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1.
Osteoarthritis Cartilage ; 27(9): 1339-1346, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31176015

RESUMO

OBJECTIVES: Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis. METHODS: Medial meniscectomy (MNX) was performed in 39 rats, while 10 underwent sham surgery. Rats were treated with KBP and/or naproxen. Nociception was assessed by mechanical and cold allodynia, weight bearing asymmetry, and burrowing behavior. Blood samples were collected for biomarker measurements, and knees for histology. Cartilage histopathology was evaluated according to the advanced Osteoarthritis Research International (OARSI) score and KBPs in vitro antiresorptive effects were assessed using human osteoclasts cultured on bone. RESULTS: The MNX animals displayed an increased nociceptive behavior. Treatment with KBP attenuated the MNX-induced osteoarthritis-associated joint pain. The cartilage histopathology was significantly lower in rats treated with KBP than in MNX animals. Bone and cartilage degradation, assessed by CTX-I and CTX-II plasma levels, were decreased in all KBP-treated groups and KBP potently inhibited bone resorption in vitro. CONCLUSIONS: Our study demonstrates the effectiveness of KBP in ameliorating osteoarthritis-associated joint pain and in protecting the articular cartilage, suggesting KBP as a potential drug candidate for osteoarthritis.


Assuntos
Agonistas dos Receptores da Amilina/uso terapêutico , Cartilagem Articular/patologia , Osteoartrite/tratamento farmacológico , Dor/prevenção & controle , Animais , Calcitonina/análogos & derivados , Cartilagem Articular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Osteoartrite/complicações , Osteoartrite/patologia , Ratos , Ratos Endogâmicos Lew , Receptores da Calcitonina/agonistas
3.
Osteoporos Int ; 30(9): 1723-1732, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31041475

RESUMO

The present systematic review aimed to evaluate bone mineral density (BMD) change and complication rates of elcatonin on treating postmenopausal osteoporosis. The result confirmed efficacy of elcatonin and safety in combination therapies of elcatonin (C-E). INTRODUCTION: Postmenopausal osteoporosis is an important issue in global aging trends. One treatment of osteoporosis is elcatonin, a kind of calcitonin. However, it has been challenged for long time because of safety. Many trials investigated on this topic, but they were designed differently. Those designs can be categorized in monotherapy of elcatonin (M-E) and C-E. Unfortunately, no synthesized evidence dealt this topic. METHODS: This study systematically identified target trials from six important databases and only included randomized controlled trial for synthesis. Two investigators assessed quality of eligible trials using the Cochrane Risk of Bias Tool, and they independently extracted data. Network meta-analysis performed Peto odds ratio (POR, used for dealing with zero cell) or weighted mean difference (WMD, for continuous data) with 95% confidence intervals (CI) and consistency H. RESULTS: Sixteen trials recruiting 2754 women with postmenopausal osteoporosis were included in our study. Elcatonin therapies and non-elcatonin medications had comparable fracture rates and bone mineral density change. Yet, C-E (WMD, - 18.93; 95% CI, - 23.97 to - 13.89) and M-E (WMD, - 13.72; 95% CI, - 19.51 to - 7.94) had significantly lower pain score than non-elcatonin medications. However, M-E (POR = 8.413, 95% CI, 2.031 to 34.859) and non-elcatonin medication (Peto OR, 7.450; 95% CI, 1.479 to 37.530) had significantly higher complication rates than placebo. No evidence detected inconsistency and small study effect in this network model. CONCLUSIONS: Based on current evidence, C-E may be considered for treating postmenopausal osteoporosis because it benefits on pain relief and complications. Moreover, it shows comparable fracture rate and bone mineral density change as compared with anti-osteoporosis and calcium supplements. Nevertheless, further trials are needed to investigate formula and dosages of elcatonin.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Calcitonina/análogos & derivados , Hormônios e Agentes Reguladores de Cálcio/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Calcitonina/efeitos adversos , Calcitonina/uso terapêutico , Hormônios e Agentes Reguladores de Cálcio/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/prevenção & controle , Dor/etiologia , Dor/prevenção & controle , Medição da Dor , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas
4.
Curr Med Res Opin ; 35(3): 447-454, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29986611

RESUMO

OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated.


