Cerebrovascular Ischemia Research Articles

Screening for Large Vessels Vasculitis in Patients with Acute Cerebrovascular ISCHEMIA

Abstract Background Systemic vasculitides are heterogeneous disabling diseases characterized by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure, Giant cell arteritis (GCA) is a granulomatous subtype of vasculitis involving large and medium-size arteries, both cranial and extra-cranial, Imaging techniques, both morphological and metabolic, are required to confirm the diagnosis of large-vessel vasculitis, Arterial duplex is a moderately sensitive but highly specific test for exclusion of temporal arteritis. Purpose The purpose of this study is Screening of large vessels vasculitis in patients with cerebrovascular Ischemia by arterial transcranial and peripheral duplex. Patient and Methods 100 patients with cerebrovascular ischemia were further categorized into 3 groups: Group A: Seventy-four (74 %) pt of acute cerebrovascular stroke diagnosed according to National Institutes of Health Stroke Scale, Group B: Twenty-one (21%) pt with TIA diagnosed according to National Institutes of Health Stroke Scale, Group C: Five (5%) pt with GCA diagnosed according to 2022 American College of Rheumatology/EULAR classification criteria for Giant cell arteritis. Results Screening for large vessels vasculitis in patients with cerebrovascular Ischemia we found that five patients (5%) had GCA 2% with ischemic stroke 3% with TIA. Conclusion Our study indicates a significantly increased risk of CVA among patients with GCA

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

Carotid Dolichoarteriopathies: A Comprehensive Overview

Carotid dolichoarteriopathies (CDA) represent a group of morphological abnormalities, with changes in the geometry and tortuosity of the carotid arteries. They were described in 1925 for the first time and were classified in three types according to the angle of torsion, in tortuosity (angle > 90°), coiling (S-shaped curve or loop) and kinking (angle < 90°). The pathophysiology of CDA is controversial and includes congenital mechanisms, genetic factors, connective tissue diseases, acquired mechanisms which can be associated with but not dependent on cardiovascular risk factors, and anomalies of the cervical spine. CDA have been associated with different cardiovascular and cerebrovascular events secondary to hemodynamic abnormalities, thromboembolism and cerebrovascular insufficiency and ischemia. However, the evidence is limited and for some authors they are more of a curiosity than a real predictor of ischemic events. Other studies support the clinical value of the diagnosis and follow-up of CDA and their understanding not only by internists, cardiologists and neurologists, but also by surgeons and otolaryngologists. Several authors proposed different therapeutic strategies to correct CDA, including surgical procedures. However, the indications and management approaches are controversial, and further randomized, multicenter, prospective studies are required to determine the most appropriate course of action. Until then, imaging techniques remain the basis for the etiologic diagnosis of cerebrovascular adverse events when all other causes have been excluded, and close clinical monitoring and follow-up of patients remain key strategies for the prevention of secondary events.

Abstract WP311: Novel Computational Framework for Modelling the Effects of Temperature on Survival Time in Ischemic Stroke

Introduction: The detrimental influence of cerebral hyperthermia is well known, with notably deleterious effects in the ischemic brain, where even mild increases (<1°C) may rapidly potentiate ischemic injury. Experimental models of ischemic hyperthermia are undermined by the lack of pragmatic means for temporally- and spatially-resolved, direct cerebral thermometry. Computational models of cerebrovascular ischemia are well-suited to such exploration, and the use of digital phantoms for sophisticated biophysical modeling has been facilitated by emergent hardware, software, and computational solutions. We present a realistic computational environment for the simulation of thermal disturbance in cerebrovascular ischemia, permitting multiscale demonstration of hemodynamic, metabolic, and thermal aberrations in ischemic brain Methods: A multi-tissue biophysical numerical model of the human head and brain was extended to incorporate the dynamics of nutritive flow, metabolic need, tissue heating, and cytotoxicity. By restricting perfusion in a region of brain using a rudimentary representation of vascularization, we could quantify tissue heating arising from impaired radiative cooling, and time-dependent cell death. The procedure was iterated with an expected proportionality between temperature and metabolic rate Results: Fig 1 demonstrates simulated hypoperfusion affecting one hemisphere with resultant cerebral hyperthermia arising from impaired countercurrent heat exchange. Incorporating the effects of hyperthermia upon metabolic demand, the downward influence of heating on survivability is apparent, with ~30-minute acceleration to cytotoxicity. Conclusion: We present a combined model for tissue physiology and survival time following ischemic stroke using a multi-tissue model of whole-head bio-thermodynamics to examine effects of critical temperature disturbance on predicted tissue survival time.

