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Objective: To investigate the association between atomoxetine or methylphenidate use and arrhythmia, heart failure (HF), stroke, and myocardial infarction (MI) in attention-deficit/hyperactivity disorder (ADHD) patients mainly focused on the people of working age., Methods: In a self-controlled case series study using a Japanese claims database, we identified events of arrhythmia, HF, stroke, and MI among 15,472 atomoxetine new users and 12,059 methylphenidate new users. Adjusted incidence rate ratios (aIRRs) of outcome events were estimated using multivariable conditional Poisson regression., Results: An increased risk of arrhythmia was observed during the first 7 days after the initial atomoxetine exposure (aIRR 6.22, 95% CI [1.90, 20.35]) and in the subsequent exposure (3.23, [1.58, 6.64]). No association was found between methylphenidate exposure and arrhythmia, nor between atomoxetine or methylphenidate exposure and HF. The limited number of stroke and MI cases prevented thorough analysis., Conclusions: Clinicians should consider monitoring for arrhythmia after patients initiating or re-initiating atomoxetine., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Y.Z. is an employee of Takeda Pharmaceutical Company Limited; however, Takeda Pharmaceutical Company Limited was not involved in this study. T.F. has been employed by the Department of Digital Health and Epidemiology, an Industry-Academia Collaboration Course supported by Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Real World Data Co., Ltd., and Mitsubishi Corporation; and has received consulting fees from Real World Data Co., Ltd. and speaker fees from Asahi Kasei Pharma Corporation and EPS Corporation. F.Y. declares no conflict of interest. M.T. received consulting fees from Eisai Co., Ltd. K.K. received research grants from Eisai Co., Ltd., Kyowa Kirin Co., Ltd., OMRON Corporation, and Toppan Inc.; consulting fees from Advanced Medical Care Inc., JMDC Inc., and Shin Nippon Biomedical Laboratories Ltd.; executive compensation from Cancer Intelligence Care Systems, Inc.; honoraria from Chugai Pharmaceutical Co., Ltd., and Pharma Business Academy.

Background: There has been concern that statin therapy may be associated with an increased risk of intracerebral hemorrhage (ICH). We investigated whether the intensity and type of statin therapy instituted after ischemic stroke (IS) were associated with risk of future ICH in a region of northern China with a high incidence of stroke., Methods: Newly diagnosed IS patients who were not treated with lipid-lowering drugs in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. The primary exposure variable was any statin prescription within 1 month of the first documented stroke diagnosis. High-intensity statin therapy was defined as atorvastatin ⩾ 80 mg, simvastatin ⩾ 80 mg, pravastatin ⩾ 40 mg, and rosuvastatin ⩾ 20 mg per day or equivalent combination. An adjusted Cox proportional hazards model was used to estimate the hazard ratio (HR) for ICH during follow-up in groups exposed and not exposed to statins., Results: Of 62,252 participants with IS and 628 ICH readmissions were recorded during a median follow-up of 3.17 years. The risk of ICH among statin users (N = 43,434) was similar to that among nonusers (N = 18,818) with an adjusted HR and 95% confidence interval (CI) of 0.86 (0.73, 1.02). Compared with non-statin therapy, patients with low/moderate-intensity therapy had a lower risk of ICH (0.62: 0.52, 0.75), while patients with high-intensity therapy had a substantially higher risk (2.12: 1.72, 2.62). For patients with different types of statin therapy, adherence to rosuvastatin had the lowest risk of ICH compared to adherence to atorvastatin (0.46: 0.34, 0.63), followed by simvastatin (0.60: 0.45, 0.81)., Conclusion: In patients with IS, any statin therapy was not associated with an increased risk of ICH. However there appeared to be differential risk according to the dose of statin with high-intensity statin therapy being associated with an increased risk of ICH, while low/moderate-intensity therapy was associated with a lower risk.

Introduction: Oxaliplatin has become the mainstay of treatment for many cancers, but its use can be accompanied by unusual side effects., Case Report: We describe herein a 74-year-old patient with pancreatic cancer who developed severe motor weakness affecting lower extremities after starting treatment with oxaliplatin on three separate occasions. Our patient also experienced slurred speech, with decreased ability to phonate and word-finding difficulty. Brain imaging studies did not suggest recent brain ischemia, and the symptoms resolved within 15-20 h., Management and Outcome: Oxaliplatin had to be discontinued due to suboptimal tolerance and a short-lived clinical response. After discontinuation of oxaliplatin, she did not experience any more similar symptoms. A score of 9 on the Naranjo nomogram supported a definite causality relationship between oxaliplatin and the observed neurologic toxicity., Discussion: Rare reports of stroke-like events have previously been described with oxaliplatin. While the exact mechanism of these phenomena is not known, alterations in neuronal sodium channels might be involved. Clinicians, pharmacists, and patients need to be aware of these rare but important side effects of oxaliplatin. Nonetheless, work-up for a cerebrovascular accident is still warranted as hypercoagulability related to malignancy can also predispose the patients to strokes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease., Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD 2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat., Trial Registry Name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356.

