RESUMO
Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.
Assuntos
Calcitonina/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Absorção Intestinal/efeitos dos fármacos , Nanocompostos/química , Administração Oral , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2/efeitos dos fármacos , Células CACO-2/metabolismo , Calcitonina/efeitos adversos , Calcitonina/sangue , Calcitonina/farmacocinética , Cálcio/sangue , Hormônios e Agentes Reguladores de Cálcio/efeitos adversos , Hormônios e Agentes Reguladores de Cálcio/sangue , Hormônios e Agentes Reguladores de Cálcio/farmacocinética , Quitosana/química , Sulfato de Dextrana/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Hipocalcemia/induzido quimicamente , Injeções Subcutâneas , Masculino , Ratos , Ratos Sprague-Dawley , Ácido Taurocólico/químicaRESUMO
Advances in pharmaceutical technology have promoted the development of colon-targeted delivery system for oral administration of bioactive peptides or proteins to enhance their bioavailability. In this study, a multi-unit nanofiber mat was fabricated by coaxial electrospinning and its feasibility as the colon-targeted delivery system for a bioactive peptide, salmon calcitonin (sCT), was investigated. Sodium alginate and sCT-loaded liposome coated with pectin served as the shell layer and core layer, respectively. An in vitro study demonstrated that the encapsulated sCT was released in a sustained and colon-targeted way. Analysis using different mathematical models showed that release followed a complex mechanism. In addition, greater amounts of sCT were released from the core-shell nanofiber mat into simulated colon fluid (SCF) than was released from a uniaxial nanofiber mat (65.2% vs. 47.8%). The use of a core-shell nanofiber mat further alleviated the burst release of sCT into simulated gastric and intestinal fluid (SGF and SIF), demonstrating the superiority of a multi-unit vehicle for colon-targeted delivery of sCT. Furthermore, 88% of the bioactivity of encapsulated sCT was retained. This multi-unit vehicle offers a better-designed vehicle for the colon-targeted sustained release of bioactive peptides or proteins and, thus, should improve oral bioavailability.
Assuntos
Calcitonina/metabolismo , Colo/metabolismo , Nanofibras/química , Pectinas/metabolismo , Administração Oral , Alginatos/administração & dosagem , Alginatos/química , Alginatos/metabolismo , Disponibilidade Biológica , Calcitonina/administração & dosagem , Calcitonina/química , Colo/química , Sistemas de Liberação de Medicamentos , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/metabolismo , Nanofibras/administração & dosagem , Tamanho da Partícula , Pectinas/administração & dosagem , Pectinas/química , Propriedades de SuperfícieRESUMO
The optimum therapy for the management of diabetes mellitus (DM) has been a controversial issue. Therefore, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids {eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); EPA/DHA ratio?=?3/2} relative to metformin in diabetic male Wistar rats. Forty rats were used for this study. They were randomly divided into 8 groups of five (5) rats each, which were treated with single or combined administration of salmon calcitonin, N-3 and metformin. DM was induced by the administration of streptozotocin (65?mg/kg b.w., i.p.), 15?min after the administration of nicotinamide (110?mg/kg b.w., i.p.). Nine days afterwards, treatments started, and they lasted for 28 days. Sct was administered at 2.5 and 5.0 IU/kg b.w./day (i.m.), while, N-3 and metformin were administered at 200 and 180?mg/kg b.w./day (p.o.) respectively. The results showed that the induced DM significantly increased pro-inflammatory markers, and significantly altered antioxidant and haematological indices. The combined administration of Sct and N-3 had synergistic effects on total bilirubin and total antioxidant capacity, but, non-synergistic actions on malondialdehyde, uric acid, interleukin-6, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, and the haematological parameters. These effects were comparable to that of metformin which showed a more or less therapeutic action than N-3. The study concluded that the antioxidant, anti-inflammatory, and haematological effects of the combined administration of Sct and N-3 is comparable to that of metformin. Nevertheless, the latter showed more or less therapeutic effects relative to N-3.
