ergoline and pasireotide

Reported rates of response to medical therapies used in Cushing's disease (CD) vary widely. The aim of this review is to analyse systematically the efficacy of medical therapies for CD and to assess the strength of the supporting evidence.. Systematic PubMed searches identified studies of medical treatment in CD. The GRADE criteria were imposed to assess the strength of evidence supporting each medication.. Fifteen studies were included. Ten studies specifically reported response rates for patients with CD. Pasireotide was the only treatment to be assessed in a randomized trial and was supported by a 'moderate' level of evidence. Response rates with pasireotide from three prospective studies were 17-29%. The remaining medications were supported by a 'low' or 'very low' level of evidence. The highest response rates were reported in small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study). Response rates were 25-50% for cabergoline (four studies) and 45% for ketoconazole (one study). Among studies that included patients with other forms of Cushing's syndrome, response rates were 53-88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study) and 38-60% for mifepristone. Again, all of these medications are supported by a 'low' level of evidence.. There is a paucity of high-quality studies of medical therapy in CD, with only one medication achieving a 'moderate' level of evidence. Caution should be employed when comparing efficacy rates owing to the variability in study design and quality.

Topics: Cabergoline; Ergolines; Female; Humans; Ketoconazole; Male; Metyrapone; Mitotane; Pituitary ACTH Hypersecretion; Somatostatin

To review available medical therapies for patients with Cushing disease and to provide a roadmap for their use in clinical practice.. PubMed searches were performed to identify all of the available published data on medical management of Cushing disease.. Medical therapy is usually not the first-line treatment for patients with Cushing disease but may be used to improve clinical manifestations of Cushing disease in patients who are not suitable candidates for surgery, following unsuccessful surgery or recurrence, or as a "bridge therapy" in those who have undergone radiotherapy. Medical therapy may also be used in preoperative preparation of patients with severe disease. Current available medical options for patients with Cushing disease include centrally acting agents, steroidogenesis inhibitors, and a glucocorticoid receptor antagonists. At present, there are no head-to-head studies comparing the efficacy, tolerability, and safety of different U.S. Food and Drug Administration (FDA)- and non-FDA-approved drugs in patients with Cushing disease. With the initiation of new studies and the completion of ongoing clinical trials, the number of FDA-approved drugs for medical treatment of Cushing disease is expected to increase.. Medical therapy has an important adjunctive role in the management of patients with Cushing disease. The decision to initiate medical treatment depends on many factors, including patient characteristics and preference. Long-term studies are needed to better define the clinical efficacy, safety, and tolerability of medical treatment of Cushing disease, including the role of combination therapies.

Topics: Adrenocorticotropic Hormone; Cabergoline; Drug Therapy, Combination; Ergolines; Humans; Ketoconazole; Mifepristone; Pituitary ACTH Hypersecretion; Somatostatin

Recently developed agents treat Cushing's disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action.. The dopamine agonist cabergoline and the somatostatin agonist pasireotide target ACTH secretion. Each has low rates of normalization of urine-free cortisol (UFC), about 40% at doses of 1-7 mg weekly and 20% at doses of 600 or 900 μg twice daily, respectively. Cabergoline, an oral agent, has a relatively benign side-effect profile, primarily asthenia. Small trials suggest that combination therapy with ketoconazole increases effectiveness. Pasireotide, a parenteral agent, is associated with types and rates of adverse events similar to those seen with other somatostatin agonists (diarrhea, nausea, cholelithiasis), except for glucose intolerance, which occurs more frequently (∼75%). It may be most effective when UFC is less than two-fold normal. A few case reports suggest that pasireotide or cabergoline may control tumor size and ACTH secretion from macroadenomas. Retinoic acid must be evaluated further. The glucocorticoid antagonist mifepristone ameliorates glucose intolerance but may not normalize other Cushingoid features.. These novel approaches provide options for treatment of patients in whom surgery has failed or is not possible, and those who decline adrenalectomy or radiation therapy.

