Salmon Calcitonin Research & Studies

Lipid-based nanocarrier systems have multiple advantages, including biocompatibility, biodegradability and drug loading capacity. Combining these findings with the concept of dissolving microneedles (MNs) would aid in the efficient delivery of peptides and improve therapeutic outcomes. Thus, MN-mediated transdermal delivery was explored for the delivery of salmon calcitonin (sCT). The delivery of sCT via MNs is a novel approach with great potential for minimally invasive therapy in chronic osteoporosis patients. This project focused on the transdermal delivery of biomolecular drugs using novel polymeric MN array patch (MAP) systems. Transdermal peptide delivery using lipid-based mixed micellar formulations could provide advantages such as improved stability and enhanced therapeutic efficacy. This work comprises the development and evaluation of dissolving MAPs loaded with Lipoid S 100® based mixed micelles. The physicochemical properties of the micelles were evaluated by loading them into a suitably fabricated and optimized MAP system. The micelle-loaded MAPs were subjected to physicochemical characterization and a 400 μm insertion depth was obtained in Parafilm M® test. Subsequently, ex vivo experiments were conducted in neonatal porcine skin to establish their insertion, dissolution and permeation potential and 42 % sCT was found to permeate in 24 h. The developed MAPs were then analysed in vivo for pharmacokinetics and organ biodistribution in a rat model, where approximately 3-fold rise in relative bioavailability was observed with MAP group. This work highlights the potential of lipid-based mixed micelles loaded MAP systems, especially for the delivery of sensitive peptide molecules such as sCT. The outcome of this research work paves the way for further exploration in this direction.

The behavioral mechanisms and the neuronal pathways mediated by amylin and its long-acting analog sCT (salmon calcitonin) are not fully understood and it is unclear to what extent sCT and amylin engage overlapping or distinct neuronal subpopulations to reduce food intake. We here hypothesize that amylin and sCT recruit different neuronal population to mediate their anorectic effects.

The behavioural responses to nicotine involve appetite-regulatory hormones; however, the effects of the anorexigenic hormone amylin on reward-related behaviours induced by nicotine remain to be established. Previous studies have shown that the amylinergic pathway regulates behavioural responses to alcohol, amphetamine and cocaine. Here, we evaluated the effects of salmon calcitonin (sCT), an amylin and calcitonin receptor (CTR) agonist, on nicotine-induced locomotor stimulation and sensitisation as well as dopamine release in the nucleus accumbens (NAc) shell. Moreover, we investigated the effects of sCT on the acquisition and expression of nicotine-induced reward in the conditioned place preference (CPP) paradigm. Finally, we performed Western Blot experiments in an attempt to identify the levels of the amylin receptor components CTRa, CTRb, and RAMP1 in reward-related areas of mice responding differently to repeated injections of sCT and nicotine in the locomotor sensitisation test. We found that sCT blocked nicotine's stimulatory and dopamine-releasing effects and prevented its ability to cause locomotor sensitisation. On the other hand, sCT did not alter nicotine-induced acquisition and expression of CPP. Lastly, sCT-nicotine treated mice from the locomotor sensitisation experiment displayed higher levels of total CTR, i.e. CTRa and CTRb together, in the reward-processing laterodorsal tegmental area (LDTg) of the brain compared to mice treated with vehicle-nicotine. Overall, the present data reveal that activation of CTR or/and amylin receptors attenuates certain nicotine-induced behaviours in male mice, further contributing to the understanding of appetite-regulatory peptides in reward regulation.

Osteoporosis therapy consists of inhibiting the osteoclasts' activity and promoting osteoblasts' osteogenesis. Salmon calcitonin (sCT) could realize both requirements, however, it is limited by the low bioavailability caused by fibrillation. Supramolecular assembly of sCT and biocompatible agents into nanoassemblies provides an opportunity to overcome these shortcomings. Herein, we used a facile method to fabricate salmon calcitonin-aspartame (sCT-APM) nanoassemblies. Supramolecular interactions could not only delay fibrillation time (from 36.9 h to 50.4 h), but also achieve sustained sCT release. Moreover, sCT-APM showed good biocompatibility and higher osteoinductive capacity than free sCT, revealing an osteogenesis improvement effect. Moreover, in vivo studies showed that sCT-APM has enhanced relative bioavailability (2.42-fold of sCT) and increased relative therapeutic efficacy (3.55-fold of sCT) through subcutaneous injection. These findings provide a convenient alternative strategy for osteoporosis therapy via supramolecular assemblies.