Assuntos
Anti-Inflamatórios/farmacologia , Calcitonina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Ácidos Graxos Ômega-3/farmacologia , Animais , Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Calcitonina/administração & dosagem , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Ácidos Graxos Ômega-3/administração & dosagem , Masculino , Metformina/farmacologia , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400 IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27 h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.
Assuntos
Calcitonina/uso terapêutico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Resultado do Tratamento , Adulto , Calcitonina/administração & dosagem , Feminino , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatos/metabolismo , Fósforo/farmacologiaRESUMO
Calcitonin (CTN), a calcium regulatory hormone, promotes calcium diuresis from the kidney and suppresses bone resorption. The objective of this study was to evaluate whether the topical and intermittent application of CTN inhibits alveolar bone resorption using ligature-induced experimental periodontitis in rats. Experimental periodontitis was induced by placing a nylon ligature around maxillary molars of 8-week-old male Wistar rats for 20 days. Thirty-two rats were divided into four groups: basal sham control group, periodontitis group, periodontitis plus 0.2 U CTN (low dose), and periodontitis plus 1.0 U CTN (high dose) group. To investigate the effects of CTN on alveolar bone resorption, CTN was topically injected into the palatal gingivae every 2 days after ligature removal (day 0). Micro-computed tomography (CT) analysis was performed for linear parameter assessment of alveolar bone on day 5 and day 14. Periodontal tissues were examined histo-pathologically to assess the differences among the study groups. Micro-CT images showed that alveolar bone resorption was induced statistically around the molar of ligatured rats on day 5 and day 14. The amount of bone resorption was more severe on day 14 than that on day 5. On day 5, only high-dose CTN treatment significantly suppressed bone resorption. In addition, both doses of CTN significantly suppressed bone resorption on day 14. Histological examination clarified that there were fewer TRAP-positive cells in the CTN treatment groups than in the periodontitis group on day 5. Local administration of CTN decreased alveolar bone resorption by regulating osteoclast activation in rats with periodontitis.
Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Periodontite/tratamento farmacológico , Administração Tópica , Perda do Osso Alveolar/patologia , Animais , Conservadores da Densidade Óssea/farmacologia , Calcitonina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Periodontite/patologia , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Fatores de Tempo , Microtomografia por Raio-XRESUMO
The objective of this study was to develop a novel anhydrous reverse micelle nanoparticles (ARM-NPs) system to overcome the sedimentation instability of peptide-containing pressurized metered-dose inhalers (pMDIs). A bottom-up method was utilized to fabricate ARM-NPs. Tertiary butyl alcohol (TBA)/water system, freeze-drying and lipid inversion method were successively used to produce the ARM-NPs for pMDI. Various characteristics of ARM-NPs were investigated including particle size, morphology, secondary structure of the peptide drug, aerosolization properties and storage stability. As revealed by the results, ARM-NPs with spherical shape possessed 147.7 ± 2.0 nm of particle size with 0.152 ± 0.021 PdI. The ARM-NPs for pMDI had satisfactory fine particle fraction (FPF) value of 46.99 ± 1.33%, while the secondary structure of the peptide drug was unchanged. Stability tests showed no pronounced sedimentation instability for over 12 weeks at 4-6 °C. Furthermore, a hypothesis was raised to explain the formation mechanism of ARM-NPs, which was verified by the differential scanning calorimetry analysis. The lecithin employed in the reverse micelle vesicles could serve as a steric barrier between peptide drugs and bulk propellant, which prevented the instability of peptide drugs in hydrophobic environment. Homogenous particle size could avoid Ostwald ripening phenomenon of particles in pMDIs. It was concluded that the ARM-NPs for pMDI could successfully overcome sedimentation instability by the steric barrier effect and homogeneous particle size.
