Synthetic mineralocorticoid

低钠血症是小细胞肺癌（SCLC）患者常见的电解质异常。低钠血症通常无症状，可能会导致恶心、疲劳、定向障碍、头痛、肌肉痉挛甚至癫痫发作等症状，特别是在血清钠水平严重快速下降的情况下。在这里，我们报告了一例小细胞肺癌患者，他患有严重的低钠血症和急性神经系统症状，在第一疗程的二线化疗后2天出现，很可能是由于在肿瘤细胞裂解过程中释放了抗利尿激素（ADH，也称为精氨酸加压素）。最初的治疗包括持续服用高渗盐水，从而改善了患者的神经状态。然而，为了使血清钠水平持续升高，需要口服0.1mg氟屈可的松进行药理学干预，每天两次。因此，我们可以得出结论，在适当的时候，盐皮质激素可用于纠正小细胞肺癌患者的低钠血症[1]。

Thirty patients with SAH were randomized and divided into two groups: controls (Group 1, 15 patients) and patients treated with 0.3 mg/day of fludrocortisone (Group 2, 15 patients). In all patients sodium and fluid intake levels were in excess of maintenance requirements in an attempt to maintain a positive water balance and a central venous pressure (CVP) of 8 to 12 cm H2O. The mean sodium and water intake levels for 14 days after SAH were significantly reduced by fludrocortisone in Group 2 (487+/-34.52 mEq/day and 5159.2+/-249.29 ml/day, respectively; p<0.01) compared with Group 1 (634.2+/-42.86 mEq/day and 6611.7+/-365.67 ml/day). Fludrocortisone significantly reduced the urinary sodium excretion (p<0.01) and urine volume (p<0.01) in parallel, and effectively prevented a negative shift in the sodium as well as water balance (p<0.01). The serum sodium level tended to decrease in Group 1, reaching 135 mEq/L on average, but not in Group 2 (p<0.01). Hyponatremia in Group 1 was always observed at the optimal range of CVP values. A decrease in serum potassium level within the range of 2.8 to 3.5 mEq/L was transiently noted in 11 patients (73.3%) of Group 2, but was easily corrected. Possible side effects of fludrocortisone, such as pulmonary edema, were not encountered.[2]

Absorption, Distribution and Excretion
Absorption of fludrocortisone following oral administration is rapid and complete. Pharmacokinetic studies have estimated the Cmax to be 0.0012 to 0.20 μg/L with a Tmax between 0.5 and 2 hours. The AUC0-∞ of fludrocortisone after oral administration has been variably estimated to be between 1.22 to 3.07 μg.h/L.
Approximately 80% of an administered dose of fludrocortisone shows up in the urine, with the other 20% likely eliminated via fecal or biliary route.
The apparent volume of distribution of fludrocortisone is 80-85 L. Distribution into CSF appears minimal - the observed ratio of CSF drug concentration versus plasma drug concentration is 1:6.
Population pharmacokinetics have estimated the plasma clearance of fludrocortisone to be 40.8 L/h.
Elimination: Renal, mostly as inactive metabolites.
Oral: Rapidly and almost completely absorbed. Parenteral: Intramuscular: Freely soluble esters (sodium phosphate, sodium succinate) - Rapidly absorbed. Poorly soluble derivatives (acetate, acetonide, diacetate, hexacetonide, tebutate) - Slowly but completely absorbed. Local: Freely soluble esters - Less rapidly absorbed than with intramuscular injection. Poorly soluble derivatives - Slowiy but completely absorbed. /Corticosteroids (glucocorticoid effects - systemic)/

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Metabolism / Metabolites
There exists is a paucity of information regarding the specific metabolic pathway _in vivo_ of fludrocortisone. The 9α-fluorination of fludrocortisone appears to greatly simplify its metabolism as compared to other corticosteroids - while oxidation via 11-hydroxysteroid dehydrogenases has been observed, this reaction is greatly impaired as the fluorine moiety appears to confer "protection" from 11β-oxidation by these enzymes. The reduction in 11β-oxidation is thought to be one of the reasons behind fludrocortisone's profound mineralocorticoid potency. An _in vitro_ study generated only two metabolites following incubation in human liver microsomes and cytosol, namely 20β-dihydrofluorocortisol and 6β-hydroxyfluorocortisol, and did not explore in detail the potential enzymes responsible for this reaction. Given that fludrocortisone is a corticosteroid, a class of medications known to be metabolized by the CYP3A family, and is not recommended to be given with strong inhibitors/inducers of CYP3A, it is likely that the CYP3A family of enzymes contributes in some way to its metabolism (though this information does not appear to have been specifically elucidated for fludrocortisone).
STUDIED WERE KIDNEY SLICES, HOMOGENATES, & ISOLATED PERFUSED KIDNEYS. MAJOR METABOLITE: 20(EPSILON)-DIHYDRO-9ALPHA-FLUOROCORTISOL. ONLY 9ALPHA-FLUOROCORTISOL, NO METABOLITES, BOUND TO CYTOSOLIC RECEPTORS.

