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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.
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2.
ACE-inhibitor/calcium antagonist combination: is this the first-choice therapy in arterial hypertension?
Taddei, S
Minerva medica. 2019;(6):546-554
Abstract
The 2018 ESH/ESC guidelines indicate that the first-choice therapy in the majority of hypertensive patients should be a fixed combination of a drug that blocks the renin-angiotensin-aldosterone system and a calcium antagonist or a diuretic. Evidence from the meta-analysis of controlled clinical trials, however, indicates that the classes of drugs that block the renin-angiotensin-aldosterone system should not be considered equivalent as ACE inhibitors have been clearly shown to outperform AT-1 antagonists in preventing myocardial infarction and total mortality. Moreover, studies such as ASCOT and ACCOMPLISH demonstrate a superiority of the ACE-inhibitor/calcium antagonist association over beta-blocker/diuretic associations and especially towards the ACE-inhibitor/diuretic combination, whereas there is no scientific evidence of efficacy with respect to cardiovascular events on the part of AT-1 antagonist/calcium antagonist combinations. Drugs such as ramipril and amlodipine are undoubtedly the reference molecules within their respective classes as numerous controlled clinical studies have demonstrated their effectiveness on cardiovascular events. It is therefore obvious that the availability of a fixed combination with both molecules is a great opportunity for the therapy of the hypertensive patient, considering also the availability of studies that demonstrate its effectiveness on intermediate endpoints associated with high tolerability. So, in accordance with the 2018 ESH/ESC guidelines, the fixed combination ramipril/amlodipine represents a first choice therapy for hypertension.
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3.
An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence.
Wacker, J, Weintraub, R, Beghetti, M
Expert review of respiratory medicine. 2019;(2):205-215
Abstract
Pulmonary hypertension is a severe condition that can develop during childhood due to several different etiologies. During the last two decades, based on a better understanding of the underlying pathobiology leading to pulmonary arterial hypertension, targeted therapies have been developed and have improved the dreadful prognosis of the condition. However, curative therapy remains elusive. Areas covered: In this article, we will review the currently available drugs in pediatric pulmonary arterial hypertension and discuss the recommended management strategies. Expert commentary: Most of the drugtrials in pulmonary hypertension have been performed in adults, with extrapolation of the results to children. Most of the pediatric studies are non-controlled. The rarity of the disease and the lack of identifiable pediatric treatment goals and satisfactory trial end-points could explain the paucity of specific pediatric studies. An evolution has been made in the last few years regarding the treatment strategy of pulmonary arterial hypertension, with evidence that early combination therapy with at least two pulmonary vasodilators was beneficial on the survival. Children with pulmonary hypertension should be referred to experienced centers early, to benefit from a comprehensive initial assessment. Serial clinical and hemodynamic re-evaluation should assess treatment response and guide potential change in therapy.
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4.
Ion Channel Pharmacology for Pain Modulation.
De Logu, F, Geppetti, P
Handbook of experimental pharmacology. 2019;:161-186
Abstract
A large series of different ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including pain. Among these channels, the voltage gated calcium channels (VGCC) are inhibited by drugs for the treatment of migraine, neuropathic pain or intractable pain. Transient receptor potential (TRP) channels are emerging as important pain transducers as they sense low pH media or oxidative stress and other mediators and are abundantly found at sites of inflammation or tissue injury. Low pH may also activate acid sensing ion channels (ASIC) and mechanical forces stimulate the PIEZO channels. While potent agonists of TRP channels due to their desensitizing action on pain transmission are used as topical applications, the potential of TRP antagonists as pain therapeutics remains an exciting field of investigation. The study of ASIC or PIEZO channels in pain signaling is in an early stage, whereas antagonism of the purinergic P2X3 channels has been reported to provide beneficial effects in chronic intractable cough. The present chapter covers these intriguing channels in great detail, highlighting their diverse mechanisms and broad potential for therapeutic utility.
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5.
Nondihydropyridine Calcium Channel Blockers for the Treatment of Proteinuria: A Review of the Literature.
