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![(a) Regulatory endocrine feedback loops that control early and late adrenal steroidogenesis. (b-e) Diurnal variation of aldosterone secretion. Baseline hormone peak times of melatonin (b), plasma renin activity (PRA) (c), aldosterone (d), and cortisol (e) [11,12]. 11b-OHase, 11b-hydroxylase; 11-DC, 11-deoxycortisol; 11-DOC, 11deoxycorticosterone; 17-OH-Preg, 17-hydroxypregnenolone; 17-OH-Prog, 17-hydroxyprogesterone; 18-OH-corticosterone, 18-hydroxycorticosterone; A4, androstenedione; ACTH, adrenocorticotropin; Ang, angiotensin; Chol, cholesterol; CMO, corticosterone methyl oxidase; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; K, potassium; Na, sodium; Preg, pregnenolone; Prog, progesterone; PVN, paraventricular nucleus; RAAS, renin-angiotensin-aldosterone system. Figure 1b-e reproduced with permission [11].](profile/Hans-Brunner/publication/257598601/figure/fig1/AS:601604973666305@1520445211009/a-Regulatory-endocrine-feedback-loops-that-control-early-and-late-adrenal.png)
(a) Regulatory endocrine feedback loops that control early and late adrenal steroidogenesis. (b-e) Diurnal variation of aldosterone secretion. Baseline hormone peak times of melatonin (b), plasma renin activity (PRA) (c), aldosterone (d), and cortisol (e) [11,12]. 11b-OHase, 11b-hydroxylase; 11-DC, 11-deoxycortisol; 11-DOC, 11deoxycorticosterone; 17-OH-Preg, 17-hydroxypregnenolone; 17-OH-Prog, 17-hydroxyprogesterone; 18-OH-corticosterone, 18-hydroxycorticosterone; A4, androstenedione; ACTH, adrenocorticotropin; Ang, angiotensin; Chol, cholesterol; CMO, corticosterone methyl oxidase; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; K, potassium; Na, sodium; Preg, pregnenolone; Prog, progesterone; PVN, paraventricular nucleus; RAAS, renin-angiotensin-aldosterone system. Figure 1b-e reproduced with permission [11].
Source publication
We describe the clinical investigation of the first generation aldosterone synthase inhibitor, LCI699, in patients with essential, uncontrolled, resistant, or secondary hypertension. LCI699 competitively reduced blood pressure at lower doses yet counterintuitive effects were observed at higher doses.
An extensive endocrine biomarker analysis was pe...
Contexts in source publication
Context 1
... gland, like blood pressure (BP) control, is circadian and governed by several factors that exert complex regulatory inter- actions. In humans, the circadian pacemaker activity medi- ates the secretion of adrenocorticotropic hormone (ACTH) and renin in the early morning, which controls the release of aldosterone with a peak level around waking ( Fig. 1b- d). Subsequently, the renin-angiotensin-aldosterone system (RAAS) and potassium are the major regulators of aldosterone synthesis in the adrenal gland, whereas ACTH and sodium remain as minor modulators. In contrast, ACTH tightly controls the release of cortisol ...
Context 2
... general and the activity of the rate-limiting enzyme aldosterone synthase in particular. Specifically, aldosterone production can be regulated by modulating either one or both of two biosynthetic steps [12]. The early step is the conversion of cholesterol to pregnenolone and the late step is the con- version of deoxycorticosterone to aldosterone (Fig. 1a). The late step converts the three substrates of aldosterone synthase [cytochrome p450 (CYP) 11B2], 11-deoxycorti- costerone, corticosterone, and 18-hydroxycorticosterone to aldosterone via three distinct reactions: an 11b-hydroxyl- ase followed by an 18-hydroxylase and a final 18-isomerase reaction. In contrast, the late synthetic step ...
