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Seizure Dec 2018The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary... (Review)
Review
The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary metabolite allopregnanolone (ALLO), with less attention being paid to its primary metabolite 5a-dihydroprogesterone (DHP). Here we review animal and clinical studies related to the anti-seizure effects of progesterone and its 5a neuroactive metabolites, including DHP and ALLO. Progesterone and its reduced metabolites all have demonstrated seizure-suppression effects in animal models - except in models of absence seizures - with the common side effects of sedation and ataxia. Progesterone and ALLO have also shown anti-seizure effects in clinical trials. A large Phase III trial has revealed that female patients with premenstrual exacerbations of seizures benefit most from progesterone therapy. A liquid suspension of ALLO has also been tested in patients with supra-refractory status epilepticus with some success in a small phase II trial. ALLO's C3 methyl analog ganaxolone is under development as an anti-seizure drug. Progesterone's anti-seizure effects are mostly independent of its genomic receptors and are, in large part, due to its active metabolites. ALLO is a potent allosteric modulator of GABA receptors. Other membrane receptors are thought to be involved in the DHP's anti-seizure actions, but their exact nature is not yet known. Potential drawbacks to the development of progesterone family compounds as anti-seizure drug are their endocrine effects. These compounds might form a basis for the future development of novel anti-seizure drugs, however, with hormonal side effects being mitigated through rational drug design.
Topics: 20-alpha-Dihydroprogesterone; Animals; Anticonvulsants; Humans; Pregnanolone; Progesterone; Seizures
PubMed: 30391663
DOI: 10.1016/j.seizure.2018.10.012 -
JAMA Cardiology Aug 2016Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing... (Review)
Review
IMPORTANCE
Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing proportions. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have proved valuable additions to the overall management of these disorders in patients without significant renal dysfunction.
OBSERVATIONS
Neurohormonal activation, including aldosteronism, in HF and RHT, has provided the pathophysiologic basis for the inclusion of MRA in the overall management of these disorders and the respective survival benefit and control of blood pressure. Furthermore, MRAs attenuate the appearance of secondary hyperparathyroidism that accompanies excretory Ca2+ losses induced by aldosteronism in which elevated parathyroid hormone levels raise the risk of adverse cardiovascular events and atraumatic bone fracture. Serial surveillance of serum electrolytes and creatinine levels is mandated to avoid serious hyperkalemia (potassium concentration >5.5 mEq/L) and its attendant risks in patients receiving MRAs.
CONCLUSIONS AND RELEVANCE
Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.
Topics: Eplerenone; Heart Failure; Humans; Hyperkalemia; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone; Ventricular Dysfunction, Left
PubMed: 27434136
DOI: 10.1001/jamacardio.2016.1878 -
Pediatric Research Nov 2023Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function...
BACKGROUND
Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation.
METHODS
Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age.
RESULTS
Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7.
CONCLUSION
Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD.
IMPACT
Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.
Topics: Infant; Female; Infant, Newborn; Humans; Glucocorticoids; Infant, Premature; Hydrocortisone; Cortisone; Premature Birth; Bronchopulmonary Dysplasia; Cortodoxone; Inflammation
PubMed: 37355738
DOI: 10.1038/s41390-023-02690-3 -
International Journal of Cardiology Dec 2015The renin-angiotensin-aldosterone system can be blocked at specific levels by using different classes of pharmacologic agents, including angiotensin-converting-enzyme... (Review)
Review
The renin-angiotensin-aldosterone system can be blocked at specific levels by using different classes of pharmacologic agents, including angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers and mineralocorticoid receptor antagonists. Broad use of the latter, such as spironolactone, has been limited by significant incidence of gynecomastia and other sex-related adverse effects. These problems can be overcome with use of eplerenone, a selective mineralocorticoid receptor antagonist. Eplerenone has been specifically developed to bind selectively to the mineralocorticoid receptors in order to minimize binding to the progesterone and androgen receptors. In the last decade, multiple scientific evidences have been accumulated showing the efficacy and safety of the drug in multiple clinical conditions, including heart failure and arterial hypertension. Eplerenone is generally well tolerated, with the most frequent adverse event being hyperkalemia, with sexual adverse events (i.e. gynecomastia) being more uncommon, due to the selectivity of eplerenone. This review focuses on the pharmacodynamic and pharmacokinetic properties of eplerenone, thus providing the scientific basis to fully understand drug-to-drug interactions, in particular, and its efficacy and tolerability, in general. Noteworthy, the activity of eplerenone in special conditions and different patient populations is summarized.
Topics: Drug Interactions; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Renin-Angiotensin System; Spironolactone
PubMed: 26404746
DOI: 10.1016/j.ijcard.2015.02.096 -
JAMA Internal Medicine Oct 2023
Topics: Humans; Hydrocortisone; Fludrocortisone; Anti-Inflammatory Agents; Drug Therapy, Combination
PubMed: 37669033
DOI: 10.1001/jamainternmed.2023.4375 -
International Journal of Molecular... May 2021Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the... (Review)
Review
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
Topics: Adaptation, Physiological; Animals; Antidepressive Agents; Chronic Disease; Corticosterone; Depressive Disorder, Major; Feedback, Physiological; Female; GABA-A Receptor Agonists; Humans; Hypothalamo-Hypophyseal System; Male; Models, Biological; Pituitary-Adrenal System; Pregnanolone; Receptors, GABA-A; Sex Characteristics; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological; gamma-Aminobutyric Acid
PubMed: 34071053
DOI: 10.3390/ijms22115495 -
The American Journal of Medicine Mar 2023
Topics: Humans; Hydrocortisone; Prednisolone; Kidney Transplantation
PubMed: 36356917
DOI: 10.1016/j.amjmed.2022.10.009 -
Current Hypertension Reports Mar 2019To review comparative efficacy and tolerability data between the two main mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, in patients with... (Review)
Review
PURPOSE OF REVIEW
To review comparative efficacy and tolerability data between the two main mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, in patients with resistant hypertension (HTN). The focus was whether spironolactone, being the classical non-selective agent that has been used for years, albeit with several anti-androgenic side effects, can be rivaled by eplerenone, an apparently weaker, but better tolerated, more selective MRA.