Rationale: Alteplase is the only approved thrombolytic agent for acute stroke. An alternative plasminogen activator, tenecteplase, has been previously shown to increase early biological effectiveness (reperfusion) resulting in early clinical recovery in acute stroke patients with target mismatch on perfusion imaging; however, phase III data are lacking., Aim and Hypothesis: In this study, we assess the efficacy and safety of tenecteplase compared to alteplase in acute stroke patients with target mismatch on perfusion imaging., Methods and Design: Tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) for Stroke Thrombolysis Evaluation (TASTE) is a multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase III non-inferiority trial (2 arms with 1:1 randomization) with an adaptive sample size re-estimation in patients with acute ischemic stroke meeting target mismatch criteria on perfusion imaging., Sample Size Estimates: Recruiting 728 patients (1:1 tenecteplase vs alteplase) would yield 90% power (two-sided alpha 0.05) to detect a treatment effect of 8% (26% modified Rankin scale (mRS) 0-1 in alteplase arm and 34% mRS 0-1 in tenecteplase arm), with an absolute non-inferiority margin of 3%. Following the pre-planned "promising zone" adaptive sample size re-estimation, the final sample size was set at 832 patients., Study Outcomes: The primary outcome measure is the proportion of patients with an mRS score of 0-1 at 3 months. Secondary outcomes include the categorical shift in mRS at 3 months; the proportion of patients with: mRS 0-2, 5-6, and 6; reduction of the National Institutes of Health Stroke Scale (NIHSS) by 8 or more points or reaching 0-1 at 24 h; symptomatic intracerebral hemorrhage within 36 h; and death., Discussion: This pivotal trial will provide important data on the role of tenecteplase in acute ischemic stroke, and the use of imaging-based treatment decision-making for stroke thrombolysis., Clinical Trial Protocol: Trial Registration: ACTRN12613000243718, EudraCT 2015-002657-36.

Background: Proton pump inhibitors (PPIs) are frequently prescribed drugs. However, it has been suggested that they are associated with an increased risk of ischemic vascular events (IVE) including stroke, although the data are inconsistent., Aims: We investigated the association between PPIs use and IVE in five observational Korean databases using a common data model (CDM)., Methods: This study included patient-based retrospective, observational cohort data of subjects aged over 18 years between January 1, 2004, and December 31, 2020, from five medical centers as part of the Observational Medical Outcomes Partnership (OMOP) CDM. Subjects who were included in both cohorts or had a previous history of ischemic stroke were excluded. After propensity matching, 8007 propensity-matched pairs between the PPIs and H 2 receptor antagonist (H 2 RA) users were included in this study., Results: In the 1:1 propensity score matching with 8007 in each group, long-term PPIs use (⩾365 days) was not associated with ischemic stroke (odds ratio (OR) = 1.05, 95% confidence interval (CI) 0.71-1.56; I 2 = 57%), ischemic stroke and transient ischemic attack (OR = 1.02, 95% CI 0.71-1.48; I 2 = 53%), and net adverse clinical events (OR = 1.08, 95% CI 0.83-1.40; I 2 = 47%) compared with H2RAs users., Conclusions: Our analysis in a large dataset found no evidence that long-term use of PPIs was associated with an increased risk of ischemic stroke.

Background: We previously reported that dual antiplatelet therapy (DAPT) with cilostazol was superior to aspirin or clopidogrel for the prevention of recurrent stroke and vascular events in a subgroup analysis of intracranial arterial stenosis in the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com), a randomized controlled trial., Aims: We conducted another subgroup analysis to investigate the benefit of DAPT with cilostazol in patients with extracranial arterial stenosis (ECAS) and those without arterial stenosis., Methods: We compared the risk of recurrent ischemic stroke, vascular events, and major bleeding between DAPT with cilostazol plus aspirin or clopidogrel and aspirin or clopidogrel alone in patients with ischemic stroke between 8 and 180 days before starting trial treatment and ECAS or without arterial stenosis., Results: The median follow-up period was 1.4 years. The risk of recurrent ischemic stroke (hazard ratio (HR): 1.04, 95% confidence interval (CI): 0.42-2.57) and vascular events (HR: 0.97, 95% CI: 0.42-2.24) did not differ between the two groups for the 253 patients with ECAS, whereas they were lower (HR: 0.36, 95% CI: 0.18-0.74 and HR: 0.47, 95% CI: 0.26-0.85, respectively) in the DAPT group for the 944 patients without arterial stenosis. The risk of major bleeding did not differ between the groups in patients with ECAS (HR: 0.58, 95% CI: 0.05-6.39) or without arterial stenosis (HR: 0.79, 95% CI: 0.27-2.26)., Conclusion: DAPT with cilostazol might be beneficial for prevention of recurrent stroke and vascular events in patients without arterial stenosis but not in those with ECAS., Data Access Statement: We will make the deidentified participant data from this research available to the scientific community with as few restrictions as feasible, while retaining exclusive use until the publication of major output.

Cerebrovascular accidents (CVAs) or strokes are part of the common thrombotic manifestations of Systemic Lupus Erythematosus (SLEs) and Antiphospholipid syndrome (APS). Such neurological thrombotic events tend to occur in patients with SLE at a higher frequency when Antiphospholipid antibodies (aPLs) are present, and tend to involve the large cerebral vessels. The mechanism of stroke in SLE can be driven by complement deposition and neuroinflammation involving the blood-brain barrier although the traditional cardiovascular risk factors remain major contributing factors. Primary prevention with antiplatelet therapy and disease activity controlling agent is the basis of the management. Anticoagulation via warfarin had been a tool for secondary prevention, especially in stroke recurrence, although the debate continues regarding the target international normalized ratio (INR). The presence of either of the three criteria antiphospholipid antibodies (aPLs) and certain non-criteria aPL can be an independent risk factor for stroke. The exact mechanism for the involvement of the large cerebral arteries, especially in lupus anticoagulant (LAC) positive cases, is still to be deciphered. The data on the role of non-criteria aPL remain very limited and heterogenous, but IgA antibodies against β2GPI and the D4/5 subunit as well as aPS/PT IgG might have a contribution. Anticoagulation with warfarin has been recommended although the optimal dosing or the utility of combination with antiplatelet agents is still unknown. Minimal data is available for direct oral anticoagulants (DOACs).

