Emerging agents for the treatment and prevention of stroke: progress in clinical trials.

INTRODUCTION: Recent years have witnessed unprecedented progress in stroke care, but unmet needs persist regarding the efficacy of acute treatment and secondary prevention. Novel approaches are being tested to enhance the efficacy of thrombolysis or provide neuroprotection in non-thrombolized patients. AREAS COVERED: The current review highlights pharmaceutical agents under evaluation in clinical trials concerning the acute, subacute, and chronic phase post-stroke. We examine the evidence in favor of tenecteplase as an alternative thrombolytic drug to alteplase, nerinetide as a promising neuroprotective agent, and glibenclamide for reducing edema in malignant hemispheric infarction. We discuss the use of ticagrelor and the promising novel category of factor XI inhibitors in the subacute phase after stroke. We offer our insights on combined rivaroxaban and antiplatelet therapy, PCSK-9 inhibitors, and other non-statin hypolipidemic agents, as well as novel antidiabetic agents that have been shown to reduce cardiovascular events in the long-term. EXPERT OPINION: Current approaches in stroke treatment and stroke prevention have already transformed stroke care from a linear one-for-all treatment paradigm to a more individualized approach that targets specific patient subgroups with novel pharmaceutical agents. This tendency enriches the therapeutic armamentarium with novel agents developed for specific stroke subgroups. ABBREVIATIONS: IVT: intravenous thrombolysis; RCTs: randomized-controlled clinical trials; TNK: Tenecteplase; COVID-19: Coronavirus 2019 Disease; EXTEND-IA TNK: The Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke trial; AIS: acute ischemic stroke; NNT: number needed to treat; MT: mechanical thrombectomy; sICH: symptomatic intracranial hemorrhage; mRS: modified Rankin Scale; AHA/ASA: American Heart Association/American Stroke Association; ESO: European Stroke Organization; NA-1: Nerinetide; ENACT: Evaluating Neuroprotection in Aneurysm Coiling Therapy; CTA: CT angiography; TIA: transient ischemic attack; CHANCE: Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events; LOF: loss-of-function; PRINCE: Platelet Reactivity in Acute Nondisabling Cerebrovascular Events; THALES: Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death; CHANCE-2: Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II; FXI: Factor XI; PACIFIC-STROKE: Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-NonCardioembolic Stroke study; COMPASS: Cardiovascular Outcomes for People Using Anticoagulation Strategies; CANTOS-ICAD: Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease; SAMMPRIS: Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis; WASID: Warfarin-Aspirin Symptomatic Intracranial Disease; SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels; LDL-C: low-density lipoprotein cholesterol; TST: Treat Stroke to Target; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PCSK9: proprotein convertase subtilisin-kexin type 9; FOURIER: Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; CLEAR: Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen; REDUCE-IT: Reduction of Cardiovascular Events With EPA Intervention Trial; STRENGTH: Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia; ACCORD: Action to Control Cardiovascular Risk in Diabetes; ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT: Veterans Affairs Diabetes Trial; GLP-1R: Glucagon-like peptide-1 receptor; SGLT2: sodium-glucose cotransporter 2; CONVINCE: COlchicine for preventioN of Vascular Inflammation in Non-CardioEmbolic stroke; PROBE: Prospective Randomized Open-label Blinded Endpoint assessment.

New Horizons in Pharmacologic Therapy for Secondary Stroke Prevention.