Assuntos
Calcitonina/administração & dosagem , Portadores de Fármacos , Inaladores Dosimetrados , Administração por Inalação , Aerossóis , Calcitonina/química , Dicroísmo Circular , Composição de Medicamentos , Estabilidade de Medicamentos , Desenho de Equipamento , Lecitinas/química , Micelas , Microscopia Eletrônica de Transmissão , Nanomedicina , Nanopartículas , Tamanho da Partícula , Pressão , Desnaturação Proteica , Estabilidade Proteica , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de Superfície , Tecnologia Farmacêutica/métodosRESUMO
OBJECTIVE: To verify the clinical efficacy on postmenopausal osteoporosis treated with acupoint injection of salmon calcitonin. METHODS: Ninety patients of postmenopausal osteoporosis were randomized into three groups, 30 cases in each one. In the acupoint injection group, Shenshu (BL 23) and Zusanli (ST 36) were selected bilaterally. The injection 4 mL was prepared with salmon calcitonin 100 U (1 mL) and 0.9% sodium chloride injection. Each acupoint was stimulated with the injection, 1 mL. In the blank group, 0.9% sodium chloride injection was applied to bilateral Shenshu (BL 23) and Zusanli (ST 36), 1 mL at each acupoint. In the intramuscular injection group, salmon calcitonin 100 U was injected at gluteus maximus. The treatment was given once every two days in the patients of the three groups and lasted for 2 months. The levels of bone mineral density (BMD), bone alkaline phosphatase (NBAP), C-terminal telopeptides of typeâ collagen (CTX), urine calcium/creatinine (Ca/Cr) and the symptom score of osteoporosis were detected in the patients of the three groups before and after treatment. RESULTS: In the patients of the three groups, NBAP and BMD in lumbar vertebra after treatment were higher than those before treatment (all P<0.05); CTX, Ca/Cr and symptom score were lower than those before treatment (all P<0.05). After treatment, NBAP was (32.7±2.5) µg/L in the acupoint injection group, higher than those in the blank group and the intramuscular injection group (both P<0.05). In the acupoint injection group, CTX was reduced to (239.7±63.6) µmmol/L and Ca/Cr was reduced to 0.525±0.274, apparently lower than those in the blank group and intramuscular injection group (both P<0.05). After treatment, in the acupoint injection group, BMD of lumbar vertebra was (0.731±0.062) g/m2, higher than the level of the rest two groups (both P<0.05). After treatment, the symptom score was 5.2±0.6 in the acupoint injection group, lower than those in the blank group and intramuscular injection group (both P<0.05). CONCLUSIONS: Salmon calcitonin injec-tion at Zusanli (ST 36) and Shenshu (BL 23) achieves significant efficacy on postmenopausal osteoporosis, stimulating osteoblast activity and inhibiting bone absorption of osteoclast.
Assuntos
Pontos de Acupuntura , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Osteoporose Pós-Menopausa/terapia , Densidade Óssea , Terapia Combinada/métodos , Feminino , HumanosRESUMO
Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant (P<0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with 20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase (P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21 days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis, and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.
Assuntos
Artrite Experimental/tratamento farmacológico , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Difosfonatos/administração & dosagem , Osteoporose Pós-Menopausa/tratamento farmacológico , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/fisiopatologia , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/microbiologia , Artrite Experimental/fisiopatologia , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/química , Remodelação Óssea/efeitos dos fármacos , Calcitonina/química , Química Farmacêutica , Difosfonatos/química , Portadores de Fármacos , Feminino , Humanos , Injeções Subcutâneas , Masculino , Mycobacterium , Osteoporose Pós-Menopausa/diagnóstico por imagem , Osteoporose Pós-Menopausa/etiologia , Osteoporose Pós-Menopausa/fisiopatologia , Ovariectomia , Polietilenoglicóis/química , Ratos Sprague-Dawley , Tecnologia Farmacêutica/métodos , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Tíbia/fisiopatologia , Fatores de Tempo , Microtomografia por Raio-XRESUMO
BACKGROUND: Many factors affect implant stability and periprosthetic bone mineral density (BMD) following total joint arthroplasty. We asked whether perioperative alendronate, risedronate, calcitonin and indomethacine administration altered (1) femoral stem shear strength and periprosthetic bone mineral density BMD in ovariectomized rats and (2) whether there were differences in the effect of these drugs. METHODS: Thirty overiectomized rats were divided into five groups and implanted with intramedullary mini-cortical screws in the femur. Four groups were treated with alendronate, risedronate, salmon calcitonin and indomethacin for 4 weeks preoperatively and 8 weeks postoperatively. RESULTS: Although alendronate and risedronate increased the periprosthetic BMD more than calcitonin, they did not alter implant fixation compared to calcitonin. Indomethacin significantly decreased the BMD around the stem and implant stability compared to all other groups. CONCLUSIONS: This study showed that perioperative treatment with bisphosphonates and calcitonin improved the BMD around the stems and implant stability. Although bisphosphonates increased the BMD more than calcitonin, there was no difference in implant stability. Indomethacin markedly decreased the periprosthetic BMD and implant stability. The main clinical significance of our study was the finding about the need to strictly avoid long-term use of high-dose nonsteroidal antiinflammatory drugs for patients who have major joint arthritis and a previous history of arthroplasty.