Anticoagulation with warfarin in Asian patients with atrial fibrillation (AF) often has been decreased as an international normalized ratio (INR) of prothrombin time 1.6-2.6 due to fear of bleeding, although universal criteria recommend an INR of 2.0-3.0. In this randomized, open-label trial, low-intensity anticoagulation (INR 1.6-2.6) was compared with standard-intensity anticoagulation (INR 2.0-3.0) with warfarin. A total 616 patients with AF and at least 1 risk factor for stroke were randomized to low-intensity anticoagulation (n = 308) and standard-intensity anticoagulation (n = 308) groups. The intention-to-treat analysis was performed to determine differences. The baseline characteristics of the two groups were comparable. New-onset stroke occurred in 2 patients (0.44% per year) in the low-intensity group and 5 patients (1.05% per year) in the standard-intensity group (HR 0.42, 95% CI 0.08-2.15). Major bleeding occurred in 4 patients (0.89% per year) in the low-intensity group and 5 patients (1.06% per year) in the standard-intensity group (HR 0.84, 95% CI 0.22-3.11). The rate of the net clinical outcome (composite of stroke, systemic embolism, major bleeding, and death) was 1.33% per year in the low-intensity group compared with 2.12% per year in the standard-intensity group (HR 0.63, 95% CI 0.23-1.72). In Asian patients with AF, clinical outcomes were not different between low-intensity and standard-intensity anticoagulation with warfarin.

Patients with atrial fibrillation (AF) have an increased risk of stroke and systemic thromboembolism. Diagnosis of AF is commonly encountered in the emergency department (ED). The purpose of this study was to assess the number of patients with new-onset AF appropriately initiated on oral anticoagulation (AC) during their ED encounter. This retrospective analysis included patients discharged from the ED from July 2016 to July 2021 with a new diagnosis of AF. Patients were excluded if they were on AC before admission. The major endpoint was to identify the percentage of patients discharged from the ED without initiating AC. Minor endpoints included the average CHA2DS2-VASc scores and the reason for not initiating AC. A total of 380 patients were included in the final analysis. Of the 245 patients found to be indicated for AC, only 131 patients (53.5%) were initiated on AC and 114 patients (46.5%) were discharged without initiating AC. Almost half of the patients who presented to the ED with a new diagnosis of AF and indicated for AC were discharged without AC.

Objective: Many epidemiological studies have observed the association of air pollutant exposure with the onset, progression, and mortality of stroke. The aim of this study was to investigate the associations of air pollutants, including SO 2 , NO 2 , O 3 , CO, and PM 10 , with stroke according to exposure duration., Methods: Data from the Korean National Health Insurance Service-Health Screening Cohort from 2002 to 2015 were obtained. The 21,240 patients who were admitted for or died due to stroke were 1:4 matched for age, sex, income, and region of residence with 84,960 control participants. The meteorological factors of mean, highest, and lowest temperatures; relative humidity; ambient atmospheric pressure; and air pollutant concentrations (SO 2 , NO 2 , O 3 , CO, and PM 10 ) were analyzed to determine their associations with stroke. The odds ratios for stroke after exposure to each meteorological factor and air pollutant at 7 and 30 days were calculated in the stroke and control groups. Subgroup analyses were conducted according to age, sex, income, and region of residence., Results: The odds ratio associated with seven days of exposure to CO was 1.16 (95% CI = 1.04-1.31) in stroke patients. For 30 days of exposure, the odds ratio associated with CO was 1.16 (95% CI = 1.02-1.32) in stroke patients. Seven and 30 days of NO 2 exposure were inversely associated with stroke. The odds ratio associated with seven days of exposure to O 3 was 1.16 (95% CI = 1.01-1.32) in ischemic stroke patients. Both ischemic and hemorrhagic stroke had negative associations with 7 and 30 days of NO 2 exposure., Conclusion: Both short- and long-term exposure to CO were related to stroke.

Background: Advanced age and type 2 diabetes (T2D) are common in patients with nonvalvular atrial fibrillation (NVAF). We evaluated the impact of age on the effectiveness and safety of rivaroxaban versus warfarin in this population., Methods: We analyzed electronic health record data from November 2010, to December 2019 including adults with NVAF and T2D, newly started on rivaroxaban or warfarin. Propensity score-overlap weighted hazard ratios (HRs) for stroke/systemic embolism (SSE), hospitalization for major or clinically relevant nonmajor bleeding (CRNMB), vascular death, major adverse limb events (MALE), major bleeding, and intracranial hemorrhage (ICH) were calculated for older (≥80 years) and younger (<80 years) cohorts., Results: We included 32 078 rivaroxaban and 83 971 warfarin users (6606 rivaroxaban and 25,335 warfarin patients were aged ≥80 years). No significant interaction for rivaroxaban versus warfarin by age was observed for any outcome, including SSE (HR = 1.05 vs 0.95), hospitalization for major or CRNMB (HR = 1.06 vs 0.90), vascular death (HR = 0.92 vs 0.90), MALE (HR = 0.80 vs 0.76), major bleeding or ICH., Conclusions: The effectiveness and safety of rivaroxaban versus warfarin remained consistent across patient age subgroups.

Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy-by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice-we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (∼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.

