25 Years of salmon calcitonin: From synthesis to therapeutic use

Azria, M.; Copp, D. Harold; Zanelli, Joan M.

doi:10.1007/bf00301940

Cited by 83 publications

(39 citation statements)

References 32 publications

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“…Analysis of available data also indicates that the response to other antiresorptive agents such as estrogen [20][21][22][23][24] or calcitonin [23,25] obtained in appropriate animal models is strikingly similar to that observed in humans. Thus, the slight increase in bone mass after initiation of estrogen therapy [26][27][28][29] or calcitonin [30][31][32] observed in postmenopausal women has been very well documented in aged ovariectomized rats [24,33].…”

Section: Predictive Value Of Preclinical Studiesmentioning

confidence: 51%

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Bonjour

Ammann

Rizzoli

1999

Osteoporosis International

100

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Osteoporosis, which is defined as a disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk, is a major health issue worldwide. Among the various strategies to prevent and cure this devastating ailment, an important objective is the development of new efficacious and safe drugs. This situation prompted the World Health Organization (WHO) to provide a comprehensive statement of guiding principles for the design, implementation and interpretation of both preclinical testing and clinical trials in osteoporosis. These guidelines, which are now available, underline the crucial importance of the preclinical evaluation, particularly for assessing the effect of an intervention on bone strength. This concept is heightened by the lack of a validated technique for noninvasively evaluating bone strength in humans and the multiple difficulties and heavy burden inherent in the evaluation of fracture rate in clinical trials. The WHO guidelines emphasize that a comprehensive and adequate preclinical program is expected to provide key information on the relationship between bone mass and strength and thus attenuate the burden of clinical studies. The present report provides a review of experimental evidence in support of the preclinical program as proposed in the WHO guidelines. This program is based on the recent development and refinement of animal models of osteoporosis that mimic the human condition according to the conceptual definition of the disease. Many preclinical studies carried out in appropriate animal models with agents that exert either antiresorbing or anabolic effects on bone indicate that they have been highly predictive of the drug action in humans in terms of both bone mass and remodeling, as well as of bone strength whenever fracture rate has been documented in clinical trials. Based on this evidence the WHO guidelines propose strategies according to which the results of preclinical evaluation will determine the end-points required in the different phases of the clinical development of the drug. Such a distribution of task assignment between preclinical and clinical programs should optimize the progress of research available to patients already suffering from or at risk of osteoporosis.

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Section: Predictive Value Of Preclinical Studiesmentioning

confidence: 51%

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Bonjour

Ammann

Rizzoli

1999

Osteoporosis International

100

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“…Therapeutic application of sCT in disorders of bone turnover is limited by eventual 'escape' or loss of clinical efficacy from the action of CT (Azria et al 1995). Recent data suggests that this is likely to be due to the rapid and sustained down-regulation of CTRs and CTR mRNA in osteoclasts, an action which is cAMP dependent (Wada et al 1996a,b).…”

Section: Implications For Receptor Regulationmentioning

confidence: 99%

“…Calcitonins, particularly 'fish-like' CTs such as sCT, are widely used therapeutically in the treatment of bone disorders, including Paget's disease, osteoporosis and hypercalcaemia of malignancy (Azria et al 1995). One of the major problems in the clinical use of CT is 'escape' from its action on bone, which is thought to be due, at least in part, to potent down-regulation of CTRs (Wada et al 1996a, b).…”

Section: Introductionmentioning

confidence: 99%

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Identification of key components in the irreversibility of salmon calcitonin binding to calcitonin receptors

Hilton¹,

Dowton²,

Houssami³

et al. 2000

Journal of Endocrinology

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This study investigates the poor reversibility of salmon calcitonin (sCT) binding to rat and human calcitonin receptors. Efficacy of CT and analogue peptides in 125 IsCT binding competition and cAMP assays was compared with the dissociation kinetics of 125 I-labelled peptides. Assessment was performed on cells stably expressing either rat or human calcitonin receptors. Dissociation kinetics of the antagonists, sCT(8-32) and AC512, revealed that binding was rapidly and completely reversible at the receptors, despite high affinity binding, suggesting that poor reversibility required the active conformation of the receptor. G protein coupling was not essential as the dissociation kinetics of 125 I-sCT binding to cell membranes did not significantly alter in the presence of GTP S. Time course experiments established that the transition to irreversibility was slow, while the reversible component of binding appeared to involve a single population of either receptor states or binding sites. Pre-bound 125 I-human CT dissociated rapidly from the receptors, indicating that not all agonists bound irreversibly. To identify structural features of sCT that contribute to its poor reversibility, dissociation kinetics of sCT analogues with various structural modifications were examined. Increasing truncation of N-terminal residues of sCT analogues led to a corresponding increase in the rate of peptide dissociation. Salmon CT peptides which had been substituted at the N-terminus by 13-21 residues of human CT (hCT) were equipotent with sCT in binding competition and cAMP accumulation assays but exhibited a dissociation rate similar to hCT. In contrast, despite lower affinity and efficacy at the receptors, the chimeric analogue sCT(1-16)-hCT(17-32) displayed poorly reversible binding, similar to sCT. Analysis of the dissociation kinetics of sCT analogues with differing -helix forming potential indicated that the ability to form -helical secondary structure was an important factor in the rate of ligand dissociation. We hypothesise that poor reversibility results from a conformational change in the receptor and/or ligand and that this is dependent, at least in part, on interaction with residues constrained within the -helix of the peptide.

