Made available in DSpace on 2014-06-11T19:30:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2001-04-18Bitstream added on 2014-06-13T21:01:52Z : No. of bitstreams: 1 almeida_jd_dr_sjc.pdf: 798214 bytes, checksum: 01a38ab886a92b48594e6df7a458da16 (MD5) / Neste trabalho foi realizado estudo comparativo dos efeitos da calcitonina e do Plumbum mettalicum 30CH na reparação óssea guiada em mandíbulas de ratos. Foram utilizados 75 ratos com idade aproximada de três meses, que foram divididos em grupo controle, tratado com calcitonina e tratado com Plumbum mettalicum 30CH, com 25 animais cada. Todos os ratos foram submetidos à cirurgia para realização de defeito ósseo na região de ângulo de mandíbula de aproximadamente 4mm, o qual foi recoberto por uma barreira de politetrafluoretileno. Após a cirurgia, o grupo tratado com calcitonina passou a receber 2 UI/kg, i.m., três vezes por semana, e o grupo tratado com Plumbum mettalicum 30CH, três gotas diluídas em água diariamente. Os animais foram sacrificados em períodos de três, sete, 14, 21 e 28 dias, sendo suas mandíbulas removidas e encaminhadas para preparação histológica. Análises densitométrica, histológica e histomorfométrica foram realizadas. Para análise estatística, utilizou-se ANOVA, teste de Tukey e teste de Scheffé ao nível de 5%. A análise densitométrica mostrou menor densidade óptica no grupo controle em todos os períodos analisados. Foi observado o preenchimento total do defeito por tecido ósseo neoformado apenas no grupo tratado com homeopatia, aos 28 dias. Nos demais grupos não foi observada união das bordas do defeito. Na análise histomorfométrica não se encontrou diferença estatística entre os grupos tratados e controle, porém o grupo tratado com Plumbum mettalicum 30CH apresentou melhores resultados que o tratado com calcitonina. Concluiu-se que, nas condições utilizadas, a reparação óssea guiada de defeitos em mandíbulas de ratos machos é favorecida pelo Plumbum mettalicum 30CH , mas não pela calcitonina. / The purpose of this work was to compare the effects of calcitonin and Plumbum mettalicum 30CH on guided mandibular bone repair of male rats. We analyzed the mandible of 75 rats, approximately three months old, which were divided into control group, group treated with calcitonin and group treated with Plumbum mettalicum 30CH. Each group was composed by 25 animals. A circumscribed bone defect of 4mm diameter was prepared in the mandibular bone, in the angle region. The defect was covered with a PTFE barrier in all animals. The group treated with calcitonin received 2UI/Kg i.m. three times a week and the group treated with homeopathy received three drops diluted in the water every day. Both treated groups began immediately after surgery. The animals were sacrificed after three, seven, 14, 21 and 28 days. Their mandibles were removed, and after routine histological processing they were submitted to densitometric, histological and histomorphometrical analysis. For statistical analysis, ANOVA, Tukey and Scheffé tests (p<0,05) were used. The densitometric analysis showed lower optical density in the group control than in the others, at all periods. Only in the group treated with Plumbum mettalicum 30CH, the defects were completely healed at the final observation period. The histomorphometrical analysis showed no statistical difference between control, calcitonin and homeopathy treated groups, however the last one had better results than the one treated with calcitonin. It was concluded that, in circumscribed mandibular defects in male rats, Plumbum mettalicum 30CH induces better bone repair than calcitonin.

Ph.D.

Zugl.: Giessen, Univ., Diss., 2009

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references (leaves 151-171). Also available in electronic version.

Univ., Diss., 2009--Giessen.

