WO2013131879A1 - Nouvelle application pour la pasireotide - Google Patents

Nouvelle application pour la pasireotide Download PDF

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Publication number
WO2013131879A1
WO2013131879A1 PCT/EP2013/054343 EP2013054343W WO2013131879A1 WO 2013131879 A1 WO2013131879 A1 WO 2013131879A1 EP 2013054343 W EP2013054343 W EP 2013054343W WO 2013131879 A1 WO2013131879 A1 WO 2013131879A1
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WO
WIPO (PCT)
Prior art keywords
pasireotide
hypertension
patients
acth
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2013/054343
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English (en)
Inventor
Herbert Schmid
Germo Hans GERICKE
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Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2013131879A1 publication Critical patent/WO2013131879A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins

Definitions

  • Present invention relates to new fields of application for pasireotide (SOM230) and any of pharmaceutically acceptable salts, in particular for the treatment of high blood pressure.
  • Pasireotide is a cyclohexapeptide with the following formula (I)
  • Pasireotide is also called cyclo[ ⁇ 4-(NH 2 -C 2 H4-NH-CO-0-)Pro ⁇ -Phg-DTrp-Lys-Tyr(4-Bzl)- Phe], in free form, in salt or complex form or in protected form, wherein Phg means -HN- CH(C 6 H 5 )-CO- and Bzl means benzyl.
  • Pasireotide is a somatostatin analogues, engineered to bind to multiple somatostatin receptor subtypes (i.e. 1 , 2, 3, and 5) to mimic the action of natural somatostatin.
  • Pasireotide has a broader receptor binding profile than octreotide or lanreotide. it binds to four of the five ssts with high affinity, with highest affinity for sstrs.
  • a comprehensive clinical development program is currently investigating the effects of pasireotide in the treatment of Gushing' s disease, acromegaly and gastroenteropancreatic neuroendocrine tumors (GEP/NETs).
  • Cushing's disease is a rare disorder of chronic hypercortisolism due to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor.
  • ACTH-secreting putitary adenomas predominatly express sstrs. This is believed to be responsible for the action of pasireotide against Cushing's disease and its success in lowering the increased Cortisol levels.
  • the present invention provides a medicament comprising pasireotide, or any one of its pharmaceutically acceptable salts, and optionally at least one pharmaceutically acceptable carrier, for use in the treatment of hypertension in patients, wherein said patient does not have dishing " s disease.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329, incorporated herein by reference). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a pharmaceutical acceptable salt of pasireotide could be an inorganic acid, a polymeric acid or an organic acid salt.
  • Acid addition salts may exist as mono- or divalent salts, e.g. depending whether 1 or 2 acid equivalents are added.
  • Preferred salts are the lactate, aspartate, benzoate, succinate and pamoate including mono- and di-salts, more preferably the aspartate di-salt and the pamoate monosalt.
  • Certain salts of pasireotide forms gel in a aqueous enviroment, such as salt of aspartate, e.g.
  • the pasireotide pharmaceutically acceptable salt is pamoate salt.
  • the term "Cushing's disease" as used herein refers to a group of patients having a mean 24- hour urinary free Cortisol >1.5x the upper limit of normal (ULN), calculated from four 24- hour samples collected within 2 weeks; morning plasma ACTH >5ng/L (>1 Jnmol/L); a confirmed pituitary source of Cushing's syndrome.
  • the ULN for the 24-hour Urine Free Cortisol was defined as 145 nmol/day.
  • Urinary free Cortisol was determined by high pressure liquid chromatography (HPLC) as described in Turpeinen et al 1997. The normal ranges of 30-145 nmol/24 hours published by Turpeinen were used for this study.
  • Adrenocorticotropic hormone also known as 'corticotropin', 'Adrenocorticotrophic hormone'
  • ACTH Adrenocorticotropic hormone
  • 'corticotropin' 'Adrenocorticotrophic hormone'
  • 'Adrenocorticotrophic hormone' is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological stress (along with corticotropin-releasing hormone from the hypothalamus). Its principal effects are increased production and release of corticosteroids and. as its name suggests, Cortisol from the adrenal cortex. Morning plasma ACTH is normally measured by HPLC method.
  • hypertension or "high blood pressure” including baseline hypertension according to the invention is defined as systolic blood pressure SBP > LlOmmllg; or diastolic blood pressure DBP > 90mmHg.