Background: Patients on dual antiplatelet therapy following percutaneous coronary intervention often have indications for concomitant oral anticoagulation, known as triple antithrombotic therapy. Majority of literature evaluating triple antithrombotic therapy fails to adequately represent patients with ST-elevation myocardial infarction and those prescribed potent P2Y12 inhibitors, ticagrelor or prasugrel. The purpose of this study was to evaluate the safety and efficacy of triple antithrombotic regimens containing ticagrelor or prasugrel versus clopidogrel after percutaneous coronary intervention in the setting of ST-elevation myocardial infarction., Methods: This was a single-center, retrospective cohort trial. The primary endpoint was net adverse clinical event, defined as the primary efficacy endpoint of death, myocardial infarction, or cerebrovascular accident and the primary safety endpoint of any bleeding event., Results: Between October 2017 and October 2019, a total of 65 patients with ST-elevation myocardial infarction were initiated on triple therapy. Forty-six patients were included in the primary analysis, of which 26 were discharged on triple antithrombotic therapy with clopidogrel and 20 discharged on potent P2Y12 inhibitors (ticagrelor or prasugrel). The primary endpoint occurred in 27% of the clopidogrel group and 40% of the potent P2Y12 inhibitor group ( P = 0.35). Bleeding occurred in 23% of the clopidogrel group and 35% of the potent P2Y12 inhibitor group ( P = 0.37)., Conclusions: This small cohort study suggests, in patients with ST-elevation myocardial infarction undergoing percutaneous coronary intervention, the net adverse clinical event rate does not differ between clopidogrel and potent P2Y12 inhibitors in the setting of triple antithrombotic therapy. The results of this exploratory analysis warrant confirmation in a larger, randomized study.

Introduction: 5-Fluorouracil is an antineoplastic agent generally used to treat various types of solid tumors. The common adverse drug reaction associated with 5-fluorouracil are myelosuppression, mucositis, diarrhea, and hand-foot syndrome. Neurological side effects such as headache, dizziness, convulsion, encephalopathy, and acute cerebellar syndrome are rare in nature., Case Presentation: We report a case of 5-fluorouracil induced cerebrovascular accident (CVA) in a patient with no risk factors for CVA before chemotherapy. A 37 years old female patient diagnosed with carcinoma rectum underwent six cycles of chemotherapy with 5- fluorouracil- calcium leucovorin- irinotecan (FOLFIRI regimen). After completing the last cycle, she developed headache, vomiting, and facial deviation along with high blood pressure (260/160 mmHg). MRI brain was done, and it revealed acute non-hemorrhagic lacunar infarct in the left half of pons. 5-fluorouracil induced CVA was suspected and was managed with dual antiplatelet, statin, and antihypertensives., Conclusion: The clinicians and clinical pharmacists must be aware about the potential of 5-FU to induce rare side effects such as CVA even in low risk patients in order to avoid permanent harm to the patient.

Objective: It has been reported that patients with antiphospholipid antibodies (aPL) and refractory migraine may experience symptomatic improvement with antithrombotic therapy, but this phenomenon has not been well studied. This study was undertaken to detail the response to trials of antithrombotic therapy in these patients., Methods: This is a retrospective study of 75 patients with refractory migraine and aPL who were given a 2-4 week trial of aspirin, clopidogrel and/or anticoagulation. Major response was defined as 50-100% improvement in frequency and/or severity of migraine; minor response: 25-49% improvement; no response: <25% improvement., Results: 66 patients were given a trial of aspirin: 47% responded (21% major); 60 patients were given a trial of clopidogrel: 83% responded (67% major); and 34 patients were given a trial of anticoagulation (usually apixaban): 94% responded (85% major). The response rate to any anti-thrombotic therapy was 89% (83% major). Many patients also noted improvement in non-headache symptoms. No patient experienced stroke. There was no major bleeding during any 2-4 week treatment trial and only 3 of 69 patients maintained on an antithrombotic regimen for a median follow up of 29.9 months (5-100) experienced major bleeding., Conclusions: There was a high rate of symptomatic response to antithrombotic therapy in this context and long-term follow up suggested an individualized symptom-derived antithrombotic regimen may be associated with a low bleeding risk. Our data support consideration of a 2-4 week trial of antithrombotic therapy, usually starting with antiplatelet therapy, in aPL-positive patients with refractory migraine, particularly if other treatment options have been exhausted. As a retrospective study, our data provide only Class IV level of evidence, but they suggest randomized controlled trials are warranted to validate these encouraging findings.

Tyrosine kinase inhibitors (TKIs) of the BCR-ABL fusion protein have dramatically changed the mortality of chronic myeloid leukemia (CML) but they carry a risk of serious vascular morbidity. While TKIs do not cure CML, daily oral administration of a TKI can control CML and TKIs are chronic medications. Interestingly, vascular complications can occur at any time a patient is on a TKI. Therefore, it is imperative that all care team members and patients are aware of and watching for possible vascular complications. In the following review, a case of arterial thrombosis secondary to the TKI ponatinib is presented as well as a discussion of thrombotic and vascular adverse events reported with TKIs. TKIs are metabolized through the cytochrome P450 system and important drug interactions to consider are reviewed. Finally, we present a multidisciplinary approach to the management of patients with CML on TKIs.