Abstract 154: Clustered Vascular Endotelial Growth Factor Nanoparticles Biomaterial for the Treatment of Moyamoya Disease

Introduction: Cerebrovascular ischemia poses a substantial neurological threat due to cerebral artery constriction. Innovative solutions, such as Vascular Endothelial Growth Factor (VEGF)-infused hydrogel biomaterials, have emerged. Hydrogels, mimicking the extracellular matrix, allow controlled VEGF delivery, prompting angiogenesis, tissue repair, and enhancing conditions like moyamoya disease. This non-invasive technique carries transformative potential. Hypothesis: Our hypothesis postulates that hyaluronic acid (HA) gels, with or without VEGF, can augment endothelial cell quantities and blood flow in fore-brain ischemic mice. Methods: We divided C57/B6 mice into four groups: control, vehicle (chronic ICA occlusion and stenosis), HA gel treatment, and Cluvena ( Cl uster VE GF Na noparticle) hydrogel treatment. Brain dissection, sectioning, and CD31 and DAPI staining were performed for cellular identification. Results: Following two weeks, CD31 staining unveiled diminished endothelial cell populations in ischemic animals, significantly differing from controls. HA gel effectively restored endothelial cell counts to control levels. DAPI analysis indicated ischemic animals displayed considerably fewer DAPI-stained cells, attesting to successful ischemia induction and ensuing damage. Biomaterial intervention revived cell counts, aligning with control conditions. Intriguingly, hydrogel-only treated animals closely mirrored Cluvena outcomes in CD31 counts. Conclusions: Therapeutic angiogenic biomaterials, whether incorporating VEGF or not, hold significant potential for ischemic conditions. Cluvena efficiently reinstated endothelial cell numbers, thus unveiling potential therapeutic avenues for moyamoya, an ischemic disease with related neurological disorders or symptoms. This minimally-invasive strategy bears the promise of revolutionizing the field of brain ischemic condition therapeutics.

Distinctive feeding vessel architecture and sparse collateralization may underlie the characteristic early temporal pole and external capsule white matter compromise in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke. Mutations in the NOTCH3 gene cause vasculopathic changes predominantly involving medium and small brain arteries leading to progressively impaired cerebrovascular autoregulation, hypoperfusion, and ischemia. Magnetic resonance neuroimaging of CADASIL patients shows progressive white matter hyperintensity and accumulation of deep infarcts. Though these findings resemble in many respects changes seen in hypertensive cerebral small vessel disease, CADASIL is distinguished by early and extensive involvement of two regions: the white matter of the anterior temporal poles and the external capsules. Despite the longstanding reliance on presence of these findings to render a diagnosis of CADASIL, to our knowledge no pathophysiologic explanation has hitherto been advanced for the early and extensive temporal pole and external capsule. This paper advances the hypothesis that two distinctive features of the vascularization of temporal polar and external capsule white matter underly their early injury in CADASIL. First, the intermediate lumen diameters (0.75–1.00 mm) and the obtuse takeoff angles of the temporopolar artery (supplying temporal pole white matter) and the lateral lenticulostriate arteries (supplying the external capsule) cause intensified radial and sheer wall stress and vessel injury. Second, the sparse collateral supply to these regions potentiates the ischemic insult from compromise of directly supplying vessels.

