Spironolactone

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Not to be confused with spirolactone.
Spironolactone (INN, BAN, USAN)[1]
Skeletal formula of spironolactone
Ball-and-stick model of the spironolactone molecule
Systematic (IUPAC) name
7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone
Clinical data
Pronunciation /spɪˌrɒnoʊˈlæktoʊn/[3]
Trade names Aldactone
AHFS/Drugs.com monograph
MedlinePlus a682627
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral[2]
Pharmacokinetic data
Protein binding 90%+[4]
Metabolism Hepatic CYP450
Biological half-life 1.3-2 hours
Excretion Urine, bile
Identifiers
CAS Number 52-01-7 YesY
ATC code C03DA01 (WHO)
PubChem CID: 5833
IUPHAR/BPS 2875
DrugBank DB00421 YesY
ChemSpider 5628 YesY
UNII 27O7W4T232 YesY
KEGG D00443 YesY
ChEBI CHEBI:9241 YesY
ChEMBL CHEMBL1393 YesY
Chemical data
Formula C24H32O4S
Molecular mass 416.574 g/mol
  • O=C5O[C@@]4([C@@]3([C@H]([C@@H]2[C@H](SC(=O)C)C/C1=C/C(=O)CC[C@]1(C)[C@H]2CC3)CC4)C)CC5
  • InChI=1S/C24H32O4S/c1-14(25)29-19-13-15-12-16(26)4-8-22(15,2)17-5-9-23(3)18(21(17)19)6-10-24(23)11-7-20(27)28-24/h12,17-19,21H,4-11,13H2,1-3H3/t17-,18-,19+,21+,22-,23-,24+/m0/s1 YesY
  • Key:LXMSZDCAJNLERA-ZHYRCANASA-N YesY
  (verify)

Spironolactone, marketed under the brand name Aldactone among others, is a medication primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease.[2] Other uses include high blood pressure, low blood potassium that does not improve with supplementation, early puberty, excessive hair growth in women,[2] and as a component of hormone replacement therapy for trans women.[5] It is taken by mouth.[2]

Common side effects include electrolyte abnormalities particularly high blood potassium, nausea, vomiting, headache, a rash, and a decreased desire for sex. In those with liver or kidney problems extra care should be taken.[2] Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy.[6] It is a steroid that blocks mineralocorticoid receptors. It also blocks androgen, and blocks progesterone. It belongs to a class of medications known as potassium-sparing diuretics.[2]

Spironolactone was introduced in 1959.[7][8] It is on the World Health Organization's List of Essential Medicines, the most important medication needed in a basic health system.[9] It is available as a generic medication.[2] The wholesale cost as of 2014 is between 0.02 and 0.12 USD per day.[10] In the United States it costs about 0.50 USD per day.[2]

Medical uses

Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism). On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy.

Spironolactone is an antagonist of the androgen receptor (AR) as well as an inhibitor of androgen production. Due to the antiandrogenic effects that result from these actions, it is frequently used off-label to treat a variety of dermatological conditions in which androgens, such as testosterone and dihydrotestosterone (DHT), play a role. Some of these uses include androgenic alopecia in men (either at low doses or as a topical formulation) and women, and hirsutism, acne, and seborrhea in women.[11] Spironolactone is the most commonly used drug in the treatment of hirsutism in the United States.[12] Higher doses of spironolactone are not recommended in males due to the high risk of feminization and other side effects. Similarly, it is also commonly used to treat symptoms of hyperandrogenism in polycystic ovary syndrome.[13]

High blood pressure

About one person in one hundred with hypertension has elevated levels of aldosterone; in these persons, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure.[14] There is no evidence of person oriented outcome at any dose in this group.[14]

Heart failure

While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of <35%.[15]

In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant Death and morbidity benefit of the drug. Patients in the study's intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently.[16] Likewise, it has shown benefit for and is recommended in patients who recently suffered a heart attack and have an ejection fraction <40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers.[17] Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.[18]

It is recommended that alternatives to spironolactone be considered if serum creatinine is >2.5 mg/dL (221µmol/L) in males or >2 mg/dL (176.8 µmol/L) in females, if glomerular filtration rate is below 30mL/min or with a serum potassium of >5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of renal function as well.[15]

According to systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone.[19]

Due to its antiandrogen properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer drug, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogen effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related drug canrenone in reducing mortality from heart failure.[20]

The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.

Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly cardiac arrythmias.

