Calcitonin Release Research Articles

Glucagon-like peptide-1(GLP-1) receptor agonists: potential to reduce fracture risk in diabetic patients?

This review summarizes current knowledge about glucagon-like peptide 1 receptor agonists (GLP-1 RA) and their effects on bone metabolism and fracture risk. Recent in vivo and in vitro experiments indicated that GLP-1 RA could improve bone metabolism. GLP-1 could affect the fat-bone axis by promoting osteogenic differentiation and inhibiting adipogenic differentiation of bone mesenchymal precursor cells (BMSCs), which express the GLP-1 receptor. GLP-1 RA may also influence the balance between osteoclasts and osteoblasts, thus leading to more bone formation and less bone resorption. Wnt/β-catenin signalling is involved in this process. Mature osteocytes, which also express the GLP-1 receptor, produce sclerostin which inhibits Wnt/β-catenin signalling by binding to low density lipoprotein receptor-related protein (LRP) 5 and preventing the binding of Wnt. GLP-1 RA also decreases the expression of sclerostin (SOST) and circulating levels of SOST. In addition, GLP-1 receptors are expressed in thyroid C cells, where GLP-1 induces calcitonin release and thus indirectly inhibits bone resorption. Furthermore, GLP-1 RA influences the osteoprotegerin(OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system by increasing OPG gene expression, and thus reverses the decreased bone mass in rats models. However, a recent meta-analysis and a cohort study did not show a significant relationship between GLP-RA use and fracture risk. Future clinical trials will be necessary to investigate thoroughly the relationship between GLP-1 RA use and fracture risk in diabetic patients.

Thyroid C-Cell Biology and Oncogenic Transformation.

The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that multiple endocrine neoplasia type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma (MTC). Thyroid C-cells are known to express RET at high levels relative to most cell types; therefore, aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET, the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations have uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular-targeted therapies.

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.

Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Do GLP-1–Based Therapies Increase Cancer Risk?

Cases of pancreatitis have been described in connection with the use of exenatide (1), liraglutide (2) and other glucagon-like peptide (GLP)-1 receptor agonists. From these findings, the following hypothesis has been generated: stimulating the GLP-1 receptor with respective agonists has a potential to cause pancreatitis, perhaps chronic pancreatitis, and in the long term, potentially even pancreatic cancer (3–5). Furthermore, in rodents like mice and rats, stimulating the GLP-1 receptor raises cAMP in thyroid C cells, initiates the release of calcitonin, and upon longer-term exposure, is accompanied by C-cell proliferation and the formation of C-cell adenomas and (medullary thyroid) carcinomas (6). Based on these findings, it was hypothesized that GLP-1–derived medications have a potential to cause medullary thyroid carcinoma in humans as well (3,7). It is the purpose of the current review to discuss the evidence in favor and against the hypothesis that GLP-1–based therapies increase cancer risk, specifically the risk for pancreatic and thyroid carcinomas in patients with type 2 diabetes treated with exenatide and sitagliptin. In principle, there could be weak or strong evidence, either in favor of or against, the hypothesis that incretin-based medications can increase the risk for pancreatic, (medullary) thyroid, or other carcinomas. For the purpose of this review, GLP-1–based therapies are GLP-1 receptor agonists such as exenatide, liraglutide, and others or dipeptidyl peptidase-4 (DPP-4) inhibitors such as sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin (8). However, almost all available data and quoted studies have specifically examined exenatide and sitagliptin, which have been available for the longest time. The questions of whether certain drugs can cause pancreatitis and whether certain drugs can cause pancreatic carcinoma are interrelated, since chronic pancreatitis increases the risk for pancreatic carcinoma approximately 26-fold compared with subjects not suffering from chronic pancreatitis (9). There is an etiological sequence leading …

Cinacalcet attenuates hypercalcemia observed in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors

Excessive secretion of parathyroid hormone-related protein (PTHrP) by tumors stimulates bone resorption and increases renal tubular reabsorption of calcium, resulting in hypercalcemia of malignancy. We investigated the ability of cinacalcet, an allosteric modulator of the calcium-sensing receptor, to attenuate hypercalcemia by assessing its effects on blood ionized calcium, serum PTHrP, and calcium-sensing receptor mRNA in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors. Cinacalcet effectively decreased hypercalcemia in a dose- and enantiomer-dependent manner; furthermore, cinacalcet normalized phosphorus levels, but did not affect serum PTHrP. Ribonuclease protection assay results demonstrated presence of PTHrP receptor, but not calcium-sensing receptor mRNA in C26-DCT tumors. The mechanism by which cinacalcet lowered serum calcium was investigated in parathyroidectomized rats (i.e., without PTH) made hypercalcemic by PTHrP. Cinacalcet attenuated PTHrP-mediated elevations in blood ionized calcium, which were accompanied by increased plasma calcitonin. Taken together these results suggest that the cinacalcet-mediated decrease in serum calcium is not the result of a direct effect on tumor cells, but rather is the result of increased calcitonin release. In summary, cinacalcet effectively reduced tumor-mediated hypercalcemia and corrected hypophosphatemia in mice. Further investigation of cinacalcet for treatment of hypercalcemia of malignancy is warranted.

Effect of GLP1R agonists taspoglutide and liraglutide on primary thyroid C-cells from rodent and man

Glucagon-like peptide 1 (GLP1) analogs have been associated with an increased incidence of thyroid C-cell hyperplasia and tumors in rodents. This effect may be due to a GLP1 receptor (GLP1R)-dependent mechanism. As the expression of GLP1R is much lower in primates than in rodents, the described C-cell proliferative lesions may not be relevant to man. Here, we aimed to establish primary thyroid cell cultures of rat and human to evaluate the expression and function of GLP1R in C-cells. In our experiments, GLP1R expression was observed in primary rat C-cells (in situ hybridization) but was not detected in primary human C-cells (mRNA and protein levels). The functional response of the cultures to the stimulation with GLP1R agonists is an indirect measure of the presence of functional receptor. Liraglutide and taspoglutide elicited a modest increase in calcitonin release and in calcitonin expression in rat primary thyroid cultures. Contrarily, no functional response to GLP1R agonists was observed in human thyroid cultures, despite the presence of few calcitonin-positive C-cells. Thus, the lack of functional response of the human cultures adds to the weight of evidence indicating that healthy human C-cells have very low levels or completely lack GLP1R. In summary, our results support the hypothesis that the GLP1R agonist-induced C-cell responses in rodents may not be relevant to primates. In addition, the established cell culture method represents a useful tool to study the physiological and/or pathological roles of GLP1 and GLP1R agonists on normal, non-transformed primary C-cells from rats and man.

Incorporation of salmon calcitonin-loaded poly(lactide-co-glycolide) (PLGA) microspheres into calcium phosphate bone cement and the biocompatibility evaluation in vitro

Slow tissue ingrowth is the major drawback for the use of calcium phosphate cements; to address the issue, salmon calcitonin–loaded biodegradable poly(lactide- co-glycolide) microspheres were incorporated into calcium phosphate cement in this study. The effects of poly(lactide- co-glycolide) weight ratio on the mechanical strength, self-setting properties, and salmon calcitonin release ability of calcium phosphate cement were systematically investigated. The in vitro degradation behavior and the cumulative mass loss (%) of the composite during incubation in phosphate-buffered saline were studied. The release of salmon calcitonin was sustained for at least 35 days, and the release rate can be tailored by adjusting the ratio of PLGA. The scanning electron microscopic images of the composites after incubation for 48 days indicated that the poly(lactide- co-glycolide) degraded completely and formed a porous structure in the calcium phosphate cement. An in vitro cell culture of the calcium phosphate cement/salmon calcitonin–poly(lactide- co-glycolide) cement provided more biocompatible than calcium phosphate cement. This composite possesses the basic performance for clinical needs, and it has potential use for treating osteoporosis and accelerating bone repair.