Evaluation of cerebrovascular events via retinal angiography during transcatheter aortic valve implantation

Objectives Patients receiving transcatheter aortic valve implantation (TAVI) are elderly with multiple comorbidities and at increased risk of perioperative cerebrovascular events. Retinal vasculature represents a surrogate of central nervous system circulation and is noninvasively achievable by retinal imaging. The aim of this study was to evaluate the applicability of retinal angiography of microvascular complications and association to cerebral ischemic events during TAVI. Design One hundred patients (male 54%, age: median 82 years, range 64–95 years) undergoing TAVI were recruited for this study. Imaging of retinal vasculature was evaluated with a handheld fundus camera before, during and 1 month after. Cerebrovascular events were determined as a part of contemporary clinical evaluation with cerebral CT and CTA imaging when symptoms occurred. Results Altogether 66/100 patients (66%) were included in the analysis. In-hospital ischemic event (transient ischemic attack, cerebral infarction) was observed in 1/66 patient (1.5%). Retinal vascular abnormalities occurred in 8/66 patients (12.1%); 4/66 patients (6.1%) were detected with a cholesterol plaque in the retinal artery, 2/66 (3%) a capillary leakage, 1/66 (1.5%) and optic disk hemorrhage and 1/66 (1.5%) a macular bleeding. No significant association between retinal vasculature abnormalities and cerebrovascular events was detected mainly due to the low event rate. Conclusions Perioperative evaluation of cerebrovascular ischemia with noninvasive imaging of retinal vasculature is possible in most patients undergoing TAVI. More data is needed to evaluate the association of cerebrovascular events and retinal microvascular abnormalities during the procedure.

Moyamoya Disease: Clinical and Radiological Characteristics in Adult Greek Patients.

The aim of our study is to present, for the first time, the clinical, radiological, and neurocognitive characteristics of Greek adult patients with Moyamoya disease (MMD). We analyzed prospectively collected data of 12 patients referred to our department from 2004 to 2019. All patients underwent a thorough diagnostic work up, including extensive clinical, neuroradiological, and neurocognitive assessment. Our study population consisted of 7 females and the median age at the time of the diagnosis was 43.5 years. No patient had a positive family history of the disease and roughly 50% were hypertensives. Ten patients presented with transient or permanent cerebrovascular ischemia and two patients suffered from hemorrhagic complications. The median NIHSS was 7.5 (0-23) and clinical status remained stable during follow-up with conservative treatment in most of the patients. The majority (83.3%) had bilateral disease confirmed by DSA. All lesions exclusively affected the anterior circulation, with 50% of patients presenting with stenoocclusive changes. No aneurysm or AVM were revealed. The most common neurocognitive deficits were in the executive and language domains. Our MMD patients had a later onset of the disease and an absence of familial occurrence. The most common manifestation was ischemia, transient or permanent, and all lesions affected the anterior circulation, whereas no vascular malformations (AVM, aneurysms) were demonstrated in brain imaging. These findings in Greek patients imply a probable different, Mediterranean phenotype.

Abstract Number ‐ 17: Robot‐assisted transcranial Doppler versus transthoracic echocardiography for right to left shunt detection: Final Results

Introduction Right to left shunt (RLS), including patent foramen ovale (PFO), is a recognized risk factor for stroke. RLS/PFO diagnosis is made by transthoracic echocardiography (TTE) which is insensitive, transesophageal echocardiography (TEE) which is invasive, and transcranial Doppler (TCD) which is noninvasive and accurate but scarce. Methods We conducted a multi‐center device clinical trial of robot‐assisted TCD (raTCD) versus TTE for RLS diagnosis in patients who presented with an event suspicious for embolic cerebrovascular ischemia. raTCD was performed with standard TCD bubble study technique. TTE bubble study was performed to local standards. The primary outcome was rate of RLS detection by raTCD versus TTE. Results 133 patients were enrolled (intention to treat, ITT) and 126 subjects had complete data. In the ITT cohort, mean age was 60 +/‐ 15 years, 46% were women, and 92% of qualifying events were diagnosed as ischemic stroke. raTCD was positive for RLS in 82 subjects (64%) and TTE was positive in 26 (20%) [absolute difference 43.4% (95% CI 34.3%‐52.5%), p < 0.001]. On prespecified secondary analysis, large RLS was detected by raTCD in 35 subjects (28%) vs 13 (10%) by TTE [absolute difference 17.5% (95% CI 10.1%‐24.8%), p < 0.001]. There were no serious adverse events. Conclusions raTCD was safe and 3 times more likely to diagnose RLS than TTE. TTE completely missed or underdiagnosed two thirds of large shunts diagnosed by raTCD. The raTCD device, used by health professionals with no prior TCD training, may allow providers to achieve the known sensitivity of TCD for RLS and PFO detection without the need for an experienced operator. TCD is the superior screen for RLS compared to TTE.

