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Pharmacological Research Aug 2023Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic... (Review)
Review
Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.
Topics: United States; Humans; Protein Kinase Inhibitors; Neoplasms; Protein Serine-Threonine Kinases; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Protein Kinases; Antineoplastic Agents
PubMed: 37454916
DOI: 10.1016/j.phrs.2023.106847 -
Ultraschall in Der Medizin (Stuttgart,... Oct 2023Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are often complicated by vasospasm and ischemia. Monitoring...
PURPOSE
Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are often complicated by vasospasm and ischemia. Monitoring with transcranial color-coded Doppler (TCCD) could be useful, but its role is not established. We studied the incidence of ultrasonographic vasospasm (uVSP) in PRES/RCVS and its relationship with ischemic lesions and clinical outcome.
MATERIALS AND METHODS
We conducted a multicenter retrospective study of all patients with PRES/RCVS from 2008 to 2020 who underwent TCCD and magnetic resonance imaging (MRI). TCCD exams were analyzed for uVSP. Diffusion-weighted MRI was analyzed for positive lesions (DWI-positive). Functional outcome was assessed by modified Rankin scale (mRS) at 90 days. The associations with outcomes were determined by logistic regression.
RESULTS
We included 80 patients (mean age of 46 (standard deviation, 17) years; 66% females; 41 with PRES, 28 with RCVS and 11 with overlap phenotype). uVSP was detected in 25 (31%) patients. DWI-positive lesions were more often detected in uVSP-positive than uVSP-negative patients (36% vs. 15%; adjusted odds ratio [aOR] 4.05 [95% CI 1.06 - 15.5], P=0.04). DWI-positive lesions were independently associated with worse functional prognosis (mRS 2-6, 43% vs. 10%; aOR, 10 [95% CI 2.6 - 43], P<0.01). Having additional uVSP further increased the odds of a worse outcome (P interaction=0.03).
CONCLUSION
Ultrasonographic vasospasm was detected in a third of patients with PRES/RCVS and was associated with brain ischemic lesions. TCCD bedside monitoring can help to stratify patients at risk for cerebral ischemia, a strong predictor of functional outcome.
Topics: Female; Humans; Middle Aged; Male; Vasoconstriction; Retrospective Studies; Posterior Leukoencephalopathy Syndrome; Magnetic Resonance Imaging; Prognosis; Vasospasm, Intracranial
PubMed: 37832534
DOI: 10.1055/a-2127-9459 -
Research and Practice in Thrombosis and... Mar 2024A State of the Art lecture titled "Cancer and Arterial Thrombosis: Therapeutic Options" was presented at the International Society on Thrombosis and Haemostasis Congress...
A State of the Art lecture titled "Cancer and Arterial Thrombosis: Therapeutic Options" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. This State of the Art review delves into the complex relationship between cancer and arterial thromboembolism (ATE), encompassing acute coronary syndrome, ischemic strokes, and peripheral arterial disease. The burden of cancer-associated ATE is not well defined, but studies indicate elevated risks, particularly in the 6 months after a cancer diagnosis. Incidence varies among cancer subtypes, with lung cancer displaying the highest rates. Additionally, the pathophysiology of cancer-associated ATE involves a multifaceted interplay of cancer-induced hypercoagulopathy, cancer therapy-related thrombosis, and personal risk factor contributors. ATEs are clinically heterogeneous and in the context of cancer have particular mechanistic differences compared with ATE patients without cancer. This requires modifications in approach and tailored management considerations. Specific etiologies contributing to ATE, such as coronary vasospasm and non-bacterial-thrombotic endocarditis, need to be considered. The diagnosis of cancer alone usually does not contraindicate patients to standard guideline-based therapies for the management of ATE, although nuances in treatment may need to be considered in light of the underlying cancer. Atrial fibrillation in cancer patients further complicates the thrombotic landscape. Cancer patients with atrial fibrillation are at a higher risk of ATE, necessitating careful consideration of anticoagulation therapy as clinical benefits and bleeding risks need to be weighed. ATE may also be a presenting sign of underlying malignancy, which requires increased awareness and focused clinical evaluation for cancer in selected cases. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
PubMed: 38660456
DOI: 10.1016/j.rpth.2024.102393 -
Journal of Neurosurgery Nov 2023Cerebral arterial vasospasm is a dreaded sequela of aneurysm rupture and can result in significant narrowing of the surrounding vasculature and subsequent cerebral...
