Calcitonin production

Calcitonin causes the deposition of calicum phosphate in the skeleton by stimulation of the bone-forming cells, and hence reduces the levels of calcium and phosphate in the blood (hypocalcemia). Completely synthetic calcitonin products such as Salmcalci-tonin (Sandoz Ltd., Switzerland) 208), Elcitonin (Toyo Jozo Co., Japan) z09), and... 

Chin, C.M. Gutierrez, M. Still, J.G. Kosutic, G. Pharmacokinetics of modified oral calcitonin product in healthy volunteers. Pharmacotherapy 2004, 24 (8), 994—1001. 

Calcitonin is secreted continuously under conditions of normocalcemia, and the synthesis of calcitonin is increased when the calcium concentrations in plasma and intracellular fluids increase. Hypermagnesemia has a similar effect on calcitonin production. In hypocalcemia, the production of calcitonin falls. The gastrointestinal hormones—gastrin, glucagon, cholecystokinin, and secretin—and high dietary calcium also stimulate calcitonin production. Long-term hypercalcemia may cause hyperplasia of the C cells. 

E. Flanigan, Fligh Performance Eiquid Chromatography in the Production and Quality Control of Salmon Calcitonin, Purdue University, West Lafayette, Ind., 1991, p. 207. 

CGRP has a wide distribution in the nervous system (19) and was the first peptide to be localized to motoneurons (124). It is also found in primary sensory neurons where it is colocalized with substance P (125). CGRP is derived from a precursor stmcturaHy related to the calcitonin precursor. The latter precursor produces two products, calcitonin itself and katacalcin, while the CGRP precursor produces one copy of CGRP (123). Like other peptides, CGRP is cleaved from its precursor by tryptic breakdown between double basic amino acid residues. 

The main role of the human thyroid gland is production of thyroid hormones (iodinated amino acids), essential for adequate growth, development, and energy metaboHsm (1 6). Thyroid underfunction is an occurrence that can be treated successfully with thyroid preparations. In addition, the thyroid secretes calcitonin (also known as thyrocalcitonin), a polypeptide that lowers excessively high calcium blood levels. Thyroid hyperfunction, another important clinical entity, can be corrected by treatment with a variety of substances known as antithyroid dmgs. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

Calcitonin and other peptide products of the calcitonin gene are known to be el-... 

An alternative therapeutic approach to osteoporosis is through the use of calcitonin (798), a peptide hormone containing 32 amino acids (the sequence is species dependent) secreted by the thyroid gland, which stimulates the production of new bone. Synthetic calcitonins corresponding to human, eel, and salmon variants, and natural calcitonin extracted from pig thyroid, are all used in medicine - they have slightly different efficacies, side effects, and tolerance levels (799). 

Prevention of osteoporosis and fracture can be achieved through limiting the resorption-remodeling process. Four main families of products can be effective in controlling bone resorption estrogens, SERMs, bisphosphonates, and calcitonin. Large, prospective randomized trials have proven the effectiveness... 

Numerous other peptides and proteins have been, or are still in development as inhalation products with the objective of systemic absorption. Examples of these are calcitonin, LH-RH antagonists, recombinant human granulocyte colony-stimulating factor and growth hormone. 

Three forms of calcitonin are available, salmon, porcine and human calcitonin. Long-term use of porcine calcitonin, being the most antigenic product, can lead to the production of neutralizing antibodies. Synthetic salmon preparations are therefore preferable. Human calcitonin is less immunogenic but it is also less active. Human calcitonin monomer has a half-life of about 10 minutes while the half-life of salmon calcitonin is considerably longer. However these half-lives are not directly related to the duration of action which varies from 30 min to 12 hours after intravenous administration and from 8 hours to 24 hours when administered subcutaneously or intramuscularly. Calcitonin is metabolized in the blood and in tissues like for example the kidneys. 

Hypocalcemia directly increases PTH synthesis and release and inhibits calcitonin release. PTH in turn restores plasma calcium by initially stimulating transport of free or labile calcium from bone into the blood. PTH also increases renal 1,25-dihydroxycholecalciferol (1,25-(0H)2D3) production, which is the most active form of D3. 1,25-(0H)2D3 induces enterocyte differentiation in the intestine, which in turn results in increased absorption of calcium. Finally, during long periods of hypocalcemia, PTH can mobilize more stable calcium deep in the hydroxyapatite of bone by activating deep osteoclasts. 

Novartis (2002). Miacalcin (Calcitonin-Salmon) T2002-84 89018101. Available at www. http //www.pharma.us.novartis.com/product/pi/pdf/miacalcin injection.pdf search = %22 Miacalcin%20(Calcitonin-Salmon)%20T2002-84%2089018101%22 downloaded 10/04/ 2006. 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

The diverse actions of AM are mediated by the 7-transmembrane G protein-coupled calcitonin receptor-like receptor (CRLR) which coassembles with subtypes 2 and 3 of a family of receptor-activity-modifying proteins (RAMPs), thus forming a receptor-coreceptor system. Binding of AM to CRLR activates Gs and triggers cAMP formation in vascular smooth muscle cells, and increases nitric oxide production in endothelial cells. Other signaling pathways are also involved. 

Morgan, D. B., Monod, A., Russell, R. G. G., Fleisch, H. Influence of dichlormethylene diphosphonate (C12MDP) and calcitonin on bone resorption, lactate production and phosphate and pyrophosphatase content of mouse calvaria treated with parathyroid hormone in vitro. Calc. Tiss. Res. 13, 287 (1973)... 

Amara, G.S., Jonas, V., Rosenfeld, M.G., Ong, E.S., Evans, R.M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products, Nature 1982, 298, 240-244. 

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

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