Assuntos
Alendronato/administração & dosagem , Artroplastia de Quadril , Densidade Óssea/efeitos dos fármacos , Calcitonina/administração & dosagem , Indometacina/administração & dosagem , Ácido Risedrônico/administração & dosagem , Absorciometria de Fóton , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Seguimentos , Osteoporose/etiologia , Osteoporose/prevenção & controle , Ovariectomia/efeitos adversos , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/prevenção & controle , Cuidados Pré-Operatórios/métodos , Ratos , Ratos WistarRESUMO
Osteoarthritis (OA) is characterized by chronic degeneration of joints, involving mainly the articular cartilage and the underlying bone, and severely impairing the quality of life of the patient. Although with limited efficacy, currently available pharmacological treatments for OA aim to control pain and to retard disease progression. Salmon calcitonin (sCT) is a drug which has been shown to have therapeutic effects in experimental arthritis by inhibiting both bone turnover and cartilage degradation and reducing the activities of matrix metalloproteinases (MMP). High molecular weight hyaluronic acid (HA) is used as a lubricant in OA therapy, and, interestingly, HA polymers may normalize the levels of MMP-1, -3 and -13. We demonstrated that sCT rapidly clears from the knee joint of rat animal model, after intra-articular (i.a.) administration, and it induces systemic effects. Here, sCT was conjugated to HA (200kDa) with the aim of prolonging the residence time of the polypeptide in the joint space by reducing its clearance. An aldehyde derivative of HA was used for N-terminal site-selective coupling of sCT. The activity of sCT was preserved, both in vitro and in vivo, after its conjugation and the i.a. injection of HA-sCT did not trigger any systemic effects in rats. The efficacy of HA-sCT treatment was tested in a rabbit OA model and clear chondro-protective effect was proven by macro- and microscopic assessments and histological findings. Our results indicate that HAylation of sCT increases the size of the polypeptide in a stable covalent manner and delays its passage into the blood stream. We conclude that HA conjugation prolongs the anti-catabolic effects of sCT in joint tissues, including the synovial membrane and cartilage.
Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Calcitonina/administração & dosagem , Ácido Hialurônico/química , Osteoartrite/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Artrite Experimental/metabolismo , Calcitonina/química , Cálcio/sangue , Cartilagem Articular/patologia , Linhagem Celular , AMP Cíclico/metabolismo , Articulação do Joelho/metabolismo , Masculino , Coelhos , Ratos Sprague-Dawley , SuínosRESUMO
This short-term study assessed the efficacy and safety of calcium carbonate combined with calcitonin in the treatment of hypercalcemia in hemodialysis patients. Patients (n=64) on hemodialysis for chronic kidney disease for more than 6 months were included based on total serum calcium more than 10.5 mg/dL. All patients were randomized (1:1) to receive calcium carbonate combined with calcitonin (Group I) or lanthanum carbonate (Group II) for 12 weeks. Blood levels of calcium, phosphorus and intact parathyroid hormone (iPTH) were measured every month, bone mass density (BMD) and coronary artery calcium scores (CACS) were measured at 3 months. During the study period, serum calcium decreased from 10.72 ± 0.39 to 10.09 ± 0.28 mg/dL (P < 0.05), serum phosphorus decreased from 6.79 ± 1.05 to 5.46 ± 1.18 mg/dL (P < 0.05), and serum iPTH levels in the Group I and Group II were not significantly different from the baseline. There were no significant differences in CACS in either group. There were no significant differences in the BMD values between Group I and baseline. In Group II, the BMD values at the lumbar spine and femoral neck were significantly lower than those before the trial and significantly lower than the corresponding values of Group I (P<0.05). Calcium carbonate combined with calcitonin and lanthanum carbonate were equally effective in the suppression of hypercalcemia in hemodialysis patients. There were no serious treatment-related adverse events in treatment with calcium carbonate combined with calcitonin.
