dihydropyridines and Stroke

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Calcium Channel Blockers; Cardiovascular Diseases; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Japan; Male; Middle Aged; Randomized Controlled Trials as Topic; Sodium Chloride Symporter Inhibitors; Stroke

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Dihydropyridines; Humans; Hypertension; Stroke

The authors reviewed the pathogenesis of cocaine-related cerebral ischemia, appraised current knowledge of its sequelae, and assessed the role of putative therapeutic agents, particularly dihydropyridine-class calcium channel antagonists.. The authors performed an OVID-based literature review of all indexed journals between 1966 and 2000.. Cocaine abuse significantly increases the risk of ischemic stroke. The principal mechanism of cocaine-induced cerebral ischemia is vasospasm of large cranial arteries or within the cortical microvasculature. Increased levels of extracellular monoamines, particularly dopamine, mediate vasospasm. Neuroanatomical and labeling studies also have shown that dopamine-innervated neurons may regulate cerebral blood flow. Indeed, dopamine-rich brain regions appear to be relatively specific targets for cocaine-induced cerebral ischemia. Neuroimaging studies show that cocaine-induced hypoperfusion can persist even after 6 months of abstinence. Hypoperfusion can result in deficits on complex and simple psychomotor tasks but perhaps not on memory or attention. Severe cerebral ischemia can directly precipitate neuronal death and degradation, a condition exacerbated by liberation of the excitatory amino acid glutamate. Dihydropyridine-class calcium channel antagonists inhibit cocaine-mediated dopamine release on neurons involved in vasospasm and the control of cortical circulation. Other causes of cerebral ischemia include thrombogenesis and vasculitis. Although antithrombotic agents have potential in alleviating cocaine's neurotoxic effects, their use may be limited by the risk of spontaneous hemorrhage.. Cocaine abuse can result in stroke, neuroischemia, and cognitive deficits that can persist even after prolonged abstinence. Dihydropyridine-class calcium channel antagonists, such as isradipine, show promise as therapeutic agents for preventing cocaine-induced cerebral ischemia.

Topics: Brain Ischemia; Calcium Channel Blockers; Cocaine-Related Disorders; Dihydropyridines; Humans; Isradipine; Stroke; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Vasospasm, Intracranial

Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6-36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine-thiazide group than in the benidipine-β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine-thiazide combination may reduce visit-to-visit BP variability more than the benidipine-β-blocker combination.

Topics: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Diuretics; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Female; Heart Diseases; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Risk Factors; Stroke; Thiazides

The aim of this study was to compare the efficacy and safety of lercanidipine and amlodipine in the treatment of hypertensive patients with acute cerebral ischemic stroke.. An open label, controlled, randomized, parallel-group study was conducted on 104 hypertensive patients (blood pressure [BP] >130/80 mmHg) diagnosed with ischemic stroke. Enrolled subjects were randomly assigned to a 4 week treatment with lercanidipine 20 mg/day or amlodipine 10 mg/day. The treatment was administered during the acute phase of the stroke, either immediately after the diagnosis or during an observation period of maximum 6 days.. Both lercanidipine and amlodipine were able to significantly reduce mean clinical systolic BP (SBP)/diastolic BP (DBP), mean 24 h ambulatory BP and day-time and night-time BP. In particular, mean clinical SBP/DBP was reduced from 168.9 ± 21.6/96.2 ± 13.6 mmHg to 147.1 ± 22.0/87.1 ± 14.0 mmHg in the lercanidipine group (p < 0.001 for SBP and p < 0.01 for DBP) and from 167.1 ± 19.9/97.8 ± 14.5 mmHg to 143.3 ± 21.9/82.8 ± 14.1 mmHg in the amlodipine-treated group (p < 0.001 for both SBP and DBP). No statistical difference was observed between the two treatments in the reduction of clinical BP. The response and normalization rates registered in the two groups of patients were also similar, with no significant difference between the two drugs. In addition, both treatments reported comparable results in terms of early morning BP surge reduction and BP stabilization, measured through trough-peak ratio and smoothness index. However lercanidipine showed a better tolerability profile than amlodipine, with fewer adverse events and a lower percentage of patients suffering from side effects.. Lercanidipine is as effective as amlodipine in the reduction and stabilization of BP in hypertensive patients after a stroke, and presents some advantages in terms of safety. Larger studies are necessary to further evaluate these preliminary findings.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Brain Ischemia; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Stroke; Treatment Outcome