Assuntos
Calcitonina/análogos & derivados , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Calcitonina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Vértebras Lombares , Osteoporose Pós-Menopausa/complicações , Fraturas da Coluna Vertebral/etiologia
5.
Artigo em Inglês | MEDLINE | ID: mdl-28614698

RESUMO

The nucleotide sequence of a sardine preprocalcitonin precursor has been determined from their ultimobranchial glands in the present study. From our analysis of this sequence, we found that sardine procalcitonin was composed of procalcitonin amino-terminal cleavage peptide (N-proCT) (53 amino acids), CT (32 amino acids), and procalcitonin carboxyl-terminal cleavage peptide (C-proCT) (18 amino acids). As compared with C-proCT, N-proCT has been highly conserved among teleosts, reptiles, and birds, which suggests that N-proCT has some bioactivities. Therefore, both sardine N-proCT and sardine CT were synthesized, and their bioactivities for osteoblasts and osteoclasts were examined using our assay system with goldfish scales that consisted of osteoblasts and osteoclasts. As a result, sardine N-proCT (10-7M) activated osteoblastic marker enzyme activity, while sardine CT did not change. On the other hand, sardine CT (10-9 to 10-7M) suppressed osteoclastic marker enzyme activity, although sardine N-proCT did not influence enzyme activity. Furthermore, the mRNA expressions of osteoblastic markers such as type 1 collagen and osteocalcin were also promoted by sardine N-proCT (10-7M) treatment; however, sardine CT did not influence their expressions. The osteoblastic effects of N-proCT lack agreement. In the present study, we can evaluate exactly the action for osteoblasts because our scale assay system is very sensitive and it is a co-culture system for osteoblasts and osteoclasts with calcified bone matrix. Both CT and N-proCT seem to influence osteoblasts and osteoclasts and promote bone formation by different actions in teleosts.


Assuntos
Calcitonina/análogos & derivados , Calcitonina/farmacologia , Osteoblastos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sequência de Bases , Calcitonina/genética , Carpa Dourada , Filogenia , Homologia de Sequência de Aminoácidos
6.
Anal Chem ; 89(13): 6992-6999, 2017 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-28590120

RESUMO

The peptide hormone calcitonin is intimately connected with human cancer development and proliferation. Its biosynthesis is reasoned to proceed via glycine-, α-hydroxyglycine-, glycyllysine-, and glycyllysyllysine-extended precursors; however, as a result of the limitations of current analytical methods, until now, there has been no procedure capable of detecting these individual species in cell or tissue samples. Therefore, their presence and dynamics in cancer had not been established. Here, we report the first methodology for the separation, detection, and quantification of calcitonin and each of its precursors in human cancer cells. We also report the discovery and characterization of O-glycosylated calcitonin and its analogous biosynthetic precursors. Through direct and simultaneous analysis of the glycosylated and nonglycosylated species, we interrogate the hormone biosynthesis. This shows that the cellular calcitonin level is maintained to mitigate effects of biosynthetic enzyme inhibitors that substantially change the proportions of calcitonin-related species released into the culture medium.


Assuntos
Calcitonina/análogos & derivados , Calcitonina/análise , Cromatografia Líquida de Alta Pressão/métodos , Glicopeptídeos/análise , Precursores de Proteínas/análise , Amidina-Liases/antagonistas & inibidores , Calcitonina/biossíntese , Calcitonina/metabolismo , Carboxipeptidase H/antagonistas & inibidores , Linhagem Celular Tumoral , Ácidos Graxos Monoinsaturados/farmacologia , Glicopeptídeos/biossíntese , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Glicosilação , Humanos , Oxigenases de Função Mista/antagonistas & inibidores , Precursores de Proteínas/biossíntese , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Extração em Fase Sólida/métodos , Succinatos/farmacologia
7.
J Pharmacol Exp Ther ; 362(1): 24-30, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28438778

RESUMO

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.


