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Differential effects of renin-angiotensine-aldosteron system inhibition, sympathoinhibition and low sodium diet on blood pressure in women with a history of preeclampsia: A double-blind, placebo-controlled cross-over trial (the PALM study).
Zoet, GA, Paauw, ND, Veerbeek, JHW, Groenhof, TKJ, Spiering, W, Verhaar, MC, Franx, A, Titia Lely, A
Pregnancy hypertension. 2022;:173-175
Abstract
Current guidelines lack sufficient evidence to recommend a specific blood pressure lowering strategy to prevent cardiovascular disease after preeclampsia. We conducted a double-blind cross-over trial to identify the most potent antihypertensive strategy: renin-angiotensin-aldosterone system (RAAS) inhibition (losartan), sympathoinhibition (moxonidine), low sodium diet and placebo (n = 10). Due to low inclusion rate our study stopped prematurely. Initiatory analyses showed no significant effect of antihypertensive strategy on office blood pressure and 24-hour blood pressure. However, nocturnal dipping was significantly higher on RAAS inhibition and low sodium diet compared to placebo and sympathoinhibition. Optimal cardiovascular prevention after preeclampsia should be further explored.
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Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials.
Wessels, AM, Tariot, PN, Zimmer, JA, Selzler, KJ, Bragg, SM, Andersen, SW, Landry, J, Krull, JH, Downing, AM, Willis, BA, et al
JAMA neurology. 2020;(2):199-209
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Abstract
IMPORTANCE Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. OBJECTIVE To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia. DESIGN, SETTING, AND PARTICIPANTS AMARANTH (first patient visit on September 30, 2014; last patient visit on October 4, 2018) and DAYBREAK-ALZ (first patient visit on July 1, 2016; last patient visit on September 28, 2018) were randomized, placebo-controlled, phase 2/3 and phase 3 clinical trials lasting 104 weeks and 78 weeks, respectively. AMARANTH and DAYBREAK-ALZ were multicenter, global, double-blind studies conducted at 257 and 251 centers, respectively, located in 15 and 18 countries or territories, respectively. A population-based sample of men and women aged 55 to 85 years who met National Institute on Aging-Alzheimer's Association criteria for early AD or mild AD dementia was screened using cognitive assessments, and the presence of amyloid was confirmed. Patients were excluded for unstable medical conditions or medication use, significant cerebrovascular pathologic findings, or a history of vitiligo and/or current evidence of postinflammatory hypopigmentation. AMARANTH screened 6871 patients; 2218 (32.3%) were randomized, and 539 patients completed the study. DAYBREAK-ALZ screened 5706 patients; 1722 (30.2%) were randomized, and 76 patients completed the study. INTERVENTIONS Patients were randomized (1:1:1) to once-daily oral doses of lanabecestat (20 mg), lanabecestat (50 mg), or placebo. MAIN OUTCOMES AND MEASURES The primary outcome measure was change from baseline on the 13-item Alzheimer Disease Assessment Scale-cognitive subscale. Secondary outcomes included Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory, Clinical Dementia Rating, Functional Activities Questionnaire, Mini-Mental State Examination, and Neuropsychiatric Inventory. Efficacy analyses were conducted on the intent-to-treat population. RESULTS Among 2218 AMARANTH patients, the mean (SD) age was 71.3 (7.1) years, and 1177 of 2218 (53.1%) were women. Among 1722 DAYBREAK-ALZ patients, the mean (SD) age was 72.3 (7.0) years, and 1023 of 1722 (59.4%) were women. Both studies were terminated early after futility analysis. There were no consistent, reproducible dose-related findings on primary or secondary efficacy measures. Psychiatric adverse events, weight loss, and hair color changes were reported in a higher percentage of patients receiving lanabecestat than placebo. CONCLUSIONS AND RELEVANCE Treatment with lanabecestat was well tolerated and did not slow cognitive or functional decline. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT02245737 and NCT02783573.
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Serum Levels of Protein-Bound Methylglyoxal-Derived Hydroimidazolone-1 are Independently Correlated with Asymmetric Dimethylarginine.