Steuber, TD, Lee, J, Holloway, A, Andrus, MR
The Annals of pharmacotherapy. 2019;(10):1050-1059
Abstract
Objective: To review the use of nondihydropyridine calcium channel blockers (non-DHP CCBs) for the treatment of proteinuria in diabetic and nondiabetic kidney disease. Data Sources: A search using PubMed and MEDLINE, Scopus, and Google Scholar was performed from 1964 through February 2019 using the following search terms alone or in combination: verapamil, diltiazem, non-dihydropyridine calcium channel blocker, proteinuria, albuminuria, microalbuminuria, kidney disease, renal disease. Study Selection and Data Extraction: All prospective English-language trials examining one or more non-DHP CCB for the treatment of proteinuria were evaluated. Data Synthesis: A total of 13 clinical trials examining the use of non-DHP CCBs to treat proteinuria alone or in combination with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) were included in the evaluation. Most studies evaluated patients with macroalbuminuria secondary to diabetes and hypertension. Verapamil was the most common agent studied. Non-DHP CCBs were effective in reducing proteinuria in diabetic kidney disease but did not reduce renal or cardiovascular outcomes in the one trial that evaluated clinical end points. They were generally well tolerated, with the most common adverse effect reported being constipation. Relevance to Patient Care and Clinical Practice: This review evaluates and summarizes the available evidence on non-DHP CCBs for treatment of proteinuria in patients with existing kidney disease. Conclusion: Non-DHP CCBs may be a reasonable therapeutic option for patients with diabetic kidney disease and persistent proteinuria despite maximum doses of ACE inhibitors or ARBs. Additionally, they may be reasonable alternatives to ACE inhibitors or ARBs if a contraindication or intolerance exists.
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6.
Pharmacogenomics of Cytochrome P450 of Nimodipine Metabolism After Aneurysmal Subarachnoid Hemorrhage.
Peacock, SH, James, C, Turnbull, MT, Cowart, JB, Reid, JM, Freeman, WD
The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses. 2019;(5):238-242
Abstract
INTRODUCTION Aneurysmal subarachnoid hemorrhage (aSAH) is a type of stroke that is life threatening with high rates of mortality, and many survivors are left with permanent neurologic deficits. Nimodipine is the treatment of choice for aSAH with the goal of reduction of delayed cerebral ischemia. It is the only evidence-based medication that has been shown to have improved outcomes for delayed cerebral ischemia; therefore, it is important for neuroscience nurses to be knowledgeable of the pharmacology and pharmacogenomics properties of this medication, including cytochrome P450 (CYP450) enzymes. METHODS AND RESULTS This article reviews the CYP450 enzyme system including a review of the pharmacotherapy and pharmacogenomics of nimodipine for patients with aSAH illustrated with case study of a patient with abnormal drug metabolism. CONCLUSION CYP450 enzymes can be inhibited or induced by multiple medications resulting in clinically significant differences in drug metabolism. Food and Drug Administration-approved medication nimodipine is the only medication shown to improve outcomes in patients with aSAH. Hence, it is important to have awareness of potential drug-to-drug interactions and pharmacogenomics of nimodipine when caring for critically ill patients with aSAH.
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7.
Intravenous and Nebulized Magnesium Sulfate for Treating Acute Asthma in Children: A Systematic Review and Meta-Analysis.
Su, Z, Li, R, Gai, Z
Pediatric emergency care. 2018;(6):390-395
Abstract
OBJECTIVE This study aimed to evaluate the efficacy of intravenous (IV) and nebulized magnesium sulfate in acute asthma in children. METHODS The PubMed, Cochrane Library, and EMBASE databases were searched. Randomized controlled trials and quasi-randomized controlled trials of IV and nebulized magnesium sulfate in pediatric acute asthma were included. The outcomes subject to meta-analysis were pulmonary function, hospitalization, and further treatment. If statistical heterogeneity was significant, random-effects models were used for meta-analysis, otherwise, fixed-effects models were applied. RESULTS Ten randomized and quasi-randomized trials (6 IV, 4 nebulized) were identified. Intravenous magnesium sulfate treatment is associated with significant effects on respiratory function (standardized mean difference, 1.94; 95% confidence interval [CI], 0.80-3.08; P = 0.0008) and hospital admission (risk ratio, 0.55; 95% CI, 0.31-0.95; P = 0.03). But nebulized magnesium sulfate treatment shows no significant effect on respiratory function (standardized mean difference, 0.19; 95% CI, -0.01-0.40; P = 0.07) or hospital admission (risk ratio, 1.11; 95% CI, 0.86-1.44; P = 0.42). CONCLUSIONS The meta-analysis revealed that IV magnesium sulfate is an effective treatment in children, with the pulmonary function significantly improved and hospitalization and further treatment decreased. But nebulized magnesium sulfate treatment showed no significant effect on respiratory function or hospital admission and further treatment.
