Calcitonin human

Irreversible aggregation can extremely limit the bioavailability and therapeutic activity of peptide-based drugs. There is therefore an urgent demand of effective strategy to control peptide aggregation. Recently, we found that tyrosine nitration at certain sites of peptide can effectively inhibit its aggregation. This minor modification may be an ideal strategy to the rational design of peptide-based drugs with low aggregation propensity yet without loss of bioactivity. Human calcitonin (hCT) is such a peptide hormone known for its hypocalcaemic effect but has limited pharmaceutical potential due to a high tendency to aggregate. In this study, by using multiple techniques including Fluorescence, TEM, Nu-PAGE and CD, we demonstrated that Y12 nitration of hCT would significantly inhibit its self-assembles, and we also found that this modification would not only reduce the cytotoxicity induced by peptide aggregation, but also had little effect on its potency. This finding may provide a novel strategy for clinically application of hCT instead of sCT.

The peptide calcitonin (CT) was initially discovered in 1962 as a novel hypocalcemic hormone. This hypocalcemic response was principally due to a potent inhibitory action of CT on osteoclast mediated bone resorption and it is this action which underlies its widespread clinical use for the treatment of bone disorders, including Paget's disease, osteoporosis and hypercalcemia of malignancy. In this article we review the basic physiology of CT action, structure-function studies on CT peptides, cloning of CT receptors and the identification of isoforms of the receptor derived from alterative splicing of the receptor mRNA. We also review the state of understanding on CT receptor mediated signaling and receptor regulation, along with developing concepts of how CT peptides interact with the receptor, including how the receptors may interact with receptor activity modifying proteins to produce novel phenotypes. Finally, current therapeutic use is reviewed, and the potential for expanded use that may come with advances in delivery of peptides or CT mimetics.

Calcitonin is a potent inhibitor of osteoclastic bone resorption and has been widely used for the treatment of osteoporosis. Nasal calcitonin, instead of injectable form, is more popular in Europe and United States, while only injectable form has been approved in Japan. The regimen, dose, frequency is remarkably different from study to study, and the standard regimen has not been established for osteoporosis. Fifty to 100 units of salmon calcitonin has been used daily intramuscularly in Europe. Recent trial using nasal calcitonin has shown the similar effects on the bone as the injectable form although the actual resorptionis not so high. In Japan, once weekly 20 units if eel calcitonin analogue injection has been approved for osteoporosis. After administration in the form of either nasal or injectable preparation, peak serum concentration reaches more than 100 pg/ml, far exceeding 10(-11) M, at which level osteoclast bone resorption is rapidly impaired with disappearance of actin ring formation. It is reflected by the decrease of urinary pyridinoline cross-links excretion. Consecutive treatment with calcitonin reduces the calcitonin receptors on the surface of osteoclasts as well as osteoclast precursors, while they are still TRAP positive, suggesting that they retain bone resorbing activity. That may be one of the mechanisms of escape phenomenon. We are not sure whether daily administration of calcitonin can avoid the escape phenomenon and can maintain the bone volume. The standard preparation should be determined by the longer clinical trials with new bone markers and bone mass measurement as the endpoints.