Comparative safety of tenecteplase vs alteplase for acute ischemic stroke.

INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.

High- vs. low-dose diclofenac and cardiovascular risks: a target trial emulation.

AIMS: To examine the dose dependency of diclofenac's cardiovascular risks. METHODS AND RESULTS: Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12). CONCLUSIONS: Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.

Synthesis, antioxidant properties and neuroprotection of α-phenyl-tert-butylnitrone derived HomoBisNitrones in in vitro and in vivo ischemia models.

We herein report the synthesis, antioxidant power and neuroprotective properties of nine homo-bis-nitrones HBNs 1-9 as alpha-phenyl-N-tert-butylnitrone (PBN) analogues for stroke therapy. In vitro neuroprotection studies of HBNs 1-9 against Oligomycin A/Rotenone and in an oxygen-glucose-deprivation model of ischemia in human neuroblastoma cell cultures, indicate that (1Z,1'Z)-1,1'-(1,3-phenylene)bis(N-benzylmethanimine oxide) (HBN6) is a potent neuroprotective agent that prevents the decrease in neuronal metabolic activity (EC50 = 1.24 ± 0.39 µM) as well as necrotic and apoptotic cell death. HBN6 shows strong hydroxyl radical scavenger power (81%), and capacity to decrease superoxide production in human neuroblastoma cell cultures (maximal activity = 95.8 ± 3.6%), values significantly superior to the neuroprotective and antioxidant properties of the parent PBN. The higher neuroprotective ability of HBN6 has been rationalized by means of Density Functional Theory calculations. Calculated physicochemical and ADME properties confirmed HBN6 as a hit-agent showing suitable drug-like properties. Finally, the contribution of HBN6 to brain damage prevention was confirmed in a permanent MCAO setting by assessing infarct volume outcome 48 h after stroke in drug administered experimental animals, which provides evidence of a significant reduction of the brain lesion size and strongly suggests that HBN6 is a potential neuroprotective agent against stroke.

Ponatinib-induced ischemic stroke in larval zebrafish for drug screening.

Conventional mammalian ischemic stroke models for drug screening are technically challenging, laborious and time-consuming. In this study, using Ponatinib as an inducer, we developed and characterized a zebrafish ischemic stroke model. This zebrafish ischemic stroke had the cerebral vascular endothelial injury, thrombosis, reduced blood flow, inflammation and apoptosis as well as the reduced motility. The zebrafish ischemic stroke model was validated with 6 known human therapeutic drugs of ischemic stroke (Aspirin, Clopidogrel, Naoxintong capsules, Edaravone, Xingnaojing injection, Shuxuening injection). The mRNA levels of the neovascularization-related gene (vegfaa) and vascular endothelial growth factor receptor gene (VEGFR), neurodevelopment related genes (mbp and α1-tubulin), brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF) were significantly downregulated; whereas apoptosis-related genes (caspase-3, caspase-7, caspase-9 and bax/bcl-2), and inflammatory factor genes (IL-1ß, IL-6, IL-10, TNF-α and NF-κB) were remarkably upregulated in the model. These results suggest that the pathophysiology of Ponatinib-induced zebrafish ischemic stroke is similar to that of human ischemic stroke patients and this whole animal model could be used to study the complex cellular and molecular pathogenesis of ischemic stroke and to rapidly identify therapeutic agents.

A comprehensive analysis of the effects of rivaroxaban on stroke or transient ischaemic attack in patients with heart failure, coronary artery disease, and sinus rhythm: the COMMANDER HF trial.