Acne in women

Because of spironolactone's antiandrogen effects, it can be quite effective in clearing severe acne conditions, such as cystic acne, caused by slightly elevated or elevated levels of testosterone in women. In reducing the levels of testosterone, excess oil that is naturally produced in the skin is also reduced. Though not the primary intended purpose of the medication, its ability to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. A significant number of patients have reported that they have seen positive results in the pairing of these two medications, although these results may not be seen for up to three months.

Hormone replacement therapy for trans women

Spironolactone is frequently used as a component of hormone replacement therapy in trans women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. It is generally recommended to be prescribed at a dose of 100–200 mg per day for this purpose,[21][22] though it is frequently used at doses up to 300–400 mg in cases of treatment-resistant individuals, and doses as high as 600 mg have been used in some clinical studies, with additional benefits from the extreme dosage observed in some patients.[23] Spironolactone significantly depresses plasma testosterone levels, reducing them to female/castrate levels at sufficient doses and in combination with estrogen. The clinical response consists of, among other effects, decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections.[23]

Comparison with other antiandrogens

There are few available options for antiandrogen therapy. Spironolactone, cyproterone acetate, and flutamide are some of the most well-known and widely used drugs.[24] Compared to cyproterone acetate, spironolactone is considerably less potent as an antiandrogen by weight and binding affinity to the androgen receptor.[25][26] However, despite this, at the doses of which they are typically used, spironolactone and cyproterone acetate have been found to be generally about equivalent in terms of effectiveness for a variety of androgen-related conditions,[27] though, cyproterone acetate has shown a slight though non-statistically-significant advantage in some studies.[28][29] Also, it has been suggested that cyproterone acetate could be more effective in cases where androgen levels are more pronounced, though this has not been proven.[27]

Flutamide, another frequently used antiandrogen which is non-steroidal and a pure androgen receptor antagonist, though much less potent by weight and binding affinity than either spironolactone or cyproterone acetate,[30][31] has been found to be more effective than either of them as an antiandrogen when it is used at the typical treatment doses.[25][32][33] Unfortunately, the uses of both cyproterone acetate and flutamide have been associated with hepatotoxicity, which can be severe with flutamide and has resulted in the withdrawal of cyproterone acetate from the United States drug market for this indication. Bicalutamide is a more potent, safer, and more tolerable alternative to flutamide, but is relatively little-studied in the treatment of androgen-dependent conditions aside from prostate cancer, though it has been used to treat hirsutism with success. Gonadotropin-releasing hormone (GnRH) analogues are another very effective option for antiandrogen therapy, but have not been widely employed for this purpose due to their high cost and limited insurance coverage despite many now being available as generics.[22] As such, spironolactone may be the only practical, safe, available, and well-supported antiandrogen option in some cases.

In a study of the predictive markers for trans women requesting breast augmentation, there was a significantly higher rate of those treated with spironolactone requesting breast augmentation compared to other antiandrogens such as cyproterone acetate or GnRH analogues, which was interpreted by the study authors as being potentially indicative that spironolactone may result in poorer breast development in comparison.[34] This may be related to the fact that spironolactone has been regarded as a comparatively weak antiandrogen relative to other options.[35]

Side effects

The most common side effect of spironolactone is urinary frequency. Other general side effects include ataxia, drowsiness, dry skin, and rashes. Because it reduces androgen levels and blocks androgen receptors, spironolactone can, in males, cause breast tenderness, gynecomastia, and physical feminization in general, as well as testicular atrophy, reversible infertility, and sexual dysfunction, including loss of libido and erectile dysfunction.[36] In females, spironolactone can cause menstrual irregularities and breast tenderness and enlargement, likely due to a combination of its progestogenic and indirect estrogenic actions.[11]

The most important potential side effect of spironolactone is hyperkalemia, which, in severe cases, can be life-threatening. Spironolactone may put patients at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the drug and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established.[37] Also, it has been shown to be immunosuppressive in the treatment of sarcoidosis.[38]

Spironolactone may rarely cause more severe side effects such as anaphylaxis, renal failure, hepatotoxicity, agranulocytosis, DRESS syndrome, Stevens-Johnson Syndrome or toxic epidermal necrolysis.[39][40] It should also be used with caution in people with some neurological disorders, anuria, acute kidney injury, or significant impairment of renal excretory function with risk of hyperkalemia.[41]

Depression

Increased glucocorticoid activity, whether from inside or outside the body, is associated with depression.[42][43] As such, it is thought that there may be a risk of depression with spironolactone treatment.[42][44][45] Some clinical research supports this contention.[34][46][47]