Current guidelines recommend the use of multiple medications for hypertension. The present study was aimed at determining which combination was optimal to prevent cardiovascular events.. We conducted a prospective, randomized, open-label, blinded-endpoint trial. Hypertensive outpatients aged between 40 and 85 years who did not achieve target blood pressure (BP<140/90 mmHg) with calcium channel blocker (CCB) benidipine 4 mg/day were randomly assigned to receive angiotensin receptor blocker (ARB), β-blocker, or thiazide diuretic in addition to benidipine.. Among a total of 3501 patients (1167, benidipine-ARB; 1166, benidipine-β-blocker; and 1168, benidipine-thiazide), 3293 patients (1110, 1089, and 1094, respectively) who received each combination treatment were included in the analysis. Median follow-up was 3.61 years. At the end of the treatment, 64.1, 66.9, and 66.0% of patients in the benidipine-ARB, benidipine-β-blocker, and benidipine-thiazide groups achieved target BP, respectively. The cardiovascular composite endpoint occurred in 41 (3.7%), 48 (4.4%), and 32 (2.9%) patients, respectively: the hazard ratio was 1.26 in the benidipine-ARB (P  = 0.3505) and 1.54 in the benidipine-β-blocker (P = 0.0567) groups compared with the benidipine-thiazide group. The secondary analyses revealed that benidipine and thiazide diuretic significantly reduced the incidence of fatal or nonfatal strokes (P = 0.0109) and benidipine and ARB significantly reduced new-onset diabetes (P = 0.0240) compared with benidipine and β-blocker. All trial treatments were safe and well tolerated.. CCB combined with ARB, β-blocker, or thiazide diuretic was similarly effective for the prevention of cardiovascular events and the achievement of target BP.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Risk Factors; Single-Blind Method; Sodium Chloride Symporter Inhibitors; Stroke; Treatment Outcome

Azelnidipine, a long-acting calcium channel blocker, is highly lipid soluble and selective for the vascular wall, and is expected to have an increasing effect on cerebral blood flow (CBF). The aim of this study is to investigate its safety and efficacy in stroke patients in the chronic stage as far as CBF is concerned using N-isopropyl-p-(123)I-iodo amphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). The patients were orally administered 8 or 16 mg of azelnidipine. Regional CBF was evaluated by (123)I-IMP SPECT using three-dimensional stereotactic region-of-interest (ROI) template (3D-SRT), a technique using anatomical standardization and ROI template consisting of 636 ROIs for the whole brain. Mean hemispheric CBF was defined as the mean value of the corpus callosum, and the precentral, central, parietal, angular and temporal gyri. Mean hemispheric and regional CBF after 1, 3 and 6 months were analyzed using a one-way repeated-measures analysis of variance. Ten post-ischemic stroke patients with hypertension were enrolled between October 2005 and October 2007, and all of them were well controlled with normal blood pressure (before: 172.3+/-16.6/88.4+/-14.0 mm Hg; 6 months: 128.7+/-15.9/70.9+/-10.1 mm Hg). No vascular events were observed during the study period. The mean hemispheric CBF was maintained during the study period (before: 46.0+/-9.7 ml per 100 g per min; 6 months: 49.3+/-11.1 ml per 100 g per min). The regional CBF was also maintained. In the chronic stage of ischemic stroke, azelnidipine could safely decrease systemic blood pressure without decreasing CBF.

