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Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study.
Sit, AJ, Gupta, D, Kazemi, A, McKee, H, Challa, P, Liu, KC, Lopez, J, Kopczynski, C, Heah, T
American journal of ophthalmology. 2021;:262-269
Abstract
PURPOSE Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT. DESIGN Double-masked, randomized, vehicle-controlled, Phase 2 trial. METHODS Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry. RESULTS Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity. CONCLUSIONS Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP.
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New film-coated tablet formulation of deferasirox is well tolerated in patients with thalassemia or lower-risk MDS: Results of the randomized, phase II ECLIPSE study.
Taher, AT, Origa, R, Perrotta, S, Kourakli, A, Ruffo, GB, Kattamis, A, Goh, AS, Cortoos, A, Huang, V, Weill, M, et al
American journal of hematology. 2017;(5):420-428
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Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.
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Effect of telmisartan on histological activity and fibrosis of non-alcoholic steatohepatitis: A 1-year randomized control trial.
Alam, S, Kabir, J, Mustafa, G, Gupta, U, Hasan, SK, Alam, AK
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association. 2016;(1):69-76
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BACKGROUND/AIM: Telmisartan can attenuate two hit pathogenesis of non-alcoholic steatohepatitis (NASH). This study aimed to observe the effect of Telmisartan on non-alcoholic fatty liver disease (NAFLD) activity score (NAS) and fibrosis score in NASH patients. PATIENTS AND METHODS A total of 50 NASH patients were randomized; 35 of group 1 were treated with Telmisartan 40/80 mg once daily with life style modification (TL) and 15 of group 2 underwent only life style modification (L) for 1 year. At the end, 20 of TL group and 10 of L group were analyzed. Those who showed NAS improvement ≥ 2 or NAS improvement ≥ 1 with fibrosis improvement ≥ 1 were considered as responders. RESULTS Baseline alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin resistance index, components of metabolic syndrome, age, and sex were similar in both groups. At the end of study, NAS improvement in TL and L groups was 2.15 ± 1.66 and 1.10 ± 0.57 (P = 0.017) and fibrosis improvement was 0.65 ± 0.93 and -0.30 ± 0.48 (P = 0.001), respectively. NAS improved by ≥ 2 in 13 (65%) and 2 (20%) patients and fibrosis score improved by ≥ 1 in 8 (40%) patients and none of the patients in TL group and L group, respectively. Telmisartan and life style modification could improve steatosis, ballooning, lobular inflammation, and fibrosis. Life style modification could improve ballooning only, but fibrosis deteriorated. TL group showed improvement in NAS and fibrosis score [P value: 0.035; odds ratio (OR) =92.07, confidence interval (CI) =1.39-6106] to the level of response by regression analysis. Weight reduction and improvement of metabolic syndrome did not influence the response. There were similar minor adverse events in both groups. CONCLUSION Telmisartan improved NAS and fibrosis score in NASH with insignificant adverse events.
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Dose Timing of an Angiotensin II Receptor Blocker/Calcium Channel Blocker Combination in Hypertensive Patients With Paroxysmal Atrial Fibrillation.
Kario, K, Hoshide, S, Uchiyama, K, Yoshida, T, Okazaki, O, Noshiro, T, Aoki, H, Mizuno, H, Matsumoto, Y
Journal of clinical hypertension (Greenwich, Conn.). 2016;(10):1036-1044
Abstract
It has long been thought that there is a close association between hypertension and atrial fibrillation (AF). However, the efficacy of an angiotensin II receptor blocker for the prevention of organ damage in hypertensive individuals with AF is still controversial. The present study was a multicentered, prospective, randomized, open-label clinical trial investigating the differences in the effect of treatment with telmisartan/amlodipine combination tablets on blood pressure (BP) levels and BP variability between morning and bedtime administration in hypertensive patients with paroxysmal AF, using ambulatory BP monitoring (ABPM) and home BP. With this treatment, the patients' 24-hour BP, nighttime BP, preawake BP, and morning BP shown by ABPM were significantly reduced, and the antihypertensive effects were similar regardless of the timing of the drug administration. The standard deviation of day-by-day home systolic BP and the maximum home systolic BP were also significantly reduced, and these effects were similar regardless of the treatment timing. The N-terminal pro-brain natriuretic peptide level was significantly decreased only in the bedtime administration group. A larger study will demonstrate whether the bedtime administration of telmisartan/amlodipine combination tablets maximizes the risk-lowering effect against AF recurrence in paroxysmal AF hypertensive patients.