AIMS: Stroke is often a devastating event among patients with heart failure with reduced ejection (HFrEF). In COMMANDER HF, rivaroxaban 2.5 mg b.i.d. did not reduce the composite of first occurrence of death, stroke, or myocardial infarction compared with placebo in patients with HFrEF, coronary artery disease (CAD), and sinus rhythm. We now examine the incidence, timing, type, severity, and predictors of stroke or a transient ischaemic attack (TIA), and seek to establish the net clinical benefit of treatment with low-dose rivaroxaban. METHODS AND RESULTS: In this double-blind, randomized trial, 5022 patients who had HFrEF(≤40%), elevated natriuretic peptides, CAD, and who were in sinus rhythm were treated with rivaroxaban 2.5 mg b.i.d. or placebo in addition to antiplatelet therapy, after an episode of worsening HF. The primary neurological outcome for this post hoc analysis was time to first event of any stroke or TIA. Over a median follow-up of 20.5 (25th-75th percentiles 20.0-20.9) months, 150 all-cause stroke (127) or TIA (23) events occurred (ischaemic stroke in 82% and haemorrhagic stroke in 11% of stroke events). Overall, 47.5% of first-time strokes were either disabling (16.5%) or fatal (31%). Prior stroke, low body mass index, geographic region, and the CHA2DS2-VASc score were predictors of stroke/TIA. Rivaroxaban significantly reduced the primary neurological endpoint of all-cause stroke or TIA compared with placebo by 32% (1.29 events vs. 1.90 events per 100 patient-years), adjusted for the time from index HF event to randomization and stratified by geographic region (adjusted hazard ratio 0.68, 95% confidence interval 0.49-0.94), with a number needed to treat of 164 patients per year to prevent one stroke/TIA event. The principal safety endpoint of fatal bleeding or bleeding into a critical space, occurred at a similar rate on rivaroxaban and placebo (0.44 events vs. 0.55 events per 100 patient-years). CONCLUSIONS: Patients with HFrEF and CAD are at risk for stroke or TIA in the period following an episode of worsening heart failure in the absence of atrial fibrillation. Most strokes are of ischaemic origin and nearly half are either disabling or fatal. Rivaroxaban at a dose of 2.5 mg b.i.d. reduced rates of stroke or TIA compared with placebo in this population. TRIAL REGISTRATION: COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure); ClinicalTrials.gov NCT01877915.

Auraptene/Naringin-Rich Fruit Juice of Citrus kawachiensis (Kawachi Bankan) Prevents Ischemia-Induced Neuronal Cell Death in Mouse Brain through Anti-Inflammatory Responses.

Cerebral ischemia/reperfusion leads to delayed neuronal cell death, resulting in brain damage. Auraptene (AUR) and naringin (NGIN), which exert neuroprotective effects in ischemic brain, are abundant in the peel of Citrus kawachiensis. Although parts of AUR/NGIN are transited from the peel to the juice during the squeezing of this fruit, these amounts in juice might be too low to exert effects. We thus prepared the AUR/NGIN-rich fruit juice of C. kawachiensis by addition of peel paste to the raw juice. The present study revealed that orally administration of the dried powder of this AUR/NGIN-rich fruit juice (2.5 g/kg/d) for 7 d to ischemic mice significantly suppressed the ischemia-induced neuronal cell death in the hippocampus, which was coincidently with the reduction of hyperactivation of microglia and astrocytes. These results suggest that AUR/NGIN-rich juice of C. kawachiensis may possess therapeutic potential for the prevention of neurodegenerative diseases via inhibition of inflammatory processes.

Neuroprotective Effects of Ginsenosides against Cerebral Ischemia.

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

Pluchea lanceolata protects hippocampal neurons from endothelin-1 induced ischemic injury to ameliorate cognitive deficits.

Ischemic brain injury is one of the leading causes of death and disability, where lack of disease modifying treatment strategies make us rely on symptomatic relief. Treatment principles from traditional systems of medicine may fill this gap and its validation in modern medicine perspective is important to bring them to mainstream. Here, we evaluated the neuroprotective efficacy of Ayurvedic medicinal herb Pluchea lanceolata in treating ischemic hippocampal injury. Focal hippocampal ischemia was modeled in Wistar rats through stereotaxic intrahippocampal injection of endothelin-1 (ET-1). Post-surgery, hydroalcoholic extract of the rhizome of Pluchea lanceolata (HAPL) was administered orally, once in a day for 14 consecutive days to ischemic rats. There were two treatment groups based on the HAPL dosage; HAPL200 (200 mg/kg body weight) and HAPL400 (400 mg/kg body weight). Comparisons were made with the ET-1 ischemic rats which received only the vehicle, and the normal surgical control. Ischemic hippocampal injury led to severe cognitive deficits as evaluated by Morris water maze and open field test, along with locomotory dysfunction noted in actophotometer test. HAPL treatment significantly attenuated these behavioural deficits in a dose dependent manner. Loss of pyramidal cells and degenerative phenotype of shrunken hyperdensed soma with pyknotic nuclei in CA1 and CA3 hippocampal neurons in ischemia were reversed after HAPL treatment. We provide first evidence for loss of dendritic architecture in ET-1 induced focal ischemic hippocampal injury using Golgi impregnation, where HAPL could salvage the dendritic branching and intersections. Intriguingly, it enhanced the dentritic arborization beyond what is noted in normal rats. Ability of HAPL to reverse oxidative stress, especially through maintaining glutathione peroxidase levels and lipid peroxidation in ischemic condition evidences that it may exert neuroprotection through its antioxidant properties. Thus, Pluchea lanceolata and its constituents provide potential alternative/adjuvant treatment strategy for ischemic hippocampal stroke.

Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study.

Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary Funding Source: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Risk of Ischemic Stroke Associated With Calcium Supplements With or Without Vitamin D: A Nested Case-Control Study.

BACKGROUND: There is controversy surrounding the risk of ischemic stroke associated with the use of calcium supplements either in monotherapy or in combination with vitamin D. METHODS AND RESULTS: A nested case-control study was performed with patients aged 40 to 89 years old, among whom a total of 2690 patients had a first episode of nonfatal ischemic stroke and for which 19 538 controls were randomly selected from the source population and frequency-matched with cases for age, sex, and calendar year. Logistic regression provided the odds ratios while adjusting for confounding factors. A sensitivity analysis was performed by restricting to patients who were new users of calcium supplements as either monotherapy or with vitamin D. Calcium supplementation with vitamin D was not associated with an increased risk of ischemic stroke (odds ratio 0.85; 95% confidence interval, 0.67-1.08) in the population as a whole or under any of the conditions examined (dose, duration, background cardiovascular risk, sex, or age). Calcium supplement monotherapy was not associated with an increased risk in the population as a whole (odds ratio 1.18; 95% confidence interval, 0.86-1.61), although a significant increased risk at high doses (≥1000 mg/day: odds ratio 2.09; 95% confidence interval, 1.25-3.49; <1000 mg: odds ratio 0.76; 95% confidence interval, 0.45-1.26) compared with nonuse was observed. The sensitivity analysis did not affect the inferences, with similar results observed among new users as to the overall study population. CONCLUSIONS: This study suggests that calcium supplements given as monotherapy at high doses may increase the risk of ischemic stroke, whereas their combination with vitamin D seems to offset this hazard.

A comparison of risperidone and haloperidol for the risk of ischemic stroke in the elderly: a propensity score-matched cohort analysis.

OBJECTIVE: With an increase in antipsychotic use in the elderly, the safety profile of antipsychotics has been emphasized. Strong concerns have been raised about whether the risk of ischemic stroke differs between risperidone and haloperidol. This study compared the risk of ischemic stroke between elderly patients taking risperidone and haloperidol. METHOD: We conducted a retrospective cohort study using the Korea Health Insurance Review and Assessment Service database, applying a propensity-matched analysis. The cohort consisted of elderly patients who were newly prescribed haloperidol or risperidone between January 1, 2006 and December 31, 2009. Patients with prior cerebrovascular diseases (ICD-10, I60-I69), transient ischemic attack (ICD-10, G45), or cerebral tumors (ICD-10, C31) during 365 days prior to the initiation date were excluded. The study subjects were selected by propensity score matching. The outcome was defined as the first hospitalization for ischemic stroke (ICD-10, I63). Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) for ischemic stroke with haloperidol compared with risperidone use. RESULTS: A total of 14,103 patients were included in the propensity-matched cohort for each drug. Overall, the incidence rate was higher for haloperidol users compared to the risperidone users (6.43 per 1000 person-years vs. 2.88 per 1000 person-years). A substantially increased risk was observed in haloperidol users (adjusted HR = 2.02, 95% CI, 1.12-3.62). CONCLUSIONS: The evidence showed that haloperidol should be prescribed in the elderly with caution.

Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension.