Topics: Aged; Azetidinecarboxylic Acid; Blood Pressure; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Cerebrovascular Circulation; Dihydropyridines; Female; Follow-Up Studies; Functional Laterality; Heart Rate; Humans; Hypertension; Image Processing, Computer-Assisted; Iofetamine; Male; Middle Aged; Prospective Studies; Radiopharmaceuticals; Stroke; Tomography, Emission-Computed, Single-Photon

Topics: Angiotensin II Type 1 Receptor Blockers; Apoptosis; Blood Pressure; Calcium; Cardiovascular Diseases; Dihydropyridines; Humans; Prevalence; Recurrence; Risk; Stroke; Time Factors; Treatment Outcome

To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years.. The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up.. Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively.. Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus; Dihydropyridines; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Enalapril; Europe; Female; Follow-Up Studies; Heart Failure; Humans; Hydrochlorothiazide; Hypertension; Incidence; Linear Models; Male; Myocardial Infarction; Nitrendipine; Stroke; Survival Rate; Time Factors; Treatment Outcome

The long-acting calcium antagonist nifedipine reduces the incidence of stroke in Eastern Asia, as shown by the Shanghai Trial Of Nifedipine in the Elderly (STONE) and the Systolic Hypertension in China (Syst-China) trials. Recent trials in Japan have shown that benidipine may be more efficient than the former drug in preventing strokes in the elderly. Benidipine, commonly prescribed in Japan for a definite depressor effect, reportedly without causing remarkable fluctuations in blood pressure (BP), is investigated herein from a chronobiological viewpoint. Eighteen subjects (nine women and nine men, 39 to 87 years of age) with essential hypertension (office and ambulatory systolic, S/diastolic, D BP values above 160/95 mm Hg and 130/80 mm Hg, respectively) were enrolled in this investigation. Ambulatory BP was monitored at 30-min intervals for at least 24 h (ABPM-630, Colin Medical) before and after 4 weeks of crossover treatment with nifedipine tablets (twice daily, 20 mg/d) and benidipine (once daily, 4 mg/d, in the morning). The results indicate that: 1) benidipine and nifedipine reduce 24-h daytime (10:00-20:00) and nighttime (00:00-06:00) averages of SBP and DBP (P < 0.001); 2) the circadian double amplitude of BP is decreased after treatment with benidipine (from 28.6 to 21.1 mm Hg SBP and from 19.7 to 15.2 mm Hg DBP; P< 0.05), while the day-night difference in SBP is increased after treatment with nifedipine (18.6 vs 27.9 mm Hg, P< 0.01); and 3) the increase in the day-night difference of heart rate (HR) is significant after treatment with benidipine (13.6 vs 18.8 beats per minute, bpm; P< 0.05), but not with nifedipine. We have previously evaluated the usefulness of the circadian amplitude of BP as a prognostic tool of cardiovascular outcome, and found that an excessive circadian SBP or DBP amplitude was associated with an increased risk of vascular disease. The fact that benidipine reduces the circadian BP amplitude may be one reason for the superiority of this treatment over nifedipine in preventing an adverse outcome. A reduced heart rate variability (HRV) also predicts adverse cardiovascular outcomes in patients with overt cardiovascular disease and in hypertensive subjects. The fact that benidipine increases the day-night difference in HR may be another reason for the positive effects of this treatment.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Calcium Channel Blockers; Chronotherapy; Circadian Rhythm; Cross-Over Studies; Dihydropyridines; Electrocardiography, Ambulatory; Female; Humans; Male; Middle Aged; Nifedipine; Stroke

Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor (ACE-I), delapril (Adecut) or a long-acting calcium (Ca)-antagonist, manidipine (Calslot) for 3 years. The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients. There were no significant differences in characteristics of patients between the two intervention groups, except for slightly lower blood pressure (P = .08) in the Ca-antagonist group at the initiation of the study. There were no significant differences in total death between the two groups. Cardiovascular events (both fatal and nonfatal) were noted in 34 of 699 patients (22.5/1000 patient-years) in the ACE-I group and 50 of 1049 patients (19.7/1000 patient-years) in the Ca-antagonist group, with no significant difference found between the two groups. The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure (SBP) is unnecessary and may be harmful in certain cases. Side effects were more frequent in the ACE-I group than in the Ca-antagonist group (P = .01). Cough was the major adverse event, occurring in 5.0% of patients in the ACE-I group. In conclusion, the study indicates that both ACE-I (delapril) and Ca-antagonist (manidipine) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients. However, tolerability of ACE-I was lower due to the adverse event of coughing.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Delayed-Action Preparations; Dihydropyridines; Female; Humans; Hypertension; Incidence; Indans; Japan; Male; Nitrobenzenes; Piperazines; Prospective Studies; Safety; Stroke; Survival Rate