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8.
The Risk for Lung Cancer Incidence with Calcium Channel Blockers: A Systematic Review and Meta-Analysis of Observational Studies.
Rotshild, V, Azoulay, L, Zarifeh, M, Masarwa, R, Hirsh-Raccah, B, Perlman, A, Muszkat, M, Matok, I
Drug safety. 2018;(6):555-564
Abstract
INTRODUCTION There are conflicting findings regarding the association between the use of calcium channel blockers (CCBs) and the risk of lung cancer. Considering the public health importance of lung cancer prevention, and emerging evidence of a significant biologic role of calcium channel regulation in the development of lung cancer, we conducted a meta-analysis to assess the risk of lung cancer in CCB users compared with non-CCB users. MATERIALS AND METHODS We conducted a comprehensive systematic search of leading medical databases for observational studies published up to December 2017 that examined CCB use and the risk of lung cancer. We used random-effects models to pool results. The impact of duration of CCB use on the estimated effect size was explored using random effects meta-regression. RESULTS Ten studies (six cohort and four case-control studies) that evaluated the overall cancer risk among 38,758 CCB users were included in the analysis. Overall risk ratio (RR) for CCB use and lung cancer was 1.15 (95% confidence interval [CI] 1.01-1.32). Subgroup analysis by duration of CCB use suggested that the observed increase in lung cancer risk was driven by the results of five studies with prolonged (≥ 4 years) exposure (RR 1.18; 95% CI 1.08-1.30). CONCLUSIONS Our analysis suggests exposure to CCBs is associated with an increased risk of lung cancer. Considering their widespread use, and the paucity of data on the long-term effects of chronic exposure to CCBs, these results are reason for concern and warrant further investigation. SYSTEMATIC REVIEW REGISTRATION The protocol for this study was registered at the PROSPERO registry of systematic reviews (registry number: CRD42017056362).
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9.
Calcium Ion Channels: Roles in Infection and Sepsis Mechanisms of Calcium Channel Blocker Benefits in Immunocompromised Patients at Risk for Infection.
D'Elia, JA, Weinrauch, LA
International journal of molecular sciences. 2018;(9)
Abstract
Immunosuppression may occur for a number of reasons related to an individual's frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile.
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10.
T-type Ca2+ Channels: T for Targetable.
Sallán, MC, Visa, A, Shaikh, S, Nàger, M, Herreros, J, Cantí, C
Cancer research. 2018;(3):603-609
Abstract
In the past decade, T-type Ca2+ channels (TTCC) have been unveiled as key regulators of cancer cell biology and thus have been proposed as chemotherapeutic targets. Indeed, in vitro and in vivo studies indicate that TTCC pharmacologic blockers have a negative impact on the viability of cancer cells and reduce tumor size, respectively. Consequently mibefradil, a TTCC blocker approved in 1997 as an antihypertensive agent but withdrawn in 1998 because of drug-drug interactions, was granted 10 years later the orphan drug status by the FDA to investigate its efficacy against brain, ovary, and pancreatic cancer. However, the existence of different channel isoforms with distinct physiologic roles, together with the lack of selective pharmacologic agents, has hindered a conclusive chemotherapeutic evaluation. Here, we review the available evidence on TTCC expression, value as prognostic markers, and effectiveness of their pharmacologic blockade on cancer cells in vitro and in preclinical models. We additionally summarize the status of clinical trials using mibefradil against glioblastoma multiforme. Finally, we discuss the future perspectives and the importance of further development of multidisciplinary research efforts on the consideration of TTCCs as biomarkers or targetable molecules in cancer. Cancer Res; 78(3); 603-9. ©2018 AACR.