The purpose of this study was to examine the relations of hormonal contraceptives and infertility drugs with the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), ischemic stroke, and cardiovascular disease. The Taiwan National Health Institute Research Database was searched for women who had taken hormonal contraceptives or infertility medications from 2000 to 2010. The two groups were age and index date matched with controls (1:4 ratios). Cox regression analysis was used to examine the risks of VTE, DTE, PE, ischemic stroke, and cardiovascular disease. A total of 32,067 women were included in the hormonal contraceptives group and 4710 in the infertility medications group (matched controls: 127,872 and 18,840, respectively). After adjustment for age, comorbidities, and other confounders, the contraceptives group had a higher risk of VTE (adjusted HR 1.14, 95% CI 1.004 to 1.30) and cardiovascular disease (adjusted HR 1.30, 95% CI 1.26 to 1.34), and lower risk of ischemic stroke (adjusted HR 0.90, 95% CI 0.86 to 0.95). The infertility medications group had a higher risk of VTE (adjusted HR 1.996, 95% CI 1.41 to 2.72) and DVT (adjusted HR 1.86, 95% CI 1.31 to 2.63), and lower risk of ischemic stroke (adjusted HR 0.82, 95% CI 0.68 to 0.99) and cardiovascular disease (adjusted HR 0.83, 95% CI 0.74 to 0.94). Hormonal contraceptives and infertility medications appear to lower the risk of ischemic stroke and increase the risk of VTE; however, their effect on the risk of other types of cardiovascular events varies., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to determine whether there is an influence of interleukin 6 ( IL-6 ) gene promoter polymorphisms on IL-6 plasma levels and its role in the development of ischemic stroke in young Indians. One hundred young patients with ischemic stroke (age ≥ 45 years) and equal number of age- and sex-matched controls were genotyped for 174G>C, -572G>C, and -597G>A promoter polymorphisms by polymerase chain reaction-restriction fragment length polymorphism. Plasma IL-6 levels were measured by enzyme-linked immunosorbent assay. Plasma IL-6 levels were significantly higher in patients as compared to controls (patients: 28.61 ± 8.61 pg/mL, controls: 7.60 ± 4.10 pg/mL, P = .001). Both -174G>C (allelic χ 2 / P value: 4.79/.028, genotypic χ 2 / P value: 5.3/.021) and -572G>C (allelic χ 2 / P value: 9.63/.00113 Genotypic χ 2 / P value: 74/.0002) polymorphisms exhibited genotypic as well as allelic significant association with the disease phenotype. Comparison was made between patients and controls for all 3 polymorphisms using a recessive model with respect to plasma IL-6 levels; no polymorphism showed any significant correlative association with the increased IL-6 levels ( P = .31, .51, .32). Interleukin 6 is an inflammatory marker that is considerably influenced by nongenetic factors and is not a good candidate gene for studying genetic components associated with ischemic stroke. It seems that the variability in IL-6 levels is an integrated effect of nongenetic influences and the inflammatory events that follow ischemic stroke instead of being its cause. It is suggested that there is no direct association between -174G>C, -572G>C, and -597G>A polymorphisms and elevated IL-6 levels in the development of ischemic stroke.

Thrombotic diathesis has been a well-known complication of oral contraceptive use for more than 50 years. This is true not only for venous thrombosis but also for an arterial one. The etiology is usually multifactorial and depends on several additional risk factors. We analyzed the prevalence of inherited and acquired thrombophilia in a cohort of 770 females who had a thrombotic event in association with oral contraceptive use (700 women with venous thromboembolism [VTE], 70 with stroke). Moreover, we tried to identify additional risk factors. Inherited thrombophilia was found in 44.5% with higher frequency in the cohort with VTE (42%) than in females with stroke (24%). The most frequent finding was factor V Leiden. Cigarette smoking was significantly more frequent in the group with stroke (50% vs 25%). The prevalence of cigarette smoking in the group with VTE did not exceed the frequency in general population. Women on oral contraceptive pills have higher risk of venous as well as arterial thrombosis. The risk of venous thrombosis is increased in females with inherited thrombophilia, whereas those with some additional acquired risk factors (especially smoking) may be predisposed to arterial thrombosis. However, the absolute risk of thrombosis in healthy women is low, far less than the risk of unintended pregnancy. Moreover, the risk may be reduced by keeping some rules before the prescription of the pills, healthy life style, and a proper choice of contraception.

We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia-hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antiβ2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-β2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-β2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks.

Objective: Conflicting data exist as to whether proton-pump inhibitors (PPIs) diminish the efficacy of clopidogrel. The aim of this study was to investigate the association between cytochrome P450 ( CYP) genetic variants and clinical adverse outcomes of concomitant use of PPIs and clopidogrel by patients., Methods: We consecutively enrolled 523 patients with ischemic stroke receiving clopidogrel. Platelet aggregation was measured before and after 7 to 10 days of clopidogrel treatment. Single-nucleotide polymorphisms of CYP3A4, CYP3A5, CYP2C19*2, and CYP2C19*3 were examined using mass spectrometry. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction (MI), and vascular death that occurred during the 1-year follow-up period. The safety outcome was hemorrhagic episodes that occurred during the 1-year follow-up period., Results: This study comprised a total of 523 patients with IS, 96.3% (155/161) patients treated with PPIs and 95.9% (347/362) in patients treated without PPIs completed 1-year follow-up. The primary outcome was observed in 69 (13.7%) patients (56 RIS, 7 MI, and 6 died). There was no significant difference in the frequencies of primary outcome and safety outcome between patients treated with or without PPIs. The frequency of primary outcome was significantly higher in patients carrying CYP2C19*2 AG/AA genotype receiving PPIs compared with the same genotype in those not receiving PPIs. The PPIs used in patients carrying CYP2C19*2 AG/AA was independently associated with the primary outcome after adjusting for other risk factors., Conclusions: The concomitant use of PPIs and clopidogrel may be associated with an increased risk of RIS, MI, or vascular death in patients with IS carrying reduced-function CYP2C19*2.