Outside of clinical trials, the prophylactic effect of dihydropyridine calcium channel blockers (CCBs) on ischemic events in patients with nonvalvular atrial fibrillation (NVAF) has not been confirmed. We compared the effect of dihydropyridine CCBs on ischemic events in anticoagulated NVAF patients. We conducted a multicenter historical cohort study at 71 centers in Japan. The inclusion criterion was taking vitamin K antagonists for NVAF. The exclusion criteria were mechanical heart valves and a history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The primary outcomes were ischemic events and ischemic strokes; the secondary outcomes were all-cause mortality, major bleeding, and hemorrhagic strokes. The mean patient age was 73 years old, and 67% of the patients were male. Seventy-eight percent of the patients had hypertension, and dihydropyridine CCBs were used by 2693 (34%) patients (CCB group). The cumulative incidences of ischemic events and ischemic strokes at 4 years in the CCB and No-CCB groups were 5.9% vs. 5.2% and 5.6% vs. 4.8%, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the CCB group for ischemic events and ischemic strokes were 1.22 (0.95-1.57) and 1.32 (1.02-1.71), respectively; the adjusted HRs (95% CIs) of the CCB group for all-cause mortality, major bleeding, and hemorrhagic strokes were 0.85 (0.69-1.04), 1.12 (0.92-1.35), and 1.08 (0.62-1.88), respectively. Dihydropyridine CCB use by anticoagulated NVAF patients significantly increased ischemic strokes in a real-world setting.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Female; Hemorrhage; Hemorrhagic Stroke; Humans; Ischemic Stroke; Male; Stroke

The purpose of this study was to identify the differences in the types of strokes seen in patients receiving intravitreal anti-vascular endothelial growth factor (VEGF) compared with normal control populations.. We performed a retrospective consecutive review of all patients receiving intravitreal anti-VEGF injections in Olmsted County, Minnesota, from January 1, 2004, to December 31, 2013, for exudative age-related macular degeneration (AMD), diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), or retinal vein occlusion (RVO). A 2-year follow-up period was required for study inclusion. Three age- and sex-matched cohorts were identified.. A total of 2,541 patients were examined. There were 690 patients identified during the study period as receiving an intravitreal injection for AMD, DME, PDR, or RVO. Of these patients, 38 (5.8%) suffered a stroke after starting intravitreal injection therapy. Of these strokes, 27 (71.1%) were ischemic, six (15.8%) were embolic, and five (13.2%) were hemorrhagic. There were no differences in the types of strokes identified among the patients receiving intravitreal injections between the case cohort and the control cohorts (P > .05 for all).. The authors' data suggest there is no predilection to the development of ischemic infarcts or hemorrhagic strokes in those patients receiving intravitreal anti-VEGF compared with control populations. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e140-e157.].

Topics: Aged; Angiogenesis Inhibitors; Aptamers, Nucleotide; Bevacizumab; Dihydropyridines; Female; Follow-Up Studies; Humans; Intravitreal Injections; Male; Middle Aged; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retinal Diseases; Retrospective Studies; Stroke; Vascular Endothelial Growth Factor A

Although several antihypertensive agents reduced the carotid intima-media thickness (IMT), it remains unclear whether those agents affect the interadventitial diameter (IAD). We aimed to examine whether cilnidipine, an L/N-type calcium channel blocker, reduced the common carotid IMT or IAD in post-stroke hypertensive patients.. The common carotid IMT and IAD were measured at the start of cilnidipine treatment and 12 months from that. The changes in the mean max-IMT or IAD between baseline and the 12-month follow-up were evaluated and compared between the thick group (max-IMT ≥1.1 mm) and the normal group (max-IMT ＜1.1 mm).. A total of 603 post-stroke hypertensive subjects (mean age=69.3 yr, 378 males) were included in the analysis. At baseline, IAD was increased stepwise according to the value of max-IMT (p for trend ＜0.001). Among them, 326 subjects were followed up for 12 months. The mean max-IMT from baseline to 12 months did not change in the normal group (－0.01 mm, 95% confidence interval [CI] －0.03 to 0.01, n=170), whereas a significant reduction was observed in the thick group (－0.09 mm, 95% CI －0.13 to －0.05, n=156). The mean IAD was significantly reduced during the study period in the normal group (－0.14 mm, 95% CI －0.22 to －0.05) as well as in the thick group (－0.12 mm, 95% CI －0.21 to －0.03).. Cilnidipine promoted the regression of common carotid IMT in post-stroke hypertensive patients, especially in the thick group. Cilnidipine also reduced the IAD in both normal and thick groups.