Context 3
... 11b-hydroxylase; 11-DC, 11-deoxycortisol; 11-DOC, 11- deoxycorticosterone; 17-OH-Preg, 17-hydroxypregnenolone; 17-OH-Prog, 17-hydroxyprogesterone; 18-OH-corticosterone, 18-hydroxycorticosterone; A4, androstenedione; ACTH, adrenocorticotropin; Ang, angiotensin; Chol, cholesterol; CMO, corticosterone methyl oxidase; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandroster- one; K, potassium; Na, sodium; Preg, pregnenolone; Prog, progesterone; PVN, paraventricular nucleus; RAAS, renin-angiotensin-aldosterone system. Figure 1b-e repro- duced with permission [11]. ...
Context 4
... again, the changes in the HPA feedback axis reflected the observed dose-dependent impairment of the ACTH stress test (Supplemental digital content: Fig. 1, http://links.lww.com/HJH/A269). The increased 11-deoxycortisol levels in the presence of stable cortisol values are indicative of an inhibitory effect on 11b- hydroxylase and explain the inferior cortisol excursions upon exogenous ACTH stimulation. The compensatory induction of endogenous ACTH stimulates adrenal steroidogenesis and ...
Context 5
... of the HPA feedback axis to compensate for an impairment of cortisol synthesis via stimulation of adrenal steroidogenesis. Because ACTH stimulates the first enzymatic steps in adrenal steroidogenesis, it stimulates the synthesis of glucocorticoids, mineralocorticoids, as well as adrenal androgens and long-term hypertrophy of the adrenal gland (Fig. ...
Citations
... The CYP11B1 gene, which codes for the 11-hydroxylase enzyme, is a modulator of cortisol production in the zona fasciculata of the adrenal cortex. Due to the high degree of sequence homology and shared 11-hydroxylase reaction between CYP11B2 and CYP11B1, it is challenging to create selective aldosterone synthase inhibitors [98]. ...
Hypertension is a critical health problem. It is also the primary cause of coronary heart disease, stroke, and renal vascular disease. The use of herbal drugs in the management of any disease is increasing. They are considered the best immune booster to fight against several types of diseases. To date, the demand for herbal drugs has been increasing because of their excellent properties. This review highlights antihypertensive drugs, polyphenols, and synbiotics for managing hypertension. Evidence is mounting in favour of more aggressive blood pressure control with lower adverse effects, especially for specific patient populations. This review aimed to present contemporary viewpoints and novel treatment options, including cutting-edge technological applications and emerging interventional and pharmaceutical therapies, as well as key concerns arising from several years of research and epidemiological observations related to the management of hypertension.
... A favourable pharmacodynamic (PD) profile would avoid inhibiting CYP11B1, CYP19A1 or CYP11B2 in a manner that compromises the adrenal stress response or gonadal sex hormone production or leads to excessive DOC production at doses that achieve maximal therapeutic inhibition of aldosterone synthesis; the pharmacokinetic (PK) profile should provide a dosedependent balanced pharmacology over 24 h with chronic oncedaily dosing. 16 Here, we report a phase 1 trial investigating DP13 as a CYP11B2 inhibitor in healthy male volunteers. The trial consisted of a singleascending dose study (part A) designed to select the dosing regimen for a multiple-ascending dose study (part B) to characterize the dosedependent safety, efficacy and selectivity profile of DP13. ...
Aims
High aldosterone is a key driver of hypertension and long‐term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants.
Methods
This randomized, double‐blind, placebo‐controlled study was conducted in two parts. In part A, a single‐ascending dose escalation, 16 participants received oral DP13 1–16 mg. Part B was a multiple‐ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing.
Results
DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone‐to‐renin ratio (ARR). Endocrine counter‐regulation resulted in the 4 mg dose no longer sustaining 24‐h aldosterone suppression after 8 days of treatment, unlike the 8‐ and 16 mg doses. There was no evidence of drug‐induced adrenal insufficiency (ACTH stress challenge).
Conclusions
In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone‐dependent hypertension and primary aldosteronism.