OBJECTIVE
Cerebral arterial vasospasm is a dreaded sequela of aneurysm rupture and can result in significant narrowing of the surrounding vasculature and subsequent cerebral ischemia. Treatment interventions are associated with distinct side effect profiles, including the risk of thrombosis and worsened ischemia, which may be associated with increased mortality-especially in older adults. An improved understanding of the likelihood of vasospasm in elderly patients would enable clinicians and patients to better consider the risks and benefits of vasospasm prophylaxis in this vulnerable population. This retrospective chart review aimed to assess the relationship between age at onset and the incidence of cerebral vasospasm among patients treated at the University of North Carolina Medical Center with spontaneous aneurysmal subarachnoid hemorrhage (aSAH).
METHODS
Electronic health record data from the Epic Systems Corp. database, compiled by the Carolina Data Warehouse for Health, were analyzed for patients older than 18 years who were previously treated for an SAH secondary to aneurysm at the University of North Carolina Medical Center within the past 10 years, ranging from June 2011 through June 2021. Logistic regression was used to calculate odds ratios and to determine the association of age with the occurrence of vasospasm following aSAH.
RESULTS
Of the 386 cases analyzed, 149 patients (38.6%) were older than 65 years at the time of aSAH. A total of 192 of the 386 patients (49.7%) developed vasospasm within the first 3-21 days following aSAH. Among the patients who developed vasospasm, only 31 of 192 patients (16.1%) were older than 65 years at the time of aneurysm rupture. Odds ratio calculations revealed that older adults (> 65 years) were 8 times less likely to develop vasospasm compared to their younger counterparts (p < 0.0001; 95% CI 5.0-13.0).
CONCLUSIONS
This study found that older patients are less likely to develop cerebral vasospasm following aSAH than are younger individuals. Age-associated changes in arteriosclerosis, inflammatory responses, and CSF dynamics may mitigate vascular narrowing in response to aSAH. This finding suggests that the aSAH treatment and vasospasm prevention paradigms should be revised to minimize potentially unnecessary interventions and avoid adverse outcomes for older adults.
Topics: Humans; Aged; Subarachnoid Hemorrhage; Retrospective Studies; Vasospasm, Intracranial; Cerebral Infarction; Aneurysm, Ruptured
PubMed: 37119113
DOI: 10.3171/2023.3.JNS222720 -
CNS & Neurological Disorders Drug... Nov 2023Cerebral vasospasm (CV) is a common severe complication of subarachnoid hemorrhage (SAH), a severe type of intracranial bleeding that is uncommon in children. The...
Cerebral vasospasm (CV) is a common severe complication of subarachnoid hemorrhage (SAH), a severe type of intracranial bleeding that is uncommon in children. The purpose of this article is to review the current literature regarding this potentially devastating complication. CV may be asymptomatic and is less common in children compared to adults. Several molecular phenomena, including inflammatory ones, contribute to its pathophysiology. Better collateral circulation and higher cerebral blood flow are protective factors in children. When clinically apparent, CV may manifest as a change in the child's neurologic status or vital signs. CV can be diagnosed using brain vessel imaging, such as computed tomography angiography, magnetic resonance angiography, digital subtraction angiography, transcranial Doppler ultrasonography, and computed tomography perfusion. A reduction of < 50% in the artery's caliber confirms the diagnosis. Besides general supportive measures and causative treatment of SAH, CV management options include the administration of calcium channel blockers and neurointerventional approaches, such as intra-arterial vasodilators and balloon angioplasty. Long-term outcomes in children are usually favorable.