Importance: Even with currently available therapies and lifestyle modifications following an ischemic stroke, there remains a substantial residual lifetime risk of stroke recurrence and cardiovascular morbidity. This review summarizes emerging novel therapeutic approaches that have demonstrated signals of efficacy for prevention of noncardioembolic stroke from phase II and phase III randomized clinical trials (RCTs) and provides an overview of drug regimens that have had promising results in primary stroke prevention and could be considered for further evaluation. Observations: After a minor acute ischemic stroke or transient ischemic attack, patients bear a high cardiovascular risk that is insufficiently addressed by long-term antiplatelet treatment. The potent combination of low-dose rivaroxaban with aspirin as an antithrombotic option for the secondary prevention in patients with clinical atherosclerosis and a history of previous stroke warrants further study. Two international RCTs are currently evaluating the utility of oral factor XI inhibitors combined with antiplatelets for secondary, noncardioembolic ischemic stroke prevention. Aggressive lipid management with statins has been shown to ameliorate ischemic stroke recurrence and total cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors are drug regimens that researchers have suggested confer additional protection against stroke recurrence, while antisense oligonucleotide therapies targeting lipoprotein(a) have been reported to hold great promise as a future therapeutic strategy to decrease the residual cardiovascular risk mediated through lipoprotein(a). Glucagon-like peptide-1 receptor agonists are newer antidiabetic medications, recently highlighted because of their consistently greater benefit on stroke reduction compared with other cardiovascular outcomes. Conclusions and Relevance: There are currently several exciting emerging opportunities in secondary stroke prevention, with RCTs investigating novel antithrombotic, hypolipidemic, anti-inflammatory, and antidiabetic agents with novel mechanisms that are likely to reduce the future burden of recurrent stroke.

Cerebrovascular disease: how serum phosphorus, vitamin D, and uric acid levels contribute to the ischemic stroke.

BACKGROUND: Associations between serum phosphorus level and the incidence of ischemic stroke are not clear. This study aimed to measure serum phosphorus, vitamin D3, and uric acid levels in ischemic stroke patients compared to a population without ischemic stroke. METHODS: In this cross-sectional study, 133 patients admitted to a neurology ward with the diagnosis of ischemic stroke were compared with a control group comprising 133 age- and gender-matching individuals. The presence of ischemic stroke was confirmed by a neurologist based on clinical signs, symptoms, brain CT scan, and MRI. Blood samples were taken from all patients in the first 24 h of admission to measure serum phosphorus, vitamin D3, calcium, and uric acid levels. RESULTS: According to the results of this study, uric acid medians in patients with stroke and controls were 4.9 [3.8-6.4] and 3.9 [3.5-4.9] mg/dL, respectively (p < 0.001). Median phosphorus and vitamin D levels were significantly lower in stroke patients than the controls (3.6 [3.02-4.21] vs. 4.2 [3.8-4.6]) and (15.1 [8.2-27.9] vs. 22.7 [10.4-39.2]), respectively. Multiple logistic regression analysis showed that the ischemic stroke was positively associated with the vitamin D level and negatively correlated with the uric acid level. The phosphorus level was not significantly predictive of ischemic stroke. CONCLUSION: Lower serum levels of vitamin D3 and higher levels of uric acid were associated with ischemic stroke. There are still unknowns about the role of these indicators on ischemic stroke and it requires further studies.

Cryptogenic Intracranial Hemorrhagic Strokes Associated with Hypervitaminosis E and Acutely Elevated α-Tocopherol Levels.

OBJECTIVES: Up to 41% of intracerebral hemorrhages (ICH) are considered cryptogenic despite a thorough investigation to determine etiology. Certain over-the-counter supplements may increase proclivity to bleeding, and we hypothesize that specifically vitamin E may have an association with ICH and acutely elevated serum levels of α-tocopherol. Our aim is to report 3 cases of recently admitted patients with hypervitaminosis E and otherwise cryptogenic ICH. METHODS: At our institution between January and December 2018, 179 patients were admitted with ICH with 73 imputed to be "cryptogenic" (without clear etiology as per Structural vascular lesions, Medication, Amyloid angiopathy, Systemic disease, Hypertension, or Undetermined and Hypertension, Amyloid angiopathy, Tumor, Oral anticoagulants, vascular Malformation, Infrequent causes, and Cryptogenic criteria). Of these, we found 3 (4.1%) clearly admitted to consistent use of vitamin E supplementation for which α-tocopherol levels were checked. We describe the clinical presentation and course of these patients and their etiologic and diagnostic evaluations including neuroimaging and α-tocopherol laboratory data. RESULTS: All patients in this series were consistently consuming higher than recommended doses of vitamin E and developed acute ICH. The first 2 patients both had subcortical (thalamic) intraparenchymal hemorrhages while the third had an intraventricular hemorrhage. Serum α-tocopherol levels in patient A, B, and C were elevated at 30.8, 46.7, and 23.3 mg/L, respectively (normal range 5.7-19.9 mg/L) with a mean of 33.6 mg/L. No clear alternate etiologies to their ICH could be conclusively determined despite thorough workups. CONCLUSIONS: In patients with cryptogenic ICH, clinicians should consider hypervitaminosis E and check serum α-tocopherol level during admission. Reviewing the patient's pharmacologic history, including over-the-counter supplements such as vitamin E, may help identify its association, and its avoidance in the future may mitigate risk. With its known vitamin K antagonism, hypo-prothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity, vitamin E may not be as benign as presumed. Its consumption in nonrecommended doses may increase ICH risk, which may be underestimated and under-reported.