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use

The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.

Thrombosis in hereditary hemorrhagic telangiectasia

Thrombosis in hereditary hemorrhagic telangiectasia

Acute worsening of CADASIL in a patient with COVID-19 infection: illustrative case

Reports of cerebrovascular ischemia and stroke occurring as predominant neurological sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), are increasingly evident within the literature. While various pathophysiological mechanisms have been postulated, including hypercoagulability, endothelial invasion, and systemic inflammation, discrete mechanisms for viral neurotropism remain unclear and controversial. The authors present a unique case study of a 64-year-old male with acute COVID-19 infection and acute worsening of previously stable cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare heritable arteriopathy due to mutation in the Notch3 gene, which is critical for vascular development and tone. Delayed cranial neuropathies, brainstem fluid-attenuated inversion recovery signal, and enhancement of olfactory and vagus nerves on magnetic resonance neurography in this patient further support viral neurotropism via cranial nerves in addition to cerebral vasculature. To the authors' knowledge, this is the first case in the literature that not only demonstrates the consequences of COVID-19 infection in a patient with altered cerebrovascular autoregulation such as CADASIL but also highlights the tropism of SARS-CoV-2 for (1) cranial nerves as a mode of entry to the central nervous system and (2) vessels as a cause of cerebrovascular ischemia.

Sensitivity and Specificity of Color Duplex Ultrasound Measurement in the Estimation of Internal Carotid Artery Stenosis

Background: Stroke is that the world's leading reason for death and major incapacity. Arterial sclerosis is answerable for over half-hour of all ischemic strokes. Plaque morphology has recently been discovered to assist within the prediction of arterial sclerosis clinical behavior and stroke risk. Purpose: The goal of this study was to gauge the frequency and diagnostic exactitude of artery Doppler imaging to detect arterial blood vessel pathology. Methods: This cross-sectional study was conducted in Combined Military Hospital, Peshawar from1st August 2019 to 31st March 2020. A total of 120 patients were randomly selected. The inclusion criteria was having ischemic cerebrovascular stroke. Doppler ultrasound was performed in every patient by a consultant radiologist. Doppler ultrasound findings were compared with Carotid artery stenosis reports. Results: Mean age in this study was 63.07±3.76 years. Mean duration of disease was 1 year ±3.32 months. Overall sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of Doppler Ultrasound were 89.5, 76.20, 45.5, 93.88 and 76.9% respectively. The areas under the ROC curves ranged between 0.89 and 0.90 for the laboratory A device and between 0.90 and 0.92 for the laboratory B device. In laboratories A and B, the areas under the ROC curves for ICA PSV were 0.90 and 0.92, respectively. Similar effects were observed when occlusion-affected patients were omitted (0.89 to 0.91, laboratory A; 0.90 to 0.93, laboratory B). Despite the fact that the diagnostic accuracy of the two devices was equivalent, two points on the ROC curves corresponding to the same cut point were infrequently near. Practical implication: The study compared the techniques of Doppler ultrasound for the diagnosis of carotid artery stenosis in patients and measured the best predicted percent angiographic stenosis differed between two vascular laboratories and paved the way for clinicians to focus of the diagnosis of carotid artery stenosis by DU. Conclusion: With the advancement in technology, the accuracy of carotid artery stenosis diagnosis has significantly improved over the decades. From measuring the narrowing carotid artery diameter to evaluating the increased velocity field near the obstruction/lesion site, the identification of additional parameters to characterize plaque vulnerability has become more important in the carotid artery. Keywords: Angiography; Carotid artery stenosis; Cerebrovascular ischemia; Doppler ultrasound sensitivity.

Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial

Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy. We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing. Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed. The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response. Takeda Oncology and Amgen.

Propofol and α2-Agonists Attenuate Microglia Activation and Restore Mitochondrial Function in an In Vitro Model of Microglia Hypoxia/Reoxygenation

Cerebrovascular ischemia is a common clinical disease encompassing a series of complex pathophysiological processes in which oxidative stress plays a major role. The present study aimed to evaluate the effects of Dexmedetomidine, Clonidine, and Propofol in a model of hypoxia/reoxygenation injury. Microglial cells were exposed to 1%hypoxia for 3 h and reoxygenated for 3 h, and oxidative stress was measured by ROS formation and the expression of inflammatory process genes. Mitochondrial dysfunction was assessed by membrane potential maintenance and the levels of various metabolites involved in energetic metabolism. The results showed that Propofol and α2-agonists attenuate the formation of ROS during hypoxia and after reoxygenation. Furthermore, the α2-agonists treatment restored membrane potential to values comparable to the normoxic control and were both more effective than Propofol. At the same time, Propofol, but not α2-agonists, reduces proliferation (Untreated Hypoxia = 1.16 ± 0.2, Untreated 3 h Reoxygenation = 1.28 ± 0.01 vs. Propofol hypoxia = 1.01 ± 0.01 vs. Propofol 3 h Reoxygenation = 1.12 ± 0.03) and microglial migration. Interestingly, all of the treatments reduced inflammatory gene and protein expressions and restored energy metabolism following hypoxia/reoxygenation (ATP content in hypoxia/reoxygenation 3 h: Untreated = 3.11 ± 0.8 vs. Propofol = 7.03 ± 0.4 vs. Dexmedetomidine = 5.44 ± 0.8 vs. Clonidine = 7.70 ± 0.1), showing that the drugs resulted in a different neuroprotective profile. In conclusion, our results may provide clinically relevant insights for neuroprotective strategies in intensive care units.

Efficacy and safety of Dengyinnaotong Capsule in patients with Cognitive impairment caused by cerebral Small Vessel Disease: study protocol of a multicenter, randomized, open-label, controlled trial (De-CSVD trial)

BackgroundCerebral small vessel disease (CSVD) is a common syndrome in the older population, with a prevalence ranging from 5% in subjects aged 50 years to almost 100% in those aged 90 years and older. It is regarded to be a major cause of vascular cognitive impairment. Existing prevention and treatment approaches have not yet shown ideal clinical outcomes. Dengyinnaotong Capsule has shown great potential for improving cognitive function. This trial (De-CSVD trial) is designed to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive function in patients with CSVD .MethodsThis multicenter, randomized, open-label, controlled trial is planned to recruit at least 270 patients with mild cognitive impairment related to CSVD in 25 centers in China. Recruitment started on 10 May 2021 and is foreseen to end on 31 December 2022. The final follow-up of participants will be completed by the end of March 2023. Participants will be randomized in a ratio of 1:1 to the experimental group (routine basic treatment plus Dengyinnaotong Capsule) or the control group (routine basic treatment). The primary outcome is the change in the Montreal Cognitive Assessment score from baseline to week 12. Secondary outcomes are changes in Shape Trail Test, Activities of Daily Living, Geriatric Depression Scale, and Dizziness Handicap Inventory score from baseline to week 12, new vascular events, and the changes in serum level of homocysteine, high-sensitivity C-reactive protein, and D-dimer from baseline to week 4 and 12, respectively. The exploratory outcome is the changes in the Tinetti performance-oriented mobility assessment score from baseline to week 12. Safety assessment is performed by monitoring vital signs, general biochemical examinations, 12-lead electrocardiogram examinations, and incidence of cardiovascular and cerebrovascular ischemia or bleeding events. Visits will be performed at week 0 (baseline, pre-randomization), week 4, and week 12 in the treatment period (post-randomization).DiscussionThis trial is the first to investigate the efficacy and safety of Dengyinnaotong Capsule on cognitive impairment in patients with CSVD. The findings of this study might provide convincing evidence regarding the efficacy of Dengyinnaotong Capsule in patients with mild cognitive impairment related to CSVD.Trial registrationChinese Clinical Trial Registry ChiCTR2100045831. Registered on 25 April 2021.