Topics: Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Humans; Hydrocortisone; Pituitary ACTH Hypersecretion; Somatostatin

Prolonged overproduction of growth hormone, like insulin-like growth factor-1 hypersecretion leads to acromegaly in adults. This is associated with several co-morbidities and increased mortality. Despite typical clinical features and modern diagnostic tools, it often takes years to diagnose from the onset of the disease. The aims of the treatment are to reduce or control tumour growth, inhibit growth hormone hypersecretion, normalize insulin-like growth factor-1 levels, treat co-morbidities and, therefore, reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonists, somatostatin analogues and growth hormone receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management. The review provides a summary of medical treatment for acromegaly.. Az acromegalia a növekedési hormon, ennélfogva az inzulinszerű növekedési faktor-1 tartós túltermelése következtében kialakuló betegség felnőttekben, amely számos szövődménnyel jár és megfelelő kezelés nélkül a mortalitás növekedéséhez vezet. Jellegzetes tünetei ellenére, valamint a korszerű biokémiai és képalkotó diagnosztikai módszerek mellett is általában több év telik el a betegség kialakulásának kezdete és a diagnózis felállítása között. Terápiás lehetőségként sebészi beavatkozás, gyógyszeres (dopaminagonista, szomatosztatinanalóg és növekedésihormonreceptor-antagonista) kezelés és radioterápia áll rendelkezésre. A kezelés célja a biztonságos növekedési hormon- és inzulinszerű növekedési faktor-1-szintek elérése, a tumor eltávolítása vagy méretének csökkentése, valamint a betegség szövődményeinek kezelése, végső fokon a mortalitás csökkentése. Az eredményes kezelés több különböző diszciplína képviselőjének megfelelő együttműködésén alapszik. A közleményben a szerző az acromegalia gyógyszeres kezelési lehetőségeit tekinti át. Orv. Hetil., 2013, 154, 1527–1534.

Topics: Acromegaly; Aminoquinolines; Antineoplastic Agents, Hormonal; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Drug Therapy, Combination; Ergolines; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Interdisciplinary Communication; Membrane Proteins; Octreotide; Patient Care Team; Peptides, Cyclic; Pituitary Neoplasms; Somatostatin

Hypercortisolism induced by Cushing disease causes high morbidity and mortality. The treatment of choice is pituitary surgery, but it often fails to achieve cure, and other treatment modalities (radiotherapy, bilateral adrenalectomy) may therefore be required. If these treatments are not effective or while waiting for their results, hypercortisolism should be controlled with drugs. The classical drug treatments are those that act by inhibiting cortisol secretion by the adrenal gland (ketoconazole, metyrapone, mitotane, etomidate). The preliminary results of a new drug (LCI699) which is a potent enzyme inhibitor of cortisol secretion have been reported. A clinical trial of the safety and efficacy of mifepristone, a glucocorticoid receptor antagonist, has just been published. The drugs deserving more attention today are those with a direct action on the tumor by inhibiting ACTH secretion: somatostatin analogues (pasireotide), dopamine agonists (cabergoline), PPAR-γ, and retinoic acid. A special review is made of the available clinical trials with pasireotide and cabergoline.

Topics: Adenoma; Adrenocorticotropic Hormone; Animals; Cabergoline; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Ergolines; Etomidate; Humans; Hydrocortisone; Imidazoles; Ketoconazole; Metyrapone; Mice; Mifepristone; Mitotane; Multicenter Studies as Topic; Pituitary ACTH Hypersecretion; Pituitary Neoplasms; PPAR gamma; Pyridines; Rats; Somatostatin; Therapies, Investigational; Tretinoin

The goals of ideal medical therapy for Cushing's disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current 'gold standard' treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found.. To summarise pituitary-targeted medical treatment of Cushing's disease.. Compounds with neuromodulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo-pituitary regulation have been investigated.. The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushing's disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently.. Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation.

Topics: Adrenocorticotropic Hormone; Animals; Cabergoline; Dopamine Agonists; Ergolines; Humans; Neurotransmitter Agents; Oligopeptides; Pituitary ACTH Hypersecretion; Pituitary Gland; Somatostatin

Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD.. 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.. 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.. Seventeen patients with de novo, residual, or recurrent CD were included.. We measured urinary free cortisol and parameters of coagulation and fibrinolysis.. 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.. 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.