Interactions

Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this drug avoid potassium supplements and salt substitutes containing potassium.[48] Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne.[49]

Research has suggested that spironolactone may be able to interfere with the effectiveness of antidepressant treatment. As the drug acts as an antagonist of the mineralocorticoid receptor, it is thought that it may reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic-pituitary-adrenal axis and increasing glucocorticoid levels.[50][51] However, other research contradicts this hypothesis and has suggested that spironolactone may actually produce antidepressant-like effects in animals.[52]

Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications.[41]

Pregnancy and breastfeeding

Spironolactone is considered Pregnancy Category C meaning that it is unclear if it is safe for use during pregnancy.[2] Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breast-feeding infants, it is generally recommended that women also not take the drug while nursing.[41]

Pharmacology

Activity profile

Spironolactone is known to possess the following pharmacological activity:[53]

There is also evidence that spironolactone may block voltage-dependent Ca2+ channels.[58][59]

Spironolactone does not have significant affinity for either of the estrogen receptors (ERα or ERβ).

Antimineralocorticoidic

Spironolactone inhibits the effects of mineralocorticoids, namely, aldosterone, by displacing them from mineralocorticoid receptors (MR) in the cortical collecting duct of renal nephrons. This decreases the reabsorption of sodium and water, while limiting the excretion of potassium (A K+ sparing diuretic). The drug has a slightly delayed onset of action, and so it takes several days for diuresis to occur. This is because the MR is a nuclear receptor which works through regulating gene transcription and gene expression, in this case to decrease the production and expression of ENaC and ROMK electrolyte channels in the distal nephrons. In addition to direct antagonism of the MRs, the antimineralocorticoid effects of spironolactone may also in part be mediated by direct inactivation of steroid 11β-hydroxylase and aldosterone synthase (18-hydroxylase), enzymes involved in the biosynthesis of mineralocorticoids. If levels of mineralocorticoids are decreased then there are lower circulating levels to compete with spironolactone to influence gene expression as mentioned above.[60]

Glucocorticoidic

Spironolactone has been shown to inhibit steroid 11β-hydroxylase, an enzyme that is essential for the production of the glucocorticoid hormone cortisol. Because of this, glucocorticoid levels might be expected to be lowered, and hence, spironolactone might have some antiglucocorticoidic effects. In clinical practice however, this has not been found to be the case; spironolactone has actually been found to increase cortisol levels, both with acute and chronic administration. Research has shown that this is due to antagonism of the MR, which suppresses negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis positively regulates the secretion of adrenocorticotropic hormone (ACTH), which in turn signals the adrenal glands, the major source of corticosteroid biosynthesis in the body, to increase production of both mineralocorticoids and glucocorticoids. Therefore, by antagonizing the MR, spironolactone causes an increase in ACTH secretion and by extension an indirect rise in cortisol levels.[61][62] As such, any antiglucocorticoid activity of spironolactone via direct suppression of glucocorticoid synthesis (at the level of the adrenals) appears to be more than fully offset by its concurrent indirect stimulatory effects on glucocorticoid production.

Spironolactone weakly binds to and acts as an antagonist of the GR, showing antiglucocorticoid properties, but only at very high concentrations.[53][63][64]

Antiandrogenic

Spironolactone mediates its antiandrogenic effects via multiple actions, including the following:

  • Direct blockade of androgens from interacting with the androgen receptor.[65][66] It should be noted however that spironolactone, similarly to other steroidal antiandrogens such as cyproterone acetate, is not a pure, or silent, antagonist of the androgen receptor, but rather a weak partial agonist with the capacity for both agonist and antagonist effects.[67][68][69] However, in the presence of significant enough levels of potent full agonists like testosterone and DHT,[69] the cases in which it is usually used even with regards to the "lower" relative levels present in females, spironolactone will behave similar to a pure antagonist. Nonetheless, there may still be a potential for spironolactone to produce androgenic effects (i.e. act as a receptor agonist) in the body at sufficiently high doses and/or in those with low enough endogenous androgen concentrations. As an example, one condition in which spironolactone is contraindicated is prostate cancer,[70] as the drug has been shown in vitro to significantly accelerate carcinoma growth in the absence of any other androgens, and was found to do so at the relatively high rate of approximately 32%, which was about 35% that of DHT (thus also indicating that its potential intrinsic activity at the androgen receptor may be somewhere around one-third that of endogenous full agonists).[67] In accordance, a case report described significant worsening of prostate cancer with spironolactone treatment in a patient with the disease, leading the authors to conclude that spironolactone has the potential for androgenic effects and that it should perhaps be considered to be a selective androgen receptor modulator (SARM).[71]
  • Inhibition of 17α-hydroxylase and 17,20-desmolase, enzymes in the androgen biosynthesis pathway, which in turn results in decreased testosterone and dihydrotestosterone (DHT) levels.[66][72][73][74] Though, its inhibition of these enzymes is said to be relatively weak.[31]
  • Activation of the progesterone receptor, as, in sufficient amounts, this results in an antigonadotropic effect due to negative feedback on the hypothalamic-pituitary-gonadal axis, which in turn reduces sex steroid production and by extension androgen levels.
  • Inhibition of 5α-reductase, the enzyme responsible for converting testosterone into the 3- to 10-fold more potent androgen dihydrotestosterone (DHT). However, there is conflicting data on the ability of spironolactone to affect this enzyme. An in vitro study of the effect of spironolactone on prostate tissue 5α-reductase activity found no change even with very high concentrations of the drug.[65] In contrast, another study, after one month of treatment of spironolactone at a dose of 100 mg per day via the oral route, found a significant in vivo inhibitory effect of spironolactone on genital skin 5α-reductase activity in hirsute women as well as an inhibitory effect of the drug on 5α-reductase activity in normal genital skin in vitro, and concluded that spironolactone directly inhibits the 5α-reductase enzyme and that the property could play a role of the beneficial effects of the drug on hirsutism.[75] However, another study of spironolactone in hirsute women, after 6 months of treatment at the same dose (100 mg/d orally), found no significant effects of the drug on the serum ratios of testosterone to DHT and its metabolites—a reliable marker of 5α-reductase activity—whereas significant changes were found with 5 mg per day oral finasteride, a well-established 5α-reductase inhibitor.[76] Finally, yet another study of spironolactone in hirsute women, after 3 months of treatment at a higher dose of 200 mg per day orally, did report significant changes, in the same metabolic markers of 5α-reductase activity.[77] In summation then, whether spironolactone actually inhibits 5α-reductase to some clinical end-point or not and how it may do so remain unclear. It can be deduced from comparison studies, however, that if it does have an effect at reducing hirsutism, it is not as effective as more potent and selective 5α-reductase inhibitors like finasteride. Supporting this conclusion is another trial in which the combination of 100 mg/d spironolactone and 5 mg/d finasteride was found to be significantly more effective than spironolactone alone in the treatment of hirsutism in women.[78]
  • Acceleration of the rate of metabolism/clearance of testosterone by enhancing the rate of peripheral conversion of testosterone into estradiol.[73]

Progestogenic

Spironolactone has weak progestogenic properties.[31][79] Its actions in this regard are a result of direct agonist activity at the progesterone receptor, but with a half-maximal potency approximately one-tenth that of its activity at the androgen receptor.[53] Spironolactone's progestogenic actions are thought to be responsible for some of its side effects,[80] including the menstrual irregularities seen in women and the undesirable serum lipid profile changes that are seen at higher doses.[30][81][82] They may also serve to augment the gynecomastia caused by the estrogenic effects of spironolactone,[83] as progesterone is known to play a role in breast development.[84]

Estrogenic

Spironolactone has some indirect estrogenic effects which it mediates via several actions, including the following:

  • By acting as an antiandrogen, as androgens suppress both estrogen production and action.[66][85]
  • Displacement of estrogens from sex hormone-binding globulin (SHBG).[72] This occurs because spironolactone binds to SHBG at a relatively high rate, as do endogenous estrogens and androgens, but estrogens like estradiol and estrone are more easily displaced than are androgens like testosterone. As a result, spironolactone blocks relatively more estrogens from interacting with SHBG than androgens, resulting in a higher ratio of free estrogens to free androgens.[86]
  • Inhibition of the conversion of estradiol to estrone, resulting in an increase in the ratio of estradiol to estrone.[87] This is important because estradiol is approximately 10 times as potent as estrone as an estrogen.[88]
  • Enhancement of the rate of peripheral conversion of testosterone to estradiol, thus further lowering testosterone levels and increasing estradiol levels.[73]