Assuntos
Calcitonina/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobina A Glicada/análise , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Receptores da Calcitonina/agonistas , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Glicemia/metabolismo , Calcitonina/farmacologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/prevenção & controle , Quimioterapia Combinada , Glucagon/sangue , Teste de Tolerância a Glucose , Hiperglicemia/sangue , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Ratos , Ratos Zucker
8.
Peptides ; 98: 23-28, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27341993

RESUMO

The frontal ganglion (FrG) in insects contributes to the modulation of feeding behavior via the regulation of foregut contraction and other neural networks. Profiling the peptides of the FrG is important to understand endocrine regulation of feeding behavior in insects. High-resolution spiral matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) identified an ion peak, corresponding to calcitonin-like diuretic hormone 31 (CT/DH) in the FrG of silkworm Bombyx mori larvae. RT-PCR confirmed that CT/DH is expressed in the FrG, as are other peptide hormones, including allatoregulatory peptides. A feeding latency assay using synthetic CT/DH revealed that it increases the time to the initiation of feeding in a dose-dependent manner. These data indicate that CT/DH is a candidate regulatory peptide that modulates the feeding behavior of B. mori.


Assuntos
Bombyx/fisiologia , Calcitonina/análogos & derivados , Comportamento Alimentar/efeitos dos fármacos , Gânglios/metabolismo , Hormônios de Inseto/metabolismo , Proteínas de Insetos/metabolismo , Animais , Bombyx/crescimento & desenvolvimento , Células Endócrinas/metabolismo , Comportamento Alimentar/fisiologia , Hormônios de Inseto/genética , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/fisiologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Fatores de Tempo
9.
J Bone Miner Metab ; 35(4): 375-384, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27465912

RESUMO

The aim of this study was to compare the efficacy of elcatonin injections and oral nonsteroidal anti-inflammatory drugs (NSAIDs) for patients with osteoporosis who have acute lumbar pain after experiencing new vertebral compression fractures. Two hundred twenty-eight Japanese female patients (mean age 77.3 years) with acute lumbar pain from osteoporotic vertebral fractures were randomly divided into two groups. Patients in one group were given an NSAID (NSAIDs group) and patients in the other group were given weekly intramuscular injections of 20 units of elcatonin (elcatonin group). All patients underwent follow-up examinations up to 6 weeks from the start of the trial. Outcome measures were the level of functional impairment according to the Japan Questionnaire for Osteoporotic Pain (JQ22), the Roland-Morris Disability Questionnaire (RDQ), and a visual analog scale (VAS) of pain intensity. Statistical analyses focused on (1) the time course of pain and functional level using linear mixed effects models to analyze the longitudinal data and (2) the effectiveness of elcatonin injection with mean difference values and 95 % confidence intervals. Significant differences were seen over time between the initial values and the postintervention values (4 and 6 weeks) in JQ22, RDQ, and VAS scores (effect size d > 0.4) in each group. The mean differences between the elcatonin group and the NSAIDs group in each measure at 4 and 6 weeks were -4.8 and -8.3 for the JQ22, -1.3 and -2.6 for the RDQ, and -11.3 and -11.5 for the VAS, shifted to elcatonin. Once weekly elcatonin injection was more effective than NSAIDs for treating acute lumbar pain and improving mobility in Japanese women with osteoporotic vertebral fractures.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Dor nas Costas/tratamento farmacológico , Calcitonina/análogos & derivados , Fraturas por Osteoporose/tratamento farmacológico , Fraturas da Coluna Vertebral/tratamento farmacológico , Doença Aguda , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Calcitonina/efeitos adversos , Calcitonina/farmacologia , Calcitonina/uso terapêutico , Intervalos de Confiança , Feminino , Humanos , Japão , Imagem por Ressonância Magnética , Fraturas por Osteoporose/complicações , Fraturas da Coluna Vertebral/complicações , Inquéritos e Questionários , Resultado do Tratamento
10.
Obesity (Silver Spring) ; 24(8): 1712-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27296301

