Spectrofluorimetric methods of stability-indicating assay of certain drugs affecting the cardiovascular system

NASA Astrophysics Data System (ADS)

Moussa, B. A.; Mohamed, M. F.; Youssef, N. F.

2011-01-01

Two stability-indicating spectrofluorimetric methods have been developed for the determination of ezetimibe and olmesartan medoxomil, drugs affecting the cardiovascular system, and validated in the presence of their degradation products. The first method, for ezetimibe, is based on an oxidative coupling reaction of ezetimibe with 3-methylbenzothiazolin-2-one hydrazone hydrochloride in the presence of cerium (IV) ammonium sulfate in an acidic medium. The quenching effect of ezetimibe on the fluorescence of excess cerous ions is measured at the emission wavelength, λem, of 345 nm with the excitation wavelength, λex, of 296 nm. Factors affecting the reaction were carefully studied and optimized. The second method, for olmesartan medoxomil, is based on measuring the native fluorescence intensity of olmesartan medoxomil in methanol at λem = 360 nm with λex = 286 nm. Regression plots revealed good linear relationships in the assay limits of 10-120 and 8-112 g/ml for ezetimibe and olmesartan medoxomil, respectively. The validity of the methods was assessed according to the United States Pharmacopeya guidelines. Statistical analysis of the results exposed good Student's t-test and F-ratio values. The introduced methods were successfully applied to the analysis of ezetimibe and olmesartan medoxomil in drug substances and drug products as well as in the presence of their degradation products.

Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies.

PubMed

Derosa, Giuseppe; Cicero, Arrigo Francesco Giuseppe; Carbone, Anna; Querci, Fabrizio; Fogari, Elena; D'Angelo, Angela; Maffioli, Pamela

2013-09-01

Hypertension is known to be one of the main risk factors for cardiovascular disease. To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL-8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp. Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy. Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers.

A Review of Current Evidence of Olmesartan Medoxomil Mimicking Symptoms of Celiac Disease.

PubMed

Sanford, Michele L; Nagel, Angela K

2015-04-01

Objective:To review the evidence of an association between olmesartan medoxomil and symptoms mimicking celiac disease.Data Sources:Literature was searched in PubMed (1965-November 2013) using the key words or MeSH terms olmesartan, enteropathy, celiac disease, sprue, and diarrhea. References from the Food and Drug Administration (FDA) and Dipiro's Pharmacotherapy eighth edition textbook were also reviewed.Data Synthesis:There have been recent implications of olmesartan medoxomil being linked to symptoms mimicking celiac disease. Investigators first identified the association in 22 patients who presented with presumed refractory celiac disease. Upon further evaluation, it was discovered that these symptoms improved when olmesartan was discontinued. In response to this report, additional case studies have been published. DeGaetani et al also further analyzed patients with seronegative villous atrophy from the Celiac Disease Center and found that olmesartan accounted for 22% of previously unclassified sprue cases. Conversely, the authors of the ROADMAP trial, which compared olmesartan to placebo, found no significant differences in the incidence of gastrointestinal adverse effects.Conclusions:There is growing evidence supporting the association between olmesartan and sprue-like symptoms; however, further research is warranted. These symptoms can be life threatening and clinicians should be aware of the potential association.

Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

PubMed

Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

2016-12-01

Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Azilsartan medoxomil plus chlorthalidone reduces blood pressure more effectively than olmesartan plus hydrochlorothiazide in stage 2 systolic hypertension.

PubMed

Cushman, William C; Bakris, George L; White, William B; Weber, Michael A; Sica, Domenic; Roberts, Andrew; Lloyd, Eric; Kupfer, Stuart

2012-08-01

Azilsartan medoxomil, an effective, long-acting angiotensin II receptor blocker, is a new treatment for hypertension that is also being developed in fixed-dose combinations with chlorthalidone, a potent, long-acting thiazide-like diuretic. We compared once-daily fixed-dose combinations of azilsartan medoxomil/chlorthalidone force titrated to a high dose of either 40/25 mg or 80/25 mg with a fixed-dose combination of the angiotensin II receptor blocker olmesartan medoxomil plus the thiazide diuretic hydrochlorothiazide force titrated to 40/25 mg. The design was a randomized, 3-arm, double-blind, 12-week study of 1071 participants with baseline clinic systolic blood pressure 160 to 190 mm Hg and diastolic blood pressure ≤119 mm Hg. Patients had a mean age of 57 years; 59% were men, 73% were white, and 22% were black. At baseline, mean clinic blood pressure was 165/96 mm Hg and 24-hour mean blood pressure was 150/88 mm Hg. Changes in clinic (primary end point) and ambulatory systolic blood pressures at week 12 were significantly greater in both azilsartan medoxomil/chlorthalidone arms than in the olmesartan/hydrochlorothiazide arm (P<0.001). Changes in clinic systolic blood pressure (mean±SE) were -42.5±0.8, -44.0±0.8, and -37.1±0.8 mm Hg, respectively. Changes in 24-hour ambulatory systolic blood pressure were -33.9±0.8, -36.3±0.8, and -27.5±0.8 mm Hg, respectively. Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given azilsartan medoxomil/chlorthalidone 40/25 mg, azilsartan medoxomil/chlorthalidone 80/25 mg, and olmesartan/hydrochlorothiazide 40/25 mg, respectively. This large, forced-titration study has demonstrated superior antihypertensive efficacy of azilsartan medoxomil/chlorthalidone fixed-dose combinations compared with the maximum approved dose of olmesartan/hydrochlorothiazide.

Population Pharmacokinetic Modeling of Olmesartan, the Active Metabolite of Olmesartan Medoxomil, in Patients with Hypertension.

PubMed

Kodati, Devender; Kotakonda, Harish Kaushik; Yellu, Narsimhareddy

2017-08-01

Olmesartan medoxomil is an orally given angiotensin II receptor antagonist indicated for the treatment of hypertension. The aim of the study was to establish a population pharmacokinetic model for olmesartan, the active metabolite of olmesartan medoxomil, in Indian hypertensive patients, and to evaluate effects of covariates on the volume of distribution (V/F) and oral clearance (CL/F) of olmesartan. The population pharmacokinetic model for olmesartan was developed using Phoenix NLME 1.3 with a non-linear mixed-effect model. Bootstrap and visual predictive check were used simultaneously to validate the final population pharmacokinetic models. The covariates included age, sex, body surface area (BSA), bodyweight, height, creatinine clearance (CL CR ) as an index of renal function and liver parameters as indices of hepatic function. A total of 205 olmesartan plasma sample concentrations from 69 patients with hypertension were collected in this study. The pharmacokinetic data of olmesartan was well described by a two-compartment linear pharmacokinetic model with first-order absorption and an absorption lag-time. The mean values of CL/F and V/F of olmesartan in the patients were 0.31565 L/h and 44.5162 L, respectively. Analysis of covariates showed that age and CL CR were factors influencing the clearance of olmesartan and the volume of distribution of olmesartan was dependent on age and BSA. The final population pharmacokinetic model was demonstrated to be appropriate and effective and it can be used to assess the pharmacokinetic parameters of olmesartan in Indian patients with hypertension.

Development of an HPLC-UV Method for the Analysis of Drugs Used for Combined Hypertension Therapy in Pharmaceutical Preparations and Human Plasma.

PubMed

Kepekci Tekkeli, Serife Evrim

2013-01-01

A simple, rapid, and selective HPLC-UV method was developed for the determination of antihypertensive drug substances: amlodipine besilat (AML), olmesartan medoxomil (OLM), valsartan (VAL), and hydrochlorothiazide (HCT) in pharmaceuticals and plasma. These substances are mostly used as combinations. The combinations are found in various forms, especially in current pharmaceuticals as threesome components: OLM, AML, and HCT (combination I) and AML, VAL, and HCT (combination II). The separation was achieved by using an RP-CN column, and acetonitrile-methanol-10 mmol orthophosphoric acid pH 2.5 (7 : 13 : 80, v/v/v) was used as a mobile phase; the detector wavelength was set at 235 nm. The linear ranges were found as 0.1-18.5  μ g/mL, 0.4-25.6  μ g/mL, 0.3-15.5  μ g/mL, and 0.3-22  μ g/mL for AML, OLM, VAL, and HCT, respectively. In order to check the selectivity of the method for pharmaceutical preparations, forced degradation studies were carried out. According to the validation studies, the developed method was found to be reproducible and accurate as shown by RSD ≤6.1%, 5.7%, 6.9%, and 4.6% and relative mean error (RME) ≤10.6%, 5.8%, 6.5%, and 6.8% for AML, OLM, VAL, and HCT, respectively. Consequently, the method was applied to the analysis of tablets and plasma of the patients using drugs including those substances.

Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

PubMed

Yoshihara, Kazutaka; Gao, Yuying; Shiga, Hiroshi; Wada, D Russell; Hisaoka, Masafumi

2005-01-01

Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. Eighty-nine healthy volunteers and 383 hypertensive patients. Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.

Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

PubMed

Yahiro, Eiji; Miura, Shin-Ichiro; Suematsu, Yasunori; Matsuo, Yoshino; Arimura, Tadaaki; Kuwano, Takashi; Imaizumi, Satoshi; Iwata, Atsushi; Uehara, Yoshinari; Saku, Keijiro

2015-01-01

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Azilsartan medoxomil/chlorthalidone: a new fixed-dose combination antihypertensive.

PubMed

Pierini, Danielle; Anderson, Katherine Vogel

2013-05-01

To evaluate the efficacy, safety, and clinical utility of the combination product azilsartan medoxomil/chlorthalidone for the treatment of hypertension. Articles indexed in PubMed through December 2012 were identified using the MeSH terms azilsartan and chlorthalidone, Edarbyclor, TAK-490, and Edarbi. Additional information was gathered from references cited in the identified publications, the package insert, and from a review of the ClinicalTrials.gov registry. English-language articles, including clinical trials and reviews involving azilsartan medoxomil/chlorthalidone or each component individually for the treatment of hypertension were reviewed. The antihypertensive combination tablet azilsartan medoxomil/chlorthalidone is the first to combine an inhibitor of the renin-angiotensin-aldosterone system with chlorthalidone, a thiazide-type diuretic. In 4 randomized controlled trials (3 published to date), azilsartan medoxomil/chlorthalidone 40 mg/12.5 mg and 40 mg/25 mg reduced blood pressure (BP) significantly more than comparators did, including an approximately 5-mm Hg greater BP reduction than olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg and azilsartan medoxomil/hydrochlorothiazide. Reductions in 24-hour ambulatory BP and clinic BP were observed, and a greater proportion of patients achieved BP targets while receiving azilsartan medoxomil/chlorthalidone. Azilsartan medoxomil/chlorthalidone was generally well tolerated, with minor, transient increases in serum creatinine and without a significant effect on potassium homeostasis. No studies have directly examined cardiovascular morbidity and mortality benefits associated with this combination. The combination of azilsartan medoxomil/chlorthalidone has demonstrated safety and efficacy in lowering BP in hypertensive patients to a greater degree than olmesartan medoxomil/hydrochlorothiazide and azilsartan medoxomil/hydrochlorothiazide. As a fixed-dose combination tablet, it offers several clinical advantages.

Development and Validation of a Chromatography Method Using Tandem UV/Charged Aerosol Detector for Simultaneous Determination of Amlodipine Besylate and Olmesartan Medoxomil: Application to Drug-Excipient Compatibility Study

PubMed Central

Brondi, Ariadne M.; Garcia, Jerusa S.

2017-01-01

A study was carried out to investigate compatibility of amlodipine besylate and olmesartan medoxomil with a variety of pharmaceutical excipients. Both drugs are antihypertensive agents that can be administered alone, in monotherapy, or in pharmaceutical association. The studies were performed using binary and ternary mixtures, and samples were stored for 3 and 6 months at 40°C under 75% relative humidity and dry conditions. For this study, a method based on high-performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of amlodipine besylate and olmesartan medoxomil in samples from pharmaceutical preformulation studies using diode array detector (DAD) and charged aerosol detector (CAD). The runtime per sample was 10 min with retention time of 7.926 min and 4.408 min for amlodipine and olmesartan, respectively. The validation was performed according to ICH guidelines. The calibration curve presents linear dynamic range from 12 to 250 μg mL−1 for amlodipine and from 25 to 500 μg mL−1 for olmesartan with coefficient of determination (R2 ≥ 0.9908) while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.0%. The excipients such as corn starch, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, polyvinylpyrrolidone, lactose monohydrate, and polyethylene glycol showed potential incompatibilities after accelerated stability testing. PMID:29391967

Efficacy and safety of long-term treatment with the combination of amlodipine besylate and olmesartan medoxomil in patients with hypertension.

PubMed

Chrysant, Steven G; Oparil, Suzanne; Melino, Michael; Karki, Sulekha; Lee, James; Heyrman, Reinilde

2009-09-01

J Clin Hypertens (Greenwich). 2009;11:475-482. (c) 2009 Wiley Periodicals, Inc.The authors report on the 44-week open-label extension of the 8-week, double-blind Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial in 1684 patients. Initial therapy was amlodipine (AML) plus olmesartan medoxomil (OM) 5+40 mg/d, up-titrated to AML+OM 10+40 mg/d plus hydrochlorothiazide (HCTZ) 12.5 mg then 25 mg if patients did not achieve blood pressure (BP) goal (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes). Baseline mean BP decreased from 164/102 mm Hg to 131/82 mm Hg at end of study, with an overall 66.7% of patients, including those with diabetes, achieving BP goal. The BP goal achievement was 80% for AML+OM 5+40 mg/d, 70.6% for AML+OM 10+40 mg/d, 66.6% for AML+OM+HCTZ 10+40+12.5 mg/d, and 46.3% for AML+OM+HCTZ 10+40+25 mg/d. Study medication was safe and well tolerated. Combination antihypertensive therapy with AML+OM+/-HTCZ, up-titrated as necessary, allowed a majority of patients to achieve BP goal.

Olmesartan/amlodipine: a review of its use in the management of hypertension

PubMed Central

Kreutz, R

2011-01-01

Combination therapy is an effective strategy to increase antihypertensive efficacy in those patients with poor blood pressure (BP) control. In order to achieve BP targets, at least 75% of patients may require combination therapy, and European guidelines advocate this approach, particularly in those patients with a high cardiovascular risk. Evidence from large, randomized controlled trials, and the European hypertension treatment guidelines is supportive of the use of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). Fixed-dose combination formulations of olmesartan medoxomil, an ARB, and the CCB amlodipine are approved in several European countries for patients with essential hypertension. The olmesartan/amlodipine combination has demonstrated greater efficacy than its component monotherapies in reducing BP in patients with mild-to-severe hypertension. Significantly greater reductions in seated diastolic BP were observed between baseline and after eight weeks of treatment with olmesartan/amlodipine, compared with equivalent doses of olmesartan or amolodipine monotherapy (P < 0.001), in the factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial. About 85% of the maximal BP reductions after the 8-week treatment period were already observed after two weeks. Uptitration as necessary, with or without hydrochlorothiazide, allowed the majority of patients to achieve BP control in a 44-week open-label extension treatment period to the COACH trial. The use of olmesartan/amlodipine allowed up to 54% of patients, with previously inadequate responses to amlodipine or olmesartan monotherapy, to achieve their BP goals. Data from post-registration studies using tight BP control and forced titration regimens have further demonstrated the high efficacy of olmesartan/amlodipine in achieving BP goal rates. Moreover, consistent reductions in BP were observed over the 24-hour dosing interval using ambulatory measurements. Olmesartan/amlodipine was generally well tolerated over the short- and long-term, with a lower frequency of peripheral edema with olmesartan/amlodipine 40/10 mg than with amlodipine 10 mg monotherapy. PMID:21490944

Azilsartan medoxomil: a new angiotensin II receptor antagonist for treatment of hypertension.

PubMed

Baker, William L; White, William B

2011-12-01

To evaluate the efficacy, safety, and clinical role of azilsartan medoxomil, an angiotensin II receptor blocker (ARB) that recently gained Food and Drug Administration approval for lowering of blood pressure (BP) in patients with hypertension. A systematic review of the literature was performed through August 2011 using MEDLINE, Web of Science, and International Pharmaceutical Abstracts and the key words and MeSH terms azilsartan, azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Abstracts presented in the last 2 years from the annual meetings of appropriate medical societies were reviewed in addition to a search of clinicaltrials.gov. Studies eligible for inclusion were in vitro or in vivo evaluations of azilsartan medoxomil, with no restrictions on patient population or indication. Data related to the patient populations and outcomes of interest were extracted from each publication. Three trials are available in full publication form with others available only as abstracts. Azilsartan medoxomil 40 mg and 80 mg daily significantly improves both systolic and diastolic BP from baseline compared with placebo, and the 80-mg dose has greater efficacy than other ARBs, including olmesartan 40 mg daily and valsartan 320 mg daily. Improvements in both 24-hour BP using ambulatory monitoring and clinic monitoring have been seen with azilsartan medoxomil as well as a higher proportion of patients reaching the goal level. Additional information shows added BP lowering when azilsartan medoxomil is combined with chlorthalidone. Adverse events are similar with azilsartan medoxomil versus other ARBs and include headache, dizziness, urinary tract infections, and fatigue. Azilsartan medoxomil is a safe and effective ARB with a unique pharmacologic profile versus other agents, including slowed angiotensin II type 1 receptor dissociation rates and improved receptor specificity. Studies have shown azilsartan medoxomil 80 mg once daily to reduce BP to a greater extent than valsartan and olmesartan, with similar safety and tolerability.

Practical efficacy of olmesartan versus azilsartan in patients with hypertension: a multicenter randomized-controlled trial (MUSCAT-4 study).

PubMed

Kakio, Yuki; Uchida, Haruhito A; Umebayashi, Ryoko; Takeuchi, Hidemi; Okuyama, Yuka; Hanayama, Yoshihisa; Wada, Jun

2017-04-01

Olmesartan and azilsartan, angiotensin II receptor blockers (ARBs), are expected to decrease blood pressure more than the other ARBs. We conducted randomized-controlled trials to compare the practical efficacy of olmesartan with azilsartan. Eighty-four patients treated with the conventional ARBs for more than 3 months were assigned randomly to receive either 20 mg of olmesartan (olmesartan medoxomil, OL group) or 20 mg of azilsartan (azilsartan, not azilsartan medoxomil, AZ group) once daily for 16 weeks. The practical efficacy on blood pressure was compared between the OL and AZ groups. Office blood pressure of both groups decreased significantly (OL group: 152/86-141/79 mmHg, P<0.05, AZ group: 149/83-135/75 mmHg; P<0.05). Diastolic home blood pressure in the AZ group decreased significantly (79±9-74±7 mmHg; P<0.05), but not in the OL group (79±11-75±10 mmHg; P=0.068). However, there were no significant differences between the groups. The dosage of olmesartan and azilsartan increased significantly and slightly for 16 weeks (OL group: 20.3-23.1 mg; P<0.05, AZ group: 20.5-23.2 mg; P<0.05), without a significant difference between groups. Furthermore, there were no significant differences in renal function, lipid profiles, brain natriuretic peptide, soluble fms-like tyrosine kinase-1, and urinary L-type fatty acid-binding protein between the two groups. Both olmesartan and azilsartan equally reduced blood pressures. Both olmesartan and azilsartan showed a renoprotective effect and were well tolerated without any major adverse events.

Solid lipid nanoparticles as an efficient drug delivery system of olmesartan medoxomil for the treatment of hypertension.

PubMed

Pandya, Nilima T; Jani, Parva; Vanza, Jigar; Tandel, Hemal

2018-05-01

The aim of the current investigation was to develop solid lipid nanoparticles of olmesartan medoxomil using hot homogenization method to improve its oral bioavailability. Central composite design was applied to optimize the formulation variables; lipid X1 (Glyceryl monostearate) and surfactant X2 (Poloxamer: Tween 80). The particle sizes were in the nanometer range and spherical shaped for all prepared solid lipid nanoparticles formulations and the zeta potential absolute values were high, predicting good long-term stability. In vitro study of olmesartan loaded solid lipid nanoparticle exhibited controlled release profile for at least 24 h. The rate and extent of drug diffusion was studied using dialysis sac, rat's stomach and intestine tissues; study demonstrated that drug release from the solid lipid nanoparticles was significantly higher than drug suspension. In vivo pharmacokinetic study of olmesartan loaded solid lipid nanoparticles revealed higher Cmax of 1610 ng/mL, higher AUC of 15492.50 ng/mL and increased relative bioavailability by almost 2.3 folds compared to marketed formulation. These results clearly indicate that olmesartan loaded solid lipid nanoparticles are shown to have enhanced bioavailability and effective therapeutic result and thus would be an excellent way to treat hypertension. Hence, these solid lipid nanoparticles could represent as a great potential for a possible alternative to conventional oral formulation in the treatment of hypertension. Copyright © 2018 Elsevier B.V. All rights reserved.

Azilsartan medoxomil: a review of its use in hypertension.

PubMed

Perry, Caroline M

2012-09-01

Azilsartan medoxomil (Edarbi®; Ipreziv™) is an orally administered angiotensin II receptor type 1 antagonist (blocker) used in the treatment of adults with essential hypertension. This article reviews data on the clinical efficacy and tolerability of azilsartan medoxomil in adults with essential hypertension and provides a summary of its pharmacological properties. Azilsartan medoxomil is a prodrug that undergoes rapid hydrolysis in the gastrointestinal tract after oral administration to the bioactive moiety azilsartan, before systemic absorption. Azilsartan medoxomil produces antihypertensive effects by selectively blocking the binding of angiotensin II to the angiotensin type 1 (AT(1)) receptor, thereby antagonizing the pressor response activity of angiotensin II. In vitro, azilsartan produced greater and more sustained AT(1) receptor binding/blockade activity than several comparator angiotensin II receptor antagonists. Azilsartan medoxomil reduces blood pressure (BP) in hypertensive adults. In addition, the drug has been shown to have pleiotropic effects (i.e. effects beyond AT(1) receptor blockade). In adults with essential hypertension, azilsartan medoxomil 20, 40 or 80 mg effectively reduced BP over a 24-hour period with once-daily administration in three major, randomized, controlled trials in which the primary endpoints were changes from baseline in 24-hour mean systolic BP (SBP) at week 6 (two trials) or week 24, assessed by ambulatory BP monitoring (ABPM). In the two 6-week trials, azilsartan medoxomil showed dose-dependent efficacy over all evaluated dosages and was more effective than placebo in lowering SBP. At the maximum approved dosage of 80 mg once daily, azilsartan medoxomil was significantly more effective than maximum dosages of olmesartan medoxomil (40 mg once daily) or valsartan (320 mg once daily), based on primary endpoint assessments. Mean reductions in clinic measurements of SBP and diastolic BP (DBP) measurements were also generally greater with azilsartan medoxomil 80 mg once daily than with the comparator drugs in these 6-week studies. Over a longer treatment period of 24 weeks, azilsartan medoxomil showed sustained BP-lowering efficacy, with the reduction in 24-hour mean SBP at week 24 significantly greater with azilsartan medoxomil 40 or 80 mg once daily than with valsartan 320 mg once daily. Mean reductions from baseline in mean clinic SBP and DBP as well as DBP by ABPM were also significantly greater with azilsartan medoxomil 40 or 80 mg once daily than with valsartan. Azilsartan medoxomil was generally well tolerated, with a tolerability profile similar to that of placebo in the 6-week trials. Across the three major trials, headache and dizziness were among the most common adverse events. Overall, rates of treatment discontinuation as a result of adverse events were low in the 6-week and 24-week trials. In conclusion, once-daily azilsartan medoxomil effectively lowers BP in adults with essential hypertension and has shown better antihypertensive efficacy than maximum therapeutic dosages of olmesartan medoxomil or valsartan in major trials of up to 24 weeks' duration. Azilsartan medoxomil is generally well tolerated and the low rates of discontinuation due to adverse events suggest that patients are likely to persist with long-term treatment. Azilsartan medoxomil is therefore a useful and attractive new option for lowering BP in patients with essential hypertension, particularly for those not able to tolerate other antihypertensive drugs. Further studies are required to evaluate the effects of azilsartan medoxomil on cardiovascular morbidity and mortality.

The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study.

PubMed

Li, Kun-Yan; Liang, Jian-Ping; Hu, Bing-Qiang; Qiu, Yu; Luo, Chen-Hui; Jiang, Yun; Lin, Xiao-Ping; Yang, Nong

2010-08-01

Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. This study investigated the relative bioavailability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-∞) were within the predetermined equivalence range (70%-143% for C(max); 80%-125% for AUC(0-t) and AUC(0-∞)), as established by the Chinese State Food and Drug Administration. Twenty-one healthy male subjects (mean age, 21 years [range, 18-25 years]; weight, 62.1 kg [range, 54.0-80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC(0-∞) values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C(max), AUC(0-48), and AUC(0-∞) were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated. Copyright © 2010 Excerpta Medica Inc. All rights reserved.

Angiotensin II receptor blocker improves the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice.

PubMed

Takada, Shingo; Kinugawa, Shintaro; Hirabayashi, Kagami; Suga, Tadashi; Yokota, Takashi; Takahashi, Masashige; Fukushima, Arata; Homma, Tsuneaki; Ono, Taisuke; Sobirin, Mochamad A; Masaki, Yoshihiro; Mizushima, Wataru; Kadoguchi, Tomoyasu; Okita, Koichi; Tsutsui, Hiroyuki

2013-04-01

NAD(P)H oxidase-induced oxidative stress is at least in part involved with lowered exercise capacity and impaired mitochondrial function in high-fat diet (HFD)-induced diabetic mice. NAD(P)H oxidase can be activated by activation of the renin-angiotensin system. We investigated whether ANG II receptor blocker can improve exercise capacity in diabetic mice. C57BL/6J mice were fed a normal diet (ND) or HFD, and each group of mice was divided into two groups: treatment with or without olmesartan (OLM; 3 mg·kg(-1)·day(-1) in the drinking water). The following groups of mice were studied: ND, ND+OLM, HFD, and HFD+OLM (n = 10 for each group). After 8 wk, HFD significantly increased body weight, plasma glucose, and insulin compared with ND, and OLM did not affect these parameters in either group. Exercise capacity, as determined by treadmill tests, was significantly reduced in HFD, and this reduction was ameliorated in HFD+OLM. ADP-dependent mitochondrial respiration was significantly decreased, and NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from HFD, which were attenuated by OLM. There were no such effects by OLM in ND. We concluded that OLM ameliorated the decrease in exercise capacity in diabetic mice via improvement in mitochondrial function and attenuation of oxidative stress in skeletal muscle. These data may have a clinical impact on exercise capacity in the medical treatment of diabetes mellitus.

Azilsartan medoxomil in the treatment of hypertension: the definitive angiotensin receptor blocker?

PubMed

Barrios, Vivencio; Escobar, Carlos

2013-11-01

Azilsartan medoxomil is the newest angiotensin receptor blocker marketed for the treatment of arterial hypertension. The aim of this article was to review the available evidence about this drug alone or combined with other antihypertensive agents in the treatment of hypertensive population. For this purpose, a search on MEDLINE and EMBASE databases was performed. The MEDLINE and EMBASE search included both medical subject headings (MeSHs) and keywords including azilsartan or azilsartan medoxomil or angiotensin receptor blockers or renin angiotensin system or chlorthalidone and hypertension. References of the retrieved articles were also screened for additional studies. There were no language restrictions. Azilsartan medoxomil has a potent and persistent ability to inhibit binding of angiotensin II to AT1 receptors, which may play a role in its superior blood pressure (BP) -lowering efficacy compared with other drugs, including ramipril, candesartan, valsartan or olmesartan, without an increase of side effects. Chlortalidone is a diuretic which significantly differs from other classic thiazides and has largely demonstrated clinical benefits in outcome trials. The fixed-dose combination of azilsartan and chlorthalidone has been shown to be more effective than other potent combinations of angiotensin receptor blockers plus hydrochlorothiazide, with a good tolerability profile.

Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines.

PubMed

Omboni, Stefano; Malacco, Ettore; Mallion, Jean-Michel; Volpe, Massimo

2015-01-01

In this paper, we present the results of a reanalysis of the data of two large randomized, double-blind, parallel group studies with a similar design, comparing the efficacy of an angiotensin-receptor blocker (olmesartan medoxomil) with that of an angiotensin-converting enzyme inhibitor (ramipril), by applying two different blood pressure targets recently recommended by hypertension guidelines for all patients, irrespective of the presence of diabetes (<140/90 mmHg), and for elderly hypertensive patients (<150/90 mmHg). The efficacy of olmesartan was not negatively affected by age, sex, hypertension type, diabetes status or other concomitant clinical conditions, or cardiovascular risk factors. In most cases, olmesartan provided better blood pressure control than ramipril. Olmesartan was significantly more effective than ramipril in male patients, in younger patients (aged 65-69 years), in those with metabolic syndrome, obesity, dyslipidemia, preserved renal function, diastolic ± systolic hypertension, and, in general, in patients with a high or very high cardiovascular risk. Interestingly, patients previously untreated or treated with two or more antihypertensive drugs showed a significantly larger response with olmesartan than with ramipril. Thus, our results confirm the good efficacy of olmesartan in elderly hypertensives even when new blood pressure targets for antihypertensive treatment are considered. Such results may be relevant for the clinical practice, providing some hint on the possible different response of elderly hypertensive patients to two different drugs acting on the renin-angiotensin system, when patients are targeted according to the blood pressure levels recommended by recent hypertension guidelines.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil ± hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial.

PubMed

Oparil, S; Chrysant, S G; Melino, M; Lee, J; Karki, S; Heyrman, R

2010-12-01

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML) + olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ≥65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5 + OM 40 mg per day, were uptitrated stepwise to AML 10 + OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ≥65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML + OM ± HCTZ was efficacious, safe and well tolerated by these subgroups.

Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats.

PubMed

Varagic, Jasmina; Ahmad, Sarfaraz; VonCannon, Jessica L; Moniwa, Norihito; Brosnihan, K Bridget; Wysocki, Jan; Batlle, Daniel; Ferrario, Carlos M

2013-05-01

We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II. mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin-angiotensin system (RAS) were measured at the completion of the experiments. Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration. Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang-(1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade.

Long-term efficacy of a combination of amlodipine and olmesartan medoxomil±hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status: a substudy of the COACH trial

PubMed Central

Oparil, S; Chrysant, S G; Melino, M; Lee, J; Karki, S; Heyrman, R

2010-01-01

A prespecified subgroup analysis of a 44-week open-label extension study is presented. The efficacy and safety of the combination of amlodipine (AML)+ olmesartan medoxomil (OM), with and without the addition of hydrochlorothiazide (HCTZ), were investigated in patients aged ⩾65 and <65 years, Blacks and non-Blacks and patients with and without type 2 diabetes. After an 8-week double-blind, placebo-controlled portion of the study, patients initiated therapy on AML 5+OM 40 mg per day, were uptitrated stepwise to AML 10+OM 40 mg per day, with the addition of HCTZ 12.5 mg, and 25 mg if blood pressure (BP) goal was not achieved (<140/90 or <130/80 mm Hg for patients with diabetes). Endpoints included the change from baseline in mean seated systolic BP, mean seated diastolic BP and achievement of BP goal. BP decreased from baseline for all treatments in each prespecified subgroup. By the end of the study, BP goal was achieved in 61.0% of patients aged ⩾65 years, 68.1% of patients aged <65 years, 63.3% of Blacks, 67.8% of non-Blacks, 26.9% of patients with diabetes and 72.9% of patients without diabetes. The combination of AML+OM±HCTZ was efficacious, safe and well tolerated by these subgroups. PMID:20200547

Design, formulation and optimization of novel soft nano-carriers for transdermal olmesartan medoxomil delivery: In vitro characterization and in vivo pharmacokinetic assessment.

PubMed

Kamran, Mohd; Ahad, Abdul; Aqil, Mohd; Imam, Syed Sarim; Sultana, Yasmin; Ali, Asgar

2016-05-30

Olmesartan is a hydrophobic antihypertensive drug with a short biological half-life, and low bioavailability, presents a challenge with respect to its oral administration. The objective of the work was to formulate, optimize and evaluate the transdermal potential of novel vesicular nano-invasomes, containing above anti-hypertensive agent. To achieve the above purpose, soft carriers (viz. nano-invasomes) of olmesartan with β-citronellene as potential permeation enhancer were developed and optimized using Box-Behnken design. The physicochemical characteristics e.g., vesicle size, shape, entrapment efficiency and skin permeability of the nano-invasomes formulations were evaluated. The optimized formulation was further evaluated for in vitro drug release, confocal microscopy and in vivo pharmacokinetic study. The optimum nano-invasomes formulation showed vesicles size of 83.35±3.25nm, entrapment efficiency of 65.21±2.25% and transdermal flux of 32.78±0.703 (μg/cm(2)/h) which were found in agreement with the predicted value generated by Box-Behnken design. Confocal laser microscopy of rat skin showed that optimized formulation was eventually distributed and permeated deep into the skin. The pharmacokinetic study presented that transdermal nano-invasomes formulation showed 1.15 times improvement in bioavailability of olmesartan with respect to the control formulation in Wistar rats. It was concluded that the response surfaces estimated by Design Expert(®) illustrated obvious relationship between formulation factors and response variables and nano-invasomes were found to be a proficient carrier system for transdermal delivery of olmesartan. Copyright © 2016 Elsevier B.V. All rights reserved.

Efficacy and tolerability of the single-pill combination of aliskiren 300 mg/amlodipine 10 mg in hypertensive patients not controlled by olmesartan 40 mg/amlodipine 10 mg.

PubMed

Axthelm, Christoph; Sieder, Christian; Meister, Franziska; Kaiser, Edelgard

2012-01-01

We aimed to investigate whether the single pill combination (SPC) of aliskiren 300 mg and amlodipine 10 mg (ALIS 300/AMLO 10) improves blood pressure (BP) reduction in hypertensive patients not adequately controlled by the SPC olmesartan 40 mg and amlodipine 10 mg (OLM 40/AMLO 10). Open-label, non-randomized single-arm study. Patients with stage 2 hypertension were titrated to the SPC OLM 40/AMLO 10 (4-week Phase 1). If hypertension was not controlled they were switched to the SPC ALIS 300/AMLO 10 (4-week Phase 2). In the optional 4-week study extension hydrochlorothiazide (HCT) 12.5 mg was added. EudraCT 2009-016693-33. In the 342 patients treated, OLM 40/AMLO 10 reduced systolic BP (SBP)/diastolic BP (DBP) by 24.5/14.5 mmHg by end of Phase 1. Those 187 patients with uncontrolled hypertension at the end of Phase 1 switched to ALIS 300/AMLO 10 experienced a further SBP reduction of 5.1 mmHg (95% confidence interval [CI] 3.7 to 6.5, p < 0.0001) and a DBP reduction of 4.8 mmHg (95% CI 3.8 to 5.8; p < 0.0001) in Phase 2. DBP or SBP responder rates were achieved by 51.3% or 44.4%, respectively, SBP and DBP normalization by 36.4%. In 65 patients whose BP was not controlled in Phase 2, SPC ALIS 300/AMLO 10/HCT 12.5 mg decreased SBP/DBP by further 8.1/6.7 mmHg (p < 0.0001 each). No deaths or serious adverse events were noted. Significant adverse events leading to study discontinuation were reported in 2.6% (Phase 1), 2.7% (Phase 2), and 0% (extension). Limitations included the open-label, single-arm non-randomized design, and the relatively short duration. In this switch study reflecting clinical practice, patients with moderate hypertension not controlled by the SPC OLM 40/AMLO 10 achieved a clinically and statistically significant reduction of blood pressure from the SPC ALIS 300/AMLO 10 and the optional addition of HCT. All drug combinations were well tolerated.

Predominance of AT1 Blockade Over Mas–Mediated Angiotensin-(1–7) Mechanisms in the Regulation of Blood Pressure and Renin–Angiotensin System in mRen2.Lewis Rats

PubMed Central

2013-01-01

BACKGROUND We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT1-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1–7) in the absence of significant changes in plasma Ang II. METHODS mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin–angiotensin system (RAS) were measured at the completion of the experiments. RESULTS Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1–7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1–7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1–7) receptor antagonist except for a mild further increase in plasma renin concentration. CONCLUSIONS Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT1-R blockade. Ang-(1–7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT1-R blockade. PMID:23459599

Development of olmesartan medoxomil optimized nanosuspension using the Box-Behnken design to improve oral bioavailability.