Tahara, N, Kojima, R, Yoshida, R, Bekki, M, Sugiyama, Y, Tahara, A, Maeda, S, Honda, A, Igata, S, Nakamura, T, et al
Rejuvenation research. 2019;(5):431-438
Abstract
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, being involved in endothelial dysfunction. Furthermore, ADMA levels have been shown to predict future cardiovascular events in patients with coronary risk factors, such as diabetes and hypertension. We have previously found that glyceraldehyde-derived advanced glycation end products (glycer-AGEs) stimulate ADMA generation in vitro and the levels are associated with ADMA, endothelial dysfunction, and vascular inflammation in humans. However, it remains unclear what structurally distinct glycer-AGEs are independent correlates of ADMA. In this study, we addressed the issue. We measured serum levels of protein-bound and free methylglyoxal-derived hydroimidazolone-1 (MG-H1) and argpyrimidine, two major structurally identified glycer-AGEs by liquid chromatography-tandem mass spectrometry in 128 outpatients, and examined the correlations of these AGEs, vascular stiffness, and inflammation with ADMA. Moreover, we examined whether the changes in serum MG-H1 and argpyrimidine levels after 4-month treatment with oral hypoglycemic agents (OHAs) were associated with those of ADMA in other 44 patients with impaired glucose tolerance or type 2 diabetes. Multiple stepwise regression analysis revealed that protein-bound MG-H1, high-density lipoprotein cholesterol (inversely), high-sensitivity C-reactive protein, and cardio-ankle vascular index were independently correlated with ADMA (R2 = 0.259). Treatment with OHAs significantly decreased ADMA levels in 44 glucose-intolerant or type 2 diabetic patients, and the changes in protein-bound MG-H1 levels were positively associated with those in ADMA values (p < 0.05). This study demonstrates that serum levels of protein-bound MG-H1 are independently correlated with ADMA and may be a therapeutic target for cardiovascular disease.
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Randomised clinical trial: safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of tegoprazan (CJ-12420), a novel potassium-competitive acid blocker, in healthy male subjects.
Han, S, Choi, HY, Kim, YH, Nam, JY, Kim, B, Song, GS, Lim, HS, Bae, KS
Alimentary pharmacology & therapeutics. 2019;(7):751-759
Abstract
BACKGROUND Tegoprazan (CJ-12420) is a potassium-competitive acid blocker (P-CAB) with therapeutic potential for gastro-oesophageal reflux disease (GERD) by reversibly suppressing gastric H+ /K+ -ATPase. AIMS To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of tegoprazan METHODS A phase I, randomised, double-blind and placebo-controlled clinical trial was conducted in 56 healthy male subjects without Helicobacter pylori infection. In the single ascending dose study, 50, 100, 200 and 400 mg tegoprazan were administered to 32 subjects. In the multiple ascending dose study, 100 and 200 mg tegoprazan were administered every 24 hours to each of the eight subjects for 7 days. In the comparative pharmacodynamics study, 40 mg esomeprazole was administered to eight subjects every 24 hours for 7 days. The assessment included safety, tolerability, pharmacodynamics through monitoring of 24-hour gastric pH and pharmacokinetics of tegoprazan in plasma and urine. RESULTS Tegoprazan was generally well tolerated. Most adverse events reported in the study were mild in intensity and resolved without any sequelae. Exposure to tegoprazan increased in a dose-proportional manner. Multiple dosing with tegoprazan showed no accumulation in plasma on day 7. The pharmacodynamic analysis revealed that tegoprazan showed rapid, dose-dependent gastric acid suppression. CONCLUSIONS Tegoprazan was well tolerated and showed rapid and potent gastric acid suppression. This supports the further development of tegoprazan as a treatment for acid-related disorders.
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The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study.