Topics: Adult; Aged; Blood Coagulation; Blood Coagulation Factors; Cabergoline; Dopamine Agonists; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Ergolines; Fibrinolysis; Humans; Hydrocortisone; Ketoconazole; Male; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Hormones, Anterior; Remission Induction; Somatostatin; Thrombophilia; Young Adult

Topics: Adult; Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Humans; Hydrocortisone; Ketoconazole; Male; Middle Aged; Pituitary ACTH Hypersecretion; Prospective Studies; Receptors, Dopamine D2; Receptors, Somatostatin; Somatostatin

The approach to acromegalic patients with persistent acromegaly after surgery and inadequate response to first-generation somatostatin receptor ligands (SRLs) should be strictly tailored. Current options include new pituitary surgery and/or radiosurgery, or alternative medical treatment with SRLs high dose regimens, pegvisomant (PEG) as monotherapy, or combined therapy with the addition of PEG or cabergoline to SRLs. A new pharmacological approach includes pasireotide, a second-generation SRL approved for patients who do not adequately respond to surgery and/or for whom surgery is not an option. No reports on efficacy and safety of combined therapy with pasireotide and pegvisomant (PEG) in acromegaly are available.. Here we report the case of a 41-year-old acromegalic man with a mixed GH/PRL pituitary adenoma post-surgical resistant to first-generation SRLs both alone and in combination with cabergoline and PEG who achieved biochemical and tumor control with the combined triple treatment with pasireotide, PEG and cabergoline without adverse events and with a good compliance to treatment.. Twelve months of therapy with pasireotide, PEG and cabergoline proved to be safe and effective in this particular patient and the clinical improvement of disease resulted in an improved compliance to treatment.

Topics: Acromegaly; Adult; Antineoplastic Agents; Cabergoline; Drug Therapy, Combination; Ergolines; Hormones; Human Growth Hormone; Humans; Male; Prognosis; Salvage Therapy; Somatostatin

Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients.. Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes.. Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224).. Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD.. BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Topics: 14-alpha Demethylase Inhibitors; ACTH-Secreting Pituitary Adenoma; Adenoma; Adolescent; Adrenalectomy; Adult; Aged; Antineoplastic Agents; Cabergoline; Comorbidity; Enzyme Inhibitors; Ergolines; Female; Follow-Up Studies; Hirsutism; Hormone Antagonists; Hormones; Humans; Hyperlipidemias; Hypertension; Hypoglycemic Agents; Ketoconazole; Male; Metyrapone; Middle Aged; Mifepristone; Muscle Weakness; Muscular Atrophy; Neurosurgical Procedures; Obesity, Abdominal; Pituitary ACTH Hypersecretion; Pituitary Irradiation; Polycystic Ovary Syndrome; Retrospective Studies; Rosiglitazone; Somatostatin; Striae Distensae; Thiazolidinediones; Treatment Outcome; Tumor Burden; Young Adult

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.. 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.. 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.

Topics: Adult; Aged; Aldosterone; Angiotensinogen; Animals; Cabergoline; Ergolines; Female; Humans; Hypertension; Iliac Artery; In Vitro Techniques; Male; Middle Aged; Pituitary ACTH Hypersecretion; Rats; Renin; Renin-Angiotensin System; Somatostatin; Vasoconstriction

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.