RESUMO

OBJECTIVE: In this study, KBP-042, a dual amylin- and calcitonin-receptor agonist, was investigated as a treatment of obesity and insulin resistance in five different doses (0.625 µg/kg-10 µg/kg) compared with saline-treated and pair-fed controls. METHODS: Rats with obesity received daily s.c. administrations for 56 days, and glucose tolerance was assessed after one acute injection, 3 weeks of treatment, and again after 7 weeks of treatment. To assess the effect on insulin sensitivity, rats received 5 µg/kg KBP-042 for 21 days before hyperinsulinemic-euglycemic clamp. RESULTS: KBP-042 induced a sustained weight loss of up to 20% without any significant weight reduction in the pair-fed groups. Decreases in adipose tissues and lipid deposition in the liver were observed, while plasma adiponectin was increased and plasma leptin levels were decreased. Acute administration of KBP-042 led to impaired glucose tolerance and increased plasma lactate, while this diabetogenic effect was reversed by chronic treatment. Finally, assessment of insulin sensitivity using the hyperinsulinemic-euglycemic clamp showed that KBP-042 increased the glucose infusion rate. CONCLUSIONS: The study indicates that KBP-042 combines two highly relevant features, namely weight loss and insulin sensitivity, and is thus an excellent candidate for chronic treatment of obesity and insulin resistance.


Assuntos
Agonistas dos Receptores da Amilina/farmacologia , Calcitonina/análogos & derivados , Resistência à Insulina , Obesidade/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Calcitonina/farmacologia , Teste de Tolerância a Glucose , Polipeptídeo Amiloide das Ilhotas Pancreáticas/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
11.
Bone ; 85: 70-80, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26851124

RESUMO

This study aimed to clarify whether elcatonin (EL) has a preventive action on bone dynamics in skeletal unloading. Seven-week-old male C57BL/6J mice with either ground control (GC) or tail suspension (TS) were administered EL 20U/kg or a vehicle (veh) three times per week and assigned to one of the following four groups: GCEL, GCveh, TSEL, and TSveh. Blood samples and bilateral femurs and tibias of the mice were obtained for analysis. After 7days of unloading, the trabecular bone mineral density in the distal femur obtained via peripheral quantitative computed tomography and the trabecular bone volume were significantly higher in the TSEL group than in the TSveh group. The bone resorption histomorphometric parameters, such as the osteoclast surface and osteoclast number, were significantly suppressed in the TSEL mice, whereas the number of preosteoclasts was significantly increased. The plasma level of tartrate-resistant acid phosphatase-5b (TRACP-5b) was significantly lower in the TSEL group than in all other groups. In the bone marrow cell culture, the number of TRACP-positive (TRACP(+)) multinucleated cells was significantly lower in the TSEL mice than in the TSveh mice, whereas the number of TRACP(+) mononucleated cells was higher in the TSEL mice. On day 4, the expression of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), cathepsin K and d2 isoform of vacuolar ATPase V0 domain (ATP6V0D2) mRNA in the bone marrow cells in the TSEL mice was suppressed, and the expression of calcitonin receptor (Calcr) mRNA on day 1 and Calcr antigen on day 4 were significantly higher in the TSveh mice than in the GCveh mice. EL prevented the unloading-induced bone loss associated with the high expression of Calcr in the bone marrow cells of mouse hindlimbs after tail suspension, and it suppressed osteoclast development from preosteoclasts to mature osteoclasts through bone-resorbing activity. This study of EL-treated unloaded mice provides the first in vivo evidence of a physiological role of EL in the inhibition of the differentiation process from preosteoclasts to osteoclasts.


Assuntos
Células da Medula Óssea/metabolismo , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/fisiopatologia , Calcitonina/análogos & derivados , Elevação dos Membros Posteriores , Osteoclastos/patologia , Receptores da Calcitonina/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/patologia , Calcitonina/farmacologia , Calcitonina/uso terapêutico , Osso Esponjoso/patologia , Osso Esponjoso/fisiopatologia , Fusão Celular , Células Cultivadas , Fêmur/patologia , Fêmur/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo
12.
Biol Pharm Bull ; 38(10): 1536-41, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26424018