  • Baseline means at the beginning of the therapy.
  • the patient having hypertension in the meantime has obesity, depression, long term stress and/or alcoholism.
  • Obesity in the meaning of present invention means a BM1 higher than 25 kg m 2 .
  • Obesity is an abnormal accumulation of body fat and is associated with various diseases, particularly cardiovascular diseases, diabetes niellitus type 2, certain types of cancer, and musculoskeletal disorders (in particular osteoarthritis). As a result, obesity has been found to reduce life expectancy.
  • Present invention in particular relates to central obesity, i.e. weight gain particularly of the trunk and face with sparing of the limbs.
  • obesity in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and hypertension.
  • Depression is a common mental disorder that presents with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration. These problems can become chronic or recurrent and lead to substantial impairments in an individual's ability to take care of his or her everyday responsibilities.
  • depression in the meaning of present invention is accompanied with increased ACTH and7or Cortisol levels and hypertension.
  • Stress in the meaning of present invention relates to the body's reaction to any stimuli that disturb its equilibrium.
  • stress according to the definition of present invention relates to long term or chronic stress, i.e. a state of prolonged tension from internal or external stressors, which may cause various physical manifestations, e.g. asthma, back pain, arrhythmias, fatigue, headaches, hypertension, irritable bowel syndrome, ulcers, and suppress the immune system.
  • Cortisol is constantly higher than normal level, causing fewer receptors to be produced on immune cells so that inflammation cannot be ended.
  • stress in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and hypertension.
  • Alcoholism in the meaning of present invention relates to a primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and
  • Alcoholism is characterized by: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; and tolerance, or the need to use more and more alcohol to achieve the same effects.
  • stress in the meaning of present invention is accompanied with increased ACTH and/or Cortisol levels and
  • pasireotide effectively reduces blood pressure through lowering the level of ACTH and/or Cortisol.
  • Targeting ACTH and/or Cortisol to treat hypertension provides a new mode of action in treating hypertension.
  • patients having hypertension have higher-than-Lower Limit of Normal (LLN) level of ACTH.
  • LLC Limit of Normal
  • AC 111 levels change with the body's natural 24-hour cycle of processes (circadian rhythms). Test is most accurate i it is performed early in the morning. Taking steroid drugs is normally stopped before test.
  • the normal value of ACTH is usually 9 - 52 pg/mL, may vary slightly among different labs.
  • higher than LLN level of ACTH refers to the level of ACTH being higher than the lower limit of normal range plasma ACTH measured in early morning (normally before 8 or 9am) by a particular method.
  • Normal range is understood as the range in which the ACTH level of the majorit health population statistically fall, preferably taking into consideration of age, gender, race, living condition etc.
  • patients having hypertension have higher-than-normal level of ACTH.
  • higher-than-normal level of ACTH refers to the level of ACTH being higher than the upper limit of normal range plasma ACTH.
  • the term "higher-than-normal level of ACTH” refers to the level of plasma ACTH measured in the morning being higher than 50pg/ml, higher than l OOpg/ml, higher than 200pg/ml, higher than 300pg/ml, higher than 500pg/ml, higher than lng/ml or even higher than 2ng/ml or even higher than 5ng/ml.
  • the measuring method is High- performance liquid chromatography (HPI.C).
  • the patient having hypertension has elevated level of ACTH of non-pituitary origin.
  • the patent having hypertension has Pseudo-Cushing's syndrome.
  • Pseudo- Cushing's syndrome is a medical condition in which patients display the signs, symptoms, and abnormal hormone levels seen in Cushing's syndrome.
  • pseudo-Cushing's syndrome is not caused by a problem with the hypothalamic-pituitary-adrenal axis as Cushing's is; it is an idiopathic condition.
  • patients having hypertension has elevated level of Cortisol.
  • the term "elevated level of Cortisol” as used here refers to the level of Cortisol higher than an individual's own normal range of Cortisol.
  • the normal range of urinary free Cortisol (UFC) for population is 10 - 100 micrograms per 24 hours (mcg/24h or ⁇ g/24h).