A Review on the Association between Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer

There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1) analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC), but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

Safety and tolerability of glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes

Conventional pharmacotherapies for type 2 diabetes effectively lower blood glucose levels but are associated with side effects that preclude their optimal use or raise safety concerns. Novel treatments based on the endogenous hormone glucagon-like peptide-1 (GLP-1) may overcome some of these obstacles. The GLP-1 receptor agonists, exenatide and liraglutide, have a lower risk of hypoglycaemia than some conventional agents and can provide significant weight loss. Although they can cause gastrointestinal symptoms, effects are transient and can be reduced by gradual dose escalation. No cardiac safety issues have been reported and animal studies suggest that they may confer cardiovascular benefits. Pancreatitis has occurred among patients receiving GLP-1 receptor agonists, but it is unclear whether this is drug-related or due to the increased risk of pancreatitis in type 2 diabetes. Despite findings in rodents that GLP-1 receptor activation of thyroid C-cells results in calcitonin release and C-cell pathology, such effects have not been seen with long-term exposure in humans. Immunogenicity does not appear to be a safety concern. In summary, currently available data indicate that GLP-1 receptor agonists provide an effective and generally well tolerated therapeutic option for the management of type 2 diabetes.

GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy. Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.

Complexation Hydrogels for the Oral Delivery of Growth Hormone and Salmon Calcitonin

The hydrogel system of poly(methacrylic acid-co-N-vinyl pyrrolidone) was evaluated for use as an oral delivery system for growth hormone and salmon calcitonin. These proteins were selected because of their therapeutic importance and the insight provided by evaluating the delivery of a therapeutic agent with a high molecular weight (growth hormone) and a drug with a high isoelectric point (salmon calcitonin). Growth hormone loading and release studies were performed for both P(MAA-co-NVP) and P(MAA-g-PEG). Loading efficiencies for the respective systems were 50.9 ± 1.8% and 57.8 ± 4.1%; weight incorporation of the protein was determined to be 3.5 ± 0.1% and 4.0 ± 0.3%. At pH 7.4, growth hormone release of 90% occurred within 45 min for P(MAA-co-NVP) microparticles; 90% release was not achieved with P(MAA-g-PEG) microparticles until 180 min. At pH 1.2, no release occurred from P(MAA-co-NVP) microparticles but 10% release occurred from P(MAA-g-PEG) microparticles. Salmon calcitonin loading and release were shown to be affected by the negative charges of deprotonated MAA; for systems with monomer molar feed ratios of 4:1, 1:1 and 1:4 MAA:NVP, loading efficiencies were determined to be 70.6 ± 3.0%, 25.3 ± 1.2%, and 1.6 ± 1.3%. Salmon calcitonin release was minimal from the copolymer with 4:1 MAA:NVP monomer feed at pH 7.4. The release improved when the pH was raised above physiological levels. These studies confirmed that P(MAA-co-NVP) was an effective oral delivery system for high molecular weight drugs, but improvements are needed before the system could be utilized for high isoelectric point therapeutic delivery.

Glucagon-Like Peptide-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell Proliferation

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.

Thermosensitive Drug Delivery System of Salmon Calcitonin: In Vitro Release, In Vivo Absorption, Bioactivity and Therapeutic Efficacies

