Acute onset heart failure due to reverse type Takotsubo cardiomyopathy caused by a single dose of 4-Fluoroamphetamine in a healthy young individual.

INTRODUCTION: 4-fluoroamphetamine (4-FA) is a novel psychoactive stimulant with a global presence on the drug market. Despite the popularity of 4-FA, data on severe adverse effects are scarce. We present a case of laboratory confirmed 4-FA mono intoxication causing acute heart failure due to a reverse type Takotsubo cardiomyopathy. CASE: A 20-year-old male with no previous medical history and no reported previous drug use, presented to the emergency department (ED) with complaints of headache, nausea and vomiting, approximately 4.5 h after the ingestion of a single 4-FA pill. After 30 min his condition deteriorated with severe hypertension, tachycardia and respiratory failure. Echocardiography showed a reverse type Takotsubo cardiomyopathy. The patient was successfully treated with mechanical ventilation, a phosphodiesterase-3-inhibitor (PDE3-inhibitor) and diuretics. Three months after hospital admission, the patient was free of complaints and his left ventricular function fully recovered. CONCLUSION: Recreational use of 4-FA may result in acute onset life-threatening cardiorespiratory toxicity, preceded by severe hypertension, even in drug-naïve patients without any medical history. Emergency physicians and cardiologists should be cautious not to underestimate life-threatening 4-FA complications.

Cushing's disease and hypertension: in vivo and in vitro study of the role of the renin-angiotensin-aldosterone system and effects of medical therapy.

OBJECTIVE/METHODS: Cushing's disease (CD) is often accompanied by hypertension. CD can be treated surgically and, given the expression of somatostatin subtype 5 and dopamine 2 receptors by corticotroph pituitary adenomas, pharmacologically. Indeed, we recently observed that stepwise medical combination therapy with the somatostatin-analog pasireotide, the dopamine-agonist cabergoline, and ketoconazole (which directly suppresses steroidogenesis) biochemically controlled CD patients and lowered their blood pressure after 80 days. Glucocorticoids (GC) modulate the renin-angiotensin-aldosterone system (RAAS) among others by increasing hepatic angiotensinogen expression and stimulating mineralocorticoid receptors (MR). This study therefore evaluated plasma RAAS components in CD patients before and after drug therapy. In addition, we studied whether cabergoline/pasireotide have direct relaxant effects in angiotensin II (Ang II)-constricted iliac arteries of spontaneously hypertensive rats, with and without concomitant GR/MR stimulation with dexamethasone or hydrocortisone. RESULTS: Baseline concentrations of angiotensinogen were elevated, while renin and aldosterone were low and suppressed, respectively, even in patients treated with RAAS-blockers. This pattern did not change after 80 days of treatment, despite blood pressure normalization, nor after 4 years of remission. In the presence of dexamethasone, pasireotide inhibited Ang II-mediated vasoconstriction. CONCLUSIONS: The low plasma renin concentrations, even under RAAS blockade, in CD may be the consequence of increased GC-mediated MR stimulation and/or the elevated angiotensinogen levels in such patients. The lack of change in RAAS-parameters despite blood pressure and cortisol normalization suggests persisting consequences of long-term exposure to cortisol excess. Finally, pasireotide may have a direct vasodilating effect contributing to blood pressure lowering.

Preoperative normalization of cortisol levels in Cushing's disease after medical treatment: consequences for somatostatin and dopamine receptor subtype expression and in vitro response to somatostatin analogs and dopamine agonists.

CONTEXT: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. OBJECTIVE: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. PATIENTS AND DESIGN: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. MAIN OUTCOME MEASURES: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. RESULTS: The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% ± 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% ± 4.2%) and cabergoline (n = 3 out of 4; -41.9% ± 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. CONCLUSIONS: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst2 protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established.

Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing's disease.

Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

Hypercoagulability in Cushing's syndrome: prevalence, pathogenesis and treatment.

Cushing's syndrome is not only accompanied by an increased prevalence of cardiovascular disease but also by a hypercoagulable state that is reflected by an increased incidence of venous thromboembolism. Overall, patients with CS have been reported to have a more than 10-fold increased risk of developing venous thromboembolism. Moreover, the incidence of postoperative thrombosis has been shown to be comparable to the risk after major orthopaedic surgery. Hypercoagulability in CS is due to both increased production of procoagulant factors with activation of the coagulation cascade and an impaired fibrinolytic capacity, resulting in a shortened activated partial thromboplastin time and an increased clot lysis time respectively. Although these abnormalities seem to improve 1 year following successful surgery, they do not yet normalize. Therefore, sustained biochemical remission might be required to fully resolve the hypercoagulable state in CS. Considering the risk of venous thromboembolism in uncontrolled CS there may be a rationale to give patients with active CS thromboprophylaxis. So far this seems warranted following surgical interventions. However, further studies are needed to determine the optimal dosage and duration of thromboprophylaxis.

Fluconazole inhibits human adrenocortical steroidogenesis in vitro.

The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC(50) 0.73 µM) and cortisol production (HAC15 cells; 81%; EC(50) 0.26 µM and primary cultures (mean EC(50) 0.75 µM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC(50) 35 µM) and primary cultures (mean EC(50) 67.7 µM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11ß-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency.

New developments in the medical treatment of Cushing's syndrome.

Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options, will be discussed.

The hypercoagulable state in Cushing's disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy.

CONTEXT: Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE: The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING: During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS: Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES: We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS: Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS: The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.