To evaluate the efficacy and safety of intranasal salmon calcitonin in the treatment of osteoporosis.

The amylin receptor (AMY) and calcitonin receptor (CTR) agonists induce acute suppression of food intake in rodents by binding to receptors in the area postrema (AP) and potentially by targeting arcuate (ARC) neurons directly. Salmon calcitonin (sCT) induces more potent, longer lasting anorectic effects compared to amylin. We thus aimed to investigate whether AMY/CTR agonists target key neuronal populations in the ARC, and whether differing brain distribution patterns could mediate the observed differences in efficacy with sCT and amylin treatment. Brains were examined by whole brain 3D imaging and confocal microscopy following subcutaneous administration of fluorescently labelled peptides to mice. We found that sCT, but not amylin, internalizes into a subset of ARC NPY neurons, along with an unknown subset of ARC, AP and dorsal vagal motor nucleus cells. ARC POMC neurons were not targeted. Furthermore, amylin and sCT displayed similar distribution patterns binding to receptors in the AP, the organum vasculosum of the lamina terminalis (OVLT) and the ARC. Amylin distributed within the median eminence with only specs of sCT being present in this region, however amylin was only detectable 10 minutes after injection while sCT displayed a residence time of up to 2 hours post injection. We conclude that AMY/CTR agonists bind to receptors in a subset of ARC NPY neurons and in circumventricular organs. Furthermore, the more sustained and greater anorectic efficacy of sCT compared to rat amylin is not attributable to differences in brain distribution patterns but may more likely be explained by greater potency at both the CTR and AMY.

The receptors of salmon calcitonin, located on certain areas of the brain such as the periaqueductal gray matter, are responsible for pain modulation.

The exact mechanism of migraine pathophysiology still remains unclear due to the complex nature of migraine pain. Salmon calcitonin (SC) exhibits antinociceptive effects in the treatment of various pain conditions. In this study, we explored the mechanisms underlying the analgesic effect of salmon calcitonin on migrane pain using glyceryltrinitrate (GTN)-induced model of migraine and ex vivo meningeal preparations in rats. Rats were intraperitoneally administered saline, GTN (10 mg/kg), vehicle, saline + GTN, SC (50 μg/kg) + GTN, and SC alone. Also, ex vivo meningeal preparations were applied topically 100 μmol/L GTN, 50 μmol/L SC, and SC + GTN. Calcitonin gene-related peptide (CGRP) contents of plasma, trigeminal neurons and superfusates were measured using enzyme-immunoassays. Dural mast cells were stained with toluidine blue. c-fos neuronal activity in trigeminal nucleus caudalis (TNC) sections were determined by immunohistochemical staining. The results showed that GTN triggered the increase in CGRP levels in plasma, trigeminal ganglion neurons and ex vivo meningeal preparations. Likewise, GTN-induced c-fos expression in TNC. In in vivo experiments, GTN caused dural mast cell degranulation, but similar effects were not seen in ex vivo experiments. Salmon calcitonin administration ameliorated GTN-induced migraine pain by reversing the increases induced by GTN. Our findings suggested that salmon calcitonin could alleviate the migraine-like pain by modulating CGRP release at different levels including the generation and conduction sites of migraine pain and mast cell behaviour in the dura mater. Therefore salmon calcitonin may be a new therapeutic choice in migraine pain relief.

Recently an association between the use of calcitonin and cancer has been postulated. We reviewed the biological rationale and performed an additional analysis of historical data with respect to the possibility. An association cannot be excluded, but the relationship is weak and causality is unlikely. The purpose of the present study is to review the strength of association and likelihood of a causal relationship between use of calcitonin and cancer. We reviewed the evidence for this association, including the molecular signaling mechanisms of calcitonin, preclinical data, an "experiment of nature," and the results of a previous meta-analysis which showed a weak association. We performed an additional meta-analysis to incorporate the data from a novel investigational oral formulation of salmon calcitonin. Review of the literature did not identify a cellular signaling mechanism of action which might account for a causal relationship or toxicologic or postmarketing data to support the thesis. Additional clinical results incorporated into previous meta-analyses weakened but did not completely negate the possibility of association. A causal association between calcitonin use and malignancy is unlikely, as there is little biological plausibility. The preponderance of nonclinical and clinical evidence also does not favor a causal relationship.

To evaluate the strength of evidence supporting a possible association between salmon calcitonin (SCT) use and cancer incidence.

