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Octreotide

Clinical data
Trade names	Sandostatin
AHFS/Drugs.com	Monograph
Routes of administration	Subcutaneous, intramuscular, intravenous
ATC code	H01CB02 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	100%; I.M.: 60% to 63% of subcutaneous dose
Protein binding	65%
Metabolism	Hepatic
Elimination half-life	1.7–1.9 hours
Identifiers
IUPAC name (4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19- amino]-16- benzyl-N--7- (1-hydroxyethyl)-13-(1H-indol-3-ylmethyl)-6,9,12, 15,18-pentaoxo-1,2-dithia-5,8,11,14,17- pentazacycloicosane-4-carboxamide
CAS Number	83150-76-9 79517-01-4 (acetate) 135467-16-2 (pamoate)
PubChem CID	54373
DrugBank	DB00104
ChemSpider	10482007
UNII	RWM8CCW8GP
CompTox Dashboard (EPA)	DTXSID0048682
Chemical and physical data
Formula	C49H66N10O10S2
Molar mass	1019.24 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES C(O)(CO)NC(=O)5CSSC(NC(=O)(N)Cc1ccccc1)C(=O)N(Cc2ccccc2)C(=O)N(Cc4cnc3ccccc34)C(=O)N(CCCCN)C(=O)N(C(C)O)C(=O)N5
InChI InChI=1S/C49H66N10O10S2/c1-28(61)39(25-60)56-48(68)41-27-71-70-26-40(57-43(63)34(51)21-30-13-5-3-6-14-30)47(67)54-37(22-31-15-7-4-8-16-31)45(65)55-38(23-32-24-52-35-18-10-9-17-33(32)35)46(66)53-36(19-11-12-20-50)44(64)59-42(29(2)62)49(69)58-41/h3-10,13-18,24,28-29,34,36-42,52,60-62H,11-12,19-23,25-27,50-51H2,1-2H3,(H,53,66)(H,54,67)(H,55,65)(H,56,68)(H,57,63)(H,58,69)(H,59,64)/t28-,29?,34-,36+,37+,38-,39-,40+,41+,42+/m1/s1 Key:DEQANNDTNATYII-RRCPSWKPSA-N
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Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was first synthesized in 1979 by the chemist Wilfried Bauer.

Uses

Approved uses

The Food and Drug Administration (FDA) has approved the usage of a salt form of this peptide, octreotide acetate, as an injectable depot formulation for the treatment of acromegaly, diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPomas).

Radiolabelling

Octreotide is used in nuclear medicine imaging by labelling with indium-111 (Octreoscan) to noninvasively image neuroendocrine and other tumours expressing somatostatin receptors. More recently, it has been radiolabelled with gallium-68, enabling imaging with positron emission tomography (PET), which provides higher resolution and sensitivity.

Octreotide can also be labelled with a variety of radionuclides, such as yttrium-90 or lutetium-177, to enable peptide receptor radionuclide therapy (PRRT) for the treatment of unresectable neuroendocrine tumours.

Off-label and experimental uses

Octreotide has also been used off-label for the treatment of severe, refractory diarrhea from other causes. It is used in toxicology for the treatment of prolonged recurrent hypoglycemia after sulfonylurea and possibly meglitinides overdose. It has also been used with varying degrees of success in infants with nesidioblastosis to help decrease insulin hypersecretion.

In patients with suspected esophageal varices, octreotide can be given to help decrease bleeding. It has been investigated for patients with pain from chronic pancreatitis, and it may be useful in the treatment of thymic neoplasms.

The drug has been used off-label, injected subcutaneously, in the management of hypertrophic pulmonary osteoarthropathy (HPOA) secondary to non-small cell lung carcinoma. Although its mechanism is not known, it appears to reduce the pain associated with HPOA.

It has been used in the treatment of malignant bowel obstruction.

Octreotide may be used in conjunction with midodrine to partially reverse peripheral vasodilation in the hepatorenal syndrome. By increasing systemic vascular resistance, these drugs reduce shunting and improve renal perfusion, prolonging survival until definitive treatment with liver transplant.

The drug has also been shown to be effective in the treatment of chylothorax.

A small study has shown that octreotide may be effective in the treatment of idiopathic intracranial hypertension.

Contraindications

Octreotide has not been adequately studied for the treatment of children, pregnant and lactating women. The drug is given to these groups of patients only if a risk-benefit analysis is positive.

Adverse effects

The most frequent adverse effects (more than 10% of patients) are headache, hypothyroidism, cardiac conduction changes, gastrointestinal reactions (including cramps, nausea/vomiting and diarrhea or constipation), gallstones, reduction of insulin release, hyperglycemia or hypoglycemia, and (usually transient) injection site reactions. Slow heart rate, skin reactions such as pruritus, hyperbilirubinemia, hypothyreosis, dizziness and dyspnea are also fairly common (more than 1%). Rare side effects include acute anaphylactic reactions, pancreatitis and hepatitis.

Some studies reported alopecia in patients who were treated by octreotide. Rats which were treated by octreotide experienced erectile disfunction in a 1998 study. A prolonged QT interval has been observed in patients, but it is uncertain whether this is a reaction to the drug or part of the patients' illnesses.

Pharmacokinetics

Octreotide is absorbed quickly and completely after subcutaneous application. Maximal plasma concentration is reached after 30 minutes. The elimination half-life is 100 minutes (1.7 hours) on average when applied subcutaneously; after intravenous injection, the substance is eliminated in two phases with half-lives of 10 and 90 minutes, respectively.

