Merits and pitfalls of mifepristone in Cushing's syndrome.

OBJECTIVE: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). DESIGN: Retrospective study of patients treated in seven European centers. METHODS: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. RESULTS: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. CONCLUSION: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

[Adrenocortical carcinoma. Diagnostic work-up and treatment]. / Das Nebennierenkarzinom. Diagnostik und Therapie.

Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. Preoperatively, a thorough hormonal work-up is mandatory, as the hormonal status may influence the perioperative management and may also provide marker hormones for monitoring of tumour recurrence. CT and MRI are equally sensitive and specific imaging tools for adrenal tumours. For discerning malignancy, assessment of the fat content of the tumour and contrast media wash-out after 10 min are of great value. Complete surgical resection of the tumour offers the only chance for cure. Open adrenalectomy via a flank or thoracoabdominal approach is the standard surgical technique. Intraoperative tumour spillage should be carefully avoided. Even after R0 resection, recurrence of the disease is frequent and regular follow-up for a minimum of 5 years is required. In advanced ACC, the treatment of choice is mitotane with or without cytotoxic chemotherapy (preferably after inclusion into the FIRM-ACT trial).

In vivo efficacy in airway disease models of N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281), a selective phosphodiesterase 4 inhibitor for inhaled administration.

N-(3,5-Dichloro-pyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide (AWD 12-281) is a highly potent and selective phosphodiesterase 4 (PDE4) inhibitor that was designed to have a metabolic profile that was optimized for topical administration. The aim of the current study was to explore the pharmacological profile of intratracheally administered AWD 12-281 in different models of asthma and chronic obstructive pulmonary disease (COPD) in comparison with steroids. To assess the anti-inflammatory potential of AWD 12-281, the antigen-induced cell infiltration in bronchoalveolar lavage fluid (BALF) of Brown Norway rats was determined. AWD 12-281 (ID50 of 7 microg/kg i.t.) as well as beclomethasone (0.1microg/kg i.t.) suppresses late-phase eosinophilia when administered intrapulmonary. Furthermore, AWD 12-281 has also strong anti-inflammatory properties when tested in lipopolysaccharide-induced acute lung neutrophilia in Lewis rats (ID50 of 0.02 microg/kg i.t.), ferrets (ID50 of 10 microg/kg i.t.), and domestic pigs (2-4 mg/pig i.t. or 1 mg/kg i.v.). In pigs, AWD 12-281 was as effective as beclomethasone (0.4 mg/pig i.t.) and dexamethasone (0.28 mg/kg i.v.), although at 3 to 10 times the dosage. The bronchodilatory activity of AWD 12-281 was assessed in sensitized guinea pigs. AWD 12-281 (1.5 mg/kg i.t., 1-h pretreatment) inhibited allergen-induced bronchoconstriction by 68% (parameter airway resistance). In sensitized BP-2 mice AWD 12-281 abolished the allergen-induced bronchial hyperresponsiveness and eosinophilia in BALF, showing dose dependence. When given orally, i.v. or i.t., AWD 12-281 has a considerably lower emetic potential than cilomilast in ferrets and roflumilast in pigs. When given topically by inhalation, no emesis could be induced in dogs up to the highest feasible dose (15 mg/kg in 50% lactose blend). These results indicate that AWD 12-281 is a unique potential new drug for the topical treatment of asthma and COPD.

Enzyme-mediated protection of the mineralocorticoid receptor against progesterone in the human kidney.

Progesterone (P) is a mineralocorticoid (MC)-antagonist in vitro. During pregnancy, plasma P concentrations exceed aldosterone concentrations at least 50-fold, but plasma aldosterone increases only 4-8-fold in a compensatory manner. Since the in vivo anti-MC activity of P seems to be only moderate, we hypothesized that P is metabolized by enzymes of MC target tissue similar to the way cortisol is metabolized by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2 in order to protect the MC receptor. We, therefore, examined P metabolism using 4-(14)C-P in subcellular fractions of human postmenopausal and male kidneys, and in homogenates of one premenopausal kidney. We found that P is converted effectively, even at high P concentrations (10(-6) mol/l), to various metabolites: 20alpha-dihydro(DH)-P; 17alpha-OH-P; 17alpha-OH,20alpha-DH-P; 5alpha-DH-P; 3beta,5alpha-tetrahydro(TH)-P; and 20alpha-DH,5alpha-DH-P. Homogenates of premenopausal kidney also showed conversion to 3alpha- and 5beta-reduced P metabolites. These results confirm the existence of an efficient renal enzyme system as a possible mechanism of an enzyme-mediated MC receptor selectivity.