  • UTC urinary free Cortisol
  • the term "elevated level of Cortisol” refers to a level higher than 80 ⁇ g /24h, higher than 100 ⁇ g /24h or higher than 120 « /24h.
  • High level of Cortisol could be caused by high level of ACTH.
  • AC 1 11 acts on the adrenal cortex to stimulate secretion of Cortisol and other steroids. in one embodiment the patient having hypertension does not have an elevated level of Cortisol or a higher than normal level of ACTH.
  • Pasireotide and any of its pharmaceutical acceptable salt exerts its inhibitory effect by binding on sstrl , 2, 3 and/or 5 expressed by cells/tissues, the secreted factors from which lead to elevated blood pressure, such as the cells/tissues secret renin or angiotensin I, etc.
  • Our data showed, although the reduction in blood pressure was strongest in those patients with normalized UFC levels during pasireotide treatment, there was no general correlation between reduction of Cortisol and reduction of blood pressure. Thus it is possible that pasireotide reduces blood pressure, in addition to or independent of the ACTH/ Cortisol/ adolsterone pathway.
  • the present invention provides a medicament comprising pasireotide and any one of its pharmaceutically acceptable salt for use in the treatment of resistant hypertension in patients.
  • the resistant hypertension is resistant to at least one diuretic drug.
  • the resistant hypertension is triple resistant hypertension.
  • a conventional anti-hypertensive drug refers to at least one anti-hypertensive drug out of any one of the following categories: (i) an inhibitor targeting the renin-angiotensin-aldosterone (RAA) hormonal system (ii) a calcium channel blocker (CCB); and (iii) a diuretic. Drugs as beta-blockers are also used commonly in treating hypertension.
  • RAA renin-angiotensin-aldosterone
  • CCB calcium channel blocker
  • Drugs as beta-blockers are also used commonly in treating hypertension.
  • An inhibitor targeting the renin-angiotensin-aldosterone includes but is limited to renin inhibitor (such as aliskiren).
  • renin inhibitor such as aliskiren
  • An ARB includes but is not limited to candesartan, eprosartan, irbesartan, losartan, olmesartan, saprisailan, tasosartan, telmisartan, valsartan, E-41 77.
  • an ACE inhibitor includes but is limited to benazepril, captopril, lisinopril, quinapril, and ramipril, and pharmaceutically acceptable salts thereof.
  • a calcium channel blocker can be selected from the group consisting of amlodipine, felodipine, isradipine, lacidipinc, nicardipine, nifedipine, niguldipine, niludipine, nimodipine. nisoldipine, nitrendipine, nivaldipine, ryosidine, anipamil, diltiazem, fendiline, flunarizine, gallopamil, m i be f radii, prenylamine, tiapamil. and verapamil, and pharmaceutically acceptable salts thereof.
  • diuretic is very broad, and refers generally to any substance that cause the kidneys to get rid of extra water and salt. There are many kinds of diuretics, and each diuretic works on different parts of the kidneys.
  • Some of the common classes of diuretics include but are not limited to bumetanide, ethacrynic acid, furosemide, torsemidc, amiloride, spironolactone, triamterene, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, metolazone, and dichlorphenamide, and pharmaceutically acceptable salts thereof.
  • Each class of diuretic has a different specific mechanism of action, but all typically share the ultimate outcome of changing the way the kidneys handle salt, water, and other substances.
  • resistant hypertension refers to the situation that despite receiving at least one conventional anti-hypertensive drug, the blood pressure of the treated patients could not reach the goal blood pressure.
  • the at least one anti-hypertensive dr g is a diuretic.
  • the anti-hypertensives are given to the full dose.
  • the term "goal blood pressure" is defined as SBP ⁇ 130mmHg and the DBP ⁇ 90mmHg.
  • resistant hypertension also encompasses the situation in the patients receive combination use of at least two drugs out of any two of the three categories of the
  • At least one of the anti-hypertensive drug is a diuretic. Further preferably, the antihypertensives are given to the full dose.
  • resistant hypertension also encompasses the situation of triple resistant.
  • triple resistant hypertension is defined as hypertension that remains above goal blood pressure in spite of concurrent use of three or more
  • antihypertensive agents belonging to different anti-hypertensive drug classes Preferably, one of the three or more anti-hypertensive agents is a diuretic.