RESUMO

The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate were continuously recorded. Elcatonin increased the diameter of retinal blood vessels but decreased mean blood pressure in a dose-dependent manner, whereas it had no significant effect on heart rate. A diminished retinal vasodilator response and significant pressor response to elcatonin were observed in rats injected intravenously with N(G)-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Intravitreal injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and SQ22536, an adenylyl cyclase inhibitor, markedly attenuated the vasodilator effects of elcatonin on retinal blood vessels. The retinal vasodilator responses to elcatonin were unaffected 2 weeks after the induction of diabetes by a combination of streptozotocin treatment and D-glucose feeding. These results suggest that elcatonin dilates rat retinal blood vessels via NO- and COX-dependent mechanisms and that the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate system plays a major role in the vasodilator mechanisms. The retinal vasodilatory effects of elcatonin seem to be preserved at early stages of diabetes.


Assuntos
Calcitonina/análogos & derivados , Vasos Retinianos/efeitos dos fármacos , Vasodilatadores/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Inibidores de Adenilil Ciclases/farmacologia , Animais , Calcitonina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Indometacina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos Wistar , Vasos Retinianos/fisiologia
13.
Eur J Pharm Biopharm ; 96: 329-37, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26347924

RESUMO

Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate its influence on intestinal cell translocation and membrane interaction. We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain provides 6- or 9-fold increase in peptide translocation at pH 7.4 and 5.5, respectively. Prolonging the chain length appears to hamper translocation, possibly due to self-association or aggregation, although the long chain acylated analogues remain superior to the unacylated peptide. For K(18)-acylation a short chain provides a moderate improvement, whereas medium and long chain analogues are highly efficient, with a 12-fold increase in permeability compared to the unacylated peptide backbone, on par with currently employed oral permeation enhancers. For K(18)-acylation the medium chain acylation appears to be optimal, as elongating the chain causes greater binding to the cell membrane but similar permeability, and we speculate that increasing the chain length further may decrease the permeability. In conclusion, acylated sCT acts as its own in vitro intestinal permeation enhancer, with reversible effects on Caco-2 cells, indicating that acylation of sCT may represent a promising tool to increase intestinal permeability without adding oral permeation enhancers.


Assuntos
Conservadores da Densidade Óssea/metabolismo , Calcitonina/análogos & derivados , Enterócitos/metabolismo , Absorção Intestinal , Receptores da Calcitonina/agonistas , Acilação , Substituição de Aminoácidos , Animais , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Células CACO-2 , Calcitonina/química , Calcitonina/genética , Calcitonina/metabolismo , Calcitonina/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Química Farmacêutica , Cricetinae , Estabilidade de Medicamentos , Enterócitos/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal/efeitos dos fármacos , Lipossomos , Manitol/metabolismo , Peso Molecular , Mutação , Estabilidade Proteica , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
14.
J Orthop Surg Res ; 10: 103, 2015 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-26138716

RESUMO

BACKGROUND: Elcatonin (ECT) is used to prevent and treat osteoporosis. However, little is known about its effect on the disuse osteoporosis (DOP). The aim of this study is to evaluate the effect of ECT on DOP caused by fracture fixation. METHODS: Forty-five male Sprague-Dawley (SD) rats, aged 6 weeks, were randomly allocated into three groups: the control group without surgery and elcatonin treatment (CTR, n = 15), the surgery group without elcatonin treatment (SUR, n = 15), and the surgery group which received elcatonin subcutaneously (SUR + ECT, n = 15). Surgery was produced by cutting the midshaft of the right femur transversely, fixing with stainless intramedullary needle, and immobilizing the right leg. All the proximal tibias from the random five rats in each group were harvested and investigated by evaluating bone mineral density (BMD), X-ray images, and histological staining respectively at the 4th, 8th, and 12th weeks after surgery. RESULTS: Both of the SUR and SUR + ECT groups obviously exhibited lower BMD values compared to the CTR group; however, the SUR + ECT group showed significantly higher BMD values (p < 0.001, p < 0.05, and p < 0.05) than the SUR group at each time point after surgery. Moreover, similar changes were observed between these groups when examining the radiographs and hematoxylin and eosin (HE) staining. CONCLUSIONS: Elcatonin attenuates disuse osteoporosis after fractures in rats, which may provide a new avenue to prevent and treat disuse osteoporosis after surgery in clinic.