Nicardia® XL (Nifedipine Extended Release): Technologically Advanced GITS Formulation Ensures Robust Efficacy and Assured Safety

Nifedipine is a classical dihydropyridine calcium channel blocker (CCB) indicated for the management of hypertension, vasospastic angina and chronic stable angina. Prestigious regulatory bodies like USFDA, EMA, CDSCO and TGA have approved long-acting Nifedipine for the management of hypertension and angina. Nifedipine was 1st introduced in United States as Adalat® (Bayer) in 1981 and in India as Nicardia® (J. B. Chemicals & Pharmaceuticals) in 1985.
 Conventional Nifedipine shows the rapid onset and short duration of action which results in prompt and marked hypotensive effect but exhibits reflex SNS activation leading to flushing, tachycardia, worsening myocardial ischemia, and cerebrovascular ischemia. Nifedipine gastrointestinal therapeutic system (GITS) formulation addresses many of the concerns surrounding the older formulations of Nifedipine. Nifedipine GITS is a gold standard once-daily formulation of Nifedipine which allows relatively constant plasma drug concentrations over 24 hours. Nifedipine GITS provides a controlled release and gradual onset of action of Nifedipine, avoiding the reflex SNS activation resulting in improved tolerability and compliance.
 Clinical studies suggest that long-acting formulations of Nifedipine have slightly greater antihypertensive actions than Amlodipine. Nifedipine was also found to be more efficient than other CCBs like Amlodipine, Nicardipine, and Isradipine in resistant hypertensive patients. The addition of Nifedipine GITS to the conventional treatment of angina pectoris is safe and reduces the need for coronary angiography and interventions.
 Several landmark trials have demonstrated that long-acting Nifedipine improves endothelial function and arterial stiffness and reduces albuminuria, LV hypertrophy, atherosclerotic plaques and cardiovascular and cerebrovascular complications.
 This comprehensive review focuses on the superiority of the Nifedipine GITS formulation over the conventional Nifedipine and elaborates on the role of long-acting Nifedipine as a CCB of choice for the management of hypertension, resistant hypertension, angina pectoris and coronary artery disease.
 Keywords – Calcium Channel Blockers, Nifedipine, Long-Acting Nifedipine, Nifedipine GITS, Nifedipine Extended Release, Nicardia XL.

Hypoglycemia: varieties of etiopathogenesis and clinic. Observations from practice

Hypoglycemic syndrome is often noted in clinical practice in the treatment of patients with diabetes mellitus (DM), especially with insulin. This syndrome is manifested by symptoms caused by neuroglycopenia (insufficient supply of glucose to the brain, which utilizes 20% of all glucose). Hypoglycemia occurs quite often, in about 40% of people with type 1 DM. The clinical syndrome of postprandial (reactive) hypoglycemia of various etiologies is considered, which is manifested by a hypoglycemic condition in the next hours after eating, especially easily digestible carbohydrates. In most cases, there is a violation of the hypothalamic regulation of carbohydrate metabolism, and the clinical picture is dominated by symptoms of activation of the sympathoadrenal system. Such hypoglycemia is usually transient, as glucose levels return to normal rapidly due to the release of counterinsular hormones. The importance of the latter in the regulation of insulin secretion is evidenced by the fact that after oral glucose loading, a higher level of insulin secretion is determined than in the case of intravenous administration of an equivalent dose. Elderly patients with hypoglycemia are more likely to develop neurological disorders than adrenergic disorders (palpitations, tremors, hunger). These symptoms may be mistaken for signs of cerebrovascular ischemia, as a result, hypoglycemia is not adequately detected and treated. In addition to the acute adverse effects of hypoglycaemia, a hypoglycaemic episode may have long-term consequences. Frequent hypoglycemic conditions have a significant psychological impact and are also a risk factor for dementia. The paper presents the data, based on scientific sources and own observations, on etiopathogenesis of hypoglycemia, as well as their most frequent clinical varieties, in particular, in the syndrome of unrecognization of hypoglycemia, postprandial hypoglycemia, in chronic insulin overdose in patients with diabetes mellitus in old age and insulinism.