... The Schumacher et al. (2013) study investigated the safety and efficacy of LCI699 in hypertensive patients [15]. The findings demonstrated that the once daily and twice daily regimens of LCI699 effectively decreased plasma aldosterone levels and reduced both SBP and DBP in patients with essential HTN, although these benefits were not as pronounced in patients with primary hyperaldosteronism or resistant HTN. ...
... The Schumacher et al. (2013) study investigated the safety and efficacy of LCI699 in hypertensive patients [15]. The findings demonstrated that the once daily and twice daily regimens of LCI699 effectively decreased plasma aldosterone levels and reduced both SBP and DBP in patients with essential HTN, although these benefits were not as pronounced in patients with primary hyperaldosteronism or resistant HTN. ...
... In contrast, the MSSBP reduction from baseline for eplerenone at a dose of 50 mg twice was -18.7 mm Hg, while it was -8.8 mmHg for the placebo group. The Schumacher et al. (2013) study demonstrates that LCI699 was useful for lowering BP in patients with essential HTN, primary hyperaldosteronism or resistant HTN [15]. Given that high doses of spironolactone have been linked to endocrine side effects, LCI699 appears to produce better control of aldosterone and potassium and may therefore be a substitute or adjunct to spironolactone for conditions, such as primary hyperaldosteronism or liver cirrhosis. ...
Systemic hypertension (HTN) is the hallmark of cardiovascular disease and the forerunner of heart failure. These associations have been established over decades of research on essential HTN. Advancements in the treatment of patients diagnosed with HTN, consisting of alpha- or beta-adrenergic receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide, or aldosterone receptor blockers known as anti-mineralocorticoids, in the presence or absence of low sodium salt diets, often fail to control blood pressure adequately to prevent morbidity and mortality. Low sodium diets have had limited success in controlling HTN because low sodium intake is associated with renin-angiotensin-aldosterone system upregulation. Therefore, upregulating aldosterone secretion, sodium, and water retention which, in turn, moves the blood pressure back toward the range of HTN dictated by the baroreceptor reset value, as a compensatory mechanism, especially in resistant HTN. These impediments to blood pressure control in HTN may have been effectively circumvented by the advent of a new class of drugs known as aldosterone synthase inhibitors, represented by baxdrostat. The mechanism of action of baxdrostat as an aldosterone synthase inhibitor demonstrates the inextricable linkage between sodium and blood pressure regulation. Theoretically, combining a low sodium diet with the activity of this aldosterone synthesis inhibitor should alleviate the adverse effect of renin-angiotensin-aldosterone system upregulation. Aldosterone synthesis inhibition should also decrease the oxidative stress and endothelial dysfunction associated with HTN, causing more endothelial nitric oxide synthesis, release, and vasorelaxation. To the best of our knowledge, this is the first systematic review to summarize evidence-based articles relevant to the use of a novel drug (aldosterone synthase inhibitor) in the treatment of HTN and cardiovascular disease. Making the current database of relevant information on baxdrostat and other aldosterone synthase inhibitors readily available will, no doubt, aid physicians and other medical practitioners in their decision-making about employing aldosterone synthase inhibitors in the treatment of patients.
... As expected, the inhibition of aldosterone synthase by baxdrostat resulted in an increase in the aldosterone precursor 11-deoxycorticosterone under both normal-and lowsalt diet conditions. However, the magnitude of increase was modest (~2-to 3-fold) compared to what has previously been observed for LCI699, where 11-deoxycorticosterone levels increased up to 10-fold [24]. ...
Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.
... Additionally, higher doses led to an impaired cortisol production. These findings drove the repurposing of osilodrostat away from the treatment of hypertension and to the treatment of endogenous hypercortisolism [18]. ...
... Aldosterone and cortisol, the main mineralocorticoid and glucocorticoid hormone, are produced from cholesterol and share some of the same precursors (shown in Fig. 1). An enzyme 11β-hydroxylase (CYP11B1) catalyzes the last step in the synthesis of cortisol while CYP11B2, also known as aldosterone synthase, is responsible for the conversion of deoxycorticosterone to aldosterone (18). While osilodrostat inhibits both enzymes, it has a greater potency for inhibition of CYP11B1 [26], thereby reducing the synthesis of aldosterone and cortisol. ...
