Platelet aggregation was determined at baseline and after 15 days of treatment. Significant reductions of arachidonic acid and collagen-induced platelet aggregation were observed. Thromboxane, but not prostacyclin, generation induced by collagen was also inhibited by policosanol
Neuroprotective effect of aminoguanidine on transient focal ischaemia in the rat brain. Cash D, Beech JS, Rayne RC, et al. Brain Res. 2001 Jun 29; 905(1-2):91-103. Using serial magnetic resonance imaging we have evaluated the effectiveness of aminoguanidine (AG) as a neuroprotective agent in a rat model of transient middle cerebral artery occlusion (MCAO). Because aminoguanidine's neuroprotective properties have primarily been ascribed to its action as iNOS inhibitor, we also performed a biochemical analysis of nitric oxide metabolites and NOS isoforms in our model of ischaemia. Daily injections of AG (100 mg/kg) or saline, were started at 6 h after the occlusion and the effects of this treatment on lesion progression monitored by T(2)-weighted MRI at 6 (pre-treatment scan), 24 and 72 h. Measurements of lesion volumes showed that between 6 and 72 h post-MCAO, lesion growth was slower in AG-treated rats than in control rats. This difference was most pronounced between 24 and 72 h post-MCAO when AG halted the lesion volume expansion observed in control rats. Measurements of plasma NOx (nitrite plus nitrate) at 0, 24, 48 and 72 h after MCAO, showed that NO levels did not differ significantly between the AG- and saline-treated groups at any time-point. Moreover, NOS activity assays revealed that no iNOS activity was present in any of the brains tested and that constitutive neuronal NOS activity was similar across the two hemispheres between both groups. The absence of iNOS protein in the ischaemic and contralateral hemispheres at 48 and 72 h after MCAO (control group only) was confirmed by Western blot analysis. These results suggest that AG treatment reduces the rate of growth of ischaemic lesions, perhaps preserving the functioning of perifocal neurons. Our observations contradict suggestions that high levels of NO generated by iNOS are partially responsible for exacerbating the neuronal damage in the postischaemic phase of MCAO. Although this does not rule out a role for AG as a neuroprotective agent via its ability to inhibit iNOS, these findings indicate that neuroprotective actions of AG may also be mediated via other cellular targets
Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients. Castano G, Mas R, Arruzazabala ML, et al. Int J Clin Pharmacol Res. 1999; 19(4):105-16. This randomized, double-blind study was undertaken to compare the effects of policosanol and pravastatin administered at 10 mg/day on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk. After 6 weeks on a lipid-lowering diet, patients with low-density lipoprotein (LDL) cholesterol levels > 3.4 mmol/l were randomized to receive, under double-blind conditions, policosanol or pravastatin 10 mg tablets that were taken with the evening meal for 8 weeks. Policosanol significantly (p < 0.00001) lowered LDL-cholesterol (19.3%), total cholesterol (13.9%) and the ratios of LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol (28.3%) and total cholesterol/HDL-cholesterol (24.4%). Pravastatin significantly (p < 0.00001) lowered LDL-cholesterol (15.6%), total cholesterol (11.8%) and the ratios (p < 0.0001) of LDL-cholesterol/HDL-cholesterol (18.9%) and total cholesterol/HDL-cholesterol (15.7%). Policosanol, but not pravastatin, significantly increased (p < 0.001) levels of HDL-cholesterol (18.4%) and reduced (p < 0.01) triglycerides (14.1%). Policosanol was more effective (p < 0.05) than pravastatin in inhibiting platelet aggregation induced by all agonists and it significantly reduced (p < 0.0001) platelet aggregation induced by arachidonic acid at 1.5 and 3 mmol/l by 42.2% and 69.5%, respectively, platelet aggregation induced by collagen 0.5 microgram/ml (p < 0.05) (16.6%) and that induced by adenosine diphosphate 1 mumol/l (p < 0.01) (20.3%). Pravastatin significantly reduced (p < 0.001) (27%) only platelet aggregation induced by arachidonic acid 3 mmol/l. Both drugs significantly decreased (p < 0.00001) endothelemia levels but final values were significantly lower (p < 0.001) in the policosanol than in the pravastatin group. Both treatments were safe and well tolerated. Pravastatin significantly (p < 0.01) increased serum levels of alanine amine transferase but individual values remained within normal. Two patients on pravastatin discontinued the study because of adverse experiences (myocardial infarction and jaundice, respectively). In conclusion, the effects of policosanol (10 mg/day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of pravastatin
Randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke. CASTCG. Lancet. 1997; 349(9066):1641-9.
