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1.
Calcium channel blockade with nimodipine reverses MRI evidence of cerebral oedema following acute hypoxia.
Rowland, MJ, Ezra, M, Winkler, A, Garry, P, Lamb, C, Kelly, M, Okell, TW, Westbrook, J, Wise, RG, Douaud, G, et al
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2019;(2):285-301
Abstract
Acute cerebral hypoxia causes rapid calcium shifts leading to neuronal damage and death. Calcium channel antagonists improve outcomes in some clinical conditions, but mechanisms remain unclear. In 18 healthy participants we: (i) quantified with multiparametric MRI the effect of hypoxia on the thalamus, a region particularly sensitive to hypoxia, and on the whole brain in general; (ii) investigated how calcium channel antagonism with the drug nimodipine affects the brain response to hypoxia. Hypoxia resulted in a significant decrease in apparent diffusion coefficient (ADC), a measure particularly sensitive to cell swelling, in a widespread network of regions across the brain, and the thalamus in particular. In hypoxia, nimodipine significantly increased ADC in the same brain regions, normalizing ADC towards normoxia baseline. There was positive correlation between blood nimodipine levels and ADC change. In the thalamus, there was a significant decrease in the amplitude of low frequency fluctuations (ALFF) in resting state functional MRI and an apparent increase of grey matter volume in hypoxia, with the ALFF partially normalized towards normoxia baseline with nimodipine. This study provides further evidence that the brain response to acute hypoxia is mediated by calcium, and importantly that manipulation of intracellular calcium flux following hypoxia may reduce cerebral cytotoxic oedema.
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Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.
Lawlor, B, Segurado, R, Kennelly, S, Olde Rikkert, MGM, Howard, R, Pasquier, F, Börjesson-Hanson, A, Tsolaki, M, Lucca, U, Molloy, DW, et al
PLoS medicine. 2018;(9):e1002660
Abstract
BACKGROUND This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
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Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm.
Stambler, BS, Dorian, P, Sager, PT, Wight, D, Douville, P, Potvin, D, Shamszad, P, Haberman, RJ, Kuk, RS, Lakkireddy, DR, et al
Journal of the American College of Cardiology. 2018;(5):489-497
Abstract
BACKGROUND There is no nonparenteral medication for the rapid termination of paroxysmal supraventricular tachycardia. OBJECTIVES The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT). METHODS This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events. RESULTS One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active compound dose groups versus placebo. In patients who converted, the median time to conversion with etripamil was <3 min. Adverse events were mostly related to the intranasal route of administration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose. CONCLUSIONS Etripamil nasal spray rapidly terminated induced SVT with a high conversion rate. The safety and efficacy results of this study provide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. (Efficacy and Safety of Intranasal MSP-2017 [Etripamil] for the Conversion of PSVT to Sinus Rhythm [NODE-1]; NCT02296190).
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Effects of Calcium-Channel Blocker Benidipine-Based Combination Therapy on Cardiac Events - Subanalysis of the COPE Trial.
Umemoto, S, Ogihara, T, Matsuzaki, M, Rakugi, H, Shimada, K, Kawana, M, Kario, K, Ohashi, Y, Saruta, T, ,
Circulation journal : official journal of the Japanese Circulation Society. 2018;(2):457-463
Abstract
BACKGROUND The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was conducted to compare the effects of regimens combining the dihydropyridine calcium-channel blocker benidipine with each of 3 secondary agent types (an angiotensin-receptor blocker (ARB), a β-blocker and a thiazide) in Japanese hypertensive outpatients who did not achieve target blood pressure (<140/90 mmHg) with benidipine 4 mg/day alone. The analysis included 3,293 patients (ARB, 1,110; β-blocker, 1,089; thiazide, 1,094) with a median follow-up of 3.61 years. The main results of the COPE trial demonstrated that the incidences of hard cardiovascular composite endpoints and fatal or non-fatal strokes were significantly higher in the benidipine/β-blocker group than in the benidipine/thiazide group.Methods and Results:We further evaluated the treatment effects on different cardiac events among the 3 benidipine-based regimens.We observed a total of 50 cardiac events, 4.2 per 1000 person-years. The incidences of total cardiac events and each cardiac event were similarly low among the 3 treatment groups. Unadjusted and multi-adjusted hazard ratios for total cardiac events showed no significant difference among the 3 treatment groups. CONCLUSIONS This subanalysis of the COPE trial demonstrated that blood pressure-lowering regimens combining benidipine with an ARB, β-blocker or thiazide diuretic were similarly effective for the prevention of cardiac events in Japanese hypertensive outpatients.