... While osilodrostat inhibits both enzymes, it has a greater potency for inhibition of CYP11B1 [26], thereby reducing the synthesis of aldosterone and cortisol. Low cortisol levels stimulate the HPA axis and ACTH from the pituitary which in the end stimulates steroidogenesis and the production of glucocorticoids, mineralocorticoids and adrenal androgens [18]. ...
Background:
Cushing disease is a very rare form of hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Clinical manifestations of Cushing disease can include central fat accumulation, arterial hypertension, glucose intolerance, skin atrophy with striae, and hypogonadism. Children are frequently diagnosed due to a growth stunt and excessive weight gain while classic cushingoid signs might be initially absent. Other children-specific presentations of Cushing disease are early or delayed puberty and hyperandrogenism in girls.
Summary:
We present the main outcomes of clinical trials of osilodrostat (Isturisa®, Recordati) for Cushing disease, and its initial development as an aldosterone synthase inhibitor. Osilodrostat is indicated only when the surgical therapy of the pituitary adenoma is not an option or has not been curative; additionally, other steroidogenesis inhibitors were briefly summarized. Clinical trials of osilodrostat in children are lacking and we describe its potential role in the pediatric population.
Key messages:
Osilodrostat is the first adrenal steroidogenesis inhibitor to be EMA- and FDA-approved (both in 2020) for the treatment of adults with Cushing syndrome/disease. Phase II and III clinical trials have shown its efficacy in normalizing 24-h urinary free cortisol and a good safety profile. Osilodrostat's pharmacological properties and safety are currently being evaluated in a small phase II trial (NCT03708900) - the first trial in the pediatric population (< 18 years) with an estimated completion date in the year 2023.
... Second, inhibitors of steroidogenic P450 enzymes tend to have fewer side effects on the endocrine system compared to steroidal antagonists (15). This approach is already being explored by laboratories in several pharmaceutical companies (16). Increasing our knowledge of P450 11B2-catalyzed reactions will support development of these and other mineralocorticoid-related therapies. ...
Human cytochrome P450 (P450) 11B2 catalyzes the formation of aldosterone, the major endogenous human mineralocorticoid. Aldosterone is important for the regulation of electrolyte homeostasis. Mutations and overexpression of P450 11B2 (also known as aldosterone synthase) can lead to hypertension, congestive heart failure, and diabetic nephropathy. The enzyme is therefore a target for drug development to manage these various disorders. P450 11B2 catalyzes aldosterone formation from 11-deoxycorticosterone through three distinct oxidation steps. It is currently unknown to which degree these reactions happen in sequence without the intermediate products dissociating from the enzyme (i.e., processively) or whether these reactions happen solely distributively, in which the intermediate products must first dissociate and then rebind to the enzyme before subsequent oxidation. We present here a comprehensive investigation of processivity in P450 11B2 catalyzed reactions using steady-state, pre-steady-state, pulse-chase, equilibrium binding titrations, and stopped-flow binding studies. We utilized the data obtained to develop a kinetic model for P450 11B2 and tested this model by enzyme kinetics simulations. We found that although aldosterone is produced processively, the enzyme preferentially utilizes a distributive mechanism that ends with the production of 18-OH corticosterone. This seemingly contradictory observation could be resolved by considering the ability of the intermediate product 18-OH corticosterone to exist as a lactol form, with the equilibrium favoring the ring-closed lactol configuration. In summary, our refined model for P450 11B2 catalysis indicates isomerization of the intermediate to a lactol can explain why P450 11B2 must produce aldosterone through a processive mechanism despite favoring a distributive mechanism.
... Osilodrostat (LCI699) is a novel aldosterone synthase (CYP11B2) inhibitor developed for the treatment of PA and essential hypertension [58][59][60]. However, an earlier proof-of concept study with patients suffering from PA reported 7-and 14-fold elevated 11-DOC levels after 0.5 mg and 1 mg of LCI699, respectively [59]. ...