Dietary and Serum Omega-6/Omega-3 Fatty Acids Are Associated with Physical and Metabolic Function in Stroke Survivors.

The purpose of this study was to quantify habitual dietary and systemic omega-6 and omega-3 fatty acids and their ratios and to determine their relationship with physical and metabolic function in a cohort of chronic adult stroke survivors. Twenty-five older chronic stroke survivors (age: 63 ± 8 years; BMI: 31 ± 7 kg/m2; mean ± SD) were assessed for fitness (VO2peak), gait speed (GS), 3 m timed up and go (TUG), and six-minute walk distance (6MWD). Plasma lipid and glucose profiles were measured, and HOMA-IR calculated. Dietary (5-day food records) and serum (mass spectrometry) omega-6/omega-3 profiles were assessed. Participants were severely deconditioned (VO2peak: 19 ± 4 mL/kg/min; GS: 0.88 ± 0.28 m/s; TUG: 12.6 ± 5.9 s; 6MWD: 295 ± 121 m) and at elevated metabolic risk (HOMA-IR: 6.3 ± 4.5). The dietary intake ratio of omega-6/omega-3 fatty acids averaged 12.6 ± 7.1 and the serum concentration ratio was 1.21 ± 0.37, which were correlated (r = 0.88, p < 0.01). Higher dietary intake and serum concentrations of omega-6/omega-3 fatty acids were associated with lower 6MWD and higher HOMA-IR, while a higher serum omega-6/omega-3 concentration index was associated with lower VO2peak (p's < 0.05). These preliminary data suggest that both dietary omega-6 and omega-3 fatty acids (quantitated as their intake ratio) and the serum concentration ratio of omega-6/omega-3 may be important indices of physical dysfunction and insulin resistance in chronic stroke survivors.

Interactions between neutrophil extracellular traps and activated platelets enhance procoagulant activity in acute stroke patients with ICA occlusion.

BACKGROUND: The role of neutrophil extracellular traps (NETs) in procoagulant activity (PCA) in stroke patients caused by thromboembolic occlusion of the internal carotid artery (ICA) remains unclear. Our objectives were to evaluate the critical role of NETs in the induction of hypercoagulability in stroke and to identify the functional significance of NETs during atherothrombosis. METHODS: The levels of NETs, activated platelets (PLTs), and PLT-derived microparticles (PMPs) were detected in the plasma of 55 stroke patients and 35 healthy controls. NET formation and thrombi were analysed using immunofluorescence. Exposed phosphatidylserine (PS) was evaluated with flow cytometry and confocal microscopy. PCA was analysed using purified coagulation complex, thrombin, and fibrin formation assays. FINDINGS: The plasma levels of NETs, activated PLTs, and PMP markers in the carotid lesion site (CLS) were significantly higher than those in the aortic blood. NETs were decorated with PS in thrombi and the CLS plasma of ICA occlusion patients. Notably, the complementary roles of CLS plasma and thrombin-activated PLTs were required for NET formation and subsequent PS exposure. PS-bearing NETs provided functional platforms for PMPs and coagulation factor deposition and thus increased thrombin and fibrin formation. DNase I and lactadherin markedly inhibited these effects. In addition, NETs were cytotoxic to endothelial cells, converting these cells to a procoagulant phenotype. Sivelestat, anti-MMP9 antibody, and activated protein C (APC) blocked this cytotoxicity by 25%, 39%, or 52%, respectively. INTERPRETATION: NETs played a pivotal role in the hypercoagulability of stroke patients. Strategies that prevent NET formation may offer a potential therapeutic strategy for thromboembolism interventions. FUNDING: This study was supported by grants from the National Natural Science Foundation of China (61575058, 81873433 and 81670128) and Graduate Innovation Fund of Harbin Medical University (YJSKYCX2018-58HYD).