Salmon calcitonin has chondroprotective effect both in vitro and in vivo, and is therefore being tested as a candidate drug for cartilage degenerative diseases. Recent studies have indicated that different chondrocyte phenotypes may express the calcitonin receptor (CTR) differentially. We tested for the presence of the CTR in chondrocytes from tri-iodothyronin (T3)-induced bovine articular cartilage explants. Moreover, investigated the effects of human and salmon calcitonin on the explants.

Osteoporosis is a slow progressive disease with develops over decades, and where intervention is needed for an extended number of years. This highlights the need for safe intervention possibilities, which have sustained beneficial effects post-treatment.

Salmon calcitonin, available as a therapeutic agent for more than 30 years, demonstrates clinical utility in the treatment of such metabolic bone diseases as osteoporosis and Paget's disease, and potentially in the treatment of osteoarthritis. This review considers the physiology and pharmacology of salmon calcitonin, the evidence based research demonstrating efficacy and safety of this medication in postmenopausal osteoporosis with potentially an effect on bone quality to explain its abilities to reduce the risk of spine fracture, the development of an oral salmon calcitonin preparation, and the therapeutic rationale for this preparation's chondroprotective effect in osteoarthritis.

The principal calcitonins used therapeutically are porcine, human (synthetic), salmon (synthetic), and eel. Of these substances, salmon calcitonin is the most potent (Reginster 1991). Injectable forms of salmon calcitonin were first indicated for use in the treatment of Paget's disease in the United States and later received an indication for use in the treatment of postmenopausal osteoporosis. The injectable [intramuscular (IM) or subcutaneous (SC)] formulation of salmon calcitonin, however, has been associated with a high rate of noncompliance in elderly patients. The recently approved nasal-spray formulation has ameliorated the difficulties inherent in parenteral administration and is considered a suitable option as an alternative therapy in patients who are not appropriate candidates for estrogen replacement therapy. (Trends Endocrinol Metab 1997;8:89-92). (c) 1997, Elsevier Science Inc.

During the development of synthetic calcitonins for therapeutic use in bone disease, a "diabetogenic" (hyperglycemic) effect was observed, particularly with salmon calcitonin. The effect was attributed by some to inhibition of insulin secretion. We have recently reported high-affinity (28 pmol/L) amylin-binding sites in certain areas of rat brain, and found that these sites also bind salmon but not rat calcitonin with comparable high affinity. Rat amylin and salmon calcitonin have been determined to have significant structural homology. In vitro and in vivo studies indicate that rat amylin can exert calcitonin-like effects on osteoclasts and on plasma calcium. Here we report that salmon calcitonin mimics the actions of rat amylin on skeletal muscle glycogen metabolism in vitro; it stimulates glycogenolysis and inhibits incorporation of radiolabeled glucose into glycogen (50% effective concentration [EC50], 0.4 +/- 0.11 nmol/L log and 8.4 +/- 0.05 nmol/L log, respectively). In anesthetized rats, salmon calcitonin, like rat amylin, rapidly increases plasma lactate concentration, followed by a slower increase in glucose concentration. Like amylin, salmon calcitonin also inhibits the insulin response to 2 mmol infused glucose (insulin increments suppressed by 52% and 57% at 10 minutes for salmon calcitonin and amylin). Other shared actions, such as suppression of appetite, stimulation of renin secretion, inhibition of gastric acid secretion, and inhibition of gastric emptying, further affirm our proposal that the exogenous peptide, salmon calcitonin, is a mimic of endogenous amylin in the rat.

We have undertaken a study of 24 hypercalcemic patients with the use of salmon calcitonin as a therapeutic agent. Seventy-five percent of the patients exhibited a clinically significant decrease in serum calcium and approximately half became normocalcemic within 2 hr. Throughout salmon calcitonin administration, the mean serum calcium of the patients was lower than the pretreatment values. Although the drug did not always lower the calcium level to normal, it often brought the hypercalcemia to more tolerable levels. During the course of calcitonin therapy, the number of patients with normal or near-normal serum calcium ranged from 31.3% (at 96 hr) to 82.4% (at 30 hr). Many of the patients improved symptomatically. The only significant side effects were nausea and vomiting in 12.5% of the patients, which necessitated cessation of therapy in only one. The drug was well tolerated in patients with azotemia. Calcitonin-induced hypocalcemia was not encountered. Salmon calcitonin can be used safely alone or in conjunction with other hypocalcemic therapies.