  • triple resistant hypertension refers to hypertension that remains above goal blood pressure in spite of concurrent use of three drugs, each out of categories (i), (ii) and (iii) respectively.
  • the antihypertensives are given to the full dose.
  • full dose in this sense means the highest dose of the respective antihypertensive depending on the age, weight and gender of the patient.
  • pasireotide may effectively reduce blood pressure through lowering the level of ACTH and thereby its down-stream mediators, including Cortisol and adolsterone, which may not be inhibited by the conventional anti-hypertensive drug.
  • the present invention provides medicament comprising pasireotide for use in treating resistant hypertension in patients having a higher than lower limit of normal (LLN) level of ACTH, preferably in patients having a higher than normal level of ACTH, with or without elevated level of Cortisol.
  • LN lower limit of normal
  • the present invention provides a medicament comprising a sustained release formulation of pasireotide.
  • WO2005/046645 describes a sustained release formulation comprising microparticles, wherein the microparticles comprises pasireotide pamoate and one branched and one linear polylactide-co-glycolide polymers.
  • WO2005/120453 discloses a liquid pharmaceutical composition
  • a liquid pharmaceutical composition comprising a polylactide-co- glycolide polymer, polyethylene glycol having a molecular weight of less than 600 Daltons, and pasireotide and its pharmaceutically acceptable salt and less than 1% of a suitable organic solvent,
  • WO2006/066868 describes an autogel formulation bases on the finding that various pasireotide salts, particularly mono- or diaspartate, mono- or diglutamate, mono- or disuccinate, acetate or citrate and water forms a gelling depot system after injection in contact with body fluid.
  • WO2008/152401 discloses the use of the fluidcrystal technology for making a sustained release formulation comprising pasireotide, at least one diacyl glycerol, at least one phosphatidyl choline and at least one oxygen containing organic solvent, wherein preferably it is ethanol.
  • sustained release formulation of pasireotide refers to a formulation comprising at least one active ingredient being pasireotide and any of its pharmaceutically acceptable salts, that, after administration, releases pasireotide over an extended period of at least two weeks, at least 21 days, preferably at least 28 days, at least one month or at 6 weeks in human body.
  • pasireotide is released in a slowly and constantly way
  • Cmin is at least higher than O.lng/ml, higher than 0.3ng/ml, higher than 0.5ng/ml.
  • the present invention provides a combination of pasireotide, or any of its pharmaceutical acceptable salts, and at least one conventional anti-hypertensive drug for simultaneous, separate or sequential use in hypertension patients.
  • Hypertension patients may benefit from this combination use as all known anti-hypertensives are different from the mode of action of Pasireotide and the mode of action of pasireotide is likely complementary.
  • the present invention provides a combination of pasireotide, or any of its pharmaceutical acceptable salts, and at least one a 1 1 beta-hydroxy lase inhibitor for simultaneous, separate or sequential use in hypertension patients.
  • the 1 lbeta-hydroxylase inhibitor is Compound B having formula (H):
  • Compound B is also called (R)-4-(6,7-Dihydro-5H-pyrrolo[l,2-c]imidazol-5-yl)-3-fluoro- benzonitrile.
  • Compound B can be synthesized or produced and characterized by methods as described in WO2007/024945.
  • the preferred salt of Compound B is phosphate salt.
  • Example 1 Pasireotide treatment is associated with improvements in hypertension: 12-month results from a large Phase III study of pasireotide in Cushing's disease
  • Baseline HTN was defined as at least one of: history of anti-HTN medications; medical history of HTN; SBP>130mmHg; or DBP>90mmHg. The addition of medications for HTN was allowed per investigator discretion.
  • COMPOUND B is a potent inhibitor of 1 1 ⁇ -hydroxylase. Since 1 1 ⁇ -hydroxylase catalyzes the final step of Cortisol synthesis, COMPOUND B is a potential new treatment for all forms of Cushing's syndrome.
  • COMPOUND B was generally well tolerated; the most frequently reported adverse events were fatigue (5/1 1), nausea (4/1 1) and headache (3/1 1). Five patients experienced ACTH levels >2xbaseline. Four patients experienced study drug-related hypokalemia (K + ⁇ 3.5mmol/L; min 3.1 mmol/L). There were no serious AEs of suspected drug relationship.
  • COMPOUND B demonstrated efficacy with a satisfactory safety profile in this proof-of-concept study in patients with Cushing's disease.

