Risk of circulatory diseases associated with proton-pump inhibitors: a retrospective cohort study using electronic medical records in Thailand.

Background: Proton-pump inhibitors (PPIs) are prescribed to treat gastric acid-related diseases, while they may also have potential risks to population health. Recent studies suggested that a potential mechanism explaining the association between PPIs and cardiovascular diseases (CVD) includes the inhibition of the nitrate-nitrite-nitric oxide (NO) pathway. However, previous observational studies showed controversial results of the association. In addition, the inhibition of the NO pathway due to PPIs use may lead to peripheral vascular diseases (PVD); however, none of the studies explore the PPI-PVD association. Therefore, this study aimed to evaluate the association of PPIs with circulatory diseases (CVD, ischemic strokes or IS, and PVD). Methods: We conducted a retrospective hospital-based cohort study from Oct 2010 to Sep 2017 in Songkhla province, Thailand. PPIs and histamine 2-receptor antagonists (H2RAs) prescriptions were collected from electronic pharmacy records, while diagnostic outcomes were retrieved from electronic medical records at Songklanagarind hospital. Patients were followed up with an on-treatment approach. Cox proportional hazard models were applied to measure the association comparing PPIs vs H2RAs after 1:1 propensity-score-matching. Sub-group analysis, multi-bias E-values, and array-based sensitivity analysis for some covariates were used to assess the robustness of associations. Results: A total of 3,928 new PPIs and 3,928 H2RAs users were included in the 1:1 propensity score-matched cohort. As compared with H2RAs, the association of PPIs with CVD, IS, and PVD, the hazard ratios were 1.76 95% CI = [1.40-2.20] for CVD, 3.53 95% CI = [2.21-5.64] for ischemic strokes, and 17.07 95% CI = [13.82-76.25] for PVD. The association between PPIs and each outcome was significant with medication persistent ratio of over 50%. In addition, the association between PPIs and circulatory diseases was robust to unmeasured confounders (i.e., smoking and alcohol). Conclusion: PPIs were associated with circulatory diseases, particularly ischemic strokes in this hospital-based cohort study, whereas, the strength of associations was robust to unmeasured confounders.

Cerebrolysin for acute ischaemic stroke.

BACKGROUND: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain, which has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2020. OBJECTIVES: To assess the benefits and harms of Cerebrolysin or Cerebrolysin-like agents for treating acute ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, and LILACS in May 2022 and a number of Russian databases in June 2022. We also searched reference lists, ongoing trials registers, and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing Cerebrolysin or Cerebrolysin-like agents started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Three review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence. MAIN RESULTS: Seven RCTs (1773 participants) met the inclusion criteria of the review. In this update we added one RCT of Cerebrolysin-like agent Cortexin, which contributed 272 participants. We used the same approach for risk of bias assessment that was re-evaluated for the previous update: we added consideration of the public availability of study protocols and reported outcomes to the selective outcome reporting judgement, through identification, examination, and evaluation of study protocols. For the Cerebrolysin studies, we judged the risk of bias for selective outcome reporting to be unclear across all studies; for blinding of participants and personnel to be low in three studies and unclear in the remaining four; and for blinding of outcome assessors to be low in three studies and unclear in four studies. We judged the risk of bias for generation of allocation sequence to be low in one study and unclear in the remaining six studies; for allocation concealment to be low in one study and unclear in six studies; and for incomplete outcome data to be low in three studies and high in the remaining four studies. The manufacturer of Cerebrolysin supported three multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged two studies to be at high risk of other bias and the remaining five studies to be at unclear risk of other bias. We judged the study of Cortexin to be at low risk of bias for incomplete outcome data and at unclear risk of bias for all other domains. All-cause death: Cerebrolysin or Cortexin probably result in little to no difference in all-cause death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.41; 6 trials, 1689 participants; moderate-certainty evidence). None of the included studies reported on poor functional outcome, defined as death or dependence at the end of the follow-up period, early death (within two weeks of stroke onset), quality of life, or time to restoration of capacity for work. Only one study clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Non-death attrition (secondary outcome): Cerebrolysin or similar peptide mixtures may result in little to no difference in non-death attrition, but the evidence is very uncertain, with a considerable level of heterogeneity (RR 0.72, 95% CI 0.38 to 1.39; 6 trials, 1689 participants; very low-certainty evidence). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.16, 95% CI 0.81 to 1.66; 3 trials, 1335 participants; moderate-certainty evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38; 3 trials, 1335 participants; moderate-certainty evidence) and an increase in the total number of people with non-fatal SAEs (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1335 participants; moderate-certainty evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent (RR 2.87, 95% CI 1.24 to 6.69; 2 trials, 1189 participants). Total number of people with adverse events: Cerebrolysin or similar peptide mixtures may result in little to no difference in the total number of people with adverse events (RR 1.03, 95% CI 0.92 to 1.14; 4 trials, 1607 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: Moderate-certainty evidence indicates that Cerebrolysin or Cerebrolysin-like peptide mixtures derived from cattle brain probably have no beneficial effect on preventing all-cause death in acute ischaemic stroke. Moderate-certainty evidence suggests that Cerebrolysin probably has no beneficial effect on the total number of people with serious adverse events. Moderate-certainty evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use.