Schmieder, RE, Wagner, F, Mayr, M, Delles, C, Ott, C, Keicher, C, Hrabak-Paar, M, Heye, T, Aichner, S, Khder, Y, et al
European heart journal. 2017;(44):3308-3317
Abstract
AIMS: Progressive aortic stiffening eventually leads to left ventricular (LV) hypertrophy and heart failure if left untreated. Anti-hypertensive agents have been shown to reverse this to some extent. The effects of sacubitril/valsartan (LCZ696), a dual-action angiotensin receptor blocker (ARB), and neprilysin inhibitor, on arterial stiffness and LV remodelling have not been investigated. METHODS AND RESULTS This was a randomized, multi-centre, double-blind, double-dummy, active-controlled, parallel group, study to compare the effects on cardiovascular remodelling of sacubitril/valsartan with those of olmesartan in patients with hypertension and elevated pulse pressure. Magnetic resonance imaging scans were used to assess LV mass and local aortic distensibility, at baseline and at 12 and 52 weeks after initiation of treatment. Central pulse and systolic pressure were determined using a SphymoCor® XCEL device at each time point. A total of 114 patients were included, with 57 in each treatment group. The mean age was 59.8 years, and 67.5% were male. Demographic characteristics did not vary between the two sets of patients. Left ventricular mass index decreased to a greater extent in the sacubitril/valsartan group compared to the olmesartan group from baseline to 12 weeks (-6.36 vs. -2.32 g/m2; P = 0.039) and from baseline to 52 weeks (-6.83 vs. -3.55 g/m2; P = 0.029). These differences remained significant after adjustment for systolic blood pressure (SBP) at follow-up (P = 0.036 and 0.019 at 12 and 52 weeks, respectively) and similar signals (though formally non-significant) were observed after adjusting for changes in SBP (P = 0.0612 and P = 0.0529, respectively). There were no significant differences in local distensibility changes from baseline to 12 or 52 weeks between the two groups; however, there was a larger reduction in central pulse pressure for the sacubitril/valsartan group compared to the olmesartan group (P = 0.010). CONCLUSION Since LV mass change correlates with cardiovascular prognosis, the greater reductions in LV mass indicate valuable advantages of sacubitril/valsartan compared to olmesartan. The finding that LV mass index decrease might be to some extent independent of SBP suggests that the effect of the dual-acting agent may go beyond those due to its BP-lowering ability.
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Comparison of Efficacy and Safety of Azilsartan and Olmesartan in Patients With Essential Hypertension.
Shiga, Y, Miura, SI, Motozato, K, Norimatsu, K, Yano, M, Hitaka, Y, Adachi, S, Kuwano, T, Inoue, K, Inoue, A, et al
International heart journal. 2017;(3):416-421
Abstract
Many patients still have high blood pressure (BP) after treatment with angiotensin II type 1 (AT1) receptor blockers (ARBs). We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective randomized clinical trial. Sixty-four hypertensive patients who were treated with ARBs other than azilsartan and olmesartan were enrolled in this study. We randomly assigned patients to changeover from their prior ARBs to either azilsartan or olmesartan, and followed the patients for 3 months. Systolic BP (SBP) in the azilsartan group was significantly decreased at 3 months, and diastolic BP (DBP) and pulse rate (PR) in the olmesartan group showed significant reductions after 3 months. There were no significant differences in ΔSBP, ΔDBP, or ΔPR (Δ = the value at 3 months minus the value at 0 months) between the groups. Serum levels of creatinine (Cr), uric acid (UA), and potassium (K) in the azilsartan group significantly increased after 3 months. While the changes in Cr, UA, and K were within the respective normal ranges, ΔSBP was positively associated with ΔCr in the azilsartan group. In conclusion, there was no difference in the depressor effects of azilsartan and olmesartan, and there were no serious changes in biochemical parameters with azilsartan and olmesartan.
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Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.
Williams, B, Cockcroft, JR, Kario, K, Zappe, DH, Brunel, PC, Wang, Q, Guo, W
Hypertension (Dallas, Tex. : 1979). 2017;(3):411-420
Abstract
Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.
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Effectiveness of monotherapy and combined therapy with calcitonin and minodronic acid hydrate, a bisphosphonate, for early treatment in patients with new vertebral fractures: An open-label, randomized, parallel-group study.