Assuntos
Calcitonina/uso terapêutico , Carbonato de Cálcio/uso terapêutico , Hipercalcemia/tratamento farmacológico , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Calcitonina/administração & dosagem , Calcitonina/efeitos adversos , Cálcio/sangue , Carbonato de Cálcio/administração & dosagem , Carbonato de Cálcio/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Hipercalcemia/etiologia , Lantânio/administração & dosagem , Lantânio/efeitos adversos , Lantânio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Insuficiência Renal Crônica/terapia , Adulto JovemRESUMO
CLINICAL SCENARIO: Mrs. JD is a 58-year-old postmenopausal woman having symptoms of hot flashes and night sweats. She has a dual-energy x-ray absorptiometry T-score of -2.4 in the femoral neck, consistent with low bone mass or osteopenia. She has a parental history of hip fracture. FRAX shows the 10-year absolute risk of major osteoporotic fracture equal to 18% and the 10-year risk of hip fracture above 3% at 3.2%, which meets the National Osteoporosis Foundation threshold. Mrs. JD is taking calcium 1,200 mg, between supplement and diet, and 1,000 IU vitamin D3 daily. How should she be treated?
Assuntos
Osteoporose Pós-Menopausa/tratamento farmacológico , Medicina de Precisão , Absorciometria de Fóton , Administração Intranasal , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Densidade Óssea , Conservadores da Densidade Óssea , Calcitonina/administração & dosagem , Calcitonina/efeitos adversos , Cálcio da Dieta/administração & dosagem , Denosumab , Difosfonatos/efeitos adversos , Difosfonatos/uso terapêutico , Feminino , Fraturas do Quadril/prevenção & controle , Fogachos , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/diagnóstico por imagem , Fraturas por Osteoporose/prevenção & controle , Cloridrato de Raloxifeno/efeitos adversos , Cloridrato de Raloxifeno/uso terapêutico , Fatores de Risco , Vitamina D/administração & dosagemRESUMO
Osteoporosis may cause bone fracture even under slight trauma. Osteoporotic fracture has become a major public health problem but until today, the treatments available are not satisfactory. Many pre-clinical testings on animals were done to find new agents that can be sourced from natural products and synthetic drugs for osteoporotic fracture healing. Animal models are more appropriate for fracture healing study than human subject due to several reasons including the ethical issues involved. The bones of rodents are similar to human in term of their morphological change and response to therapy. Small rodents such as rats and mice are suitable animal models for fracture healing studies as they have a similar bone remodeling system to human. To date, there is no specific guideline to carry out fracture healing studies in animal models for the evaluation of new agents. This paper highlights the protocols of various fracture and fixation methods for experimental osteoporotic fracture healing using rodent models.
Assuntos
Modelos Animais de Doenças , Consolidação da Fratura/efeitos dos fármacos , Fraturas Ósseas/tratamento farmacológico , Osteoporose/complicações , Animais , Calcitonina/administração & dosagem , Calcitonina/uso terapêutico , Cálcio/administração & dosagem , Cálcio/uso terapêutico , Terapia de Reposição de Estrogênios , Fixação de Fratura , Fraturas Ósseas/etiologia , Humanos , Camundongos , Osteoporose/tratamento farmacológico , Preparações de Plantas/administração & dosagem , Preparações de Plantas/uso terapêutico , Ratos , Fatores de Risco , Vitamina D/administração & dosagem , Vitamina D/uso terapêuticoRESUMO
BACKGROUND: Lumbar spinal stenosis with neurogenic claudication is one of the most commonly diagnosed and treated pathological spinal conditions. It frequently afflicts the elderly population. OBJECTIVES: To systematically review the evidence for the effectiveness of nonoperative treatment of lumbar spinal stenosis with neurogenic claudication. SEARCH METHODS: CENTRAL, MEDLINE, CINAHL, and Index to Chiropractic Literature (ICL) databases were searched up to June 2012. SELECTION CRITERIA: Randomized controlled trials published in English, in which at least one arm provided data on nonoperative treatments DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. Risk of bias in each study was independently assessed by two review authors using the 12 criteria recommended by the Cochrane Back Review Group (Furlan 2009). Dichotomous outcomes were expressed as relative risk, continuous outcomes as mean difference or standardized mean difference; uncertainty was expressed with 95% confidence intervals. If possible a meta-analysis was performed, otherwise results were described qualitatively. GRADE was used to assess the quality of the evidence. MAIN RESULTS: From the 8635 citations screened, 56 full-text articles were assessed and 21 trials (1851 participants) were included. There was very low-quality evidence from six trials that calcitonin is no better than placebo or paracetamol, regardless of mode of administration or outcome assessed. From single small trials, there was low-quality evidence for prostaglandins, and very low-quality evidence for gabapentin or methylcobalamin that they improved walking distance. There was very low-quality evidence from a single trial that epidural steroid injections improved pain, function, and quality of life, up to two weeks, compared with home exercise or inpatient physical therapy. There was low-quality evidence from a single trial that exercise is of short-term benefit for leg pain and function compared with no treatment. There was low and very low-quality evidence from six trials that multimodal nonoperative treatment is less effective than indirect or direct surgical decompression with or without fusion. A meta-analysis of two trials comparing direct decompression with or without fusion to multimodal nonoperative care found no significant difference in function at six months (mean difference (MD) -3.66, 95% CI -10.12 to 2.80) and one year (MD -6.18, 95% CI -15.03 to 2.66), but at 24 months a significant difference was found favouring decompression (MD -4.43, 95% CI -7.91 to -0.96). AUTHORS' CONCLUSIONS: Moderate and high-quality evidence for nonoperative treatment is lacking and thus prohibits recommendations for guiding clinical practice. Given the expected exponential rise in the prevalence of lumbar spinal stenosis with neurogenic claudication, large high-quality trials are urgently needed.
Assuntos
Claudicação Intermitente/terapia , Vértebras Lombares , Neuralgia/terapia , Estenose Espinal/terapia , Idoso , Analgesia Epidural , Calcitonina/administração & dosagem , Terapia por Exercício/métodos , Feminino , Humanos , Claudicação Intermitente/etiologia , Perna (Membro)/irrigação sanguínea , Perna (Membro)/inervação , Masculino , Pessoa de Meia-Idade , Neuralgia/etiologia , Prostaglandinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estenose Espinal/complicaçõesRESUMO
One of the major challenges faced by therapeutic polypeptides remains their invasive route of delivery. Oral administration offers a potential alternative to injections; however, this route cannot be currently used for peptides due to their limited stability in the stomach and poor permeation across the intestine. Here, we report mucoadhesive devices for oral delivery that are inspired by the design of transdermal patches and demonstrate their capabilities in vivo for salmon calcitonin (sCT). The mucoadhesive devices were prepared by compressing a polymeric matrix containing carbopol, pectin and sodium carboxymethylcellulose (1:1:2), and were coated on all sides but one with an impermeable and flexible ethyl cellulose (EC) backing layer. Devices were tested for in vitro dissolution, mucoadhesion to intestinal mucosa, enhancement of drug absorption in vitro (Caco-2 monolayer transport) and in vivo in rats. Devices showed steady drug release with ≈75% cumulative drug released in 5h. Devices also demonstrated strong mucoadhesion to porcine small intestine to withstand forces up to 100 times their own weight. sCT-loaded mucoadhesive devices exhibited delivery of sCT across Caco-2 monolayers and across the intestinal epithelium in vivo in rats. A ≈52-fold (pharmacokinetic) and ≈44-fold (pharmacological) enhancement of oral bioavailability was observed with mucoadhesive devices when compared to direct intestinal injections. Oral delivery of devices in enteric coated capsules resulted in significant bioavailability enhancement.
Assuntos
Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/instrumentação , Resinas Acrílicas/química , Adesividade , Administração Oral , Animais , Conservadores da Densidade Óssea/farmacocinética , Células CACO-2 , Calcitonina/farmacocinética , Carboximetilcelulose Sódica/química , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Pectinas/química , Ratos , Ratos Sprague-Dawley , SuínosRESUMO
BACKGROUND/AIM: In addition to damage of the bones that support the remaining teeth, degradation of osteoporotic oral bones also lead to a consequent reduction of supporting tissues and the loss of dentures retention. The aim of this study was to assess the clinical and radiographic outcomes following injection of a calcitonin and calcium solution into the buccal aspects of edentulous mandibles. METHODS: The experimental group of 67 edentulous patients diagnosed with osteoporosis, and the control group of 19 nonosteoporotic edentulous patients were treated with the calcitonin and calcium once solution per month. Mandibular bone density was measured from panoramic radiographs, supplemented by T scores of skeletal density in the experimental group. RESULTS: After the therapy, measurements showed moderate increases in bone density, compensating for up to 4% of the total loss of minerals and solidity of denture-bearing areas of osteoporotic mandibles. Osteoporosis affected women earlier than men in this study. CONCLUSION: Application of a calcitonin and calcium solution is a suitable method of preprosthetic therapy for edentulous osteoporotic patients.
Assuntos
Calcitonina/uso terapêutico , Cálcio/uso terapêutico , Mandíbula/diagnóstico por imagem , Boca Edêntula/tratamento farmacológico , Osteoporose/complicações , Absorciometria de Fóton , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Calcitonina/administração & dosagem , Cálcio/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Boca Edêntula/diagnóstico por imagem , Boca Edêntula/etiologia , Osteoporose/diagnóstico por imagem , Osteoporose/tratamento farmacológico , Radiografia Panorâmica , Resultado do TratamentoRESUMO
We studied the effect of Russian preparation of porcine calcitonin (calcitrin, 1 U/100 g) and blockers of Ca(2+) channels nifedipine (1 mg/kg, blocker of chemosensitive Ca(2+) channels) and isoptin (5 mg/kg, blocker of voltage-dependent Ca(2+) channels) on glucose metabolism. Calcitonin produced a pronounced hyperglycemic effect in rats. A close negative correlation was found between glucose level and total calcium content. Injection of calcitonin reduced glucose tolerance in rats. Isoptin and nifedipine reduced plasma calcium level and did not affect significantly the blood glucose levels, did not change the pattern of alimentary hyperglycemia in response to glucose load, completely abolished the hyperglycemic effect of calcitonin, and prevented calcitonin-induced impairment of glucose tolerance.