Safety issues have been raised about dabigatran. We aimed to investigate the occurrence of safety outcomes in patients who had atrial fibrillation and a risk of stroke. We analyzed 439 patients prescribed dabigatran (n = 220) or warfarin (n = 219). Ischemic stroke occurred in 15 (6.8%) patients in the warfarin group versus 5 (5.2%) patients in the 110-mg group versus 1 (0.8%) patient in the 150-mg dabigatran group (P = .015). Intracranial hemorrhage occurred in 6 (2.7%) patients in the warfarin group versus 3 (2.4%) patients in the 150-mg dabigatran group (P = .104). Death from any cause occurred in 10 (4.6%) patients in the warfarin group versus 1 (1.0%) patient in the 110-mg dabigatran group (P = .005). Dabigatran was associated with less ischemic stroke and death from any cause than warfarin. Dabigatran may be a better option for stroke prophylaxis, where recommended monitoring with warfarin is suboptimal., (© The Author(s) 2014.)

Background: The National Salt Reduction Initiative, in which food producers agree to lower sodium to levels deemed feasible for different foods, is expected to significantly reduce sodium intake if expanded to a large sector of food manufacturers., Objective: Given recent data on the relationship between sodium intake, hypertension, and associated cardiovascular disease at a population level, we sought to examine risks and benefits of the program., Design: To estimate the impact of further expanding the initiative on hypertension, myocardial infarction (MI) and stroke incidence, and related mortality, given food consumption patterns across the United States, we developed and validated a stochastic microsimulation model of hypertension, MI, and stroke morbidity and mortality, using data from food producers on sodium reduction among foods, linked to 24-hour dietary recalls, blood pressure, and cardiovascular histories from the National Health and Nutrition Examination Survey., Results: Expansion of the initiative to ensure all restaurants and manufacturers reach agreed-upon sodium targets would be expected to avert from 0.9 to 3.0 MIs (a 1.6%-5.4% reduction) and 0.5 to 2.8 strokes (a 1.1%-6.2% reduction) per 10,000 Americans per year over the next decade, after incorporating consumption patterns and variations in the effect of sodium reduction on blood pressure among different demographic groups. Even high levels of consumer addition of table salt or substitution among food categories would be unlikely to neutralize this benefit. However, if recent epidemiological associations between very low sodium and increased mortality are causal, then older women may be at risk of increased mortality from excessively low sodium intake., Conclusions: An expanded National Salt Reduction Initiative is likely to significantly reduce hypertension and hypertension-related cardiovascular morbidity but may be accompanied by potential risks to older women., (© The Author(s) 2015.)

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., (© The Author(s) 2015.)

Central post-stroke pain (CPSP) is a neuropathic pain syndrome that often develops in a delayed manner after thalamic stroke. Here, we describe a new model of CPSP by stereotaxic thalamic injection of endothelin-1. Stroke rats (n = 12), but not saline-injected controls (n = 12), developed a progressive, contralateral cutaneous thermal hyperalgesia over 4 weeks, without motor deficits. Lesions were highly focal and mainly affected the ventral posterior thalamic complex. Tchis model reproduces the infarct location and delayed hypersensitivity typical of CPSP, and may be useful to investigate its pathophysiology and test therapies targeting recovery and pain after thalamic stroke.

Ambient particulate matter (PM) pollution is estimated to be responsible for 3.2 million deaths annually worldwide. Although many studies have demonstrated PM as a serious risk factor for cardiovascular diseases, less is known on its association with cerebrovascular events. Over the last decade, however, an increasing number of studies have provided data showing a relationship between PM exposure and ischemic stroke (IS). In this article, we will report on existing epidemiologic findings for an association between PM exposure and IS based on a systemic literature search. Thus, despite inconsistencies in the results, currently available data suggest that PM exposure is a risk factor for IS, especially in patients with preexisting illnesses. With regards to the mechanisms leading to PM-dependent vascular damage, in particular proinflammatory, prooxidative, as well as proatherogenic pathways have been suggested to be involved. Notably, to date there is only one study published, which demonstrates the influence of PM exposure on cerebrovascular function. We will discuss reasonable approaches for future neurovascular research in this field.

We conducted a case-crossover study to evaluate the comparative risk of ischemic stroke associated with the use of risperidone, quetiapine and olanzapine in geriatric patients using the Korean Health Insurance Review and Assessment Service database. Cases included elderly patients >64 years old who had experienced their first ischemic stroke (International Classification of Disease, Tenth Revision (ICD-10), I63) hospitalization from July 2005 to June 2006 and who had been without prior cerebrovascular diseases (ICD-10, I60-I69), or transient ischemic attack (ICD-10, G45). Exposures to risperidone, quetiapine and olanzapine were assessed during the 30 days prior to the stroke episode. We set two control periods with lengths which were the same as the hazard periods. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated by conditional logistic regression. A total of 1601 cases of ischemic stroke with a mean age of 75.6 (±6.7) years were identified, among which 933 (58.3%) were female. An increased risk of ischemic stroke was associated with the use of risperidone (aOR=3.5, 95% CI 3.3-4.6) and quetiapine (aOR=2.7, 95% CI 2.0-3.6) during the 30 days prior to stroke: however, no significant risk was observed with olanzapine (aOR=1.2, 95% CI 0.7-2.0). The increased stroke risk in demented patients, assessed within 30 days after exposure, was also observed with olanzapine. However, the sample of olanzapine users was small and underpowered.