BACKGROUND AND PURPOSE: Limited studies have investigated the risk of cerebrovascular events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in subjects at high risk. We examined the short-term (defined as 30-day period) effect of selective and nonselective NSAIDs use on the risk of ischemic and hemorrhagic stroke in patients with hypertension. METHODS: We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan. We identified 1653 hypertensive subjects with stroke (defined as International Classification of Diseases-Ninth Revision-CM-codes: 433.x, 434.x, and 436.x for ischemic stroke; 430 and 431 for hemorrhagic stroke) in 2010. We investigated the transient effect of NSAIDs use on stroke using conditional logistic regressions with the adjustment of potential confounders. RESULTS: The results suggested that NSAIDs use during the 30 days before stroke was associated with a 1.57-fold increased risk of ischemic stroke, but not of hemorrhagic stroke (adjusted odds ratio, 1.57; 95% confidence interval, 1.26-1.97 for ischemic stroke; and adjusted odds ratio, 1.38; 95% confidence interval, 0.79-2.40 for hemorrhagic stroke). When classifying NSAIDs into selective and nonselective groups, nonselective NSAIDs use significantly increased the risk of ischemic stroke (adjusted odds ratio, 1.55; 95% confidence interval, 1.24-1.94), but not of hemorrhagic stroke (adjusted odds ratio, 1.56; 95% confidence interval, 0.90-2.73). CONCLUSIONS: The results demonstrate an increased risk of stroke, specifically ischemic stroke among hypertensive subjects with NSAIDs use. It would be important to closely monitor the transient effect of initial NSAIDs treatment, particularly in patients with hypertension.

Impact and interaction of low estimated GFR and B vitamin therapy on prognosis among ischemic stroke patients: the Vitamin Intervention for Stroke Prevention (VISP) trial.

BACKGROUND: Low estimated glomerular filtration rate (eGFR) has been linked to higher risk of primary stroke, but little is known about the relation of low eGFR to recurrent vascular risk after stroke. B Vitamin therapy has been used to lower homocysteine levels, but its interaction with kidney function on future major vascular events has not been assessed. The objective of this study was to conduct a secondary analysis based on the Vitamin Intervention for Stroke Prevention (VISP) trial to clarify these issues. STUDY DESIGN: In the VISP trial, patients with a prior ischemic stroke were randomly assigned to receive the high- or low-dose B vitamin therapy. The trial did not find a difference between randomly assigned groups. The present study is a secondary analysis of the VISP trial. SETTING & PARTICIPANTS: We analyzed the database of a multicenter trial comprising 3,673 patients with recent ischemic stroke who were followed up for 2 years. PREDICTOR: We subdivided the cohort based on eGFR into 6 groups (≥105, 90-104, 75-89, 60-74, 45-59, and <45 mL/min/1.73 m²) for the analyses and used eGFR of 60-74 mL/min/1.73 m² as the reference category. Low eGFR was defined as <45 mL/min/1.73 m². OUTCOMES: The primary end point for this analysis was major vascular events, defined as the composite of nonfatal ischemic stroke, nonfatal myocardial infarction, and vascular death (whichever event came first). The secondary end point was recurrent ischemic stroke. Also, the effects of high-dose B vitamin treatment on future major vascular events according to baseline eGFR categories were analyzed and reported separately. RESULTS: Mean baseline eGFR was 73.9 ± 21.8 (SD) mL/min/1.73 m². 471 major vascular events during an average of 20 months of follow-up, including 300 recurrent strokes, were recorded. Baseline low eGFR was associated with increased risk of major vascular events (HR, 1.83; 95% CI, 1.32-2.52; P < 0.001) and recurrent stroke (HR, 1.53; 95% CI, 1.01-2.32; P = 0.04) after adjustment for traditional vascular risk factors and homocysteine level. At baseline eGFR <45 mL/min/1.73 m², high-dose B vitamin therapy compared to low dose showed a trend of higher risk of future major vascular events (HR, 1.49; 95% CI, 0.95-2.34; P = 0.08). The overall P value for interaction between B vitamin dose and eGFR was not significant (P = 0.6). LIMITATIONS: No data for albuminuria. CONCLUSIONS: Low eGFR is associated with higher risk of future major vascular events and recurrent stroke after a recent ischemic stroke.

[Ingestion of anabolic steroids and ischaemic stroke. A clinical case report and review of the literature]. / Ingesta de esteroides anabolizantes e ictus isquemico. Presentacion de un caso clinico y revision de la bibliografia.