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Biological Half-Life
The plasma half-life of fludrocortisone has been variably reported to be between 1-3.5 hours, though prescribing information gives an approximate half-life of 18-36 hours.
> or = 3.5 hours (plasma); 18-36 hours (biological).

Protein Binding
Fludrocortisone is 70-80% protein bound in plasma, mostly to albumin and corticosteroid-binding globulin.

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Interactions
Concurrent use /of sodium-containing foods or medications/ with fludrocortisone in the treatment of Type IV renal tubular acidosis may result in hypernatremia, edema, and potentially severe increases in blood pressure;adjustment of sodium intake may be required.
In one published case report, lithium antagonized the mineralocorticoid effects of fludrocortisone; increased fludrocortisone dose and dietary sodium supplementation were required during concurrent use.
Risk of severe hypokalemia /when fludrocortisone is used concurrently with hypokalemia-causing medications/; monitoring of serum potassium concentration and cardiac function and potassium supplementation may be required.
Phenytoin and rifampin have been reported to increase 6-beta-hydroxylation of fludrocortisone, via induction of p450 liver enzymes; fludrocortisone dosage increase may be required.
For more Interactions (Complete) data for FLUDROCORTISONE (24 total), please visit the HSDB record page.

[1]. Small Cell Lung Cancer Patient with Profound Hyponatremia and Acute Neurological Symptoms: An Effective Treatment with Fludrocortisone. Case Rep Oncol Med. 2015;2015:286029.
[2]. Improved efficiency of hypervolemic therapy with inhibition of natriuresis by fludrocortisone in patients with aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery. 1999, 91(6):947-952.
[3]. Does fludrocortisone influence autobiographical memory retrievalA study in patients with major depression, patients with borderline personality disorder and healthy controls. Stress. 2015 Nov;18(6):718-22.

Therapeutic Uses
Anti-Inflammatory Agents, Steroidal; Mineralocorticoids, Synthetic
Fludrocortisone is used in the treatment of Type IV renal tubular acidosis associated with hyporeninemic hypoaldosteronism. Fludrocortisone is also used as an aid in diagnosing the cause of the condition. Effectiveness of fludrocortisone therapy indicated that the condition is caused by hyporeninemic hypoaldosteronism rather than by renal tubular transport dysfunction. /NOT included in US product labeling/
Fludrocortisone is used in conjunction with increased sodium intake in the treatment of idiopathic orthostatic hypotension. /NOT included in US product labeling/
Fludrocortisone is indicated in salt-losing forms of adrenogenital syndrome. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for FLUDROCORTISONE (8 total), please visit the HSDB record page.

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Drug Warnings
Most adverse reactions of fludrocortisone are caused by the drug's mineralocorticoid activity (retention of sodium and water). When fludrocortisone is used in the small dosages recommended, the glucocorticoid side effects are not usually a problem, however, these effects should be kept in mind, particularly when fludrocortisone is used over a prolonged period of time or in conjunction with cortisone or a similar glucocorticoid.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
To evaluate tolerance of fludrocortisone in older patients with hypotensive disorders... 64 patients over 65 years (mean age 80 years) with one or more hypotensive disorders (orthostatic hypotension, vasodepressor carotid sinus syncope, and/or vasodepressor neurocardiogenic syncope /were given/ fludrocortisone in daily doses of 100 ug (corrected) (72%), 50 ug (corrected) (27%), and 200 ug (corrected) (one patient). ... During follow up, 13 patients died of unrelated causes. Of the remainder 33% discontinued fludrocortisone at a mean of five months. Reasons for discontinuing treatment were hypertension, five; cardiac failure, four; depression, three; edema, three; and unspecified, two. In those who continued treatment supine systolic and diastolic blood pressure did not differ significantly from baseline (follow up two to 21 months). Hypokalemia developed in 24% at a mean of eight months; in no case was treatment withdrawn because of hypokalemia. Fludrocortisone, even in low doses, is poorly tolerated in the long term in older patients with hypotensive disorders.
The mechanism of recumbent hypertension induced by fludrocortisone was studied in 7 patients with orthostatic hypotension. All showed increases in blood pressure in the recumbent and standing positions, and hypertensive levels were achieved on recumbency in 4 of them. Hypertensive retinopathy developed in 2 patients and cardiomegaly in one. Initial blood pressure elevations were associated with sodium retention and plasma volume expansion. However, with long term treatment, plasma volume decreased to control levels despite further blood pressure increases. Treatment did not affect plasma levels of catecholamines but did enhance pressor responsiveness to infused norepinephrine in some subjects. Hemodynamic studies indicated that hypertension in the recumbent position was related to increases in total peripheral vascular resistance and not to changes in cardiac output. Clinically, hypertension in the recumbent position is an important risk of fludrocortisone treatment in patients with orthostatic hypotension. This unusual model of chronic mineralocorticoid induced hypertension is not volume dependent but is related to increased peripheral vascular resistance.
For more Drug Warnings (Complete) data for FLUDROCORTISONE (13 total), please visit the HSDB record page.

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Pharmacodynamics
Fludrocortisone is a synthetic mineralocorticoid used to replace endogenous [aldosterone] in conditions resulting in missing or inadequate endogenous synthesis. It acts on the kidneys to increase both sodium reabsorption and potassium excretion. As its effects are exerted at the transcriptional level, a single dose of fludrocortisone may work over the course of 1-2 days despite a relatively short plasma half-life. Like other systemic corticosteroids, fludrocortisone may mask signs of infection by depressing the normal immune response - infections occurring during fludrocortisone therapy should be promptly treated with appropriate antimicrobial therapy.

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There is evidence that stimulation of mineralocorticoid receptors (MR) enhances memory in healthy subjects and in patients with major depression (MDD). In contrast, in patients with borderline personality disorder (BPD), this effect seems to be task dependent. The aim of this study was to investigate the effect of MR stimulation on autobiographical memory retrieval in healthy individuals, patients with MDD, and patients with BPD. We conducted a placebo-controlled study in an intra-individual cross-over design. Twenty-four patients with MDD, 37 patients with BPD, and 67 healthy participants completed an autobiographical memory test after receiving 0.4 mg fludrocortisone, a mineralocorticoid receptor preferring agonist, or placebo in a randomized order. Healthy subjects, patients with MDD, and patients with BPD did not differ in their autobiographical memory retrieval. Furthermore, the administration of fludrocortisone had no effect on autobiographical memory. In conclusion, the stimulation of MR does not influence autobiographical memory retrieval in healthy subjects, patients with MDD, and patients with BPD. Our results do not support a role of MR in autobiographical memory.[3]

C21H29FO5

380.45

380.199

C, 66.30; H, 7.68; F, 4.99; O, 21.03

127-31-1

Fludrocortisone acetate;514-36-3;Fludrocortisone-d5;Fludrocortisone-d2; 127-31-1 (free); 514-36-3 (acetate) ; 339-01-5 (hemisuccinate)

31378

White to off-white solid powder

1.7

94.8

3

6

2

27

734

7

C[C@@]12[C@](C(CO)=O)(O)CC[C@@]1([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3(F)[C@@H](O)C2)=O

AAXVEMMRQDVLJB-BULBTXNYSA-N

InChI=1S/C21H29FO5/c1-18-7-5-13(24)9-12(18)3-4-15-14-6-8-20(27,17(26)11-23)19(14,2)10-16(25)21(15,18)22/h9,14-16,23,25,27H,3-8,10-11H2,1-2H3/t14-,15-,16-,18-,19-,20-,21-/m0/s1

(8S,9R,10S,11S,13S,14S,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one

Fludrocortisone, Florinef, fludrocortisone; 127-31-1; Astonin-H; Alflorone; Fluohydrisone; Fluorocortisol; Fluorocortisone; Fluohydrocortisone; Astonin, 9α-fluorocortisol, 9α-fluorohydrocortisone, Fludrocortisone acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~262.85 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.57 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.57 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
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