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1.
Nimodipine Reappraised: An Old Drug With a Future.
Carlson, AP, Hänggi, D, Macdonald, RL, Shuttleworth, CW
Current neuropharmacology. 2020;(1):65-82
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Abstract
Nimodipine is a dihydropyridine calcium channel antagonist that blocks the flux of extracellular calcium through L-type, voltage-gated calcium channels. While nimodipine is FDAapproved for the prevention and treatment of neurological deficits in patients with aneurysmal subarachnoid hemorrhage (aSAH), it affects myriad cell types throughout the body, and thus, likely has more complex mechanisms of action than simple inhibition of cerebral vasoconstriction. Newer understanding of the pathophysiology of delayed ischemic injury after a variety of acute neurologic injuries including aSAH, traumatic brain injury (TBI) and ischemic stroke, coupled with advances in the drug delivery method for nimodipine, have reignited interest in refining its potential therapeutic use. In this context, this review seeks to establish a firm understanding of current data on nimodipine's role in the mechanisms of delayed injury in aSAH, TBI, and ischemic stroke, and assess the extensive clinical data evaluating its use in these conditions. In addition, we will review pivotal trials using locally administered, sustained release nimodipine and discuss why such an approach has evaded demonstration of efficacy, while seemingly having the potential to significantly improve clinical care.
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Cinnarizine as an alternative recommendation for migraine prophylaxis: a narrative review.
Togha, M, Martami, F, Abdollahi, M, Mozafari, M, Cheraghali, H, Rafiee, P, Shafaei, M
Expert review of neurotherapeutics. 2020;(9):943-951
Abstract
INTRODUCTION Despite the available prophylactic and acute drugs for migraine management, this disabling disorder remains undertreated especially among pediatrics. In this review, the authors aim at assessing the preventive role cinnarizine plays in treating migraine based on previously published studies. AREAS COVERED Randomized clinical trials, randomized controlled trials, non-randomized open-label trials, and retrospective studies concerning cinnarizine in migraine prevention in children and adults were reviewed. Especial attention was given to the response rate, migraine characteristics, and tolerability. EXPERT OPINION The majority of reviewed trials demonstrated that cinnarizine is comparable to the conventional drugs used in migraine prophylaxis. However, most of the reviewed studies were limited by a non-controlled open-label design. Due to poor planning and possibility of high placebo responses, particularly in children and adolescents, the interpretation of open-label studies' results should be done cautiously. The evidence shows that cinnarizine's effectiveness was more promising in pediatric migraineurs and adults with migraine-associated vertigo such as vestibular migraine. Therefore, while the efficacy of cinnarizine cannot be dismissed, before reaching a definite conclusion on its effectiveness, it is necessary to do further high-quality RCTs among both children and adults.
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3.
Therapeutic advances in Dravet syndrome: a targeted literature review.
Strzelczyk, A, Schubert-Bast, S
Expert review of neurotherapeutics. 2020;(10):1065-1079
Abstract
INTRODUCTION Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. AREAS COVERED This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. EXPERT OPINION Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
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Beta-Blockers, Calcium Channel Blockers, and Mortality in Stable Coronary Artery Disease.
Cruz Rodriguez, JB, Alkhateeb, H
Current cardiology reports. 2020;(3):12
Abstract
PURPOSE OF REVIEW To examine the current clinical evidence behind the use of calcium channel blockers (CCB) and beta-blockers (BB) for the treatment of patients with stable coronary artery disease (SCAD) and their effect on mortality. RECENT FINDINGS Current evidence suggests that BB use as a first line antianginal medication is associated with lower 5-year all-cause mortality only in patients who had MI within a year. This could be driven due to their effects reducing the sympathetic neuro-hormonal activation of more acutely ill patients. The use of CCB as an antianginal therapy, although proven effective in multiple trials both as monotherapy and combined with other agents, has not shown mortality benefit. Both BB and CCB are effective antianginals, and the selection among them depends on the patient clinical presentation and comorbidities. BB are the only ones that have shown survival benefit in SCAD, particularly the first year post-MI.
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5.
The Interplay Between Depression and Parkinson´s Disease: Learning the Link Through Ca2+/cAMP Signaling.