Effects of pretreatment of ethanolic extract of Siegesbeckia pubescens Makino on cerebral ischemia in rats

BackgroundCerebral ischemia is characterized by inadequate blood supply to the brain to fulfill its metabolic demand. It is a leading cause of stroke. The objective of this study aimed to elucidate the effects of ethanolic extract of Siegesbeckia pubescens (EESP) Makino against cerebral ischemia in rats. MethodsSixty male Sprague-Dawley (SD) rats were distributed into 5 groups (n = 12) viz., low dose (2.5 g/kg/day) EESP group, high dose (5 g/kg/day) EESP group, Nimodipine group, untreated control, and sham-operated control. The reference group received 16 mg/kg/day of nimodipine, while the untreated and sham-operated control was given 20 ml/kg of distilled water. The middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia. On the 7th day of the trial, neurological evaluation and biochemical assays were carried out. After that, rats were sacrificed, and the brain infarct area was analyzed with image processing software. ResultsThe extent of neurologic deficits, infarct area, concentration of superoxide dismutase (SOD), and malondialdehyde (MDA) was significantly altered by the EESP when compared with untreated control and Sham-operated control. ConclusionsTaken together, these results reported protective effects of EESP on cerebrovascular ischemia that perhaps correlate with its mechanism of free radical scavenging. Our findings may provide insight into treating cerebral ischemia and give a new research era for further study.

The Circulating Biomarker Fractalkine and Platelet-Derived Growth Factor BB are Correlated with Carotid Plaque Vulnerability Assessed by Computed Tomography Angiography

ObjectivesAlthough studies have demonstrated that inflammatory and lipid/ lipoproteins-related biomarkers, genetic mutations, and epigenetic mechanisms could be candidates for diagnosis and prognosis of ischemic stroke, there is still no consensus on how to identify vulnerable plaques based on circulating biomarkers. Materials and methodsHistological and immunohistochemical staining were performed in the aorta sections of ApoE-/- and WT mice. Eighty-nine patients who underwent CTA were included in this study. The degree of carotid stenosis and the wall features of plaque components were quantitatively analyzed. And the serum concentration of FKN and PDGF-BB were measured. Results(1) The type V vulnerable atherosclerotic plaques deposited on the aortas of ApoE-/- mice after feeding with western diet for 16 weeks. And the expression of CX3CR1 and PDGFR-β increased in the areas of atherosclerotic plaques, especially inside the fibrous cap of plaque. (2) Patients with symptomatic carotid stenosis showed larger LNRC, smaller calcified plaques and more plaque ulceration detected by CTA than asymptomatic stenosis patients. Plaque ulceration and size of LNRC were high risk factors for stroke while plaque calcification was less frequently associated with cerebrovascular ischemia. (3) The serum concentration of FKN was lower and of PDGF-BB was higher in the patients with carotid artery stenosis. Correlation analysis suggested that FKN and PDGF-BB correlated positively with carotid plaque calcification and LNRC respectively. ConclusionsFor prediction it is recommended to combine circulating biomarkers (FKN and PDGF-BB) and imaging biomarkersfor comprehensive diagnosis and risk stratification in carotid atherosclerotic stroke.