Octreotide

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Octreotide
Octreotide.svg
File:Octreotide3d.png
Systematic (IUPAC) name
(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-19-
[[(2R)-2-amino-3-phenyl-propanoyl]amino]-16-
benzyl-N-[(2R,3R)-1,3-dihydroxybutan-2-yl]-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
Clinical data
Trade names Sandostatin
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Subcutaneous, intramuscular, intravenous
Pharmacokinetic data
Bioavailability 60% (IM), 100% (SC)
Protein binding 40–65%
Metabolism Hepatic
Biological half-life 1.7–1.9 hours
Excretion Urine (32%)
Identifiers
CAS Number 83150-76-9 YesY
Template:CAS (acetate)
Template:CAS (pamoate)
ATC code H01CB02 (WHO)
PubChem CID: 448601
IUPHAR/BPS 2055
DrugBank DB00104 YesY
ChemSpider 395352
UNII RWM8CCW8GP YesY
KEGG D00442 N
ChEMBL CHEMBL1680 N
Chemical data
Formula C49H66N10O10S2
Molecular mass 1019.24 g/mol
  • C[C@H]([C@H]1C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)CCCCN)Cc2c[nH]c3c2cccc3)Cc4ccccc4)NC(=O)[C@@H](Cc5ccccc5)N)C(=O)N[C@H](CO)[C@@H](C)O)O
  • 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-OULOTJBUSA-N
 NYesY (what is this?)  (verify)

Octreotide (brand name Sandostatin,[1] 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.

Medical uses

Tumors

Octreotide is used for the treatment of growth hormone producing tumors (acromegaly and gigantism), pituitary tumors that secrete thyroid stimulating hormone (thyrotropinoma), diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas).

Bleeding esophageal varices

Octreotide is often given as an infusion for management of acute haemorrhage from esophageal varices in liver cirrhosis on the basis that it reduces portal venous pressure, though current evidence suggests that this effect is transient and does not improve survival.[2]

Radiolabelling

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Octreotide is used in nuclear medicine imaging by labelling with indium-111 (Octreoscan) to noninvasively image neuroendocrine and other tumours expressing somatostatin receptors.[3] More recently, it has been radiolabelled with carbon-11[4] as well as 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.

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.[5][6]

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 diarrhoea or constipation), gallstones, reduction of insulin release, hyperglycemia[7] or hypoglycemia, and (usually transient) injection site reactions. Slow heart rate, skin reactions such as pruritus, hyperbilirubinemia, hypothyroidism, dizziness and dyspnoea are also fairly common (more than 1%). Rare side effects include acute anaphylactic reactions, pancreatitis and hepatitis.[5][6] One study reported a possible association with rheumatoid arthritis.[8]

Some studies reported alopecia in patients who were treated by octreotide.[9] Rats which were treated by octreotide experienced erectile dysfunction in a 1998 study.[10]

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.[5]

Identifiers
Symbol N/A
OPM superfamily 167
OPM protein 1soc

Interactions

Octreotide can reduce the intestinal resorption of ciclosporin, possibly making it necessary to increase the dose.[11] Patients with diabetes mellitus might need less insulin or oral antidiabetics when treated with octreotide. The bioavailability of bromocriptine is increased;[6] besides being an antiparkinsonian, bromocriptine is also used for the treatment of acromegaly.

Pharmacological effects

Since octreotide resembles somatostatin in physiological activities, it can:

It has also been shown to produce analgesic effects, most probably acting as a partial agonist at the mu opioid receptor.[12][13]

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.[5][6]

Research

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. Several clinical trials also proves the effect of octreotide as acute treatment (abortive agent) in cluster headache, where it shows that administration of subcutaneous octreotide is effective when compared with placebo.[14]

Octreotide has been used experimentally to treat obesity, particularly obesity caused by lesions in the hunger and satiety centers of the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure.[15] The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brain's feeding and satiety centers, respectively.[16][17] The VMH is sometimes injured by ongoing treatment for acute lymphoblastic leukemia (ALL) or surgery or radiation to treat posterior cranial fossa tumors.[15] With the VMH disabled and no longer responding to peripheral energy balance signals, "Efferent sympathetic activity drops, resulting in malaise and reduced energy expenditure, and vagal activity increases, resulting in increased insulin secretion and adipogenesis."[18] "VMH dysfunction promotes excessive caloric intake and decreased caloric expenditure, leading to continuous and unrelenting weight gain. Attempts at caloric restriction or pharmacotherapy with adrenergic or serotonergic agents have previously met with little or only brief success in treating this syndrome."[15] In this context, octreotide suppresses the excessive release of insulin and may increase its action, thereby inhibiting excessive adipose storage. In a small clinical trial in eighteen pediatric patients with intractable weight gain following therapy for ALL or brain tumors and other evidence of hypothalamic dysfunction, octreotide reduced body mass index (BMI) and insulin response during glucose tolerance test, while increasing parent-reported physical activity and quality of life (QoL) relative to placebo.[15] In a separate placebo-controlled trial of obese adults without known hypothalamic lesions, obese patients who received long-acting octreotide lost weight and reduced their BMI compared to patients receiving placebo; post hoc analysis suggested greater effects in patients receiving the higher dose of the drug, and among "Caucasian patients having insulin secretion greater than the median of the cohort." "There were no statistically significant changes in QoL scores, body fat, leptin concentration, Beck Depression Inventory, or macronutrient intake", although patients taking octreotide had higher blood glucose after a glucose tolerance test than those receiving placebo.[19]

Octreotide has also been investigated for patients with pain from chronic pancreatitis.[20]

It has been used in the treatment of malignant bowel obstruction.[21]

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.[22] Similarly, octreotide can be used to treat refractory chronic hypotension.[23]

While successful treatment has been demonstrated in case reports,[24][25] larger studies have failed to demonstrate efficacy in treating chylothorax.[26]

A small study has shown that octreotide may be effective in the treatment of idiopathic intracranial hypertension.[27][28]

See also

References

  1. Official manufacturer website for up-to-date dosing & safety information: http://www.sandostatin.com
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  3. Medscape: Octreoscan review
  4. Joshua Chin, Matthew Vesnaver, Vadim Bernard-Gauthier, Erin Saucke-Lacelle, Björn Wängler, Carmen Wängler, Ralf Schirrmacher. Amino Acids: Direct one-step labeling of cysteine residues on peptides with 11C-methyl triflate for the synthesis of PET radiopharmaceuticals. Amino Acids. 2013 Aug 7. PMID 23921782
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  12. 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
  13. 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
  14. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study.
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  27. Greek Researchers Investigate Octreotide Hypertension Research Foundation, accessed 2011-01-02
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