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  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne de nouveaux domaines d'application de la pasireotide, en particulier pour le traitement de l'hypertension artérielle et/ou de niveaux élevés de cortisol, les nouveaux domaines étant l'obésité, la dépression, le stress et/ou l'alcoolisme.
PCT/EP2013/054343 2012-03-07 2013-03-05 Nouvelle application pour la pasireotide WO2013131879A1 (fr)

Applications Claiming Priority (4)

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US201261607724P 2012-03-07 2012-03-07
US61/607,724 2012-03-07
US201261623113P 2012-04-12 2012-04-12
US61/623,113 2012-04-12

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015512923A (ja) * 2012-04-12 2015-04-30 ノバルティス アーゲー ソマトスタチンアナログの１１ベータ−水酸化酵素阻害剤との組合せ
DE102015206921A1 (de) 2015-04-16 2016-10-20 Bekon Holding Ag Bioreaktor mit Drainagerinne

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WO2005046645A1 (fr) 2003-11-14 2005-05-26 Novartis Ag Composition pharmaceutique
WO2005120453A1 (fr) 2004-06-09 2005-12-22 Novartis Ag Compositions pharmaceutiques comprenant un polyethylene glycol de poids moleculaire inferieur a 600 daltons
WO2006066868A2 (fr) 2004-12-22 2006-06-29 Novartis Ag Composes organiques
WO2007024945A1 (fr) 2005-08-25 2007-03-01 Novartis Ag Derives imidazolo condenses utilises pour inhiber l'aldosterone synthase et l'aromatase
WO2008152401A1 (fr) 2007-06-15 2008-12-18 Camurus Ab Formulations de peptides à libération retardée

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WO2005046645A1 (fr) 2003-11-14 2005-05-26 Novartis Ag Composition pharmaceutique
WO2005120453A1 (fr) 2004-06-09 2005-12-22 Novartis Ag Compositions pharmaceutiques comprenant un polyethylene glycol de poids moleculaire inferieur a 600 daltons
WO2006066868A2 (fr) 2004-12-22 2006-06-29 Novartis Ag Composes organiques
WO2007024945A1 (fr) 2005-08-25 2007-03-01 Novartis Ag Derives imidazolo condenses utilises pour inhiber l'aldosterone synthase et l'aromatase
WO2008152401A1 (fr) 2007-06-15 2008-12-18 Camurus Ab Formulations de peptides à libération retardée

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"Remington's Pharmaceutical Sciences, 18th Ed.", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
CALHOUN DAVID A ET AL: "Effects of a Novel Aldosterone Synthase Inhibitor for Treatment of Primary Hypertension Results of a Randomized, Double-Blind, Placebo- and Active-Controlled Phase 2 Trial", CIRCULATION, vol. 124, no. 18, November 2011 (2011-11-01), pages 1945, XP002694470 *
M. BOSCARO ET AL: "Treatment of Pituitary-Dependent Cushing's Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial", JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 94, no. 1, 1 January 2008 (2008-01-01), pages 115 - 122, XP055057780, ISSN: 0021-972X, DOI: 10.1210/jc.2008-1008 *
NORLELA SUKOR: "Endocrine hypertension Current understanding and comprehensive management review", EUROPEAN JOURNAL OF INTERNAL MEDICINE, ELSEVIER, AMSTERDAM, NL, vol. 22, no. 5, 7 May 2011 (2011-05-07), pages 433 - 440, XP028291912, ISSN: 0953-6205, [retrieved on 20110514], DOI: 10.1016/J.EJIM.2011.05.004 *
SACERDOTE ALAN ET AL: "Hypertension in patients with Cushing's disease: pathophysiology, diagnosis, and management", CURRENT HYPERTENSION REPORTS, CURRENT SCIENCE LTD, GB, vol. 7, no. 3, 1 June 2005 (2005-06-01), pages 212 - 218, XP009116121, ISSN: 1522-6417, DOI: 10.1007/S11906-005-0013-4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015512923A (ja) * 2012-04-12 2015-04-30 ノバルティス アーゲー ソマトスタチンアナログの１１ベータ−水酸化酵素阻害剤との組合せ
DE102015206921A1 (de) 2015-04-16 2016-10-20 Bekon Holding Ag Bioreaktor mit Drainagerinne

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