Tanaka, S, Yoshida, A, Kono, S, Ito, M
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 2017;(3):536-541
Abstract
BACKGROUND Evidence related to the effectiveness of combination drug therapy for the treatment of osteoporosis is currently considered insufficient. Therefore, this study was performed to clarify the effects of monotherapy, and combination therapy, with a bisphosphonate (minodronic acid hydrate), a bone resorption inhibitor, and calcitonin (elcatonin), which is effective for the alleviation of pain due to vertebral fractures in osteoporotic patients. METHODS Study participants comprised of 51 female subjects with post-menopausal osteoporosis, whose main complaint was acute lower back pain caused by vertebral fractures. Subjects were randomly allocated into three groups and then administered with either intramuscular injections of elcatonin at a dose of 20 units weekly, minodronic acid hydrate at a dose of 1 mg daily, or a combination of these two drugs. As primary endpoints, time-dependent changes in levels of pain were assessed using a visual analog scale from baseline to 6 months of duration. In addition, we examined the effects of monotherapies, and a combination therapy on bone resorption, with changes in bone mineral density at 4 sites and advanced hip assessment parameters from baseline to 6 months. A two-tailed significance level of 5% was used for hypothesis testing. RESULTS Elcatonin monotherapy showed some alleviation of pain immediately after any vertebral fractures, which was more than in the minodronic acid hydrate monotherapy group. In addition, the minodronic acid hydrate monotherapy group experienced more effective inhibited bone resorption than the elcatonin monotherapy group. In the combination therapy, the efficacy for alleviating pain and inhibiting bone resorption was equivalent to the effect observed in the elcatonin and minodronic acid hydrate monotherapy groups respectively, with further improved values of bone mineral density observed in the femoral neck and lumbar vertebrae, and in parameters of advanced hip assessment compared with both monotherapy groups. CONCLUSIONS Combination therapy with elcatonin and minodronic acid hydrate appears to be an effective treatment for osteoporosis patients with lower back pain, caused by fresh vertebral fractures.
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Climbazole boosts activity of retinoids in skin.
Adamus, J, Feng, L, Hawkins, S, Kalleberg, K, Lee, JM
International journal of cosmetic science. 2017;(4):411-418
Abstract
OBJECTIVE To explore whether climbazole enhances retinoid-associated biological activities in vitro and in vivo. METHODS Primary human dermal fibroblasts (HDFs) were treated from six to 48 h with either retinoids (retinol, retinyl propionate, retinyl palmitate) alone or in combination with climbazole, and then assessed for cellular retinoic acid-binding protein 2 (CRABP2) mRNA expression by RT-qPCR. Next, skin equivalent (SE) cultures were topically treated with retinol or retinyl propionate, with or without climbazole, and then measured for biological changes in retinoid biomarkers. Lastly, an IRB-approved clinical study was conducted on the outer forearm of 16 subjects to ascertain the effects of low (0.02%) or high (0.1%) levels of retinol, retinyl propionate (0.5%), climbazole (0.5%) or a combination of retinol (0.02%)/climbazole (0.5%). Indicators of retinoid activities were measured after 3 weeks. RESULTS Treatment of HDFs with retinol or retinyl propionate was unaffected by climbazole but alone, resulted in a significantly (P < 0.01) higher sustained CRABP2 mRNA expression than those treated with retinyl palmitate or vehicle control. In SEs, climbazole combined with either retinol or retinyl propionate boosted retinoid related activity greater than the retinoid only, reflected by a dose-response, downregulation of loricrin (LOR) and induction of keratin 4 (KRT4) proteins. In vivo, retinol (0.1%) and retinyl propionate (0.5%) significantly increased most evaluated biomarkers, as expected. Low-dose retinol or climbazole alone did not increase these biomarkers; however, in combination, significant (P < 0.05) increases in retinoid and ageing biomarkers were detected. CONCLUSION Climbazole boosted retinoid activity both in the SE model, after a combined topic treatment with either retinol or retinyl propionate, and in vivo, in combination with a low level of retinol. Based upon the evidence presented here, we suggest that the topical skin application of climbazole in combination with retinoids could deliver skin ageing benefits more than a less robust retinoid alone.
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Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.
Miura, M, Sakata, Y, Miyata, S, Shiba, N, Takahashi, J, Nochioka, K, Takada, T, Saga, C, Shinozaki, T, Sugi, M, et al
Circulation journal : official journal of the Japanese Circulation Society. 2016;(10):2155-64
Abstract
BACKGROUND There is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF. METHODS AND RESULTS Among 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01). CONCLUSIONS LVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).