Risk of Cardiovascular Events and Lipid Profile Change in Patients with Breast Cancer Taking Aromatase Inhibitor: A Systematic Review and Meta-Analysis.

Cardiovascular disease (CVD) is one of the most common comorbidities in breast cancer survivors. Recently, the target population and treatment period for aromatase inhibitor (AI) treatment in breast cancer patients has been expanding. However, information on adverse CVD events from the long-term use of AI is still lacking. The aim of this study was to investigate the CVD side effects of AI treatment and to evaluate the changes in lipid profile during AI treatment. A systematic search of PubMed (Medline), EMBASE, and Cochrane Library databases reporting on cardiovascular outcomes or lipid profiles change in adult female breast cancer patients (>19 years old) with AI was performed. The pooled analysis of 25 studies showed that the prevalence rate of any type of cardiovascular disease was 6.08 per 100 persons (95% CI 2.91-10.31). Angina was the most common type of heart-related cardiovascular event accounting for 3.85 per 100 persons, followed by any type of stroke (3.34) and venous thromboembolism (2.95). Ischemic stroke (OR 1.39, 95% CI 1.07-1.81) and myocardial infarction (OR 1.30, 95% CI 0.88-1.93) were more common in AI compared with tamoxifen, whereas the prevalence of venous thromboembolism (OR 0.61, 95% CI 0.37-1) was significantly lower in the AI group. In addition, treatment with AI for 6-12 months showed a decrease in HDL-cholesterol and an increase in LDL-cholesterol and total cholesterol. Various CVDs can occur when using AI, and in particular, the risk of MI and ischemic stroke increases in comparison with the adverse effect of tamoxifen. The occurrence of CVD might be related to the deterioration of the lipid profile after AI treatment. Therefore, a customized individualization strategy considering each patient's CV risk factors is needed during AI treatment.

Treatment of ChAdOx1 nCoV-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia Related Acute Ischemic Stroke.

Recently cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and thrombosis following the adenoviral vector vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported. A mechanism similar to heparin-induced thrombocytopenia was proposed with antibodies to platelet factor 4 (PF4). Vaccine related arterial thrombosis in the brain is rare but life-threatening and optimal treatment is not established. We report clinical, laboratory, imaging findings and treatment in a 51-year-old female presenting with acute left middle cerebral artery (MCA) occlusion 7 days after the first dose of ChAdOx1 nCoV-19 vaccine. Due to low platelet count and suspicion of VITT she was not eligible for intravenous thrombolysis (IVT) and proceeded to mechanical thrombectomy (MER) with successful recanalization four hours after onset of symptoms. Treatment with intravenous immunoglobulin (IVIG) and heparin pentasaccharide fondaparinux was initiated. Presence of anti-PF4 antibodies was confirmed. The patient improved clinically with normalization of platelet count. Clinicians should be alert of VITT in patients with acute ischemic stroke after ChAdOx1 nCov-19 vaccination and low platelet counts. MER showed to be feasible and effective. We propose considering MER in patients with VITT and large vessel occlusion despite thrombocytopenia. High-dose IVIG should be started immediately. Alternative anticoagulation to heparin should be started 24 hours after stroke onset unless significant hemorrhagic transformation occurred. Platelet transfusion is contraindicated and should be considered only in severe hemorrhagic complications. Restenosis or reocclusion of the revascularized artery is possible due to the hypercoagulable state in VITT and angiographic surveillance after the procedure is reasonable.

Conjugated equine estrogen used in postmenopausal women associated with a higher risk of stroke than estradiol.

This study aimed to evaluate the risk of ischemic stroke (IS) in hormone therapy (HT) with oral conjugated equine estrogen (CEE) and estradiol (E2) in postmenopausal women in Taiwan. A retrospective cohort study was conducted using the Taiwan National Health Insurance Research Database, a population-based healthcare claims dataset. Eligible women, aged 40-65 years, who received HT with E2 and CEE orally were enrolled. The primary outcome was IS. Propensity score matching with menopausal age and comorbidities was used. Cox proportional hazard regression models were used to calculate the incidence and hazard ratios (HRs) for IS. The mean menopausal ages of the E2 and CEE groups were 50.31 ± 4.99 and 50.45 ± 5.31 years, respectively. After adjusting for age and comorbidities, the incidence of IS was 1.17-fold higher in the women treated with CEE than in those treated with E2 (4.24 vs. 3.61/1000 person-years), with an adjusted HR (aHR) of 1.23 (95% confidence interval [CI] 1.05-1.44). Moreover, HT with CEE initiated within 5 years of menopause had a higher HR than E2 (aHR = 1.20; 95% CI 1.02-1.42). In conclusion, HT with oral CEE might be associated with a higher risk of IS than E2 in postmenopausal Taiwanese women. The use of HT with CEE should be cautioned with the risk of IS.

Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats.

Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate ischemic brain damage in the females and underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial function owing to a defect in the activity of cytochrome c oxidase. Here, we investigated the global metabolomic profile of brains of adolescent female Sprague-Dawley rats exposed to N ± OC. Rats were randomly exposed to saline or N + /-OC for 16-21 days followed by random allocation into two cohorts. One cohort underwent transient middle cerebral artery occlusion and histopathology was performed 30 days later. From the second cohort, cortical tissues were collected for an unbiased global metabolomic profile. Pathway enrichment analysis showed significant decrease in glucose, glucose 6-phosphate and fructose-6-phosphate, along with a significant increase in pyruvate in the N + /-OC exposed groups when compared to saline (p < 0.05), suggesting alterations in the glycolytic pathway which were confirmed by Western blot analyses of glycolytic enzymes. Infarct volume quantification showed a significant increase following N alone or N + OC as compared to saline control. Because glucose metabolism is critical for brain physiology, altered glycolysis deteriorates neural function, thus exacerbating ischemic brain damage.

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

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

Synthesis of Novel Aryloxyethylamine Derivatives and Evaluation of Their in Vitro and in Vivo Neuroprotective Activities.

A series of aryloxyethylamine derivatives were designed, synthesized and evaluated for their biological activity. Their structures were confirmed by 1 H-NMR, 13 C-NMR, FT-IR and HR-ESI-MS. The preliminary screening of neuroprotection of compounds in vitro was detected by MTT, and the anti-ischemic activity in vivo was tested using bilateral common carotid artery occlusion in mice. Most of these compounds showed potential neuroprotective effects against the glutamate-induced cell death in differentiated rat pheochromocytoma cells (PC12 cells), especially for (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone, (4-bromophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone, (4-chlorophenyl)(1-{2-[(naphthalen-2-yl)oxy]ethyl}piperidin-4-yl)methanone, (4-chlorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone and {1-[2-(4-bromophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone, which exhibited potent protection of PC12 cells at three doses (0.1, 1.0, 10 µM). Compounds (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, (4-fluorophenyl){1-[2-(naphthalen-2-yloxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone and {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone possessed the significant prolongation of the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all five doses tested (200, 100, 50, 25, 12.5 mg/kg) and had significant neuroprotective activity. In addition, (4-fluorophenyl){1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}methanone, {1-[2-(4-methoxyphenoxy)ethyl]piperidin-4-yl}(4-methoxyphenyl)methanone and {1-[2-(4-chlorophenoxy)ethyl]piperidin-4-yl}(4-chlorophenyl)methanone possessed outstanding neuroprotection in vitro and in vivo. These compounds can be used as a promising neuroprotective agents for future development of new anti-ischemic stroke agents. Basic structure-activity relationships are also presented.

Acute ischaemic stroke following cisplatin-based chemotherapy for testicular cancer.

Cisplatin is a widely used chemotherapeutic agent for many cancer types. Its toxicity profile includes drug-induced vascular damage. Clinicians should be aware of its varied presentation, including acute and chronic vascular events involving the arterial and venous system. This is a case of an otherwise well 32-year-old man with testicular cancer who received bleomycin/etoposide/cisplatin, and presented following two cycles of chemotherapy with homonymous hemianopia secondary to acute stroke. Acute arterial complications are rare, but clinicians should maintain a high index of suspicion for such events, even in a patient who otherwise has no vascular risk factors. Primary and secondary prevention measures including lifestyle modifications (smoking cessation, diet and exercise), blood pressure and cholesterol management, and antiplatelet therapy should be considered in patients exposed to cisplatin, during and following their treatment.

Alcohol exposure-induced neurovascular inflammatory priming impacts ischemic stroke and is linked with brain perivascular macrophages.

Alcohol abuse is a major public health problem worldwide, causing a wide range of preventable morbidity and mortality. In this translational study, we show that heavy drinking (HD) (≥6 standard drinks/day) is independently associated with a worse outcome for ischemic stroke patients. To study the underlying mechanisms of this deleterious effect of HD, we performed an extensive analysis of the brain inflammatory responses of mice chronically exposed or not to 10% alcohol before and after ischemic stroke. Inflammatory responses were analyzed at the parenchymal, perivascular, and vascular levels by using transcriptomic, immunohistochemical, in vivo 2-photon microscopy and molecular MRI analyses. Alcohol-exposed mice show, in the absence of any other insult, a neurovascular inflammatory priming (i.e., an abnormal inflammatory status including an increase in brain perivascular macrophages [PVM]) associated with exacerbated inflammatory responses after a secondary insult (ischemic stroke or LPS challenge). Similar to our clinical data, alcohol-exposed mice showed larger ischemic lesions. We show here that PVM are key players on this aggravating effect of alcohol, since their specific depletion blocks the alcohol-induced aggravation of ischemic lesions. This study opens potentially new therapeutic avenues aiming at blocking alcohol-induced exacerbation of the neurovascular inflammatory responses triggered after ischemic stroke.