Bergantin, LB
Current protein & peptide science. 2020;(12):1223-1228
Abstract
BACKGROUND Parkinson´s disease (PD) and depression have an interplay at multiple cellular levels, a phenomenon which is translated into clinical data showing that depressive patients presented an enhanced risk for developing PD. The pathogenesis of both diseases is under intensive debate as correlated to dysregulations related to Ca2+ signaling. OBJECTIVE Then, revealing this interplay between these diseases may provide novel insights into the pathogenesis of them. METHODS Publications involving Ca2+ signaling, PD and depression (alone or combined) were collected by searching PubMed and EMBASE. RESULTS Not surprisingly, calcium (Ca2+) channel blockers (CCBs), classical antihypertensive medicines, have been demonstrated off-label effects, such as alleviating both PD and depression symptoms. DISCUSSION A mechanism under debate for the antiparkinsonism and antidepressant effects associated to CCBs is focused on the restoration of Ca2+ signaling dysregulations. In addition, previous studies have observed that CCBs can affect Ca2+/cAMP signaling. CONCLUSION Thus, this article discussed the role of Ca2+/cAMP signaling in the interplay between depression and PD, including the implications for the pharmacotherapy involving CCBs.
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6.
Coronary Artery Spasm: New Insights.
Matta, A, Bouisset, F, Lhermusier, T, Campelo-Parada, F, Elbaz, M, Carrié, D, Roncalli, J
Journal of interventional cardiology. 2020;:5894586
Abstract
Coronary artery spasm (CAS) defined by a severe reversible diffuse or focal vasoconstriction is the most common diagnosis among INOCA (ischemia with no obstructive coronary artery disease) patients irrespective to racial, genetic, and geographic variations. However, the prevalence of CAS tends to decrease in correlation with the increasing use of medicines such as calcium channel blockers, angiotensin converting enzyme inhibitor, and statins, the controlling management of atherosclerotic risk factors, and the decreased habitude to perform a functional reactivity test in highly active cardiac catheterization centers. A wide spectrum of clinical manifestations from silent disease to sudden cardiac death was attributed to this complex entity with unclear pathophysiology. Multiple mechanisms such as the autonomic nervous system, endothelial dysfunction, chronic inflammation, oxidative stress, and smooth muscle hypercontractility are involved. Regardless of the limited benefits proffered by the newly emerged cardiac imaging modalities, the provocative test remains the cornerstone diagnostic tool for CAS. It allows to reproduce CAS and to evaluate reactivity to nitrates. Different invasive and noninvasive therapeutic approaches are approved for the management of CAS. Long-acting nondihydropyridine calcium channel blockers are recommended for first line therapy. Invasive strategies such as PCI (percutaneous coronary intervention) and CABG (coronary artery bypass graft) have shown benefits in CAS with significant atherosclerotic lesions. Combination therapies are proposed for refractory cases.
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7.
Management of Alternating Hemiplegia of Childhood: A Review.
Samanta, D
Pediatric neurology. 2020;:12-20
Abstract
Alternating hemiplegia of childhood is a severe neurological disorder with infantile-onset recurrent episodes of hemiplegia on either side of the body and other paroxysmal events such as seizures, dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction, primarily due to de novo pathogenic mutations in the ATP1A3 gene. The burden of neuromorbidities is significant and includes epilepsy; attention-deficit/hyperactivity disorder; behavioral difficulties; motor, cognitive, adaptive, and learning impairment; ataxia; movement disorders; and migraine. Comprehensive multispecialty clinic with the availability of various specialists with considerable experience in alternating hemiplegia of childhood is beneficial. A comprehensive treatment plan including strict maintenance of a diary about different paroxysmal events is helpful. Disease-modifying therapy of alternating hemiplegia of childhood does not exist, and several agents such as benzodiazepines, flunarizine, topiramate, ketogenic diet, triheptanoin, steroid, amantadine, memantine, aripiprazole, oral ATP, coenzyme Q, acetazolamide, dextromethorphan, and vagus nerve stimulator have been tried with various rates of success by aborting attacks or reducing the frequency or severity of paroxysmal spells. The apparent efficacy of flunarizine is based on its use in hundreds of patients, albeit in open-label experience, but most of the other agents' reports of efficacy were from single case reports or case series of only a handful of patients. Besides reviewing existing data about individual agent active against paroxysmal events, we also review the management principles for coexisting neurological issues. However, with rapid advancement in the understanding of molecular pathogenesis and network abnormality of this disease, the treatment paradigm of alternating hemiplegia of childhood may significantly alter over the next decade.