Assuntos
Calcitonina/análogos & derivados , Fixação de Fratura/efeitos adversos , Osteoporose/prevenção & controle , Animais , Densidade Óssea , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Calcitonina/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Masculino , Osteoporose/etiologia , Osteoporose/patologia , Radiografia , Distribuição Aleatória , Ratos Sprague-Dawley
15.
Eur J Pharmacol ; 762: 229-38, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26027795

RESUMO

KBP-042 is a synthetic peptide dual amylin- and calcitonin-receptor agonist (DACRA) developed to treat type 2 diabetes by inducing a significant weight loss while improving glucose homeostasis. In this study the aim was to compare two different formulations: An oral formulation (1mg/kg) to subcutaneous formulations of KBP-042 (2.5µg/kg, 5.0µg/kg and 7.5µg/kg) with comparable pharmacokinetic profiles. Furthermore to examine if differences in mode of action between the two different routes of administration in high-fat fed Sprague-Dawley rats were present. It was established that the subcutaneous administrations of KBP-042 were able to dose-dependently cause a significant weight-loss, reduce food intake, and improve glucose homeostasis without increasing insulin secretion, effects comparable to those observed with oral administration. At the same time, s.c. KBP-042 suppressed the inappropriate glucagon response better than the oral formulation. Furthermore, KBP-042 was found to reduce incretins GLP-1 and GIP and considerably, improve gastric emptying, and to alleviate leptin resistance, as well as insulin resistance. In conclusion, the subcutaneous route of administration was found to have the same beneficial effects on blood glucose homeostasis and weight loss as well as resistance towards important insulin and leptin, albeit with a markedly lower variation in both exposure and biological responses. These data support the application of subcutaneously delivered peptide for mechanistic studies, and highlight the potential of developing s.c. KBP-042 as a therapy for T2D.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Calcitonina/análogos & derivados , Homeostase/efeitos dos fármacos , Resistência à Insulina , Peptídeos/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Calcitonina/administração & dosagem , Calcitonina/farmacocinética , Calcitonina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Esvaziamento Gástrico/efeitos dos fármacos , Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas/agonistas , Leptina/metabolismo , Masculino , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores da Calcitonina/agonistas
16.
J Bone Miner Metab ; 33(4): 432-9, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25123562

RESUMO

Calcitonin has been reported to reduce acute and chronic back pain in osteoporotic patients. The additive effect of calcitonin with a bisphosphonate on chronic back pain remains unclear. The purpose of this study was to evaluate the effect of combining elcatonin (eel calcitonin) with risedronate for patients with chronic back pain. Forty-five postmenopausal women diagnosed as having osteoporosis with chronic back pain persisting for more than 3 months, after excluding women with fresh vertebral fractures within the last 6 months, were randomly allocated to a risedronate group (risedronate alone, n = 22) and a combined group (risedronate and elcatonin, n = 23). The study period was 6 months. Pain was evaluated with a visual analogue scale (VAS) and the Roland-Morris questionnaire (RDQ). Back extensor strength, bone mineral density, and quality of life on the SF-36 and the Japanese osteoporosis quality of life score were also evaluated. Significant improvements were found in the combined group for VAS at final follow-up compared with baseline and 3 months, mental health status on the SF-36, and JOQOL domains for back pain and general health. The JOQOL domain for back pain improved significantly, but no change was found in the VAS or other domains in the risedronate group. Bone mineral density increased significantly in the two groups, but no significant difference was found between the groups. Back extensor strength did not change in both groups. In conclusion, the use of elcatonin in addition to risedronate for more than 3 months reduced chronic back pain. The additional therapy of risedronate with elcatonin may be a useful and practical choice for the treatment of osteoporosis with chronic back pain persisting more than 3 months.


Assuntos
Dor nas Costas/tratamento farmacológico , Conservadores da Densidade Óssea/uso terapêutico , Calcitonina/análogos & derivados , Osteoporose Pós-Menopausa/tratamento farmacológico , Manejo da Dor/métodos , Ácido Risedrônico/administração & dosagem , Idoso , Dor nas Costas/psicologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Calcitonina/uso terapêutico , Dor Crônica/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/psicologia , Medição da Dor , Qualidade de Vida , Ácido Risedrônico/uso terapêutico , Inquéritos e Questionários , Resultado do Tratamento
17.
Am J Physiol Endocrinol Metab ; 307(1): E24-33, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24801386

RESUMO

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and ß-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.