Evidence for a trigger function of valproic acid in xenobiotic-induced hepatotoxicity.

The influence of the antiepileptic drug, valproic acid (2-n-propylpentanoic acid), on the hepatocellular capacity, to cope with an extrinsic oxidative stress was investigated. Freshly isolated rat hepatocytes exposed to therapeutic concentrations of valproic acid (0.25-1.0 mmol/l) were less resistant than controls, as evidenced by a significant cytotoxic response after challenge of the cells with a non-toxic dose of allyl alcohol (2-propen-1-ol). Valproic acid alone was not toxic to hepatocytes even at ten times higher concentrations (10 mmol/l), suggesting that cell damage was not a mere additive effect. Incubation with valproic acid plus allyl alcohol induced an irreversible depletion of hepatocellular glutathione, in contrast to allyl alcohol alone which induced a transient loss. Hepatocytes treated with valproic acid plus allyl alcohol were protected by N-acetylcysteine, a precursor of glutathione. These findings indicate that valproic acid affects hepatocellular defence mechanisms and suggest that a predisposition of hepatocytes to oxidative stress may play a role in the fatal hepatotoxicity of valproic acid in epileptic patients.

Progesterone metabolism in the human kidney and inhibition of 11beta-hydroxysteroid dehydrogenase type 2 by progesterone and its metabolites.

Progesterone binds with high affinity to the mineralocorticoid (MC) receptor, but confers only very low agonistic MC activity. Therefore, progesterone is a potent MC antagonist in vitro. Although progesterone reaches up to 100 times higher plasma levels in late pregnancy than aldosterone, the in vivo MC antagonistic effect of progesterone seems to be relatively weak. One explanation for this phenomenon could be local metabolism of progesterone in the human kidney, similar to the inactivation of cortisol to cortisone by the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. We studied the metabolism of progesterone in the human kidney in vitro and found reduction to 20alpha-dihydro (DH)-progesterone as the main metabolite. Ring-A reduction to 5alpha-DH-progesterone, 20alpha-DH-5alpha-DH-progesterone, and 3beta,5alpha-tetrahydro (TH)-progesterone was also documented. We further showed for the first time that 17-hydroxylation of progesterone (17alpha-OH-progesterone, 17alpha-OH, 20alpha-DH-progesterone), normally localized in the adrenals and the gonads, occurs in the human adult kidney. We found no formation of deoxycorticosterone from progesterone in the human adult kidney. Using human kidney cortex microsomes, we tested the inhibitory potency of progesterone and its metabolites on the 11beta-HSD type 2. The most potent inhibitor was progesterone itself (IC50 = 4.8 x 10(-8) mol/L), followed by 5alpha-DH-progesterone (IC50 = 2.4 x 10(-7) mol/L), 20alpha-DH-progesterone, 3beta,5alpha-TH-progesterone, 17alpha-OH-progesterone, and 20alpha-DH-5alpha-DH-progesterone (IC50 between 7.7 x 10(-7) mol/L and 1.3 x 10(-6) mol/L). The least potent inhibitor was 17alpha-OH,20alpha-DH-progesterone. In addition to progesterone metabolism by the kidney, the inhibition of 11beta-HSD type 2 by progesterone and its metabolites could be a second explanation for the weak MC-antagonist activity of progesterone in vivo. Inhibition of 11beta-HSD type 2 leads to an increase of intracellular cortisol in a way that the local equilibrium between the MC agonist cortisol and the antagonist progesterone is shifted to the agonist side.