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5.
Tolerability, pharmacokinetics, and pharmacodynamics of mirogabalin in healthy subjects: Results from phase 1 studies.
Brown, K, Mendell, J, Ohwada, S, Hsu, C, He, L, Warren, V, Dishy, V, Zahir, H
Pharmacology research & perspectives. 2018;(5):e00418
Abstract
Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose studies, and 1 open-label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high-fat meal) conditions. Forty-eight and 47 healthy volunteers completed the single- and multiple-dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment-emergent adverse events (TEAEs)-dizziness and somnolence-were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3-30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%-72% urinary excretion). Exposure increased in a dose-proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.
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The influence of CYP3A5*3 and BCRPC421A genetic polymorphisms on the pharmacokinetics of felodipine in healthy Chinese volunteers.
Xiang, Q, Li, C, Zhao, X, Cui, YM
Journal of clinical pharmacy and therapeutics. 2017;(3):345-349
Abstract
WHAT IS KNOWN AND OBJECTIVE The role of CYP3A5 in drug metabolism has been receiving attention because CYP3A5 may be more involved in the metabolism of CYP3A substrates in vivo than previously thought. The polymorphism of transporters, such as P-gp (P-glycoprotein) and breast cancer-related protein (BCRP), influences the metabolism of these substrates, and felodipine is a substrate of P-gp. The aim of this study was to evaluate the pharmacogenetic variability in the disposition of felodipine in healthy Chinese subjects. METHODS A single dose of 5 mg felodipine was orally administered to 45 healthy Chinese subjects. The serum concentration of felodipine was measured by using LC/MS/MS. We detected the SNPs of cytochromes P450 enzymes and transporters, which play vital roles in drug metabolism and have a high frequency of mutation in Chinese population. RESULTS AND DISCUSSION The area under the plasma concentration-time curve (AUC) within the time points 0 to 72 h (AUC(0-72) ) after felodipine administration was significantly higher in subjects possessing the BCRP421AA alleles than in those with the BCRP421 CC or CA genotype (P = 0·034). The subjects with CYP3A5*3/*3 (n = 27) had higher felodipine exposure than CYP3A5*1/*3 (n = 15) (P = 0·035). WHAT IS NEW AND CONCLUSION This study showed that the genetic polymorphisms of CYP3A5*3 and BCRPC421A might explain the variability in the pharmacokinetics of felodipine in the Chinese population.
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7.
Parathyroid Hormone and the Use of Diuretics and Calcium-Channel Blockers: The Multi-Ethnic Study of Atherosclerosis.
Zaheer, S, de Boer, I, Allison, M, Brown, JM, Psaty, BM, Robinson-Cohen, C, Ix, JH, Kestenbaum, B, Siscovick, D, Vaidya, A
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2016;(6):1137-45
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Abstract
Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine-sensitive calcium channels are expressed on parathyroid cells and may play a role in parathyroid hormone (PTH) regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared with non-TZ use (44.4 versus 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared with non-users of each medication class (LD: 60.7 versus 45.5 pg/mL, p < 0.0001; CCB: 49.5 versus. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β = -3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: β = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β = +5.0 pg/mL, p < 0.0001), whereas non-dihydropyridine use was not (β = +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these medications to the development of skeletal outcomes. © 2016 American Society for Bone and Mineral Research.
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Calcium-Channel Blockers and Dementia Risk in Older Adults - National Health Insurance Service - Senior Cohort (2002-2013).