Study on the therapeutic material basis and effect of Acanthopanax senticosus (Rupr. et Maxim.) Harms leaves in the treatment of ischemic stroke by PK-PD analysis based on online microdialysis-LC-MS/MS method.

Leaves of Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASL) have revealed significant biological activity in the treatment of ischemic stroke diseases. However, there was no in-depth study of the therapeutic material basis and effect of ASL from the pharmacokinetics-pharmacodynamics (PK-PD) analysis level. In this study, a method based on microdialysis coupled with ultra-performance liquid chromatography combined with triple quadruple mass spectrometry (MD-UPLC-QQQ-MS) was established to simultaneously and continuously collect and quantify the active compounds and endogenous neuroactive substances related to therapeutic effect in plasma and hippocampus of fully awake ischemic stroke rats. The acquired data were analyzed by the PK-PD analysis method. It was found that hyperoside, quercitrin, quercetin, and caffeic acid could pass through the blood-brain barrier, and quercetin needed a longer intake time than quercitrin and hyperoside, but the passage rate was higher. The exposure of the four compounds in the hippocampus affected the contents of seven neuroactive substances in different ways and was depicted graphically (concentration-time effect). In addition, the study found that the brain index and brain water content of ischemic stroke rats were significantly reduced after the oral administration of ASL. ASL observably regulated the content or activity of six important biochemical indexes in rats. On the one hand, this study verified that ASL could regulate ischemic stroke in many aspects. On the other hand, a visualized method to express the relationship between pharmacokinetics and pharmacodynamics in the hippocampus of cerebral ischemic areas was established. This research gives a hand to the study on the therapeutic material basis and effect of traditional Chinese medicine mechanism.

Combination therapy with an Xa inhibitor and antihypertensive agent improved anticoagulant activity in patients with nonvalvular atrial fibrillation: the hypertension and atrial fibrillation treated by rivaroxaban for the morning and night with sYnergy with calcium antagonists (HARMONY) study.

Background: Anticoagulant activity and blood pressure increase in the morning. The aim of this study was to evaluate changes of anticoagulant activity, blood pressure and target organ damage in patients with nonvalvular atrial fibrillation (AF) given combination treatment with Xa inhibitor and antihypertensive agent.Methods: We enrolled 72 patients with nonvalvular AF. Rivaroxaban (10-15 mg) was continuously administered once daily over 8 weeks (study period I). For subjects (n = 50) who exhibited uncontrolled morning hypertension (home systolic blood pressure [SBP]≥125 mmHg) at the end of study period I (at 8 weeks), nifedipine CR (20-40 mg) was added at bedtime, and rivaroxaban administration was continued an additional 8 weeks. We assessed prothrombin fragment 1 + 2 (optimal range: 69-229 pmol/L) and D-dimer (negative D-dimer measurement: <1.0 µg/mL).Results: The percentage of patients with optimal-range prothrombin fragment 1 + 2 was significantly increased at 4 weeks compared to baseline (70.8% vs. 86.1%, p = .033). In period II, office and home morning SBP were reduced at 12 compared to 8 weeks (office SBP: 135.2 ± 15.7 vs. 125.6 ± 18.4mmHg, p < .001; home morning SBP: 133.5 ± 10.5 vs. 119.9 ± 12.1mmHg, p<.001).The percentage of patients with negative D-dimer  was increased at 8 weeks compared to baseline (92% vs. 100%, p = .044), and remained at 100% at 16 weeks.Conclusions: Xa inhibitor therapy improved anticoagulant activity, and additional antihypertensive therapy maintained the anticoagulant activity in patients with nonvalvular AF.

From clinical appearance to accurate management in acute ischemic stroke patients: With the guidance of innovative traditional Chinese medicine diagnosis.