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8.
Managing Hypertension Using Combination Therapy.
Smith, DK, Lennon, RP, Carlsgaard, PB
American family physician. 2020;(6):341-349
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Abstract
More than 70% of adults treated for primary hypertension will eventually require at least two antihypertensive agents, either initially as combination therapy or as add-on therapy if monotherapy and lifestyle modifications do not achieve adequate blood pressure control. Four main classes of medications are used in combination therapy for the treatment of hypertension: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). ACEIs and ARBs should not be used simultaneously. In black patients, at least one agent should be a thiazide diuretic or a calcium channel blocker. Patients with heart failure with reduced ejection fraction should be treated initially with a beta blocker and an ACEI or ARB (or an angiotensin receptor-neprilysin inhibitor), followed by add-on therapy with a mineralocorticoid receptor antagonist and a diuretic based on volume status. Treatment for patients with chronic kidney disease and proteinuria should include an ACEI or ARB plus a thiazide diuretic or a calcium channel blocker. Patients with diabetes mellitus should be treated similarly to those without diabetes unless proteinuria is present, in which case combination therapy should include an ACEI or ARB.
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9.
The Interactions Between Alzheimer's Disease and Major Depression: Role of Ca2+ Channel Blockers and Ca2+/cAMP Signalling.
Bergantin, LB
Current drug research reviews. 2020;(2):97-102
Abstract
BACKGROUND The interactions between Alzheimer's Disease (AD) and major depression can be translated into clinical data showing that depressive patients have had an enhanced risk for developing AD (later in life). The cellular mechanisms involved in these interactions remain under intensive debate in the literature. In addition, the role of a Ca2+ homeostasis dysregulation in the pathogenesis of neurodegenerative diseases, like AD, and major depression has been under intensive discussion. OBJECTIVE Thus, revealing the interplay between AD and major depression may provide novel insights into the pathogenesis of these diseases. METHODS Publications involving Ca2+ signalling pathways, AD, and major depression (alone or combined) were collected by searching multiple databases to find the maximum number of relevant citations (using a search strategy with high sensitivity for studies of etiology). RESULTS Ca2+ Channel Blockers (CCBs), classically prescribed for hypertensive patients, have been demonstrating neuroprotective effects, such as decreasing the incidence of AD in hypertensive patients, including alleviating major depression symptoms. A mechanism under debate is focused on the restoration of the Ca2+ homeostasis. Indeed, previous studies of our own have correlated Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) in controlling both the neurotransmitter release and neuronal death. These studies also observed that CCBs can affect Ca2+/cAMP signalling. CONCLUSION This review discussed the plausible role of Ca2+/cAMP signalling in the neuroprotective effects of CCBs, including the participation of Ca2+/cAMP signalling in the interactions between major depression and AD. Considering both AD and major depression have become highly prevalent medical problems in the world, the comprehension of the interactions between these diseases could improve drug development.
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10.
How CaV1.2-bound verapamil blocks Ca2+ influx into cardiomyocyte: Atomic level views.
Li, W, Shi, G
Pharmacological research. 2019;:153-157
Abstract
The first clinically used antiarrhythmic, antianginal and anti-hypertensive phenylalkylamine, verapamil's cardiovascular activity is inextricably linked to its ability to antagonize Ca2+ overload via blocking CaV1.2, a cardiac L-type Ca2+ channel of undisputed physiological and pharmacological importance in cardiovascular disorders such as myocardial ischemia-reperfusion injury. From a structural point of view, however, the action mechanism of verapamil is still elusive. Therefore, incorporating previous findings for verapamil and CaV1.2, this review article puts forward two experimental data-derived and -supported 3D structure models for CaV1.2's α1 subunit and its verapamil-bound form. Furthermore, this article suggests three biophysical mechanisms, namely competitive binding, steric hindrance and electrostatic repulsion, towards an atomic level understanding of how verapamil blocks the L-type Ca2+ current mediated by CaV1.2 in reality, which can be useful for the design and development of next-generation Ca2+ antagonists to provide safer and more effective treatment of cardiovascular diseases.