Topics: Aged; Antihypertensive Agents; Calcium Channel Blockers; Calcium Channels, L-Type; Carotid Artery Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Dihydropyridines; Female; Follow-Up Studies; Humans; Hypertension; Male; Prognosis; Stroke

Blood pressure control is important in post-stroke hypertensive patients and antihypertensive treatment is recommended for such patients. Ca-channel blockers are recommended as the medications of choice for the treatment of post-stroke patients. Here, we report the results of a large-scale prospective post-marketing surveillance study of post-stroke hypertensive patients (n = 2667, male 60.4%, 69.0 ± 10.9 years) treated with cilnidipine, with regard to blood pressure control and adverse reactions. Cilnidipine treatment caused a decrease in both clinic and home blood pressures 2 months after the beginning of treatment, and the decreased blood pressure was maintained until the end of 12 months' observation. The proportion of patients in whom clinic blood pressure was well controlled (<140/90 mmHg) increased from 21.5% to 65.3% in cilnidipine treatment, with no differences in effectiveness among the various clinical subtypes of stroke. In total, 346 adverse events occurred, with an overall incidence of 8.9% (238 of 2667 patients). In the elderly group, specifically, a fall and a hip fracture each occurred in 1 (0.1%) patient. These results indicate that cilnidipine was effective in treating uncontrolled blood pressure and was well tolerated in Japanese post-stroke hypertensive patients in a real-world clinical setting.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Stroke

Calcium channel blockers (CCBs) have been proved to have beneficial effects on cardiovascular (CV) outcomes, especially in stroke. Lercanidipine, a highly lipophilic CCB, lacks data regarding long-term outcomes including: CV, stroke, renal and all-cause mortality. This retrospective cohort study aims to clarify this.. A total of 144,630 newly diagnosed hypertension (HTN) patients (age: 18-65 years) in 2005 from the Taiwan's National Health Insurance Research Database were enrolled in this observational study. A pure hypertension population was fetched by excluding all chronic diseases in the Charlson Comorbidities Index. Patients were stratified into the lercanidipine group (n = 1303) and the propensity-score-matched comparative group (nifedipine, amlodipine or felodipine, n = 15,301).. Compared to other CCBs, lercanidipine didn't have a significant difference on the study endpoints. In individual head-to-head comparisons, lercanidipine was shown to be superior to nifedipine in incident stroke with an adjusted HR with 95% CI of 0.526 (0.347-0.797) (p = .0025). The key limitations were that personal variables, such as smoking habits, alcohol intake, body mass index and physical activity and blood pressure profiles were not available in the nationwide registry database.. In newly diagnosed patients with hypertension, lercanidipine was superior to nifedipine in the six-year period when the analyzed endpoint was stroke.

Topics: Adolescent; Adult; Aged; Amlodipine; Blood Pressure; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Felodipine; Female; Humans; Hypertension; Male; Middle Aged; Retrospective Studies; Stroke; Taiwan; Young Adult

The ischemic stroke cascade is composed of several pathophysiological events, providing multiple targets for pharmacological intervention. JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-4,11-dihydro-1H-pyrido[2,3-b][1,5]benzodiazepine) is a novel hybrid molecule, in which a benzodiazepine portion is covalently linked to a dihydropyridine ring, forming a new chemical entity with potential multisite neuroprotective activity. In the present study, JM-20 prevented PC-12 cell death induced either by glutamate, hydrogen peroxide or KCN-mediated chemical hypoxia. This molecule also protected cerebellar granule neurons from glutamate or glutamate plus pentylenetetrazole-induced damage at very low micromolar concentrations. In rat liver mitochondria, JM-20, at low micromolar concentrations, prevented the Ca2+-induced mitochondrial permeability transition, as assessed by mitochondrial swelling, membrane potential dissipation and organelle release of the pro-apoptotic protein cytochrome c. JM-20 also inhibited the mitochondrial hydrolytic activity of F1F0-ATP synthase and Ca2+ influx. Therefore, JM-20 may be a multi-target neuroprotective agent, promoting reductions in neuronal excitotoxic injury and the protection of the mitochondria from Ca2+-induced impairment as well as the preservation of cellular energy balance.