The search for a safe and effective method of contraception has been ongoing for centuries. During the last century, a variety of hormonal contraceptives, including combined hormonal oral contraceptives (COCs), have been introduced into the market. COCs have evolved through modifications of different hormonal components to minimize the risk of thrombotic events including stroke, myocardial infarction, and venous thrombosis. The evolution of COC development led to the reduction in the estrogen dose, in an attempt to lower the risk of vascular diseases. Although the risk of thrombotic events due to COC use has been substantially reduced since their inception, the quest for developing safer methods of birth control continues. It is of great interest to study coagulation effects of newer COCs, as well as progestin only, as rigorously as older COCs.

A 23-year-old woman developed ischemic stroke (IS) 8 to 12 hours after ingestion of sumatriptan (ST) and then developed mucosal bleeding secondary to acute thrombocytopenia likely due to dipyridamole (DP) on the 10th day poststroke. Sumatriptan-associated IS and DP-induced thrombocytopenia are rare events in themselves and their sequential occurrence in the same patient is quite exceptional. We compare our case to other similar cases in the literature.

Behavioral and Psychological Symptoms of Dementia (BPSD) are increasingly recognized as a major risk factor for caregiver burden, institutionalization, greater impairment in activities of daily living (ADLs), more rapid cognitive decline, and a poorer quality of life. BPSD contribute significantly to the direct and indirect costs of caring for patients with dementia even after adjusting for the severity of cognitive impairment and other co-morbidities. Research on these symptoms has indicated a complex interplay between the biological, psychological and social factors involved in the disease process. Although some psychotropic medications have shown modest efficacy in the treatment of these behaviors, their use has generated controversy due to increasing recognition of the side effects of these medications especially the antipsychotic medications. In this review, we examine the risk of cerebrovascular adverse events (CVAEs) and death with antipsychotic medications when used to treat elderly patients with dementia.

Objectives: to evaluate the existing literature on a proposed interaction between clopidogrel and proton pump inhibitors (PPIs) and discuss its implications for clinicians treating patients with this combination therapy., Background: each year millions of patients receive antiplatelet therapy. A number of these patients are prescribed PPIs concomitantly to reduce the risk of gastrointestinal side effects associated with antiplatelet therapy. Several studies have been published recently addressing a potential adverse drug-drug interaction between clopidogrel and PPIs., Methods: literature was evaluated through Pubmed using the terms clopidogrel, PPI, prasugrel, cytochrome P450, genetic polymorphisms, H( 2) blockers, famotidine, genetic cytochrome P450 polymorphisms, and drug interaction. Articles with these terms were considered for evaluation. In addition, reference citations from publications identified in the searches were further reviewed and analyzed., Results: none of the currently published studies were specifically designed to evaluate this drug-drug interaction or address the clinical relevance of this interaction prospectively. Conflicting evidence raised concerns but the information did not conclude with certainty a cause-and-effect relationship between concomitant use of the drugs and emerging safety issues. However, the Food and Drug Administration issued a public-health warning on the possible interaction between clopidogrel and PPIs, predominantly with omeprazole, in November 2009., Conclusions: controversies exist on a potential drug-drug interaction between clopidogrel and PPIs. Although further studies are warranted, several studies indicated that there was a drug-drug interaction through this combination therapy with detrimental clinical outcomes and increased costs. Studies suggested that the use of a PPI may make clopidogrel less effective resulting in a higher risk of myocardial infarction, stroke, or death. Until additional information becomes available clinicians should consider discontinuing PPI use if no clear indication is documented. Alternative options like H(2)-receptor antagonists should be considered. Upon availability, genetic testing may provide additional valuable information.

Objectives: Tegaserod, a partial 5-HT(4) agonist previously approved for treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, was suspended from US marketing in 2007, based on pooled clinical trial results which contained a signal suggesting increased risk of cardiovascular ischemic events (CVIEs). We sought to evaluate whether there was an association between tegaserod and CVIE in a setting of routine clinical practice., Methods: This was a matched cohort study conducted within a large US health insurance database, involving 52 229 patients who initiated tegaserod and 52 229 patients with similar characteristics who did not initiate tegaserod. Participants were followed for up to 6 months for the occurrence of CVIE (myocardial infarction, acute coronary syndrome, coronary revascularization, and stroke). Outcomes were identified using insurance claims and were confirmed by review of medical records. We conducted as-matched analyses providing hazard ratios (HRs) along with 95% confidence intervals (95% CI) and as-treated analyses accounting for changes in dispensed therapy., Results: There was no increased risk of CVIE associated with tegaserod treatment. The as-matched association between tegaserod and ischemic cardiovascular outcomes (HR = 0.95, 95% CI 0.73-1.23) and stroke (HR = 0.90, 95% CI 0.46-1.77) did not change substantially in the as-treated analyses (cardiovascular relative risk [RR] = 1.14, 95% CI 0.83-1.56; stroke: RR = 1.09, 95% CI = 0.49-2.02). The results were largely unaffected by adjustment for characteristics or subgroup analyses., Conclusion: In this observational study of tegaserod use, we found no evidence for an increased risk of CVIE in tegaserod users.

The objective was to evaluate the cardiovascular risks associated with rosiglitazone in diabetic patients. We conducted matched nested case-control studies in a retrospective population-based cohort of all elderly diabetic patients living in Quebec throughout 2001 and 2002. Study end-points were: all-cause and cardiovascular death, hospital admission for AMI, CHF and stroke.Twenty controls per case, matched for age, gender and date of cohort entry, were randomly drawn from each case's risk set. Conditional logistic regressions were adjusted for co-morbidities and other drug exposures. The risk of hospital admission for AMI (HR 1.41, 95% CI 1.21-1.65) and CHF (HR 1.94, 95% CI 1.71-2.19) was increased by the use of rosiglitazone. However, exposure to rosiglitazone was not associated with an increased risk of cardiovascular mortality (HR 0.88, 95% CI 0.69-1.12) and all-causes mortality (HR 0.87, 95% CI 0.76-0.99).The risk of hospital admission for stroke was not significantly affected by rosiglitazone use. Further studies are needed to better understand the mechanisms explaining these associations.