PubMed

Nagaraj, K; Narendar, D; Kishan, V

2017-07-01

The aim of the present investigation was to enhance the oral bioavailability of olmesartan medoxomil by improving its solubility and dissolution rate by preparing nanosuspension (OM-NS), using the Box-Behnken design. In this, four factors were evaluated at three levels. Independent variables include: concentration of drug (X 1 ), concentration of surfactant (X 2 ), concentration of polymer (X 3 ) and number of homogenization cycles (X 4 ). Based on preliminary studies, the size (Y 1 ), zeta potential (ZP) (Y 2 ) and % drug release at 5 min (Y 3 ) were chosen as dependent responses. OM-NS was prepared by high pressure homogenization method. The size, PDI, ZP, assay, in vitro release and morphology of OM-NS were characterized. Further, the pharmacokinetic (PK) behavior of OM-NS was evaluated in male wistar rats. Statistically optimized OM-NS formulation exhibited mean particle size of 492 nm, ZP of -27.9 mV and 99.29% release in 5 min. OM-NS showed more than four times increase in its solubility than pure OM. DSC and XRD analyses indicated that the drug incorporated into OM-NS was in amorphous form. The morphology of OM-NS was found to be nearly spherical with high dispersity by scanning electron microscopic studies. The PK results showed that OM lyophilized nanosuspension (NS) exhibited improved PK properties compared to coarse powder suspension and marketed tablet powder suspension (TS). Oral bioavailability of lyophilized NS was increased by 2.45 and 2.25 folds when compared to marketed TS and coarse powder suspension, respectively. Results of this study lead to conclusion that NS approach was effective in preparing OM formulations with enhanced dissolution and improved oral bioavailability.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-10-01

[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Azilsartan medoxomil: a new Angiotensin receptor blocker.

PubMed

Zaiken, Kathy; Cheng, Judy W M

2011-11-01

Azilsartan medoxomil is an angiotensin receptor blocker, approved on February 25, 2011 by the US Food and Drug Administration (FDA) for hypertension management. The purpose of this study was to review the pharmacology, pharmacokinetics, efficacy, safety profile, and role of azilsartan for hypertension management. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE and Current Contents (both 1966 to August 31, 2011) using the search terms azilsartan, TAK-491, TAK-536, pharmacology, pharmacokinetics, pharmacodynamics, pharmacoeconomics, and cost-effectiveness. The FDA Web site and manufacturer prescribing information were also reviewed to identify other relevant information. Compared with olmesartan 40 mg daily, azilsartan 80 mg reduced mean systolic blood pressure (SBP) by an additional 2.1 mm Hg (P = 0.038), whereas azilsartan 40 mg was noninferior to olmesartan 40 mg. Azilsartan 40 mg or 80 mg added to chlorthalidone 25 mg daily significantly reduced SBP to a greater extent than did chlorthalidone alone (P < 0.05), but there was no difference between azilsartan 40 mg and 80 mg (40 mg: -31.72 mm Hg; 80 mg: -31.3 mm Hg [P > 0.05]). When coadministered with amlodipine 5 mg daily, both azilsartan 40 mg and 80 mg + amlodipine decreased SBP significantly more than amlodipine alone (amlodipine: -13.6 mm Hg; with azilsartan 40 mg: -24.79 mm Hg; with azilsartan 80 mg: -24.51 mm Hg [P < 0.05]). Compared with ramipril 10 mg daily, both azilsartan 40 mg and 80 mg resulted in significantly (P < 0.001) greater reductions in mean SBP (-20.63 and -21.24 mm Hg, respectively; ramipril: -12.22 mm Hg). The most common adverse events reported were dizziness (4%), dyslipidemia (3.3%), and diarrhea (2%). At the recommended dose of 80 mg once daily, azilsartan is reported to be an efficacious BP-lowering agent. With once-daily dosing and a favorable side-effect profile, azilsartan is an attractive option for the treatment of hypertension. There is a lack of data supporting the use of azilsartan for improvement in cardiovascular outcomes; therefore, azilsartan is not approved for indications other than the treatment of hypertension. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Efficacy of an amlodipine/olmesartan treatment algorithm in patients with or without type 2 diabetes and hypertension (a secondary analysis of the BP-CRUSH study).

PubMed

Nesbitt, S D; Shojaee, A; Maa, J-F; Weir, M R

2013-07-01

A prespecified subgroup analysis of an open-label, multicenter, single-arm, dose-titration study is presented. The efficacy and safety of 20-week treatment with an amlodipine (AML)/olmesartan medoxomil (OM)±hydrochlorothiazide (HCTZ) algorithm were assessed in patients with hypertension and type 2 diabetes mellitus (T2DM) who were uncontrolled by antihypertensive monotherapy. Eligible patients received AML/OM 5/20 mg for 4 weeks, followed by stepwise uptitration to AML/OM 5/40 mg, AML/OM 10/40 mg, AML/OM 10/40 mg+HCTZ 12.5 mg and AML/OM 10/40 mg+HCTZ 25 mg at 4-week intervals if blood pressure (BP) remained uncontrolled. The primary end point was the achievement of the seated cuff systolic BP (SeSBP) goal (<140 mm Hg, or <130 mm Hg for patients with T2DM) at week 12. Seated cuff BP was significantly reduced from baseline at all titration dose periods. At week 12, the cumulative SeSBP goal was achieved by 57.9% and 80.1% of patients in the T2DM and non-T2DM subgroups, respectively. Treatment was well tolerated, with low rates of peripheral edema. In summary, switching to a treatment algorithm based on AML/OM±HCTZ after failed monotherapy was safe and improved BP control in patients with hypertension and T2DM.

Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients.

PubMed

Ogawa, Hisao; Kim-Mitsuyama, Shokei; Matsui, Kunihiko; Jinnouchi, Tomio; Jinnouchi, Hideaki; Arakawa, Kikuo

2012-10-01

It is unknown whether high-dose angiotensin II receptor blocker therapy or angiotensin II receptor blocker + calcium channel blocker combination therapy is better in elderly hypertensive patients with high cardiovascular risk. The objective of the study was to compare the efficacy of these treatments in elderly, high-risk Japanese hypertensive patients. The OlmeSartan and Calcium Antagonists Randomized (OSCAR) study was a multicenter, prospective, randomized, open-label, blinded-end point study of 1164 hypertensive patients aged 65 to 84 years with type 2 diabetes or cardiovascular disease. Patients with uncontrolled hypertension during treatment with olmesartan 20 mg/d were randomly assigned to receive 40 mg/d olmesartan (high-dose angiotensin II receptor blocker) or a calcium channel blocker + 20 mg/d olmesartan (angiotensin II receptor blocker + calcium channel blocker). The primary end point was a composite of cardiovascular events and noncardiovascular death. During a 3-year follow-up, blood pressure was significantly lower in the angiotensin II receptor blocker + calcium channel blocker group than in the high-dose angiotensin II receptor blocker group. Mean blood pressure at 36 months was 135.0/74.3 mm Hg in the high-dose angiotensin II receptor blocker group and 132.6/72.6 mm Hg in the angiotensin II receptor blocker + calcium channel blocker group. More primary end points occurred in the high-dose angiotensin II receptor blocker group than in the angiotensin II receptor blocker + calcium channel blocker group (58 vs 48 events, hazard ratio [HR], 1.31, 95% confidence interval, 0.89-1.92; P=.17). In patients with cardiovascular disease at baseline, more primary events occurred in the high-dose angiotensin II receptor blocker group (HR, 1.63, P=.03); in contrast, fewer events were observed in the subgroup without cardiovascular disease (HR, 0.52, P=.14). This treatment-by-subgroup interaction was significant (P=.02). The angiotensin II receptor blocker and calcium channel blocker combination lowered blood pressure more than the high-dose angiotensin II receptor blocker and reduced the incidence of primary end points more than the high-dose angiotensin II receptor blocker in patients with cardiovascular disease. The addition of a second antihypertensive agent is more effective at lowering blood pressure than simply doubling the dose of an existing agent. Copyright © 2012 Elsevier Inc. All rights reserved.

Azilsartan Medoxomil, an Angiotensin II Receptor Antagonist for the Treatment of Hypertension.

PubMed

Hjermitslev, Marie; Grimm, Daniela G; Wehland, Markus; Simonsen, Ulf; Krüger, Marcus

2017-10-01

Azilsartan (AZL) medoxomil was approved by the United States Food and Drug Administration in 2011 for the treatment of hypertension and has shown promising results both in blood pressure (BP) reduction and in tolerability, but has not yet been taken into practice to the same extent as other angiotensin II receptor blockers (ARBs) that have been on the market for a longer period. AZL antagonizes the AT 1 receptor for angiotensin II (ANG II), whereas angiotensin-converting enzyme inhibitors block the conversion of angiotensin I to ANG II, but not alternative routes of formation of ANG II. The bioavailability of AZL is about 60% and it has a t max of 1.5-3 hr and a half-life of approximately 11 hr. With its IC 50 of 7.4 nM after 5 hr of drug washout in radioligand assays, AZL has a tighter and longer-lasting binding to the AT 1 receptor by several orders of magnitude than other ARBs, which might lead to a more effective reduction in BP. Clinical studies have revealed that AZL doses of 40 and 80 mg/day reduce BP significantly better than maximal clinical doses of valsartan or olmesartan, while being well tolerated and exhibiting a spectrum of adverse effects comparable to those of other ARBs. These properties of AZL might lower the risk of cardiovascular disease and thereby reduce mortality rates. However, the existing mortality studies have not found this correlation, which should be further investigated. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-06-01

(+)-Dapoxetine hydrochloride; Abatacept, Adalimumab, Agalsidase beta, Alemtuzumab, Alglucosidase alfa, Aliskiren fumarate, Ambrisentan, Amlodipine, Aripiprazole, Atrasentan, Azacitidine, Azelnidipine; Belotecan hydrochloride, Bevacizumab, Bilastine, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, CG-100649, Cinacalcet hydrochloride, Clindamycin phosphate/ benzoyl peroxide; Dasatinib, Denosumab, Duloxetine hydrochloride, Dutasteride, Dutasteride/tamsulosin; Ecogramostim, Eculizumab, Eltrombopag olamine, EndoTAG-1, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe; FAHF-2, Fondaparinux sodium; Gefitinib, Golimumab; HEV-239, HSV-TK; Imatinib mesylate, Indium 111 ((111)In) ibritumomab tiuxetan, Influenza vaccine(surface antigen, inactivated, prepared in cell culture), Insulin glargine; Kisspeptin-54; Lidocaine/prilocaine, Lomitapide; Maraviroc, Mirodenafil hydrochloride, MK-8141, MVA-Ag85A; Nilotinib hydrochloride monohydrate; Olmesartan medoxomil; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pitavastatin calcium, Prasugrel; Recombinant human relaxin H2, RHAMM R3 peptide, Rivaroxaban, Rosuvastatin calcium, RRz2; Sagopilone, Salinosporamide A, SB-509, Serlopitant, Sirolimus-eluting stent, Sorafenib, Sunitinib malate; Tadalafil, Temsirolimus, Teriparatide, TG-4010, Tositumomab/iodine (I131) tositumomab; Velusetrag Hydrochloride; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Olmesartan with azelnidipine versus with trichlormethiazide on home blood pressure variability in patients with type II diabetes mellitus.

PubMed

Ushigome, Emi; Matsumoto, Shinobu; Oyabu, Chikako; Ushigome, Hidetaka; Yokota, Isao; Hasegawa, Goji; Nakamura, Naoto; Tanaka, Muhei; Yamazaki, Masahiro; Fukui, Michiaki

2017-03-01

The aim of the present study was to compare the effects of olmesartan combined with azelnidipine versus olmesartan combined with trichlormethiazide, on home blood pressure (BP) and pressure variability in type II diabetes mellitus patients using home BP telemonitoring system. We performed an open-label cross-over pilot study of 28 patients with type II diabetes mellitus. Patients received combination treatment with either olmesartan 20 mg plus azelnidipine 16 mg or olmesartan 20 mg plus trichlormethiazide 1 mg for more than 6 weeks each in a cross-over method. The coefficient of morning systolic BP variability in the olmesartan plus azelnidipine group was significantly lower than that in the olmesartan plus trichlormethiazide group (6.4 ± 1.9 vs. 7.5 ± 2.6, P = .004). There were no significant differences in mean morning systolic BP between the two groups. Using home BP telemonitoring for hypertensive patients with type II diabetes, this study revealed for the first time that the olmesartan with azelnidipine combination is superior to the olmesartan with trichlormethiazide combination in reducing home BP variability. Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized, double-blind, 8-week study.

PubMed

Cheung, Deanna G; Aizenberg, Diego; Gorbunov, Vladimir; Hafeez, Kudsia; Chen, Chien-Wei; Zhang, Jack

2018-01-01

A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double-blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8-week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24-hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (-4.3 mm Hg vs -1.1 mm Hg, P < .001). Reductions in 24-hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg. ©2018 Wiley Periodicals, Inc.

Brain regions involved in subprocesses of small-space episodic object-location memory: a systematic review of lesion and functional neuroimaging studies.

PubMed

Zimmermann, Kathrin; Eschen, Anne

2017-04-01

Object-location memory (OLM) enables us to keep track of the locations of objects in our environment. The neurocognitive model of OLM (Postma, A., Kessels, R. P. C., & Van Asselen, M. (2004). The neuropsychology of object-location memory. In G. L. Allen (Ed.), Human spatial memory: Remembering where (pp. 143-160). Mahwah, NJ: Lawrence Erlbaum, Postma, A., Kessels, R. P. C., & Van Asselen, M. (2008). How the brain remembers and forgets where things are: The neurocognition of object-location memory. Neuroscience & Biobehavioral Reviews, 32, 1339-1345. doi: 10.1016/j.neubiorev.2008.05.001 ) proposes that distinct brain regions are specialised for different subprocesses of OLM (object processing, location processing, and object-location binding; categorical and coordinate OLM; egocentric and allocentric OLM). It was based mainly on findings from lesion studies. However, recent episodic memory studies point to a contribution of additional or different brain regions to object and location processing within episodic OLM. To evaluate and update the neurocognitive model of OLM, we therefore conducted a systematic literature search for lesion as well as functional neuroimaging studies contrasting small-space episodic OLM with object memory or location memory. We identified 10 relevant lesion studies and 8 relevant functional neuroimaging studies. We could confirm some of the proposals of the neurocognitive model of OLM, but also differing hypotheses from episodic memory research, about which brain regions are involved in the different subprocesses of small-space episodic OLM. In addition, we were able to identify new brain regions as well as important research gaps.

TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus

PubMed Central

Hurtado-Zavala, Joaquin I.; Ramachandran, Binu; Ahmed, Saheeb; Halder, Rashi; Bolleyer, Christiane; Awasthi, Ankit; Stahlberg, Markus A.; Wagener, Robin J.; Anderson, Kristin; Drenan, Ryan M.; Lester, Henry A.; Miwa, Julie M.; Staiger, Jochen F.; Fischer, Andre; Dean, Camin

2017-01-01

TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine—via α2β2-containing nicotinic receptors—to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity. PMID:28722015

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-05-01

O(6)-Benzylguanine; (-)-Gossypol; Abatacept, AC-2592, Adalimumab, AIDSVAX gp120 B/E, Alemtuzumab, Aliskiren fumarate, ALVAC E120TMG, Ambrisentan, Amlodipine, Anakinra, Aripiprazole, Armodafinil, Atomoxetine hydrochloride, Avotermin; Bevacizumab, BIBW-2992, Bortezomib, Bosentan, Botulinum toxin type B; Canakinumab, CAT-354, Ciclesonide, CMV gB vaccine, Corifollitropin alfa, Daptomycin, Darbepoetin alfa, Dasatinib, Denosumab; EndoTAG-1, Eplerenone, Esomeprazole sodium, Eszopiclone, Etoricoxib, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; F-50040, Fesoterodine fumavate, Fondaparinux sodium, Fulvestrant; Gabapentin enacarbil, Golimumab; Imatinib mesylate, Inhalable human insulin, Insulin glargine, Ivabradine hydrochloride; Lercanidipine hydrochloride/enalapril maleate, Levosimendan, Liposomal vincristine sulfate, Liraglutide; MDV-3100, Mometasone furoate/formoterol fumavate, Multiepitope CTL peptide vaccine, Mycophenolic acid sodium salt, Nabiximols, Natalizumab, Nesiritide; Obeticholic acid, Olmesartan medoxomil, Omalizumab, Omecamtiv mecarbil; Paclitaxel-eluting stent, Paliperidone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, Polymyxin B nonapeptide, PORxin-302, Prasugrel, Pregabalin, Pridopidine; Ranelic acid distrontium salt, Rasagiline mesilate, rDEN4delta30-4995, Recombinant human relaxin H2, rhFSH, Rilonacept, Rolofylline, Rosiglitazone maleate/metformin hydrochloride, Rosuvastatin calcium, Rotigotine; Salcaprozic acid sodium salt, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, Temsirolimus, Tenofovir, Tenofovir disoproxil fumarate, Teriparatide, Tiotropium bromide, Tocilizumab, Tolvaptan, Tozasertib, Treprostinil sodium; Ustekinumab; Vardenafil hydrochloride hydrate, Varenicline tartrate, Vatalanib succinate, Voriconazole, Vorinostat; Zotarolimus-eluting stent. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-12-01

Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity. prous.com. This issue focuses on the following selection of drugs: 131I-chTNT; Abatacept, adalimumab, alemtuzumab, APC-8015, aprepitant, atazanavir sulfate, atomoxetine hydrochloride, azimilide hydrochloride; Bevacizumab, bortezomib, bosentan, buserelin; Caspofungin acetate, CC-4047, ChAGCD3, ciclesonide, clopidogrel, curcumin, Cypher; Dabigatran etexilate, dapoxetine hydrochloride, darbepoetin alfa, darusentan, denosumab, DMXB-Anabaseine, drospirenone, drospirenone/estradiol, duloxetine hydrochloride, dutasteride; Edodekin alfa, efaproxiral sodium, elaidic acid-cytarabine, erlotinib hydrochloride, ertapenem sodium, escitalopram oxalate, eszopiclone, etonogestrel/testosterone decanoate, exenatide; Fulvestrant; Gefitinib, glycine, GVS-111; Homoharringtonine; ICC-1132, imatinib mesylate, iodine (I131) tositumomab, i.v. gamma-globulin; Levetiracetam, levocetirizine, lintuzumab, liposomal nystatin, lumiracoxib, lurtotecan; Manitimus, mapatumumab, melatonin, micafungin sodium, mycophenolic acid sodium salt; Oblimersen sodium, OGX-011, olmesartan medoxomil, omalizumab, omapatrilat, oral insulin; Parathyroid hormone (human recombinant), pasireotide, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, phVEGF-A165, pimecrolimus, pitavastatin calcium, plerixafor hydrochloride, posaconazole, pramlintide acetate, prasterone, pregabalin, PT-141; Quercetin; Ranolazine, rosuvastatin calcium, rubitecan, rupatadine fumarate; Sardomozide, sunitinib malate; Tadalafil, talactoferrin alfa, tegaserod maleate, telithromycin, testosterone transdermal patch, TH-9507, tigecycline, tiotropium bromide, tipifarnib, tocilizumab, treprostinil sodium; Valdecoxib, vandetanib, vardenafil hydrochloride hydrate, voriconazole. Copyright 2005 Prous Science. All rights reserved.

The association between optimal lifestyle-related health behaviors and employee productivity.

PubMed

Katz, Abigail S; Pronk, Nicolaas P; Lowry, Marcia

2014-07-01

To investigate the association between lifestyle-related health behaviors including sleep and the cluster of physical activity, no tobacco use, fruits and vegetables intake, and alcohol consumption termed the "Optimal Lifestyle Metric" (OLM), and employee productivity. Data were obtained from employee health assessments (N = 18,079). Regression techniques were used to study the association between OLM and employee productivity, sleep and employee productivity, and the interaction of both OLM and sleep on employee productivity. Employees who slept less or more than 7 or 8 hours per night experienced significantly more productivity loss. Employees who adhered to all four OLM behaviors simultaneously experienced less productivity loss compared with those who did not. Adequate sleep and adherence to the OLM cluster of behaviors are associated with significantly less productivity loss.

Comparison of Efficacy and Safety of Azilsartan and Olmesartan in Patients With Essential Hypertension.

PubMed

Shiga, Yuhei; Miura, Shin-Ichiro; Motozato, Kota; Norimatsu, Kenji; Yano, Masaya; Hitaka, Yuka; Adachi, Sen; Kuwano, Takashi; Inoue, Ken; Inoue, Asao; Fujisawa, Kazuaki; Shirotani, Tetsuro; Kusumoto, Takaaki; Ideishi, Munehito; Saku, Keijiro

2017-05-31

Many patients still have high blood pressure (BP) after treatment with angiotensin II type 1 (AT 1 ) 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.

Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study)

PubMed Central

Osaka, Shunji; Yaoita, Hiroko; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi; Sakino, Hisakuni

2016-01-01

Background: Angiotensin II receptor blockers (ARBs) have been widely used to treat hypertension and large-scale clinical studies have shown various benefits. In this study, we compared olmesartan with azilsartan, the newest ARB. Methods: The subjects were outpatients who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. The primary endpoints were the levels of plasma renin activity, angiotensin II, and aldosterone. Results: Home blood pressure exceeded 140/90 mmHg and additional antihypertensive medication was administered to 12 patients (20 episodes) in the azilsartan group versus 4 patients (4 episodes) in the olmesartan group, with the number being significantly higher in the azilsartan group. After 1 year of treatment, both angiotensin II and aldosterone levels were significantly lower in the olmesartan group than the azilsartan group. Left ventricular mass index was also significantly lower in the olmesartan group than the azilsartan group. Conclusion: This study showed that olmesartan reduces angiotensin II and aldosterone levels more effectively than azilsartan. Accordingly, it may be effective in patients with increased renin-angiotensin-aldosterone system activity after cardiac surgery or patients with severe cardiac hypertrophy. PMID:27086671

Changeover Trial of Azilsartan and Olmesartan Comparing Effects on the Renin-Angiotensin-Aldosterone System in Patients with Essential Hypertension after Cardiac Surgery (CHAOS Study).

PubMed

Sezai, Akira; Osaka, Shunji; Yaoita, Hiroko; Arimoto, Munehito; Hata, Hiroaki; Shiono, Motomi; Sakino, Hisakuni

2016-06-20

Angiotensin II receptor blockers (ARBs) have been widely used to treat hypertension and large-scale clinical studies have shown various benefits. In this study, we compared olmesartan with azilsartan, the newest ARB. The subjects were outpatients who were clinically stable after cardiac surgery. Sixty patients were randomized to receive either azilsartan or olmesartan for 1 year and were switched to the other drug for the following 1 year. The primary endpoints were the levels of plasma renin activity, angiotensin II, and aldosterone. Home blood pressure exceeded 140/90 mmHg and additional antihypertensive medication was administered to 12 patients (20 episodes) in the azilsartan group versus 4 patients (4 episodes) in the olmesartan group, with the number being significantly higher in the azilsartan group. After 1 year of treatment, both angiotensin II and aldosterone levels were significantly lower in the olmesartan group than the azilsartan group. Left ventricular mass index was also significantly lower in the olmesartan group than the azilsartan group. This study showed that olmesartan reduces angiotensin II and aldosterone levels more effectively than azilsartan. Accordingly, it may be effective in patients with increased renin-angiotensin-aldosterone system activity after cardiac surgery or patients with severe cardiac hypertrophy.

Efficacy and Safety of Sacubitril/Valsartan (LCZ696) Compared With Olmesartan in Elderly Asian Patients (≥65 Years) With Systolic Hypertension.

PubMed

Supasyndh, Ouppatham; Wang, Jian'an; Hafeez, Kudsia; Zhang, Ying; Zhang, Jack; Rakugi, Hiromi

2017-11-06

Systolic hypertension is common in elderly patients and remains a challenge to treat effectively. The efficacy and safety of sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, vs. olmesartan was evaluated in elderly Asian patients (≥65 years) with systolic hypertension. In this randomized, double-blind, 14-week study, patients initially received once-daily sacubitril/valsartan 100 mg or olmesartan 10 mg, increased to sacubitril/valsartan 200 mg or olmesartan 20 mg at week 4. At week 10, for patients with blood pressure (BP) >140/90 mm Hg, the doses were up-titrated to sacubitril/valsartan 400 mg or olmesartan 40 mg. The primary assessment was superiority of sacubitril/valsartan vs. olmesartan in reducing office mean sitting (ms) systolic BP (msSBP) from baseline at week 10. Secondary efficacy assessments included changes from baseline in ms diastolic BP (msDBP), ms pulse pressure (msPP), 24-hour mean ambulatory (ma) BP (maBP), and maPP at week 10; msBP and msPP at weeks 4 and 14. Overall, 588 patients were randomized (mean age, 70.7 years; baseline msBP, 160.3/84.9 mm Hg; msPP, 75.4 mm Hg). At week 10, sacubitril/valsartan provided superior msSBP reductions vs. olmesartan (22.71 vs. 16.11 mm Hg, respectively; P < 0.001); similarly, reductions from baseline in other BP and PP assessments were significantly greater with sacubitril/valsartan. At week 14, despite more patients requiring up-titration in the olmesartan group, msBP and msPP reductions from baseline were significantly greater with sacubitril/valsartan. Both treatments were generally well-tolerated. Sacubitril/valsartan is more effective than olmesartan in reducing BP in elderly Asian patients with systolic hypertension. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Anti-Melanogenic Effect of Oenothera laciniata Methanol Extract in Melan-a Cells.

PubMed

Kim, Su Eun; Lee, Chae Myoung; Kim, Young Chul

2017-01-01

We evaluated the antioxidant activity and anti-melanogenic effects of Oenothera laciniata methanol extract (OLME) in vitro by using melan-a cells. The total polyphenol and flavonoid content of OLME was 66.3 and 19.0 mg/g, respectively. The electron-donating ability, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity, and superoxide dismutase (SOD)-like activity of OLME (500 μg/mL) were 94.5%, 95.6%, and 63.6%, respectively. OLME and arbutin treatment at 50 μg/mL significantly decreased melanin content by 35.5% and 14.2%, respectively, compared to control ( p < 0.05). OLME and arbutin treatment at 50 μg/mL significantly inhibited intra-cellular tyrosinase activity by 22.6% and 12.6%, respectively, compared to control ( p < 0.05). OLME (50 μg/mL) significantly decreased tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor-M (MITF-M) mRNA expression by 57.1%, 67.3%, 99.0%, and 77.0%, respectively, compared to control ( p < 0.05). Arbutin (50 μg/mL) significantly decreased tyrosinase, TRP-1, and TRP-2 mRNA expression by 24.2%, 42.9%, and 48.5%, respectively, compared to control ( p < 0.05). However, arbutin (50 μg/mL) did not affect MITF-M mRNA expression. Taken together, OLME showed a good antioxidant activity and anti-melanogenic effect in melan-a cells that was superior to that of arbutin, a well-known skin-whitening agent. The potential mechanism underlying the anti-melanogenic effect of OLME was inhibition of tyrosinase activity and down-regulation of tyrosinase, TRP-1, TRP-2, and MITF-M mRNA expression.

Anti-Melanogenic Effect of Oenothera laciniata Methanol Extract in Melan-a Cells

PubMed Central

Kim, Su Eun; Lee, Chae Myoung; Kim, Young Chul

2017-01-01

We evaluated the antioxidant activity and anti-melanogenic effects of Oenothera laciniata methanol extract (OLME) in vitro by using melan-a cells. The total polyphenol and flavonoid content of OLME was 66.3 and 19.0 mg/g, respectively. The electron-donating ability, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity, and superoxide dismutase (SOD)-like activity of OLME (500 μg/mL) were 94.5%, 95.6%, and 63.6%, respectively. OLME and arbutin treatment at 50 μg/mL significantly decreased melanin content by 35.5% and 14.2%, respectively, compared to control (p < 0.05). OLME and arbutin treatment at 50 μg/mL significantly inhibited intra-cellular tyrosinase activity by 22.6% and 12.6%, respectively, compared to control (p < 0.05). OLME (50 μg/mL) significantly decreased tyrosinase, tyrosinase-related protein-1 (TRP-1), TRP-2, and microphthalmia-associated transcription factor-M (MITF-M) mRNA expression by 57.1%, 67.3%, 99.0%, and 77.0%, respectively, compared to control (p < 0.05). Arbutin (50 μg/mL) significantly decreased tyrosinase, TRP-1, and TRP-2 mRNA expression by 24.2%, 42.9%, and 48.5%, respectively, compared to control (p < 0.05). However, arbutin (50 μg/mL) did not affect MITF-M mRNA expression. Taken together, OLME showed a good antioxidant activity and anti-melanogenic effect in melan-a cells that was superior to that of arbutin, a well-known skin-whitening agent. The potential mechanism underlying the anti-melanogenic effect of OLME was inhibition of tyrosinase activity and down-regulation of tyrosinase, TRP-1, TRP-2, and MITF-M mRNA expression. PMID:28133514

Role of angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis in the hypotensive effect of azilsartan.

PubMed

Iwanami, Jun; Mogi, Masaki; Tsukuda, Kana; Wang, Xiao-Li; Nakaoka, Hirotomo; Ohshima, Kousei; Chisaka, Toshiyuki; Bai, Hui-Yu; Kanno, Harumi; Min, Li-Juan; Horiuchi, Masatsugu

2014-07-01

The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT1) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT1 receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-α mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT1 receptor blockade.

Applying Online Monitoring for Nuclear Power Plant Instrumentation and Control

NASA Astrophysics Data System (ADS)

Hashemian, H. M.

2010-10-01

This paper presents a practical review of the state-of-the-art means for applying OLM data acquisition in nuclear power plant instrumentation and control, qualifying or validating the OLM data, and then analyzing it for static and dynamic performance monitoring applications. Whereas data acquisition for static or steady-state OLM applications can require sample rates of anywhere from 1 to 10 seconds to 1 minutes per sample, for dynamic data acquisition, higher sampling frequencies are required (e.g., 100 to 1000 Hz) using a dedicated data acquisition system capable of providing isolation, anti-aliasing and removal of extraneous noise, and analog-to-digital (A/D) conversion. Qualifying the data for use with OLM algorithms can involve removing data `dead' spots (for static data) and calculating, examining, and trending amplitude probability density, variance, skewness, and kurtosis. For static OLM applications with redundant signals, trending and averaging qualification techniques are used, and for single or non-redundant signals physical and empirical modeling are used. Dynamic OLM analysis is performed in the frequency domain and/or time domain, and is based on the assumption that sensors' or transmitters' dynamic characteristics are linear and that the input noise signal (i.e., the process fluctuations) has proper spectral characteristics.

Effects of olmesartan on the renin-angiotensin-aldosterone system for patients with essential hypertension after cardiac surgery--investigation using a candesartan change-over study.

PubMed

Sezai, Akira; Soma, Masayoshi; Hata, Mitsumasa; Yoshitake, Isamu; Unosawa, Satoshi; Wakui, Shinji; Shiono, Motomi

2011-01-01

Various angiotensin II receptor blockers are widely used for the treatment of hypertension in recent years. The results of large-scale clinical studies have shown that they have various efficacies: not only hypotensive effects but also organ protective effects. In this study, the effects of a change-over from candesartan to olmesartan on renin-angiotensin-aldsterone system, cardiomegaly and peripheral circulation were studied. Participants enrolled in this trial were outpatients with essential hypertension after cardiac surgery who had received candesartan for more than one year. Fifty-six patients switched from candesartan to olmesartan. The primary endpoints were 1) renin activity, angiotensin II, aldosterone, and 2) left ventricular mass index (LVMI). It was clear that angiotensin II and aldosterone are decreased by the potent hypotensive effects of olmesartan in a change-over from candesartan to olmesartan. Since LVMI and BNP were decreased, inhibitory effects on myocardial hypertrophy were also confirmed. In the present study, left ventricular hypertrophy and on arterial compliance were inhibited by a decrease in angiotensin II and aldosterone due to the change-over to olmesartan. In the future, protective effects on organs will be clarified by long-term observations.

Evaluation of NO2 predictions by the plume volume molar ratio method (PVMRM) and ozone limiting method (OLM) in AERMOD using new field observations.

PubMed

Hendrick, Elizabeth M; Tino, Vincent R; Hanna, Steven R; Egan, Bruce A

2013-07-01

The U.S. Environmental Protection Agency (EPA) plume volume molar ratio method (PVMRM) and the ozone limiting method (OLM) are in the AERMOD model to predict the 1-hr average NO2/NO(x) concentration ratio. These ratios are multiplied by the AERMOD predicted NO(x) concentration to predict the 1-hr average NO2 concentration. This paper first briefly reviews PVMRM and OLM and points out some scientific parameterizations that could be improved (such as specification of relative dispersion coefficients) and then discusses an evaluation of the PVMRM and OLM methods as implemented in AERMOD using a new data set. While AERMOD has undergone many model evaluation studies in its default mode, PVMRM and OLM are nondefault options, and to date only three NO2 field data sets have been used in their evaluations. Here AERMOD/PVMRM and AERMOD/OLM codes are evaluated with a new data set from a northern Alaskan village with a small power plant. Hourly pollutant concentrations (NO, NO2, ozone) as well as meteorological variables were measured at a single monitor 500 m from the plant. Power plant operating parameters and emissions were calculated based on hourly operator logs. Hourly observations covering 1 yr were considered, but the evaluations only used hours when the wind was in a 60 degrees sector including the monitor and when concentrations were above a threshold. PVMRM is found to have little bias in predictions of the C(NO2)/C(NO(x)) ratio, which mostly ranged from 0.2 to 0.4 at this site. OLM overpredicted the ratio. AERMOD overpredicts the maximum NO(x) concentration but has an underprediction bias for lower concentrations. AERMOD/PVMRM overpredicts the maximum C(NO2) by about 50%, while AERMOD/OLM overpredicts by a factor of 2. For 381 hours evaluated, there is a relative mean bias in C(NO2) predictions of near zero for AERMOD/PVMRM, while the relative mean bias reflects a factor of 2 overprediction for AERMOD/OLM. This study was initiated because the new stringent 1-hr NO2 NAAQS has prompted modelers to more widely use the PVMRM and OLM methods for conversion of NO(x) to NO2 in the AERMOD regulatory model. To date these methods have been evaluated with a limited number of data sets. This study identified a new data set of ambient pollutant and meteorological monitoring near an isolated power plant in Wainwright, Alaska. To supplement the existing evaluations, this new data were used to evaluate PVMRM and OLM. This new data set has been and will be made available to other scientists for future investigations.

Sleep and Movement Differentiates Actions of Two Types of Somatostatin-Expressing GABAergic Interneuron in Rat Hippocampus

PubMed Central

Katona, Linda; Lapray, Damien; Viney, Tim J.; Oulhaj, Abderrahim; Borhegyi, Zsolt; Micklem, Benjamin R.; Klausberger, Thomas; Somogyi, Peter

2014-01-01

Summary Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3. PMID:24794095

Use of multiattribute utility theory for formulary management in a health system.

PubMed

Chung, Seonyoung; Kim, Sooyon; Kim, Jeongmee; Sohn, Kieho

2010-01-15

The application, utility, and flexibility of the multiattribute utility theory (MAUT) when used as a formulary decision methodology in a Korean medical center were evaluated. A drug analysis model using MAUT consisting of 10 steps was designed for two drug classes of dihydropyridine calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). These two drug classes contain the most diverse agents among cardiovascular drugs on Samsung Medical Center's drug formulary. The attributes identified for inclusion in the drug analysis model were effectiveness, safety, patient convenience, and cost, with relative weights of 50%, 30%, 10%, and 10%, respectively. The factors were incorporated into the model to quantify the contribution of each attribute. For each factor, a utility scale of 0-100 was established, and the total utility score for each alternative was calculated. An attempt was made to make the model adaptable to changing health care and regulatory circumstances. The analysis revealed amlodipine besylate to be an alternative agent, with the highest total utility score among the dihydropyridine CCBs, while barnidipine hydrochloride had the lowest score. For ARBs, losartan potassium had the greatest total utility score, while olmesartan medoxomil had the lowest. A drug analysis model based on the MAUT was successfully developed and used in making formulary decisions for dihydropyridine CCBs and ARBs for a Korean health system. The model incorporates sufficient utility and flexibility of a drug's attributes and can be used as an alternative decision-making tool for formulary management in health systems.

Clinical efficacy and safety of olmesartan/hydrochlorothiazide combination therapy in patients with essential hypertension

PubMed Central

Ruilope, Luis M

2008-01-01

Hypertension is a major risk factor for cardiovascular disease that contributes to the premature death of millions of people each year, and identification and treatment of hypertension continues to be a challenge. Guidelines recommend that many patients will require two or more antihypertensive agents from different classes. Combining an angiotensin II receptor blocker (ARB) with hydrochlorothiazide (HCTZ) has been shown in clinical studies to increase the antihypertensive efficacy of both agents compared with either agent alone. This review covers several clinical trials and aims to examine several aspects of the efficacy of the combination of olmesartan and HCTZ, including dose-responsiveness, long-term efficacy, goal rate achievement, and efficacy in patients with moderate to severe hypertension. The results presented here demonstrate that olmesartan is effective when added to HCTZ monotherapy or when HCTZ is added to olmesartan monotherapy, both over the short and long term. Moderate to severe hypertension responds well to olmesartan/HCTZ combination therapy, and the great majority of patients are able to achieve recommended blood pressure targets. Thus olmesartan/HCTZ is a well-tolerated option for patients who fail to respond to monotherapy and as initial therapy in those who require large reductions in diastolic blood pressure or systolic blood pressure to achieve goal blood pressure. PMID:19337537

Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study.