Topics: Animals; Benzodiazepines; Brain Ischemia; Calcium; Cell Death; Cerebellum; Cytochromes c; Dihydropyridines; Glutamic Acid; Hydrogen Peroxide; Hydrolysis; Liver; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Proton-Translocating ATPases; Mitochondrial Swelling; Neurons; Neuroprotective Agents; Niacin; Oxidative Stress; PC12 Cells; Pentylenetetrazole; Phosphates; Potassium Cyanide; Rats; Stroke

An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

Topics: Age Factors; Animals; Azetidinecarboxylic Acid; Blood Pressure; Brain Injuries; Chemokine CCL2; Collagen Type IV; Dihydropyridines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation; Heart Rate; Imidazoles; Laser-Doppler Flowmetry; Male; Matrix Metalloproteinase 9; Motor Activity; Oxidative Stress; Rats; Rats, Inbred SHR; Stroke; Tetrazoles

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Brain Ischemia; Dihydropyridines; Diuretics; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Risk Factors; Stroke; Survival Analysis; Vasodilator Agents

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Combined Modality Therapy; Dihydropyridines; Drug Combinations; Enalapril; Humans; Hypertension; Physical Fitness; Stroke

Ischemic stroke may initiate a reperfusion injury leading to brain damage cascades where inflammatory mechanisms play a major role. Therefore, the necessity for the novel stroke-protecting agents whose the mechanism of action is focused on their anti-inflammatory potency is still on the agenda for drug designers. Our previous studies demonstrated that cerebrocrast (a 1,4-dihydropyridine derivative) and mildronate (a representative of the aza-butyrobetaine class) possessed considerable anti-inflammatory and neuroprotective properties in different in vitro and in vivo model systems. The present study investigated their stroke-protecting ability in an endothelin-1 (ET-1)-induced ischemic stroke model in rats.. Male Wistar rats were pretreated (for 7 days, per os) with cerebrocrast (0.1 mg/kg), mildronate (100 mg/kg), or their combination, followed by the intracerebral injection of ET-1. Functional and behavioral tests were carried out up to 14 days after the ET-1 injection. Ex vivo, the number of degenerated neurons and the infarction size in the cerebral cortical tissue were assessed histologically.. Cerebrocrast and mildronate effectively normalized ET-1-induced disturbances in neurological status, improved the muscle tone, and decreased the number of degenerated cortical cells. Both drugs also reduced the infarction size, and cerebrocrast showed at least a 2-fold higher activity than mildronate. The combination of both drugs did not cause a more pronounced effect in comparison with the action of drugs administered separately.. The 1,4-dihydropyridine and aza-butyrobetaine structures may serve for the design of novel stroke-protecting agents to prevent severe neurological poststroke consequences.

Topics: Animals; Dihydropyridines; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Endothelin-1; Male; Methylhydrazines; Neuroprotective Agents; Rats; Rats, Wistar; Stroke

Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion-induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension.

Topics: Animals; Antihypertensive Agents; Calcium Channel Blockers; Cell Death; Dihydropyridines; Hippocampus; Ischemia; Neurons; Pyramidal Cells; Rats; Rats, Inbred SHR; Stroke

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Calcium Channel Blockers; Dihydropyridines; Female; Humans; Hypertension; Male; Sodium Chloride Symporter Inhibitors; Stroke

Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

Topics: Animals; Azetidinecarboxylic Acid; Biliverdine; Brain Ischemia; Dihydropyridines; Free Radical Scavengers; Granulocyte Colony-Stimulating Factor; Neuroprotective Agents; Rats; Stem Cells; Stroke; Tissue Scaffolds