The purpose of the study was to investigate the risk of stroke with typical and atypical anti-psychotics in elderly subjects, weighting for a number of known risk factors, including dementia. Data were retrospectively drawn from the primary care setting from the Health Search Database, which stores information on about 1.5% of the total Italian population served by general practitioners. All elderly patients (65+ years) prescribed an anti-psychotic in monotherapy from January 2000 to June 2003 were selected for the study. A cohort of patients not exposed to anti-psychotics was taken from the same database. Subjects who had previously had a stroke were excluded. The main outcome measure was the incidence of first-ever stroke during exposure to an anti-psychotic.The sample included non-users (69,939), users of atypicals (599), butyrophenones (749), phenotiazines (907) and substituted benzamides (1,968). The crude incidence of stroke in subjects not exposed to anti-psychotics was 12.0/1000 person-years. Risk was significantly higher for those on butyrophenones (47.1/1000), phenotiazines (72.7/1000) and in the atypical anti-psychotic group (47.4/1000). Substituted benzamides had an almost significant higher risk (25.0/1000). Cox regression modelling, weighting for demographic and clinical variables with non-users as the reference group, showed that the risk for stroke was 5.79 times for phenotiazines, 3.55 times for butyrophenones, and 2.46 times for atypicals. Clinicians should be cautious in prescribing phenotiazines and butyrophenones in elderly patients, since the risk for stroke would seem comparable or even greater than with atypicals.

A chemical worker working with urea-formaldehyde resin hazard for 20 years suffered cerebral ischemia in association with an increase of blood beta2-glycoprotein I-dependent anticardiolipin antibody (aCL)-IgG and IgM isotype, and a prolongation of activated partial thromboplastin time (aPTT). Major histocompatibility complex antigen showed DR4 positivity. On follow-up for over 6 years, aCL-IgG and aPTT decreased to reference range but aCL-IgM was still abnormally high despite a cessation of exposure. This patient highlights the induction of antibody-mediated thrombosis in chronic chemical exposure, especially in an individual with subclinical autoimmune disorder. The role of environment for coagulopathic vascular thrombosis is warranted for investigation.

Following changes in the safety information on the use of risperidone and olanzapine in elderly patients with dementia, data from prescription-event monitoring (PEM) studies of risperidone, quetiapine and olanzapine were examined. The aim was to compare incidence rates for events reported as cerebrovascular accident (CVA) and transient ischaemic attack (TIA) during the first 180 days of treatment in patients prescribed atypical antipsychotics for dementia or other indications, because of the possible association between dementia and stroke in users of atypical antipsychotics. A retrospective analysis of data from the three observational studies was conducted using Poisson regression modelling and survival analysis. Within the risperidone, quetiapine and olanzapine cohorts, 23 (0.30%), 6 (0.35%) and 10 (0.11%) patients respectively, were reported to have had a CVA/TIA event. Age, sex and indication (dementia or other) were identified as important confounding variables; age being the most important. The crude rate ratios (RRs) for CVA/TIA for risperidone or quetiapine vs. olanzapine indicated an approximate threefold relative difference in rate during the first six months but after adjustment for age, sex and indication, the RRs were non-significant (1.2 (95% CI 0.5,3.0) and 2.1 (95% CI 0.6,7.7), respectively). For risperidone vs. quetiapine, crude and adjusted RRs were not significantly different. Of the three drugs, the time to event was shortest for risperidone and also shortest for risperidone or quetiapine users where the indication was dementia. The age and sex adjusted RR of CVA/TIA in patients prescribed risperidone for dementia vs. other indications was 6.7 (95% CI 2.4,18.9). The adjusted RRs for quetiapine, according to indication, could not be calculated due to missing information on age and sex. There were no cases of CVA/TIA with dementia for olanzapine, thus the RRs and time to event curves according to indication could not be examined. This study revealed no significant difference in the adjusted RR of CVA/TIA events in the first 180 days of treatment in patients prescribed risperidone or quetiapine when compared with olanzapine. However, dementia appears to be an important risk factor. These results should be considered alongside other pharmacoepidemiological studies on this topic.

17beta-estradiol reduces cell death after global and focal ischemia and subarachnoid hemorrhage in rodents. Presently, we tested whether estrogen improves outcome after intracerebral hemorrhage (ICH) in male rats. Rats were implanted subcutaneously with 0.05, 0.25, or 0.50 mg pellets of estrogen (21-day release) or subjected to a sham procedure. Two weeks after implantation, they were given a striatal ICH via an infusion of collagenase. The three estrogen groups had significantly smaller lesions at a 7-day survival. Some rats had core temperature measured with an implanted telemetry probe, which also measured whole-body movements. Estrogen did not affect temperature nor activity levels after ICH. A second study with 0.25 mg pellets, administered once or twice, showed persistent histologic protection (30 days) and some functional benefit (e.g., elevated beam). A spectrophotometric hemoglobin assay showed that the 0.25 mg dose significantly reduced hemorrhagic blood volume at 12 hours after ICH. Regardless, estrogen did not lessen cerebral edema at 2 days after ICH and functional benefits were not consistently found on all tests (e.g., cylinder task). In summary, estrogen pretreatment reduces injury after ICH, in part by reducing bleeding. Estrogen may thus lessen injury and improve outcome after ICH in humans.