Efficacy and safety of a combination antihypertensive drug (olmesartan plus azelnidipine): "Issues with hypertension studies in real-world practice".

Background: This study investigated whether a combination drug containing an angiotensin II receptor blocker (ARB) and a calcium channel blocker (CCB) could provide effective antihypertensive therapy.Methods: A multicenter, prospective, open-label study was conducted at the clinics of Clinical Research Network. The subjects had uncontrolled blood pressure (BP) despite ARB or CCB monotherapy. The effect on both office and home BP was examined after patients switched to a combination drug (REZ: containing 20 mg of olmesartan [OL] and 16 mg of azelnidipine [AZ]).Results: A total of 78 patients were enrolled. After switching to REZ, a significant and sustained reduction of office BP was observed. The proportion of patients who achieved the target for both office and home BP was an increase from 0% to 55%. Switching from amlodipine to REZ resulted in a significant and sustained decrease of office and home BP. There was also a significant decrease of home pulse rate (PR), but office PR was unchanged. To determine the accuracy of the BP and PR values reported by patients, the frequency of each number as the first digit was determined. The frequency of "0" was extremely high for both office and home BP values, and the same was noted for home PR values.Conclusion: The results of this study suggested that switching from a single drug to combination therapy with REZ could achieve a stronger antihypertensive effect. However, concern was raised regarding the methods of BP and PR measurement and recording in this clinical trial involving general practitioners.

Comparison of Azelnidipine and Trichlormethiazide in Japanese Type 2 Diabetic Patients with Hypertension: The COAT Randomized Controlled Trial.

OBJECTIVE: This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. METHODS: In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. RESULTS: Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. CONCLUSIONS: Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension. TRIAL REGISTRATION: UMIN 000006081.

Olmesartan medoxomil and azelnidipine therapy in patients with hypertension and chronic kidney disease in Japan.

BACKGROUND: In the present investigation we extracted data on hypertensive patients with chronic kidney disease (CKD) who were enrolled in 3 studies - 2 studies of the angiotensin receptor blocker (ARB) olmesartan medoxomil (OLM), lasting 12 weeks and 2 years, respectively, and one of the calcium channel blocker (CCB) azelnidipine (AZ) lasting 12 weeks - to assess the effects of OLM and AZ on blood pressure (BP), estimated glomerular filtration rate (eGFR) and proteinuria in hypertensive patients with CKD in the setting of daily clinical practice. METHODS: The 3 studies followed open prospective cohort designs that represented daily clinical practice in Japan. Patients with CKD at baseline were selected. Change of BP, eGFR and proteinuria on OLM therapy or AZ therapy were analyzed. RESULTS: At 12 weeks, OLM (n=1,317) and AZ (n=952) therapies exhibited similar BP-lowering effects. AZ led to a significantly (p=0.0069) greater increase of eGFR compared with OLM, while OLM tended to improve proteinuria to a greater extent than AZ. Treatment with OLM for 2 years (n=109) significantly improved proteinuria but did not alter eGFR. CONCLUSION: This study shows that OLM and AZ reduced BP and proteinuria without decreasing eGFR in Japanese hypertensive patients with CKD in the setting of daily clinical practice.

Azelnidipine-induced chyloperitoneum in a patient with microscopic polyangiitis.

A 76-year-old man developed fever and appetite loss, and then was referred to our hospital because of rapidly progressive renal insufficiency; his serum creatinine increased from 1.2 to 5.9 mg/dl within 1 month. On admission, his blood pressure was 166/92 mmHg, and laboratory findings showed signs of inflammation, anemia, proteinuria, and hematuria. Chest computed tomography (CT) suggested interstitial pneumonia, while a renal biopsy revealed that small arteries and arterioles were affected, and there was pauci-immune glomerulonephritis with cellular and fibrocellular crescents. In addition, an increased myeloperoxidase antineutrophil cytoplasmic antibody titer confirmed microscopic polyangiitis. Treatment with oral prednisolone was initiated and seemed to successfully resolve the vasculitis activity. On the 11th day of admission, a calcium channel blocker, azelnidipine, was added to treat hypertension. Two days later, the patient developed abdominal distension, and abdominal CT showed massive ascites. The ascitic fluid was a milky white transudate with a normal leukocyte count. Neither clinical manifestations nor laboratory findings suggestive of liver cirrhosis, malignancy, infectious peritonitis, or bowel perforation were observed. On the 18th day of admission, azelnidipine was discontinued in view of reports of calcium channel blocker-induced chyloperitoneum in patients undergoing peritoneal dialysis. Immediately, the abdominal distension disappeared, and the ascites appeared to decrease. Azelnidipine appears to have been responsible for the chyloperitoneum. Since a few cases of secondary vasculitis developing chyloperitoneum have been previously reported, vasculitis may have played a role in the development of chyloperitoneum.