Calcium channel blockers (CCBs) have been reported to reduce the incidence of stroke in hypertensive patients. CCBs are also commonly used to treat patients with angina pectoris (AP). However, there are very few reports on their effects on cardiovascular events, including stroke and end-stage renal disease (ESRD), in patients with AP. This study was designed to assess the differences among CCBs regarding the occurrence of cardiovascular events in patients with AP.. Clinical records of 226 patients with AP who had received treatment with CCBs in hospital from January 1, 1993 to December 31, 2006 were reviwed. The influence of patient characteristics and medication on the occurrence of cardiovascular events was evaluated (median follow-up period: 4.4 years). Of these 226 patients, 155 were treated with benldipine (CAS 91599-74-5), 36 with diltiazem (CAS 33286-22-5), and 35 were treated with nifedipine (CAS 21629-25-4).. Cox proportional hazard regression analysis showed that benidipine was the only CCB that significantly reduced the occurrence of cardiovascular events (HR = 0.39, p < 0.05). Benidipine treatment was associated with higher cardiovascular- and cardiac event-free rates than diltiazem treatment, and higher stroke- and ESRD-free rates than nifedipine.. This study demonstrated that benidipine prevents the occurrence of cardiovascular events in patients with AP, suggesting that benidipine contributes to a favorable long-term prognosis of such patients.

Topics: Aged; Angina Pectoris; Calcium Channel Blockers; Dihydropyridines; Diltiazem; Female; Heart Diseases; Humans; Kidney Failure, Chronic; Male; Nifedipine; Prognosis; Proportional Hazards Models; Retrospective Studies; Stroke; Treatment Outcome

The long-acting dihydropyridine calcium channel blocker, azelnidipine, is suggested to inhibit sympathetic nerve activity. We previously demonstrated that oxidative stress in the rostral ventrolateral medulla (RVLM) activates sympathetic nerve activity. The aim of the present study was to determine whether oral administration of azelnidipine inhibits sympathetic nerve activity and if so to determine whether the effect is mediated by antioxidant effect in the RVLM. Azelnidipine, hydralazine, or vehicle was orally administered for 28 days to stroke-prone spontaneously hypertensive rats. Reductions in systolic blood pressure were similar in azelnidipine and hydralazine groups. Heart rate was significantly higher in the hydralazine group than in the control, but not altered in the azelnidipine group. Urinary norepinephrine excretion as an indicator of sympathetic nerve activity was significantly lower in the azelnidipine group, whereas it was significantly higher in the hydralazine group than in the control. Levels of thiobarbituric acid-reactive substances and nicotinamide adenine dinucleotide phosphate oxidase activity were significantly lower in the azelnidipine group than in control. Superoxide dismutase activity was significantly increased in the azelnidipine group more than in the control. These results suggest that azelnidipine decreases an indicator of sympathetic nerve activity by antioxidant effect mediated through inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity and activation of superoxide dismutase in the RVLM of stroke-prone spontaneously hypertensive rats.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; Heart Rate; Hydralazine; Hypertension; Male; Medulla Oblongata; NADPH Oxidases; Norepinephrine; Oxidative Stress; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Superoxide Dismutase; Sympathetic Nervous System; Thiobarbituric Acid Reactive Substances

Oxidative stress is associated with exacerbation of renal injuries in hypertension. In clinical studies benidipine hydrochloride (benidipine), a dihydropyridine calcium channel blocker with antioxidant activity, reduced oxidative stress. However, the mechanism of suppression of oxidative stress remains to be fully characterized. Reactive oxygen species production by polymorphonuclear leukocyte plays important pathological roles in hypertension. Therefore, we examined the effects of benidipine both on reactive oxygen species production of human polymorphonuclear leukocytes and oxidative stress of an animal model. Human peripheral polymorphonuclear leukocytes or polymorphonuclear leukocyte-like differentiated HL-60 cells were used to examine effects of benidipine (0.1-30 microM) on formyl-Met-Leu-Phe-induced reactive oxygen species production, calcium mobilization, NADPH oxidase activation and phosphorylation of protein kinase C substrates. High-salt (8% NaCl) loaded stroke-prone spontaneously hypertensive rats were treated with or without benidipine (1, 3, 10 mg/kg/day) for 2 weeks, and thiobarbituric acid reactive substances, a plasma oxidative stress marker, and renal expression of oxidative stress-induced genes were measured. Benidipine concentration-dependently suppressed formyl-Met-Leu-Phe-induced reactive oxygen species production in polymorphonuclear leukocytes more potently than other calcium channel blockers such as amlodipine, azelnidipine, nitrendipine and nifedipine. Benidipine partially inhibited all of intracellular Ca(2+) elevation, protein kinase C activation and NADPH oxidase activation. Salt loading in stroke-prone spontaneously hypertensive rats augmented plasma thiobarbituric acid reactive substances levels; renal dysfunction; and renal expression of transforming growth factor-beta, collagen I and collagen III mRNAs; which were attenuated by benidipine treatment. These results indicate that benidipine prevents the polymorphonuclear leukocyte-derived reactive oxygen species production, which is due at least in part to its antioxidant action and inhibition of Ca(2+)/protein kinase C/NADPH oxidase signaling. The attenuation of reactive oxygen species production might contribute to the drug's reduction of oxidative stress and renal injuries in hypertension.