PubMed

Imai, E; Chan, J C N; Ito, S; Yamasaki, T; Kobayashi, F; Haneda, M; Makino, H

2011-12-01

The renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor (ACEI). We examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment. Five hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5% [n = 424] received concomitant ACEI), were given either once-daily olmesartan (10-40 mg) (n = 288) or placebo (n = 289) over 3.2 ± 0.6 years (mean±SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24; p = 0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%). Olmesartan was well tolerated but did not improve renal outcome on top of ACEI. ClinicalTrials.gov NCT00141453.

[Antihypertensive Efficacy of Fixed Combination Azilsartan Medoxomil / Chlorthalidone in Patients With Uncontrolled Arterial Hypertension].

PubMed

Kobalava, Z D; Villevalde, S V; Kulakov, V V

2017-11-01

To study effects of a fixed azilsartan medoxomil/chlorthalidone combination (Edarbi Clo) on clinical, ambulatory and central blood pressure (BP) in patients with uncontrolled arterial hypertension (AH)). Patients (n=25) with uncontrolled AH were given fixed azilsartan medoxomil/chlorthalidone combination (40 / 12.5 mg / day) for 4 weeks. After 4 weeks, in patients who did not achieve target BP levels the dose was increased up to 40 / 25 mg / day. Duration of the study was 12 weeks. After 12 weeks of treatment 88 % of patients achieved target clinical BP (.

Antihypertensive efficacy of hydrochlorothiazide vs chlorthalidone combined with azilsartan medoxomil.

PubMed

Bakris, George L; Sica, Domenic; White, William B; Cushman, William C; Weber, Michael A; Handley, Alison; Song, Eric; Kupfer, Stuart

2012-12-01

Chlorthalidone has proven efficacy to reduce cardiovascular morbidity and mortality, yet it is infrequently used in practice. This study provides a direct comparison of chlorthalidone with hydrochlorothiazide, each combined with the angiotensin receptor blocker azilsartan medoxomil, on blood pressure reduction and control rates. This is a randomized, double-blind, titrate-to-target blood pressure trial comparing the single-pill combination of azilsartan medoxomil and chlorthalidone versus co-administration of azilsartan medoxomil and hydrochlorothiazide in participants with stage 2 primary hypertension. After 2 weeks of treatment with azilsartan medoxomil 40 mg alone, all participants also received 12.5 mg of diuretic for 4 weeks (up to week 6) and were titrated to 25 mg for another 4 weeks (up to week 10) if they failed to achieve target blood pressure. The primary end point was change in clinic systolic blood pressure. Target blood pressure was defined as clinic blood pressure <140/90 mm Hg for participants without diabetes or chronic kidney disease or <130/80 mm Hg for participants with diabetes or chronic kidney disease. The mean age of the 609 participants was 56.4 years, and the mean baseline clinic blood pressure was 164.6/95.4 mm Hg. The primary end point analysis at week 6 demonstrated a greater reduction of clinic systolic blood pressure for the chlorthalidone (-35.1 mm Hg) versus hydrochlorothiazide combination (-29.5 mm Hg) (mean difference, -5.6 mm Hg; 95% confidence interval, -8.3 to -2.9; P <.001). The mean difference in 24-hour ambulatory systolic blood pressure at week 6 was -5.8 mm Hg (95% confidence interval, -8.4 to -3.2; P <.001), favoring the azilsartan medoxomil/chlorthalidone group. The percentage of participants achieving target clinic blood pressure at week 6 was greater for the chlorthalidone versus hydrochlorothiazide combination (64.1% vs 45.9%, P <.001). Drug discontinuations due to adverse events were not statistically significantly different between groups (9.3% vs 7.3%, P = .38), and hypokalemia was uncommon in both groups. Chlorthalidone combined with azilsartan medoxomil provides better blood pressure reduction and a higher likelihood of achieving blood pressure control than hydrochlorothiazide combined with azilsartan medoxomil. This benefit occurred without a difference in safety measurements. Copyright © 2012 Elsevier Inc. All rights reserved.

Potential coeliac disease markers and autoimmunity in olmesartan induced enteropathy: A population-based study.

PubMed

Esteve, Maria; Temiño, Rocío; Carrasco, Anna; Batista, Lissette; Del Val, Adolfo; Blé, Michel; Santaolaria, Santos; Molina-Infante, Javier; Soriano, Germán; Agudo, Sandra; Zabana, Yamile; Andújar, Xavier; Aceituno, Montserrat; Ribes, Josepa; Madridejos, Rosa; Fernández-Bañares, Fernando

2016-02-01

(1) Assess the population-based incidence of severe olmesartan-associated enteropathy. (2) To describe patients of the Spanish registry. (3) Evaluate markers of potential coeliac disease and associated autoimmunity. Crude incidence rates in the area of Terrassa (Catalonia) were calculated. Clinical characteristics of patients in the Spanish registry were collected. Duodenal lymphocyte subpopulations and anti-TG2 IgA deposits were assessed in a subset of patients. Annual incidence rates (2011-2014) ranged from 0 to 22 cases per 10(4) treated patients. Twenty patients were included in the Spanish registry. Nineteen (95%) exhibited villous atrophy and 16 (80%) had severe enteropathy. Lupus-like disease occurred during olmesartan treatment in 3 patients. HLA-DQ2/DQ8 was positive in 64%. Markers of potential coeliac disease were present in 4 out of 8 patients (positive anti-TG2 deposits and/or increased CD3+gammadelta+ intraepithelial lymphocytes and reduced CD3-). Histopathological changes and clinical manifestations including autoimmune disorders improved after olmesartan discontinuation but not after gluten-free diet, irrespective of the presence or absence of coeliac markers. Incidence of severe olmesartan-associated enteropathy was low. Autoimmune phenomena were present in a subset of cases and reversed after olmesartan removal. A genetic coeliac disease background and the presence of potential coeliac markers might uncover predisposing factors. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Olmesartan-induced Enteropathy Manifesting as Wernicke-Korsakoff Syndrome.

PubMed

Uehara, Takanori; Ikusaka, Masatomi; Ohira, Yoshiyuki; Noda, Kazutaka; Suzuki, Shingo; Shikino, Kiyoshi; Kondo, Takeshi; Kajiwara, Hideki; Ikegami, Akiko; Hirota, Yusuke

Cases of sprue-like enteropathy associated with olmesartan have sporadically been encountered since it was first reported in 2012, and their most characteristic manifestation is severe diarrhea. We herein report the first case of sprue-like enteropathy manifesting as Wernicke-Korsakoff syndrome due to vitamin B1 malabsorption with only minimally increased bowel movements. When patients are receiving olmesartan and they complain of nonspecific chronic gastrointestinal symptoms, it is important to consider changing the drugs before any serious malabsorption syndrome develops.

Olmesartan-induced Enteropathy Manifesting as Wernicke-Korsakoff Syndrome

PubMed Central

Uehara, Takanori; Ikusaka, Masatomi; Ohira, Yoshiyuki; Noda, Kazutaka; Suzuki, Shingo; Shikino, Kiyoshi; Kondo, Takeshi; Kajiwara, Hideki; Ikegami, Akiko; Hirota, Yusuke

2016-01-01

Cases of sprue-like enteropathy associated with olmesartan have sporadically been encountered since it was first reported in 2012, and their most characteristic manifestation is severe diarrhea. We herein report the first case of sprue-like enteropathy manifesting as Wernicke-Korsakoff syndrome due to vitamin B1 malabsorption with only minimally increased bowel movements. When patients are receiving olmesartan and they complain of nonspecific chronic gastrointestinal symptoms, it is important to consider changing the drugs before any serious malabsorption syndrome develops. PMID:27980272

Network models provide insights into how oriens–lacunosum-moleculare and bistratified cell interactions influence the power of local hippocampal CA1 theta oscillations

PubMed Central

Ferguson, Katie A.; Huh, Carey Y. L.; Amilhon, Bénédicte; Manseau, Frédéric; Williams, Sylvain; Skinner, Frances K.

2015-01-01

Hippocampal theta is a 4–12 Hz rhythm associated with episodic memory, and although it has been studied extensively, the cellular mechanisms underlying its generation are unclear. The complex interactions between different interneuron types, such as those between oriens–lacunosum-moleculare (OLM) interneurons and bistratified cells (BiCs), make their contribution to network rhythms difficult to determine experimentally. We created network models that are tied to experimental work at both cellular and network levels to explore how these interneuron interactions affect the power of local oscillations. Our cellular models were constrained with properties from patch clamp recordings in the CA1 region of an intact hippocampus preparation in vitro. Our network models are composed of three different types of interneurons: parvalbumin-positive (PV+) basket and axo-axonic cells (BC/AACs), PV+ BiCs, and somatostatin-positive OLM cells. Also included is a spatially extended pyramidal cell model to allow for a simplified local field potential representation, as well as experimentally-constrained, theta frequency synaptic inputs to the interneurons. The network size, connectivity, and synaptic properties were constrained with experimental data. To determine how the interactions between OLM cells and BiCs could affect local theta power, we explored how the number of OLM-BiC connections and connection strength affected local theta power. We found that our models operate in regimes that could be distinguished by whether OLM cells minimally or strongly affected the power of network theta oscillations due to balances that, respectively, allow compensatory effects or not. Inactivation of OLM cells could result in no change or even an increase in theta power. We predict that the dis-inhibitory effect of OLM cells to BiCs to pyramidal cell interactions plays a critical role in the resulting power of network theta oscillations. Overall, our network models reveal a dynamic interplay between different classes of interneurons in influencing local theta power. PMID:26300744

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension.

PubMed

Weber, Michael A; White, William B; Sica, Domenic; Bakris, George L; Cao, Charlie; Roberts, Andrew; Kupfer, Stuart

2014-04-01

The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. This was a randomized, controlled, double-blind study of 6 weeks' duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153-154/93 mmHg) and clinic BP (165-166/94-95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2009-04-01

(+)-Dapoxetine hydrochloride, [(123)I]-BZA, 9-Aminocamptothecin; Abacavir sulfate/lamivudine, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Alvocidib hydrochloride, Ambrisentan, Amsilarotene, Anacetrapib, Anakinra, Apricitabine, Aripiprazole, Arsenic trioxide, Atazanavir sulfate, Atazanavir/ritonavir, Atrasentan, Azacitidine; Banoxantrone, Bazedoxifene acetate, Bevacizumab, Bexarotene, Biphasic insulin aspart, Bortezomib, Bosentan, Bromfenac; Cachectin, Calcipotriol/betamethasone dipropionate, Canakinumab, Carfilzomib, CAT-354, CCX-282, Certolizumab pegol, Cetuximab, Choline fenofibrate, Clevudine, Clofarabine, CNTO-328, Corifollitropin alfa, Crofelemer; Daptomycin, Darbepoetin alfa, Darunavir, Dasatinib, Decitabine, Deferasirox, Denosumab, Duloxetine hydrochloride, Dutasteride; Emtricitabine, Enfuvirtide, Entecavir, Epoetin zeta, Erlotinib hydrochloride, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Farglitazar, Febuxostat, Fosamprenavir calcium, FX-06; Gabapentin enacarbil, Gefitinib; HIVIS DNA; Imatinib mesylate, INCB- 18424, Indacaterol, Inotuzumab ozogamicin, Insulin detemir; JNJ-26854165; Lacosamide, Landiolol, Laromustine, Lenalidomide, Liposomal doxorubicin, L-NAME, Lopinavir, Lopinavir/ritonavir, Lumiracoxib; Maraviroc, Mepolizumab, Methoxy polyethylene glycol- epoetin-beta, Miglustat, MK-0493, MVA-CMDR, Mycophenolic acid sodium salt; Natalizumab, Nepafenac, Neratinib, Neridronic acid, Nesiritide, Nilotinib hydrochloride monohydrate; Olmesartan medoxomil, Omacetaxine mepesuccinate, Omalizumab; Paclitaxel poliglumex, Palifermin, Patupilone, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ ribavirin, Pemetrexed disodium, PHA-848125, Pitavastatin calcium, Posaconazole, Povidone-iodine liposome complex, Prasugrel, Pregabalin, Prucalopride; Raltegravir potassium, Retigabine, Revaprazan hydrochloride, rhFSH, Rilpivirine, Rivaroxaban, Romidepsin, Rosuvastatin calcium, RWJ-676070; SAR-109659, Sitagliptin phosphate monohydrate, Sorafenib, Stavudine/Lamivudine/Nevirapine, Sunitinib malate; Tadalafil, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Tenofovir disoproxil fumarate/emtricitabine/efavirenz, Teriparatide, Tigecycline, Tiotropium bromide, Tipifarnib, Tipranavir, Tocilizumab, Trifluridine/TPI; UP-780; Vandetanib, Vardenafil hydrochloride hydrate, Vatalanib succinate, Vitespen, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan; Zoledronic acid monohydrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

Patient Adherence to Olmesartan/Amlodipine Combinations: Fixed Versus Extemporaneous Combinations.

PubMed

Levi, Miriam; Pasqua, Alessandro; Cricelli, Iacopo; Cricelli, Claudio; Piccinni, Carlo; Parretti, Damiano; Lapi, Francesco

2016-03-01

Lack of adherence to prescribed therapies is often a cause of suboptimal blood pressure control in patients with hypertension. To enhance patients' adherence to treatment, fixed-dose combinations of active substances with complementary mechanisms of action have been developed. An angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) is often combined with a calcium channel blocker. Olmesartan is the most used ARB in combination therapy. In Italy, in September 2011, a fixed-dose combination of olmesartan/amlodipine (olmesartan/amlodipine 20/5 mg, 40/5 mg, or 40/10 mg) was introduced to treat patients with hypertension for whom control of blood pressure is not reached with either olmesartan or amlodipine alone. Prior research on adherence to olmesartan/amlodipine combinations was carried out in local contexts (e.g., claims databases of Italian regions or local health authorities), and/or it was limited by the fact that adherence was assessed against monotherapies already known for their low compliance profile, such as diuretics. To compare adherence with olmesartan/amlodipine fixed-dose combination (FDC) and extemporaneous combination in primary care in Italy. A nationwide, population-based study was conducted by using the Health Search IMS Health Longitudinal Patient Database. Patients aged > 17 years, affected by hypertension and treated with the FDC or extemporaneous combination of olmesartan/amlodipine, were identified. Adherence to these 2 therapeutic regimens was estimated by calculating the proportion of days covered (PDC). Patients were classified into 3 levels of adherence: high (PDC ≥ 80%), intermediate (PDC = 40%-79%), or low (PDC < 40%). In the 6-month follow-up, FDC showed higher adherence compared with an extemporaneous combination (55.1% vs. 15.9%, P < 0.001). This difference was confirmed in a multivariable logistic regression model clustered on patient identifier (odds ratio = 6.65; 95% CI = 3.10-14.26; P < 0.001). The proportion of patients adherent to FDC varied from 60.4% for the 40/5 mg formulation to 47.5% for the 40/10 mg formulation. These findings suggest that higher adherence may be achieved with FDCs than with extemporaneous combinations. To improve the degree of adherence, general practitioners may consider prescribing fixed combinations of antihypertensive agents as soon as monotherapies fail to achieve the expected therapeutic objective.

Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension

PubMed Central

White, William B.; Sica, Domenic; Bakris, George L.; Cao, Charlie; Roberts, Andrew; Kupfer, Stuart

2014-01-01

Objective The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg. Methods This was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring. Results The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%). Conclusion Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine. PMID:24445723

Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism.

PubMed

Seese, Ronald R; Maske, Anna R; Lynch, Gary; Gall, Christine M

2014-06-01

A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T(+) Itpr3(tf)/J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2+ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.

[Fixed drug combinations in hypertension: a budget impact analysis for the Spanish Health System on the marketing of a fixed combination of olmesartan/amlodipine].

PubMed

Belén Ferro-Rey, M; Roca-Cusachs, Alex; Sicras-Mainar, Antoni; Alvarez-Martín, Carlos; de Salas-Cansado, Marina

2011-07-01

To carry out a budget impact analysis (BIA) of olmesartan/amlodipine (20/5, 40/5 and 40/10mg) marketed as a fixed combination (FC) in its approved indication for the National Health System (NHS). We developed a decision tree model in order to estimate usual hypertension treatment algorithm in Spanish clinical practice. The BIA has been developed from the perspective of the NHS for a period of 3 years (years 2010-2012). Spanish hypertensive population ≥ 35 years old. Introduction into the market of a fixed combination (FC) olmesartan/amlodipine in Spain. Expected costs to be assumed by the Spanish NHS (RRP-VAT) for hypertensive population able to be treated with the FC versus currently assumed costs by the NHS with free combination olmesartan and amlodipine. Estimated pharmaceutical costs in hypertensive population treated with olmesartan and amlodipine (2 pills) would be €25.2M (1(st) year), €26.4M (2011), €27.6M (2012), with a total 3-year period of €79.2M. According to patient tree model, the population able to be treated with FC would be 71,283 patients (2010), with a growth rate of 4.8% in the successive years, which supposes an annual cost of €21.2M (2010), €21.8M (2011) and €22.4M (2012), with a total 3-year period of €65.4M. The BIA shows savings of €13.8M in a total 3-year period. The BIA of FC olmesartan/amlodipine could generate net savings of €13.8M for the NHS in the period ranging from years 2010 to 2012. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Effects of angiotensin receptor blockade (ARB) on mortality and cardiovascular outcomes in patients with long-term haemodialysis: a randomized controlled trial.

PubMed

Iseki, Kunitoshi; Arima, Hisatomi; Kohagura, Kentaro; Komiya, Ichiro; Ueda, Shinichiro; Tokuyama, Kiyoyuki; Shiohira, Yoshiki; Uehara, Hajime; Toma, Shigeki

2013-06-01

Hypertension is a major risk factor for death and cardiovascular disease (CVD) in patients undergoing chronic haemodialysis (HD), but there is uncertainty surrounding the effects of blood pressure (BP) lowering on this high-risk patient group. In a multicenter, prospective, randomized, open-label, blinded-endpoint trial, 469 patients with chronic HD and elevated BP (140-199/90-99 mmHg) were assigned to receive the angiotensin receptor blockade (ARB) olmesartan (at a dose of 10-40 mg daily; n = 235) or another treatment that does not include angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors (n = 234). The primary outcomes were the following: (i) composite of death, nonfatal stroke, nonfatal myocardial infarction and coronary revascularization and (ii) all-cause death. During a mean follow-up of 3.5 years, the mean BP was 0.9/0.0 mmHg lower in the olmesartan group than in the control group (not significant). A total of 68 patients (28.9%) in the olmesartan group and 67 patients (28.6%) in the control group had subsequent primary composite endpoints [hazard ratio (HR) in the olmesartan group 1.00, 95% confidence interval (CI) 0.71-1.40, P = 0.99]. All-cause deaths occurred in 38 patients (16.2%) in the olmesartan group and 39 (16.7%) in the control group (HR, 0.97; 95% CI, 0.62-1.52, P = 0.91). Olmesartan did not alter the risks of serious adverse events. BP-lowering treatment with an ARB did not significantly lower the risks of major cardiovascular events or death among patients with hypertension on chronic HD. (Cochrane Renal Group Prospective Trial Register number CRG010600030).

[Azilsartan Medoxomil Capabilities in Arterial Hypertension and Obesity].

PubMed

Vasyuk, Y A; Shupenina, E Y; Nesvetov, V V; Nesterova, E A; Golubkova, E I

2016-12-01

Arterial hypertension (AH) is one of the most common cardiovascular disease. Angiotensin II (AT II), the hormone of renin-angiotensin-aldosterone system, realizes its negative effects through AT 1 receptors - application point of angiotensin receptor blockers (ARB). Due to different dissociation AT 1 receptors properties some ARBs are more effective than others. Multiply multicenter randomized and observational studies approve the effectiveness and safety of azilsartan medoxomil in patients with AH 1-2 grade. Several preclinical studies have shown the additional properties of azilsartan, including increase of insulin sensitivity, cardio- and nephron protection in obesity. In our clinical case we showed the positive influence of azilsartan medoxomil on clinic and ambulatory blood pressure, 24-hour aortic stiffness parameters, longitudinal left ventricular strain in patient with AH and obesity.

28. Photocopied from Photo 588 OLM, Olmstead Folder #1, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

28. Photocopied from Photo 588 - OLM, Olmstead Folder #1, Engineering Department, Utah Power & Light Co., Salt Lake City, Utah. STATION INTERIOR, DECEMBER 5, 1908. - Telluride Power Company, Olmsted Hydroelectric Plant, mouth of Provo River Canyon West of U.S. Route 189, Orem, Utah County, UT

75 FR 27366 - OLMS Listens: Office of Labor-Management Standards Stakeholder Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-14

... Labor-Management Reporting and Disclosure Act (LMRDA), specifically with regard to the scope of the... DEPARTMENT OF LABOR Office of Labor-Management Standards OLMS Listens: Office of Labor-Management Standards Stakeholder Meeting AGENCY: Office of Labor-Management Standards, Department of Labor. ACTION...

23. Photocopied from Photo 664OLM, Olmstead Folder #1, Engineering Department, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

23. Photocopied from Photo 664-OLM, Olmstead Folder #1, Engineering Department, Utah Power & Light Co., Salt Lake City, Utah. INTERIOR OF STATION, APRIL 8, 1909. - Telluride Power Company, Olmsted Hydroelectric Plant, mouth of Provo River Canyon West of U.S. Route 189, Orem, Utah County, UT

22. Photocopied from Photo 505OLM, Olmstead Folder #1, Engineering Department, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

22. Photocopied from Photo 505-OLM, Olmstead Folder #1, Engineering Department, Utah Power & Light Co., Salt Lake City, Utah. OLD PENSTOCKS, JANUARY 25, 1908. - Telluride Power Company, Olmsted Hydroelectric Plant, mouth of Provo River Canyon West of U.S. Route 189, Orem, Utah County, UT

24. Photocopied from Photo 669OLM, Olmstead Folder #1, Engineering Department, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

24. Photocopied from Photo 669-OLM, Olmstead Folder #1, Engineering Department, Utah Power & Light Co., Salt Lake City, Utah. NEW PENSTOCK, APRIL 8, 1909. - Telluride Power Company, Olmsted Hydroelectric Plant, mouth of Provo River Canyon West of U.S. Route 189, Orem, Utah County, UT

From Interactive Open Learner Modelling to Intelligent Mentoring: STyLE-OLM and Beyond

ERIC Educational Resources Information Center

Dimitrova, Vania; Brna, Paul

2016-01-01

STyLE-OLM (Dimitrova 2003 "International Journal of Artificial Intelligence in Education," 13, 35-78) presented a framework for interactive open learner modelling which entails the development of the means by which learners can "inspect," "discuss" and "alter" the learner model that has been jointly…

29 CFR 215.7 - The Special Warranty.

Code of Federal Regulations, 2010 CFR

2010-07-01

... time to time, the Department may update this Special Warranty Arrangement to reflect developments in... Department of Labor; a copy of the current arrangement will be included on the OLMS Web site. (c) The Federal..., and a list of those transit providers. A sample format is posted on the OLMS Web site to facilitate...

Toward an Organizational Model of Change in Elementary Schools: The Contribution of Organizational Learning Mechanisms

ERIC Educational Resources Information Center

Schechter, Chen; Qadach, Mowafaq

2012-01-01

Purpose: This study explored a theoretical model that links teachers' perceived uncertainty and teachers' sense of collective efficacy with organizational learning mechanisms (OLMs) in elementary schools. OLMs serve as a mediator construct. Research Design: For testing the primary theoretical model, 801 teachers from 61 elementary schools (33…

Computational models of O-LM cells are recruited by low or high theta frequency inputs depending on h-channel distributions

PubMed Central

Sekulić, Vladislav; Skinner, Frances K

2017-01-01

Although biophysical details of inhibitory neurons are becoming known, it is challenging to map these details onto function. Oriens-lacunosum/moleculare (O-LM) cells are inhibitory cells in the hippocampus that gate information flow, firing while phase-locked to theta rhythms. We build on our existing computational model database of O-LM cells to link model with function. We place our models in high-conductance states and modulate inhibitory inputs at a wide range of frequencies. We find preferred spiking recruitment of models at high (4–9 Hz) or low (2–5 Hz) theta depending on, respectively, the presence or absence of h-channels on their dendrites. This also depends on slow delayed-rectifier potassium channels, and preferred theta ranges shift when h-channels are potentiated by cyclic AMP. Our results suggest that O-LM cells can be differentially recruited by frequency-modulated inputs depending on specific channel types and distributions. This work exposes a strategy for understanding how biophysical characteristics contribute to function. DOI: http://dx.doi.org/10.7554/eLife.22962.001 PMID:28318488

Monitoring health and reproductive status of olms (Proteus anguinus) by ultrasound

PubMed Central

Lukač, Maja; Cizelj, Ivan; Mutschmann, Frank; Szentiks, Claudia Anita; Jelić, Dušan; Hermes, Robert; Göritz, Frank; Braude, Stanton; Hildebrandt, Thomas Bernd

2017-01-01

The olm (Proteus anguinus) is a troglomorphic, neotenous amphibian with extraordinary life expectancy and unique adaptations that deserve further investigation. A low reproductive rate and habitat decline render it threatened by extinction. Establishing captive populations for maintenance and artificial breeding may one day become crucial to the species. Longitudinal, in-vivo assessment of inner organs is invaluable to our understanding of reproductive physiology, health, and behavior. Using ultrasound, we measured heart rate and assessed health and reproductive status of 13 captive olms at Zagreb Zoo. Heart rate averaged 42.9 ± 4.6 bpm (32–55 bpm), as determined via pulsed-wave Doppler at 4–12 MHz. By using frequencies of up to 70 MHz (ultrasound biomicroscopy), inner organs were visualized in detail. Assessment of the gastrointestinal tract provided insights into feeding status and digestive processes. Several subclinical pathologies were detected, including biliary sludge, subcutaneous edema, ascites, and skin lesions. Detection of skin lesions by ultrasound was more sensitive than visual adspection. Olms with ultrasonographically detected skin lesions tested positive for Saprolegnia and were treated. Three of the four affected individuals survived and subsequently tested negative for Saprolegnia. Sex was reliably determined; only one individual proved male. The reason for this extreme female-biased sex-ratio remains unknown. However, as most of the individuals were flushed from the caves by strong currents in spring, the sample may not be representative of natural populations. In female olms, different stages of ovarian follicular development were observed with diameters ranging between 0.1 and 1.1 mm. Results were confirmed by comparing ultrasound, necropsy, and histological findings of one dead specimen. In summary, ultrasound proved a valuable tool to support conservation and captive breeding programs by allowing non-invasive assessment of physiological parameters, clinical condition, and reproductive status in olms. PMID:28809953

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy

PubMed Central

Angeloni, Emiliano

2016-01-01

Background Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). Objective To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. Methods PubMed, Embase, and Cochrane Library were searched using search terms “ azilsartan”, “chlorthalidone,” “pharmacology,” “pharmacokinetics,” “pharmacodynamics,” “pharmacoeconomics,” and “cost-effectiveness.” To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Results Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Conclusion Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo. PMID:27103882

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy.

PubMed

Angeloni, Emiliano

2016-01-01

Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. PubMed, Embase, and Cochrane Library were searched using search terms " azilsartan", "chlorthalidone," "pharmacology," "pharmacokinetics," "pharmacodynamics," "pharmacoeconomics," and "cost-effectiveness." To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo.

Impact of FDA-Approved Drugs on the Prostaglandin Transporter OATP2A1/SLCO2A1.

PubMed

Kamo, Shunsuke; Nakanishi, Takeo; Aotani, Rika; Nakamura, Yoshinobu; Gose, Tomoka; Tamai, Ikumi

2017-09-01

To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored the impact of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty-one and 10 drugs were found to inhibit and enhance 6-CF uptake by more than 50%, respectively. Effect of the 51 drugs on 6-CF uptake was positively correlated with that on PGE 2 uptake (r = 0.64, p < 0.001). Among those, 5 drugs not structurally related to prostaglandins, suramin, pranlukast, zafirlukast, olmesartan medoxomil, and losartan potassium, exhibited more than 90% PGE 2 uptake inhibition. Inhibitory affinity of suramin to OATP2A1 was the highest (IC 50,2A1 of 0.17 μM), and its IC 50 values to MRP4-mediated PGE 2 transport (IC 50,MRP4 ) and PGE 2 synthesis in human U-937 cells treated with phorbol 12-myristate 13-acetate (IC 50,Syn ) were 73.6 and 336.7 times higher than IC 50,2A1 , respectively. Moreover, structure-activity relationship study in 29 nonsteroidal anti-inflammatory drugs contained in the library displayed inhibitory activities of anthranilic acid derivatives, but enhancing effects of propionic acid derivatives. These results demonstrate that suramin is a potent selective inhibitor of OATP2A1, providing a comprehensive information about drugs in clinical use that interact with OATP2A1. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

29 CFR 471.22 - What actions may the Director of OLMS take in the case of intimidation and interference?

Code of Federal Regulations, 2010 CFR

2010-07-01

...-MANAGEMENT STANDARDS, DEPARTMENT OF LABOR NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS OBLIGATIONS OF FEDERAL CONTRACTORS AND SUBCONTRACTORS; NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR... 29 Labor 2 2010-07-01 2010-07-01 false What actions may the Director of OLMS take in the case of...

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis

PubMed Central

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Background Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. Aim To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Methods Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Results Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. Conclusions This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. PMID:25339518

A New Perspective of Negotiation-Based Dialog to Enhance Metacognitive Skills in the Context of Open Learner Models

ERIC Educational Resources Information Center

Suleman, Raja M.; Mizoguchi, Riichiro; Ikeda, Mitsuru

2016-01-01

Negotiation mechanism using conversational agents (chatbots) has been used in Open Learner Models (OLM) to enhance learner model accuracy and provide opportunities for learner reflection. Using chatbots that allow for natural language discussions has shown positive learning gains in students. Traditional OLMs assume a learner to be able to manage…

ROBUST ONLINE MONITORING FOR CALIBRATION ASSESSMENT OF TRANSMITTERS AND INSTRUMENTATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramuhalli, Pradeep; Tipireddy, Ramakrishna; Lerchen, Megan E.

Robust online monitoring (OLM) technologies are expected to enable the extension or elimination of periodic sensor calibration intervals in operating and new reactors. Specifically, the next generation of OLM technology is expected to include newly developed advanced algorithms that improve monitoring of sensor/system performance and enable the use of plant data to derive information that currently cannot be measured. These advances in OLM technologies will improve the safety and reliability of current and planned nuclear power systems through improved accuracy and increased reliability of sensors used to monitor key parameters. In this paper, we discuss an overview of research beingmore » performed within the Nuclear Energy Enabling Technologies (NEET)/Advanced Sensors and Instrumentation (ASI) program, for the development of OLM algorithms to use sensor outputs and, in combination with other available information, 1) determine whether one or more sensors are out of calibration or failing and 2) replace a failing sensor with reliable, accurate sensor outputs. Algorithm development is focused on the following OLM functions: • Signal validation – fault detection and selection of acceptance criteria • Virtual sensing – signal value prediction and acceptance criteria • Response-time assessment – fault detection and acceptance criteria selection A GP-based uncertainty quantification (UQ) method previously developed for UQ in OLM, was adapted for use in sensor-fault detection and virtual sensing. For signal validation, the various components to the OLM residual (which is computed using an AAKR model) were explicitly defined and modeled using a GP. Evaluation was conducted using flow loop data from multiple sources. Results using experimental data from laboratory-scale flow loops indicate that the approach, while capable of detecting sensor drift, may be incapable of discriminating between sensor drift and model inadequacy. This may be due to a simplification applied in the initial modeling, where the sensor degradation is assumed to be stationary. In the case of virtual sensors, the GP model was used in a predictive mode to estimate the correct sensor reading for sensors that may have failed. Results have indicated the viability of using this approach for virtual sensing. However, the GP model has proven to be computationally expensive, and so alternative algorithms for virtual sensing are being evaluated. Finally, automated approaches to performing noise analysis for extracting sensor response time were developed. Evaluation of this technique using laboratory-scale data indicates that it compares well with manual techniques previously used for noise analysis. Moreover, the automated and manual approaches for noise analysis also compare well with the current “gold standard”, hydraulic ramp testing, for response time monitoring. Ongoing research in this project is focused on further evaluation of the algorithms, optimization for accuracy and computational efficiency, and integration into a suite of tools for robust OLM that are applicable to monitoring sensor calibration state in nuclear power plants.« less

SMILI?: A Framework for Interfaces to Learning Data in Open Learner Models, Learning Analytics and Related Fields

ERIC Educational Resources Information Center

Bull, Susan; Kay, Judy

2016-01-01

The SMILI? (Student Models that Invite the Learner In) Open Learner Model Framework was created to provide a coherent picture of the many and diverse forms of Open Learner Models (OLMs). The aim was for SMILI? to provide researchers with a systematic way to describe, compare and critique OLMs. We expected it to highlight those areas where there…

Prevalence of Toxocara antibodies among patients clinically suspected to have ocular toxocariasis: A retrospective descriptive study in Sri Lanka.

PubMed

Iddawela, Devika; Ehambaram, Kiruthiha; Bandara, Pemindra

2017-04-24

Human toxocariasis, caused by Toxocara canis, T. cati, and T. vitulorum of dogs, cats and ruminants respectively, is recognized as an important zoonotic infection worldwide. The typical clinical syndromes of toxocariasis in humans are ocular larva migrans (OLM) and visceral larva migrans (VLM). The most commonly affected sites of OLM are the peripheral retina and/or vitreous humor. In Sri Lanka, there is a dearth of information on prevalence of ocular infection in our population. Therefore, the present study was carried out to determine the prevalence of Toxocara antibodies in suspected OLM patients and to describe demographic factors and clinical manifestations of seropositive patients. A total of 250 clinically suspected ocular toxocariasis cases referred by consultant eye surgeons to the Department of Parasitology, University of Peradeniya were studied between the years 1995 to April 2015. Data (age, sex, fundoscopic findings) were gathered from the referral letters. Each serum sample was subjected to Toxocara excretory - secretory antigen ELISA (TES - ELISA). Out of the 250 cases, 155 (62%) were seropositive. The age range of the seropositive cases was 1 to 78 years with the mean age of 27 years. The highest seropositivity (25/155) was observed within the age group of 10 to 14 years. The most frequent clinical presentation of seropositive OLM cases were unilateral reduced vision and red eye. The other symptoms include tearing, photophobia and leukokoria. A high proportion of seropositive OLM cases had uveitis (34.19%) followed by reduced vision (21.94%), vitritis (12.9%) and choroiditis (7.74%). However none of these clinical manifestations were significantly associated with TES-ELISA seropositivity except vitreits (X 2  = 8.557, p = 0.003). In conclusion, the results of this study showed high seroprevalence of toxocariasis among clinically suspected OLM cases confirming the toxoplasmic etiology. This high rate of Toxocara seropositivity in ocular patients should alert ophthalmologists in Sri Lanka to include toxocariasis in the differential diagnosis of ocular diseases presented with the symptoms and signs stated above.

The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice.

PubMed

Wang, Xingxu; Ye, Yong; Gong, Hui; Wu, Jian; Yuan, Jie; Wang, Shijun; Yin, Peipei; Ding, Zhiwen; Kang, Le; Jiang, Qiu; Zhang, Weijing; Li, Yang; Ge, Junbo; Zou, Yunzeng

2016-08-01

Angiotensin II (AngII) type 1 receptor blockers (ARBs) have been effectively used in hypertension and cardiac remodeling. However, the differences among them are still unclear. We designed this study to examine and compare the effects of several ARBs widely used in clinics, including Olmesartan, Candesartan, Telmisartan, Losartan, Valsartan and Irbesartan, on the ACE-AngII-AT1 axis and the ACE2-Ang(1-7)-Mas axis during the development of cardiac remodeling after pressure overload. Although all of the six ARBs, attenuated the development of cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) for 2 or 4weeks in the wild-type mice evaluated by echocardiography and hemodynamic measurements, the degree of attenuation by Olmesartan, Candesartan and Losartan tended to be larger than that of the other three drugs tested. Additionally, the degree of downregulation of the ACE-AngII-AT1 axis and upregulation of the ACE2-Ang(1-7)-Mas axis was higher in response to Olmesartan, Candesartan and Losartan administration in vivo and in vitro. Moreover, in angiotensinogen-knockdown mice, TAC-induced cardiac hypertrophy and heart failure were inhibited by Olmesartan, Candesartan and Losartan but not by Telmisartan, Valsartan and Irbesartan administration. Furthermore, only Olmesartan and Candesartan could downregulate the ACE-AngII-AT1 axis and upregulate the ACE2-Ang(1-7)-Mas axis in vitro. Our data suggest that Olmesartan, Candesartan and Losartan could effectively inhibit pressure overload-induced cardiac remodeling even when with knockdown of Ang II, possibly through upregulation of the expression of the ACE2-Ang(1-7)-Mas axis and downregulation of the expression of the ACE-AngII-AT1 axis. In contrast, Telmisartan, Valsartan and Irbesartan only played a role in the presence of AngII, and Losartan had no effect in the presence of AngII in vitro. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.

PubMed

Williams, Bryan; Cockcroft, John R; Kario, Kazuomi; Zappe, Dion H; Brunel, Patrick C; Wang, Qian; Guo, Weinong

2017-03-01

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. © 2017 American Heart Association, Inc.

Robust Online Monitoring for Calibration Assessment of Transmitters and Instrumentation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ramuhalli, Pradeep; Coble, Jamie B.; Shumaker, Brent

Robust online monitoring (OLM) technologies are expected to enable the extension or elimination of periodic sensor calibration intervals in operating and new reactors. These advances in OLM technologies will improve the safety and reliability of current and planned nuclear power systems through improved accuracy and increased reliability of sensors used to monitor key parameters. In this article, we discuss an overview of research being performed within the Nuclear Energy Enabling Technologies (NEET)/Advanced Sensors and Instrumentation (ASI) program, for the development of OLM algorithms to use sensor outputs and, in combination with other available information, 1) determine whether one or moremore » sensors are out of calibration or failing and 2) replace a failing sensor with reliable, accurate sensor outputs. Algorithm development is focused on the following OLM functions: • Signal validation • Virtual sensing • Sensor response-time assessment These algorithms incorporate, at their base, a Gaussian Process-based uncertainty quantification (UQ) method. Various plant models (using kernel regression, GP, or hierarchical models) may be used to predict sensor responses under various plant conditions. These predicted responses can then be applied in fault detection (sensor output and response time) and in computing the correct value (virtual sensing) of a failing physical sensor. The methods being evaluated in this work can compute confidence levels along with the predicted sensor responses, and as a result, may have the potential for compensating for sensor drift in real-time (online recalibration). Evaluation was conducted using data from multiple sources (laboratory flow loops and plant data). Ongoing research in this project is focused on further evaluation of the algorithms, optimization for accuracy and computational efficiency, and integration into a suite of tools for robust OLM that are applicable to monitoring sensor calibration state in nuclear power plants.« less

Prolonged remission from hepatic encephalopathy with rifaximin: results of a placebo crossover analysis.

PubMed

Bajaj, J S; Barrett, A C; Bortey, E; Paterson, C; Forbes, W P

2015-01-01

Rifaximin therapy reduced risk of hepatic encephalopathy (HE) recurrence and HE-related hospitalisations during a 6-month, randomised, placebo-controlled trial (RCT) and a 24-month open-label maintenance (OLM) study. However, the impact of crossover from placebo to rifaximin therapy is unclear. To study the impact of crossing over from placebo to rifaximin treatment on breakthrough HE and hospitalisation rates using a within-subjects design. Adults with cirrhosis and history of overt HE episodes, currently in HE remission, received placebo during the RCT and crossed over to rifaximin 550 mg twice daily during the OLM study. Rate of breakthrough overt HE episodes, hospitalisations and incidence and rate of adverse events (AEs) were analysed during RCT and first 6 months of OLM. Of 82 patients randomised to placebo in the RCT who crossed over to the OLM study, 39 experienced an HE episode during the RCT compared with 14 during the OLM study (P < 0.0001). Significantly lower rates of HE events were observed with rifaximin treatment compared with placebo treatment (P < 0.0001). Rates of HE-related hospitalisation were numerically lower during rifaximin treatment compared with placebo treatment, although not significant. Rates of most common AEs, serious AEs and infection-related AEs were similar between the two treatments. This analysis confirms the repeatability of results from the RCT on safety and efficacy of rifaximin 550 mg twice daily in reducing the risk of hepatic encephalopathy recurrence, and suggests these findings are translatable outside of a rigorous, controlled trial setting. © 2014 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Depressor and Anti-Inflammatory Effects of Angiotensin II Receptor Blockers in Metabolic and/or Hypertensive Patients With Coronary Artery Disease: A Randomized, Prospective Study (DIAMOND Study)

PubMed Central

Adachi, Sen; Miura, Shin-ichiro; Shiga, Yuhei; Arimura, Tadaaki; Kuwano, Takashi; Kitajima, Ken; Ike, Amane; Sugihara, Makoto; Iwata, Atsushi; Nishikawa, Hiroaki; Morito, Natsumi; Saku, Keijiro

2016-01-01

Background We compared the efficacy and safety of azilsartan to those of olmesartan in a prospective, randomized clinical trial. Methods Forty-four hypertensive patients who had coronary artery disease (CAD) were enrolled. We randomly assigned patients to changeover from their prior angiotensin II receptor blockers (ARBs) to either azilsartan or olmesartan, and followed the patients for 12 weeks. Results Office systolic blood pressure (SBP) in the azilsartan group was significantly decreased after 12 weeks. SBP and diastolic blood pressure (DBP) after 12 weeks in the azilsartan group were significantly lower than those in the olmesartan group. The percentage of patients who reached the target BP at 12 weeks (78%) in the azilsartan group was significantly higher than that at 12 weeks (45%) in the olmesartan group. There were no significant changes in pentraxin-3, high-sensitively C-reactive protein or adiponectin in blood after 12 weeks in either group. Although serum levels of creatinine (Cr) in the azilsartan group significantly increased, these changes were within the respective normal range. Conclusion In conclusion, the ability of azilsartan to reduce BP may be superior to that of prior ARBs with equivalent safety in hypertensive patients with CAD. PMID:27635180

Efficacy of azilsartan medoxomil with chlorthalidone in hypertension.

PubMed

Baker, William L; Nigro, Stefanie C; White, William B

2014-07-01

Azilsartan medoxomil (AZL) is the most recently approved angiotensin receptor blocker (ARB) for treating patients with hypertension. A fixed-dose combination product with AZL and the thiazide-like diuretic chlorthalidone (CLD) is now available to treat individuals who require additional blood pressure lowering. For this review, a literature search was conducted using MEDLINE and the keywords and MeSH terms azilsartan, azilsartan medoxomil, chlorthalidone, thiazide, blood pressure and hypertension. References for retrieved articles were also scanned for relevant citations. No language restrictions were used. AZL is structurally related to candesartan and has been shown to provide more potent angiotensin receptor antagonism versus other ARBs. CLD is a thiazide-like diuretic with a longer half-life and greater blood pressure lowering efficacy than hydrochlorothiazide. The combination of AZL plus CLD has superior efficacy to other ARBs alone or in combination with hydrochlorothiazide based on extensive evaluation in clinical trials. This superior efficacy is not offset by a large imbalance in clinically important adverse events.

Cerebrovasculoprotective Effects of Azilsartan Medoxomil in Diabetes

PubMed Central

Abdelsaid, Mohammed; Coucha, Maha; Ergul, Adviye

2014-01-01

We have shown that Goto-Kakizaki (GK) rats, a lean model of type 2 diabetes, develop significant cerebrovascular remodeling by 18 weeks of age, which is characterized by increased media thickness and matrix deposition. While early glycemic control prevents diabetes-mediated remodeling of the cerebrovasculature, whether the remodeling can be reversed is unknown. Given that angiotensin II Type 1 receptor blockers (ARBs) reverse pathological vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new ARB, is vasculoprotective by preventing and reversing cerebrovascular remodeling in diabetes. Control Wistar and diabetic GK rats (n=6–8/group), were treated with vehicle (water) or azilsartan medoxomil (3 mg/kg/day) from 14 to 18 or 18 to 22 weeks of age before or after vascular remodeling is established, respectively. Blood glucose and blood pressure were monitored and middle cerebral artery structure and function were evaluated using pressurized arteriography. Blood glucose was higher in GK rats compared to Wistar rats. Azilsartan treatment lowered blood glucose in diabetes with no effect on blood pressure. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross sectional area compared to controls, which were corrected by azilsartan treatment when started at the onset of diabetes or later after vascular remodeling is established. Azilsartan medoxomil offers preventive and therapeutic vasculoprotection in diabetes-induced cerebrovascular remodeling and myogenic dysfunction and this is independent of blood pressure. PMID:24999268

Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a randomized study

PubMed Central

2013-01-01

Background Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are renoprotective but both may increase serum potassium concentrations in patients with chronic kidney disease (CKD). The proportion of affected patients, the optimum follow-up period and whether there are differences between drugs in the development of this complication remain to be ascertained. Methods In a randomized, double-blind, phase IV, controlled, crossover study we recruited 30 patients with stage 3 CKD under restrictive eligibility criteria and strict dietary control. With the exception of withdrawals, each patient was treated with olmesartan and enalapril separately for 3 months each, with a 1-week wash-out period between treatments. Patients were clinically assessed on 10 occasions via measurements of serum and urine samples. We used the Cochran–Mantel–Haenszel statistics for comparison of categorical data between groups. Comparisons were also made using independent two-sample t-tests and Welch’s t-test. Analysis of variance (ANOVA) was performed when necessary. We used either a Mann–Whitney or Kruskal-Wallis test if the distribution was not normal or the variance not homogeneous. Results Enalapril and olmesartan increased serum potassium levels similarly (0.3 mmol/L and 0.24 mmol/L respectively). The percentage of patients presenting hyperkalemia higher than 5 mmol/L did not differ between treatments: 37% for olmesartan and 40% for enalapril. The mean e-GFR ranged 46.3 to 48.59 ml/mint/1.73 m2 in those treated with olmesartan and 46.8 to 48.3 ml/mint/1.73 m2 in those with enalapril and remained unchanged at the end of the study. The decreases in microalbuminuria were also similar (23% in olmesartan and 29% in enalapril patients) in the 4 weeks time point. The percentage of patients presenting hyperkalemia, even after a two month period, did not differ between treatments. There were no appreciable changes in sodium and potassium urinary excretion. Conclusions Disturbances in potassium balance upon treatment with either olmesartan or enalapril are frequent and without differences between groups. The follow-up of these patients should include control of potassium levels, at least after the first week and the first and second month after initiating treatment. Trial registration The trial EudraCT “2008-002191-98”. PMID:23915518

Optimization of Ligninolytic Enzyme Activity and Production Rate with Ceriporiopsis subvermispora for Application in Bioremediation by Varying Submerged Media Composition and Growth Immobilization Support

PubMed Central

Babič, Janja; Likozar, Blaž; Pavko, Aleksander

2012-01-01

Response surface methodology (central composite design of experiments) was employed to simultaneously optimize enzyme production and productivities of two ligninolytic enzymes produced by Ceriporiopsis subvermispora. Concentrations of glucose, ammonium tartrate and Polysorbate 80 were varied to establish the optimal composition of liquid media (OLM), where the highest experimentally obtained activities and productivities were 41 U L−1 and 16 U L−1 day−1 for laccase (Lac), and 193 U L−1 and 80 U L−1 day−1 for manganese peroxidase (MnP). Considering culture growth in OLM on various types of immobilization support, the best results were obtained with 1 cm beech wood cubes (BWCM). Enzyme activities in culture filtrate were 152 U L−1 for Lac and 58 U L−1 for MnP, since the chemical composition of this immobilization material induced higher Lac activity. Lower enzyme activities were obtained with polyurethane foam. Culture filtrates of OLM and BWCM were applied for dye decolorization. Remazol Brilliant Blue R (RBBR) was decolorized faster and more efficiently than Copper(II)phthalocyanine (CuP) with BWCM (80% and 60%), since Lac played a crucial role. Decolorization of CuP was initially faster than that of RBBR, due to higher MnP activities in OLM. The extent of decolorization after 14 h was 60% for both dyes. PMID:23109859

Accurate and Fully Automatic Hippocampus Segmentation Using Subject-Specific 3D Optimal Local Maps Into a Hybrid Active Contour Model

PubMed Central

Gkontra, Polyxeni; Daras, Petros; Maglaveras, Nicos

2014-01-01

Assessing the structural integrity of the hippocampus (HC) is an essential step toward prevention, diagnosis, and follow-up of various brain disorders due to the implication of the structural changes of the HC in those disorders. In this respect, the development of automatic segmentation methods that can accurately, reliably, and reproducibly segment the HC has attracted considerable attention over the past decades. This paper presents an innovative 3-D fully automatic method to be used on top of the multiatlas concept for the HC segmentation. The method is based on a subject-specific set of 3-D optimal local maps (OLMs) that locally control the influence of each energy term of a hybrid active contour model (ACM). The complete set of the OLMs for a set of training images is defined simultaneously via an optimization scheme. At the same time, the optimal ACM parameters are also calculated. Therefore, heuristic parameter fine-tuning is not required. Training OLMs are subsequently combined, by applying an extended multiatlas concept, to produce the OLMs that are anatomically more suitable to the test image. The proposed algorithm was tested on three different and publicly available data sets. Its accuracy was compared with that of state-of-the-art methods demonstrating the efficacy and robustness of the proposed method. PMID:27170866

How online learning modules can improve the representational fluency and conceptual understanding of university physics students

NASA Astrophysics Data System (ADS)

Hill, M.; Sharma, M. D.; Johnston, H.

2015-07-01

The use of online learning resources as core components of university science courses is increasing. Learning resources range from summaries, videos, and simulations, to question banks. Our study set out to develop, implement, and evaluate research-based online learning resources in the form of pre-lecture online learning modules (OLMs). The aim of this paper is to share our experiences with those using, or considering implementing, online learning resources. Our first task was to identify student learning issues in physics to base the learning resources on. One issue with substantial research is conceptual understanding, the other with comparatively less research is scientific representations (graphs, words, equations, and diagrams). We developed learning resources on both these issues and measured their impact. We created weekly OLMs which were delivered to first year physics students at The University of Sydney prior to their first lecture of the week. Students were randomly allocated to either a concepts stream or a representations stream of online modules. The programme was first implemented in 2013 to trial module content, gain experience and process logistical matters and repeated in 2014 with approximately 400 students. Two validated surveys, the Force and Motion Concept Evaluation (FMCE) and the Representational Fluency Survey (RFS) were used as pre-tests and post-tests to measure learning gains while surveys and interviews provided further insights. While both streams of OLMs produced similar positive learning gains on the FMCE, the representations-focussed OLMs produced higher gains on the RFS. Conclusions were triangulated with student responses which indicated that they have recognized the benefit of the OLMs for their learning of physics. Our study shows that carefully designed online resources used as pre-instruction can make a difference in students’ conceptual understanding and representational fluency in physics, as well as make them more aware of their learning processes. In particular, the representations-focussed modules offer more advantages.

Cerebrovasculoprotective effects of azilsartan medoxomil in diabetes.

PubMed

Abdelsaid, Mohammed; Coucha, Maha; Ergul, Adviye

2014-11-01

We have shown that Goto-Kakizaki (GK) rats, a lean model of type 2 diabetes, develop significant cerebrovascular remodeling by the age of 18 weeks, which is characterized by increased media thickness and matrix deposition. Although early glycemic control prevents diabetes-mediated remodeling of the cerebrovasculature, whether the remodeling can be reversed is unknown. Given that angiotensin II type 1 receptor blockers reverse pathologic vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new angiotensin II type 1 receptor blocker, is vasculoprotective by preventing and reversing cerebrovascular remodeling in diabetes. Control Wistar and diabetic GK rats (n = 6-8 per group) were treated with vehicle (water) or azilsartan medoxomil (3 mg/kg/d) from the age of 14 to 18 or 18 to 22 weeks before or after vascular remodeling is established, respectively. Blood glucose and blood pressure were monitored and middle cerebral artery structure and function were evaluated using pressurized arteriography. Blood glucose was higher in GK rats compared with Wistar rats. Azilsartan treatment lowered blood glucose in diabetic animals with no effect on blood pressure. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross-sectional area compared with control group animals, which were corrected by azilsartan treatment when started at the onset of diabetes or later after vascular remodeling is established. Azilsartan medoxomil offers preventive and therapeutic vasculoprotection in diabetes-induced cerebrovascular remodeling and myogenic dysfunction and this is independent of blood pressure. Published by Elsevier Inc.

Fractionation of visuo-spatial memory processes in bipolar depression: a cognitive scaffolding account.

PubMed

Gallagher, P; Gray, J M; Kessels, R P C

2015-02-01

Previous studies of neurocognitive performance in bipolar disorder (BD) have demonstrated impairments in visuo-spatial memory. The aim of the present study was to use an object-location memory (OLM) paradigm to assess specific, dissociable processes in visuo-spatial memory and examine their relationship with broader neurocognitive performance. Fifty participants (25 patients with BD in a current depressive episode and 25 matched healthy controls) completed the OLM paradigm which assessed three different aspects of visuo-spatial memory: positional memory, object-location binding, and a combined process. Secondary neurocognitive measures of visuo-spatial memory, verbal memory, attention and executive function were also administered. BD patients were significantly impaired on all three OLM processes, with the largest effect in exact positional memory (d = 1.18, p < 0.0001). General deficits were also found across the secondary neurocognitive measures. Using hierarchical regression, verbal learning was found to explain significant variance on the OLM measures where object-identity was present (the object-location binding and combined processes) and accounted for the group difference. The group difference in precise positional memory remained intact. This study demonstrates that patients with bipolar depression manifest deficits in visuo-spatial memory, with substantial impairment in fine-grain, positional memory. The differential profile of processes underpinning the visuo-spatial memory impairment suggests a form of 'cognitive scaffolding', whereby performance on some measures can be supported by verbal memory. These results have important implications for our understanding of the functional cognitive architecture of mood disorder.

Gateways to clinical trials.

PubMed

Bayes, M; Rabasseda, X; Prous, J R

2005-10-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: (-)-Epigallocatechin gallate, (Z)-4-hydroxytamoxifen; Ad.muIFN-beta AD-237, adalimumab, adefovir dipivoxil, agalsidase alfa, alemtuzumab, almotriptan, ALVAC vCP1452, alvimopan hydrate, ambrisentan, anakinra, anti-IFN-gamma MAb; Bimatoprost, BMS-188797, BMS-214662, bortezomib, bosentan, bovine lactoferrin; Caffeine, canertinib dihydrochloride, canfosfamide hydrochloride, cannabidiol, caspofungin acetate, cetuximab, cH36, ChimeriVax-JE, ciclesonide, cilansetron, cinacalcet hydrochloride, clopidogrel, CpG-7909, Cypher; Daptomycin, darbepoetin alfa, darifenacin hydrobromide, decitabine, denufosol tetrasodium, Dexamet, diindolemethane, drotrecogin alfa (activated), duloxetine hydrochloride, DX-9065a; E-7010, edaravone, efalizumab, eicosapentaenoic acid/docosahexaenoic acid, elacridar, eletriptan, emtricitabine, epratuzumab, erlotinib hydrochloride, ertapenem sodium, eszopiclone, everolimus, ezetimibe; Fludarabine, fondaparinux sodium; gamma-Hydroxybutyrate sodium, gavestinel sodium, gefitinib, granisetron-Biochronomer; Human Albumin, human insulin; Imatinib mesylate, indiplon, interleukin-2 XL, isatoribine, ISS-1018, i.v. gamma-globulin, ivabradine hydrochloride, ixabepilone; Lanthanum carbonate, L-arginine hydrochloride, liposomal doxorubicin, LY-450139; Magnesium sulfate, melatonin, motexafin gadolinium, mycophenolic acid sodium salt; Natalizumab, nesiritide, niacin/lovastatin; OGX-011, olmesartan medoxomil, omalizumab, ospemifene; PACAP38, panitumumab, parathyroid hormone (human recombinant), parecoxib sodium, patupilone, pegfilgrastim, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ribavirin, pemetrexed disodium, pimecrolimus, pirfenidone, posaconazole, prasterone, pregabalin; R-112, ramelteon, ranolazine, rasagiline mesilate, rebimastat, roflumilast, rosuvastatin calcium, rotigotine hydrochloride, rupatadine fumarate; S-3013, S-3304, semustine, sitaxsentan sodium, St. John's Wort extract; Tadalafil, tamoxifen, Taxus, Tc-99m-EDDA-HYNIC-TOC, TH-9507, tiotropium bromide, tipifarnib, tocilizumab, tolvaptan, torcetrapib, TR-14035, tramadol hydrochloride/acetaminophen, treprostinil diethanolamine, troglitazone, troxacitabine; Valdecoxib, valganciclovir hydrochloride, vandetanib, vardenafil hydrochloride hydrate, VAS-991, veglin, vinflunine, voriconazole; White sweet potato extract; Ximelagatran. (c) 2005 Prous Science. All rights reserved.

Pharmacokinetic evaluation and clinical utility of azilsartan medoxomil for the treatment of hypertension.

PubMed

Angeli, Fabio; Verdecchia, Paolo; Pascucci, Chiara; Poltronieri, Cristina; Reboldi, Gianpaolo

2013-03-01

Azilsartan medoxomil is a newly approved angiotensin-receptor blocker for the management of hypertension. It is a prodrug that is quickly hydrolyzed to the active moiety azilsartan, a potent and highly selective angiotensin-receptor blocker with estimated bioavailability of ∼ 60%. This new agent induces a potent and long-lasting antihypertensive effect. The effective therapeutic antihypertensive dosages of azilsartan medoxomil in humans vary from 40 to 80 mg/day. The authors review the results of clinical trials published in journals indexed in Medline, Scopus and Google Scholar. Primarily the authors discuss articles that analyze the safety and efficacy of azilsartan in lowering blood pressure. Clinical trials have demonstrated that azilsartan is superior to other angiotensin-receptor blockers in lowering blood pressure. However, the clinical blood pressure trials of azilsartan published to date have been mainly conducted in patients without serious comorbidities and it is not clear if azilsartan has advantages over other angiotensin-receptor blockers in the treatment of these types of hypertensive patients. In addition, it remains to be determined whether the specific pharmacologic and pharmacokinetic characteristics of azilsartan will have a clinically significant impact on long-term cardiovascular outcomes.

Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System

PubMed Central

Takami, Takeshi; Okada, Sadanori; Saito, Yoshihiko; Nishijima, Yoko; Kobori, Hiroyuki; Nishiyama, Akira

2018-01-01

Purpose Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension. Methods Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks. Results Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 μg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (−39.4 vs 0.27, P = 0.0024) and Δu-AGT (−11.9 vs −0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP. Conclusion Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects. PMID:29683146

Effects of Olmesartan and Azilsartan on Albuminuria and the Intrarenal Renin-Angiotensin System.

PubMed

Takami, Takeshi; Okada, Sadanori; Saito, Yoshihiko; Nishijima, Yoko; Kobori, Hiroyuki; Nishiyama, Akira

2018-01-01

Olmesartan and azilsartan decrease blood pressure more effectively than other angiotensin receptor blockers (ARBs). ARBs additionally decrease the urinary albumin to creatinine ratio (UACR), a urinary albumin marker, and urinary angiotensinogen (u-AGT), an intrarenal renin-angiotensin system activity marker. We examined the effects of these ARBs on blood pressure, UACR, and u-AGT in patients with uncontrolled hypertension. Patients with uncontrolled hypertension treated with conventional ARBs, excluding olmesartan and azilsartan, for over 8 weeks were enrolled. We randomly switched patients from their prior ARBs to either olmesartan or azilsartan, and followed them for 24 weeks. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and central systolic blood pressure (cSBP) significantly decreased at 24 weeks. UACR and u-AGT also decreased at 24 weeks in both groups. There were no significant differences in SBP, DBP, cSBP, UACR, or u-AGT between the groups. Therefore, we combined both groups for further analyses. After combining, SBP (160.5 ± 16.4 to 139.6 ± 15.6 mm Hg, P < 0.0001), DBP (88.4 ± 13.7 to 80.7 ± 13.2 mm Hg, P = 0.008), cSBP (167.4 ± 20.8 to 146.6 ± 24.6 mm Hg, P < 0.0001), UACR (13.8 to 9.0 mg/g Cre, P = 0.0096), and u-AGT (4.13 to 2.32 μg/g Cre, P = 0.0074) significantly decreased at 24 weeks. Patients with microalbuminuria (UACR ≥ 30 mg/g Cre) had significantly greater ΔUACR (-39.4 vs 0.27, P = 0.0024) and Δu-AGT (-11.9 vs -0.61, P = 0.0235) than patients without microalbuminuria. The changes in u-AGT were significantly associated with changes in UACR (r = 0.411, P = 0.046); however, there was no significant relationship between the changes in u-AGT and those in SBP or DBP. Olmesartan and azilsartan decreased blood pressure, UACR, and u-AGT more than the other ARBs, and exerted depressor and renoprotective effects.

Conformation and structural changes of diblock copolymers with octopus-like micelle formation in the presence of external stimuli

NASA Astrophysics Data System (ADS)

Dammertz, K.; Saier, A. M.; Marti, O.; Amirkhani, M.

2014-04-01

External stimuli such as vapours and electric fields can be used to manipulate the formation of AB-diblock copolymers on surfaces. We study the conformational variation of PS-b-PMMA (polystyrene-block-poly(methyl methacrylate)), PS and PMMA adsorbed on mica and their response to saturated water or chloroform atmospheres. Using specimens with only partial polymer coverage, new unanticipated effects were observed. Water vapour, a non-solvent for all three polymers, was found to cause high surface mobility. In contrast, chloroform vapour (a solvent for all three polymers) proved to be less efficient. Furthermore, the influence of an additional applied electric field was investigated. A dc field oriented parallel to the sample surface induces the formation of polymer islands which assemble into wormlike chains. Moreover, PS-b-PMMA forms octopus-like micelles (OLMs) on mica. Under the external stimuli mentioned above, the wormlike formations of OLMs are able to align in the direction of the external electric field. In the absence of an electric field, the OLMs disaggregate and exhibit phase separated structures under chloroform vapour.

Seizures as imbalanced up states: excitatory and inhibitory conductances during seizure-like events

PubMed Central

Cressman, John R.; Schiff, Steven J.

2013-01-01

Precisely timed and dynamically balanced excitatory (E) and inhibitory (I) conductances underlie the basis of neural network activity. Normal E/I balance is often shifted in epilepsy, resulting in neuronal network hyperexcitability and recurrent seizures. However, dynamics of the actual excitatory and inhibitory synaptic conductances (ge and gi, respectively) during seizures remain unknown. To study the dynamics of E and I network balance, we calculated ge and gi during the initiation, body, and termination of seizure-like events (SLEs) in the rat hippocampus in vitro. Repetitive emergent SLEs in 4-aminopyridine (100 μM) and reduced extracellular magnesium (0.6 mM) were recorded in the identified CA1 pyramidal cells (PC) and oriens-lacunosum moleculare (O-LM) interneurons. Calculated ge/gi ratio dynamics showed that the initiation stage of the SLEs was dominated by inhibition in the PCs and was more balanced in the O-LM cells. During the body of the SLEs, the balance shifted toward excitation, with ge and gi peaking in both cell types at nearly the same time. In the termination phase, PCs were again dominated by inhibition, whereas O-LM cells experienced persistent excitatory synaptic barrage. In this way, increased excitability of interneurons may play roles in both seizure initiation (Žiburkus J, Cressman JR, Barreto E, Schiff SJ. J Neurophysiol 95: 3948–3954, 2006) and in their termination. Overall, SLE stages can be characterized in PC and O-LM cells by dynamically distinct changes in the balance of ge and gi, where a temporal sequence of imbalance shifts with the changing firing patterns of the cellular subtypes comprising the hyperexcitable microcircuits. PMID:23221405

Polymorphs and solvatomorphs of azilsartan medoxomil: Elucidation of solvent-induced construction and conformational diversity

NASA Astrophysics Data System (ADS)

Zhang, Xian-Rui; He, Sai-Fei; Zhang, Shuo; Li, Jing; Li, Shan; Liu, Jin-Song; Zhang, Lei

2017-02-01

Two polymorphs (AM-A and AM-B) of azilsartan medoxomil (AM) and four AM solvatomorphs with toluene (AM-TOL), 1,4-dioxane (AM-DIO), chloroform (AM-TCM) and N,N-dimethylacetamide (AM-DMA) have been prepared by the hydrolysis of azilsartan medoxomil potassium in aqueous-organic solutions. In the crystal structures of two polymorphs and three solvatomorphs (AM-TOL, AM-DIO and AM-TCM), two asymmetric AM molecules form the dimeric cycle-like structures via intermolecular Nsbnd H⋯N hydrogen bonds in R22 (26) ring, while AM-DMA shows intramolecular Nsbnd H⋯O hydrogen bond between AM and DMA molecules. The hydrogen bonds (Csbnd H⋯O or Csbnd H⋯N) and π···π (or Csbnd H···π) interactions are helpful to stabilize the conformational diversity of AM. The solvent-induced experiment shows that solvent molecules have great influence on the solvatomorph formation and DIO can form the most steady solvatomorph than other solvents. The thermal study demonstrates that toluene molecules in three solvatomorphs (AM-TOL, AM-DIO and AM-TCM) are the most difficult to remove from the cage. Our results illustrate that the solvent plays significant role in tuning the size of the cage and producing the conformational diversity of AM molecules.

An investigation on nursing, midwifery and health care students' learning motivation in Turkey.

PubMed

Kosgeroglu, Nedime; Acat, M Bahaddin; Ayranci, Unal; Ozabaci, Nilufer; Erkal, Sibel

2009-09-01

The aim was to determine differences between the dimensions of motivational learning and sociodemographic characteristics of nursing, midwifery and health care students. For the purpose of collecting data on learning-oriented motivations, occupational learning motivation scale (OLMS) was used. The OLMS was designed to assess the constructs of extrinsic, intrinsic and negative factors for learning, cognitive and lifelong learning goals. The mean levels of the items "willingness to help people", "fear of making mistakes" and "willingness to work with those likely to motivate them" were all determined to be high. Significant differences were revealed for the sex of the students (p<0.05).

FAULT PROPAGATION AND EFFECTS ANALYSIS FOR DESIGNING AN ONLINE MONITORING SYSTEM FOR THE SECONDARY LOOP OF A NUCLEAR POWER PLANT PART OF A HYBRID ENERGY SYSTEM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Huijuan; Diao, Xiaoxu; Li, Boyuan

This paper studies the propagation and effects of faults of critical components that pertain to the secondary loop of a nuclear power plant found in Nuclear Hybrid Energy Systems (NHES). This information is used to design an on-line monitoring (OLM) system which is capable of detecting and forecasting faults that are likely to occur during NHES operation. In this research, the causes, features, and effects of possible faults are investigated by simulating the propagation of faults in the secondary loop. The simulation is accomplished by using the Integrated System Failure Analysis (ISFA). ISFA is used for analyzing hardware and softwaremore » faults during the conceptual design phase. In this paper, the models of system components required by ISFA are initially constructed. Then, the fault propagation analysis is implemented, which is conducted under the bounds set by acceptance criteria derived from the design of an OLM system. The result of the fault simulation is utilized to build a database for fault detection and diagnosis, provide preventive measures, and propose an optimization plan for the OLM system.« less

Role of ionotropic glutamate receptors in LTP in rat hippocampal CA1 oriens-lacunosum moleculare interneurons

PubMed Central

Oren, Iris; Nissen, Wiebke; Kullmann, Dimitri M.; Somogyi, Peter; Lamsa, Karri P.

2009-01-01

Some interneurons of the hippocampus exhibit NMDA receptor-independent long-term potentiation (LTP) that is induced by presynaptic glutamate release when the postsynaptic membrane potential is hyperpolarized. This ‘anti-Hebbian’ form of LTP is prevented by postsynaptic depolarization or by blocking AMPA and kainate receptors. Although both AMPA and kainate receptors are expressed in hippocampal interneurons, their relative roles in anti-Hebbian LTP are not known. Because interneuron diversity potentially conceals simple rules underlying different forms of plasticity, we focus on glutamatergic synapses onto a subset of interneurons with dendrites in stratum oriens and a main ascending axon that projects to stratum lacunosum-moleculare, the O-LM cells. We show that anti-Hebbian LTP in O-LM interneurons has consistent induction and expression properties, and is prevented by selective inhibition of AMPA receptors. The majority of the ionotropic glutamatergic synaptic current in these cells is mediated by inwardly rectifying Ca2+ -permeable AMPA receptors. Although GluR5-containing kainate receptors contribute to synaptic currents at high stimulus frequency, they are not required for LTP induction. Glutamatergic synapses on O-LM cells thus behave in a homogeneous manner, and exhibit LTP dependent on Ca2+-permeable AMPA receptors. PMID:19176803

No Effects of Non-invasive Brain Stimulation on Multiple Sessions of Object-Location-Memory Training in Healthy Older Adults.

PubMed

Külzow, Nadine; Cavalcanti de Sousa, Angelica Vieira; Cesarz, Magda; Hanke, Julie-Marie; Günsberg, Alida; Harder, Solvejg; Koblitz, Swantje; Grittner, Ulrike; Flöel, Agnes

2017-01-01

Object-location memory (OLM) is known to decline with normal aging, a process accelerated in pathological conditions like mild cognitive impairment (MCI). In order to maintain cognitive health and to delay the transition from healthy to pathological conditions, novel strategies are being explored. Tentative evidence suggests that combining cognitive training and anodal transcranial direct current stimulation (atDCS), both reported to induce small and often inconsistent behavioral improvements, could generate larger or more consistent improvements or both, compared to each intervention alone. Here, we explored the combined efficacy of these techniques on OLM. In a subject-blind sham-controlled cross-over design 32 healthy older adults underwent a 3-day visuospatial training paired with either anodal (20 min) or sham (30 s) atDCS (1 mA, temporoparietal). Subjects were asked to learn the correct object-location pairings on a street map, shown over five learning blocks on each training day. Acquisition performance was assessed by accuracy on a given learning block in terms of percentage of correct responses. Training success (performance on last training day) and delayed memory after 1-month were analyzed by mixed model analysis and were controlled for gender, age, education, sequence of stimulation and baseline performance. Exploratory analysis of atDCS effects on within-session (online) and between-session (offline) memory performance were conducted. Moreover, transfer effects on similar trained (visuospatial) and less similar (visuo-constructive, verbal) untrained memory tasks were explored, both immediately after training, and on follow-up. We found that atDCS paired with OLM-training did not enhance success in training or performance in 1-month delayed memory or transfer tasks. In sum, this study did not support the notion that the combined atDCS-training approach improves immediate or delayed OLM in older adults. However, specifics of the experimental design, and a non-optimal timing of atDCS between sessions might have masked beneficial effects and should be more systematically addressed in future studies.

[Hronotherapy Aspects of Efficiency Azilsartan Medoxomil in Combination Therapy in Patients With Hypertension and Metabolic Syndrome].

PubMed

Skibitskiy, V V; Fendrikova, A V; Sirotenko, D V; Skibitskiy, A V

2016-10-01

Determination of the effectiveness and safety of different dosing regimens during the day (in the morning or at bedtime) combination therapy including azilsartan medoxomil in patients with essential hypertension and metabolic syndrome (MS). The study included 60 patients with uncontrolled hypertension and MS (age median - 59 (54-65) years). Patients were randomized in two groups: group 1 (n=30) received azilsartan medoxomil 40 mg/day, and indapamide retard 1,5 mg/day in the morning; group 2 (n=30)- azilsartan medoxomoil 40 mg at bedtime and indapamide retard 1,5 mg in the morning. All patients at baseline, and after 4 and 12weeks assessed levels of office blood pressure (BP), heart rate (HR); at baseline and after 12 weeks was conducted ambulatory BPmonitoring (ABPM). Evaluated the main indicators of circadian blood pressure profile, as well as the central aortic pressure (CAP) and the rigidity of the vascular wall: systolic, diastolic, and mean arterial pressure in the aorta, aortic augmentation index, pulse wave velocity in the aorta, the augmentation index. Study results were processed using the program Statistica 6.1 by methods nonparametric statistics. Regardless of the regimen used azilsartan destination as part of combination therapy after 4 weeks showed a significant (p<0.05) reduction in SBP and DBP. After 12 weeks of observation target blood pressure was recorded 27 (90%) patients of group 1 and 29 (96.7%)- group2. As a result of ABPM after 12 weeks of treatment in both groups showed a statistically significant (p<0.05) improvement in all parameters investigated. However, positive changes such indicators as an index time of hypertension in the day and night hours, SBP, DBP, and BP variability during the night, the morning rise of systolic as well as the speed of morning rise in SBP and DBP were more pronounced in the appointment azilsartan medoxomil at bedtime compared to morning reception. The use of both treatment regimens provided significant (p<0.05) increase frequency registration profile dippear and reduction - non-dipper. Importantly, irrespective of the time of taking the drugs in both groups occurred significant (p <0.05), and a comparable improvement in rigidity and CAP vascular wall. When combined with essential hypertension and MS azilsartana use of combination drug therapy provided achievement of the target values of blood pressure in the majority of patients, a significant improvement in the main indicators of ABPM, CAP, and the rigidity of the vascular wall, as well as the normalization of daily profile of blood pressure in the majority of patients, regardless of dosing regimen during the day. However, the combination of indapamide retard morning - azilsartan medoxomil at bedtime accompanied by a significantly greater positive changes most ABPM parameters, especially at night.

Evaluations of the Antimicrobial Activities and Chemical Compositions of Body Fat from the Amphibians Leptodactylus macrosternum Miranda-Ribeiro (1926) and Leptodactylus vastus Adolf Lutz (1930) in Northeastern Brazil

PubMed Central

Cabral, Mario Eduardo Santos; Dias, Diógenes de Queiroz; Sales, Débora Lima; Oliveira, Olga Paiva; Teles, Diego Alves; Filho, João Antonio de Araujo; de Sousa, José Guilherme Gonçalves; Coutinho, Henrique Douglas Melo; da Costa, José Galberto Martins; Kerntopf, Marta Regina; Alves, Rômulo Romeu da Nóbrega; Almeida, Waltécio de Oliveira

2013-01-01

Leptodactylus macrosternum and L. vastus (family: Leptodactylidae) are commonly encountered in the “Caatinga” biome in northern Brazil. The body fat of L. vastus is used as a zootherapeutic for treating a number of human maladies. The aim of this work was to determine the chemical composition of the body fats of L. macrosternum and L. vastus and to evaluate their antimicrobial activities as well as the ecological implications of their use in traditional folk medicine. Oils were extracted from body fat located in the ventral region of L. macrosternum (OLM) and L. vastus (OLV) using hexane as a solvent. The fatty acids were identified by GC-MS. The antimicrobial activities of the oils, either alone or in combination with antibiotics and antifungal drugs, were tested on standard strains of microorganisms as well as on multiresistant strains of Escherichia coli and Staphylococcus. OLM contained 40% saturated and 60% unsaturated fatty acids, while OLV contained 58.33% saturated and 41.67% unsaturated fatty acids. Our results indicated that both OLM and OLV demonstrated relevant antimicrobial activities (with MIC 256 μg/mL for both) against Pseudomonas aeruginosa and Candida krusei. However, no antimicrobial effects were observed when these oils were combined with antibiotics or antifungal drugs. PMID:23710241

AT1 receptor blocker azilsartan medoxomil normalizes plasma miR-146a and miR-342-3p in a murine heart failure model.

PubMed

Kaneko, Manami; Satomi, Tomoko; Fujiwara, Shuji; Uchiyama, Hidefumi; Kusumoto, Keiji; Nishimoto, Tomoyuki

Our study measured circulating microRNA (miRNA) levels in the plasma of calsequestrin (CSQ)-tg mouse, a severe heart failure model, and evaluated whether treatment with angiotensin II type 1 receptor blocker, azilsartan medoxomil (AZL-M) influenced their levels using miRNA array analysis. MiR-146a, miR-149, miR-150, and miR-342-3p were reproducibly reduced in the plasma of CSQ-tg mice. Among them, miR-146a and miR-342-3p were significantly restored by AZL-M, which were associated with improvement of survival rate and reduction of congestion. These results suggest that miRNA, especially miR-146a and miR-342-3p, could be used as potential biomarkers for evaluating the efficacy of anti-heart failure drugs.

No Effects of Non-invasive Brain Stimulation on Multiple Sessions of Object-Location-Memory Training in Healthy Older Adults

PubMed Central

Külzow, Nadine; Cavalcanti de Sousa, Angelica Vieira; Cesarz, Magda; Hanke, Julie-Marie; Günsberg, Alida; Harder, Solvejg; Koblitz, Swantje; Grittner, Ulrike; Flöel, Agnes

2018-01-01

Object-location memory (OLM) is known to decline with normal aging, a process accelerated in pathological conditions like mild cognitive impairment (MCI). In order to maintain cognitive health and to delay the transition from healthy to pathological conditions, novel strategies are being explored. Tentative evidence suggests that combining cognitive training and anodal transcranial direct current stimulation (atDCS), both reported to induce small and often inconsistent behavioral improvements, could generate larger or more consistent improvements or both, compared to each intervention alone. Here, we explored the combined efficacy of these techniques on OLM. In a subject-blind sham-controlled cross-over design 32 healthy older adults underwent a 3-day visuospatial training paired with either anodal (20 min) or sham (30 s) atDCS (1 mA, temporoparietal). Subjects were asked to learn the correct object-location pairings on a street map, shown over five learning blocks on each training day. Acquisition performance was assessed by accuracy on a given learning block in terms of percentage of correct responses. Training success (performance on last training day) and delayed memory after 1-month were analyzed by mixed model analysis and were controlled for gender, age, education, sequence of stimulation and baseline performance. Exploratory analysis of atDCS effects on within-session (online) and between-session (offline) memory performance were conducted. Moreover, transfer effects on similar trained (visuospatial) and less similar (visuo-constructive, verbal) untrained memory tasks were explored, both immediately after training, and on follow-up. We found that atDCS paired with OLM-training did not enhance success in training or performance in 1-month delayed memory or transfer tasks. In sum, this study did not support the notion that the combined atDCS-training approach improves immediate or delayed OLM in older adults. However, specifics of the experimental design, and a non-optimal timing of atDCS between sessions might have masked beneficial effects and should be more systematically addressed in future studies. PMID:29375290

On the Controls of Leaf-Water Oxygen Isotope Ratios in the Atmospheric Crassulacean Acid Metabolism Epiphyte Tillandsia usneoides1[W][OA

PubMed Central

Helliker, Brent R.

2011-01-01

Previous theoretical work showed that leaf-water isotope ratio (δ18OL) of Crassulacean acid metabolism epiphytes was controlled by the δ18O of atmospheric water vapor (δ18Oa), and observed δ18OL could be explained by both a non-steady-state model and a “maximum enrichment” steady-state model (δ18OL-M), the latter requiring only δ18Oa and relative humidity (h) as inputs. δ18OL, therefore, should contain an extractable record of δ18Oa. Previous empirical work supported this hypothesis but raised many questions. How does changing δ18Oa and h affect δ18OL? Do hygroscopic trichomes affect observed δ18OL? Are observations of changes in water content required for the prediction of δ18OL? Does the leaf need to be at full isotopic steady state for observed δ18OL to equal δ18OL-M? These questions were examined with a climate-controlled experimental system capable of holding δ18Oa constant for several weeks. Water adsorbed to trichomes required a correction ranging from 0.5‰ to 1‰. δ18OL could be predicted using constant values of water content and even total conductance. Tissue rehydration caused a transitory change in δ18OL, but the consequent increase in total conductance led to a tighter coupling with δ18Oa. The non-steady-state leaf water models explained observed δ18OL (y = 0.93*x − 0.07; r2 = 0.98) over a wide range of δ18Oa and h. Predictions of δ18OL-M agreed with observations of δ18OL (y = 0.87*x − 0.99; r2 = 0.92), and when h > 0.9, the leaf did not need to be at isotopic steady state for the δ18OL-M model to predict δ18OL in the Crassulacean acid metabolism epiphyte Tillandsia usneoides. PMID:21300917

On the controls of leaf-water oxygen isotope ratios in the atmospheric Crassulacean acid metabolism epiphyte Tillandsia usneoides.

PubMed

Helliker, Brent R

2011-04-01

Previous theoretical work showed that leaf-water isotope ratio (δ(18)O(L)) of Crassulacean acid metabolism epiphytes was controlled by the δ(18)O of atmospheric water vapor (δ(18)O(a)), and observed δ(18)O(L) could be explained by both a non-steady-state model and a "maximum enrichment" steady-state model (δ(18)O(L-M)), the latter requiring only δ(18)O(a) and relative humidity (h) as inputs. δ(18)O(L), therefore, should contain an extractable record of δ(18)O(a). Previous empirical work supported this hypothesis but raised many questions. How does changing δ(18)O(a) and h affect δ(18)O(L)? Do hygroscopic trichomes affect observed δ(18)O(L)? Are observations of changes in water content required for the prediction of δ(18)O(L)? Does the leaf need to be at full isotopic steady state for observed δ(18)O(L) to equal δ(18)O(L-M)? These questions were examined with a climate-controlled experimental system capable of holding δ(18)O(a) constant for several weeks. Water adsorbed to trichomes required a correction ranging from 0.5‰ to 1‰. δ(18)O(L) could be predicted using constant values of water content and even total conductance. Tissue rehydration caused a transitory change in δ(18)O(L), but the consequent increase in total conductance led to a tighter coupling with δ(18)O(a). The non-steady-state leaf water models explained observed δ(18)O(L) (y = 0.93*x - 0.07; r(2) = 0.98) over a wide range of δ(18)O(a) and h. Predictions of δ(18)O(L-M) agreed with observations of δ(18)O(L) (y = 0.87*x - 0.99; r(2) = 0.92), and when h > 0.9, the leaf did not need to be at isotopic steady state for the δ(18)O(L-M) model to predict δ(18)O(L) in the Crassulacean acid metabolism epiphyte Tillandsia usneoides.

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed‐Dose Combination in Healthy Adults

PubMed Central

Karim, Aziz; Munsaka, Melvin

2016-01-01

Abstract Azilsartan medoxomil is a long‐acting angiotensin II receptor blocker used to treat hypertension as monotherapy or in fixed‐dose combination (FDC) with chlorthalidone. This study assessed the effects of food intake on the plasma pharmacokinetics of the active moiety, azilsartan, and of chlorthalidone when administered as separate tablets or in FDC. Cohort 1 (n = 24) received azilsartan medoxomil (80 mg) and chlorthalidone (25 mg) once in a fasted condition and once 30 minutes after the initiation of a high‐fat meal (fed). Cohort 2 (n = 24) received the same drugs as an FDC tablet in the fasted and fed conditions. In cohort 1, the fed‐fasted ratios for AUC0–inf and Cmax were 108.3 (101.6–115.5) and 103.7 (94.3–114.1), respectively, for azilsartan and 112.3 (106.5–118.4) and 100.3 (90.6–111.1), respectively, for chlorthalidone. In cohort 2, the corresponding ratios were 78.6 (67.6–91.4) and 78.6 (64.4–96.0) for azilsartan and 101.0 (96.5–86.7) and 75.9 (66.5–86.7) for chlorthalidone. The combination therapies were well tolerated, and food intake had no consistent effect on adverse events. Food intake had a somewhat greater effect on plasma pharmacokinetics after administration of the FDC tablet than after administration of separate tablets, but the effects of food on the plasma pharmacokinetics of the FDC were not expected to be clinically meaningful. PMID:27514506

Olmesartan

MedlinePlus

... or in combination with other medications to treat high blood pressure in adults and children 6 years of age ... smoothly and the heart to pump more efficiently.High blood pressure is a common condition and when not treated, ...

78 FR 12798 - Extension of Information Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-25

... contracts for purchases under the Simplified Acquisition Threshold. OLMS administers the enforcement... violation of proposed 29 CFR part 471. Total Burden Cost (capital/startup): $12.50 ($0.50 per response x 25...

Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus.

PubMed

Katona, Linda; Micklem, Ben; Borhegyi, Zsolt; Swiejkowski, Daniel A; Valenti, Ornella; Viney, Tim J; Kotzadimitriou, Dimitrios; Klausberger, Thomas; Somogyi, Peter

2017-04-01

Long-range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O-LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin-labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave-ripples, most projection cells, including a novel SOM+ GABAergic back-projecting cell, increased their activity similar to bistratified cells, but unlike O-LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O-LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior- and network state-dependent binding of neuronal assemblies amongst functionally-related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Blockade of AT1 Receptors Protects the Blood–Brain Barrier and Improves Cognition in Dahl Salt-Sensitive Hypertensive Rats

PubMed Central

Pelisch, Nicolas; Hosomi, Naohisa; Ueno, Masaki; Nakano, Daisuke; Hitomi, Hirofumi; Mogi, Masaki; Shimada, Kenji; Kobori, Hiroyuki; Horiuchi, Masatsugu; Sakamoto, Haruhiko; Matsumoto, Masayasu; Kohno, Masakazu; Nishiyama, Akira

2011-01-01

BACKGROUND The present study tested the hypothesis that inappropriate activation of the brain renin–angiotensin system (RAS) contributes to the pathogenesis of blood–brain barrier (BBB) disruption and cognitive impairment during development of salt-dependent hypertension. Effects of an angiotensin II (AngII) type-1 receptor blocker (ARB), at a dose that did not reduce blood pressure, were also examined. METHODS Dahl salt-sensitive (DSS) rats at 6 weeks of age were assigned to three groups: low-salt diet (DSS/L; 0.3% NaCl), high-salt diet (DSS/H; 8% NaCl), and high-salt diet treated with ARB, olmesartan at 1 mg/kg. RESULTS DSS/H rats exhibited hypertension, leakage from brain microvessels in the hippocampus, and impaired cognitive functions, which were associated with increased brain AngII levels, as well as decreased mRNA levels of tight junctions (TJs) and collagen-IV in the hippocampus. In DSS/H rats, olmesartan treatment, at a dose that did not alter blood pressure, restored the cognitive decline, and ameliorated leakage from brain microvessels. Olmesartan also decreased brain AngII levels and restored mRNA expression of TJs and collagen-IV in DSS/H rats. CONCLUSIONS These results suggest that during development of salt-dependent hypertension, activation of the brain RAS contributes to BBB disruption and cognitive impairment. Treatment with an ARB could elicit neuroprotective effects in cognitive disorders by preventing BBB permeability, which is independent of blood pressure changes. PMID:21164491

77 FR 63872 - Senior Executive Service; Appointment of Members to the Performance Review Board

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-17

... Resources--Kim L.H. Green. Rotating Membership ASP Kathleen E. Franks, Director, Office of Regulatory and... OLMS Stephen J. Willertz, Director, Office of Enforcement and International Union Audits--appointment...

Liquid chromatography/tandem mass spectrometry study of forced degradation of azilsartan medoxomil potassium.

PubMed

Swain, Debasish; Patel, Prinesh N; Palaniappan, Ilayaraja; Sahu, Gayatri; Samanthula, Gananadhamu

2015-08-15

Azilsartan medoxomil potassium (AZM) is a new antihypertensive drug introduced in the year 2011. The presence of degradation products not only affects the quality, but also the safety aspects of the drug. Thus, it is essential to develop an efficient analytical method which could be useful to selectively separate and identify the degradation products of azilsartan medoxomil potassium. AZM was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions. Separation of the drug and degradation products was achieved by a liquid chromatography (LC) method using an Acquity UPLC(®) C18 CSH column with mobile phase consisting of 0.02% trifluoroacetic acid and acetonitrile using a gradient method. Identification and characterization of the degradation products was carried out using LC/electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOFMS). A total of five degradation products (DP 1 to DP 5) were formed under various stress conditions and their structures were proposed with the help of tandem mass spectrometry (MS/MS) experiments and accurate mass data. A common degradation product (DP 4) was observed under all the degradation conditions. DP 1, DP 2 and DP 5 were observed under acid hydrolytic conditions whereas DP 3 was observed under alkaline conditions. AZM was found to degrade under hydrolytic, oxidative and photolytic stress conditions. The structures of all the degradation products were proposed. The degradation pathway for the formation of degradation products was also hypothesized. A selective method was developed to quantify the drug in the presence of degradation products which is useful to monitor the quality of AZM. Copyright © 2015 John Wiley & Sons, Ltd.

Effects of Food Intake on the Pharmacokinetics of Azilsartan Medoxomil and Chlorthalidone Alone and in Fixed-Dose Combination in Healthy Adults.

PubMed

Dudkowski, Caroline; Karim, Aziz; Munsaka, Melvin

2016-09-01

Azilsartan medoxomil is a long-acting angiotensin II receptor blocker used to treat hypertension as monotherapy or in fixed-dose combination (FDC) with chlorthalidone. This study assessed the effects of food intake on the plasma pharmacokinetics of the active moiety, azilsartan, and of chlorthalidone when administered as separate tablets or in FDC. Cohort 1 (n = 24) received azilsartan medoxomil (80 mg) and chlorthalidone (25 mg) once in a fasted condition and once 30 minutes after the initiation of a high-fat meal (fed). Cohort 2 (n = 24) received the same drugs as an FDC tablet in the fasted and fed conditions. In cohort 1, the fed-fasted ratios for AUC0-inf and Cmax were 108.3 (101.6-115.5) and 103.7 (94.3-114.1), respectively, for azilsartan and 112.3 (106.5-118.4) and 100.3 (90.6-111.1), respectively, for chlorthalidone. In cohort 2, the corresponding ratios were 78.6 (67.6-91.4) and 78.6 (64.4-96.0) for azilsartan and 101.0 (96.5-86.7) and 75.9 (66.5-86.7) for chlorthalidone. The combination therapies were well tolerated, and food intake had no consistent effect on adverse events. Food intake had a somewhat greater effect on plasma pharmacokinetics after administration of the FDC tablet than after administration of separate tablets, but the effects of food on the plasma pharmacokinetics of the FDC were not expected to be clinically meaningful. © 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Simultaneous quantitative analysis of olmesartan, amlodipine and hydrochlorothiazide in their combined dosage form utilizing classical and alternating least squares based chemometric methods.

PubMed

Darwish, Hany W; Bakheit, Ahmed H; Abdelhameed, Ali S

2016-03-01

Simultaneous spectrophotometric analysis of a multi-component dosage form of olmesartan, amlodipine and hydrochlorothiazide used for the treatment of hypertension has been carried out using various chemometric methods. Multivariate calibration methods include classical least squares (CLS) executed by net analyte processing (NAP-CLS), orthogonal signal correction (OSC-CLS) and direct orthogonal signal correction (DOSC-CLS) in addition to multivariate curve resolution-alternating least squares (MCR-ALS). Results demonstrated the efficiency of the proposed methods as quantitative tools of analysis as well as their qualitative capability. The three analytes were determined precisely using the aforementioned methods in an external data set and in a dosage form after optimization of experimental conditions. Finally, the efficiency of the models was validated via comparison with the partial least squares (PLS) method in terms of accuracy and precision.

Azilsartan: Novel Angiotensin Receptor Blocker.

PubMed

Dargad, Ramesh R; Parekh, Jai D; Dargad, Rohit R; Kukrety, Shweta

2016-03-01

To describe the efficacy and safety profile of the new angiotensin receptor blocker (ARB), "Azilsartan Medoxomil", reviewing data available from both clinical and pre-clinical studies. We completed a review of the English literature from PubMed using the keywords- azilsartan medoxomil, angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACEi) and hypertension. Many clinical trials have been conducted comparing the efficacy of azilsartan with other ARB's and also with the ACEi ramipril. The trials have shown azilsartan to be more effective in reducing the mean 24-hour systolic blood pressure compared to its counterparts. Azilsartan is a recently approved ARB and appears to be more efficacious in reducing blood pressure (BP) than the other ARBs with a similar safety and tolerability profile. Azilsartan's very high affinity to and slow dissociation from the angiotensin 1 receptor (AT1R) along with its inverse agonistic properties make it a very good candidate for clinical effects beyond simple BP control, potentially counteracting cardiac hypertrophy, cardiac fibrosis and insulin resistance, together with improved reno-protection and atherosclerotic plaque stabilization.

Clinical evaluation of a new intracranial pressure monitoring device.

PubMed

Stendel, R; Heidenreich, J; Schilling, A; Akhavan-Sigari, R; Kurth, R; Picht, T; Pietilä, T; Suess, O; Kern, C; Meisel, J; Brock, M

2003-03-01

Continuous monitoring of intracranial pressure (ICP) still plays a key role in the management of patients at risk from intracranial hypertension. Numerous ICP-measuring devices are available. The aim of the present study was to investigate the clinical characteristics and the magnetic resonance imaging (MRI) compatibility of the recently developed Neurovent-P(REHAU AG+CO, REHAU, Germany) ICP monitoring device. In a prospective two-center study, a total of 98 patients with severe head injury, subarachnoid haemorrhage, intracerebral haemorrhage, and non-traumatic brain edema underwent intraparenchymal monitoring of ICP using the Neurovent-P. A control group comprising 50 patients underwent implantation of the Camino-OLM-110-4B ICP monitor. The zero drift of the probes was determined before and after the ICP recording period. Technical and medical complications were documented. The MRI compatibility of the Neurovent-P ICP probe was investigated by evaluating artifacts caused by the probe, probe function and temperature changes during MRI, and probe movement caused by the magnetic field. The mean zero drift was 0.2+/-0.41 mmHg (maximum 3 mmHg) for the Neurovent-P ICP probes and 0.4+/-0.57 mmHg (maximum 12 mmHg) for the Camino-OLM-110-4B ICP probes. No significant correlation was identified between the extent of zero drift following the removal of the probes and the length of monitoring. Intraparenchymal haemorrhage spatially related to the probe occurred in 1 out of 50 (2%) patients with a Camino-OLM-110-4B probe and in 1 out of 98 (1%) with a Neurovent-P. Damage of the probe due to kinking or overextension of the cable or glass fiber occurred in 4 of the 50 (8%) Camino-OLM-110-4B ICP probes and in 5 of the 98 (5%) Neurovent-P probes. On T2-weighted MR images, the Neurovent-P ICP probe induced only small artifacts with very good discrimination of the surrounding tissue. On T1-weighted MR images, there was a good imaging quality but artifact-related local disturbances in signal occurred. There was no temperature change in the Neurovent-P probe and in the surrounding brain tissue during MR imaging. The Neurovent-P ICP measuring system is a safe and reliable tool for ICP monitoring. Handling of the Neurovent-P system is safe when performed properly.

Gateways to clinical trials.

PubMed

Tomillero, A; Moral, M A

2010-06-01

[¹¹C]RAC; (18)F-Fluoromisonidazole; 89-12; 9-[¹⁸F]Fluoropropyl-(+)-dihydrotetrabenazine; Adalimumab, Adecatumumab, ADMVA, ADXS-11-001, Aflibercept, Agatolimod sodium, AGS-004, Alglucosidase alfa, Aliskiren fumarate, Alvocidib hydrochloride, AMG-108, AMG-853, Apixaban, Aripiprazole, Armodafinil, Atazanavir sulfate, Atomoxetine hydrochloride; Bevacizumab, BioMatrix Flex drug eluting stent, Biphasic insulin aspart, Bortezomib, Bosentan; Caspofungin acetate, Cediranib, Cetuximab, ChimeriVax-Dengue, Choriogonadotropin alfa, Cinacalcet hydrochloride, Cizolirtine citrate, Clofarabine, Cocaine conjugate vaccine, CX-717; Darbepoetin alfa, Dasatinib, Decitabine, Denosumab, Desvenlafaxine succinate, Dexamethasone sodium phosphate, Dienogest, Diphencyprone, Doripenem, DTaP-HepB-IPV, Dutasteride; E-7010, Ecallantide, Ecstasy, Eicosapentaenoic acid/docosahexaenoic acid, Emtricitabine, Enfuvirtide, Erlotinib hydrochloride, Eszopiclone, Etonogestrel/ethinyl estradiol, Etoricoxib, Everolimus, Everolimus-eluting coronary stent EVT-201, Ezetimibe, Ezetimibe/simvastatin; Ferumoxytol, Fesoterodine fumavate, Figitumumab, Filgrastim, Fingolimod hydrochloride, Fluticasone furoate, Fluval P, Fluzone, Fondaparinux sodium, Fulvestrant, Fungichromin; Gamma-hydroxybutyrate sodium, Gefitinib, GHB-01L1, GLY-230, GSK-1349572; Hib-MenCY-TT, Hib-TT, HPV-6/11/16/18, Hydrocodone bitartrate; IC-51, Icatibant acetate, Imatinib mesylate, Immunoglobulin intravenous (human), Indetanib, Influenza A (H1N1) 2009 Monovalent Vaccine, Inhalable human insulin, Insulin glargine, Insulin glulisine, Interferon-beta, Ispinesib mesylate, Ixabepilone; Laromustine, Latanoprost/timolol maleate, L-Citrulline, Lenalidomide, Lexatumumab, Linezolid, Lopinavir/ritonavir, Lutropin alfa; Mapatumumab, MDX-066, MDX-1388, Mepolizumab, Methoxy polyethylene glycol-epoetin-beta, Metreleptin, Micafungin sodium, Mometasone furoate/oxymetazoline hydrochloride, Mx-dnG1, Mycophenolic acid sodium salt; Nabiximols, Natalizumab, Nemonoxacin, Norelgestromin/ethinyl estradiol; Oblimersen sodium, Ocriplasmin, Olmesartan medoxomil, Omacetaxine mepesuccinate; Paclitaxel-eluting stent, Pagoclone, Paliperidone, Panitumumab, Pazopanib hydrochloride, PCV7, Pegaptanib octasodium, Peginterferon alfa-2a, Peginterferon alfa-2b/ ribavirin, Pegvisomant, Pemetrexed disodium, Perifosine, Pimecrolimus, Pitavastatin calcium, Plerixafor hydrochloride, Plitidepsin, Posaconazole, Pregabalin, Progesterone capriate; Raltegravir potassium, Ramucirumab, Ranelic acid distrontium salt, Rasburicase, Recombinant Bet V1, Recombinant human insulin, rhFSH, Rolofylline, Romidepsin, Romiplostim, Rosuvastatin calcium; Sapacitabine, Sevelamer carbonate, Sinecatechins, Sirolimus-eluting stent, Sitagliptin phosphate monohydrate, SN-29244, Sorafenib, Sugammadex sodium, Sunitinib malate; Tadalafil, Tafenoquine, Talnetant, Tanezumab, Tapentadol hydrochloride, Tasocitinib citrate, Technosphere/Insulin, Telcagepant, Tenofovir disoproxil fumarate, Teriparatide, Ticagrelor, Tigecycline, Tiotropium bromide, Tipifarnib, Tocilizumab, TS-041; Ulipristal acetate, Urtoxazumab, Ustekinumab; Vandetanib, Varenicline tartrate, Vicriviroc, Voriconazole, Vorinostat, VRC-HIVADV014-00-VP, VRC-HIVDNA016-00-VP; Zoledronic acid monohydrate. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

Cell type dependence and variability in the short-term plasticity of EPSCs in identified mouse hippocampal interneurones

PubMed Central

Losonczy, Attila; Zhang, Limei; Shigemoto, Ryuichi; Somogyi, Peter; Nusser, Zoltan

2002-01-01

Synapses exhibit different short-term plasticity patterns and this behaviour influences information processing in neuronal networks. We tested how the short-term plasticity of excitatory postsynaptic currents (EPSCs) depends on the postsynaptic cell type, identified by axonal arborizations and molecular markers in the hippocampal CA1 area. Three distinct types of short-term synaptic behaviour (facilitating, depressing and combined facilitating–depressing) were defined by fitting a dynamic neurotransmission model to the data. Approximately 75 % of the oriens-lacunosum-moleculare (O-LM) interneurones received facilitating EPSCs, but in three of 12 O-LM cells EPSCs also showed significant depression. Over 90 % of the O-LM cells were immunopositive for somatostatin and mGluR1α and all tested cells were decorated by strongly mGluR7a positive axon terminals. Responses in eight of 12 basket cells were described well with a model involving only depression, but the other cells displayed combined facilitating–depressing EPSCs. No apparent difference was found between the plasticity of EPSCs in cholecystokinin- or parvalbumin-containing basket cells. In oriens-bistratified cells (O-Bi), two of nine cells showed facilitating EPSCs, another two depressing, and the remaining five cells combined facilitating–depressing EPSCs. Seven of 10 cells tested for somatostatin were immunopositive, but mGluR1α was detectable only in two of 11 tested cells. Furthermore, most O-Bi cells projected to the CA3 area and the subiculum, as well as outside the hippocampal formation. Postsynaptic responses to action potentials recorded in vivo from a CA1 place cell were modelled, and revealed great differences between and within cell types. Our results demonstrate that the short-term plasticity of EPSCs is cell type dependent, but with significant heterogeneity within all three interneurone populations. PMID:12096061

Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells.

PubMed

Min, Li-Juan; Mogi, Masaki; Li, Jian-Mei; Iwanami, Jun; Iwai, Masaru; Horiuchi, Masatsugu

2005-09-02

Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10(-12) mol/L) and with a lower dose of Ang II (10(-10) mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.

Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

PubMed

Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

2015-12-01

For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors. © 2015 Wiley Periodicals, Inc.

78 FR 41953 - Agency Information Collection Activities; Submission for OMB Review; Comment Request; Labor...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-12

... DEPARTMENT OF LABOR Office of the Secretary Agency Information Collection Activities; Submission for OMB Review; Comment Request; Labor Organization and Auxiliary Reports ACTION: Notice. SUMMARY: The Department of Labor (DOL) is submitting the Office of Labor Management Standards (OLMS) sponsored information...

29 CFR 471.11 - What are the procedures for filing and processing a complaint?

Code of Federal Regulations, 2014 CFR

2014-07-01

..., DEPARTMENT OF LABOR NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS OBLIGATIONS OF FEDERAL CONTRACTORS AND SUBCONTRACTORS; NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS General Enforcement... filed with the Office of Labor-Management Standards (OLMS) or the Office of Federal Contract Compliance...

29 CFR 471.11 - What are the procedures for filing and processing a complaint?

Code of Federal Regulations, 2013 CFR

2013-07-01

..., DEPARTMENT OF LABOR NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS OBLIGATIONS OF FEDERAL CONTRACTORS AND SUBCONTRACTORS; NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS General Enforcement... filed with the Office of Labor-Management Standards (OLMS) or the Office of Federal Contract Compliance...

29 CFR 471.11 - What are the procedures for filing and processing a complaint?

Code of Federal Regulations, 2010 CFR

2010-07-01

..., DEPARTMENT OF LABOR NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS OBLIGATIONS OF FEDERAL CONTRACTORS AND SUBCONTRACTORS; NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS General Enforcement... filed with the Office of Labor-Management Standards (OLMS) or the Office of Federal Contract Compliance...

29 CFR 471.11 - What are the procedures for filing and processing a complaint?

Code of Federal Regulations, 2012 CFR

2012-07-01

..., DEPARTMENT OF LABOR NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS OBLIGATIONS OF FEDERAL CONTRACTORS AND SUBCONTRACTORS; NOTIFICATION OF EMPLOYEE RIGHTS UNDER FEDERAL LABOR LAWS General Enforcement... filed with the Office of Labor-Management Standards (OLMS) or the Office of Federal Contract Compliance...

78 FR 75948 - Senior Executive Service; Appointment of Members to the Performance Review Board

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-13

... Resources Center--Sydney T. Rose Executive Secretary--Director, Executive Resources--Kim L.H. Green... H. Moore, Deputy Assistant Secretary for Operations and Analysis--appointment expires on 09/30/16..., New York--appointment expires on 09/30/16 OLMS Stephen J. Willertz, Director, Office of Enforcement...

78 FR 8022 - Reorganization and Delegation of Authority; Technical Amendments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-05

... 20210, olms-public@dol.gov , (202) 693-0123 (this is not a toll-free number), (800) 877-8339 (TTY/TDD... administrative enforcement framework. Further, Secretary's Order No. 02-2012, 77 FR 69378, also delegated... of agency organization, procedure, or practice'' from proposed rulemaking (i.e., notice-and-comment...

Principals' Sense of Uncertainty and Organizational Learning Mechanisms

ERIC Educational Resources Information Center

Schechter, Chen; Asher, Neomi

2012-01-01

Purpose: The purpose of the present study is to examine the effect of principals' sense of uncertainty on organizational learning mechanisms (OLMs) in schools. Design/methodology/approach: Data were collected from 130 school principals (90 women and 40 men) from both Tel-Aviv and Central districts in Israel. After computing the correlation between…

OLMS: Online Learning Management System for E-Learning

ERIC Educational Resources Information Center

Ippakayala, Vinay Kumar; El-Ocla, Hosam

2017-01-01

In this paper we introduce a learning management system that provides a management system for centralized control of course content. A secure system to record lectures is implemented as a key feature of this application. This feature would be accessed through web camera and mobile recording. These features are mainly designed for e-learning…

Guiding Learners into Reengagement through the SCALE Environment: An Empirical Study

ERIC Educational Resources Information Center

Verginis, Ilias; Gouli, Evangelia; Gogoulou, Agoritsa; Grigoriadou, Maria

2011-01-01

The paper presents the facilities offered by the open learner model maintained in the web-based, adaptive, activity-oriented learning environment SCALE (Supporting Collaboration and Adaptation in a Learning Environment), in order to guide online students who become disengaged and support their reengagement. The open learner model (OLM_SCALE)…

Clinical pharmacokinetics of Azilsartan medoxomil for the treatment of cardiovascular disease: A review

NASA Astrophysics Data System (ADS)

Sangeetha, D.; Senthil Kumar, M.

2017-11-01

Hypertension related cardiovascular complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil is a precise blocker of angiotensin 1 receptor that prevent angiotenin binding, resulting in vasodilation and decrease the effects of aldosterone. Azilsartan is a recently approved angiotensin 1 receptor blocker and appears to be more efficacious in reducing blood pressure than other blockers with a similar safety and tolerability profile. Its very high affinity to and slow dissociation from the angiotensin 1 receptor along with its inverse agonistic properties make it a very good candidate for clinical effects beyond simple blood pressure control, potentially counteracting cardiac hypertrohy and cardiac fibrosis. In drug discovery and the development is to optimize candidate selection for the target therapeutic area and to predict the dose and dosing regime for initial clinical trials with due consern to the requirements for effective treatment in the target therapeutic area these are the main role of preclinical pharmacokinetics. Both the pharmaceutical target and drug disposition like absorption, clearance and distribution of new chemical entities with clear understanding and consideration is required for the type of agent and in sequence for the successful approach.

New treatment options in the management of hypertension: appraising the potential role of azilsartan medoxomil

PubMed Central

Volpe, Massimo; Savoia, Carmine

2012-01-01

Renin–angiotensin–system (RAS) activation plays a key role in the development of hypertension and cardiovascular disease. Drugs that antagonize the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) have proven clinical efficacy in reducing blood pressure values and cardiovascular morbidity and mortality. ACE inhibitors partially inhibit plasma ACE, and angiotensin II generation. Thus, ARBs, which block selectively type 1 angiotensin II receptor (AT1R), have been developed and used in the clinical management of hypertension and cardiovascular disease. Experimental and clinical trials with ARBs indicate that this class of drug represents an effective, safe and well tolerated therapeutic option for the prevention and care of hypertension, even though there is no proven superiority as compared to ACE inhibitors except for the better tolerability. Most ARBs may not completely inhibit the AT1R at the approved clinical doses. Azilsartan medoxomil is a newly approved ARB for the management of hypertension. This ARB induces a potent and long-lasting antihypertensive effect and may have cardioprotective properties. This article reviews the current evidence on the clinical effectiveness of azilsartan in hypertension. PMID:22457601

Efficacy of olmesartan amlodipine in Colombian hypertensive patients (soat study).

PubMed

Buendia, Richard; Zambrano, Monica

2017-04-26

Emerging evidence has shown a significant deficit in the control of hypertension (blood pressure <140/90 mmHg) among Hispanics or Latinos in about 65%. This study aims to determine the efficacy of the combination in fixed doses of olmesartan and amlodipine (20/5, 40/5, and 40/10 mg) in hypertensive patients treated in daily clinical practice by Colombian doctors. This was an observational, retrospective, open-label, multi-center, non-comparative study. The primary outcome was a change in systolic and diastolic blood pressure from the baseline to week 12; the secondary outcome was the proportion of patients achieving a target blood pressure of <140/90 mmHg. Safety and tolerability were also evaluated. For analysis, a student t test was used for paired data, McNemar test, and ANCOVA. A total of 428 patients were enrolled from 16 centers in Colombia. At 12 weeks, patients' systolic blood pressure decreased in response to all three doses: by 27.75 ± 20.73 mmHg in 20/5 mg, 31.13 ± 22.23 mmHg in 40/5 mg, and 46.96 ± 20.15 mmHg in 40/10 mg (all p < 0.001). Furthermore, the diastolic blood pressure decreased by 14.19 ± 12.89 mmHg in 20/5 mg, 16.25 ± 10.87 mmHg in 40/5 mg, and 24.83 ± 10.41 mmHg in 40/10 mg (all p < 0.001). The percentage of patients achieving target blood pressure was 71.31% in 20/5 mg, 70.16% in 40/5 mg, and 63.33% in 40/10 mg. This study demonstrates the efficacy of the combination in fixed doses of olmesartan and amlodipine in the treatment of Colombian hypertensive patients.

Composition and Characteristics of Particles in the Ocean: Evidence for Present Day Resuspension.

DTIC Science & Technology

1980-11-01

various depths in the water column was identified and counted to compare this material to that on the seafloor. Sediment Traps Foramin ifera Planktonic...determined as a fraction of the total number of particles counted. Foramin ifera Planktonic foraminifera are one of the major components of material >l5Olm in

a2* Nicotinic Acetylcholine Receptors Influence Hippocampus-Dependent Learning and Memory in Adolescent Mice

ERIC Educational Resources Information Center

Lotfipour, Shahrdad; Mojica, Celina; Nakauchi, Sakura; Lipovsek, Marcela; Silverstein, Sarah; Cushman, Jesse; Tirtorahardjo, James; Poulos, Andrew; Elgoyhen, Ana Belén; Sumikawa, Katumi; Fanselow, Michael S.; Boulter, Jim

2017-01-01

The absence of a2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of a2* nAChRs ("Chrna2"[superscript L9'S/L9'S] and…

29 CFR 471.2 - What employee notice clause must be included in Government contracts?

Code of Federal Regulations, 2010 CFR

2010-07-01

... the language set forth in appendix A to subpart A of part 471 in every Government contract, other than..., appendix A to subpart A. (c) Adaptation of language. The Director of OLMS may find that an Act of Congress... contractor must provide the notice in the language employees speak. The employee notice must be placed: (1...

Advances in molecular identification, taxonomy, genetic variation and diagnosis of Toxocara spp.

PubMed

Chen, Jia; Zhou, Dong-Hui; Nisbet, Alasdair J; Xu, Min-Jun; Huang, Si-Yang; Li, Ming-Wei; Wang, Chun-Ren; Zhu, Xing-Quan

2012-10-01

The genus Toxocara contains parasitic nematodes of human and animal health significance, such as Toxocara canis, Toxocara cati and Toxocara vitulorum. T. canis and T. cati are among the most prevalent parasites of dogs and cats with a worldwide distribution. Human infection with T. canis and T. cati, which can cause a number of clinical manifestations such as visceral larva migrans (VLMs), ocular larva migrans (OLMs), eosinophilic meningoencephalitis (EME), covert toxocariasis (CT) and neurotoxocariasis, is considered the most prevalent neglected helminthiasis in industrialized countries. The accurate identification Toxocara spp. and their unequivocal differentiation from each other and from other ascaridoid nematodes causing VLMs and OLMs has important implications for studying their taxonomy, epidemiology, population genetics, diagnosis and control. Due to the limitations of traditional (morphological) approaches for identification and diagnosis of Toxocara spp., PCR-based techniques utilizing a range of genetic markers in the nuclear and mitochondrial genomes have been developed as useful alternative approaches because of their high sensitivity, specificity, rapidity and utility. In this article, we summarize the current state of knowledge and advances in molecular identification, taxonomy, genetic variation and diagnosis of Toxocara spp. with prospects for further studies. Copyright © 2012 Elsevier B.V. All rights reserved.

ON-LINE MONITORING OF I&C TRANSMITTERS AND SENSORS FOR CALIBRATION VERIFICATION AND RESPONSE TIME TESTING WAS SUCCESSFULLY IMPLEMENTED AT ATR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erickson, Phillip A.; O'Hagan, Ryan; Shumaker, Brent

The Advanced Test Reactor (ATR) has always had a comprehensive procedure to verify the performance of its critical transmitters and sensors, including RTDs, and pressure, level, and flow transmitters. These transmitters and sensors have been periodically tested for response time and calibration verification to ensure accuracy. With implementation of online monitoring techniques at ATR, the calibration verification and response time testing of these transmitters and sensors are verified remotely, automatically, hands off, include more portions of the system, and can be performed at almost any time during process operations. The work was done under a DOE funded SBIR project carriedmore » out by AMS. As a result, ATR is now able to save the manpower that has been spent over the years on manual calibration verification and response time testing of its temperature and pressure sensors and refocus those resources towards more equipment reliability needs. More importantly, implementation of OLM will help enhance the overall availability, safety, and efficiency. Together with equipment reliability programs of ATR, the integration of OLM will also help with I&C aging management goals of the Department of Energy and long-time operation of ATR.« less

Essential roles of angiotensin II in vascular endothelial growth factor expression in sleep apnea syndrome.

PubMed

Takahashi, Susumu; Nakamura, Yutaka; Nishijima, Tsuguo; Sakurai, Shigeru; Inoue, Hiroshi

2005-09-01

Hypoxia-induced endothelial cell dysfunction has been implicated in increased cardiovascular disease associated with obstructive sleep apnea syndrome (OSAS). OSAS mediates hypertension by stimulating angiotensin II (Ang II) production. Hypoxia and Ang II are the major stimuli of vascular endothelial growth factor (VEGF), which is a potent angiogenic cytokine and also contributes to the atherogenic process itself. We observed serum Ang II and VEGF levels and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression. Compared to controls, subjects with OSAS had significantly increased levels of serum Ang II and VEGF and VEGF mRNA expression in their leukocytes. To examine whether Ang II stimulates VEGF expression in OSAS, we treated PBMCs obtained from control subjects with Ang II and with an Ang II receptor type 1 (AT(1)) blocker, olmesartan. We observed an increased expression of VEGF in the Ang II-stimulated PBMCs and decreased in VEGF mRNA and protein expression in the PBMCs treated with olmesartan. These findings suggest that the Ang II-AT(1) receptors pathway potentially are involved in OSAS and VEGF-induced vascularity and that endothelial dysfunction might be linked to this change in Ang II activity within leukocytes of OSAS patients.

Improving Adherence to Treatment and Reducing Economic Costs of Hypertension: The Role of Olmesartan-Based Treatment.

PubMed

Costa, Francesco Vittorio

2017-09-01

Poor adherence to antihypertensive treatment is the single most important factor of unsatisfactory blood pressure (BP) control. This review focuses on therapy-related factors affecting adherence and suggests how to improve it with a wise choice of treatment schedule. Complex drug treatment schemes, poor tolerability and drug substitutions are frequent causes of poor adherence which, in turn, causes insufficient BP control, greater incidence of cardiovascular events and, finally, higher global health costs. The effects of prescribing generic drugs and of drug substitutions on adherence is also discussed. In terms of adherence, generic drugs do not seem to be better than branded drugs, unless patients have to bear very high "out of pocket" expenses to buy original drugs, suggesting no advantages in switching drug with the mere goal of reducing the cost of therapy. An important role in improving adherence (and thus cardiovascular events and health expenditure) is also played by the availability of fixed-dose combinations; among antihypertensive drugs, angiotensin receptor blockers (ARBs) are those associated with higher levels of adherence and persistence. Among ARBs, olmesartan stands out for a wide choice of effective fixed-dose combinations.

Spectrophotometric and Spectrofluorimetric Studies on Azilsartan Medoxomil and Chlorthalidone to Be Utilized in Their Determination in Pharmaceuticals

PubMed Central

Ebeid, Walid M; Elkady, Ehab F; El-Zaher, Asmaa A; El-Bagary, Ramzia I; Patonay, Gabor

2014-01-01

The recently approved angiotensin II receptor blocker, azilsartan medoxomil (AZL), was determined spectrophotometrically and spectrofluorimetrically in its combination with chlorthalidone (CLT) in their combined dosage form. The UV-spectrophotometric technique depends on simultaneous measurement of the first derivative spectra for AZL and CLT at 286 and 257 nm, respectively, in methanol. The spectrofluorimetric technique depends on measurement of the fourth derivative of the synchronous spectra intensities of AZL in presence of CLT at 298 nm in methanol. The effects of different solvents on spectrophotometric and spectrofluorimetric responses were studied. For, the spectrofluorimetric study, the effect of pH and micelle-assisted fluorescence enhancement were also studied. Linearity, accuracy, and precision were found to be satisfactory over the concentration ranges of 8–50 μg mL−1 and 2–20 μg mL−1 for AZL and CLT, respectively, in the spectrophotometric method as well as 0.01–0.08 μg mL−1 for AZL in the spectrofluorimetric method. The methods were successfully applied for the determination of the studied drugs in their co-formulated tablets. The developed methods are inexpensive and simple for the quality control and routine analysis of the cited drugs in bulk and in pharmaceuticals. PMID:24855334

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study.

PubMed

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5-25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics.

Assessment of the environmental fate and effects of azilsartan, a selective antagonist of angiotensin II type 1.

PubMed

Weltman, R; Brands, C M J; Corral, E; Desmares-Koopmans, M J E; Migchielsen, M H J; Oudhoff, K A; de Roode, D F

2012-06-01

In this paper the results of a thorough evaluation of the environmental fate and effects of azilsartan are presented. Azilsartan medoxomil is administered as a pro-drug for the treatment of patients with essential hypertension. The pro-drug is converted by hydrolysis to the active pharmaceutical ingredient azilsartan. Laboratory tests to evaluate the environmental fate and effects of azilsartan medoxomil were conducted with azilsartan and performed in accordance with OECD test guidelines. The predicted environmental concentration (PEC) in surface water was estimated at 0.32 μg L(-1) (above the action limit of 0.01 μg L(-1)), triggering a Phase II assessment. Azilsartan is not readily biodegradable. Results of the water sediment study demonstrated significant shifting of azilsartan metabolites to sediment. Based on the equilibrium partitioning method, metabolites are unlikely to pose a risk to sediment-dwelling organisms. Ratios of the predicted environmental concentrations (PECs) to the predicted-no-effect concentrations (PNECs) did not exceed the relevant triggers, and the risk to aquatic, sewage treatment plant (STP), groundwater and sediment compartments was concluded acceptable. A terrestrial assessment was not triggered. Azilsartan poses an acceptable risk to the environment. Copyright © 2012 Elsevier Ltd. All rights reserved.

Efficacy and safety of azilsartan medoxomil, an angiotensin receptor blocker, in Korean patients with essential hypertension.

PubMed

Juhasz, Attila; Wu, Jingtao; Hisada, Michie; Tsukada, Tomoka; Jeong, Myung Ho

2018-01-01

This was a phase 3, randomized, double-blind, placebo-controlled study. Adult Korean patients with essential hypertension and a baseline mean sitting clinic systolic blood pressure (scSBP) ≥150 and ≤180 mmHg were randomized to 6-week treatment with placebo ( n  = 65), azilsartan medoxomil (AZL-M) 40 mg ( n  = 132), or AZL-M 80 mg ( n  = 131). The primary endpoint was the change from baseline to week 6 in trough scSBP. The least-squares mean (standard error) change from baseline in trough scSBP in the placebo, AZL-M 40-mg, and 80-mg groups at week 6 were - 8.8 (2.00), - 22.1 (1.41), and - 23.7 (1.40) mmHg, respectively ( p  < 0.001 for AZL-M 40 and 80 mg vs placebo). No clinically meaningful heterogeneity in efficacy was observed between subgroups (age, sex, diabetes status) and the overall population. Treatments were well tolerated and adverse events were similar between groups. Results of this study confirm a positive benefit-risk profile of AZL-M for essential hypertension in Korean adults. Clinicaltrial.gov; identifier number: NCT02203916. Registered July 28, 2014 (retrospectively registered).

Evaluation of the angiotensin II receptor blocker azilsartan medoxomil in African-American patients with hypertension.

PubMed

Johnson, Wallace; White, William B; Sica, Domenic; Bakris, George L; Weber, Michael A; Handley, Alison; Perez, Alfonso; Cao, Charlie; Kupfer, Stuart; Saunders, Elijah B

2017-07-01

The efficacy and safety of azilsartan medoxomil (AZL-M) were evaluated in African-American patients with hypertension in a 6-week, double-blind, randomized, placebo-controlled trial, for which the primary end point was change from baseline in 24-hour mean systolic blood pressure (BP). There were 413 patients, with a mean age of 52 years, 57% women, and baseline 24-hour BP of 146/91 mm Hg. Treatment differences in 24-hour systolic BP between AZL-M 40 mg and placebo (-5.0 mm Hg; 95% confidence interval, -8.0 to -2.0) and AZL-M 80 mg and placebo (-7.8 mm Hg; 95% confidence interval, -10.7 to -4.9) were significant (P≤.001 vs placebo for both comparisons). Changes in the clinic BPs were similar to the ambulatory BP results. Incidence rates of adverse events were comparable among the treatment groups, including those of a serious nature. In African-American patients with hypertension, AZL-M significantly reduced ambulatory and clinic BPs in a dose-dependent manner and was well tolerated. © The Authors and Takeda Development Centers, Americas, Inc and Takeda Pharmaceuticals International. The Journal of Clinical Hypertension published by Wiley Periodicals, Inc.

HHE/LORAN-C Surveying.

DTIC Science & Technology

1982-11-01

N* I. Khednipin.CeldegN. CG-D-Y4-82 4. Id ed I.ld j. D* NIUVin 1982U /LIAC WH ,. Peb- olm..,, Cede 9. Pwmln,, OWe, .omee . en Adoe., 10 . Wei Uat Me... 10 PRE-SURVEY PLANNING ..a-C ..hin.at.......................... 11 Overviewon of S ..... ........... 1......... ... .16 R eWaypoint Defintion...TDSS Statistics Summary.. ....................... 29 9 Example of Range-Range Waypoint Calculation.................30 10 Summary of Range-Range Waypoint

Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study.

PubMed

Williams, Bryan; Cockcroft, John R; Kario, Kazuomi; Zappe, Dion H; Cardenas, Pamela; Hester, Allen; Brunel, Patrick; Zhang, Jack

2014-02-04

Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12-24 weeks, if the BP target has not been attained (msSBP <140 and ms diastolic BP <90 mm Hg), amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.

A Comparative Clinicopathologic Study of Collagenous Gastritis in Children and Adults: The Same Disorder With Associated Immune-mediated Diseases.

PubMed

Ma, Changqing; Park, Jason Y; Montgomery, Elizabeth A; Arnold, Christina A; McDonald, Oliver G; Liu, Ta-Chiang; Salaria, Safia N; Limketkai, Berkeley N; McGrath, Kevin M; Musahl, Tina; Singhi, Aatur D

2015-06-01

Collagenous gastritis is a rare condition characterized by surface epithelial damage, subepithelial collagen deposition, and a lamina propria inflammatory infiltrate. Previous studies have proposed 2 clinicopathologic subtypes: (1) children (18 y of age or younger) presenting with severe anemia, nodular gastric mucosa, and isolated gastric disease; and (2) adults with chronic watery diarrhea that is associated with diffuse collagenous involvement of the gastrointestinal tract. However, notable exceptions exist. In fact, broad variability in clinical presentation, etiology, treatment and disease course has been reported. To better define the clinicopathologic features of collagenous gastritis, we have collected 10 pediatric and 21 adult cases and describe their clinical, endoscopic, pathologic, and follow-up findings. Both children and adults presented with similar clinical symptoms such as anemia (50%, 35%, respectively), epigastric/abdominal pain (50%, 45%), and diarrhea (40%, 55%). Concomitant immune disorders were identified in 2 (20%) children and 3 (14%) adults. Further, 7 of 17 (41%) adults were taking medications associated with other immune-related gastrointestinal diseases including olmesartan and antidepressants. Histologically, there were no differences between children and adults with collagenous gastritis in the location of gastric involvement, mean collagenous layer thickness, and prominence of eosinophils (P>0.05). Extragastric collagenous involvement was also seen with comparable frequencies in each cohort (44%, 59%). Follow-up information was available for 22 of 31 (71%) patients and ranged from 2 to 122 months (mean, 33.6 mo). Despite medical management in most cases, persistence of symptoms or collagenous gastritis on subsequent biopsies was seen in 100% of children and 82% of adults. Of note, treatment for 1 adult patient involved cessation of olmesartan resulting in resolution of both symptoms and subepithelial collagen deposition on subsequent biopsies. Contrary to prior reports, no clinicopathologic differences were identified among pediatric and adult patients with collagenous gastritis. Whereas collagenous gastritis remains an enigmatic condition, our findings suggest that immune abnormalities and medications, such as olmesartan, may be possible triggers. However, current treatment options have had limited success and, thus, highlight the need for improved therapeutic regimens.

Toxocariasis: Clinical Aspects, Epidemiology, Medical Ecology, and Molecular Aspects

PubMed Central

Despommier, Dickson

2003-01-01

Toxocariasis is caused by a series of related nematode species (ascarids) that routinely infect dogs and cats throughout the world. The eggs from these ascarids are common environmental contaminants of human habitation, due largely to the fact that many kinds of dogs and cats serve as pets, while countless others run wild throughout the streets of most urban centers. The eggs, present in dog and cat feces, become infectious within weeks after they are deposited in the local environment (e.g., sandboxes, city parks, and public beaches, etc.). Humans, particularly children, frequently ingest these eggs by accident and become infected. Infection in humans, in contrast to their definitive hosts, remains occult, often resulting in disease caused by the migrating larval stages. Visceral larva migrans (VLM) and ocular larva migrans (OLM) are two clinical manifestations that result in definable syndromes and present as serious health problems wherever they occur. Diagnosis and treatment of VLM and OLM are difficult. These issues are summarized in this review, with emphasis on the ecology of transmission and control of spread to both humans and animals through public health initiatives employing treatment of pets and environmental intervention strategies that limit the areas that dogs and cats are allowed within the confines of urban centers. PMID:12692098

Safety and tolerability of azilsartan medoxomil in subjects with essential hypertension: a one-year, phase 3, open-label study

PubMed Central

Handley, Alison; Lloyd, Eric; Roberts, Andrew; Barger, Bruce

2016-01-01

Abstract This 56-week phase 3, open-label, treat-to-target study, involving 2 consecutive, non-randomized cohorts, evaluated the safety and tolerability of azilsartan medoxomil (AZL-M) in essential hypertension (mean baseline blood pressure [BP] 152/100 mmHg). All subjects (n = 669) initiated AZL-M 40 mg QD, force-titrated to 80 mg QD at week 4, if tolerated. From week 8, subjects could receive additional medications, starting with chlorthalidone (CLD) 25 mg QD (Cohort 1) or hydrochlorothiazide (HCTZ) 12.5–25 mg QD (Cohort 2), if required, to reach BP targets. Adverse events (AEs) were reported in 75.9% of subjects overall in the two cohorts (73.8% Cohort 1, 78.5% Cohort 2). The most common AEs were dizziness (14.3%), headache (9.9%) and fatigue (7.2%). Transient serum creatinine elevations were more frequent with add-on CLD. Clinic systolic/diastolic BP (observed cases at week 56) decreased by 25.2/18.4 mmHg (Cohort 1) and 24.2/17.9 mmHg (Cohort 2). These results demonstrate that AZL-M is well tolerated over the long term and provides stable BP improvements when used in a treat-to-target BP approach with thiazide-type diuretics. PMID:26817604

EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy--rationale and design of the EARLY hypertension registry.

PubMed

Gitt, Anselm K; Baumgart, Peter; Bramlage, Peter; Mahfoud, Felix; Potthoff, Sebastian A; Senges, Jochen; Schneider, Steffen; Buhck, Hartmut; Schmieder, Roland E

2013-07-02

Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. The "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice.

Initial Process and Expected Outcomes for Preliminary Identification of Routes to Yucca Mountain, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thrower, A.; Best, R.; Finewood, L.

2008-07-01

The Department of Energy's (DOE's) Office of Civilian Radioactive Waste Management (OCRWM) is responsible for developing and implementing a safe, secure and efficient transportation system to ship spent nuclear fuel (SNF) and high-level radioactive waste (HLW) from commercial and DOE sites to the proposed Yucca Mountain repository. The Office of Logistics Management (OLM) within OCRWM has begun to work with stakeholders to identify preliminary national suites of highway and rail routes that could be used for future shipments OLM is striving to develop a planning-basis set of routes that will support long-lead time logistical analyses (i.e., five or more yearsmore » before shipment). The results will represent a starting point for discussions between DOE and corridor jurisdictions, and for shipping arrangements between DOE and carriers. This fulfills a recommendation of the National Academy of Sciences report on SNF and HLW transportation that 'DOE should identify and make public its suite of preferred highway and rail routes for transporting spent fuel and high level waste to a federal repository as soon as practicable to support State, Tribal and local planning, especially for emergency responder preparedness'. OLM encourages and supports participation of program stakeholders in a process to identify suites of national routes. The principal objective is to identify preliminary suites of national routes that reflect responsible consideration of the interests of a broad cross-section of stakeholders. This will facilitate transportation planning activities to help meet program goals, including providing an advanced planning framework for State and Tribal authorities; supporting a pilot program for providing funding under Section 180(c) of the Nuclear Waste Policy Act; allowing sufficient time for security and operational reviews in advance of shipments to Yucca Mountain; and supporting utility planning and readiness for transportation operations. Concepts for routing and routing criteria have been considered by several state regional groups supported by cooperative agreements with OLM. OCRWM is also working with other Federal agencies, transportation service providers and others involved in the transportation industry to ensure the criteria are consistent with operating practices and regulations. These coordination efforts will ensure the experience, knowledge, and expertise of those involved are considered in the process to identify the preliminary national suites of routes. This paper describes the current process and timeline for preliminary identification and analyses of routes. In conclusion: The path toward developing a safe, secure, and efficient transportation system for shipments of SNF and HLW to Yucca Mountain will require the participation of many interested parties. Real cooperative planning is sometimes challenging, and requires a commitment from all involved parties to act in good faith and to employ their best efforts in developing mutually beneficial solutions. Identifying routes to the proposed repository at Yucca Mountain, and engaging in planning and preparedness activities with affected jurisdictions and other stakeholders, will take time. OCRWM is committed to a cooperative approach that will ultimately enhance safety, security, efficiency and public confidence. (authors)« less

Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study

PubMed Central

Williams, Bryan; Cockcroft, John R; Kario, Kazuomi; Zappe, Dion H; Cardenas, Pamela; Hester, Allen; Brunel, Patrick; Zhang, Jack

2014-01-01

Introduction Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. Methods and analysis In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12–24 weeks, if the BP target has not been attained (msSBP <140  and ms diastolic BP <90 mm Hg), amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. Ethics and dissemination The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. Clinical trials identifier EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301. PMID:24496699

Online Monitoring Technical Basis and Analysis Framework for Large Power Transformers; Interim Report for FY 2012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nancy J. Lybeck; Vivek Agarwal; Binh T. Pham

The Light Water Reactor Sustainability program at Idaho National Laboratory (INL) is actively conducting research to develop and demonstrate online monitoring (OLM) capabilities for active components in existing Nuclear Power Plants. A pilot project is currently underway to apply OLM to Generator Step-Up Transformers (GSUs) and Emergency Diesel Generators (EDGs). INL and the Electric Power Research Institute (EPRI) are working jointly to implement the pilot project. The EPRI Fleet-Wide Prognostic and Health Management (FW-PHM) Software Suite will be used to implement monitoring in conjunction with utility partners: the Shearon Harris Nuclear Generating Station (owned by Duke Energy for GSUs, andmore » Braidwood Generating Station (owned by Exelon Corporation) for EDGs. This report presents monitoring techniques, fault signatures, and diagnostic and prognostic models for GSUs. GSUs are main transformers that are directly connected to generators, stepping up the voltage from the generator output voltage to the highest transmission voltages for supplying electricity to the transmission grid. Technical experts from Shearon Harris are assisting INL and EPRI in identifying critical faults and defining fault signatures associated with each fault. The resulting diagnostic models will be implemented in the FW-PHM Software Suite and tested using data from Shearon-Harris. Parallel research on EDGs is being conducted, and will be reported in an interim report during the first quarter of fiscal year 2013.« less

Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.

PubMed

Lanier, Gregg; Sankholkar, Kedar; Aronow, Wilbert S

2014-01-01

Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.

Single‐Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment

PubMed Central

Karim, Aziz; Zhao, Zhen; Alonso, Alberto B.; Garg, Dyal; Preston, Richard A.

2017-01-01

Abstract Azilsartan medoxomil (AZL‐M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose‐dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M‐II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single‐center, open‐label, phase 1 parallel‐group study that examined the single‐dose (day 1) and multiple‐dose (days 4–8) — 40 mg — pharmacokinetics of AZL and M‐II in 16 subjects with mild and moderate hepatic impairment by Child‐Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M‐II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M‐II. Single and multiple doses of AZL‐M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL‐M is required for subjects with mild and moderate hepatic impairment. PMID:28750149

Pharmacokinetic-pharmacodynamic modeling of the antihypertensive interaction between azilsartan medoxomil and chlorthalidone in spontaneously hypertensive rats.

PubMed

Kumar Puttrevu, Santosh; Ramakrishna, Rachumallu; Bhateria, Manisha; Jain, Moon; Hanif, Kashif; Bhatta, Rabi Sankar

2017-05-01

A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the time course of blood pressure following oral administration of azilsartan medoxomil (AZM) and/or chlorthalidone (CLT) in spontaneously hypertensive (SH) rats. The drug concentration and pharmacological effects, including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tail-cuff manometry, respectively. Sequential PK-PD analysis was performed, wherein the plasma concentration-time data was modeled by one compartmental analysis. Subsequently PD parameters were calculated to describe the time-concentration-response relationship using indirect response (IDR) PK-PD model. The combination of AZ and CLT had greater BP lowering effect compared to AZ or CLT alone, despite of no pharmacokinetic interaction between two drugs. These findings suggest synergistic antihypertensive pharmacodynamic interaction between AZ and CLT noncompetitively, which was simulated by inhibitory function of AZ and stimulatory function of CLT after concomitant administration of the two drugs. The present model was able to capture the turnover of blood pressure adequately at different time points at two different dose levels. The current PK-PD model was successfully utilized in the simulation of PD effect at a dose combination of 0.5 and 2.5 mg/kg for AZ and CLT, respectively. The developed preclinical PK-PD model may provide guidance in the optimization of dose ratio of individual drugs in the combined pharmacotherapy of AZ and CLT at clinical situations.

EARLY Treatment with azilsartan compared to ACE-inhibitors in anti-hypertensive therapy – rationale and design of the EARLY hypertension registry

PubMed Central

2013-01-01

Background Arterial hypertension is highly prevalent but poorly controlled. Blood pressure (BP) reduction substantially reduces cardiovascular morbidity and mortality. Recent randomized, double-blind clinical trials demonstrated that azilsartan medoxomil (AZM) is more effective in reducing BP than the ubiquitary ACE inhibitor ramipril. Therefore, we aimed to test whether these can be verified under clinical practice conditions. Methods/Design The “Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy” (EARLY) registry is a prospective, observational, national, multicenter registry with a follow-up of up to 12 months. It will include up to 5000 patients on AZM or ACE-inhibitor monotherapy in a ratio of 7 to 3. A subgroup of patients will undergo 24-hour BP monitoring. EARLY has two co-primary objectives: 1) Description of the safety profile of azilsartan and 2) achievement of BP targets based on recent national and international guidelines for patients treated with azilsartan in comparison to those treated with ACE-inhibitors. The most important secondary endpoints are the determination of persistence with treatment and the documentation of cardiovascular and renal events. Recruitment commenced in January 2012 and will be completed by February 2013. Conclusions The data obtained will supplement previous results from randomized controlled trials to document the potential value of utilizing azilsartan medoxomil in comparison to ACE-inhibitor treatment for target BP achievement in clinical practice. PMID:23819631

Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

PubMed

Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

2016-05-01

Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

Single-dose pharmacokinetics and safety of azilsartan medoxomil in children and adolescents with hypertension as compared to healthy adults.

PubMed

Webb, Nicholas J A; Wells, Thomas; Tsai, Max; Zhao, Zhen; Juhasz, Attila; Dudkowski, Caroline

2016-04-01

This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]). Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg. Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine). This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).

Construction of ivermectin producer by domain swaps of avermectin polyketide synthase in Streptomyces avermitilis.

PubMed

Zhang, Xiaolin; Chen, Zhi; Li, Meng; Wen, Ying; Song, Yuan; Li, Jilun

2006-10-01

Ivermectin, 22, 23-dihydroavermectin B1, is commercially important in human, veterinary medicine, and pesticides. It is currently synthesized by chemical reduction of the double bond between C22 and C23 of avermectins B1, which are a mixture of B1a (>80%) and B1b (<20%) produced by fermentation of Streptomyces avermitilis. The cost of ivermectin is much higher than that of avermectins B1 owing to the necessity of region-specific hydrogenation at C22-C23 of avermectins B1 with rhodium chloride as the catalyst for producing ivermectin. Here we report that ivermectin can be produced directly by fermentation of recombinant strains constructed through targeted genetic engineering of the avermectin polyketide synthase (PKS) in S. avermitilis Olm73-12, which produces only avermectins B and not avermectins A and oligomycin. The DNA region encoding the dehydratase (DH) and ketoreductase (KR) domains of module 2 from the avermectin PKS in S. avermitilis Olm73-12 was replaced by the DNA fragment encoding the DH, enoylreductase, and KR domains from module 4 of the pikromycin PKS of Streptomyces venezuelae ATCC 15439 using a gene replacement vector pXL211. Twenty-seven of mutants were found to produce a small amount of 22, 23-dihydroavermectin B1a and avermectin B1a and B2a by high performance liquid chromatography and liquid chromatography mass spectrometry analysis. This study might provide a route to the low-cost production of ivermectin by fermentation.

Population Pharmacokinetics and Exposure-Response of a Fixed-Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With Stage 2 Hypertension.

PubMed

Tsai, Max C; Wu, Jingtao; Kupfer, Stuart; Vakilynejad, Majid

2016-08-01

Population pharmacokinetic and exposure-response models for azilsartan medoxomil (AZL-M) and chlorthalidone (CLD) were developed using data from an 8-week placebo-controlled phase 3, factorial study of 20, 40, and 80 mg AZL-M every day (QD) and 12.5 and 25 mg CLD QD in fixed-dose combination (FDC) in subjects with moderate to severe essential hypertension. A 2-compartment model with first-order absorption and elimination was developed to describe pharmacokinetics. An Emax model for exposure-response analysis evaluated AZL-M/CLD effects on ambulatory systolic blood pressure (SBP). Estimated oral clearance and apparent volume of distribution (central compartment) were 1.47 L/h and 3.98 L for AZL, and 4.13 L/h and 62.1 L for CLD. Age as a covariate had the largest effect on AZL and CLD exposure (±20% change). Predicted maximal SBP responses (Emax ) were -15.6 and -23.9 mm Hg for AZL and CLD. Subgroup analysis identified statistically significant Emax differences for black vs nonblack subjects, whereby the reduced AZL response in black subjects was offset by greater response to CLD. The estimated Emax for AZL and CLD was generally greater in subjects with higher baseline BP. In conclusion, no dose adjustments to AZL-M or CLD are warranted based on identified covariates, and antihypertensive efficacy of AZL-M/CLD combination therapy is comparable in black and nonblack subjects. © 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Single-Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment.

PubMed

Dudkowski, Caroline; Karim, Aziz; Zhao, Zhen; Alonso, Alberto B; Garg, Dyal; Preston, Richard A

2018-01-01

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4-8) - 40 mg - pharmacokinetics of AZL and M-II in 16 subjects with mild and moderate hepatic impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and moderate hepatic impairment. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Pharmaceutical Industry-Sponsored Meals and Physician Prescribing Patterns for Medicare Beneficiaries.

PubMed

DeJong, Colette; Aguilar, Thomas; Tseng, Chien-Wen; Lin, Grace A; Boscardin, W John; Dudley, R Adams

2016-08-01

The association between industry payments to physicians and prescribing rates of the brand-name medications that are being promoted is controversial. In the United States, industry payment data and Medicare prescribing records recently became publicly available. To study the association between physicians' receipt of industry-sponsored meals, which account for roughly 80% of the total number of industry payments, and rates of prescribing the promoted drug to Medicare beneficiaries. Cross-sectional analysis of industry payment data from the federal Open Payments Program for August 1 through December 31, 2013, and prescribing data for individual physicians from Medicare Part D, for all of 2013. Participants were physicians who wrote Medicare prescriptions in any of 4 drug classes: statins, cardioselective β-blockers, angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers (ACE inhibitors and ARBs), and selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs). We identified physicians who received industry-sponsored meals promoting the most-prescribed brand-name drug in each class (rosuvastatin, nebivolol, olmesartan, and desvenlafaxine, respectively). Data analysis was performed from August 20, 2015, to December 15, 2015. Receipt of an industry-sponsored meal promoting the drug of interest. Prescribing rates of promoted drugs compared with alternatives in the same class, after adjustment for physician prescribing volume, demographic characteristics, specialty, and practice setting. A total of 279 669 physicians received 63 524 payments associated with the 4 target drugs. Ninety-five percent of payments were meals, with a mean value of less than $20. Rosuvastatin represented 8.8% (SD, 9.9%) of statin prescriptions; nebivolol represented 3.3% (7.4%) of cardioselective β-blocker prescriptions; olmesartan represented 1.6% (3.9%) of ACE inhibitor and ARB prescriptions; and desvenlafaxine represented 0.6% (2.6%) of SSRI and SNRI prescriptions. Physicians who received a single meal promoting the drug of interest had higher rates of prescribing rosuvastatin over other statins (odds ratio [OR], 1.18; 95% CI, 1.17-1.18), nebivolol over other β-blockers (OR, 1.70; 95% CI, 1.69-1.72), olmesartan over other ACE inhibitors and ARBs (OR, 1.52; 95% CI, 1.51-1.53), and desvenlafaxine over other SSRIs and SNRIs (OR, 2.18; 95% CI, 2.13-2.23). Receipt of additional meals and receipt of meals costing more than $20 were associated with higher relative prescribing rates. Receipt of industry-sponsored meals was associated with an increased rate of prescribing the brand-name medication that was being promoted. The findings represent an association, not a cause-and-effect relationship.

Gateways to clinical trials.

PubMed

Bayés, M; Rabasseda, X; Prous, J R

2005-06-01

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables have been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abiraterone acetate, acyline, adalimumab, adenosine triphosphate, AEE-788, AIDSVAX gp120 B/B, AK-602, alefacept, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alprazolam, amdoxovir, AMG-162, aminolevulinic acid hydrochloride, aminolevulinic acid methyl ester, aminophylline hydrate, anakinra, anecortave acetate, anti-CTLA-4 MAb, APC-8015, aripiprazole, aspirin, atazanavir sulfate, atomoxetine hydrochloride, atorvastatin calcium, atrasentan, AVE-5883, AZD-2171; Betamethasone dipropionate, bevacizumab, bimatoprost, biphasic human insulin (prb), bortezomib, BR-A-657, BRL-55730, budesonide, busulfan; Calcipotriol, calcipotriol/betamethasone dipropionate, calcium folinate, capecitabine, capravirine, carmustine, caspofungin acetate, cefdinir, certolizumab pegol, CG-53135, chlorambucil, ciclesonide, ciclosporin, cisplatin, clofarabine, clopidogrel hydrogensulfate, clozapine, co-trimoxazole, CP-122721, creatine, CY-2301, cyclophosphamide, cypher, cytarabine, cytolin; D0401, darbepoetin alfa, darifenacin hydrobromide, DASB, desipramine hydrochloride, desloratadine, desvenlafaxine succinate, dexamethasone, didanosine, diquafosol tetrasodium, docetaxel, doxorubicin hydrochloride, drotrecogin alfa (activated), duloxetine hydrochloride, dutasteride; Ecallantide, efalizumab, efavirenz, eletriptan, emtricitabine, enfuvirtide, enoxaparin sodium, estramustine phosphate sodium, etanercept, ethinylestradiol, etonogestrel, etonogestrel/ethinylestradiol, etoposide, exenatide; Famciclovir, fampridine, febuxostat, filgrastim, fludarabine phosphate, fluocinolone acetonide, fluorouracil, fluticasone propionate, fluvastatin sodium, fondaparinux sodium; Gaboxadol, gamma-hydroxybutyrate sodium, gefitinib, gelclair, gemcitabine, gemfibrozil, glibenclamide, glyminox; Haloperidol, heparin sodium, HPV 16/HPV 18 vaccine, human insulin, human insulin; Icatibant, imatinib mesylate, indium 111 (111In) ibritumomab tiuxetan, infliximab, INKP-100, iodine (I131) tositumomab, IoGen, ipratropium bromide, ixabepilone; L-870810, lamivudine, lapatinib, laquinimod, latanoprost, levonorgestrel, licochalcone a, liposomal doxorubicin, lopinavir, lopinavir/ritonavir, lorazepam, lovastatin; Maraviroc, maribavir, matuzumab, MDL-100907, melphalan, methotrexate, methylprednisolone, mitomycin, mitoxantrone hydrochloride, MK-0431, MN-001, MRKAd5 HIV-1 gag/pol/nef, MRKAd5gag, MVA.HIVA, MVA-BN Nef, MVA-Muc1-IL-2, mycophenolate mofetil; Nelfinavir mesilate, nesiritide, NSC-330507; Olanzapine, olmesartan medoxomil, omalizumab, oral insulin, osanetant; PA-457, paclitaxel, paroxetine, paroxetine hydrochloride, PCK-3145, PEG-filgrastim, peginterferon alfa-2a, peginterferon alfa-2b, perillyl alcohol, pexelizumab, pimecrolimus, pitavastatin calcium, porfiromycin, prasterone, prasugrel, pravastatin sodium, prednisone, pregabalin, prinomastat, PRO-2000, propofol, prostate cancer vaccine; Rasagiline mesilate, rhBMP-2/ACS, rhBMP-2/BCP, rhC1, ribavirin, rilpivirine, ritonavir, rituximab, Ro-26-9228, rosuvastatin calcium, rosuvastatin sodium, rubitecan; Selodenoson, simvastatin, sirolimus, sitaxsentan sodium, sorafenib, SS(dsFv)-PE38, St. John's Wort extract, stavudine; Tacrolimus, tadalafil, tafenoquine succinate, talaglumetad, tanomastat, taxus, tegaserod maleate, telithromycin, tempol, tenofovir, tenofovir disoproxil fumarate, testosterone enanthate, TH-9507, thalidomide, tigecycline, timolol maleate, tiotropium bromide, tipifarnib, torcetrapib, trabectedin, travoprost, travoprost/timolol, treprostinil sodium; Valdecoxib, vardenafil hydrochloride hydrate, varenicline, VEGF-2 gene therapy, venlafaxine hydrochloride, vildagliptin, vincristine sulfate, voriconazole, VRX-496, VX-385; Warfarin sodium; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Zanolimumab, zidovudine. Copyright (c) 2005 Prous Science. All rights reserved.