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Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia.
Taher, AT, Porter, JB, Viprakasit, V, Kattamis, A, Chuncharunee, S, Sutcharitchan, P, Siritanaratkul, N, Origa, R, Karakas, Z, Habr, D, et al
British journal of haematology. 2015;(2):284-90
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Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).
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Dietary flavonoids added to pharmacological antihypertensive therapy are effective in improving blood pressure.
de Jesús Romero-Prado, MM, Curiel-Beltrán, JA, Miramontes-Espino, MV, Cardona-Muñoz, EG, Rios-Arellano, A, Balam-Salazar, LB
Basic & clinical pharmacology & toxicology. 2015;(1):57-64
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Epidemiological studies have suggested that the daily intake of flavonoids is associated with a decreased risk of developing cardiovascular disease. Our purpose was to evaluate the effect of the addition of dietary flavonoids (DF) to antihypertensive treatment (AHT), based on telmisartan (Tms) or captopril (Cpr), on blood pressure (BP), body mass index (BMI), waist/hip ratio, leptin, lipid profile and inflammation in hypertensive young patients. An open-label, randomized, controlled trial was performed among 79 patients aged 20-55 years with grade I or grade II systemic arterial hypertension. The subjects were assigned to one of four groups for AHT plus DF during 6 months: Cpr (n = 14), Cpr + DF (n = 19), Tms (n = 25) and Tms + DF (n = 21). DF consisted of dark chocolate, dehydrated red apple and green tea in an infusion to obtain a daily dose of 425.8 ± 13.9 mg epicatechin equivalents. The BP and anthropometric parameters were measured every 2 weeks. Lipid profile, leptin and hsCRP were determined by standard methods. The combination AHT-DF produced an additional and significant reduction in (i) SBP/DBP of -5/-4 mmHg, being -7/-5 for Cpr + DF and -4/-3 for Tms + DF; (ii) triglyceride levels (-30.6%) versus AHT alone (-9.6%); and (iii) leptin: Cpr + DF versus Tms + DF (p < 0.005). Finally, C-reactive protein plasma levels were reduced significantly in all groups independently of the applied treatment. We conclude that the addition of flavonoids to pharmacological antihypertensive therapy shows additional benefits on BP, lipid profile, leptin, obesity and inflammation.
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Protective effect of telmisartan against endothelial dysfunction after coronary drug-eluting stent implantation in hypertensive patients.
Terashima, M, Kaneda, H, Nasu, K, Matsuo, H, Habara, M, Ito, T, Tanaka, N, Rathore, S, Kinoshita, Y, Kimura, M, et al
JACC. Cardiovascular interventions. 2012;(2):182-90
Abstract
OBJECTIVES The aim of this prospective, randomized study was to evaluate the effects of telmisartan, compared with the calcium-channel blocker amlodipine, on endothelial function after coronary drug-eluting stent (DES) implantation in hypertensive patients. BACKGROUND DES implantation impairs local endothelial function, which may be associated with future cardiovascular events. Telmisartan, which has unique peroxisome proliferator-activated-receptor-gamma-mediated effects in addition to its renin-angiotensin system-inhibition effects, has favorable effects on endothelial function. METHODS Fifty-one hypertensive patients with coronary artery stenosis but without coronary artery spasm, treated with a sirolimus-eluting stent, were randomly assigned to either the telmisartan (25 cases) or amlodipine (26 cases) treatment groups. At baseline and at 3 months after DES implantation, endothelium-dependent and -independent vasomotion were evaluated by quantitative coronary angiography under the condition of medication withdrawal. The mean luminal diameter of a 20-mm coronary segment, beginning 5 mm distal to the stent, was measured before and after infusion of intracoronary acetylcholine (10(-7), 10(-6) mol/l) and then again after infusion of nitroglycerin. RESULTS Blood pressure was comparable between groups at baseline and after 3 months. Vasoconstriction after acetylcholine infusion at 3 months (impaired endothelial function) was less pronounced in the telmisartan group than in the amlodipine group (p<0.0001), although there was no significant difference between the 2 groups before DES implantation. The response to nitroglycerin did not differ between groups before or at 3 months after DES implantation. CONCLUSIONS Telmisartan, compared with amlodipine, significantly ameliorated endothelial dysfunction after DES implantation in terms of vasoconstriction induced by acetylcholine.