A randomized, double-blind, four-arm parallel-group study of the efficacy and safety of azelnidipine and olmesartan medoxomil combination therapy compared with each monotherapy in Japanese patients with essential hypertension: the REZALT study.

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.

Azelnidipine and amlodipine anti-coronary atherosclerosis trial in hypertensive patients undergoing coronary intervention by serial volumetric intravascular ultrasound analysis in Juntendo university (ALPS-J).

PURPOSE: Many trials have shown that calcium channel blockers (CCBs) can reduce the cardiovascular (CV) events in patients with coronary artery disease (CAD). The mechanisms of this effect could be associated with plaque regression due to the anti-atherosclerotic properties of CCBs. The goal of this study is to determine the effects of CCB on volumetric quantitative changes of coronary plaques accessed by intravascular ultrasound (IVUS). To confirm this hypothesis, a multicenter randomized trial of CCBs treatment with azelnidipine or amlodipine will be conducted in hypertensive CAD patients undergoing elective percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients who have hypertension and are scheduled for PCI will be enrolled. Subjects will be randomized to azelnidipine or amlodipine and observed for 48 weeks. The primary endpoint will be the percent change of coronary plaque volume. The secondary endpoint will include inflammatory markers, antioxidant activity, and incidence of composite cardiovascular events. CONCLUSIONS: In this study, we will investigate the improvement of coronary plaque with IVUS by treatment with two dihydropyridine CCBs in hypertensive patients undergoing elective PCI. This result will lead to the discovery of more effective drug therapy for inhibition of coronary events.

In half of hypertensive diabetics, co-administration of a calcium channel blocker and an angiotensin-converting enzyme inhibitor achieved a target blood pressure of <130/80 mmHg: the azelnidipine and temocapril in hypertensive patients with type 2 diabetes (ATTEST) study.

We conducted a multicenter, randomized, open-label, ascending dose study to investigate the efficacy and safety of combination therapy using the calcium channel blocker azelnidipine and angiotensin-converting enzyme (ACE) inhibitor temocapril in hypertensive diabetics. Patients received monotherapy with 8 mg azelnidipine (group A, n=112) or 2 mg temocapril (group T, n=111) for 4 weeks. If the target blood pressure (<130/80 mmHg) was not achieved, doses were doubled. If it was still not achieved, both drugs were coadministered at week 8, and, if needed, another antihypertensive drug was added after week 16. The treatment period was 52 weeks. Blood pressure was decreased significantly beginning at week 8 (p<0.0001 in both groups), and the systolic and diastolic blood pressure at the end of the treatment period was 128.2+/-11.1/76.4+/-8.1 mmHg. Overall, 53.8% (113/210) of patients achieved the target blood pressure by the end of the study. The effect during the monotherapy period (through week 8) was greater in group A than in group T (systolic, p=0.0475; diastolic, p=0.0001). Laboratory tests showed significant decreases in the urine albumin:creatinine ratio (p=0.0006), high-sensitivity C-reactive protein concentration (p=0.0073), and urine 8-isoprostane concentration (p=0.0215) at the end of the treatment period, as compared with baseline values. No adverse events caused safety problems. In conclusion, combination therapy using azelnidipine and temocapril is an effective treatment for hypertensive diabetics.

Misincorporation of the proline analog azetidine-2-carboxylic acid in the pathogenesis of multiple sclerosis: a hypothesis.

The misconstruction of proteins as a result of the displacement of one of more proline residues by their congener, azetidine-2-carboxylic acid (Aze), can result in various disorders. A number of lines of evidence suggest that multiple sclerosis may be among these. This concept adheres to the current view that multiple sclerosis lesions originate in the myelin sheath and that the underlying molecular abnormality involves the myelin basic protein. The Aze hypothesis posits that myelin basic protein and possibly other closely related molecules are misassembled in sites of lesion formation because of the substitution of Aze for one or more prolines within consensual epitopes. These include a highly conserved myelin basic protein hexapeptide sequence, PRTPPP, and an alpha helix bounded by prolyls. Recent studies have focused on the immunopathogenetic effects of posttranslational modification of this region. This hypothesis proposes that the domain is structurally, functionally, and antigenically altered by the intrusion of Aze in place of proline and that such misassembly may involve other proteins and adversely affect interactions with neighboring molecules. This report reviews evidence supporting the hypothesis that ingestion of Aze in the diet, in conjunction with genetic susceptibility, may predispose or contribute to the pathogenesis of multiple sclerosis.

