• 1
    Colao A, Baldelli R, Marzullo P, et al. Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy. J Clin Endocrinol Metab. 2000; 85:193199.
  • 2
    Fatti LM, Scacchi M, Lavezzi E, et al. Effects of treatment with somatostatin analogues on QT interval duration in acromegalic patients. Clin Endocrinol (Oxf). 2006; 65:626630.
  • 3
    Lombardi G, Colao A, Ferone D, et al. Cardiovascular aspects in acromegaly: effects of treatment. Metabolism. 1996; 45:5760.
  • 4
    Lombardi G, Colao A, Marzullo P, Biondi B, Palmieri E, Fazio S. Improvement of left ventricular hypertrophy and arrhythmias after lanreotide-induced GH and IGF-I decrease in acromegaly. A prospective multi-center study. J Endocrinol Invest. 2002; 25:971976.
  • 5
    Pecori Giraldi F, Toja PM, Michailidis G, et al. High prevalence of prolonged QT interval duration in male patients with Cushing's disease. Exp Clin Endocrinol Diabetes. 2011; 119:221224.
  • 6
    Smith WH, Nair RU, Adamson D, Kearney MT, Ball SG, Balmforth AJ. Somatostatin receptor subtype expression in the human heart: differential expression by myocytes and fibroblasts. J Endocrinol. 2005; 187:379386.
  • 7
    Bubinski R, Kus W, Goch J. Effect of somatostatin on the conduction system of the heart. Kardiol Pol. 1993; 38:258262.
  • 8
    Arizona CERT. Drugs that prolong the QT interval and/or induce torsades de pointes ventricular arrhythmia. 2011. Available at: (last accessed September 2013).
  • 9
    Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D. The effect of acute hyperglycaemia on QTc duration in healthy man. Diabetologia. 2000; 43:571575.
  • 10
    Colao A, Petersenn S, Newell-Price J, et al. A 12-month Phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012; 366:914924.
  • 11
    Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pituitary dependent Cushing's disease with the multi-receptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009; 94:115122.
  • 12
    Novartis Pharma AG. Signifor Summary of Product Characteristics. 2012. Available at: (last accessed February 2013).
  • 13
    FDA. Guidance for Industry: E14 Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarryhthmic drugs. 2005. Available at: (last accessed October 2013).
  • 14
    Hosmane B, Locke C. A simulation study of power in thorough QT/QTc studies and a normal approximation for planning purposes. Drug Inf J. 2005; 39:447455.
  • 15
    Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika. 1986; 73:751754.
  • 16
    Li J, Birmingham B, Mosqueda-Garcia R, Sander N, Newbold P, Sager P. Evaluation of a drug-induced QT/QTc prolongation in the presence of the drug induced changes in heart rate by using population PK/PD modeling approach: sibenadet experience. Clin Pharmacol Ther. 2008; 83(S41–S42):abst OII-E-2.
  • 17
    Dmitrienko A, Smith B. Analysis of QT interval in clinical trials. Drug Inf J. 2002; 36:269279.
  • 18
    Dmitrienko A, Smith B. Repeated-measures models in the analysis of QT interval. Pharmaceut Statist. 2003; 2:175190.
  • 19
    Alexandraki KI, Kaltsas GA, Vouliotis AI, et al. Specific electrocardiographic features associated with Cushing's disease. Clin Endocrinol (Oxf). 2011; 74:558564.
  • 20
    Sullivan JT, Woodruff M, Lettieri J, et al. Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone. Antimicrob Agents Chemother. 1999; 43:27932797.
  • 21
    Bloomfield DM, Kost JT, Ghosh K, et al. The effect of moxifloxacin on QTc and implications for the design of thorough QT studies. Clin Pharmacol Ther. 2008; 84:475480.
  • 22
    Stass H, Kubitza D. Pharmacokinetics and elimination of moxifloxacin after oral and intravenous administration in man. J Antimicrob Chemother. 1999; 43(Suppl. B):8390.
  • 23
    Zhang J. Testing for positive control activity in a thorough QTc study. J Biopharm Stat. 2008; 18:517528.
  • 24
    Florian JA, Tornoe CW, Brundage R, Parekh A, Garnett CE. Population pharmacokinetic and concentration—QTc models for moxifloxacin: pooled analysis of 20 thorough QT studies. J Clin Pharmacol. 2011; 51:11521162.
  • 25
    Dixon R, Job S, Oliver R, et al. Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects. Br J Clin Pharmacol. 2008; 66:396404.
  • 26
    Petersenn S, Schopohl J, Barkan A, et al. Pasireotide (SOM230) demonstrates efficacy and safety in patients with acromegaly: a randomized, multicenter, Phase II trial. J Clin Endocrinol Metab. 2010; 95:27812789.
  • 27
    Petersenn S, Farrall AJ, Block C, et al. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. Pituitary. 2013; Mar 26:[Epub ahead of print]
  • 28
    Cozzi R, Attanasio R. Octreotide for acromegaly. Expert Rev Endocrinol Metab. 2007; 2:129145.
  • 29
    Ma P, Wang Y, Van Der Hoek J, et al. Pharmacokinetic-pharmacodynamic comparison of a novel multiligand somatostatin analog, SOM230, with octreotide in patients with acromegaly. Clin Pharmacol Ther. 2005; 78:6980.
  • 30
    Petersenn S, Unger N, Hu K, et al. Pasireotide (SOM230), a novel multi-receptor-targeted somatostatin analogue, is well tolerated when administered as a continuous 7-day subcutaneous infusion in healthy male volunteers. J Clin Pharmacol. 2012; 52:10171027.
  • 31
    Beglinger C, Hu K, Wang Y, et al. Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study. Endocrine. 2012; 42:366374.
  • 32
    Golor G, Hu K, Ruffin M, et al. A first-in-man study to evaluate the safety, tolerability and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers. Drug Des Dev Ther. 2012; 6:7179.
  • 33
    Petersenn S, Hu K, Maldonado M, et al. Tolerability and dose-proportional pharmacokinetics of pasireotide administered as a single dose or two divided doses in healthy male volunteers: a single-center, open-label, ascending-dose study. Clin Ther. 2012; 34:677688.
  • 34
    Novartis Pharmaceuticals. Signifor Prescribing Information. 2012. Available at: (last accessed February 2013).