Orientador: Yasmin Rodarte Carvalho / Banca: Yasmin Rodarte Carvalho / Banca: Darcy de Oliveira Tosello / Banca: Suzana Cantanhede Orsini Machado de Sousa / Banca: Rosilene Fernandes da Rocha / Banca: Luiz Antonio Guimarães Cabral / Resumo: Neste trabalho foi realizado estudo comparativo dos efeitos da calcitonina e do Plumbum mettalicum 30CH na reparação óssea guiada em mandíbulas de ratos. Foram utilizados 75 ratos com idade aproximada de três meses, que foram divididos em grupo controle, tratado com calcitonina e tratado com Plumbum mettalicum 30CH, com 25 animais cada. Todos os ratos foram submetidos à cirurgia para realização de defeito ósseo na região de ângulo de mandíbula de aproximadamente 4mm, o qual foi recoberto por uma barreira de politetrafluoretileno. Após a cirurgia, o grupo tratado com calcitonina passou a receber 2 UI/kg, i.m., três vezes por semana, e o grupo tratado com Plumbum mettalicum 30CH, três gotas diluídas em água diariamente. Os animais foram sacrificados em períodos de três, sete, 14, 21 e 28 dias, sendo suas mandíbulas removidas e encaminhadas para preparação histológica. Análises densitométrica, histológica e histomorfométrica foram realizadas. Para análise estatística, utilizou-se ANOVA, teste de Tukey e teste de Scheffé ao nível de 5%. A análise densitométrica mostrou menor densidade óptica no grupo controle em todos os períodos analisados. Foi observado o preenchimento total do defeito por tecido ósseo neoformado apenas no grupo tratado com homeopatia, aos 28 dias. Nos demais grupos não foi observada união das bordas do defeito. Na análise histomorfométrica não se encontrou diferença estatística entre os grupos tratados e controle, porém o grupo tratado com Plumbum mettalicum 30CH apresentou melhores resultados que o tratado com calcitonina. Concluiu-se que, nas condições utilizadas, a reparação óssea guiada de defeitos em mandíbulas de ratos machos é favorecida pelo Plumbum mettalicum 30CH , mas não pela calcitonina. / Abstract: The purpose of this work was to compare the effects of calcitonin and Plumbum mettalicum 30CH on guided mandibular bone repair of male rats. We analyzed the mandible of 75 rats, approximately three months old, which were divided into control group, group treated with calcitonin and group treated with Plumbum mettalicum 30CH. Each group was composed by 25 animals. A circumscribed bone defect of 4mm diameter was prepared in the mandibular bone, in the angle region. The defect was covered with a PTFE barrier in all animals. The group treated with calcitonin received 2UI/Kg i.m. three times a week and the group treated with homeopathy received three drops diluted in the water every day. Both treated groups began immediately after surgery. The animals were sacrificed after three, seven, 14, 21 and 28 days. Their mandibles were removed, and after routine histological processing they were submitted to densitometric, histological and histomorphometrical analysis. For statistical analysis, ANOVA, Tukey and Scheffé tests (p<0,05) were used. The densitometric analysis showed lower optical density in the group control than in the others, at all periods. Only in the group treated with Plumbum mettalicum 30CH, the defects were completely healed at the final observation period. The histomorphometrical analysis showed no statistical difference between control, calcitonin and homeopathy treated groups, however the last one had better results than the one treated with calcitonin. It was concluded that, in circumscribed mandibular defects in male rats, Plumbum mettalicum 30CH induces better bone repair than calcitonin. / Doutor

Migraine is a debilitating neurological disorder, which affects over 10% of the general population. In addition to headache, migraine includes a host of associated symptoms, such as nausea and hypersensitivity to light, noise, and touch. While great strides have been made in migraine treatment in recent decades, the basic biological and pathophysiological mechanisms underlying migraine are still not well understood. Pain signals travel via a polysynaptic pathway from the periphery to the cortex, where conscious perception of pain occurs. This multi-neuron pathway produces a message that can be modified at any step of its transit. One peptide that may modify this pathway is calcitonin gene-related peptide (CGRP). CGRP is a potent vasodilator and neuromodulator, and mounting evidence suggests CGRP may play a causative role in migraine. CGRP levels are increased during migraine, but can be reduced upon successful treatment with drugs in the triptan class. Importantly, injection of CGRP into migraine patients can elicit a delayed, migraine-like headache. Finally, CGRP receptor antagonists are clinically effective in providing relief to migraine patients. In addition to CGRP, the CGRP gene (CALCA) expresses another peptide that may also be relevant to migraine. Procalcitonin (proCT) is a recognized biomarker for sepsis, but emerging evidence suggests it may have actions similar to CGRP in migraine. First, proCT has biological activity at the CGRP receptor. Second, proCT is reported to be increased during migraine. We hypothesized that regulation of CGRP and proCT may be altered in migraineurs, and that migraineurs may also be sensitized to the effects of these peptides. To study the role of these peptides in migraine pathways, a number of methods have been employed. Studies exploring regulation of gene expression were performed in cultured trigeminal ganglia, as well as primary cultures of trigeminal and cortical glia. These studies show that the Calca gene can be regulated by a number of stimuli, including hypoxia and reactive oxygen species. These insults have the ability to induce CALCA gene and peptide expression to varying degrees on different cell types. In addition to in vitro experiments on Calca gene regulation, the in vivo effects of CGRP on mouse behavior were also investigated. Animals were genetically sensitized to CGRP via overexpression of the rate-limiting CGRP receptor subunit. In these animals, injection of CGRP is sufficient to induce light aversion, which is used to model photophobia. Physiological and biochemical triggers of migraine were tested using this behavioral paradigm. While stress and mast cell degranulation are sufficient to induce light aversion, the role of CGRP in these events remains unclear, as both CGRP sensitized and control animals displayed a light aversion phenotype. Together, these studies show the dynamic regulation of the Calca gene in migraine pathways as well as highlight some of the challenges of modeling a complex disease in an animal model.

Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget's disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through β-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC) (Emisphere Technologies, Cedar Knolls, NJ). Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis) failed to meet key end points, and in December 2011, Novartis Pharma AG announced that it would not pursue further clinical development of oral calcitonin for postmenopausal osteoporosis or osteoarthritis. A unique feature of calcitonin is that it is able to uncouple bone turnover, reducing bone resorption without affecting bone formation and therefore increasing bone mass and improving bone quality. This effect, however, may be dose-dependent, with higher doses inhibiting both resorption and formation. Because so many factors affect the pharmacokinetics and pharmacodynamics of calcitonin, especially orally administered calcitonin, much work remains to be done to explore the full pharmacologic spectrum and potential of calcitonin and determine the optimum dose and timing of administration, as well as water and food intake.

No description available.

Amylin, a 37 amino acid peptide secreted from pancreatic beta cells upon stimulation by meal/glucose, belongs to the family of the calcitonin or calcitonin gene-related peptide (CGRP) and shares up to 50% homology with CGRP, which is a well-documented pain-related peptide. The amylin receptor is composed of a calcitonin receptor (CTR) and receptor activity modifying proteins (RAMPs). Numerous studies have shown that amylin plays an important role in glucose homeostasis and food intake. Few studies have been conducted with respect to the effect of amylin in the central or peripheral neuraxis. In this thesis, immunohistochemical study revealed a dense network of amylin-immunoreactive (irAMY) cell processes in the superficial dorsal horn of the mice. Numerous dorsal root ganglion and trigeminal ganglion cells expressed moderate to strong irAMY. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed amylin receptor mRNA in the mouse spinal cord, brain stem, cortex, hypothalamus and hippocampus. The nociceptive or antinociceptive effects of amylin were evaluated in the tail flick and acetic acid-induced writhing test. Amylin (1-10 µg, i.t.) reduced the number of writhing in a dose-dependent manner. Pretreatment of the mice with the amylin receptor antagonist salmon calcitonin (8-32) [sCT(8-32)]or AC187 by i.t. antagonized the effect of amylin on acetic acid-induced writhing test. Locomotor activity was not significantly modified by amylin injected either i.p. (0.01-1 mg/kg) or i.t. (1-10 µg). Measurement of c-fos mRNA by RT-PCR or proteins by Western blot showed that the levels were up-regulated in the spinal cord of mice in acetic acid-induced visceral pain model and the increase was attenuated by pretreatment with amylin. Pretreatment of sCT[8-32] or AC187 significantly reversed the effect of amylin on c-fos expression in the spinal cord. As the neuronal response to amylin is closely dependent on the molecular property of amylin receptor, the localization, internalization and regulation of the calcitonin and amylin receptor were examined in the second part of the thesis. Immunofluorescence microscopy demonstrated the surface expression of CTRa, and intracellular distribution of RAMP1. Moreover, co-expression of CTRa translocated the RAMP1 to the cell surface and generated the amylin receptor phenotype. Both immunocytochemistry and on cell western analysis showed the internalization of CTRa and amylin receptor (CTRa/RAMP1) stimulated by different agonists, which was partially ß-arrestin dependent. Moreover, RAMP1 did not change the surface expression pattern of CTRa, but co-localized with the receptor with and without agonist treatment. sCT and amylin activated the ERK1/2 in HEK293 cells stably expressing amylin receptors, indicating the involvement of MAPK in amylin receptor signaling cascade. Collectively, these results led us to conclude that 1) irAMY is expressed in dorsal root ganglion neurons with their cell processes projecting to the superficial layers of the dorsal horn, and that the peptide by interacting with amylin receptors in the spinal cord may be antinociceptive; 2) RAMP1 does not change the pattern of CTR cell-surface localization and internalization, but receptor phenotype, presumably through a direct or indirect effect on the ligand-binding site; 3) amylin internalizes the amylin receptor (CTRa/RAMP1 complex); which is partially ß-arrestin dependent. Our studies extend the current knowledge of amylin on the spinal cord and new insight on the cellular and molecular mechanism underlying the antinociceptive effect of amylin. Also we demonstrate for the first time agonist induced-internalization of CTR/RAMP complex and its possible regulation pathway. / Pharmacology