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“…CGRP receptor blockade has been reported both to stimulate (27) and to have no effect (2) on food intake. CT appears to be produced primarily by endocrine cells in the thyroid (4). CT is thought to act primarily as a hormone to increase bone resorption and renal Ca 2ϩ excretion in response to a rise in plasma Ca 2ϩ levels.…”

mentioning

confidence: 99%

Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats

Reidelberger

Kelsey

Heimann

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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Heimann. Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats. Am J Physiol Regulatory Integrative Comp Physiol 282: R1395-R1404, 2002. First published January 17, 2002 10.1152/ajpregu.00597. 2001.-We previously demonstrated that amylin inhibits food intake and gastric emptying in rats with half-maximal effective doses (ED 50s) of 8 and 3 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 and maximal inhibitions of 78 and 60%, respectively. In this study of identical design, rats received intravenous infusions of salmon calcitonin (sCT), rat calcitonin (rCT), rat calcitonin gene-related peptide (rCGRP), and rat adrenomedullin (rADM) for 3 h at dark onset, and food intake was measured for 17 h or for 15 min and gastric emptying of saline was measured during the final 5 min. sCT, rCGRP, and rADM inhibited food intake with estimated ED50s of 0.5, 26, and 35 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 and maximal inhibitions of 88, 90, and 49%, respectively. rCT was not effective at doses up to 100 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 . sCT, rCGRP, rADM, and rCT inhibited gastric emptying with ED50s of 1, 130, 160, and 730 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 and maximal inhibitions of 60, 66, 60, and 33%, respectively. These results suggest that amylin and sCT may act by a common mechanism to decrease food intake, which includes inhibition of gastric emptying.calcitonin; calcitonin gene-related peptide; adrenomedullin; anorexia; potency AMYLIN (ALSO CALLED ISLET amyloid polypeptide) is a 37-amino acid peptide that is cosecreted with insulin from the pancreas in response to a meal (11, 51). Amylin has also been detected in gut endocrine cells (35), visceral sensory neurons (36), and throughout the brain (44). Exogenous amylin potently reduces food intake (1, 3, 39), body weight (1), adiposity (41), gastric emptying (10, 39), and gastric acid secretion (15) when administered systemically or into the brain. We recently demonstrated that the minimal effective intravenous dose for amylin-induced inhibition of food intake and gastric emptying in rats (1 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) increases plasma amylin by an amount comparable to that produced by a meal (3,39). We also demonstrated that in suppressing feeding and gastric emptying, amylin is at least as potent and efficacious as CCK (39), a physiological inhibitor of food intake and gastric emptying.These results support the hypothesis that amylin acts as a hormonal signal to the brain to inhibit gastric emptying and food intake and that amylin produces satiety, in part, through inhibition of gastric emptying.Calcitonin gene-related peptide (CGRP), calcitonin (CT), and adrenomedullin (ADM), together with amylin, form a family of structurally related peptides with overlapping biological actions (Fig. 1). Each of these peptides inhibits food intake (13,22,32,45) and gastric emptying (8,20,30,38) when administered systemically or into the brain. The teleost peptide salmon CT (sCT) appears to be significantly more potent than either amylin (29) or mammalian CTs (8, 29, 47) in decreasing food intake and gastric emp...

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25 Years of salmon calcitonin: From synthesis to therapeutic use

Cited by 83 publications

References 32 publications

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Importance of Preclinical Studies in the Development of Drugs for Treatment of Osteoporosis: A Review Related to the 1998 WHO Guidelines

Identification of key components in the irreversibility of salmon calcitonin binding to calcitonin receptors

Effects of amylin-related peptides on food intake, meal patterns, and gastric emptying in rats

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