Pharmacological effects

Since octreotide resembles somatostatin in physiological activities, it can:

• inhibit secretion of many hormones, such as gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, TSH, and vasoactive intestinal peptide,
• reduce secretion of fluids by the intestine and pancreas,
• reduce gastrointestinal motility and inhibit contraction of the gallbladder,
• inhibit the action of certain hormones from the anterior pituitary,
• cause vasoconstriction in the blood vessels, and
• reduce portal vessel pressures in bleeding varices.

It has also been shown to produce analgesic effects, most probably acting as a partial agonist at the mu opioid receptor.

Interactions

Octreotide can reduce the intestinal resorption of ciclosporin, possibly making it necessary to increase the dose. Patients with diabetes mellitus might need less insulin or oral antidiabetics when treated with octreotide. The bioavailability of bromocriptine is increased; besides being an antiparkinsonian, bromocriptine is also used for the treatment of acromegaly.

See also

• Octreotate, a closely related peptide

References

1. Medscape: Octreoscan review
2. Abid S, Jafri W, Hamid S; et al. (2009). "Terlipressin vs. octreotide in bleeding esophageal varices as an adjuvant therapy with endoscopic band ligation: a randomized double-blind placebo-controlled trial". Am. J. Gastroenterol. 104 (3): 617–23. doi:10.1038/ajg.2008.147. PMID 19223890. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
3. Uhl W, Anghelacopoulos SE, Friess H, Büchler MW (1999). "The role of octreotide and somatostatin in acute and chronic pancreatitis". Digestion. 60 Suppl 2: 23–31. doi:10.1159/000051477. PMID 10207228.{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. Shima Y, Ohtsu A, Shirao K, Sasaki Y (2008). "Clinical efficacy and safety of octreotide (SMS201-995) in terminally ill Japanese cancer patients with malignant bowel obstruction". Japanese journal of clinical oncology. 38 (5): 354–9. doi:10.1093/jjco/hyn035. PMID 18490369. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
5. Skagen C, Einstein M, Lucey MR, Said A (2009). "Combination Treatment With Octreotide, Midodrine, and Albumin Improves Survival in Patients With Type 1 and Type 2 Hepatorenal Syndrome". J Clin Gastroenterol. 43 (7): 680–5. doi:10.1097/MCG.0b013e318188947c. PMID 19238094. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
6. Dalokay Kilic, MD, Ekber Sahin, MD, Oner Gulcan, MD, Bulent Bolat, MD, Riza Turkoz, MD, Ahmet Hatipoglu, MD (2005). "Octreotide for Treating Chylothorax after Cardiac Surgery". Texas Heart Institute Journal. 32 (3): 437–39. PMC 1336729. PMID 16392238.{{cite journal}}: CS1 maint: multiple names: authors list (link)
7. Marcia L. Buck, Pharm.D., FCCP (2004). "Octreotide for the Management of Chylothorax in Infants and Children". Pediatric Pharmacotherapy. 10 (10).{{cite journal}}: CS1 maint: multiple names: authors list (link)
8. Greek Researchers Investigate Octreotide Hypertension Research Foundation, accessed 2011-01-02
9. G. N. Panagopoulos, S. N. Deftereos, G. A. Tagaris, M. Gryllia, T. Kounadi, O. Karamani, D. Panagiotidis, E. Koutiola-Pappa, C. E. Karageorgiou, G. Piadites (2007-07-10). "Octreotide: A therapeutic option for idiopathic intracranial hypertension". Neurology, Neurophysiology and Neuroscience. Retrieved 2011-01-02.{{cite journal}}: CS1 maint: multiple names: authors list (link)
10. ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
11. ^ Dinnendahl, V, Fricke, U, ed. (2010). Arzneistoff-Profile (in German). Vol. 8 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-98-46-3.{{cite book}}: CS1 maint: multiple names: editors list (link)
12. Hovind, P; Simonsen, L; Bülow, J (2010). "Decreased leg glucose uptake during exercise contributes to the hyperglycaemic effect of octreotide". Clinical physiology and functional imaging. 30 (2): 141–5. doi:10.1111/j.1475-097X.2009.00917.x. PMID 20132129.
13. Van Der Lely, AJ; De Herder, WW; Lamberts, SW (1997). "A risk-benefit assessment of octreotide in the treatment of acromegaly". Drug safety : an international journal of medical toxicology and drug experience. 17 (5): 317–24. PMID 9391775.
14. Kapicioglu, S; Mollamehmetoglu, M; Kutlu, N; Can, G; Ozgur, GK (1998). "Inhibition of penile erection in rats by a long-acting somatostatin analogue, octreotide (SMS 201-995)". British journal of urology. 81 (1): 142–5. PMID 9467491.
15. Maurer R, Gaehwiler BH, Buescher HH, Hill RC, Roemer D. Opiate antagonistic properties of an octapeptide somatostatin analog. Proceedings of the National Academy of Sciences USA. 1982 Aug;79(15):4815-7. PMID 6126877
16. Allen MP, Blake JF, Bryce DK, Haggan ME, Liras S, McLean S, Segelstein BE. Design, synthesis and biological evaluation of 3-amino-3-phenylpropionamide derivatives as novel mu opioid receptor ligands. Bioorganic and Medicinal Chemistry Letters. 2000 Mar 20;10(6):523-6. PMID 10741545
17. Klopp, T, ed. (2010). Arzneimittel-Interaktionen (in German) (2010/2011 ed.). Arbeitsgemeinschaft für Pharmazeutische Information. ISBN 978-3-85200-207-1.

• Hormonal agents
• Peptides