Clinical study with azelnidipine in patients with essential hypertension. Antiarteriosclerotic and cardiac hypertrophy-inhibitory effects and influence on autonomic nervous activity.

A dihydropyridine calcium (Ca) antagonist, azelnidipine (CAS 123524-52-7, Calblock), exhibits hypotensive effects for a prolonged duration, and has been reported to have a strong antiarteriosclerotic action due to its high affinity for vascular tissues and antioxidative action. It has also been reported that azelnidipine does not cause tachycardia associated with the baroreceptor reflex due to vasodilatation. In this study, the antiarteriosclerotic and cardiac hypertrophy-inhibitory effects, and the autonomic nervous activity in essential hypertension of azelnidipine were investigated. The study was performed using the following 2 protocols: 1) Pulse wave velocity (PWV), carotid arterial intima media thickness (IMT), echocardiography, high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), adiponectin, brain natriuretic peptide (BNP), and 8-isoprostane were measured after an initial treatment with azelnidipine. 2) The treatment was switched to azelnidipine in patients who had previously been under treatment with amlodipine for essential hypertension, and 123I-metaiodobenzylguanidine myocardial scintigraphy (123I-MIBG), measurements of plasma norepinephrine, atrial natriuretic peptide (ANP), and BNP, Holter electrocardiography, and heart rate variability analysis were performed. PWV, IMT, hs-CRP, IL-6, and TNF-alpha significantly decreased. The levels of 8-isoprostane, an antioxidative marker, were also significantly decreased, while adioponectin levels were significantly increased after the initial treatment with azelnidipine. After switching from amlodipine, azelnidipine exhibited a hypotensive effects comparable to amlodipine, and significantly decreased heart rate and the total number of extrasystoles. Noradrenaline levels and the LF/HF ratio were significantly decreased, and the washout rate was significantly reduced on 123I-MIBG myocardial scintigraphy. These findings suggest that azelnidipine inhibits the enhancement of sympathetic nervous activity and the progression of arteriosclerosis through its antioxidative effects.

Azelnidipine.

Azelnidipine is a new dihydropyridine calcium channel antagonist with selectivity for L-type calcium channels that has recently been approved in Japan for the treatment of patients with hypertension. Results from clinical trials showed that, in 95 patients with mild-to-moderate hypertension, long-term treatment with azelnidipine effectively controls blood pressure (BP). The mean reduction from baseline in sitting systolic/diastolic BP after 1 year of treatment was 27.8/16.6 mm Hg. Among 172 patients with uncontrolled hypertension receiving non-calcium channel antagonist antihypertensive agents, the addition of azelnidipine therapy significantly reduced mean BP in a noncomparative, 1-year study (a reduction from 165.7/95.4 mm Hg at baseline to 138.2/79.9 mm Hg at study end). The antihypertensive efficacy of azelnidipine in patients with mild-to-moderate hypertension was shown to be similar to that of amlodipine or nitrendipine in randomised, double-blind studies. Azelnidipine and amlodipine controlled 24-hour BP to a similar extent. Azelnidipine is generally well tolerated; vasodilator adverse events such as as headache and hot facial flushes account for most of the adverse events. Its use is not associated with reflex tachycardia.

A derivative of a rigid glutamate analog protects the retina from excitotoxicity.

In the retina, the activation of metabotropic glutamate receptors (mGluRs) reduces the toxic effect of N-methyl-D-aspartate (NMDA). We have induced NMDA-mediated excitotoxicity in the adult rat retina by a single intraocular injection of NMDA. The damage that resulted was estimated by assessing the NMDA-induced loss of retinal choline acetyltransferase (ChAT) activity. The new rigid glutamate analog, dimethyl ester of (+/-)-trans-azetidine-2,4-dicarboxylic acid (t-DMADA), with a putative mGluR-agonistic activity, protected the retina from NMDA-induced loss of ChAT activity. This study demonstrated that t-DMADA can be considered a prototype of new retino-protective agents.