OBJECTIVE: To investigate the correlation between simplified classification and laboratory indicators in patients with acute ischemic stroke, also provide accurate evidences for simplified classification and guide clinical interventions and treatment. METHODS: Two hundred patients with acute ischemic stroke were classified into four types according to the characteristics of Traditional Chinese Medicine syndrome: phlegm-heat syndrome, phlegm-dampness syndrome, qi deficiency syndrome, and yin deficiency syndrome. The differences between the types of syndromes and the correlation between laboratory indicators and syndromes were analyzed. RESULTS: Among the 200 patients with acute ischemic stroke, there were significant differences in the level of low-density lipoprotein (LDL-C) (p < .05) between patients with phlegm-heat syndrome and other three types. There were significant differences in the levels of homocysteine (HCY) and fibrinogen (Fib) between patients with yin deficiency syndrome and other three types (p < .05). In addition, there were statistically significant differences in blood glucose (Glu), glycosylated hemoglobin (HBA1c), and total cholesterol (CHO) between phlegm-heat syndrome and qi deficiency syndrome (p < .05). There were significant differences in the levels of Glu, HBA1c, D-2 polymer (D-D), and C-reactive protein (CRP)s between patients with phlegm-heat syndrome and phlegm-dampness syndrome (p < .05). There were statistically significant differences in the levels of CRP and urea nitrogen between patients with yin deficiency syndrome and phlegm-dampness syndrome and qi deficiency syndrome (p < .05). CONCLUSIONS: The four-type simplified classification of Integrated TCM and Western medicine in acute ischemic stroke has specific laboratory data to support. Simplified classification with TCM treatment and intervention of different patients improves the survival and treatment, which is an innovative, easy-to-master clinical diagnosis and treatment model.

Zinc Homeostasis in Platelet-Related Diseases.

Zn2+ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn2+-deficient diets, accounting for 1-4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn2+ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn2+ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn2+ uptake in the gut using different nutritional supplementation of Zn2+ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn2+ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn2+ in hemostasis. Storage protein metallothionein maintains or releases Zn2+ in the cytoplasm, and the dynamic change of this cytoplasmic Zn2+ pool is regulated by the redox status of the cell. An increase of labile Zn2+ pool can be toxic for the cells, and therefore cytoplasmic Zn2+ levels are tightly regulated by several Zn2+ transporters located on the cell surface and also on the intracellular membrane of Zn2+ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn2+ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn2+ transport and the physiological role of Zn2+ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn2+ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn2+ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases.

The effect of uric acid on sleep quality after acute ischemic stroke.

Sleep disturbance is a common psychiatric complication after stroke. Oxidative stress has been an important pathophysiological mechanism of sleep disturbance. However, no study has explored the relationship between uric acid (UA) and post-stroke sleep quality. This prospective study included 191 patients who were followed up for two months after acute ischemic stroke. Serum UA levels were measured at admission and divided into 3 tertiles (≤251 µmol/L, 252-326 µmol/L, ≥327 µmol/L). Patients in the 3rd tertile of UA levels had a lower incidence of poor sleep quality than those belonging to 2nd or 1st tertile, respectively (9.7% vs. 27.7% vs. 35.9%; P = 0.002). Furthermore, high UA levels (≥327 µmol/L) were independently associated with low risk of poor sleep quality (OR = 0.129, 95%CI = 0.031-0.528, P = 0.004) after adjusting for demographics, cardiovascular risk factors, stroke severity, functional outcome and depressive symptoms. High modified Rankin Scale score and depressive symptoms were associated with increased risk of poor sleep quality after stroke (OR = 1.836, 95%CI = 1.035-3.354, P = 0.038) and (OR = 5.082, 95%CI = 1.709-15.115, P = 0.003). In conclusion, high UA levels may reduce the risk of poor sleep quality after acute ischemic stroke. Further randomized controlled trials are necessary in examining whether appropriate UA supplement could provide a potential prevention or therapeutic target for sleep disturbance after stroke.

Severity of Vitamin D Deficiency Predicts Mortality in Ischemic Stroke Patients.