The purpose of this study was to develop a biodegradable triblock copolymer, mPEG-PLGA-mPEG-based delivery system for long-term controlled release of salmon calcitonin (sCT) after single subcutaneous injection. The delivery system was prepared by dissolving sCT into polymer solution. In vitro release of sCT from the delivery systems was studied in phosphate buffer saline (PBS, pH 7.4) at 37 degrees C. Stability of released sCT and sCT remaining in gel formulation was evaluated using circular dichroism, HPLC and MALDI-TOF mass spectrometry. In vivo absorption and therapeutic efficacy of sCT from the polymeric formulations were examined in female wistar rats and methylprednisolone acetate (MPA)-induced osteoporosis rat model, respectively. The polymeric formulations of sCT showed long term controlled release (~20 to 40 days) of sCT in its conformationally and chemically stable form. The sCT polymeric formulations controlled the release of sCT over ~20 to 40 days and prevented MPA induced osteoporosis in vivo. The released sCT was biologically active in terms of lowering serum calcium level. The triblock copolymer delivery systems controlled the release of sCT in vitro and in vivo in chemically and conformationally stable as well as biologically active and therapeutically effective form.

New peptidic active ingredient to reduce discomfort and painful sensations in sensitive skin

IFSCC Magazines, 12 (2009) (1) 25–30Approximately 40% of the population (all skin categories and phototypes) complain of sensitive skin. Sensitive skin is healthy but overresponsive, meaning it reacts faster and more intensely to several parameters including environmental factors such as temperature changes and the sun, use of cosmetic products, and certain medicines. It experiences discomfort, tingling, burning and intolerance to certain types of products, a condition referred to as neurosensitivity characterized by a lower threshold of tolerance. Currently, all of the causes are not known but an increase in the permeability of the stratum corneum and an exaggeration of the nerve response are considered to be involved in the phenomenon of sensitive skin. Lifestyle factors including tobacco, alcohol, stress, fatigue and emotions also have an effect. A new synthetic tetrapeptide, N‐acetyl‐L‐tyrosyl‐L‐prolyl‐L‐phenylalanyl‐L‐phenylalaninamide (Ac‐YPFF‐NH2), mimicking a natural opioid peptide was developed with the aim to decrease skin nerve ending stimulation. This tetrapeptide was demonstrated in vitro to reduce cutaneous overreactivity by decreasing release of calcitonin gene‐related peptide from sensory neurons via an agonist effect on the μ opioid receptors and in vivo to improve the comfort of sensitive skin by decreasing unpleasant sensations and pain induced by heat and capsaicin. This tetrapeptide targeting an exaggerated nerve response helps to relieve sensitive skin by normalizing the tolerance threshold for environmental factors or certain topically applied uncomfortable products or skincare treatments.Keywords: Calcitonin gene‐related peptide, μ opioid receptor, nerve endings, peptide, sensitive skin

CAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines.

Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

Medullary thyroid carcinoma and biomarkers: past, present and future

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Improving Oral Absorption of Samon Calcitonin by Trimyristin Lipid Nanoparticles

Solid lipid nanoparticles (SLN) composed of trimyristin (solid lipid) and poloxamer 407 (surfactant) were prepared by a w/o/w emulsion technique for the incorporation of Salmon calcitonin, and further explored as protein carriers for oral delivery. Trimyristin SLN showed a mean size diameter of 200 nm with an association efficiency for calcitonin of approx. 86%. The morphology of SLN was investigated by cryo-SEM and by AFM, revealing spheroid shape SLN with a smooth surface. The in vitro release of calcitonin occurred for a period of 8 h, under both gastric and intestinal simulated pH conditions, predicting suitable properties for oral administration. The pharmacological activity of the protein was evaluated following oral dosage of calcitonin-loaded SLN in rats. SLN lowered the basal blood calcium levels by up to 20% with 500 IU/kg dose sustaining hypocalcaemia over 8 h. The results indicate that incorporation of Salmon calcitonin into trimyristin SLN is a key factor for the improvement of the efficiency of such carriers for oral delivery of proteins.

Future Preventive Therapy: Are There Promising Drug Targets?

The primary headaches are among the most prevalent neurological disorders, afflicting up to 16% in Europe and 22% in USA of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene‐related peptide (CGRP) but not with other neuronal messengers. The specific purpose of this review is to describe the various anatomical aspects of neurotransmitters and mechanisms in the human cranial circulation and to elucidate a possible role for a specific agonist/antagonist in the treatment of primary headaches. Some of the drugs have emerged from laboratory science in the last decade, but most by coincidence when treating other disorders. The difference between an acute or a prophylactic antimigraine medication may simply reśide in the fact that the former includes an acute vasoconstrictor ability and has a shorter receptor binding time.