Topics: Animals; Antioxidants; Calcium; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; HL-60 Cells; Humans; Hypertension; Male; NADP; Neutrophils; Oxidative Stress; Rats; Rats, Inbred SHR; Reactive Oxygen Species; Sodium Chloride, Dietary; Stroke

Changes in myocardial expression of Na+/K+-ATPase alpha-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with 1 mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [3H]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with Kd approximately 25 and approximately 200 nM, ascribed to the alpha3 and alpha2 isoforms, respectively. Bmax of alpha3 was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, Bmax of alpha2 was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a Bmax reduction of 20% (P<0.05), an effect blocked by lacidipine. These effects were largely confirmed by immunoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous alpha1 isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na+/K+-ATPase alpha3 subunit, which was not found in SHRSP; the level of the alpha2 isoform was similar in untreated SHRSP and WKY; salt-loading of SHRSP promoted reduction of the alpha2 isoform, and this effect was completely hampered by lacidipine.

Topics: Animals; Calcium Channel Blockers; Cardiomegaly; Dihydropyridines; Heart Ventricles; Hypertension; Isoenzymes; Male; Ouabain; Protein Subunits; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Chloride, Dietary; Sodium-Potassium-Exchanging ATPase; Stroke

Topics: Aged; Antihypertensive Agents; Blood Pressure; Dihydropyridines; Felodipine; Female; Heart Rate; Humans; Hypertension; Male; Middle Aged; Stroke

Topics: Aged; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Europe; Follow-Up Studies; Humans; Hypertension; Randomized Controlled Trials as Topic; Stroke; Survival Rate

The molecular mechanism of glomerular injury in hypertension remains to be clarified. In this study, to examine the possible role of platelet-derived growth factor (PDGF) receptors in hypertensive glomerular injury, we specifically measured glomerular PDGF receptor tyrosine phosphorylation in various models of hypertensive rats using immunoprecipitation and Western blot analysis. A high-salt diet significantly enhanced glomerular PDGF beta-receptor tyrosine phosphorylation of Dahl-salt sensitive rats (DS-rats) without an increase in its protein levels, and this enhancement was associated with an elevation of blood pressure and glomerular injury. Stroke-prone spontaneously hypertensive rats (SHRSP) at hypertensive phase also had higher glomerular PDGF beta-receptor tyrosine phosphorylation levels than control Wistar-Kyoto rats (WKY), while SHR did not. Thus, DS-rats and SHRSP, which are well known to represent severe glomerular injury, had the enhanced PDGF beta-receptor tyrosine phosphorylation, while SHR, a hypertensive model without significant glomerular injury had no increased tyrosine phosphorylation. Treatment of DS-rats or SHRSP with benidipine, a calcium channel blocker, significantly lessened the increase in glomerular PDGF beta-receptor tyrosine phosphorylation, reduction of urinary protein and albumin excretion. These results suggest that the enhanced activation of glomerular PDGF beta-receptors may be responsible for the development of hypertensive glomerular injury and that the suppression of this receptor activation by a calcium channel blocker may contribute to its renal protective effects.

Topics: Albuminuria; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Genetic Predisposition to Disease; Hypertension; Kidney Glomerulus; Male; Phosphorylation; Proteinuria; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Platelet-Derived Growth Factor beta; Stroke; Tyrosine