Hwang, D, Kim, S, Choi, H, Oh, IH, Kim, BS, Choi, HR, Kim, SY, Won, CW
Circulation journal : official journal of the Japanese Circulation Society. 2016;(11):2336-2342
Abstract
BACKGROUND Some disagreements surround the effects of calcium-channel blockers (CCBs) on the risk of dementia. The purpose of this study was to investigate the protective effects of CCBs on dementia among elderly hypertensive Koreans.Methods and Results:We conducted a large population-based cohort study using the senior cohort database of the Korean National Health Insurance Service (2002-2013). Subjects were elderly hypertensive Koreans older than 60 years of age. A total of 18,423 patients (CCB user group: 13,692 patients; non-CCB antihypertensive user group: 4,731 patients) were statistically analyzed using the Cox proportional hazard regression model to estimate the adjusted hazard ratio (aHR) and confidence intervals (CIs) of dementia associated with CCB use. There were 2,881 cases (21.0%) of dementia in the CCB user group and 1,124 cases (23.8%) in the non-user group. CCB use significantly reduced the risk of total dementia (aHR 0.81, 95% CI 0.75-0.87, P<0.0001), Alzheimer's dementia (aHR 0.80, 95% CI 0.72-0.88, P<0.0001), and vascular dementia (aHR 0.81, 95% CI 0.70-0.94, P=0.0067). CONCLUSIONS CCB use had a protective effect on the risk of dementia among elderly hypertensive Koreans. (Circ J 2016; 80: 2336-2342).
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Adding Hydrochlorothiazide to Olmesartan/Amlodipine Increases Efficacy in Patients With Inadequate Blood Pressure Control on Dual-Combination Therapy.
Rump, LC, Ammentorp, B, Laeis, P, Scholze, J
Journal of clinical hypertension (Greenwich, Conn.). 2016;(1):60-9
Abstract
This randomized, parallel-group study in patients inadequately controlled on olmesartan medoxomil/amlodipine (OLM/AML) 40/10 mg assessed the effects of adding hydrochlorothiazide (HCTZ) 12.5 mg and 25 mg, using seated blood pressure (SeBP) measurements and ambulatory blood pressure (BP) monitoring. Enrolled patients were screened and tapered off of therapy if required. All patients received OLM/AML 40/10 mg and those with mean seated BP (SeBP) ≥140/90 mm Hg after 8 weeks (n=808) were randomized (1:1:1) to continue with OLM/AML 40/10 mg or receive OLM/AML/HCTZ 40/10/12.5 or 40/10/25 mg for a further 8 weeks. The primary endpoint was the change in seated diastolic BP (SeDBP) from the start to the end of the randomized treatment period. The addition of HCTZ 25 mg significantly reduced SeDBP (-2.8 mm Hg; P<.0001), lowered seated systolic BP (SeSBP) and ambulatory DBP and SBP, and improved BP goal rates. In patients uncontrolled on OLM/AML 40/10 mg, adding HCTZ led to further BP reductions, particularly in ambulatory BP.
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Incremental Blood Pressure-Lowering Effect of Titrating Amlodipine for the Treatment of Hypertension in Patients Including Those Aged ≥55 Years.
Jeffers, BW, Bhambri, R, Robbins, J
American journal of therapeutics. 2015;(4):278-87
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Abstract
Small reductions in blood pressure reduce the risk of cardiovascular events. Here, we report 2 post hoc pooled analyses assessing the antihypertensive effect of amlodipine in patients who had not responded to 5 mg and were uptitrated to 10 mg. The first analysis assessed subgroups of patients aged either younger than 55 years or 55 years or older and the second analysis pooled all patients irrespective of age. Of 706 patients in the age-related analysis, a statistically significant decrease in blood pressure from baseline was observed {for younger than 55 years [N = 253]: systolic blood pressure = -12.8 [standard error (SE) = 0.90] mm Hg, diastolic blood pressure = -8.0 [SE = 0.55] mm Hg; for 55 years or older [N = 453]: systolic blood pressure = -12.1 [SE = 0.66] mm Hg, diastolic blood pressure = -6.7 [SE = 0.39] mm Hg; all P < 0.0001}. In total, 45.8% and 39.3% of patients aged younger than 55 and 55 years or older, respectively, achieved their blood pressure goals. Adverse events were experienced by 62 (24.5%) patients aged younger than 55 years and 136 (30.0%) patients aged 55 years or older. Similar efficacy and safety results were seen in the all patient pooled analysis. Titration of amlodipine from 5 mg to 10 mg significantly decreased blood pressure in older hypertensive patients, which is clinically relevant because increased age is associated with hypertension and cardiovascular events.