Pharmacokinetics

Spironolactone has a very short half-life.[80] It is rapidly and extensively converted (>80%) into canrenone/canrenoic acid,[89][90] and canrenone is its major circulating metabolite.[91] Canrenone is an antagonist of the MR similarly to spironolactone,[89] but is more potent in comparison.[92] In addition, canrenone inhibits steroidogenic enzymes such as 11β-hydroxylase, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase similarly to spironolactone, but once again is more potent in doing so in comparison.[91] Based on the above, the antimineralocorticoid effects of spironolactone are considered to be largely due to canrenone.[89]

In vitro, canrenone binds to and blocks the androgen receptor (AR).[66] However, relative to spironolactone, canrenone is described as having very weak affinity to the androgen receptor.[35] In accordance, replacement of spironolactone with canrenone in male patients has been found to reverse spironolactone-induced gynecomastia, suggesting that canrenone is comparatively much less potent in vivo as an antiandrogen.[66] As such, based on the above, the antiandrogen effects of spironolactone are considered to be largely due to its unchanged form, rather than due to metabolization into canrenone, or possibly due to other metabolites.[66][90][93]

Canrenone and 7α-methylthiospironolactone have been determined to be the major hepatic metabolites of spironolactone.[94][95] More recently however, it has been suggested that 7α-methylthiospironolactone may actually be the most important active metabolite of spironolactone.[95] It occurs at higher plasma levels than canrenone, and has a higher affinity for the MR.[95] 7α-Methylthiospironolactone has been relatively little-studied, and relatively little overall is known about it.[94] Other known metabolites of spironolactone include 7α-thiospironolactone, 6β-hydroxy-7α-methylthiospironolactone, the 7α-methyl ethyl ester of spironolactone, and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.[96]

Spironolactone has an onset of action of about 2–3 hours after taking the first dose, with a half-life of about 1–2 hours.[citation needed] It is highly plasma protein bound. Spironolactone is metabolized by the liver, from which it is partially eliminated with the majority being handled by the kidneys. Minimal amounts are handled by biliary excretion.[4] The bioavailability of spironolactone improves significantly when it is taken with food.[97][98]

Spironolactone induces the enzyme CYP3A4, which can result in interactions with various drugs.[99] It is not metabolized by CYP3A4, unlike the related drug eplerenone.[100]

Spironolactone bodies

File:Spironolactone bodies.png
Micrograph of an adrenal gland spironolactone bodies. H&E stain.

Long-term administration of spironolactone gives the histologic characteristic of spironolactone bodies in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin.[101]

See also

References

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  50. ↑ Holsboer, F. The Rationale for Corticotropin-Releasing Hormone Receptor (CRH-R) Antagonists to Treat Depression and Anxiety. J. Psychiatr. Res. 33, 181–214 (1999).
  51. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  52. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  53. ↑ 53.0 53.1 53.2 Lua error in package.lua at line 80: module 'strict' not found.
  54. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  55. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  56. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  57. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  58. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  59. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  60. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  61. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  62. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  63. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  64. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  65. ↑ 65.0 65.1 Lua error in package.lua at line 80: module 'strict' not found.
  66. ↑ 66.0 66.1 66.2 66.3 66.4 66.5 Lua error in package.lua at line 80: module 'strict' not found.
  67. ↑ 67.0 67.1 Lua error in package.lua at line 80: module 'strict' not found.
  68. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  69. ↑ 69.0 69.1 Lua error in package.lua at line 80: module 'strict' not found.
  70. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  71. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  72. ↑ 72.0 72.1 Lua error in package.lua at line 80: module 'strict' not found.
  73. ↑ 73.0 73.1 73.2 Lua error in package.lua at line 80: module 'strict' not found.
  74. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  75. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  76. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  77. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  78. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  79. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  80. ↑ 80.0 80.1 Lua error in package.lua at line 80: module 'strict' not found.
  81. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  82. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  83. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  84. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  85. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  86. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  87. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  88. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  89. ↑ 89.0 89.1 89.2 Lua error in package.lua at line 80: module 'strict' not found.
  90. ↑ 90.0 90.1 Lua error in package.lua at line 80: module 'strict' not found.
  91. ↑ 91.0 91.1 Lua error in package.lua at line 80: module 'strict' not found.
  92. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  93. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  94. ↑ 94.0 94.1 Lua error in package.lua at line 80: module 'strict' not found.
  95. ↑ 95.0 95.1 95.2 Lua error in package.lua at line 80: module 'strict' not found.
  96. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  97. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  98. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  99. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  100. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  101. ↑ Lua error in package.lua at line 80: module 'strict' not found.

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