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Octreotide

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Octreotide
3D structure of octreotide. PDB: 6VC1​
Clinical data
Trade namesSandostatin, Bynfezia Pen, Mycapssa, others
AHFS/Drugs.comMonograph
MedlinePlusa693049
License data
Pregnancy
category
  • AU: C
Routes of
administration		Subcutaneous, intramuscular, intravenous, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60% (IM), 100% (SC)
Protein binding40–65%
MetabolismLiver
Elimination half-life1.7–1.9 hours
ExcretionUrine (32%)
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC49H66N10O10S2
Molar mass1019.25 g·mol−1
3D model (JSmol)
  • 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 ☒N
  • Key:DEQANNDTNATYII-OULOTJBUSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Octreotide, sold under the brand name Sandostatin among others, 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 and binds predominantly to the somatostatin receptors SSTR2 and SSTR5.[5]

It was approved for use in the United States in 1988.[2][1] Octreotide was approved for medical use in the European Union in 2022.[4] As of June 2020, octreotide is the first oral somatostatin analog (SSA) approved by the FDA.[6] It is on the World Health Organization's List of Essential Medicines.[7]

Medical uses

[edit]

Tumors

[edit]

Octreotide is used for the treatment of growth hormone producing tumors (acromegaly and gigantism), when surgery is contraindicated, pituitary tumors that secrete thyroid-stimulating hormone (thyrotropinoma),[citation needed] diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas). Octreotide is also used in mild cases of glucagonoma when surgery is not an option.[8][9]

Bleeding esophageal varices

[edit]

Octreotide is often given as an infusion for management of acute hemorrhage 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.[10]

Radiolabeling

[edit]
Further information: Octreotide scan

Octreotide is used in nuclear medicine imaging by labeling with indium-111 (Octreoscan) to noninvasively image neuroendocrine and other tumours expressing somatostatin receptors.[11] It has been radiolabeled with carbon-11[12] as well as gallium-68 (using edotreotide), enabling imaging with positron emission tomography (PET).

Acromegaly

[edit]

In June 2020, octreotide (Mycapssa) was approved for medical use in the United States with an indication for the long-term maintenance treatment in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide.[13][6] Mycapssa is the first oral somatostatin analog (SSA) approved by the FDA.[6]

Hypoglycemia

[edit]

Octreotide is also used in the treatment of refractory hypoglycemia or congenital hyperinsulinism in neonates[14] and sulphonylurea-induced hypoglycemia in adults.

Contraindications

[edit]

Octreotide has not been adequately studied for the treatment of children as well as pregnant and lactating women. The medication is given to these groups only if a risk-benefit analysis is positive.[15][16]

Adverse effects

[edit]

The most common adverse effects are headache, hypothyroidism, cardiac conduction changes, gastrointestinal reactions (including cramps, nausea/vomiting and diarrhoea or constipation), gallstones, reduction of insulin release, hyperglycemia[17] or sometimes 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.[15][16]

Some studies reported alopecia in those who were treated by octreotide.[18] Rats which were treated by octreotide experienced erectile dysfunction in a 1998 study.[19]

A prolonged QT interval has been observed, but it is uncertain whether this is a reaction to the medication or the result of an existing illness.[15]

Interactions

[edit]

Octreotide can reduce the intestinal reabsorption of ciclosporin, possibly making it necessary to increase the dose.[20] People with diabetes mellitus might need less insulin or oral antidiabetics when treated with octreotide, as it inhibits glucagon secretion more strongly and for a longer time span than insulin secretion.[15] The bioavailability of bromocriptine is increased;[16] besides being an antiparkinsonian, bromocriptine is also used for the treatment of acromegaly.

Pharmacology

[edit]

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.[21][22]

Pharmacokinetics

[edit]

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.[15][16]

History

[edit]

Octreotide acetate was approved for use in the United States in 1988.[1][2]

In January 2020, approval of octreotide acetate in the United States was granted to Sun Pharmaceutical under the brand name Bynfezia Pen for the treatment of:[2][23][24]

Society and culture

[edit]
[edit]

In September 2022, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Mycapssa, intended for the treatment of adults with acromegaly.[25] The applicant for this medicinal product is Amryt Pharmaceuticals DAC.[25] Mycapssa was approved for medical use in the European Union in December 2022.[4][26]

Research

[edit]

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 meglitinide overdose. It has also been used with varying degrees of success in infants with nesidioblastosis to help decrease insulin hypersecretion. Several clinical trials have demonstrated the effect of octreotide as acute treatment (abortive agent) in cluster headache, where it has been shown that administration of subcutaneous octreotide is effective when compared with placebo.[27]

Octreotide has also been investigated in people with pain from chronic pancreatitis.[28]

It has been used in the treatment of malignant bowel obstruction.[29]

Octreotide may be used in conjunction with midodrine to partially reverse peripheral vasodilation in the hepatorenal syndrome. By increasing systemic vascular resistance, these medications reduce shunting and improve renal perfusion, prolonging survival until definitive treatment with liver transplant.[30] Similarly, octreotide can be used to treat refractory chronic hypotension.[31][unreliable medical source?]