Assuntos
Fármacos Antiobesidade/administração & dosagem , Calcitonina/análogos & derivados , Hipoglicemiantes/administração & dosagem , Receptores da Calcitonina/antagonistas & inibidores , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas/antagonistas & inibidores , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Calcitonina/administração & dosagem , Resistência à Insulina , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Resultado do Tratamento , Perda de Peso/efeitos dos fármacos
18.
Biol Pharm Bull ; 37(2): 322-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24492729

RESUMO

Oxaliplatin frequently causes peripheral neuropathy. Clinical studies have indicated that pregabalin ameliorates oxaliplatin-induced peripheral neuropathy. However, pregabalin frequently causes dizziness and somnolence. We previously reported that elcatonin, a synthetic analog of eel calcitonin, attenuated oxaliplatin-induced cold and mechanical allodynia in rats. The aim of the present study was to compare the anti-allodynic effects of elcatonin and pregabalin in the rats developing the oxaliplatin-induced neuropathy. Male Sprague-Dawley rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)) to induce cold and mechanical allodynia. We assessed the effects of subcutaneous elcatonin (20 U/kg) and oral pregabalin (30 mg/kg) on cold and mechanical allodynia by cold stimulation (8°C) to the hind paw of the rats and the von Frey test, respectively. Elcatonin reversed the effects of oxaliplatin-induced cold and mechanical allodynia in rats for a longer time period than pregabalin does. These results suggested that elcatonin might be useful for the clinical treatment of oxaliplatin-induced neuropathy.


Assuntos
Analgésicos/uso terapêutico , Antineoplásicos/efeitos adversos , Calcitonina/análogos & derivados , Hiperalgesia/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ácido gama-Aminobutírico/análogos & derivados , Analgésicos/farmacologia , Animais , Calcitonina/farmacologia , Calcitonina/uso terapêutico , Temperatura Baixa , Hiperalgesia/induzido quimicamente , Masculino , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Oxaliplatina , Medição da Dor , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Pregabalina , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêutico
19.
Mater Sci Eng C Mater Biol Appl ; 33(6): 3111-20, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23706190

RESUMO

Different valuable compounds, which can be employed in medicine or in other industries (i.e. food, agrochemical, pharmaceutical) can be recovered from by-products and waste from the fish canning industries. They include lipids, proteins, bio-polymers, minerals, amino acids and enzymes; they can be extracted from wastewaters and/or from solid residues (head, viscera, skin, tails and flesh) generated along the canning process, through the filleting, cooking, salting or smoking stages. In this review, the opportunities for the extraction and the valorisation of bioactive compounds from sardine, sardine-type fish and mackerel canning residues are examined and discussed. These are amongst the most consumed fishes in the Mediterranean area; moreover, canning is one of the most important and common methods of preservation. The large quantities of by-products generated have great potentials for the extraction of biologically desirable high added value compounds.


Assuntos
Calcitonina/análogos & derivados , Peixes/metabolismo , Animais , Osso e Ossos/química , Calcitonina/química , Colágeno/química , Durapatita/química , Gelatina/química , Águas Residuárias/química
20.
PLoS One ; 8(2): e54299, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23393556

RESUMO

INTRODUCTION: Previous work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects. METHODS: Using the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed. RESULTS: Whilst eCT alone was inactive, it synergised at 1 µg/kg with low doses of Dex (7.5 or 15 µg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them. CONCLUSIONS: We present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond.


Assuntos
Artrite Experimental/tratamento farmacológico , Calcitonina/uso terapêutico , Glucocorticoides/uso terapêutico , Animais , Calcitonina/administração & dosagem , Calcitonina/efeitos adversos , Calcitonina/análogos & derivados , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/efeitos adversos , Imuno-Histoquímica , Ratos
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