BACKGROUND: Vitamin D (VD) deficiency is considered an independent risk factor for death due to cardiovascular events including ischemic stroke (IS). We assessed the hypothesis that decreased levels of 25-hydroxyvitamin D (25-OH-D) are associated with increased risk of mortality in patients with IS. METHODS: Serum 25-OH-D, intact parathyroid hormone (iPTH), and intact fibroblast growth factor 23 (iFGF23) levels were assessed in serum of 240 consecutive patients admitted within the 24 hours after the onset of IS. Mortality data was obtained from the local registry office. RESULTS: Only three subjects (1.3%) had an optimal 25-OH-D level (30-80 ng/mL), 25 (10.4%) had a mildly reduced (insufficient) level, 61 (25.4%) had moderate deficiency, and 151 (62.9%) had a severe VD deficiency. 20% subjects had secondary hyperparathyroidism. The serum 25-OH-D level was significantly lower than that in 480 matched subjects (9.9 ± 7.1 vs. 21.0 ± 8.7 ng/mL). Of all the patients, 79 (32.9%) died during follow-up observation (44.9 months). The mortality rates (per year) were 4.81 and 1.89 in a group with and without severe VD deficiency, respectively (incidence rate ratio: 2.52; 95% CI: 1.44-4.68). There was no effect of secondary hyperparathyroidism and iFGF23 levels on mortality rates. Age, 25 - OH - D < 10 ng/mL, and functional status (modified Rankin scale) were significant factors increasing the risk of death in multivariable Cox proportional hazard regression test. CONCLUSIONS: Severe VD deficiency is an emerging, strong negative predictor for survival after IS, independent of age and functional status. VD supplementation in IS survivals may be considered due to high prevalence of its deficiency. However, it is uncertain whether it will improve their survival.

A NMR-Based Metabonomics Approach to Determine Protective Effect of a Combination of Multiple Components Derived from Naodesheng on Ischemic Stroke Rats.

Naodesheng (NDS) is a widely used traditional Chinese medicine (TCM) prescription for the treatment of ischemic stroke. A combination of 10 components is derived from NDS. They are: Notoginsenoside R1, ginsenoside Rg1, ginsenoside b1, ginsenoside Rd, hydroxysafflor yellow A, senkyunolide I, puerarin, daidzein, vitexin, and ferulic acid. This study aimed to investigate the protective effect of the ten-component combination derived from NDS (TCNDS) on ischemic stroke rats with a middle cerebral artery occlusion (MCAO) model by integrating an NMR-based metabonomics approach with biochemical assessment. Our results showed that TCNDS could improve neurobehavioral function, decrease the cerebral infarct area, and ameliorate pathological features in MCAO model rats. In addition, TCNDS was found to decrease plasma lactate dehydrogenase (LDH) and malondialdehyde (MDA) production and increase plasma superoxide dismutase (SOD) production. Furthermore, 1H-NMR metabonomic analysis indicated that TCNDS could regulate the disturbed metabolites in the plasma, urine, and brain tissue of MCAO rats, and the possible mechanisms were involved oxidative stress, energy metabolism, lipid metabolism, amino acid metabolism, and inflammation. Correlation analysis were then performed to further confirm the metabolites involved in oxidative stress. Correlation analysis showed that six plasma metabolites had high correlations with plasma LDH, MDA, and SOD. This study provides evidence that an NMR-based metabonomics approach integrated with biochemical assessment can help to better understand the underlying mechanisms as well as the holistic effect of multiple compounds from TCM.

Gender, hyperandrogenism and vitamin D deficiency related functional and morphological alterations of rat cerebral arteries.

Hyperandrogenism is a risk factor of cerebrovascular diseases as androgens can alter markedly the regulation of cerebrovascular tone. We examined the combined impact of androgen excess and vitamin D deficiency (VDD), a common co-morbidity in hyperandrogenic disorders, on remodeling and testosterone-induced vascular responses of anterior cerebral arteries (ACA) in order to evaluate the interplay between androgens and VDD in the cerebral vasculature. Male and female Wistar rats were either fed with vitamin D deficient or vitamin D supplemented diet. Half of the female animals from both groups received transdermal testosterone treatment. After 8 weeks, vessel lumen, wall thickness and testosterone-induced vascular tone of isolated ACA were determined using pressure microangiometry and histological examination. Androgen receptor protein expression in the wall of cerebral arteries was examined using immunohistochemistry. In female rats only combined VDD and testosterone treatment decreased the lumen and increased the wall thickness of ACA. In males, however VDD by itself was able to decrease the lumen and increase the wall thickness. Vascular reactivity showed similar alterations: in females, testosterone constricted the ACA only after combined VDD and hyperandrogenism, whereas in males VDD resulted in increased testosterone-induced contractions in spite of decreased androgen receptor expression. In conclusion, a marked interplay between hyperandrogenism and VDD results in inward remodeling and enhanced testosterone-induced constrictions of cerebral arteries, which might compromise the cerebral circulation and thus, increase the risk of stroke in the long term. In addition, the early cerebrovascular manifestation of VDD appears to require androgen excess and thus, depends on gender.

Circulating Selenium Concentration Is Inversely Associated With the Prevalence of Stroke: Results From the Canadian Health Measures Survey and the National Health and Nutrition Examination Survey.

Background Observational studies have suggested that selenium (Se) may have beneficial effects against certain cardiovascular outcomes, with a possible U-shaped association. We assessed the hypothesis that blood Se concentration might be inversely associated with the prevalence of stroke and the relationship would be nonlinear. Methods and Results Data collected from adult participants (aged ≥20 years) in the Canadian Health Measures Survey ( CHMS 2007-2011, n=7065) and the US National Health and Nutrition Examination Survey ( NHANES 2011-2012, n=5030) were analyzed. A total of 82 (1.16%) and 202 (4.02%) stroke cases were identified in CHMS and NHANES . Respondents with stroke had lower Se levels than those without stroke, with a mean difference of 16 µg/L and 12 µg/L for CHMS and NHANES , respectively. Respondents with high blood Se concentration (tertile 3) had a lower prevalence of stroke compared with those with low Se concentration (tertile 1). The adjusted odds ratios were 0.38 (95% CI : 0.15, 0.92) and 0.57 (95% CI : 0.31, 1.03) for CHMS and NHANES , respectively. A continuous decreasing trend of stroke with whole blood selenium was observed in CHMS , whereas the curve plateaued starting at 190 µg/L for NHANES , based on the cubic restricted spline regression. Sensitivity analysis using the serum and urinary Se concentrations demonstrates that our results were consistent across different selenium biomarkers. Conclusions We observed inverse cross-sectional associations between whole blood Se and the prevalence of stroke in representative samples of the Canadian and the US population.

What is the Current Role for Vitamin D and the Risk of Stroke?

INTRODUCTION: Increasing evidence supports the relationship between vitamin D and stroke. Vitamin D has now been proposed as a prognostic biomarker also for functional outcome in stroke patients. METHODS: A revision of the data suggests that low vitamin D is associated more with ischemic than with haemorrhagic stroke, even if the role of optimal vitamin D levels for vascular wall is still unclear. Vitamin D deficiency induces with different mechanisms an alteration of vascular wall. RESULTS: However, to date, the research supporting the effectiveness of vitamin D supplementation in stroke and in post-stroke recovery is still inadequate and conclusive evidences have not been published. CONCLUSION: In this review, we provide a better understanding of the role of vitamin D in stroke.

Rivaroxaban concentrations in acute stroke patients with different dosage forms.

BACKGROUND: The crushed-tablet rivaroxaban concentration has been previously reported to be lower than the non-crushed concentration. However, the rivaroxaban concentration of fine granules has not yet been investigated. The anticoagulation intensity of rivaroxaban with fine granules, tablets, and crushed tablets was compared in acute stroke patients to assess the efficacy of each form. METHODS AND FINDINGS: Hospitalized patients over 75 years old with acute stroke who started taking rivaroxaban from April 2012 to September 2017 were included. Blood samples were drawn just before and 4 hours after taking rivaroxaban on a median of 5 days after treatment initiation for concentration measurements (C0h, C4h) based on an anti-factor Xa chromogenic assay. Of 114 patients (49 female, 83±5 years old), 97 had ischemic strokes, 9 had transient ischemic attacks, and 8 had intracerebral hemorrhages. Rivaroxaban was administered a median of 7 days after onset. Of these, 38 patients were given the 15 mg dose, and 76 were given the 10 mg dose. In the 15 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group, with no significant difference compared to the tablet group [C0h: 27.6±6.8 vs 4.0±4.1 (P = 0.01) vs. 33.3±25.2 ng/ml, (P = 0.51), respectively], as was C4h [223.0±66.6 vs 103.0±79.5 (P = 0.02) vs. 229.5±121.6 ng/ml (P = 0.88)]. In the 10 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group and comparable to that in the tablet group [23.2±7.9 vs 7.5±6.2 (P<0.01) vs 19.0±15.8 ng/ml, (P = 0.35)], as was C4h [150.7±85.4 vs 85.1±46.8 (P<0.01) vs 189.8±92.7 ng/ml (P = 0.18)]. CONCLUSIONS: The rivaroxaban concentration with fine granules was consistent with that in the tablet group and higher than that in the crushed tablet group.

Targets, Treatments, and Outcomes Updates in Diabetic Stroke.

GOAL: Due to multiple failures to translate basic research, the need for novel therapeutic targets and strategies is still urgent to save a larger number of the stroke patients' population and to reduce the toxicity of the current stroke therapy. METHOD: We summarize the most recent, within past 5 years, basic and clinical diabetic stroke research findings. FINDINGS: We aim to examine the most current understanding of stroke and neurovascular unit integrity, especially in presence of hyperglycemia and/or diabetes mellitus. From there, we are comparing the meaningful findings that aim at treating diabetic stroke to see where they differ, where they succeed, and where they open questions for new therapeutic strategies. CONCLUSION: The need for more clinically effective neuroprotective strategies is still mismatched with the bench side findings.

Vitamin B 12 deficiency and hyperhomocysteinaemia in outpatients with stroke or transient ischaemic attack: a cohort study at an academic medical centre.

OBJECTIVE: We sought to assess the current magnitude of the opportunity for secondary stroke prevention with B vitamins. DESIGN: A cohort study. SETTING: The Urgent TIA (Transient Ischaemic Attack) Clinic at an academic medical centre. MAIN OUTCOME MEASURES: We assessed the prevalence of biochemical vitamin B12 deficiency (B12Def, serum B12 <156 pmol/L), hyperhomocysteinaemia (HHcy; plasma total homocysteine [tHcy] >14 µmol/L) and metabolic B12 deficiency (MetB12Def, serum B12 <258 pmol/L and HHcy) between 2002 and 2017, by age group and by stroke subtype. RESULTS: Data were available in 4055 patients. B12Def was present in 8.2% of patients overall; it declined from 10.9% of patients referred before 2009 to 5.4% thereafter (p=0.0001). MetB12Def was present in 10.6% of patients, and HHcy was present in 19.1% of patients. Among the patients aged ≥80 years, MetB12Def was present in 18.1% and HHcy in 35%. Among the 3410 patients whose stroke subtype was determined, HHcy was present in 18.4% of patients: 23.3% of large artery atherosclerosis, 18.1% of cardioembolic, 16.3% of small vessel disease, 10.8% of other unusual aetiologies and 13.6% of undetermined subtypes (p=0.0001). CONCLUSIONS: Despite a decline in our referral area since 2009, B12Def, MetB12Def and HHcy remain common in patients with stroke/TIA. Because these conditions are easily treated and have serious consequences, all patients with stroke/TIA should have their serum B12 and tHcy measured.

Post-stroke fatigue as an indicator of underlying bioenergetics alterations.

Approximately half of stroke survivors suffer from clinically significant fatigue, contributing to poor quality of life, depression, dependency, and increased mortality. The etiology of post-stroke fatigue is not well understood and treatment is limited. This study tested the hypothesis that systemic aerobic energy metabolism, as reflected by platelet oxygen consumption, is negatively associated with fatigue and systemic inflammation is positively associated with fatigue in chronic ischemic stroke survivors. Data on self-reported level of fatigue, platelet oxygen consumption rates (OCR) and plasma inflammatory markers were analyzed from 20 ischemic stroke survivors. DNA copy number for two mitochondrial genes was measured as a marker of platelet mitochondrial content. Basal and protonophore-stimulated maximal platelet OCR showed a biphasic relationship to fatigue. Platelet OCR was negatively associated with low to moderate fatigue but was positively associated with moderate to high fatigue. DNA copy number was not associated with either fatigue or platelet OCR. Fatigue was negatively associated with C-reactive protein but not with other inflammatory markers. Post-stroke fatigue may be indicative of a systemic cellular energy dysfunction that is reflected in platelet energy metabolism. The biphasic relationship of fatigue to platelet OCR may indicate an ineffective bioenergetic compensatory response that has been observed in other pathological states.