... The other study [63] observed a trend towards decreased blood pressure; however, as antihypertensive medication was not restricted, a medication bias cannot be excluded. Further, four phase II studies in patients with different forms of hypertension revealed astonishing results: Lower doses of LCI699 reduced and higher doses increased blood pressure [60]. The authors interpreted the latter result by the supra-physiological 11-DOC concentrations. ...
Patients with uncontrolled hypertension are at risk for cardiovascular complications. The majority of them suffers from unidentified forms of hypertension and a fraction has so-called secondary hypertension with an identifiable cause. The patient's medications, its use of certain herbal supplements and over-the-counter agents represent potential causal factors for secondary hypertension that are often overlooked. The current review focuses on drugs that are likely to elevate blood pressure by affecting the human endocrine system at the level of steroid synthesis or metabolism, mineralocorticoid receptor activity, or by affecting the catecholaminergic system. Drugs with known adverse effects but where benefits outweigh their risks, drug candidates and market withdrawals are reviewed. Finally, potential therapeutic strategies are discussed.
... У цьому відношенні вибір препарату з групи блокаторів кальцієвих каналів (БКК) для нормалізації АТ у хворих на ГХ у поєднанні з ВХДК є обґрунтованим і найбільш корисним [7,8]. ...
... LCI699, on the other hand, was reported to show attenuated secretion of cortisol in cosyntropin stimulation in dose-and time-dependent manner in following studies. 96,97 Relatively high dosage of LCI699 (more than 2 mg/day) has been considered to cause hypocortisolism and concomitant feedback activation of HPA axis because of its inhibitory effect on CYP11B1. Subsequently, Amar et al. reported that high dosage of eplerenone (100-200 mg/day) showed better clinical profiles of blood pressure and potassium metabolism, when compared to relatively low dosage of LCI699 (1-2 mg/day) by sequential administration of these 2 agents. ...
Primary aldosteronism (PA) is now considered as one of leading causes of secondary hypertension, accounting for 5-10% of all hypertensive patients and more strikingly 20% of those with resistant hypertension. Importantly, those with the unilateral disease could be surgically cured when diagnosed appropriately. On the other hand, only a very limited portion of those suspected to have PA has been screened, diagnosed, or treated to date. With current advancement in medical technologies and genetic research, expanding knowledge of PA has been accumulated and recent achievements have also been documented in the care of those with PA. This review is aimed to have focused description on updated topics of the following; importance of PA screening both in the general and specialized settings and careful interpretation of screening data, recent achievements in hormone assays and sampling methods and their clinical relevance, and expanding knowledge on PA genetics. Improvement in workup processes and novel treatment options, as well as better understanding of the PA pathogenesis based on genetic research, might be expected to result in increased cure and better care of the patients.
... Следующее поколение ИАС должно снижать уровень АЛ в крови, подавляя фермент, отвечающий за его синтез, -АС. Новые ингибиторы АС будут не только эффективно снижать АД, но и предотвращать развитие неблагоприятных последствий, продлевая жизнь пациентов и способствуя снижению высокого уровня общей смертности от данной патологии [73][74][75][76][77][78][79][80]. ...
В огляді надані дані зарубіжної та вітчизняної літератури щодо патогенетичної ролі альдостерону, рівнів альдостеронсинтази і поліморфізмів гена даного ферменту у хворих на різні форми артеріальної гіпертензії, при асоційованих з нею захворюваннях серця і судин, фібриляції передсердь, метаболічному синдромі, патології нирок, головного мозку. Розглядаються функції альдостерону, рівнів альдостеронсинтази і поліморфізмів гена даного ферменту в серцево-судинному ремоделюванні, можливості застосування даних маркерів для диференційно-діагностичних цілей, перспективи терапевтичного використання інгібіторів альдостеронсинтази серед різних категорій хворих з ознаками артеріальної гіпертензії.