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Effect of telmisartan on paroxysmal atrial fibrillation recurrence in hypertensive patients with normal or increased left atrial size.
Fogari, R, Zoppi, A, Maffioli, P, Mugellini, A, Preti, P, Perrone, T, Derosa, G
Clinical cardiology. 2012;(6):359-64
Abstract
BACKGROUND Hypertension is the most prevalent and potentially modifiable risk factor for atrial fibrillation (AF). In a previous secondary prevention study, the authors observed that the angiotensin II receptor blocker telmisartan was more effective than the calcium channel blocker amlodipine in preventing AF relapse in hypertensive patients with normal atrial size. HYPOTHESIS Telmisartan may be more effective than amlodipine in preventing AF recurrence in hypertensive patients with paroxysmal AF and normal or increased left atrial dimension (LAD). METHODS The authors assigned 378 mild hypertensive outpatients in sinus rhythm, but with ≥2 episodes of AF in the previous 6 months, to 1 of 2 groups. Group 1 comprised patients with LAD <40 mm in females and <45 mm in males. Group 2 comprised patients with LAD >40 mm and <45 mm in females and >45 mm and <50 mm in males. In both groups, patients were randomly treated with telmisartan or amlodipine for 1 year. RESULTS Systolic and diastolic blood pressure were similarly reduced by telmisartan and amlodipine in both groups. The AF recurrence rate was significantly lower in the telmisartan-treated patients than in the amlodipine-treated patients in both group 1 (12 vs 39, P < 0.01) and group 2 (40 vs 59, P < 0.05). Under telmisartan, the AF recurrence rate was significantly lower in group 1 than in group 2 (12.9% vs 42.1%, P < 0.05). Time to a first AF relapse was significantly longer with telmisartan than with amlodipine in both group 1 (176 ± 94 days vs 74 ± 61 days, P < 0.05) and group 2 (119 ± 65 days vs 38 ± 35 days, P < 0.05). CONCLUSIONS Telmisartan was more effective than amlodipine in preventing AF recurrences in hypertensive patients with paroxysmal AF.
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Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the TRANSCEND study.
Barzilay, JI, Gao, P, Rydén, L, Schumacher, H, Probstfield, J, Commerford, P, Dans, A, Ferreira, R, Keltai, M, Paolasso, E, et al
Diabetes care. 2011;(9):1902-7
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OBJECTIVE Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia. RESEARCH DESIGN AND METHODS Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care. RESULTS During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo. CONCLUSIONS There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.
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Effects of telmisartan on arterial stiffness assessed by the cardio-ankle vascular index in hypertensive patients.
Kinouchi, K, Ichihara, A, Sakoda, M, Kurauchi-Mito, A, Murohashi-Bokuda, K, Itoh, H
Kidney & blood pressure research. 2010;(4):304-12
Abstract
BACKGROUND/AIMS: This study was conducted to determine the effect of telmisartan on the cardio-ankle vascular index (CAVI), a novel blood pressure (BP)-independent marker for arterial stiffness in hypertensive patients. METHODS One hundred consecutive hypertensive patients were randomly assigned either to a group treated with calcium channel blocker (CCB)-based therapy or a group treated with telmisartan-based therapy. Clinical and biological parameters were then measured before and 12 months after the start of this study. RESULTS CAVI, the logarithm of urinary albumin excretion, and BP were reduced significantly after telmisartan-based therapy. The decreases in 24-hour diastolic BP and daytime systolic BP associated with telmisartan-based therapy were significantly greater than those associated with CCB-based therapy. Both therapies significantly and similarly decreased the clinical BP, 24-hour systolic BP, daytime diastolic BP and serum levels of low-density lipoprotein cholesterol. No significant differences in the metabolic parameters were observed between the two therapies. CONCLUSION Telmisartan-based therapy had beneficial effects on arterial stiffness assessed by CAVI, albuminuria, 24-hour BP and metabolism compared with CCB-based therapy. Since these markers are known to influence the future risk of cardiovascular events, telmisartan could be a useful drug for hypertensive patients.