RECENT FINDINGS
Evidence has accumulated that resistant HTN is generally volume-dependent, attributable to varying degrees of aldosterone excess with its attendant renal effects of sodium and fluid retention. Such aldosteronism may be due to an underestimated occurrence of primary aldosteronism; however, it more commonly occurs separately from it and independent from angiotensin II. The aldosterone-induced volume excess placed at the root of the development of resistant HTN in a large number of patients, together with the extrarenal deleterious effects of aldosterone, such as endothelial dysfunction, vascular remodeling and increased arterial stiffness, cardiac hypertrophy, and fibrosis can all be counterbalanced by the administration of MRAs. In the absence of a direct comparison between spironolactone and eplerenone, and in light of compelling evidence provided by the recently reported results of the PATHWAY-2 and ReHOT studies, spironolactone has been established as the most effective add-on anti-aldosterone therapy in resistant HTN. The data on use of eplerenone continue to emerge and are quite encouraging. Despite the lack of direct comparative data, the weight of evidence regarding efficacy is currently in favor of spironolactone. However, the data on the efficacy of eplerenone are promising but still being accumulated suggesting this agent as an alternative to spironolactone and certainly as the preferred choice for those not tolerating spironolactone, especially for patients developing anti-androgenic side effects like breast tenderness, gynecomastia/mastodynia, and/or sexual dysfunction. Both these agents appear to have several other pleiotropic effects that confer cardioprotection and renoprotection beyond their antihypertensive effect. Potassium levels and renal function need to be closely monitored during administration of these therapies. Future comparative studies may shed more light on these issues, while emerging newer agents may offer better and safer therapeutic options.
Topics: Aldosterone; Antihypertensive Agents; Eplerenone; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Spironolactone
PubMed: 30826898
DOI: 10.1007/s11906-019-0924-0 -
Sovremennye Tekhnologii V Meditsine 2021This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the... (Review)
Review
This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered.
Topics: Medroxyprogesterone; Medroxyprogesterone Acetate; Megestrol; Progesterone; Progestins
PubMed: 34513071
DOI: 10.17691/stm2021.13.1.11 -
The Journal of Neuroscience : the... Mar 2021NMDARs are ligand-gated ion channels that cause an influx of Na and Ca into postsynaptic neurons. The resulting intracellular Ca transient triggers synaptic plasticity....
NMDARs are ligand-gated ion channels that cause an influx of Na and Ca into postsynaptic neurons. The resulting intracellular Ca transient triggers synaptic plasticity. When prolonged, it may induce excitotoxicity, but it may also activate negative feedback to control the activity of NMDARs. Here, we report that a transient rise in intracellular Ca (Ca challenge) increases the sensitivity of NMDARs but not AMPARs/kainate receptors to the endogenous inhibitory neurosteroid 20-oxo-5β-pregnan-3α-yl 3-sulfate and to its synthetic analogs, such as 20-oxo-5β-pregnan-3α-yl 3-hemipimelate (PAhPim). In cultured hippocampal neurons, 30 μm PAhPim had virtually no effect on NMDAR responses; however, following the Ca challenge, it inhibited the responses by 62%; similarly, the Ca challenge induced a 3.7-fold decrease in the steroid IC on recombinant GluN1/GluN2B receptors. The increase in the NMDAR sensitivity to PAhPim was dependent on three cysteines (C849, C854, and C871) located in the carboxy-terminal domain of the GluN2B subunit, previously identified to be palmitoylated (Hayashi et al., 2009). Our experiments suggested that the Ca challenge induced receptor depalmitoylation, and single-channel analysis revealed that this was accompanied by a 55% reduction in the probability of channel opening. Results of modeling indicate that receptor palmitoylation promotes anchoring of the GluN2B subunit carboxy-terminal domain to the plasma membrane and facilitates channel opening. Depalmitoylation-induced changes in the NMDAR pharmacology explain the neuroprotective effect of PAhPim on NMDA-induced excitotoxicity. We propose that palmitoylation-dependent changes in the NMDAR sensitivity to steroids serve as an acute endogenous mechanism that controls NMDAR activity. There is considerable interest in negative allosteric modulators of NMDARs that could compensate for receptor overactivation by glutamate or gain-of-function mutations in neurodevelopmental disorders. By a combination of electrophysiological, pharmacological, and computational techniques we describe a novel feedback mechanism regulating NMDAR activity. We find that a transient rise in intracellular Ca increases NMDAR sensitivity to inhibitory neurosteroids in a process dependent on GluN2B subunit depalmitoylation. These results improve our understanding of the molecular mechanisms of steroid action at the NMDAR and indeed of the basic properties of this important glutamate-gated ion channel and may aid in the development of therapeutics for treating neurologic and psychiatric diseases related to overactivation of NMDARs without affecting normal physiological functions.
Topics: Animals; HEK293 Cells; Hippocampus; Humans; Lipoylation; Male; Neuroprotection; Pregnanes; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate
PubMed: 33526476
DOI: 10.1523/JNEUROSCI.2654-20.2021