INTRODUCTION. Anabolic-androgenic steroids are synthetic substances derived from testosterone that are employed for their trophic effect on muscle tissue, among other uses. Their consumption can give trigger a series of adverse side effects on the body, including the suppression of the hypothalamus-pituitary-gonadal axis as well as liver, psychiatric and cardiovascular disorders. The most common effects are altered fat profiles and blood pressure values, cardiac remodelling, arrhythmias or myocardial infarcts. CASE REPORT. We report the case of a young male, with a background of anabolic-androgenic steroids abuse, who visited because of an acute neurological focus in the right hemisphere related with an ischaemic stroke. The aetiological study, including cardiac monitoring, echocardiograph and imaging studies (magnetic resonance and arteriography) and lab findings (thrombophilia, serology, autoimmunity, tumour markers) showed no alterations. CONCLUSIONS. The association between consumption of anabolic-androgenic steroids and cardiovascular pathologies is known, but its relation with cerebrovascular disease has not received so much attention from researchers.

Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats.

Different garlic products reduce the cerebral ischemic damage due to their antioxidant properties. In this work, we investigated the effect of aged garlic extract (AGE) on cyclooxygenase-2 (COX-2) protein levels and activity, and its role as a possible mechanism of neuroprotection in a cerebral ischemia model. Animals were subjected to 1 h of ischemia plus 24 h of reperfusion. AGE (1.2 ml/kg weight, i.p.) was administered at onset of reperfusion. To evaluate the damage induced by cerebral ischemia, the neurological deficit, the infarct area, and the histological alterations were measured. As an oxidative stress marker to deoxyribonucleic acid, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were determined. Finally, as inflammatory markers, TNFα levels and COX-2 protein levels and activity were measured. AGE treatment diminished the neurological alterations (61.6%), the infarct area (54.8%) and the histological damage (37.7%) induced by cerebral ischemia. AGE administration attenuated the increase in 8-OHdG levels (77.8%), in TNFα levels (76.6%), and in COX-2 protein levels (73.6%) and activity (30.7%) induced after 1 h of ischemia plus 24 h of reperfusion. These data suggest that the neuroprotective effect of AGE is associated not only to its antioxidant properties, but also with its capacity to diminish the increase in TNFα levels and COX-2 protein expression and activity. AGE may have the potential to attenuate the cerebral ischemia-induced inflammation.

Xylometazoline abuse induced ischemic stroke in a young adult.

INTRODUCTION: substance abuse is an important cause of ischemic stroke in the young. This includes over-the-counter dietary supplements and cough and cold remedies, which were reported to be an independent risk factor for hemorrhagic stroke. CASE REPORT: this article describes a young male patient with acute ischemic infarctions in the posterior inferior cerebellar and posterior cerebral artery territories bilaterally, the right cerebral peduncle, the left pontine tegmentum, and lateral pons following abuse of xylometazoline-containing nasal decongestant for 10 years. CONCLUSION: this is the first report in the literature of posterior circulation strokes because of chronic xylometazoline abuse. We hope to contribute to increase knowledge and awareness of the public about these serious complications of cough-and-cold remedies as well as dietary supplements containing sympathomimetics.

Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials.

OBJECTIVE: To evaluate the effect of vitamin E supplementation on incident total, ischaemic, and haemorrhagic stroke. DESIGN: Systematic review and meta-analysis of randomised, placebo controlled trials published until January 2010. DATA SOURCES: Electronic databases (Medline, Embase, Cochrane Central Register of Controlled Trials) and reference lists of trial reports. Selection criteria Randomised, placebo controlled trials with ≥1 year of follow-up investigating the effect of vitamin E on stroke. Review methods and data extraction Two investigators independently assessed eligibility of identified trials. Disagreements were resolved by consensus. Two different investigators independently extracted data. Risk ratios (and 95% confidence intervals) were calculated for each trial based on the number of cases and non-cases randomised to vitamin E or placebo. Pooled effect estimates were then calculated. RESULTS: Nine trials investigating the effect of vitamin E on incident stroke were included, totalling 118 765 participants (59 357 randomised to vitamin E and 59 408 to placebo). Among those, seven trials reported data for total stroke and five trials each for haemorrhagic and ischaemic stroke. Vitamin E had no effect on the risk for total stroke (pooled relative risk 0.98 (95% confidence interval 0.91 to 1.05), P=0.53). In contrast, the risk for haemorrhagic stroke was increased (pooled relative risk 1.22 (1.00 to 1.48), P=0.045), while the risk of ischaemic stroke was reduced (pooled relative risk 0.90 (0.82 to 0.99), P=0.02). There was little evidence for heterogeneity among studies. Meta-regression did not identify blinding strategy, vitamin E dose, or morbidity status of participants as sources of heterogeneity. In terms of absolute risk, this translates into one additional haemorrhagic stroke for every 1250 individuals taking vitamin E, in contrast to one ischaemic stroke prevented per 476 individuals taking vitamin E. CONCLUSION: In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.