Topics: Adult; Aged; Cabergoline; Circadian Rhythm; Dopamine Agonists; Ergolines; Female; Humans; Hydrocortisone; Ketoconazole; Male; Middle Aged; Pituitary ACTH Hypersecretion; Quality of Life; Somatostatin; Surveys and Questionnaires; Young Adult

Pituitary adenomas can cause specific syndromes due to hormone excess and/or determine sellar mass symptoms. Pituitary cell growth can sometimes be influenced by medical therapy, such as for somatotroph adenomas treated with somatostatin analogs or prolactinomas treated with dopaminergic drugs. However, nonfunctioning pituitary adenomas (NFAs) are still orphans of medical therapy. Everolimus (RAD001), a derivative of rapamycin, is a well-known immunosuppressant drug, which has been recently shown to have antineoplastic activity in several human cancers.. The objective of the study was to investigate the possible antiproliferative effects of RAD001 in human NFAs.. We collected 40 NFAs that were dispersed in primary cultures, treated without or with 1 nm to 1 microm RAD001, 10 nm cabergoline, 10 nm SOM230 (a somatostatin receptor multiligand), and/or 50 nm IGF-I. Cell viability and apoptosis were evaluated after 48 h, and vascular endothelial growth factor (VEGF) secretion was assessed after an 8-h incubation. Somatostatin and dopamine subtype 2 receptor expression was investigated by quantitative PCR.. In 28 cultures (70%), Everolimus significantly reduced cell viability (by approximately 40%; P < 0.05 vs. control), promoted apoptosis (+30%; P < 0.05 vs. control), inhibited p70S6K activity (-20%), and blocked IGF-I proliferative and antiapoptotic effects. In selected tissues cotreatment with SOM230, but not cabergoline, exerted an additive effect. Everolimus did not affect VEGF secretion but blocked the stimulatory effects of IGF-I on this parameter.. Everolimus reduced NFA cell viability by inducing apoptosis, with a mechanism likely involving IGF-I signaling but not VEGF secretion, suggesting that it might represent a possible medical treatment of invasive/recurrent NFAs.

Topics: Adenoma; Aged; Apoptosis; Cabergoline; Cell Line, Tumor; Cell Survival; Ergolines; Everolimus; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Pituitary Neoplasms; Receptors, Somatostatin; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Somatostatin; Vascular Endothelial Growth Factor A

Ten percent of patients with prolactinoma fail to respond with normalization of prolactin (PRL) and tumor shrinkage under dopamine agonist (DA) therapy. The resistance to treatment is linked to a loss of dopamine receptor 2 (D2DR). Prolactinomas express somatostatin (SST) receptor subtypes, SSTR1, 2, and 5. The aim of this study was to determine whether different SST compounds could overcome the resistance to DA in prolactinomas.. The efficacy of SSTR1, SSTR2, and SSTR5 ligands; the universal SST ligand, SOM230; and the chimeric SST-DA compound, BIM-23A760, was compared with cabergoline in suppressing PRL secretion from primary cultures of ten prolactinomas (six DA responders and four DA resistant). Receptor mRNAs were assessed by quantitative PCR.. The mean mRNA levels for D2DR, SSTR1, SSTR2, and SSTR5 were 92.3+/-47.3, 2.2+/-1.4, 1.1+/-0.7, and 1.6+/-0.6 copy/copy beta-glucuronidase (beta-Gus) respectively. The SSTR1 agonist, BIM-23926, did not suppress PRL in prolactinomas. In a DA-resistant prolactinoma, it did not inhibit [(3)H]thymidine incorporation. The SSTR5 compound, BIM-23206, produced a dose-dependent inhibition of PRL release similar to that of cabergoline in three DA-sensitive prolactinomas. BIM-23A760 produced a maximal PRL inhibition superimposable to that obtained with cabergoline with a lower EC(50) (0.5+/-0.1 vs 2.5+/-1.5 pmol/l). In DA-resistant prolactinomas, BIM-23206 and SOM230 were ineffective. Cabergoline and BIM-23A760 produced a partial inhibition of PRL secretion (19+/-6 and 21+/-3% respectively).. Although the SSTRs are expressed in prolactinomas, the somatostatinergic ligands analyzed do not appear to be highly effective in suppressing PRL. D2DR remains the primary target for effective treatment of prolactinomas.

Topics: Adult; Antineoplastic Agents; Cabergoline; Dopamine; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Ergolines; Female; Growth Hormone-Secreting Pituitary Adenoma; Humans; Ligands; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Receptors, Dopamine D2; Receptors, Somatostatin; RNA, Messenger; Somatostatin; Tumor Cells, Cultured