Nitric oxide-related brain damage in acute ischemic stroke. Castillo J, Rama R, Davalos A. Stroke. 2000 Apr; 31(4):852-7. BACKGROUND AND PURPOSE: The neurotoxic and neuroprotective role of nitric oxide (NO) in experimental cerebral ischemia has generated considerable debate. The aim of this study was to analyze the relationship between NO metabolite (NO-m) concentrations in cerebrospinal fluid (CSF) and clinical and neuroimaging parameters of brain injury in patients with acute ischemic stroke. METHODS: We studied 102 patients and 24 control subjects who were included in a larger previous study conducted to analyze risk factors of progressing stroke. NO generation was calculated by quantifying nitrates and nitrites with a colorimetric assay in CSF samples obtained within the first 24 hours from symptoms onset. Early neurological deterioration was defined as a fall of 1 or more points in Canadian Stroke Scale score between admission and 48 hours after inclusion. Infarct volume was measured on days 4 to 7 by cranial CT. RESULTS: Median NO-m concentrations [quartiles] were 2.1 [1.0, 4.5] micromol/mL in patients and 1.0 [1.0, 1.0] micromol/mL in control subjects (P<0.0001). In 45 patients with subsequent early neurological deterioration, NO-m levels in CSF were significantly higher than in those with stable stroke (4.0 [1.7, 7.8] versus in 1. 6 [1.0, 2.5] micromol/mL, P<0.0001). There was a moderate correlation between NO-m and infarct volume (coefficient 0.39, P5.0 micromol/mL were significantly associated with early neurological worsening (OR 5.7, 95% CI 1.2 to 27.4; P=0.030) independent of other important factors related to progressing stroke, such as CSF glutamate levels. CONCLUSIONS: Our clinical findings suggest an important role of NO generation in acute ischemic stroke. Increased NO-m in CSF are associated with a greater brain injury and early neurological deterioration
Total plasma antioxidant capacity predicts thrombosis-prone status in NIDDM patients. Ceriello A, Bortolotti N, Pirisi M, et al. Diabetes Care. 1997 Oct; 20(10):1589-93. OBJECTIVE: To explore the hypothesis that a relationship exists between free radical activity and abnormalities in hemostasis in NIDDM. RESEARCH DESIGN AND METHODS: The use of the total radical-trapping antioxidant parameter (TRAP) has very recently been proposed to explore the antioxidant property of a plasma and their mutual cooperation. In the present study, TRAP, vitamin E, vitamin C, vitamin A, uric acid, protein-bound SH (thiol) groups, fibrinogen, prothrombin fragments F1 + 2, and D-dimer have been evaluated in 46 NIDDM patients and 47 healthy matched control subjects. RESULTS: In NIDDM patients, TRAP, vitamin A, SH groups, and uric acid were significantly reduced, whereas the level of vitamin E was significantly increased. Vitamin C was similar in the two groups. Fibrinogen, prothrombin fragment 1 + 2, and D-dimer were increased in diabetic patients. TRAP, but no single other antioxidant, had a strong inverse association with fibrinogen, prothrombin fragment 1 + 2, and D-dimer. CONCLUSIONS: These findings are consistent with the hypothesis that oxidative stress may condition coagulation activation in diabetics. However, the data suggest that it is the total antioxidant capacity rather than any single plasma antioxidant that is the most relevant parameter
Testosterone supplementation improves spatial and verbal memory in healthy older men. Cherrier MM, Asthana S, Plymate S, et al. Neurology. 2001 Jul 10; 57(1):80-8. OBJECTIVE: To determine the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. BACKGROUND: Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with reductions in muscle mass, osteoporosis, decreased sexual activity, and changes in cognition. METHODS: Twenty-five healthy, community-dwelling volunteers, aged 50 to 80 years, completed a randomized, double-blind, placebo-controlled study. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Cognitive evaluations were conducted at baseline, week 3, and week 6 of treatment by use of a battery of neuropsychologic tests. RESULTS: Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Because of aromatization of testosterone, estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with baseline and the placebo group, although improvements were not evident for all measures. CONCLUSIONS: The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. However, it remains unclear whether these improvements in cognition are attributable to increased testosterone or estradiol levels, or both. The potential role of testosterone vs its metabolites on cognition requires further research
Neuroprotection in acute stroke. Chua HC, Ng PY. Ann Acad Med Singapore. 2001 Mar; 30(2):134-42. PURPOSE: To highlight recent advances in neuroprotection in acute stroke. DATA SOURCES: A MEDLINE search was conducted from January 1985 to November 2000. Key words included neuroprotection, cerebrovascular, subarachnoid haemorrhage, perioperative stroke, hypothermia and apopotosis. All articles in English were considered for review. Additional articles were identified from the references of the retrieved articles and cross-referencing selected articles. DATA EXTRACTION: All clinical studies and review articles and abstracts were reviewed. DATA SYNTHESIS: The neuronal cells of the central nervous system are susceptible to various forms of insult such as ischaemia and haemorrhage. Each step along the ischaemic cascade is a potential target for therapeutic intervention. Neuroprotective agents are designed to minimise cellular injury and salvage brain tissue. In cerebral ischaemia, only thrombolysis had been shown to improve clinical outcome. Neuroprotective therapy has definite benefits in animals but not in humans. It may potentially extend the time window for thrombolysis. In aneurysmal subarachnoid haemorrhage, the only agent with proven efficacy is nimodipine. Research is ongoing in the development of new drugs. Currently several phase III trials are in progress. CONCLUSION: There is substantial optimism in the development of neuroprotective therapy to improve outcome in stroke patients
A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Clark WM, Warach SJ, Pettigrew LC, et al. Neurology. 1997 Sep; 49(3):671-8. Citicoline (CDP-choline) is a key intermediary in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. It has been shown to produce beneficial effects in both animal models and non-US clinical stroke trials. This study comprised a randomized (3 doses of citicoline to 1 placebo), vehicle-controlled, double-blind trial at 21 US centers. Treatment was to be started within 24 hours of stroke onset and was continued orally for 6 weeks. Final outcome assessments were at 12 weeks. Two hundred fifty-nine patients were enrolled, with approximately 65 in each of the four groups. Mean time from stroke onset to treatment was 14.5 hours, and there were no significant differences in baseline characteristics between the four groups except for patient weight. A significant difference between the groups, favoring citicoline treatment, was seen in terms of functional outcome as measured by the Barthel Index and Rankin scale, neurologic evaluation as measured by the National Institutes of Health (NIH) stroke scale, and cognitive function as measured by the Mini Mental Status Examination. When the baseline NIH stroke scale was used as a covariate, both the 500-mg citicoline group and the 2,000-mg citicoline group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. This study suggests that oral citicoline can be used safely with minimal side effects in acute stroke treatment. Citicoline appears to improve functional outcome and reduce neurologic deficit with 500 mg of citicoline appearing to be the optimal dose
A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Clark WM, Williams BJ, Selzer KA, et al. Stroke. 1999 Dec; 30(12):2592-7. BACKGROUND AND PURPOSE: Citicoline (cytidine-5'-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects. METHODS: The current trial was a 33-center, randomized, double-blind, efficacy trial in 394 patients comparing placebo (n=127) with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week posttreatment follow-up period. Patients with acute (24 hours) ischemic strokes clinically assessed to be in the middle cerebral artery territory with National Institutes of Health Stroke Scale (NIHSS) > or = 5 were enrolled. RESULTS: Mean time to treatment was 12 hours, and mean age was 71 for placebo and 70 for citicoline. Although mean baseline NIHSS were similar for both groups, there was a higher percentage of placebo patients with NIHSS <8 (34% vs 22%; P or = 95 at 12 weeks (last observation carried forward: placebo 40%; citicoline 40%) or mortality rate (placebo 18%; citicoline 17%). However, post hoc analyses in a subgroup of patients with baseline NIHSS > or = 8 found that citicoline-treated patients were more likely to have a full recovery (Barthel > or = 95): placebo 21%; citicoline 33%; P=0.05; whereas no difference was seen in patients with baseline NIHSS0.1. CONCLUSIONS: The results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit
Efficacy of antioxidant therapies in transient focal ischemia in mice. Clark WM, Rinker LG, Lessov NS, et al. Stroke. 2001 Apr; 32(4):1000-4. BACKGROUND AND PURPOSE: Ginkgo biloba extract (EGb) and alpha-lipoic acid (LA) are commercially available "antioxidant supplements" with a variety of actions that may be beneficial during acute stroke. These actions include inhibiting platelet and leukocyte activation and adhesion, reducing free radical generation, and increasing cerebral blood flow. Both EGb and LA have been shown to be neuroprotective in cell culture and global central nervous system ischemia models. In this study we investigated the neuroprotective efficacy of EGb and LA in a clinically relevant, transient focal central nervous system ischemic model. METHODS: In the EGb study, 60 adult C57blk mice were randomized to treatment with EGb given orally (via gavage) for 7 days: low dose, 50 EGb mg/kg daily; high dose, 100 mg/kg daily; matched placebo. On day 7, reversible middle cerebral artery occlusion was produced by advancing a silicone-coated 8-0 filament into the internal carotid artery for 45 minutes followed by reperfusion. At 24 hours, the animals were evaluated on a 28-point clinical scale, and infarct volume was determined with the use of triphenyltetrazolium chloride. In the LA study, 24 C57blk mice were treated with 100 mg/kg SC of LA or placebo 1.5 hours before transient MCAO, as in the EGb study. RESULTS: In the EGb study, values for infarct volume at 24 hours were as follows (mean+/-SD): low dose (n=18), 13+/-5 mm(3); high dose (n=22), 22+/-12 mm(3); placebo (n=20), 20+/-10 mm(3) (P:=0.03 overall; P=0.02, low dose versus placebo). Infarct percentage of hemisphere values were as follows: low dose, 14+/-5%; high dose, 21+/-11%; placebo, 20+/-9% (P=0.03 overall; P=0.02, low dose versus placebo). Ten percent of the high-dose group showed significant intracerebral hemorrhage (ICH) within the infarct, while no ICH was seen in the other groups. Neurological function scores were as follows: low dose, 11.8+/-1.5; high dose, 11.4+/-1.7; placebo, 11.3+/-1.8 (P=NS). In the LA study, infarct volume was as follows: 100 mg/kg LA (n=12), 16.8+/-8.3 mm(3); placebo (n=12), 27.2+/-14.6 mm(3) (P<0.05). LA also produced a significant improvement in neurological function at 24 hours: LA, 9.5+/-1.2; placebo, 11.2+/-1.8 (P="0.02)." There was no evidence of ICH in any of the animals. CONCLUSIONS: Both oral EGb and LA therapies produced significant reductions in stroke infarct volume. However, for EGb this beneficial effect appears to be dose related, with higher doses potentially increasing the risk of ICH
Citicoline treatment for experimental intracerebral hemorrhage in mice. Clark WMG-RL. Stroke. 1998; 29(10):2136-40.
Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Cockroft KM, Meistrell M, III, Zimmerman GA, et al. Stroke. 1996 Aug; 27(8):1393-8. BACKGROUND AND PURPOSE: During a cerebral infarction, a complex cascade of cytotoxic events ultimately determines the volume of brain cell loss. The studies presented here demonstrate that aminoguanidine, an experimental therapeutic currently in clinical trials to prevent diabetic complications, is cerebroprotective in focal cerebral infarction. METHODS: Adult Lewis rats (n = 6 to 12 per group) were anesthetized with ketamine and subjected to focal cerebral infarction by tandem permanent occlusion of the right middle cerebral artery and ipsilateral common carotid artery (CCA), followed by temporary occlusion of the contralateral CCA. Infarct volume (cortical) was assessed 24 hours after the onset of ischemia by planimetric analysis of coronal brain slices stained with tetrazolium. RESULTS: Aminoguanidine (320 mg/kg IP) administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume (7.6 +/- 2.6% of hemisphere in controls versus 1.3 +/- 0.2% of hemisphere in aminoguanidine-treated rats; P < .05). Administration of aminoguanidine conferred significant cerebroprotection even when administered 1 or 2 hours after the onset of ischemia (88% and 85% reduction from control, respectively; P < .05). Cerebroprotection by aminoguanidine was independent of systemic physiological variables known to influence stroke size (eg, temperature, mean arterial blood pressure, blood glucose, and arterial pH, PCO2, and PO2). CONCLUSIONS: These results indicate that the stroke-reducing properties of aminoguanidine are dose and time dependent, with substantial cerebroprotection persisting even with drug delivery up to 2 hours after the onset of ischemia. It is now plausible to pursue development of aminoguanidine as an experimental therapeutic in stroke, and possible mechanisms of these cerebroprotective effects are under consideration
Silent infarcts in stroke patients: patient characteristics and effect on 2-year outcome. Corea F, Henon H, Pasquier F, et al. J Neurol. 2001 Apr; 248(4):271-8. Although silent infarcts (SIs) are frequent in stroke patients, their clinical significance remains controversial, and their effect on stroke outcome remains unclear. This study evaluated the prevalence of SI on computed tomography, associated factors, and the effect on outcome in stroke patients. We studied 202 consecutive patients admitted for acute ischaemic or haemorrhagic stroke with clinical deficits lasting more than 24 h. Survivors were followed up for 24 months; no patient was lost to follow-up. Patients with Rankin scores of 2 or lower were considered separately. New vascular events were also recorded. Computed tomography showed that one-fourth of patients (52/202) had at least one SI; these were located in deep hemispheric areas in 46 patients, superficial hemispheric areas in 5, and the posterior fossa in 7. Logistic regression analysis showed the factors independently associated with SI to be severe leukoaraiosis (OR 1.71, 95% CI 1.26-2.31) and small-vessel occlusion as presumed cause of the index stroke (OR 2.66, 95% CI 1.22-5.79). SI did not affect vital or functional outcome or the occurrence of new vascular events within 2 years after stroke. Whether they affect cognitive outcome remains under evaluation over a longer follow-up period
CDP-choline for cerebrovascular disorders: clinical evaluation and evaluation of electrophysiological symptomology. Corso AAM. Clin Ter. 1982;(102):379-86.
A functional MRI study of subjects recovered from hemiparetic stroke. Cramer SC, Nelles G, Benson RR, et al. Stroke. 1997 Dec; 28(12):2518-27. BACKGROUND AND PURPOSE: Stroke recovery mechanisms remain incompletely understood, particularly for subjects with cortical stroke, in whom limited data are available. We used functional magnetic resonance imaging to compare brain activations in normal controls and subjects who recovered from hemiparetic stroke. METHODS: Functional magnetic resonance imaging was performed in ten stroke subjects with good recovery, five with deep, and five with cortical infarcts. Brain activation was achieved by index finger-tapping. Statistical parametric activation maps were obtained using a t test and a threshold of P < .001. In five bilateral motor regions, the volume of activated brain for each stroke subject was compared with the distribution of activation volumes among nine controls. RESULTS: Control subjects activated several motor regions. During recovered hand finger-tapping, stroke subjects activated the same regions as controls, often in a larger brain volume. In the unaffected hemisphere, sensorimotor cortex activation was increased in six of nine stroke subjects compared with controls. Cerebellar hemisphere contralateral and premotor cortex ipsilateral to this region, as well as supplementary motor areas, also had increased activation. In the stroke hemisphere, activation exceeding controls was uncommon, except that three of five cortical strokes showed peri-infarct activation foci. During unaffected hand finger-tapping, increased activation by stroke subjects compared with controls was uncommon; however, decreased activation was seen in unaffected sensorimotor cortex, suggesting that this region's responsiveness increased to the ipsilateral hand and decreased to contralateral hand movements. Use of a different threshold for defining activation (P < .01) did not change the overall findings (kappa = ".75)." CONCLUSIONS: Recovered finger-tapping by stroke subjects activated the same motor regions as controls but to a larger extent, particularly in the unaffected hemisphere. Increased reliance on these motor areas may represent an important component of motor recovery. Functional magnetic resonance imaging studies of subjects who recovered from stroke provide evidence for several processes that may be related to restoration of neurologic function
Comparative study of the efficacy and tolerability of policosanol and lovastatin in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. Crespo N, Illnait J, Mas R, et al. Int J Clin Pharmacol Res. 1999; 19(4):117-27. This randomized, double-blind study was undertaken to compare the efficacy and tolerability of policosanol (10 mg/day) and lovastatin (20 mg/day) in patients with hypercholesterolemia and noninsulin dependent diabetes mellitus. After 6 weeks on a lipid lowering diet, 53 patients were randomized to receive either policosanol or lovastatin tablets that were taken o.i.d. for 12 weeks under double-blind conditions. Both groups were similar at randomization. Policosanol significantly (p < 0.001) lowered low-density lipoprotein (LDL)-cholesterol (20.4%), total cholesterol (14.2%) and the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (23.7%). Lovastatin significantly (p < 0.01) lowered LDL-cholesterol (16.8%), total cholesterol (14.0%) and the ratio (p < 0.05) of LDL-cholesterol to HDL-cholesterol (14.9%). Triglyceride levels did not significantly change after therapy. Policosanol, but not lovastatin, significantly increased (p < 0.01) levels of HDL-cholesterol (7.5%). Comparison between groups showed that changes in HDL-cholesterol induced by policosanol were significantly greater (p < 0.01) than those induced by lovastatin. Both treatments were safe and well tolerated. Lovastatin moderately but significantly (p < 0.05) increased levels of aspartate aminotransferase, creatine phosphokinase and alkaline phosphatase. Adverse reactions were more frequent in the lovastatin group (p < 0.01) than in the policosanol group. In conclusion, policosanol administered at 10 mg/day produces more advantageous changes in HDL-cholesterol and has a better safety and tolerability profile than lovastatin 20 mg/day
Dissociated patterns of nocturnal prolactin, cortisol, and growth hormone secretion after stroke. Culebras A, Miller M. Neurology. 1984 May; 34(5):631-6. The secretory activity of the hypothalamic-pituitary axis is influenced by suprahypothalamic regulatory mechanisms. To evaluate the effect of brain lesions on hormonal patterns, we investigated eight patients convalescing from hemispheric stroke and five sex- and age-matched healthy volunteers. Studies were conducted during two consecutive nights with continuous polygraphic recording and sequential blood sampling. Nocturnal plasma hormone measurements showed a normal rhythm of cortisol (a marker of ACTH), elevated prolactin concentrations (p less than 0.05) and low growth hormone values (p less than 0.05). The study suggests that major suprahypothalamic lesions influence hypothalamic function so as to facilitate prolactin secretion and inhibit growth hormone release. They have no effect on the more basic pattern of ACTH-cortisol secretion, however
Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. D'Orlando KJ, Sandage BW, Jr. Neurol Res. 1995 Aug; 17(4):281-4. Citicoline is approved in Europe and Japan for use in stroke, head trauma and other neurological disorders. It is presently being evaluated in phase II/III stroke trials in the United States. Exogenous administration of CDP-choline provides both choline and cytidine which access the brain and serve as substrates for the synthesis of phosphatidylcholine, a primary neuronal membrane component; the choline also enhances brain acetylcholine synthesis. Membrane repair and regeneration is necessary for recovery from stroke. Furthermore, citicoline may alleviate free fatty acid-induced toxicity which accompanies ischemic insult. Data from many pre-clinical and clinical trials support the hypothesis that citicoline may be a safe and effective treatment for stroke
Delay in neurological attention and stroke outcome. Cerebrovascular Diseases Study Group of the Spanish Society of Neurology. Davalos A, Castillo J, Martinez-Vila E. Stroke. 1995 Dec; 26(12):2233-7. BACKGROUND AND PURPOSE: Despite efforts to reduce the delay between stroke onset and new interventional treatments, no studies have analyzed the repercussions of early neurological attention on the clinical outcome of stroke patients. METHODS: Data were obtained from 721 patients admitted consecutively for a transient ischemic attack or stroke to the neurology departments of 18 Spanish hospitals that followed the same diagnostic and therapeutic guidelines in the acute phase. Factors assessed were age, sex, Canadian Stroke Scale score on admission, previous Barthel Index, and delay before attention by the first physician, by emergency services, by a neurologist, and before hospitalization. Patients' outcomes were classified as good (Barthel Index > 60) or poor (Barthel Index < or = "60" or in-hospital death) depending on patient's functional capacity on discharge. The individual contribution of each of these variables on clinical outcome was estimated with logistic regression analysis. RESULTS: Patients in worse neurological condition on admission presented earlier to the first physician, emergency department, and neurologist. The mortality rate was not significantly modified by early or late presentation at the different medical stages. Logistic regression analysis revealed that the relative risk of poor outcome in patients seen by the neurologist after the first 6 hours from symptom onset was 5.6 (95% confidence interval, 3.4 to 9.2) (P < .0001). Multiple linear regression analysis showed that the delay before the patient received neurological attention correlated positively with the duration of hospitalization (P < .0001). The delays before the patient was seen by the first physician or the emergency department and before hospitalization were not independently related to clinical outcome or length of hospitalization. CONCLUSIONS: Early neurological attention in acute stroke is related to better functional outcome and shorter hospitalization
Concentration-response relationships for salicylate-induced ototoxicity in normal volunteers. Day RO, Graham GG, Bieri D, et al. Br J Clin Pharmacol. 1989 Dec; 28(6):695-702. 1. Ototoxicity is a common and troublesome side-effect of high-dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2. In order to investigate the relationships between aspirin dose, total and unbound plasma salicylate concentrations and ototoxicity, eight normal volunteers were dosed with aspirin 1.95, 3.25, 4.55 and 5.85 g day-1 for 1 week at each dose level, the doses being administered in random order and double-blind, 2 weeks apart. 3. Ototoxic effects measured were hearing loss in decibels (dB) over six frequencies and tinnitus intensity, estimated both by electronic matching and a fixed interval scale (FIS). Measurements were taken after steady-state concentrations of salicylate had been achieved. 4. Total and unbound plasma salicylate concentrations increased disproportionately with increasing daily doses of aspirin. The increase in the unbound salicylate was relatively greater since the percentage of salicylate unbound in plasma increased over the dose range investigated from a mean of 3.9% to 10.4%. 5. Hearing loss and tinnitus intensity increased progressively with the aspirin dosage and increasing concentrations of total and unbound plasma salicylate concentrations. These ototoxic symptoms were observed at lower concentrations of total salicylate than previously reported. 6. There was a linear relationship between hearing loss and unbound salicylate concentrations. 7. Further work is required to test the hypothesis that unbound plasma salicylate concentration is a better predictor of salicylate-induced ototoxicity than total plasma salicylate concentration
Treatment of acute ischemic stroke with piracetam. Members of the Piracetam in Acute Stroke Study (PASS) Group. De Deyn PP, Reuck JD, Deberdt W, et al. Stroke. 1997 Dec; 28(12):2347-52. BACKGROUND AND PURPOSE: Piracetam, a nootropic agent with neuroprotective properties, has been reported in pilot studies to increase compromised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome. We performed a multicenter, randomized, double-blind trial to test whether piracetam conferred benefit when given within 12 hours of the onset of acute ischemic stroke to a large group of patients. METHODS: Patients received placebo or 12 g piracetam as an initial intravenous bolus, 12 g daily for 4 weeks and 4.8 g daily for 8 weeks. The primary end point was neurologic outcome after 4 weeks as assessed by the Orgogozo scale. Functional status at 12 weeks as measured by the Barthel Index was the major secondary outcome. CT scan was performed within 24 hours of the onset of stroke but not necessarily before treatment. Analyses based on the intention to treat were performed in all randomized patients (n = 927) and in an "early treatment" population specified in the protocol as treatment within 6 hours of the onset of stroke but subsequently redefined as less than 7 hours after onset (n = 452). RESULTS: In the total population, outcome was similar with both treatments (the mean Orgogozo scale after 4 weeks: piracetam 57.7, placebo 57.6; the mean Barthel Index after 12 weeks: piracetam 55.8, placebo 53.1). Mortality at 12 weeks was 23.9% (111/464) in the piracetam group and 19.2% (89/463) in the placebo group (relative risk 1.24, 95% confidence interval, 0.97 to 1.59; P = .15). Deaths were fewer in the piracetam group in those patients in the intention-to-treat population admitted with primary hemorrhagic stroke. Post hoc analyses in the early treatment subgroup showed differences favoring piracetam relative to placebo in mean Orgogozo scale scores after 4 weeks (piracetam 60.4, placebo 54.9; P = .07) and Barthel Index scores at 12 weeks (piracetam 58.6, placebo 49.4; P = .02). Additional analyses within this subgroup, confined to 360 patients with moderate and severe stroke (initial Orgogozo scale score < 55), showed significant improvement on piracetam in both outcomes (P < .02). CONCLUSIONS: Piracetam did not influence outcome when given within 12 hours of the onset of acute ischemic stroke. Post hoc analyses suggest that piracetam may confer benefit when given within 7 hours of onset, particularly in patients with stroke of moderate and severe degree. A randomized, placebo-controlled, multicenter study, the Piracetam Acute Stroke Study II (PASS II) will soon begin
The clinical safety of high-dose piracetam--its use in the treatment of acute stroke. De Reuck J, Van Vleymen B. Pharmacopsychiatry. 1999 Mar; 32 Suppl 1:33-7. Recent post-marketing surveillance reports have confirmed the benign safety profile and lack of organ toxicity shown by piracetam during its 25 years of clinical usage. Tolerance has proved equally good with the more recent use of larger doses (up to 24 g/day) for the long-term control of cortical myoclonus and when given intravenously to patients with acute stroke. This paper provides a brief review of these findings and records the safety of piracetam as found in the Piracetam in Acute Stroke Study (PASS), a randomized multicenter placebo-controlled study in 927 patients with acute ischemic stroke. Patients receive one intravenous bolus injection of placebo or 12 g piracetam, piracetam 12 g daily for 4 weeks and maintenance treatment for 8 weeks. The major results have been reported (De Deyn et al., Stroke 28 [1997] 2347-2352). Safety was assessed taking into account adverse events including abnormal laboratory test results and mortality. Death within 12 weeks occurred more frequently in the piracetam group but the difference from placebo was not significant. Of many potential risk, prognostic and treatment-related factors examined by logistic regression, 6 contributed significantly to death of which the most important were initial severity of stroke and age. Neither treatment nor any treatment-related factor contributed significantly to death. Adverse events were similar in frequency, type and severity in piracetam and placebo groups. Events of cerebral, non-cerebral and uncertain origin likewise occurred with similar frequency. Few patients discontinued because of adverse events. There was no difference between treatments in the frequency of events associated with bleeding, including hemorrhagic transformation of infarction. An important finding was that, of 31 patients with primary hemorrhagic stroke enrolled, 3 piracetam-treated patients died compared with 6 on placebo. The results suggest that piracetam in high dosage may be given to patients with acute stroke without significant adverse effects
Predictors of brain morphology for the men of the NHLBI twin study. DeCarli C, Miller BL, Swan GE, et al. Stroke. 1999 Mar; 30(3):529-36. BACKGROUND AND PURPOSE: Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy, accumulation of abnormal cerebral white matter signals, and clinically silent stroke. We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy, amount of abnormal white matter, and stroke on MRI. METHODS: Subjects were the 414 surviving members of the prospective National Heart, Lung, and Blood Institute Twin Study, who have been examined on 4 separate occasions, spanning the 25 years between 1969-1973 and 1995-1997. Quantitative measures of brain volume, volume of abnormal white matter signal (WMHI), and volume of stroke, when present, were obtained from those participating in the fourth examination. RESULTS: The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72. 5+/-2.9 years at final examination. Average blood pressure (BP) levels were normal, although 32% of the subjects had received or were currently taking antihypertensive medications. As a group, 31% had symptomatic cardiovascular disease, 11% had symptomatic cerebrovascular disease, and 8% had symptomatic peripheral vascular disease. Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume. Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes. In addition, the magnitude of orthostatic BP change was significantly associated with WMHI volume. Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease, without significant differences in the prevalence of hypertension treatment. CONCLUSIONS: Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease. Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease, extensive WMHI may be a subclinical expression of cerebrovascular disease. Careful treatment of midlife BP elevations may diminish these later-life brain changes
C-reactive protein in ischemic stroke: an independent prognostic factor. Di Napoli M, Papa F, Bocola V. Stroke. 2001 Apr; 32(4):917-24. BACKGROUND AND PURPOSE: There is growing evidence of the prognostic importance of C-reactive protein (CRP) in ischemic stroke. However, the independent value of CRP at different stages after stroke has not been established. Therefore, we assessed the prognostic values of CRP in ischemic stroke. We also compared the relation of CRP at admission and discharge with 1-year outcome. METHODS: One hundred ninety-three patients were included in a derivation set (n=128) and a validation set (n=65). Serum CRP was measured, within 24 hours after index ischemic stroke, within 48 to 72 hours, and at hospital discharge. We examined the association between the level of CRP at different stages after stroke and outcome. We adjusted for the possible confounding effect using a multivariate Cox proportional hazard model. RESULTS: A cutoff point of 1.5 mg/dL for CRP at discharge provided optimum sensitivity and specificity for adverse outcome, based on the receiver operator curves. CRP at admission (hazard ratio [HR] 2.78, 95% CI 1.45 to 5.33; P=0.0021) and discharge (HR 9.42, 95% CI 4.27 to 19.05; P<0.0001) were predictors of the combined end point of new vascular events or death at 1 year. CRP at hospital discharge was the strongest independent marker of adverse outcome (HR 7.42, 95% CI 2.75 to 20.03; P="0.0001)." These results were confirmed in the validation set (HR 15.66, 95% CI 3.36 to 72.97; P="0.0005)." CONCLUSIONS: CRP is a marker of increased 1-year risk in ischemic stroke. CRP at discharge is better related to later outcome and could be of greater utility for risk stratification. These findings are consistent with the hypothesis that elevated CRP may predict future cardiovascular events or death
Subacute but not acute generation of nitric oxide in focal cerebral ischemia. Fassbender K, Fatar M, Ragoschke A, et al. Stroke. 2000 Sep; 31(9):2208-11. BACKGROUND AND PURPOSE: Excessive release of nitric oxide (NO) has been implicated in the pathophysiology of neurodegeneration in ischemic stroke. We compared intracerebral release of indicators of NO generation at the acute and subacute stages of transient focal cerebral ischemia. METHODS: In vivo microdialysis in the rat striatum was performed at the acute (first hours) and subacute (after 24 or 48 hours) stages of cerebral ischemia or sham operation to monitor intracerebral release of the stable NO metabolites nitrite and nitrate. RESULTS: Whereas only a nonsignificant trend toward increased release of these NO metabolites was evidenced in acute cerebral ischemia, a significant NO generation was observed subacutely, 48 hours after induction of cerebral ischemia. Aminoguanidine, a selective inhibitor of inducible NO synthase, suppressed this delayed release of nitrite and nitrate. CONCLUSIONS: Whereas these observations do not support a major NO generation in acute cerebral ischemia, they indicate an inducible NO synthase-dependent NO generation predominantly at the subacute phase of ischemic neurodegeneration. Therefore, NO generation may play a pathophysiological role in delayed ischemic neurodegeneration
Vinpocetine treatment in acute ischaemic stroke: a pilot single-blind randomized clinical trial. Feigin VL, Doronin BM, Popova TF, et al. Eur J Neurol. 2001 Jan; 8(1):81-5. The aim of the study was to assess the safety and feasibility of a clinical trial on the effect of vinpocetine, a synthetic ethyl ester of apovincamine, in acute ischaemic stroke. Thirty consecutive patients with computed tomography verified diagnosis of acute ischaemic stroke, who could receive drug treatment within 72 h of stroke onset, were enrolled. The patients were randomly allocated to receive either low-molecular weight dextran alone or in combination with vinpocetine. Poor outcome was defined as being dead or having a Barthel index of < 70 or a Rankin score of 3--5. Intention-to-treat analysis was applied. One-tenth of all hospitalized patients with acute ischaemic stroke were eligible for the trial. Thirty eligible patients were treated with either low-molecular weight dextran alone (mean age 57.9 +/- 11.6 years, n = "15)" or in combination with vinpocetine (mean age 60.8 +/- 6.6 years, n = "15)." The two treatment groups were comparable with respect to major prognostic variables. A relative risk (RR) reduction of poor outcome at 3 months follow-up was 30% (RR = "0.7;" 95% confidence interval [CI] 0.1--3.4), as defined by the modified Barthel Index, and 60% as defined by the modified Ranking score (RR = "0.4," 95% CI: 0.1--1.7). The National Institute of Health (NIH--NINDS) Stroke Scale score was marginally significantly better in the vinpocetine treated group at 3 months of follow-up (P = "0.05," ANOVA). No significant adverse effects were seen. This pilot study shows that a full-scale randomized double-blind, placebo-controlled trial of vinpocetine treatment in acute ischaemic stroke is feasible and warranted
Pregnenolone sulfate enhances post-training memory processes when injected in very low doses into limbic system structures: the amygdala is by far the most sensitive. Flood JF, Morley JE, Roberts E. Proc Natl Acad Sci U S A. 1995 Nov 7; 92(23):10806-10. Immediate post-training, stereotactically guided, intraparenchymal administration of pregnenolone sulfate (PS) into the amygdala, septum, mammillary bodies, or caudate nucleus and of PS, dehydroepiandrosterone sulfate, and corticosterone into the hippocampus was performed in mice that had been weakly trained in a foot-shock active avoidance paradigm. Intrahippocampal injection of PS resulted in memory enhancement (ME) at a lower dose than was found with dehydroepiandrosterone sulfate and corticosterone. Intraamygdally administered PS was approximately 10(4) times more potent on a molar basis in producing ME than when PS was injected into the hippocampus and approximately 10(5) times more potent than when injected into the septum or mammillary bodies. ME did not occur on injection of PS into the caudate nucleus over the range of doses tested in the other brain structures. The finding that fewer than 150 molecules of PS significantly enhanced post-training memory processes when injected into the amygdala establishes PS as the most potent memory enhancer yet reported and the amygdala as the most sensitive brain region for ME by any substance yet tested
Natural statins and stroke risk. Furberg CD. Circulation. 1999 Jan 19; 99(2):185-8.
Review of Medical Physiology. Ganong WF. 1995;
A double blind placebo controlled trial of ginkgo biloba extract in acute cerebral ischaemia. Garg RK, Nag D, Agrawal A. J Assoc Physicians India. 1995 Nov; 43(11):760-3. A double blind placebo controlled trial was conducted in 55 patients of acute ischaemic stroke. Twenty one and twenty six patients were randomly allotted in group A and group B respectively. In group A, the patients received 40 mg Ginkgo biloba extract at 6 hourly intervals along with routine management. The placebo tablets were dispensed in the tablet form of same size, shape and colour and were given in the same way. After the patients were subjected to computerized tomographic (CT) scan to confirm acute ischaemic infarction, they were assessed on Mathew's scale and reassessed, at 2 weeks and 4 weeks of drug/placebo administration. Both groups showed significant improvement in Mathew's scale score after 2 weeks and 4 weeks. The difference in degree of change was negligible (p > 0.05) in either group. Estimation of relative changes of neurological deficit based on baseline values also showed negligible (p > 0.05) difference. A trial of Ginkgo biloba extract within 6 hours of stroke in a larger dose and in larger sample could be beneficial clinically in patients of cerebral ischaemic infarct, and needs further study. The usefulness of the plant extract has been demonstrated clinically and experimentally in more than 40 trials of chronic cerebral ischaemia, done elsewhere. This was not evident in our study as our study group was different (more than 48 hours after stroke). There appears to be no contraindication or adverse effect of this medication (Ginkgo biloba) in acute ischaemic stroke
Stroke mortality in blacks. Disturbing trends. Gillum RF. Stroke. 1999 Aug; 30(8):1711-5. BACKGROUND: Despite long-term declines in US stroke mortality rates, declines have slowed in the past decade and targets for blacks for the years 2000 and 2010 seem attainable only by extraordinary measures, if at all. This review focuses attention on key aspects of this problem. Data from the US National Center for Health Statistics and reports of population-based studies of stroke mortality published since 1987 retrieved by computerized literature searches were reviewed. SUMMARY OF REVIEW: The third leading cause of death in black women and the sixth in black men in the United States in 1996, stroke accounted for 10 509 deaths in women and 7972 in men among blacks: 7.92% and 5.33%, respectively, of the total deaths. Age-adjusted death rates per 100 000 were black women, 39.2; white women, 22.9; black men, 50.9; and white men, 26.3. Available data indicate that compared with US whites, US blacks have greater mortality rates for every stroke subtype, with the likely exception of cerebral infarction due to extracranial carotid artery occlusion. These differences will persist into the 21st century. The number of stroke deaths in blacks increased by >8% between 1992 and 1996. CONCLUSIONS: Increased research on stroke in blacks is needed to develop more effective strategies for primary and secondary prevention of stroke to reduce the high burden of premature mortality and morbidity. Renewed efforts to prevent and control stroke risk factors (in particular elevated blood pressure, diabetes, and smoking) are needed among US blacks
Primary prevention of ischemic stroke: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Goldstein LB, Adams R, Becker K, et al. Circulation. 2001 Jan 2; 103(1):163-82.
. Results after 90 days of stroke treatment with CDP-choline, concerning a double blind test. Goyas JY. 1980;
[Vitamin C in treatment of certain cardiovascular diseases]. Grzegorczyk K, Rutkowski M, Drozda R. Pol Merkuriusz Lek. 2001 Feb; 10(56):122-5. The human organism is incapable of producing vitamin C by biosynthesis. We are therefore totally dependent on the presence of this vitamin in our diet. Vitamin C is capable of essentially influencing the course of many metabolic processes, and it is therefore used in the treatment and prophylaxis of many diseases, including those that are a consequence of the activity of the so-called reactive forms of oxygen. The presence of vitamin C in the anti-oxidant protective system is believed to be very important, since it can react with the free radicals of oxygen and other oxidants, and "sweep" them away. Therefore, attention is more and more frequently focused on the possibility of using vitamin C in the treatment of those circulatory diseases that are believed to be associated with the action of free radicals. Routine administration of vitamin C should be therefore recommended in the treatment of patients with coronary arterial disease, treatment of patients after cardiac infarction or cerebral stroke, or in the treatment of arterial hypertension
Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Hankey GJ, Sudlow CL, Dunbabin DW. Cochrane Database Syst Rev. 2000;(2):CD001246. BACKGROUND: The most widely studied and prescribed antiplatelet agent for the prevention of stroke and other serious vascular events among high vascular risk patients is aspirin. Aspirin inhibits platelet activation by inhibiting platelet cyclooxygenase and thromboxane production, and reduces the odds of a serious vascular event by about a quarter. The thienopyridines (ticlopidine and clopidogrel) inhibit platelet activation by a different mechanism to aspirin (blocking the ADP receptor on platelets), and so may be more effective than aspirin. OBJECTIVES: The objective of this review was to determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for the prevention of serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk of such events, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (most recent search: March 1999) and the Antithrombotic Trialists' database, and also contacted Sanofi pharmaceutical company. SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing ticlopidine or clopidogrel with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Additional data were sought from the principal investigators of the largest trial. MAIN RESULTS: Four trials involving a total of 22,656 high vascular risk pa |