Acute neuroprotection by the synaptic blocker botulinum neurotoxin E in a rat model of focal cerebral ischaemia.

Evidence indicates that accumulation of excitotoxic mediators, such as glutamate, contributes to neuronal damage after an ischaemic insult. It is not clear, however, whether this accumulation is due to excess synaptic release or to impaired uptake. To test a role for synaptic release, here we investigated the neuroprotective potential of the synaptic blocker botulinum neurotoxin E (BoNT/E), that prevents vesicle fusion via the cleavage of the SNARE (soluble NSF-attachment receptor) protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Focal ischaemia was induced in vivo by infusing the potent vasoconstricting peptide endothelin-1 (ET-1) into the CA1 area of the hippocampus in adult rats; BoNT/E or vehicle were administered into the same site 20 min later. Injection of ET-1 was found to produce a transient and massive increase in glutamate release that was potently antagonized by BoNT/E. To assess whether blocking transmitter release translates into neuroprotection, the extent of the ischaemic damage was determined 24 h and 6 weeks after the insult. We found that BoNT/E administration consistently reduced the loss of CA1 pyramidal neurons at 24 h. The neuroprotective effect of BoNT/E, however, was no longer significant at 6 weeks. These data provide evidence that blockade of synaptic transmitter release delays neuronal cell death following focal brain ischaemia, and underline the importance of assessing long-term neuroprotection in experimental stroke studies.

Aggressive statin treatment, very low serum cholesterol levels and haemorrhagic stroke: is there an association?

PURPOSE OF REVIEW: To assess the potential association between haemorrhagic stroke and achieving very low serum cholesterol levels with aggressive statin treatment. RECENT FINDINGS: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study showed a reduction in both fatal and nonfatal stroke but an increase in the risk for haemorrhagic stroke during high-dose atorvastatin treatment. However, post-hoc analyses of this trial showed that this increased risk is primarily observed in elderly men with a history of haemorrhagic stroke. In addition, there was no relationship between baseline or on-treatment low-density lipoprotein cholesterol (LDL-C) levels and haemorrhagic stroke. SUMMARY: Existing data suggest that low LDL-C levels during intensive statin treatment are not associated with an increased risk for haemorrhagic stroke, except in patients with a history of intracerebral haemorrhage. In patients with a history of ischaemic stroke, intensive statin treatment substantially reduces the risk for both recurrent ischaemic stroke and for coronary heart disease (CHD) events. Any possible excess of haemorrhagic stroke is greatly outweighed by the protective effect against ischaemic stroke and CHD events.

Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential.

BACKGROUND AND PURPOSE: New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia. METHODS: Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations. A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used. Blood-brain barrier basal lamina components, matrix metalloproteinases (MMPs), hemorrhage formation, infarct size, edema, and behavior outcome were assessed. RESULTS: Minocycline did not affect t-PA fibrinolysis. However, minocycline treatment at 3 mg/kg IV decreased total protein expression of both MMP-2 (P=0.0034) and MMP-9 (P=0.001 for 92 kDa and P=0.0084 for 87 kDa). It also decreased the incidence of hemorrhage (P=0.019), improved neurologic outcome (P=0.0001 for Bederson score and P=0.0391 for paw grasp test), and appeared to decrease mortality. MMP inhibition was associated with decreased degradation in collagen IV and laminin-alpha1 (P=0.0001). CONCLUSIONS: Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis. These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA.