scholarly journals LY3045697: Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase

2017 ◽  
Vol 18 (3) ◽  
pp. 147032031771788 ◽  
Author(s):  
Joanne Sloan-Lancaster ◽  
Eyas Raddad ◽  
Amy Flynt ◽  
Yan Jin ◽  
James Voelker ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Healthy Subjects ◽  
Adrenocorticotropic Hormone ◽  
Randomized Clinical Trials ◽  
Ion Homeostasis ◽  
Plasma Aldosterone ◽  
Complete Suppression ◽  
Multiple Dosing ◽  
Plasma Aldosterone Concentration ◽  
Aldosterone Synthase

Introduction: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects. Materials and methods: Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects. Pharmacodynamics was assessed following oral potassium challenge and intravenous adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active comparator. Results: A total of 51 subjects participated in the two studies, which included 38 males and 13 females (of non-childbearing potential), from 18–65 years old. LY3045697 caused rapid dose and concentration-dependent unstimulated plasma aldosterone concentration reduction seen as early as 4 h after the first dose at dose levels as low as 1 mg, and reaching near complete suppression at high doses. The potency (IC50) decreased significantly upon multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone challenge plasma aldosterone concentration increase was dose-dependently blunted by LY3045697 with high potency with a dose as low as 0.1 mg resulting in substantial effect, and with an overall IC50 of 0.38 ng/ml. Minor reductions in cortisol were observed only at the top dose of 300 mg. LY3045697 is generally safe and tolerated, and exhibits linear pharmacokinetics. Conclusions: LY3045697 is a potent and highly selective aldosterone synthase inhibitor with selectivity for CYP11B2, offering a substantial potential advantage over previous aldosterone synthase inhibitors evaluated in the clinic.

Effects of cereal fibers on short-chain fatty acids in healthy subjects and patients: a meta-analysis of randomized clinical trials

2021 ◽  
Author(s):  
Junying Bai ◽  
Yan Li ◽  
Wenhui Zhang ◽  
Mingcong Fan ◽  
Haifeng Qian ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Clinical Trials ◽  
Clinical Studies ◽  
Healthy Subjects ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Cereal Fiber ◽  
Obese Subjects

Cereal fiber supplementation significantly affected fecal SCFA concentrations in randomized clinical studies. A more significant impact appeared in overweight and obese subjects with BMI >29 kg m−2 than in individuals with BMI ≤29 kg m−2.

Circadian rhythm in recognition threshold of salt taste in healthy subjects

1990 ◽  
Vol 259 (5) ◽  
pp. R931-R935 ◽  
Author(s):  
A. Fujimura ◽  
H. Kajiyama ◽  
T. Tateishi ◽  
A. Ebihara
Keyword(s):  
Circadian Rhythm ◽  
Healthy Subjects ◽  
Plasma Renin ◽  
Sodium Concentration ◽  
Plasma Aldosterone ◽  
Recognition Threshold ◽  
Plasma Aldosterone Concentration ◽  
Salt Taste ◽  
Young Subjects ◽  
Positive Correlations

The circadian rhythm in recognition threshold of salt taste was examined in six healthy young subjects. Plasma aldosterone (PA) and cortisol concentrations, plasma renin activity (PRA), salivary sodium concentration, and salt recognition thresholds were measured every 3 h for a 24-h period. The salt recognition threshold and salivary sodium concentration exhibited similar circadian rhythms, with the lowest values recorded in the afternoon. Positive correlations were observed between the recognition threshold and salivary sodium (P less than 0.001) and between cortisol and PA (P less than 0.001). There was no correlation between PRA and PA. A negative correlation was observed between PA and salivary sodium concentration (P less than 0.01). These data indicate that the recognition threshold for salt taste has a circadian rhythm in young healthy subjects. This rhythm appears to be related to daily variations in the plasma aldosterone concentration and its subsequent effects on salivary sodium concentration.

scholarly journals Evaluation of various confirmatory tests for the diagnosis of aldosterone-producing adenoma

2020 ◽  
Vol 21 (2) ◽  
pp. 147032032091961
Author(s):  
Satoshi Kidoguchi ◽  
Naoki Sugano ◽  
Ruri Kawauchi ◽  
Daisuke Nakashima ◽  
Naomi Hayashi-Ishikawa ◽  
...  
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Challenge Test ◽  
Plasma Aldosterone ◽  
Stimulation Test ◽  
Saline Infusion ◽  
Infusion Test ◽  
Venous Sampling ◽  
Plasma Aldosterone Concentration ◽  
Hormone Stimulation ◽  
Confirmatory Tests

Introduction: Adrenal venous sampling is useful for discriminating unilateral and bilateral hypersecretion in patients with primary aldosteronism, but it is relatively invasive. To determine the site of hypersecretion more non-invasively, we evaluated predictors of unilateral hypersecretion. Materials and methods: We evaluated the baseline characteristics and the results of confirmatory tests of 123 patients with primary aldosteronism who underwent adrenal venous sampling. Results: Unilateral hypersecretion was identified in 22.0%. The plasma aldosterone concentration and aldosterone–renin ratio were significantly higher and serum potassium concentration and plasma renin activity were significantly lower in patients with unilateral hypersecretion. Plasma aldosterone concentrations after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were significantly higher among patients with unilateral hypersecretion. The plasma aldosterone concentration reduction ratio in saline infusion test and plasma aldosterone concentration elevation ratio during rapid adrenocorticotropic hormone stimulation test were significantly higher in patients with unilateral hypersecretion. However, areas under the curve for these parameters were not superior to the values after confirmatory tests. Conclusions: The plasma aldosterone concentration values after captopril challenge test, saline infusion test and rapid adrenocorticotropic hormone stimulation test were useful for identifying patients with unilateral hypersecretion. However, value changes or ratios during confirmatory tests are less useful for this aim.

Evaluation of Biochemical Conditions Allowing Bypass of Confirmatory Testing in The Workup of Primary Aldosteronism: A Retrospective Study in a French Hypertensive Population

2019 ◽  
Vol 51 (03) ◽  
pp. 172-177 ◽  
Author(s):  
Maud Vivien ◽  
Emilie Deberles ◽  
Remy Morello ◽  
Aimi Haddouche ◽  
David Guenet ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Dynamic Testing ◽  
Challenge Test ◽  
Plasma Aldosterone ◽  
Aldosterone Secretion ◽  
Plasma Aldosterone Concentration ◽  
Hypertensive Patients ◽  
Hypertensive Population ◽  
Tertiary Center ◽  
Aldosterone To Renin Ratio

AbstractThe diagnostic workup for primary aldosteronism includes a screening step using the aldosterone-to-renin ratio (ARR) and a confirmatory step based on dynamic testing of aldosterone secretion autonomy. International guidelines suggest that precise clinical and biochemical conditions may allow the bypassing of the confirmatory step, however, data which validate hormone thresholds defining such conditions are lacking. At our tertiary center, we retrospectively examined a cohort of 173 hypertensive patients screened for PA by the ARR, of whom 120 had positive screening and passed a saline infusion test (SIT) or a captopril challenge test (CCT). Fifty-nine had PA, including 34 Conn adenomas and 25 with idiopathic aldosteronism (IA). Using a threshold of 160 pmol/l, post-SIT plasma aldosterone concentration (PAC) identified PA with 86.4% sensitivity, 94.7% specificity, and a negative predictive value of 92.3%. Of those subjects with a high ARR and a PAC above 550 pmol/l, 93% had a positive SIT, while 100% of subjects with a high ARR, but a PAC under 240 pmol/l had a negative SIT. Our results thus validate the biochemical conditions defined in the French and US guidelines for bypassing the confirmatory step in the workup for PA diagnosis.

Hormonal changes in normal and polycythemic high-altitude natives

1995 ◽  
Vol 79 (3) ◽  
pp. 795-800 ◽  
Author(s):  
A. M. Antezana ◽  
J. P. Richalet ◽  
I. Noriega ◽  
M. Galarza ◽  
G. Antezana
Keyword(s):  
High Altitude ◽  
Systolic Pressure ◽  
Plasma Aldosterone ◽  
Control Group ◽  
Protective Mechanism ◽  
Hormonal Changes ◽  
Plasma Aldosterone Concentration ◽  
Pulmonary Arterial ◽  
Exercise Induced ◽  
Acute And Chronic Exposure

Acute and chronic exposure to high-altitude (HA) hypoxia inhibits the renin-angiotensin-aldosterone system and may modify the release of atrial natriuretic peptide (ANP) in sea-level (SL) natives. In HA natives, the release of these hormones could be influenced by changes in blood volume or pulmonary arterial pressure. Twenty-four men residing in La Paz, Bolivia, at 3,600 m were separated into two groups: one normocythemic (HAN; with hematocrit < 57%; n = 13) and the other polycythemic (HAP; with hematocrit > 57%; n = 11). A control group of 9 SL residents was studied in normoxia (SLN) as well as after 4 days spent at 4,350 m (SLH). The groups were tested for plasma active renin (PAR), plasma aldosterone concentration, ANP, and potassium and norepineprine concentrations at rest and after a maximal exercise. Pulmonary arterial systolic pressure was assessed by a Doppler technique. It was observed that PAR and plasma aldosterone concentration at rest and after exercise were lower in the SLH than in the SLN group. PAR and norepineprine concentration were higher among highlanders than in the SLN group. Renin response to exercise was normal among the HAN group and slightly decreased among the HAP group, and an exercise-induced increase in aldosterone was attenuated in both HA groups. Aldosterone response to renin was maintained among the SLH group but was attenuated in the HA groups, possibly owing to a protective mechanism against salt and water retention. Resting and exercise ANP was lower in the HA groups than in the SLN group.

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