Assuntos
Conservadores da Densidade Óssea/antagonistas & inibidores , Calcitonina/antagonistas & inibidores , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hiperglicemia/prevenção & controle , Nifedipino/uso terapêutico , Verapamil/uso terapêutico , Animais , Conservadores da Densidade Óssea/administração & dosagem , Calcitonina/administração & dosagem , Cálcio/sangue , Bloqueadores dos Canais de Cálcio/farmacologia , Glucose/metabolismo , Teste de Tolerância a Glucose , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Masculino , Nifedipino/farmacologia , Ratos , Ratos Wistar , Suínos , Verapamil/farmacologiaRESUMO
Aminoprocalcitonin (N-PCT), a neuroendocrine peptide derived from procalcitonin, reduces food intake and body weight when administered centrally in rats. We have recently shown that N-PCT is expressed in brain areas known to be involved in energy homeostasis, including the paraventricular nucleus (PVN) of the hypothalamus, which contains a prominent population of corticotrophin-releasing factor (CRF)-synthesising neurones. CRF plays a pivotal role in the regulation of the hypothalamic-pituitary adrenal (HPA) axis and food intake. However, little is known about functional interactions of N-PCT and CRF. In the present study, we found endogenous N-PCT protein in the rat PVN. We also showed N-PCT immunoreactivity in PVN co-localised with NeuN, a neuronal marker, or glial fibrillary acidic protein, an astrocyte marker. Double staining immunohistochemistry revealed that N-PCT co-localised with CRF in parvocellular neurones of the PVN. Intracerebroventricular N-PCT administration increased CRF mRNA and content in the hypothalamus, suggesting that N-PCT stimulates the HPA axis and suppresses food intake and body weight via CRF-dependent pathways. In keeping with this, i.c.v. co-injection of D-Phe-CRF(12-41), a CRF receptor antagonist, significantly attenuated N-PCT-induced reduction in food intake and body weight in a dose-dependent manner. Furthermore, i.c.v. administration of N-PCT increased plasma adrenocorticotrophic hormone and corticosterone concentrations and induced the expression of Fos protein, a marker of neuronal activity, in parvocellular CRF neurones. These data collectively support the hypothesis that N-PCT inhibits food intake and body weight and stimulates the HPA axis via CRF-mediated pathways.
Assuntos
Calcitonina/administração & dosagem , Calcitonina/farmacologia , Hormônio Liberador da Corticotropina/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Precursores de Proteínas/administração & dosagem , Precursores de Proteínas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Calcitonina/imunologia , Calcitonina/metabolismo , Peptídeo Relacionado com Gene de Calcitonina , Sistema Nervoso Central/efeitos dos fármacos , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Sistema Hipotálamo-Hipofisário/metabolismo , Imuno-Histoquímica , Injeções Intraventriculares , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Precursores de Proteínas/imunologia , Precursores de Proteínas/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Estimulação QuímicaRESUMO
OBJECTIVES: There are very few published studies of agents having the potential to improve bone health in children with inflammatory bowel disease (IBD). The objective of this study was to establish the efficacy and safety of intranasal calcitonin in improving bone mineral density (BMD) in young patients with IBD and to define additional factors that impact bone mineral accrual. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial in 63 participants, ages 8-21 years, with a spinal BMD Z-score ≤ -1.0 s.d. measured by dual energy X-ray absorptiometry. Subjects were randomized to 200 IU intranasal calcitonin (n=31) or placebo (n=32) daily. All received age-appropriate calcium and vitamin D supplementation. Subsequent BMD measurements were obtained at 9 and 18 months. RESULTS: Intranasal calcitonin was well tolerated. Adverse event frequency was similar in both treatment groups, and such events were primarily minor, reversible, and limited to the upper respiratory tract. The BMD Z-score change documented at screening and 9 months and screening and 18 months did not differ between the two therapeutic arms. In participants with Crohn's disease, the spinal BMD Z-score improved between screening and 9 months (change in spine BMD Z-score (ΔZSBMD)(9-0)) in the calcitonin group (ΔZSBMD(9-0)(calcitonin)=0.21 (0.37), ΔZSBMD(9-0)(placebo)=-0.15 (0.5), P=0.02); however, this was only a secondary subgroup analysis. Bone mineral accrual rate during the trial did not lead to normalization of BMD Z-score in this cohort. Factors favoring higher bone mineral accrual rate were lower baseline BMD and higher baseline body mass index Z-score, improvement in height Z-score, higher serum albumin, hematocrit and iron concentration, and more hours of weekly weight-bearing activity. Factors associated with lower bone mineral accrual rate were more severe disease-as indicated by elevated inflammatory markers, need for surgery, hospitalization, and the use of immunomodulators-and higher daily caffeine intake. CONCLUSIONS: Intranasal calcitonin is well tolerated but does not offer a long-term advantage in youth with IBD and decreased BMD. Bone mineral accrual rate remains compromised in youth with IBD and low BMD raising concerns for long-term bone health outcomes. Improvement in nutritional status, catch-up linear growth, control of inflammation, increase in weight-bearing activity, and lower daily caffeine intake may be helpful in restoring bone density in children with IBD and low BMD.