Synthesis of octreotide and derivative thereof can be carried out by two methods. The first method is synthesized initially by fragment condensation solution phase procedures. The synthetic process of octreotide has been described by Bauer et al. (1). The second method is the synthese by solidphase procedures. Edward et al. (2) isolated side chain protected octreotide with a total yield of 14% by cleaving the protected peptide from the resin with threoninol. Arano et al. (3) carried out another solid phase method for octreotide. and produced it in overall 31.8% yield based on the starting FmocThr(tBu)-ol-resin. The basic difference from the other procedures already described is that the introduction of the threoninol is carried out upon the protected peptidic structure (resin-free), which, when appropriately activated, leads quantitatively and without needing to make temporary protections upon the threoninol, to the protected precursor of octreotide, which in turn, with a simple acid treatment leads to octreotide with very high yields.At first the Fmoc-Cys-Cl-trityl-resin was prepared. The incorporation of the Fmoc-Cys(trt)-OH residue upon 2Cl-Trt resin is accomplished with an excess of 1 eq. of Fmoc-Cys(Trt) and 2.5 eq. of N,N'-diisopropylethylamine (DIEA).2.93 g (5.0 mmol) of Fmoc-Cys(Trt) are incorporated upon 5 g of resin (f = 1.28 mmol/g of resin, 6.4 mmol). The resin and the amino acid are weighed in separate containers and left to dry in a vacuum with KOH, for a minimum of two hours. A 1/1 solution of DIEA and CH2Cl2 (DCM) (dry on a 4A sieve) is
prepared. The already dry amino acid is dissolved with dry DCM at a concentration of 0.1 g of resin per ml, adding the minimum quantity of dry DMF to complete the dissolution. 1/3 of the 1.8 ml (12.5 mmol) DIEA solution is added to this transparent solution in 1.8 ml of DCM. This is thoroughly homogenized and added to the dry resin. It is subjected to vigorous magnetic agitation for five minutes and the rest of the DIEA is added to the reaction; the mixture is allowed to react for forty minutes more. Then, 4 ml of dry MeOH are added and allowed to react for 10 minutes, after which the resin is filtered and the washings described below are carried out.
Octreotide acetate is used by SC injection in the palliative treatment of patients with metastatic
carcinoid tumors, which are tumors of the endocrine system, GI tract, and lung
(gastroenteropancreatic). Carcinoid tumors secrete increasing amounts of vasoactive
substances, including histamine, serotonin, bradykinin, and prostaglandins. Octreotide acetate
inhibits or suppresses the release of these vasoactive substances and, thus, is useful in treating
the severe diarrhea, facial flushing, and wheezing episodes that accompany carcinoid tumors. In
addition, it finds use in the palliative management of VIP-secreting tumors (VIPomas, usually
pancreatic tumors). Patients with VIPomas suffer a profuse, watery diarrhea syndrome, and
octreotide acetate is able to help by decreasing the release of damaging intestinal tumor cell
secretions. Octreotide also helps to reduce hypokalemia by correcting electrolyte imbalances.An excessive secretion of GH from the pituitary can cause the disorder known as acromegaly,
which is characterized by a progressive enlargement of the head, face, hands, feet, and thorax.
Inasmuch as octreotide acetate is able to decrease the secretion of GH from the pituitary, it is
used in treating patients with acromegaly who are unresponsive to previous pituitary radiation
therapy or surgery. It is used in the treatment of acromegaly, because it reduces the blood
levels of both GH and insulin-like growth factor-I (IGF-I). The long-acting repository form of
octreotide acetate also is used in treating acromegaly, carcinoid tumors, and VIPomas, but in
monthly depot injections.Octreotide for IV injection is used in the treatment of acute bleeding from esophageal varices.
Variceal bleeding occurs in about half the patients with cirrhosis of the liver and is responsible
for about one-third of deaths in these patients. Octreotide is a potent vasoconstrictor that
reduces portal and collateral blood flow by constricting visceral vessels, which leads to reduced
portal blood pressure and decreases the bleeding.
Veterinary Drugs and Treatments
Octreotide may be useful in the adjunctive treatment of hyperinsulinemia
in patients with insulinomas (especially dogs, ferrets).
Response is variable, presumably dependent on whether the tumor
cells have receptors for somatostatin. Octreotide may also be useful
in the diagnosis and symptomatic treatment of gastrinomas in dogs
or cats. It may be of use in the treatment of acute pancreatitis, but
more research is needed before it can be recommended for this use
in veterinary patients.
Octreotide acetate, a long-acting octapeptide analogue of somatostatin, has a half-life of
approximately 100 minutes. A comparison of the primary structures of octreotide and
somatostatin suggests little similarity, but from earlier work at the Salk Institute it was known
that not all the residues in somatostatin were necessary to elicit its full biological activity. Other
studies suggested that the essential fragment for its activity was the tetrapeptide Phe7-Trp8-
Lys9-Thr10. These earlier studies helped in the design of the potent drug now known as octreotide acetate. This drug suppresses the secretion of gastroenteropancreatic
peptides, such as gastrin, vasoactive intestinal peptide (VIP), insulin, and glucagon, as well as
pituitary GH. Furthermore, it is more potent than natural somatostatin in inhibiting the release of
glucagon, insulin, and GH.
Octreotide acetate (Sandostatin) is a synthetic peptide
analogue of the hormone somatostatin. Its actions include
inhibition of the pituitary secretion of growth
hormone and an inhibition of pancreatic islet cell secretion
of insulin and glucagon. Unlike somatostatin, which
has a plasma half-life of a few minutes, octreotide has a
plasma elimination half-life of 1 to 2 hours. Excretion of
the drug is primarily renal.
Octreotide is a long-acting somatostatin analog indicated for symptomatic control in
acromegaly and gastroenteropancreatic tumors. Other potential uses under investigation
include diabetes, psoriasis and Alzheimer's disease.
Antiulcer, Growth hormone inhibitor