Mechanical stretch-induced serotonin release from pulmonary neuroendocrine cells: implications for lung development

Pulmonary neuroendocrine cells (PNEC) produce amine (serotonin, 5-HT) and peptides (e.g., bombesin, calcitonin) with growth factor-like properties and are thought to play an important role in lung development. Because physical forces are essential for lung growth and development, we investigated the effects of mechanical strain on 5-HT release in PNEC freshly isolated from rabbit fetal lung and in the PNEC-related tumor H727 cell line. Cultures exposed to sinusoidal cyclic stretch showed a significant 5-HT release inhibitable with gadolinium chloride (10 nM), a blocker of mechanosensitive channels. In contrast to hypoxia (Po2 approximately 20 mmHg), stretch-induced 5-HT release was not affected by Ca2+-free medium or nifedipine (50 microM), excluding the exocytic pathway. In H727 cells, stretch failed to release calcitonin, a peptide stored within dense core vesicles (DCV), whereas hypoxia caused massive calcitonin release. 5-HT released by mechanical stretch is derived predominantly from the cytoplasmic pool, because it is rapid ( approximately 5 min) and is releasable from early (20 days of gestation) fetal PNEC containing few DCV. Both mechanical stretch and hypoxia upregulated expression of tryptophan hydroxylase, the rate-limiting enzyme of 5-HT synthesis. We conclude that mechanical strain is an important physiological stimulus for the release of 5-HT from PNEC via mechanosensitive channels with potential effects on lung development and resorption of lung fluid at the time of birth.

Treatment of xerostomia in prosthetic patients

Xerostomia is a clinical condition caused by a decrease in the production of saliva, it may present itself as a local symptom, as part of a systemic disease such as Sjogren's syndrome, diabetics, alcoholism or as side effects of medications or following therapeutic radiation to the head and neck regions. Xerostomia can lead to difficulties in patients receiving prosthetic treatments. The comfort and retention of removable dentures depend largely on the lubricating ability of the saliva and dry mucosa that can compromise the retention of prosthesis. Furthermore, saliva flow facilitates mastication, formation of food bolos and swallowing, and plays an important role in articulation and speech. Blom et al[1] demonstrated a significant increase in salivary flow during and after acupuncture treatment in patients with severe xerostomia. In a long-term follow-up of patients treated with acupuncture for xerostomia, Blom and Lundeberg[2] showed that acupuncture could significantly result in improvement in salivary flow rate for up to 6 months. They also showed that additional acupuncture therapy could maintain such improvement in salivary flow rate for up to 3 years. Furthermore, Johnstone et al[3] demonstrated that acupuncture could provide palliation in patients with pilocarpine-resistant xerostomia following head and neck radiotherapy. Dawidson et al.[45] found the release of several neuropeptides in the saliva of healthy subjects could be increased by acupuncture. The same researchers also demonstrated that the increased release of calcitonin generated peptide (CGRP) could be one of the factors that increase the salivary flow rate in xerostomic patients treated with acupuncture. With more patients willing to try alternative treatment and with increasing published data available for clinicians, the ancient Chinese acupuncture has been given a new lease of life with the interpretation of Western science. Not only has it been shown that acupuncture provides more than just placebo effects, but also it has been demonstrated in various controlled trials to have a role in mainstream dentistry, especially in the management of gagging reflex, temporomandibular dysfunction and xerostomia. More standardized clinical trials are needed to demonstrate the effect of acupuncture. Serious adverse effects following acupuncture are rare, however, it is the responsibility of the clinicians wishing to practice acupuncture to have a good understanding of acupuncture philosophy and proper training in the field, and therefore be able to prevent, recognize and manage adverse effects when they occur.