While successful treatment has been demonstrated in case reports,[32][33] larger studies have failed to demonstrate efficacy in treating chylothorax.[34]

A small study has shown[when?] that octreotide may be effective in the treatment of idiopathic intracranial hypertension.[35][unreliable medical source?][36]

Obesity

[edit]

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.[37] 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.[38][39] The ventromedial hypothalamus is sometimes injured by ongoing treatment for acute lymphoblastic leukemia or surgery or radiation to treat posterior cranial fossa tumors.[37] With the ventromedial hypothalamus 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."[40] "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."[37] 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 subjects with intractable weight gain following therapy for acute lymphoblastic leukemia 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.[37] In a separate placebo-controlled trial of obese adults without known hypothalamic lesions, obese subjects who received long-acting octreotide lost weight and reduced their BMI compared to subjects receiving placebo; post hoc analysis suggested greater effects in participants receiving the higher dose of the medication, and among "Caucasian subjects 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 subjects taking octreotide had higher blood glucose after a glucose tolerance test than those receiving placebo.[41]

References

[edit]
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  2. ^ a b c d "Bynfezia Pen- octreotide acetate injection". DailyMed. 19 February 2020. Archived from the original on 19 September 2022. Retrieved 19 April 2021.
  3. ^ "Mycapssa- octreotide capsule, delayed release". DailyMed. 21 August 2024. Retrieved 30 September 2024.
  4. ^ a b c "Mycapssa EPAR". European Medicines Agency. 14 September 2022. Retrieved 24 December 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ^ Hofland LJ, Lamberts SW (January 1996). "Somatostatin receptors and disease: role of receptor subtypes". Baillière's Clinical Endocrinology and Metabolism. 10 (1): 163–176. doi:10.1016/s0950-351x(96)80362-4. hdl:1765/60433. PMID 8734455.
  6. ^ a b c "Chiasma Announces FDA Approval of Mycapssa (Octreotide) Capsules, the First and Only Oral Somatostatin Analog". Chiasma (Press release). 26 June 2020. Archived from the original on 30 June 2020. Retrieved 30 June 2020.
  7. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
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  27. ^ Matharu MS, Levy MJ, Meeran K, Goadsby PJ (October 2004). "Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study". Annals of Neurology. 56 (4): 488–94. doi:10.1002/ana.20210. PMID 15455406. S2CID 23879669.
  28. ^ Uhl W, Anghelacopoulos SE, Friess H, Büchler MW (1999). "The role of octreotide and somatostatin in acute and chronic pancreatitis". Digestion. 60 (2): 23–31. doi:10.1159/000051477. PMID 10207228. S2CID 24011709.
  29. ^ Shima Y, Ohtsu A, Shirao K, Sasaki Y (May 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.
  30. ^ Skagen C, Einstein M, Lucey MR, Said A (August 2009). "Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome". Journal of Clinical Gastroenterology. 43 (7): 680–5. doi:10.1097/MCG.0b013e318188947c. PMID 19238094. S2CID 19747120.
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  32. ^ Kilic D, Sahin E, Gulcan O, Bolat B, Turkoz R, Hatipoglu A (2005). "Octreotide for treating chylothorax after cardiac surgery". Texas Heart Institute Journal. 32 (3): 437–9. PMC 1336729. PMID 16392238.
  33. ^ Siu SL, Lam DS (2006). "Spontaneous neonatal chylothorax treated with octreotide". Journal of Paediatrics and Child Health. 42 (1–2): 65–7. doi:10.1111/j.1440-1754.2006.00788.x. PMID 16487393. S2CID 24561126.
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  35. ^ "Intracranial Hypertension Research Foundation". ihrfoundation.org. 17 May 2011. Archived from the original on 19 December 2010. Retrieved 30 September 2024.
  36. ^ Panagopoulos GN, Deftereos SN, Tagaris GA, Gryllia M, Kounadi T, Karamani O, et al. (July 2007). "Octreotide: a therapeutic option for idiopathic intracranial hypertension". Neurology, Neurophysiology, and Neuroscience: 1. PMID 17700925.{{cite journal}}: CS1 maint: overridden setting (link)
  37. ^ a b c d Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, et al. (June 2003). "Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial". The Journal of Clinical Endocrinology and Metabolism. 88 (6): 2586–92. doi:10.1210/jc.2002-030003. PMID 12788859.{{cite journal}}: CS1 maint: overridden setting (link)
  38. ^ Flier JS (January 2004). "Obesity wars: molecular progress confronts an expanding epidemic". Cell. 116 (2): 337–50. doi:10.1016/S0092-8674(03)01081-X. PMID 14744442.
  39. ^ Boulpaep EL, Boron WF (2003). Medical physiologya: A cellular and molecular approach. Philadelphia: Saunders. p. 1227. ISBN 978-0-7216-3256-8.
  40. ^ Lustig RH (2011). "Hypothalamic obesity after craniopharyngioma: mechanisms, diagnosis, and treatment". Frontiers in Endocrinology. 2: 60. doi:10.3389/fendo.2011.00060. PMC 3356006. PMID 22654817.
  41. ^ Lustig RH, Greenway F, Velasquez-Mieyer P, Heimburger D, Schumacher D, Smith D, et al. (February 2006). "A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion". International Journal of Obesity. 30 (2): 331–41. doi:10.1038/sj.ijo.0803074. PMC 1540404. PMID 16158082.{{cite journal}}: CS1 maint: overridden setting (link)
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