Growth of 3-D flower/grass-like metal oxide nanoarchitectures based on catalyst-assisted oxidation method

NASA Astrophysics Data System (ADS)

Hu, Lijiao; Ju, Yang; Hosoi, Atsushi

2014-03-01

Cu2O grass-like and ZnO flower-like nanoarchitectures were fabricated directly on Cu powders and Zn powders using a novel thermal oxidation stress-induced (TOS) method based on catalyst assistance at a low temperature of 150°C under moderate humid atmosphere. The experiments of Al powder were also carried out based on TOS method. Overlapping migration (OLM) of Cu and Zn atoms and toothpaste squeezing migration (TSM) of Al atoms caused by different atom densities in metal oxide materials were studied.

Development, validation and application of the liquid chromatography tandem mass spectrometry method for simultaneous quantification of azilsartan medoxomil (TAK-491), azilsartan (TAK-536), and its 2 metabolites in human plasma.

PubMed

Kuze, Yoji; Kogame, Akifumi; Jinno, Fumihiro; Kondo, Takahiro; Asahi, Satoru

2015-09-15

Azilsartan medoxomil potassium salt (TAK-491) is an orally administered angiotensin II type 1 receptor blocker for the treatment of hypertension and is an ester-based prodrug that is rapidly hydrolyzed to the pharmacologically active moiety, azilsartan (TAK-536), during absorption. TAK-536 is biotransformed to the 2 metabolites M-I by decarboxylation and M-II by dealkylation. In this study, we developed and validated a LC/MS/MS method which can simultaneously determine 4 analytes, TAK-491, TAK-536, M-I and M-II. The bioanalytical method can be outlined as follows: two structural analogues are used as the internal standards. The analytes and the IS are extracted from human plasma using solid phase extraction. After evaporating, the residue is reconstituted and injected into a LC/MS/MS system with an ESI probe and analyzed in the positive ion mode. Separation is performed through a conventional reversed-phase column with a mobile phase of water/acetonitrile/acetic acid (40:60:0.05, v/v/v) mixture at a flow rate of 0.2mL/min. The total run time is 8.5min. The calibration range is 1-2500ng/mL in human plasma for all the analytes. Instability issues of the prodrug, TAK-491, were overcome and all the validation results met the acceptance criteria in accordance with the regulatory guideline/guidance. As a result of the clinical study, the human PK profiles of TAK-536, M-I and M-II were successfully obtained and also it was confirmed that TAK-491 was below the LLOQ (1ng/mL) in the human plasma samples. Copyright © 2015 Elsevier B.V. All rights reserved.

A meta-analysis of randomized controlled trials of azilsartan therapy for blood pressure reduction.

PubMed

Takagi, Hisato; Mizuno, Yusuke; Niwa, Masao; Goto, Shin-Nosuke; Umemoto, Takuya

2014-05-01

Although there have been a number of azilsartan trials, no meta-analysis of the findings has been conducted to date. We performed the first meta-analysis of randomized controlled trials of azilsartan therapy for the reduction of blood pressure (BP) in patients with hypertension. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched from the beginning of the records through March 2013 using web-based search engines (PubMed and OVID). Eligible studies were prospective randomized controlled trials of azilsartan (including azilsartan medoxomil) vs. any control therapy that reported clinic or 24-h mean BP as an outcome. For each study, data for the changes from baseline to final clinic systolic BP (SBP) and diastolic BP (DBP) in both the azilsartan group and the control group were used to generate mean differences and 95% confidence intervals (CIs). Of 27 potentially relevant articles screened initially, 7 reports of randomized trials of azilsartan or azilsartan medoxomil therapy enrolling a total of 6152 patients with hypertension were identified and included. Pooled analysis suggested a significant reduction in BP changes among patients randomized to 40 mg of azilsartan vs. control therapy (clinic SBP: -4.20 mm Hg; 95% CI: -6.05 to -2.35 mm Hg; P<0.00001; clinic DBP: -2.58 mm Hg; 95% CI: -3.69 to -1.48 mm Hg; P<0.00001; 24-h mean SBP: -3.33 mm Hg; 95% CI: -4.74 to -1.93 mm Hg; P<0.00001; 24-h mean DBP: -2.12 mm Hg; 95% CI: -2.74 to -1.49 mm Hg; P<0.00001). In conclusion, azilsartan therapy appears to provide a greater reduction in BP than control therapy in patients with hypertension.

Single-center evaluation of the single-dose pharmacokinetics of the angiotensin II receptor antagonist azilsartan medoxomil in renal impairment.

PubMed

Preston, Richard A; Karim, Aziz; Dudkowski, Caroline; Zhao, Zhen; Garg, Dyal; Lenz, Oliver; Sica, Domenic A

2013-05-01

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a pro-drug and not detected in blood after oral administration because of rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite M-II and minor metabolites. The objective of this study was to determine the effect of renal impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase I parallel-group study which examined the single-dose (40-mg) pharmacokinetics of AZL and M-II in 24 subjects with mild, moderate, or severe renal impairment or end-stage renal disease requiring hemodialysis (n = 6 per group), respectively, and healthy matched subjects (n = 24). Renal impairment/disease did not cause clinically meaningful increases in exposure to AZL. M-II exposure was higher in all renally impaired subjects and highest in those with severe impairment (approx fivefold higher vs. control). M-II is pharmacologically inactive; increased exposure was not considered important in dose selection for AZL-M in subjects with renal impairment. Hemodialysis did not significantly remove AZL or M-II. Renal impairment had no clinically meaningful effect on the plasma protein binding of AZL or M-II. Single doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with any degree of renal impairment, including end-stage renal disease.

Pharmacovigilance database search discloses ClC-K channels as a novel target of the AT1 receptor blockers valsartan and olmesartan.

PubMed

Imbrici, Paola; Tricarico, Domenico; Mangiatordi, Giuseppe Felice; Nicolotti, Orazio; Lograno, Marcello Diego; Conte, Diana; Liantonio, Antonella

2017-07-01

Human ClC-K chloride channels are highly attractive targets for drug discovery as they have a variety of important physiological functions and are associated with genetic disorders. These channels are crucial in the kidney as they control chloride reabsorption and water diuresis. In addition, loss-of-function mutations of CLCNKB and BSND genes cause Bartter's syndrome (BS), whereas CLCNKA and CLCNKB gain-of-function polymorphisms predispose to a rare form of salt sensitive hypertension. Both disorders lack a personalized therapy that is in most cases only symptomatic. The aim of this study was to identify novel ClC-K ligands from drugs already on the market, by exploiting the pharmacological side activity of drug molecules available from the FDA Adverse Effects Reporting System database. We searched for drugs having a Bartter-like syndrome as a reported side effect, with the assumption that BS could be causatively related to the block of ClC-K channels. The ability of the selected BS-causing drugs to bind and block ClC-K channels was then validated through an integrated experimental and computational approach based on patch clamp electrophysiology in HEK293 cells and molecular docking simulations. Valsartan and olmesartan were able to block ClC-Ka channels and the molecular requirements for effective inhibition of these channels have been identified. These results suggest additional mechanisms of action for these sartans further to their primary AT 1 receptor antagonism and propose these compounds as leads for designing new potent ClC-K ligands. © 2017 The British Pharmacological Society.

Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

PubMed

Aoki, Motokuni; Kawahata, Hirohisa; Sotobayashi, Daisuke; Yu, Hisahiro; Moriguchi, Atsushi; Nakagami, Hironori; Ogihara, Toshio; Morishita, Ryuichi

2015-08-01

Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome. Elderly bedridden women (aged >75 years) receiving antihypertensive therapy treated with CCB were recruited in the present study. The participants were divided into two groups--CCB group and ARB group--and followed up to 12 months. Markers of bone resorption were markedly increased, suggesting accelerated bone resorption in the participants of the present study. In the follow-up period, the patients treated with a CCB showed a significant decrease in bone mineral density in a time-dependent manner, accompanied by a significant increase in bone resorption markers, whereas treatment with olmesartan inhibited bone loss, associated with attenuation of increased bone resorption markers. Bone mineral density of femoral neck in the CCB group was significantly lower than that in the ARB group at 6 months. The present study showed inhibitory effects of an ARB on bone resorption in hypertensive patients with accelerated bone resorption, such as elderly bedridden women, and indicated an important role of the renin-angiotensin system in bone metabolism. In elderly hypertensive patients, ARB might be expected to have additional beneficial potential to maintain bone health in bedridden patients. © 2014 Japan Geriatrics Society.

Diana Reference Manual. Revision 3,

DTIC Science & Technology

1983-02-28

will help the reader to understand DIANA. Section 1. 1. 1 presents those principles that motivated the original design of DIAN. and Section 1. 1. 2...parenthesized node whose offspring was the addition, since ADA’s parsing rules require the parentheses. The motivation for this requirement Is to ease the...3.7. a 41neA~olm S3.I. C, S.1. F] 51. 52 number 3.1, 3.2.8] 33, 33 numw_d [3.2.83e 35 number rep C4.4.0] 43 nummicUteral [4:4.0] 43 ps4 . I.A 46

Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

PubMed

de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

2018-07-01

Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

Virtual sensors for robust on-line monitoring (OLM) and Diagnostics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tipireddy, Ramakrishna; Lerchen, Megan E.; Ramuhalli, Pradeep

Unscheduled shutdown of nuclear power facilities for recalibration and replacement of faulty sensors can be expensive and disruptive to grid management. In this work, we present virtual (software) sensors that can replace a faulty physical sensor for a short duration thus allowing recalibration to be safely deferred to a later time. The virtual sensor model uses a Gaussian process model to process input data from redundant and other nearby sensors. Predicted data includes uncertainty bounds including spatial association uncertainty and measurement noise and error. Using data from an instrumented cooling water flow loop testbed, the virtual sensor model has predictedmore » correct sensor measurements and the associated error corresponding to a faulty sensor.« less

Critical evaluation of the efficacy and tolerability of azilsartan.

PubMed

De Caterina, Alberto R; Harper, Andrew R; Cuculi, Florim

2012-01-01

Appropriate control of blood pressure (BP) in hypertensive patients still represents the major therapeutic goal in the treatment of hypertension. Despite the growing attention and wide range of antihypertensive agents available in the clinical scenario, the target of BP below the advised thresholds of 140/90 mmHg is, unfortunately, often unreached. For this reason, the search for new antihypertensive agents is still ongoing. Azilsartan medoxomil, a new angiotensin receptor blocker that has been recently introduced in the clinical arena, represents the eighth angiotensin receptor blocker currently available for BP control. The aim of this paper is to describe the efficacy and safety profile of this new compound, reviewing available data obtained from both pre-clinical and clinical studies.

Critical evaluation of the efficacy and tolerability of azilsartan

PubMed Central

De Caterina, Alberto R; Harper, Andrew R; Cuculi, Florim

2012-01-01

Appropriate control of blood pressure (BP) in hypertensive patients still represents the major therapeutic goal in the treatment of hypertension. Despite the growing attention and wide range of antihypertensive agents available in the clinical scenario, the target of BP below the advised thresholds of 140/90 mmHg is, unfortunately, often unreached. For this reason, the search for new antihypertensive agents is still ongoing. Azilsartan medoxomil, a new angiotensin receptor blocker that has been recently introduced in the clinical arena, represents the eighth angiotensin receptor blocker currently available for BP control. The aim of this paper is to describe the efficacy and safety profile of this new compound, reviewing available data obtained from both pre-clinical and clinical studies. PMID:22661897

Reconstructing the δ(18) O of atmospheric water vapour via the CAM epiphyte Tillandsia usneoides: seasonal controls on δ(18) O in the field and large-scale reconstruction of δ(18) Oa.

PubMed

Helliker, Brent R

2014-03-01

Using both oxygen isotope ratios of leaf water (δ(18) OL ) and cellulose (δ(18) OC ) of Tillandsia usneoides in situ, this paper examined how short- and long-term responses to environmental variation and model parameterization affected the reconstruction of the atmospheric water vapour (δ(18) Oa ). During sample-intensive field campaigns, predictions of δ(18) OL matched observations well using a non-steady-state model, but the model required data-rich parameterization. Predictions from the more easily parameterized maximum enrichment model (δ(18) OL-M ) matched observed δ(18) OL and observed δ(18) Oa when leaf water turnover was less than 3.5 d. Using the δ(18) OL-M model and weekly samples of δ(18) OL across two growing seasons in Florida, USA, reconstructed δ(18) Oa was -12.6 ± 0.3‰. This is compared with δ(18) Oa of -12.4 ± 0.2‰ resolved from the growing-season-weighted δ(18) OC . Both of these values were similar to δ(18) Oa in equilibrium with precipitation, -12.9‰. δ(18) Oa was also reconstructed through a large-scale transect with δ(18) OL and the growing-season-integrated δ(18) OC across the southeastern United States. There was considerable large-scale variation, but there was regional, weather-induced coherence in δ(18) Oa when using δ(18) OL . The reconstruction of δ(18) Oa with δ(18) OC generally supported the assumption of δ(18) Oa being in equilibrium with precipitation δ(18) O (δ(18) Oppt ), but the pool of δ(18) Oppt with which δ(18) Oa was in equilibrium - growing season versus annual δ(18) Oppt - changed with latitude. © 2013 John Wiley & Sons Ltd.

Uncovering a Nuisance Influence of a Phenological Trait of Plants Using a Nonlinear Structural Equation: Application to Days to Heading and Culm Length in Asian Cultivated Rice (Oryza Sativa L.).

PubMed

Onogi, Akio; Ideta, Osamu; Yoshioka, Takuma; Ebana, Kaworu; Yamasaki, Masanori; Iwata, Hiroyoshi

2016-01-01

Phenological traits of plants, such as flowering time, are linked to growth phase transition. Thus, phenological traits often influence other traits through the modification of the duration of growth period. This influence is a nuisance in plant breeding because it hampers genetic evaluation of the influenced traits. Genetic effects on the influenced traits have two components, one that directly affects the traits and one that indirectly affects the traits via the phenological trait. These cannot be distinguished by phenotypic evaluation and ordinary linear regression models. Consequently, if a phenological trait is modified by introgression or editing of the responsible genes, the phenotypes of the influenced traits can change unexpectedly. To uncover the influence of the phenological trait and evaluate the direct genetic effects on the influenced traits, we developed a nonlinear structural equation (NSE) incorporating a nonlinear influence of the phenological trait. We applied the NSE to real data for cultivated rice (Oryza sativa L.): days to heading (DH) as a phenological trait and culm length (CL) as the influenced trait. This showed that CL of the cultivars that showed extremely early heading was shortened by the strong influence of DH. In a simulation study, it was shown that the NSE was able to infer the nonlinear influence and direct genetic effects with reasonable accuracy. However, the NSE failed to infer the linear influence in this study. When no influence was simulated, an ordinary bi-trait linear model (OLM) tended to infer the genetic effects more accurately. In such cases, however, by comparing the NSE and OLM using an information criterion, we could assess whether the nonlinear assumption of the NSE was appropriate for the data analyzed. This study demonstrates the usefulness of the NSE in revealing the phenotypic influence of phenological traits.

Uncovering a Nuisance Influence of a Phenological Trait of Plants Using a Nonlinear Structural Equation: Application to Days to Heading and Culm Length in Asian Cultivated Rice (Oryza Sativa L.)

PubMed Central

Onogi, Akio; Ideta, Osamu; Yoshioka, Takuma; Ebana, Kaworu; Yamasaki, Masanori; Iwata, Hiroyoshi

2016-01-01

Phenological traits of plants, such as flowering time, are linked to growth phase transition. Thus, phenological traits often influence other traits through the modification of the duration of growth period. This influence is a nuisance in plant breeding because it hampers genetic evaluation of the influenced traits. Genetic effects on the influenced traits have two components, one that directly affects the traits and one that indirectly affects the traits via the phenological trait. These cannot be distinguished by phenotypic evaluation and ordinary linear regression models. Consequently, if a phenological trait is modified by introgression or editing of the responsible genes, the phenotypes of the influenced traits can change unexpectedly. To uncover the influence of the phenological trait and evaluate the direct genetic effects on the influenced traits, we developed a nonlinear structural equation (NSE) incorporating a nonlinear influence of the phenological trait. We applied the NSE to real data for cultivated rice (Oryza sativa L.): days to heading (DH) as a phenological trait and culm length (CL) as the influenced trait. This showed that CL of the cultivars that showed extremely early heading was shortened by the strong influence of DH. In a simulation study, it was shown that the NSE was able to infer the nonlinear influence and direct genetic effects with reasonable accuracy. However, the NSE failed to infer the linear influence in this study. When no influence was simulated, an ordinary bi-trait linear model (OLM) tended to infer the genetic effects more accurately. In such cases, however, by comparing the NSE and OLM using an information criterion, we could assess whether the nonlinear assumption of the NSE was appropriate for the data analyzed. This study demonstrates the usefulness of the NSE in revealing the phenotypic influence of phenological traits. PMID:26859143

Lipid and blood pressure control for the prevention of cardiovascular disease in hypertensive patients: a subanalysis of the OMEGA study.

PubMed

Teramoto, Tamio; Kawamori, Ryuzo; Miyazaki, Shigeru; Teramukai, Satoshi; Sato, Yuki; Okuda, Yasuyuki; Shirayama, Masayuki

2015-01-01

The aim of this analysis was to investigate the relationships between dyslipidemia, achieved blood pressure (BP) values and the lipid levels, as well as the control of four cardiovascular risk factors (BP, low-density lipoprotein: LDL cholesterol, hemoglobin A1c: HbA1c and smoking) and the incidence of cardiovascular disease (CVD), in Japanese patients receiving antihypertensive therapy. A total of 13,052 patients with no history of CVD were included in this subanalysis of the prospective observational OMEGA study in Japanese hypertensive patients treated with olmesartan. Multivariable Cox regression models were used to evaluate the relationship with the risk of CVD. The incidence of CVD during the 36-month study period was 5.59/1,000 patient-years among the patients with dyslipidemia (n = 6,297) and 5.57/1,000 patient-years among the patients without dyslipidemia (n = 6,755), with no significant differences between the two groups. Higher achieved BP values tended to be associated with an increased CVD risk in both the patients with and without dyslipidemia. In addition, the risk of CVD tended to be higher in the patients with an achieved LDL cholesterol level of ≥ 120 mg/dL than in those with an LDL level of ＜ 120 mg/dL (trend p = 0.0005) and in the patients with an achieved high-density lipoprotein cholesterol level of ＜ 60 mg/dL than in those with an HDL level of ≥ 60 mg/dL (trend p = 0.0017). Furthermore, the risk of CVD was higher among the patients with fewer controlled risk factors than among those with control of all four risk factors (trend p ＜ 0.0001). In order to prevent CVD in olmesartan-treated hypertensive patients with no history of CVD, it is important to control both the lipid and BP levels and aim for comprehensive risk factor control.

Benchmarking transportation logistics practices for effective system planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thrower, A.W.; Dravo, A.N.; Keister, M.

2007-07-01

This paper presents preliminary findings of an Office of Civilian Radioactive Waste Management (OCRWM) benchmarking project to identify best practices for logistics enterprises. The results will help OCRWM's Office of Logistics Management (OLM) design and implement a system to move spent nuclear fuel (SNF) and high-level radioactive waste (HLW) to the Yucca Mountain repository for disposal when that facility is licensed and built. This report suggests topics for additional study. The project team looked at three Federal radioactive material logistics operations that are widely viewed to be successful: (1) the Waste Isolation Pilot Plant (WIPP) in Carlsbad, New Mexico; (2)more » the Naval Nuclear Propulsion Program (NNPP); and (3) domestic and foreign research reactor (FRR) SNF acceptance programs. (authors)« less

Treatment efficacy of anti-hypertensive drugs in monotherapy or combination

PubMed Central

Paz, Marco A.; de-La-Sierra, Alejandro; Sáez, Marc; Barceló, María Antonia; Rodríguez, Juan José; Castro, Sonia; Lagarón, Cristina; Garrido, Josep M; Vera, Pilar; Coll-de-Tuero, Gabriel

2016-01-01

Abstract Background: The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients’ characteristics associated with best performance of the drugs will improve management of hypertensive patients. Objective: To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers. Study eligibility criteria: Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ≥50 or ≥25 if the study was a crossover, follow-up of at least 8 weeks, and available required data. Study appraisal and synthesis methods: Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework. Main Outcome(s) and Measure(s): Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination. Results: Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases. Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/m2 were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats. Limitations: Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses. Conclusions and implications: Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised. PMID:27472680

The retinal phenotype of Grk1−/− is compromised by a Crb1rd8 mutation

PubMed Central

Pak, Joseph S.; Lee, Eun-Jin

2015-01-01

Purpose Well-established laboratory mouse lines are important in creating genetically engineered knockout mouse models; however, these routinely used inbred strains are prone to spontaneous and deleterious mutations. One of these strains, the commonly used C57BL/6N (B6N), was discovered to carry a point mutation in the Crumbs homolog 1 (Crb1rd8) gene, which codes for a developmental protein involved in tight junction formation at the outer limiting membrane (OLM). This mutation disrupts photoreceptor polarity and leads to retinal degeneration. It was hypothesized that the G-protein receptor kinase 1 knockouts (Grk1−/−), which were based on the B6N strain, would exhibit abnormal morphological phenotypes in their offspring not related to GRK1’s major phosphorylation function. The hypothesis was tested by examining Grk1−/− with or without the Crb1rd8 mutation. Methods The mice strains tested were C57BL/6J (B6J), B6N, and Grk1−/− on either a B6J (Grk1−/−;B6J) or B6N background (Grk1−/−;B6N) and were verified with PCR genotype analysis for Grk1−/− and Crb rd8. The mice were bred and raised in complete darkness until 1 or 3 months of age and then exposed to 1,000 lux light for 24 h, followed by processing for immunohistochemistry (IHC) analysis on the retinal structure to investigate the morphological effects of light exposure. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to detect photoreceptor apoptosis. Results The microanatomy of the retinal sections revealed disorganization of the outer nuclear layer (ONL) in the B6N and Grk1−/−;B6N mice and a significant decrease in the thickness of the ONL in the 3-month-old Grk1−/−;B6N mice. The adherens-junction-associated protein, Zona occludens-1 (ZO-1), formed a continuous line at the OLM in the 1- and 3-month-old control B6J and Grk1−/−;B6J mice. In contrast, the B6N and Grk1−/−;B6N retinas showed discontinuous and fragmented staining for ZO-1 at the OLM at both ages. After the mice were exposed to light, TUNEL analysis showed a significant increase in photoreceptor cell death in the Grk1−/−;B6J and Grk1−/−;B6N retinas versus either the B6J or B6N retinas at 1 and 3 months of age and a small significant difference between the Grk1−/−;B6J and Grk1−/−;B6N retinas at 1 month. In addition, glial fibrillary acidic protein (GFAP) expression was enhanced in the Grk1−/−;B6J and Grk1−/−;B6N retinas at 1 and 3 months. Occasional sprouting processes of rod bipolar cells were detected in the B6N and Grk1−/−;B6N retinas, but sprouting was not detected in the B6J or Grk1−/−;B6J retinas at either age. Conclusions The B6N strain background exhibited abnormal phenotypes in the Grk1−/−;B6N retina. This study demonstrates that the B6N background can influence the phenotype of a genetic mouse knockout and introduces potential visual functional consequences of the Crb1 mutation. PMID:26664249

The efficacy and tolerability of azilsartan in obese insulin-resistant mice with left ventricular pressure overload.

PubMed

Tarikuz Zaman, A K M; McLean, Danielle L; Sobel, Burton E

2013-10-01

Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.

What do we know about Indonesian tropical lakes? Insights from high frequency measurement

NASA Astrophysics Data System (ADS)

Budi Santoso, Arianto; Triwisesa, Endra; Fakhrudin, Muh.; Harsono, Eko; Agita Rustini, Hadiid

2018-02-01

When measuring ecological variables in lakes, sampling frequency is critical in capturing an environmental pattern. Discrete sampling of traditional monitoring programs is likely to result in vital knowledge gaps in understanding any processes particularly those with fine temporal scale characteristics. The development of high frequency measurements offer a sophisticated range of information in recording any events in lakes at a finer time scale. We present physical indices of a tropical deep Lake Maninjau arrayed from OnLine Monitoring System (OLM). It is revealed that Lake Maninjau mostly has a diurnal thermal stratification pattern. The calculated lake stability (Schmidt stability), however, follows a seasonal pattern; low in December-January and around August, and high in May and September. Using a 3D numerical model simulation (ELCOM), we infer how wind and solar radiation intensity control lake’s temperature profiles. In this review, we highlight the needs of high frequency measurement establishment in Indonesian tropical lakes to better understand the unique processes and to support the authorities’ decision making in maximizing the provision of ecosystem services supplied by lakes and reservoirs.

Epidemiology of human toxocariasis in Poland - A review of cases 1978-2009.

PubMed

Borecka, Anna; Kłapeć, Teresa

2015-01-01

Toxocariasis is a helminthozoonosis due to the infection of humans with larvae belonging to the Toxocara genus. Humans become infected as a result of accidental consumption of infected eggs containing third stage larvae (L3) nematodes from Toxocara canis or Toxocara cati species. Toxocariasis was recognized for the first time in the early 1950s, and the first cases of toxocariasis in Poland were described a few years later. Toxocariasis is clinically classified into several types: classic and incomplete visceral larva migrans (VLM) syndrome, ocular larva migrans (OLM) syndrome, neurological toxocariasis (NLM), covert toxocariasis and asymptomatic toxocariasis. In 1994-2005, 18,367 sera of people suspected of being infected with Toxocara were analysed, 1.8-76% had anti- Toxocara antibodies. In the period 1978-2009, 1,022 clinical cases of toxocariasis were recognized in Poland. In the opinion of the authors, in order to reduce the frequency of toxocariasis in human populations, some prophylaxis should undertaken, e.g. public education of zoonotic diseases, systematic control of animal, deworming of pets, cleaning pets' faeces by the owners.

Adverse event potentially due to an interaction between ibrutinib and verapamil: a case report.

PubMed

Lambert Kuhn, E; Levêque, D; Lioure, B; Gourieux, B; Bilbault, P

2016-02-01

Ibrutinib is a recently approved oral anticancer agent with pharmacokinetics that is very sensitive to metabolic inhibition. We report a serious side effect of ibrutinib potentially attributable to interaction with the moderate CYP3A4 inhibitor verapamil. A patient with mantle cell lymphoma was admitted to our emergency department with severe diarrhoea. During a prescription review, the clinical pharmacist identified a potential drug interaction between ibrutinib and verapamil present in a branded combination product also containing trandolapril. Ibrutinib was discontinued for 5 days, and verapamil was stopped. Lercanidipine 10 mg daily was prescribed as an alternative antihypertensive drug. The patient was discharged after 3 days with symptomatic treatment for his diarrhoea. Three months later, the patient maintained control with ibrutinib and olmesartan, but without verapamil. This is the first description of a serious side effect of ibrutinib likely due to an interaction with the CYP3A4 inhibitor verapamil. Prescriptions of ibrutinib must be carefully checked to identify possible interactions with CYP3A4 inhibitors and patients monitored accordingly. © 2016 John Wiley & Sons Ltd.

The renin-angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril in clinical trials versus routine practice: insights from the prospective EARLY registry.

PubMed

Bramlage, Peter; Schmieder, Roland E; Gitt, Anselm K; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Potthoff, Sebastian A

2015-12-19

Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not. Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-). Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5%) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1%; P<0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1%) than in the RCT+ AZL-M group (64.1%), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1%). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5%) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility. These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.

[Molecular techniques applied in species identification of Toxocara].

PubMed

Fogt, Renata

2006-01-01

Toxocarosis is still an important and actual problem in human medicine. It can manifest as visceral (VLM), ocular (OLM) or covert (CT) larva migrans syndroms. Complicated life cycle of Toxocara, lack of easy and practical methods of species differentiation of the adult nematode and embarrassing in recognition of the infection in definitive hosts create difficulties in fighting with the infection. Although studies on human toxocarosis have been continued for over 50 years there is no conclusive answer, which of species--T. canis or T. cati constitutes a greater risk of transmission of the nematode to man. Neither blood serological examinations nor microscopic observations of the morphological features of the nematode give the satisfied answer on the question. Since the 90-ths molecular methods were developed for species identification and became useful tools being widely applied in parasitological diagnosis. This paper cover the survey of methods of DNA analyses used for identification of Toxocara species. The review may be helpful for researchers focused on Toxocara and toxocarosis as well as on detection of new species. The following techniques are described: PCR (Polymerase Chain Reaction), RFLP (Restriction Fragment Length Polymorphism), RAPD (Random Amplified Polymorphic DNA) and SSCP (Single Strand Conformation Polymorphism).

The European Scientist - Symposium on the era and work of Franz Xaver von Zach (1754 - 1832)

NASA Astrophysics Data System (ADS)

Balázs, Lajos G.; Brosche, Peter; Duerbeck, Hilmar W.; Zsoldos, Endre

On June 16, 1754, the birth of the second son of its leading physician was registered in the "Militärmatriken" of the Invalides' Hospital at Pest, Hungary. The father was Joseph Zach from Olmüutz and the mother Clara née Sontag. The son received the names Joannes Franciscus Xaverius Vitus Fridericus, and later became a geodesist and astronomer. For these professions, he acted around 1800 not only as a kind of international information centre, but he moreover stimulated the work of other colleagues and carried out important observations and reductions. He studied and published historical sources, and his journals constitute themselves more an ocean than a source of the history of our science, an ocean which is still to be explored for as yet undetected islands. At the occasion of the 250th birthday of Franz Xaver von Zach, Hungarian colleagues took the initiative to commemorate him by a symposium at the seat of the Hungarian Academy of Sciences, which was held on September 15-17, 2004. This book contains contributions that are based on lectures given at the Budapest symposium "The European Scientist". All papers are written English.

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study

PubMed Central

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Background: Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Methods: Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. Results: AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Conclusion: Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research. PMID:27536242

Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study.

PubMed

Georgiopoulos, Georgios; Katsi, Vasiliki; Oikonomou, Dimitrios; Vamvakou, Georgia; Koutli, Evangelia; Laina, Aggeliki; Tsioufis, Constantinos; Nihoyannopoulos, Petros; Tousoulis, Dimitrios

2016-01-01

Hypertension related cardiovascular (CV) complications could be amplified by the presence of metabolic co-morbidities. Azilsartan medoxomil (AZL-M) is the eighth approved member of angiotensin II receptor blockers (ARBs), a drug class of high priority in the management of hypertensive subjects with diabetes mellitus type II (DMII). Under this prism, we performed a systematic review of the literature for all relevant articles in order to evaluate the efficacy, safety, and possible clinical role of AZL-M in hypertensive diabetic patients. AZL-M was found to be more effective in terms of reducing indices of blood pressure over alternative ARBs or angiotensin-converting enzyme (ACE) inhibitors with minimal side effects. Preclinical studies have established pleiotropic effects for AZL-M beyond its primary antihypertensive role through differential gene expression, up-regulation of membrane receptors and favorable effect on selective intracellular biochemical and pro-atherosclerotic pathways. Indirect but accumulating evidence from recent literature supports the efficacy and safety of AZL-M among diabetic patients. However, no clinical data exist to date that evince a beneficial role of AZL-M in patients with metabolic disorders on top of its antihypertensive effect. Further clinical studies are warranted to assess the pleiotropic cardiometabolic benefits of AZL-M that are derived from preclinical research.

ICP measurement accuracy: the effect of temperature drift. Design of a laboratory test for assessment of ICP transducers.

PubMed

Morgalla, M H; Mettenleiter, H; Katzenberger, T

1999-01-01

Intracranial pressure (ICP) monitoring has become the mainstay of multimodal neuromonitoring of comatous patients after head injury. In the presence of rising ICP and faced with pressures, difficult to control, aggressive measures, such as hypothermia may be used. The ICP readings should not be influenced by temperature changes. A laboratory test was designed to simulate temperature variations between 20 degrees C and 45 degrees C at different pressure levels under physiological conditions. Five types of transducers were examined: Epidyn Braun Melsungen, ICT/B-Titan Gaeltec, Camino-OLM-110-4B, Codman MicroSensor ICP-Transducer, Neurovent ICP transducer Rehau Ag+Co. Tests were performed at 6 different pressure levels between 0 mmHg and 50 mmHg. The results show very low drifts of less than 0.15 mmHg degree C-1 for Codman, Epidyn and Neurovent. Gaeltec and Camino exhibited higher drifts of 0.18 mmHg and 0.2 mmHg degree C-1 respectively. Within the temperature range from 35 degrees C to 42 degrees C all probes tested show insignificant temperature drift. Whether these results also apply to other types of transducers needs further evaluation. Problems and requirements related to the design of a laboratory test for the in vitro assessment of ICP transducers are discussed in detail.

Diagnostic and Prognostic Models for Generator Step-Up Transformers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vivek Agarwal; Nancy J. Lybeck; Binh T. Pham

In 2014, the online monitoring (OLM) of active components project under the Light Water Reactor Sustainability program at Idaho National Laboratory (INL) focused on diagnostic and prognostic capabilities for generator step-up transformers. INL worked with subject matter experts from the Electric Power Research Institute (EPRI) to augment and revise the GSU fault signatures previously implemented in the Electric Power Research Institute’s (EPRI’s) Fleet-Wide Prognostic and Health Management (FW-PHM) Suite software. Two prognostic models were identified and implemented for GSUs in the FW-PHM Suite software. INL and EPRI demonstrated the use of prognostic capabilities for GSUs. The complete set of faultmore » signatures developed for GSUs in the Asset Fault Signature Database of the FW-PHM Suite for GSUs is presented in this report. Two prognostic models are described for paper insulation: the Chendong model for degree of polymerization, and an IEEE model that uses a loading profile to calculates life consumption based on hot spot winding temperatures. Both models are life consumption models, which are examples of type II prognostic models. Use of the models in the FW-PHM Suite was successfully demonstrated at the 2014 August Utility Working Group Meeting, Idaho Falls, Idaho, to representatives from different utilities, EPRI, and the Halden Research Project.« less

Update on Baylisascariasis, a Highly Pathogenic Zoonotic Infection

PubMed Central

Morassutti, Alessandra Loureiro; Kazacos, Kevin R.

2016-01-01

SUMMARY Baylisascaris procyonis, the raccoon roundworm, infects a wide range of vertebrate animals, including humans, in which it causes a particularly severe type of larva migrans. It is an important cause of severe neurologic disease (neural larva migrans [NLM]) but also causes ocular disease (OLM; diffuse unilateral subacute neuroretinitis [DUSN]), visceral larva migrans (VLM), and covert/asymptomatic infections. B. procyonis is common and widespread in raccoons, and there is increasing recognition of human disease, making a clinical consideration of baylisascariasis important. This review provides an update for this disease, especially its clinical relevance and diagnosis, and summarizes the clinical cases of human NLM and VLM known to date. Most diagnosed patients have been young children less than 2 years of age, although the number of older patients diagnosed in recent years has been increasing. The recent development of recombinant antigen-based serodiagnostic assays has aided greatly in the early diagnosis of this infection. Patients recovering with fewer severe sequelae have been reported in recent years, reinforcing the current recommendation that early treatment with albendazole and corticosteroids should be initiated at the earliest suspicion of baylisascariasis. Considering the seriousness of this zoonotic infection, greater public and medical awareness is critical for the prevention and early treatment of human cases. PMID:26960940

LC-MS screening techniques for wastewater analysis and analytical data handling strategies: Sartans and their transformation products as an example.

PubMed

Letzel, Thomas; Bayer, Anne; Schulz, Wolfgang; Heermann, Alexandra; Lucke, Thomas; Greco, Giorgia; Grosse, Sylvia; Schüssler, Walter; Sengl, Manfred; Letzel, Marion

2015-10-01

A large number of anthropogenic trace contaminants such as pharmaceuticals, their human metabolites and further transformation products (TPs) enter wastewater treatment plants on a daily basis. A mixture of known, expected, and unknown molecules are discharged into the receiving aquatic environment because only partial elimination occurs for many of these chemicals during physical, biological and chemical treatment processes. In this study, an array of LC-MS methods from three collaborating laboratories was applied to detect and identify anthropogenic trace contaminants and their TPs in different waters. Starting with theoretical predictions of TPs, an efficient workflow using the combination of target, suspected-target and non-target strategies for the identification of these TPs in the environment was developed. These techniques and strategies were applied to study anti-hypertensive drugs from the sartan group (i.e., candesartan, eprosartan, irbesartan, olmesartan, and valsartan). Degradation experiments were performed in lab-scale wastewater treatment plants, and a screening workflow including an inter-laboratory approach was used for the identification of transformation products in the effluent samples. Subsequently, newly identified compounds were successfully analyzed in effluents of real wastewater treatment plants and river waters. Copyright © 2015 Elsevier Ltd. All rights reserved.

Urinary adiponectin and albuminuria in non-diabetic hypertensive patients: an analysis of the ESPECIAL trial.

PubMed

Han, Seung Seok; Bae, Eunjin; Ahn, Shin Young; Kim, Sejoong; Park, Jung Hwan; Shin, Sung Joon; Lee, Sang Ho; Choi, Bum Soon; Chin, Ho Jun; Lim, Chun Soo; Kim, Suhnggwon; Kim, Dong Ki

2015-08-01

Although adiponectin levels have been reported to be correlated with albuminuria, this issue remains unresolved in non-diabetic hypertensive subjects, particularly when urinary adiponectin is considered. Urinary adiponectin levels were examined using an enzyme-linked immunosorbent assay in 229 participants. who used olmesartan as a hypertensive agent. Their albuminuria levels were measured for 16 weeks after randomization and initiation of conventional or intensive diet education. Linear or logistic regression models were applied, as appropriate, to explore the relationship with albuminuria itself or its response after the intervention. Urinary adiponectin levels were positively related to baseline albuminuria level (r = 0.529). After adjusting for several covariates, the adiponectin level was associated with the albuminuria level (β = 0.446). Among the 159 subjects with baseline macroalbuminuria, the risk of consistent macroalbuminuria (> 300 mg/day) at 16 weeks was higher in the 3(rd) tertile of adiponectin than in the 1(st) tertile (odds ratio = 6.9), despite diet education. In contrast, among all subjects, the frequency of the normoalbuminuria achievement (< 30 mg/day) at 16 weeks was higher in the 1(st) tertile than in the 3(rd) tertile (odds ratio = 13.0). Urinary adiponectin may be a useful biomarker for albuminuria or its response after treatment in non-diabetic hypertensive patients.

Baylisascaris Larva Migrans

USGS Publications Warehouse

Kazacos, Kevin R.; Abbott, Rachel C.; van Riper, Charles

2016-05-26

SummaryBaylisascaris procyonis, the common raccoon roundworm, is the most commonly recognized cause of clinical larva migrans (LM) in animals, a condition in which an immature parasitic worm or larva migrates in a host animal’s tissues, causing obvious disease. Infection with B. procyonis is best known as a cause of fatal or severe neurologic disease that results when the larvae invade the brain, the spinal cord, or both; this condition is known as neural larva migrans (NLM). Baylisascariasis is a zoonotic disease, that is, one that is transmissible from animals to humans. In humans, B. procyonis can cause damaging visceral (VLM), ocular (OLM), and neural larva migrans. Due to the ubiquity of infected raccoons around humans, there is considerable human exposure and risk of infection with this parasite. The remarkable disease-producing capability of B. procyonis in animals and humans is one of the most significant aspects of the biology of ascarids (large roundworms) to come to light in recent years. Infection with B. procyonis has important health implications for a wide variety of free-ranging and captive wildlife, zoo animals, domestic animals, as well as human beings, on both an individual and population level. This report, eighth in the series of U.S. Geological Survey Circulars on zoonotic diseases, will help us to better understand the routes of Baylisascaris procyonis infections and how best to adequately monitor this zoonotic disease.

Electrosmog and autoimmune disease.

PubMed

Marshall, Trevor G; Heil, Trudy J Rumann

2017-02-01

Studies in mice have shown that environmental electromagnetic waves tend to suppress the murine immune system with a potency similar to NSAIDs, yet the nature of any Electrosmog effects upon humans remains controversial. Previously, we reported how the human Vitamin-D receptor (VDR) and its ligand, 1,25-dihydroxyvitamin-D (1,25-D), are associated with many chronic inflammatory and autoimmune diseases. We have shown how olmesartan, a drug marketed for mild hypertension, acts as a high-affinity partial agonist for the VDR, and that it seems to reverse disease activity resulting from VDR dysfunction. We here report that structural instability of the activated VDR becomes apparent when observing hydrogen bond behavior with molecular dynamics, revealing that the VDR pathway exhibits a susceptibility to Electrosmog. Further, we note that characteristic modes of instability lie in the microwave frequency range, which is currently populated by cellphone and WiFi communication signals, and that the susceptibility is ligand dependent. A case series of 64 patient-reported outcomes subsequent to use of a silver-threaded cap designed to protect the brain and brain stem from microwave Electrosmog resulted in 90 % reporting "definite" or "strong" changes in their disease symptoms. This is much higher than the 3-5 % rate reported for electromagnetic hypersensitivity in a healthy population and suggests that effective control of environmental Electrosmog immunomodulation may soon become necessary for successful therapy of autoimmune disease.

The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

PubMed Central

Mourad, Jean-Jacques

2008-01-01

Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC) therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB), amlodipine, with angiotensin receptor blockers (ARBs), valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined. PMID:19337545

Angiotensin II type 1 receptor blockers prevent tumor necrosis factor-alpha-mediated endothelial nitric oxide synthase reduction and superoxide production in human umbilical vein endothelial cells.

PubMed

Kataoka, Hiroki; Murakami, Ryuichiro; Numaguchi, Yasushi; Okumura, Kenji; Murohara, Toyoaki

2010-06-25

Decrease in endothelial nitric oxide synthase (eNOS) expression is one of the adverse outcomes of endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha) is known to decrease eNOS expression and is an important mediator of endothelial dysfunction. We hypothesized that an angiotensin II type 1 (AT1) receptor blocker would improve endothelial function via not only inhibition of the angiotensin II signaling but also inhibition of the TNF-alpha-mediated signaling. Therefore we investigated whether an AT1 receptor blocker would restore the TNF-alpha-induced decrease in eNOS expression in cultured human umbilical vein endothelial cells (HUVEC). Pretreatment of HUVEC with an antioxidant (superoxide dismutase, alpha-tocopherol) or AT1 receptor blockers (olmesartan or candesartan) restored the TNF-alpha-dependent reduction of eNOS. The AT1 receptor blocker decreased the TNF-alpha-dependent increase of 8-isoprostane. The superoxide dismutase activities in HUVEC were stable during AT1 receptor blocker treatment, and the AT1 receptor blocker did not scavenge superoxide directly. The AT1 receptor blocker also decreased TNF-alpha-induced phosphorylation of I kappaB alpha and cell death. These results suggest that AT1 receptor blockers are able to ameliorate TNF-alpha-dependent eNOS reduction or cell injury by inhibiting superoxide production or nuclear factor-kappaB activation. (c) 2010 Elsevier B.V. All rights reserved.

Azilsartan improves glycemic status and reduces kidney damage in zucker diabetic fatty rats.

PubMed

Hye Khan, Md Abdul; Neckář, Jan; Haines, Jasmine; Imig, John D

2014-08-01

Azilsartan medoxomil (AZL-M), an angiotensin II receptor blocker, demonstrates antihypertensive and organ protective effects in hypertension. We investigated the efficacy of AZL-M to ameliorate metabolic syndrome and kidney damage associated with type 2 diabetes using Zucker diabetic fatty (ZDF) rats. ZDF rats were treated with vehicle or AZL-M for 8 weeks. Zucker diabetic lean (ZDL) rats were used as controls. Urine and plasma samples were collected for biochemical analysis, and kidney tissues were used for histopathological and immunohistopathological examination at the end of the 8-week protocol. ZDF rats were diabetic with hyperglycemia and impaired glucose tolerance, and AZL-M ameliorated the diabetic phenotype. ZDF rats were hypertensive compared with ZDL rats (181±6 vs. 129±7mm Hg), and AZL-M decreased blood pressure in ZDF rats (116±7mm Hg). In ZDF rats, there was marked renal damage with elevated proteinuria, albuminuria, nephrinuria, 2-4-fold higher tubular cast formation, and glomerular injury compared with ZDL rats. AZL-M treatment reduced renal damage in ZDF rats. ZDF rats demonstrated renal inflammation and oxidative stress with elevated urinary monocyte chemoattractant protein 1 excretion, renal infiltration of macrophages, and elevated kidney malondialdehyde levels. AZL-M reduced oxidative stress and inflammation in ZDF rats. Overall, we demonstrate that AZL-M attenuates kidney damage in type 2 diabetes. We further demonstrate that anti-inflammatory and antioxidative activities of AZL-M contribute to its kidney protective action. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Simultaneous determination of azilsartan and chlorthalidone in rat and human plasma by liquid chromatography-electrospray tandem mass spectrometry.

PubMed

Ramakrishna, Rachumallu; Puttrevu, Santosh Kumar; Bhateria, Manisha; Bala, Veenu; Sharma, Vishnu L; Bhatta, Rabi Sankar

2015-05-15

Azilsartan medoxomil (AZM), an ester prodrug of azilsartan (AZ), and chlorthalidone (CLT) have recently been approved as a combination therapy for the management of hypertension. This is the first report which described a selective and sensitive method for the simultaneous quantification of AZ and CLT in rat and human plasma using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). AZ and CLT were extracted from plasma by liquid-liquid extraction technique and separated on a C18 reverse phase column using ammonium acetate (10mM, pH 4)-mixture of methanol and acetonitrile (8:92, v/v) as a mobile phase at a flow rate of 0.7mL/min. Detection was performed by electrospray ionization (ESI) operated in negative multiple reaction monitoring (MRM) mode. The lower limit of quantitation (LLOQ) of this method was 1ng/mL and the calibration curves were linear (r(2)≥0.995) over the concentration range of 1-4000ng/mL for both the analytes. The intra- and inter-day precision and accuracy were well within the acceptable limits. The mean extraction recoveries were found to be about 80% and no matrix effect was observed. AZ and CLT were found to be stable under all relevant storage conditions. The method was successfully applied to the oral pharmacokinetic study of AZM and CLT in rats. Further, the sensitivity of the method enabled the determination of protein binding of AZ and CLT in human plasma. Copyright © 2015 Elsevier B.V. All rights reserved.

Personalised Single-Pill Combination Therapy in Hypertensive Patients: An Update of a Practical Treatment Platform.

PubMed

Volpe, Massimo; Tocci, Giuliano; de la Sierra, Alejandro; Kreutz, Reinhold; Laurent, Stéphane; Manolis, Athanasios J; Tsioufis, Kostantinos

2017-12-01

Despite the improvements in the management of hypertension during the last three decades, it continues to be one of the leading causes of cardiovascular morbidity and mortality worldwide. Effective and sustained reductions in blood pressure (BP) reduce the incidence of myocardial infarction, stroke, congestive heart failure and cardiovascular death. However, the proportion of patients who achieve the recommended BP goal (< 140/90 mmHg) is persistently low, worldwide. Poor adherence to therapy, complex therapeutic regimens, clinical inertia, drug-related adverse events and multiple risk factors or comorbidities contribute to the disparity between the potential and actual BP control rate. Previously we published a practical therapeutic platform for the treatment of hypertension based on clinical evidence, guidelines, best practice and clinical experience. This platform provides a personalised treatment approach and can be used to improve BP control and simplify treatment. It uses long-acting, effective and well-tolerated angiotensin receptor blocker (ARB) olmesartan, in combination with a calcium channel blocker amlodipine, and/or a thiazide diuretic hydrochlorothiazide. These drugs were selected based on the availability in most European Countries of single-pill, fixed formulations in a wide range of doses for both dual- and triple-drug combinations. The platform approach could be applied to other ARBs or angiotensin-converting enzyme inhibitors available in single-pill, fixed-dose combinations. Here, we present an update, which takes into account the results of the recently published studies and extends the applicability of the platform to common conditions that are often neglected or poorly considered in clinical practice guidelines.

Expression of renin–angiotensin system components in the early bovine embryo

PubMed Central

Pijacka, Wioletta; Hunter, Morag G; Broughton Pipkin, Fiona; Luck, Martin R

2012-01-01

The renin–angiotensin system (RAS), mainly associated with the regulation of blood pressure, has been recently investigated in female reproductive organs and the developing foetus. Angiotensin II (Ang II) influences oviductal gamete movements and foetal development, but there is no information about RAS in the early embryo. The aim of this study was to determine whether RAS components are present in the pre-implantation embryo, to determine how early they are expressed and to investigate their putative role at this stage of development. Bovine embryos produced in vitro were used for analysis of RAS transcripts (RT-PCR) and localisation of the receptors AGTR1 and AGTR2 (immunofluorescent labelling). We also investigated the effects of Ang II, Olmesartan (AGTR1 antagonist) and PD123319 (AGTR2 antagonist) on oocyte cleavage, embryo expansion and hatching. Pre-implanted embryos possessed AGTR1 and AGTR2 but not the other RAS components. Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst. AGTR1 was mainly localised in granular-like structures in the cytoplasm, suggesting its internalisation into clathrin-coated vesicles, and AGTR2 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells. Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control. These results, the first on RAS in the early embryo, suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself. This may be a route by which the maternal RAS influences blastocyst hatching and early embryonic development. PMID:23781300

Azilsartan: a newly approved angiotensin II receptor blocker.

PubMed

Lam, Sum

2011-01-01

Hypertension is a common chronic disease that leads to significant cardiovascular morbidity and mortality. Blood pressure control is essential to prevent end-organ complications, such as stroke, myocardial infarction, heart failure, or kidney disease. Azilsartan is the eighth angiotensin II receptor blocker approved for the management of hypertension, alone or in combination with other agents. At the approved dosage, it reduces systolic blood pressure by 12 to 15 mm Hg and diastolic blood pressure by 7 to 8 mm Hg. A higher dose of azilsartan (80 mg) was superior to valsartan 320 mg or olmesartan 40 mg in lowering systolic blood pressure in short-term studies. Additional blood pressure reduction is expected when azilsartan is used adjunctively with a diuretic. However, the effects of azilsartan on cardiovascular morbidity or mortality are still lacking. Azilsartan is well tolerated; the most common side effects are headache and diarrhea. No cases of hyperkalemia have been reported in 6-week clinical trials. Worsening of renal function and hypotension should be monitored, particularly in those with baseline risk factors. It is unknown whether azilsartan would join angiotensin-converting enzyme inhibitors and other angiotensin receptor blockers as the preferred hypertensive agents for end-organ protection. At this time, azilsartan should be considered as an alternative agent for mild-to-moderate hypertension, or as an adjunctive therapy when preferred agents fail to maintain optimal blood pressure control. It is also an option for those patients who have contraindications or cannot tolerate other antihypertensive agents, including dry cough induced by angiotensin-converting enzyme inhibitors.

Azilsartan/chlorthalidone combination therapy for blood pressure control.

PubMed

Cheng, Judy Wm

2013-01-01

Edarbyclor(®) is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms "azilsartan", "chlorthalidone", "pharmacology", "pharmacokinetics", "pharmacodynamics", "pharmacoeconomics", and "cost-effectiveness". The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual patient.

Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker.

PubMed

Kajiya, Takashi; Ho, Christopher; Wang, Jiaming; Vilardi, Ryan; Kurtz, Theodore W

2011-12-01

Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24-h blood pressure more effectively than maximally recommended doses of older ARBs. Although azilsartan is considered to be an unusually potent angiotensin II type 1 (AT1) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. We investigated pleiotropic features of azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-α (PPARα), PPARδ, leptin, adipsin, and adiponectin. The effects of azilsartan on adipocyte differentiation and gene expression were observed at concentrations of azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, azilsartan inhibited cell proliferation at concentrations as low as 1 μmol/l, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 μmol/l. Antiproliferative effects of azilsartan were also observed in cells lacking AT1 receptors. In addition, azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 h after washout of drug from the incubation media. These findings suggest that azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT1 receptors and/or reduction in blood pressure.

Azilsartan compared to ACE inhibitors in anti-hypertensive therapy: one-year outcomes of the observational EARLY registry.

PubMed

Gitt, Anselm K; Bramlage, Peter; Potthoff, Sebastian A; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ehmen, Martina; Ouarrak, Taoufik; Senges, Jochen; Schmieder, Roland E

2016-03-08

Azilsartan medoxomil (AZL-M), has been demonstrated to be more effective than the other sartans currently in use; however, there is insufficient information available comparing it with ACE-inhibitors. Therefore, we aimed to compare the efficacy, safety, and tolerability of AZL-M with that of ACE-inhibitors in a real life clinical setting. The EARLY registry is a prospective, observational, national, multicentre registry with a follow-up period of 12 months. There were two principal objectives: 1) documentation of the achievement of target BP values set according to recent national and international guidelines, and 2) description of the safety profile of AZL-M. A total of 3 849 patients with essential arterial hypertension were recruited from primary care offices in Germany. Patients who initiated monotherapy at baseline comprising either AZL-M or an ACE-inhibitor were included at a ratio of seven to three. Results demonstrated that a blood pressure target of <140/90 mmHg was achieved by a significantly greater proportion of patients in the AZL-M group (61.1 %) compared with the ACE-inhibitor group (56.4 %; p < 0.05; OR, 1.21; 95 % CI, 1.03-1.42), with this finding maintained after adjusting for differences in baseline characteristics. AZL-M appeared to have an equivalent safety profile to the ACE-inhibitors, with a similar incidence of adverse events in the two patient groups (p = 0.73). These data add to the results of previous randomized controlled clinical trials suggesting that, compared with other agents that target the renin-angiotensin system, AZL-M provides statistically significant albeit small improvements in blood pressure control.

Direct Involvement of the Master Nitrogen Metabolism Regulator GlnR in Antibiotic Biosynthesis in Streptomyces.

PubMed

He, Juan-Mei; Zhu, Hong; Zheng, Guo-Song; Liu, Pan-Pan; Wang, Jin; Zhao, Guo-Ping; Zhu, Guo-Qiang; Jiang, Wei-Hong; Lu, Yin-Hua

2016-12-16

GlnR, an OmpR-like orphan two-component system response regulator, is a master regulator of nitrogen metabolism in the genus Streptomyces In this work, evidence that GlnR is also directly involved in the regulation of antibiotic biosynthesis is provided. In the model strain Streptomyces coelicolor M145, an in-frame deletion of glnR resulted in markedly increased actinorhodin (ACT) production but reduced undecylprodigiosin (RED) biosynthesis when exposed to R2YE culture medium. Transcriptional analysis coupled with DNA binding studies revealed that GlnR represses ACT but activates RED production directly via the pathway-specific activator genes actII-ORF4 and redZ, respectively. The precise GlnR-binding sites upstream of these two target genes were defined. In addition, the direct involvement of GlnR in antibiotic biosynthesis was further identified in Streptomyces avermitilis, which produces the important anthelmintic agent avermectin. We found that S. avermitilis GlnR (GlnRsav) could stimulate avermectin but repress oligomycin production directly through the respective pathway-specific activator genes, aveR and olmRI/RII To the best of our knowledge, this report describes the first experimental evidence demonstrating that GlnR regulates antibiotic biosynthesis directly through pathway-specific regulators in Streptomyces Our results suggest that GlnR-mediated regulation of antibiotic biosynthesis is likely to be universal in streptomycetes. These findings also indicate that GlnR is not only a master nitrogen regulator but also an important controller of secondary metabolism, which may help to balance nitrogen metabolism and antibiotic biosynthesis in streptomycetes. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice.

PubMed

Gray, Nora E; Zweig, Jonathan A; Caruso, Maya; Martin, Marjoen D; Zhu, Jennifer Y; Quinn, Joseph F; Soumyanath, Amala

2018-06-19

Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways. Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins. CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin. These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Reassessment of the Unique Mode of Binding between Angiotensin II Type 1 Receptor and Their Blockers

PubMed Central

Matsuo, Yoshino; Saku, Keijiro; Karnik, Sadashiva S.

2013-01-01

While the molecular structures of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) are very similar, they are also slightly different. Although each ARB has been shown to exhibit a unique mode of binding to AT1 receptor, different positions of the AT1 receptor have been analyzed and computational modeling has been performed using different crystal structures for the receptor as a template and different kinds of software. Therefore, we systematically analyzed the critical positions of the AT1 receptor, Tyr113, Tyr184, Lys199, His256 and Gln257 using a mutagenesis study, and subsequently performed computational modeling of the binding of ARBs to AT1 receptor using CXCR4 receptor as a new template and a single version of software. The interactions between Tyr113 in the AT1 receptor and the hydroxyl group of olmesartan, between Lys199 and carboxyl or tetrazole groups, and between His256 or Gln257 and the tetrazole group were studied. The common structure, a tetrazole group, of most ARBs similarly bind to Lys199, His256 and Gln257 of AT1 receptor. Lys199 in the AT1 receptor binds to the carboxyl group of EXP3174, candesartan and azilsartan, whereas oxygen in the amidecarbonyl group of valsartan may bind to Lys199. The benzimidazole portion of telmisartan may bind to a lipophilic pocket that includes Tyr113. On the other hand, the n-butyl group of irbesartan may bind to Tyr113. In conclusion, we confirmed that the slightly different structures of ARBs may be critical for binding to AT1 receptor and for the formation of unique modes of binding. PMID:24260317

Comparison of aldosterone synthesis in adrenal cells, effect of various AT1 receptor blockers with or without atrial natriuretic peptide.

PubMed

Miura, Shin-Ichiro; Nakayama, Asuka; Tomita, Sayo; Matsuo, Yoshino; Suematsu, Yasunori; Saku, Keijiro

2015-01-01

Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10(-7) and 10(-8 )M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10(-8) and 10(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach.

PubMed

Nixon, R M; Müller, E; Lowy, A; Falvey, H

2009-05-01

To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension. Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90-115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination. In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was -15.32 mmHg (95% CI: -17.09, -13.63) and -11.3 mmHg (95% CI: -12.15, -10.52) and for 320 mg was -15.85 mmHg (95% CI: -17.60, -14.12) and -11.97 mmHg (95% CI: -12.81, -11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was -12.01 mmHg (95% CI: -13.78, -10.25) and -9.37 mmHg (95% CI: -10.18, -8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated. Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.

Hypertension management: rationale for triple therapy based on mechanisms of action.

PubMed

Neutel, Joel M; Smith, David H G

2013-10-01

An estimated 25% of patients will require 3 antihypertensive agents to achieve blood pressure (BP) control; combination therapy is thus an important strategy in hypertension treatment. This review discusses the triple-therapy combination of an angiotensin receptor blocker (ARB) or direct renin antagonist (DRI) with a calcium channel blocker (CCB) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single-agent therapy. DRIs and ARBs target the renin-angiotensin-aldosterone system (RAAS) at the initial and final steps, respectively, and both classes lower BP by reducing the effects of angiotensin-2; however, ARBs may trigger a compensatory increase in renin activity. Dihydropyridine CCBs target L-type calcium channels and lower BP through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (SNS) and RAAS. Thiazide diuretics lower BP initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the SNS and RAAS. The combination of an agent targeting the RAAS with a CCB and diuretic is rational, and triple combinations of valsartan/amlodipine/hydrochlorothiazide, olmesartan/amlodipine/hydrochlorothiazide, and aliskiren/amlodipine/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual-component combinations. In addition, single-pill, fixed-dose combinations can address barriers to BP control including clinical inertia and poor adherence. Fixed-dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved BP control. © 2012 John Wiley & Sons Ltd.

Kruppel-like Factor 4 Protein Regulates Isoproterenol-induced Cardiac Hypertrophy by Modulating Myocardin Expression and Activity*

PubMed Central

Yoshida, Tadashi; Yamashita, Maho; Horimai, Chihiro; Hayashi, Matsuhiko

2014-01-01

Kruppel-like factor 4 (KLF4) plays an important role in vascular diseases, including atherosclerosis and vascular injury. Although KLF4 is expressed in the heart in addition to vascular cells, the role of KLF4 in cardiac disease has not been fully determined. The goals of this study were to investigate the role of KLF4 in cardiac hypertrophy and to determine the underlying mechanisms. Cardiomyocyte-specific Klf4 knockout (CM Klf4 KO) mice were generated by the Cre/LoxP technique. Cardiac hypertrophy was induced by chronic infusion of the β-adrenoreceptor agonist isoproterenol (ISO). Results showed that ISO-induced cardiac hypertrophy was enhanced in CM Klf4 KO mice compared with control mice. Accelerated cardiac hypertrophy in CM Klf4 KO mice was accompanied by the augmented cellular enlargement of cardiomyocytes as well as the exaggerated expression of fetal cardiac genes, including atrial natriuretic factor (Nppa). Additionally, induction of myocardin, a transcriptional cofactor regulating fetal cardiac genes, was enhanced in CM Klf4 KO mice. Interestingly, KLF4 regulated Nppa expression by modulating the expression and activity of myocardin, providing a mechanical basis for accelerated cardiac hypertrophy in CM Klf4 KO mice. Moreover, we showed that KLF4 mediated the antihypertrophic effect of trichostatin A, a histone deacetylase inhibitor, because ISO-induced cardiac hypertrophy in CM Klf4 KO mice was attenuated by olmesartan, an angiotensin II type 1 antagonist, but not by trichostatin A. These results provide novel evidence that KLF4 is a regulator of cardiac hypertrophy by modulating the expression and the activity of myocardin. PMID:25100730

Differential pharmacology and benefit/risk of azilsartan compared to other sartans.

PubMed

Kurtz, Theodore W; Kajiya, Takashi

2012-01-01

Azilsartan, an angiotensin II type 1 (AT(1)) receptor blocker (ARB), was recently approved by regulatory authorities for treatment of hypertension and is the 8th ARB to join the clinical market. This article discusses the medical reasons for introducing a new AT(1) receptor blocker and reviews the experimental and clinical studies that have compared the functional properties of azilsartan to those of other ARBs. The main question addressed is: Does azilsartan have distinguishing features that should motivate choosing it over any of the other sartans for use in clinical practice? Based on studies conducted to date in hypertensive patients without serious comorbidities, azilsartan appears to be characterized by a superior ability to control 24-hour systolic blood pressure (BP) relative to other widely used ARBs including valsartan, olmesartan, and candesartan, and presumably others as well (eg, losartan). Compared to these other ARBs, azilsartan may increase the BP target control and response rate by an absolute value of 8%-10%. Greater antihypertensive effects of azilsartan might be due in part to its unusually potent and persistent ability to inhibit binding of angiotensin II to AT(1) receptors. Preclinical studies have indicated that azilsartan may also have potentially beneficial effects on cellular mechanisms of cardiometabolic disease and insulin sensitizing activity that could involve more than just blockade of AT(1) receptors and/or reduction in BP. However, the clinical relevance of these additional actions is unknown. Given that the general ability of antihypertensive drugs to protect against target organ damage is largely mediated by their ability to decrease BP, the enhanced antihypertensive effects of azilsartan should serve to justify clinical interest in this ARB relative to other molecules in the class that have a lower capacity to reduce BP.

Differential pharmacology and benefit/risk of azilsartan compared to other sartans

PubMed Central

Kurtz, Theodore W; Kajiya, Takashi

2012-01-01

Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), was recently approved by regulatory authorities for treatment of hypertension and is the 8th ARB to join the clinical market. This article discusses the medical reasons for introducing a new AT1 receptor blocker and reviews the experimental and clinical studies that have compared the functional properties of azilsartan to those of other ARBs. The main question addressed is: Does azilsartan have distinguishing features that should motivate choosing it over any of the other sartans for use in clinical practice? Based on studies conducted to date in hypertensive patients without serious comorbidities, azilsartan appears to be characterized by a superior ability to control 24-hour systolic blood pressure (BP) relative to other widely used ARBs including valsartan, olmesartan, and candesartan, and presumably others as well (eg, losartan). Compared to these other ARBs, azilsartan may increase the BP target control and response rate by an absolute value of 8%–10%. Greater antihypertensive effects of azilsartan might be due in part to its unusually potent and persistent ability to inhibit binding of angiotensin II to AT1 receptors. Preclinical studies have indicated that azilsartan may also have potentially beneficial effects on cellular mechanisms of cardiometabolic disease and insulin sensitizing activity that could involve more than just blockade of AT1 receptors and/or reduction in BP. However, the clinical relevance of these additional actions is unknown. Given that the general ability of antihypertensive drugs to protect against target organ damage is largely mediated by their ability to decrease BP, the enhanced antihypertensive effects of azilsartan should serve to justify clinical interest in this ARB relative to other molecules in the class that have a lower capacity to reduce BP. PMID:22399858

Azilsartan/chlorthalidone combination therapy for blood pressure control

PubMed Central

Cheng, Judy WM

2013-01-01

Background Edarbyclor® is a combined angiotensin receptor blocker (ARB) and thiazide-like diuretic (azilsartan and chlorthalidone), and was approved on December 20, 2011 by the US Food and Drug Administration (FDA) for hypertension management. Objective To review the pharmacology, pharmacokinetics, efficacy, safety, tolerability, and role of azilsartan plus chlorthalidone for hypertension management. Methods Peer-reviewed clinical trials, review articles, and relevant treatment guidelines, were identified from the databases MEDLINE and Current Contents (both 1966 to February 15, 2013, inclusive) using search terms “azilsartan”, “chlorthalidone”, “pharmacology”, “pharmacokinetics”, “pharmacodynamics”, “pharmacoeconomics”, and “cost-effectiveness”. The FDA website, as well as manufacturer prescribing information, was also reviewed to identify other relevant information. Results Azilsartan is a new ARB with high affinity for the angiotensin 1 receptor, approved by the FDA for hypertension management. Unlike other ARBs, azilsartan has no clinical data supporting improvement in cardiovascular outcomes, and is not approved for indications other than hypertension, which a select few other ARBs may be used for (eg, diabetic nephropathy and heart failure). Chlorthalidone is a longer acting thiazide-like diuretic that has been demonstrated to improve cardiovascular outcomes. Combination treatment with azilsartan/chlorthalidone is effective for reducing blood pressure. Compared to olmesartan/hydrochlorothiazide and azilsartan/hydrochlorothiazide combinations, azilsartan/chlorthalidone appears to be more efficacious for reducing blood pressure. Conclusions Azilsartan/chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure >20 mmHg systolic or >10 mmHg diastolic above goal). Cost to patients and insurance coverage will probably determine whether azilsartan/chlorthalidone will be the most appropriate combination therapy for an individual patient. PMID:23807859

Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks

PubMed Central

Srivastava, Shashikant; Deshpande, Devyani; Pasipanodya, Jotam; Nuermberger, Eric; Swaminathan, Soumya; Gumbo, Tawanda

2016-01-01

Background. When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0–24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0–24/MIC ratios when treated with the same dose. Methods. We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0–24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0–24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum. Results. The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0–24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3–4 times daily. Conclusions. The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible. PMID:27742641

Adoption of new drugs by physicians: a survival analysis.

PubMed

Garjón, Francisco Javier; Azparren, Ana; Vergara, Iván; Azaola, Borja; Loayssa, Jose Ramón

2012-03-08

New drugs often substitute others cheaper and with a risk-benefit balance better established. Our aim was to analyse the diffusion of new drugs during the first months of use, examining the differences between family physicians and specialists. Prescription data were obtained of cefditoren, duloxetine, etoricoxib, ezetimibe, levocetirizine, olmesartan, pregabalin and tiotropium 36 months after their launching. We obtained the monthly number of prescriptions per doctor and the number prescribers of each drug by specialty. After discarding those with less than 10 prescriptions during this period, physicians were defined as adopters if the number of prescriptions was over the 25th percentile for each drug and level (primary or secondary care). The diffusion of each drug was studied by determining the number of adopter family physicians throughout the study period. Among the group of adopters, we compared the month of the first prescription by family physicians to that of other specialists using the Kaplan-Meier method. The adoption of the drugs in primary care follows an exponential diffusion curve that reaches a plateau at month 6 to 23. Tiotropium was the most rapidly and widely adopted drug. Cefditoren spread at a slower rate and was the least adopted. The diffusion of etoricoxib was initially slowed down due to administrative requirements for its prescription. The median time of adoption in the case of family physicians was 4-6 months. For each of the drugs, physicians of a specialty other than family physicians adopted it first. The number of adopters of a new drug increases quickly in the first months and reaches a plateau. The number of adopter family physicians varies considerably for different drugs. The adoption of new drugs is faster in specialists. The time of adoption should be considered to promote rational prescribing by providing timely information about new drugs and independent medical education.

Adoption of new drugs by physicians: a survival analysis

PubMed Central

2012-01-01

Background New drugs often substitute others cheaper and with a risk-benefit balance better established. Our aim was to analyse the diffusion of new drugs during the first months of use, examining the differences between family physicians and specialists. Methods Prescription data were obtained of cefditoren, duloxetine, etoricoxib, ezetimibe, levocetirizine, olmesartan, pregabalin and tiotropium 36 months after their launching. We obtained the monthly number of prescriptions per doctor and the number prescribers of each drug by specialty. After discarding those with less than 10 prescriptions during this period, physicians were defined as adopters if the number of prescriptions was over the 25th percentile for each drug and level (primary or secondary care). The diffusion of each drug was studied by determining the number of adopter family physicians throughout the study period. Among the group of adopters, we compared the month of the first prescription by family physicians to that of other specialists using the Kaplan-Meier method. Results The adoption of the drugs in primary care follows an exponential diffusion curve that reaches a plateau at month 6 to 23. Tiotropium was the most rapidly and widely adopted drug. Cefditoren spread at a slower rate and was the least adopted. The diffusion of etoricoxib was initially slowed down due to administrative requirements for its prescription. The median time of adoption in the case of family physicians was 4-6 months. For each of the drugs, physicians of a specialty other than family physicians adopted it first. Conclusions The number of adopters of a new drug increases quickly in the first months and reaches a plateau. The number of adopter family physicians varies considerably for different drugs. The adoption of new drugs is faster in specialists. The time of adoption should be considered to promote rational prescribing by providing timely information about new drugs and independent medical education. PMID:22401169

Repaglinide-irbesartan drug interaction: effects of SLCO1B1 polymorphism on repaglinide pharmacokinetics and pharmacodynamics in Chinese population.

PubMed

Pei, Qi; Liu, Jun-Yan; Yin, Ji-Ye; Yang, Guo-Ping; Liu, Shi-Kun; Zheng, Yi; Xie, Pan; Guo, Cheng-Xian; Luo, Mi; Zhou, Hong-Hao; Li, Xi; Liu, Zhao-Qian

2018-05-11

On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed. IC 50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [C max ] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0-8 h [AUC 0-8 ] increased 34% (P = 0.004), while the minimum blood glucose concentration [C min ] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan. SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

Effects of blood pressure on renal and cardiovascular outcomes in Asian patients with type 2 diabetes and overt nephropathy: a post hoc analysis (ORIENT-blood pressure).

PubMed

Imai, Enyu; Ito, Sadayoshi; Haneda, Masakazu; Harada, Atsushi; Kobayashi, Fumiaki; Yamasaki, Tetsu; Makino, Hirofumi; Chan, Juliana C N

2016-03-01

Blood pressure (BP) control may have different effects on cardiovascular (CV) and renal outcomes in diabetes. We examined the impact of systolic BP (SBP) on renal and CV outcomes in a post hoc analysis in the Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial. We stratified mean follow-up SBP into three categories (≤130, 131-140 and >140 mmHg) and used a Cox regression model to estimate the hazard ratio (HR, 95% confidence interval) for the outcomes. The composite renal outcome was doubling of serum creatinine, end-stage renal disease and all-cause death. The composite CV outcome included CV death, nonfatal stroke, nonfatal myocardial infarction, hospitalization for unstable angina or heart failure, revascularization and lower extremity amputation. We also compared the slope of estimated glomerular filtration rate (eGFR) in all three groups. After a mean follow-up period of 3.2 years, the follow-up SBP was linearly associated with risk of renal outcomes in all 566 patients. In patients with heavy proteinuria (≥1 g/gCr), a follow-up SBP > 130 mmHg was associated with an HR of 2.33 (1.62-3.36) for renal outcomes with referent to SBP ≤ 130 mmHg. In patients without history of CV disease, a follow-up SBP > 140 mmHg was associated with an HR of 2.04 (1.23-3.40) for CV outcomes with referent to SBP < 140 mmHg. The median (interquartile range) slopes of eGFR were -3.27 (-6.90, -1.63), -4.53 (-8.08, -2.29) and -7.13 (-10.90, -3.99) dL/mg/year in patients with SBP ≤ 130, 131-140 and > 140 mmHg, respectively (P = 0.008 between ≤130 and 131-140, P < 0.001 between ≤ 130 and > 140 mmHg). In Asian type 2 diabetic patients with chronic kidney disease and heavy proteinuria, reduction of SBP ≤ 130 mmHg was associated with greater renoprotection than cardioprotection. However, our results emphasize the need to individualize BP targets in type 2 diabetes. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.