PubMed: 38013445
DOI: 10.2174/0118715273274147231104160152 -
Neurocritical Care Aug 2023One of the most serious complications after subarachnoid hemorrhage (SAH) is delayed cerebral ischemia, the cause of which is multifactorial. Delayed cerebral ischemia... (Review)
Review
One of the most serious complications after subarachnoid hemorrhage (SAH) is delayed cerebral ischemia, the cause of which is multifactorial. Delayed cerebral ischemia considerably worsens neurological outcome and increases the risk of death. The targets of hemodynamic management of SAH have widely changed over the past 30 years. Hypovolemia and hypotension were favored prior to the era of early aneurysmal surgery but were subsequently replaced by the use of hypervolemia and hypertension. More recently, the concept of goal-directed therapy targeting euvolemia, with or without hypertension, is gaining preference. Despite the evolving concepts and the vast literature, fundamental questions related to hemodynamic optimization and its effects on cerebral perfusion and patient outcomes remain unanswered. In this review, we explain the rationale underlying the approaches to hemodynamic management and provide guidance on contemporary strategies related to fluid administration and blood pressure and cardiac output manipulation in the management of SAH.
Topics: Humans; Subarachnoid Hemorrhage; Brain Ischemia; Hemodynamics; Cerebral Infarction; Hypertension; Vasospasm, Intracranial
PubMed: 37160848
DOI: 10.1007/s12028-023-01738-w -
Coronary Artery Spasm During Pulsed Field vs Radiofrequency Catheter Ablation of the Mitral Isthmus.JAMA Cardiology Jan 2024In treating atrial fibrillation, pulsed field ablation (PFA) is a novel energy modality with comparable efficacy to conventional thermal ablation, such as radiofrequency...
IMPORTANCE
In treating atrial fibrillation, pulsed field ablation (PFA) is a novel energy modality with comparable efficacy to conventional thermal ablation, such as radiofrequency ablation (RFA), but with the benefit of some preferentiality to myocardial tissue ablation. Studies have demonstrated important safety advantages, including the absence of esophageal injury or pulmonary vein stenosis and only rare phrenic nerve injury. However, there is emerging evidence of coronary artery vasospasm provoked by PFA.
OBJECTIVE
To compare the incidence and severity of left circumflex arterial vasospasm between PFA and RFA during adjacent ablation along the mitral isthmus.
DESIGN, SETTING, AND PARTICIPANTS
This prospective cohort study enrolled consecutive adult patients receiving first-ever PFA or RFA of the mitral isthmus during catheter ablation of atrial fibrillation in 2022 with acute follow-up at a single referral European center.
EXPOSURE
A posterolateral mitral isthmus line was created using either a multielectrode pentaspline PFA catheter (endocardial ablation) or a saline-irrigated RFA catheter. Simultaneous diagnostic coronary angiography was performed before, during, and after catheter ablation. Nitroglycerin was planned for spasm persisting beyond 20 minutes or for significant electrocardiographic changes.
MAIN OUTCOMES AND MEASURES
The frequency and severity of left circumflex arterial vasospasm was assessed and monitored, as were time to remission and any need for nitroglycerin administration.
RESULTS
Of 26 included patients, 19 (73%) were male, and the mean (SD) age was 65.5 (9.3) years. Patients underwent either PFA (n = 17) or RFA (n = 9) along the mitral isthmus. Coronary spasm was observed in 7 of 17 patients (41.2%) undergoing PFA: in 7 of 9 (77.8%) when the mitral isthmus ablation line was situated superiorly and in 0 of 8 when situated inferiorly. Conversely, coronary spasm did not occur in any of the 9 patients undergoing RFA. Of 5 patients in whom crossover PFA was performed after RFA failed to achieve conduction block, coronary spasm occurred in 3 (60%). Most instances of spasm (9 of 10 [90%]) were subclinical, with 2 (20%) requiring nitroglycerin administration. The median (range) time to resolution of spasm was 5 (5-25) minutes.
CONCLUSION AND RELEVANCE
When creating a mitral isthmus ablation line during catheter ablation of atrial fibrillation, adjacent left circumflex arterial vasospasm frequently occurred with PFA and not RFA but was typically subclinical.
Topics: Adult; Humans; Male; Aged; Female; Atrial Fibrillation; Coronary Vasospasm; Nitroglycerin; Prospective Studies; Catheter Ablation; Heart Atria
PubMed: 38019505
DOI: 10.1001/jamacardio.2023.4405 -
Journal of the American Heart... Jul 2023Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide...
Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane-induced changes in iNOS expression were measured. N-(3-(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1-way ANOVA and 2-way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at <0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N-(3-(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild-type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N-(3-(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning-induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.
Topics: Mice; Male; Animals; Nitric Oxide Synthase Type II; Subarachnoid Hemorrhage; Isoflurane; Mice, Inbred C57BL; Brain Ischemia; Cerebral Infarction; Mice, Knockout; Vasospasm, Intracranial
PubMed: 37449587
DOI: 10.1161/JAHA.123.029975 -
Frontiers in Neurology 2024Methamphetamine (meth) is a potent and addictive central nervous system stimulant with increasing use. Stroke is one severe possible complication of meth use. Due to... (Review)
Review
Methamphetamine (meth) is a potent and addictive central nervous system stimulant with increasing use. Stroke is one severe possible complication of meth use. Due to high levels of manufacturing in Mexico, the western United States has experienced greater consequences of meth use. The literature reviewed herein is comprised of case studies and series, and it suggests that hemorrhagic stroke (including hypertensive-like intracerebral hemorrhage and aneurysmal subarachnoid hemorrhage), as opposed to ischemic stroke, is the more common type of neurovascular complication of meth use. Meth-related strokes are a particular concern for younger patients with stroke and may be a partial explanation for increasing stroke rates in this age group. We describe two cases (one intraparenchymal hemorrhage and one ischemic stroke) in young patients (<50 years old) with recent meth use to illustrate clinical characteristics and therapeutic considerations. There are several proposed pathophysiological explanations for meth-associated hemorrhagic stroke including an induced hypertensive surge, vasospasm, blood brain barrier breakdown, chronic hypertension, aneurysm development and rupture, and very rarely associated vasculitis. The increased risk of ischemic stroke related to meth use is less well supported in the literature, but this may, in part, be related to a lack of appropriately designed and powered research studies. Proposed mechanisms for ischemic stroke complications of meth use include those affecting blood vessels such as accelerated atherosclerosis, chronic hypertension, vasospasm, and vasculitis, plus mechanisms that affect the heart including cardiomyopathy, arrhythmias, and infective endocarditis (especially with injection drug use). Standard therapeutic interventions for acute stroke and approaches to secondary stroke prevention seem appropriate for meth-associated strokes, with the addition of abstinence from continued meth use. There is no evidence for any meth-specific stroke treatments. Finally, the prolonged duration of meth withdrawal is described. Larger, prospective studies of meth-related strokes are needed to allow for a better understanding and improved care for this often-devastating consequence of an increasingly prevalent cause of strokes in young patients.
PubMed: 38721123
DOI: 10.3389/fneur.2024.1397677 -
Brain Sciences Jul 2023Early brain injury (EBI) subsequent to subarachnoid hemorrhage (SAH) is strongly associated with delayed cerebral ischemia and poor patient prognosis. Based on... (Review)
Review
Early brain injury (EBI) subsequent to subarachnoid hemorrhage (SAH) is strongly associated with delayed cerebral ischemia and poor patient prognosis. Based on investigations into the molecular mechanisms underlying EBI, neurovascular dysfunction resulting from SAH can be attributed to a range of pathological processes, such as microvascular alterations in brain tissue, ionic imbalances, blood-brain barrier disruption, immune-inflammatory responses, oxidative stress, and activation of cell death pathways. Research progress presents a variety of promising therapeutic approaches for the preservation of neurological function following SAH, including calcium channel antagonists, endothelin-1 receptor blockers, antiplatelet agents, anti-inflammatory agents, and anti-oxidative stress agents. EBI can be mitigated following SAH through neuroprotective measures. To enhance our comprehension of the relevant molecular pathways involved in brain injury, including brain ischemia-hypoxic injury, neuroimmune inflammation activation, and the activation of various cell-signaling pathways, following SAH, it is essential to investigate the evolution of these multifaceted pathophysiological processes. Facilitating neural repair following a brain injury is critical for improving patient survival rates and quality of life.
PubMed: 37509013
DOI: 10.3390/brainsci13071083