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1.
Lancet Diabetes Endocrinol ; 7(12): 899-911, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31676222

RESUMO

BACKGROUND: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. METHODS: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between -2·5 and -4·0 if no previous radiographic vertebral fracture, or between -1·5 and -4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than -4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). FINDINGS: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43-40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45-60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40-0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39-0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68-0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42-0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40-0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66-0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95-1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90-1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02-1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58-1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98-1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02-1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10-1·71; p=0·0051). INTERPRETATION: Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.


Assuntos
Compostos de Bifenilo/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Compostos de Bifenilo/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Método Duplo-Cego , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/prevenção & controle , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/prevenção & controle , Humanos , Osteoporose Pós-Menopausa/complicações , Fraturas por Osteoporose/prevenção & controle , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle , Resultado do Tratamento
2.
Artigo em Espanhol | LILACS | ID: lil-511359

RESUMO

Las diversas amenazas actuales al ejercicio de la medicina requieren que el médico tome conciencia de su rol en la sociedad, identifique los valores permanentes de la profesión y los transmita a las nuevas generaciones. Esto lleva a buscar una definición del profesionalismo médico concebido básicamente como una relación de ayuda, pero en la cual las complejidades del desarrollo científico y tecnológico han creado situaciones enteramente nuevas en las cuales no siempre resulta fácil distinguir el actual bien del actuar mal. De la naturaleza de la medicina y sus valores permanentes por un lado y de la consideración de la rectitud del actuar médico por otro surge un código no escrito de conducta médica que llamamos profesionalismo. Diversas instituciones a nivel internacional se han ocupado de definir el profesionalismo médico, identificar sus componentes y describir las conductas que atentan contra sus principios. La transmisión de los valores del profesionalismo se hace principalmente a través del ejemplo y de la instauración de una cultura de buena actuación profesional en las escuelas de medicina, considerando las particularidades de cada disciplina. En una universidad católica el profesionalismo cobra sentido trascendente como manifestación del amor al prójimo dentro de una antropología que tiene su origen, sentido y trascendencia en la persona de Cristo.


The practice of medicine is currently subjected to threats that require physicians to become more aware of their role in society, to identify the permanent values of the profession and to be able to hand them over to newer generations. This leads to a search for a definition of medical professionalism conceived basically as a relationship of aid but in which the complexities of scientific and technological development have created entirely new situations in which right or wrong doing are not easy to distinguish from each other. From the nature of medicine and its permanent values on the one hand and from the consideration of the righteousness of medical actions on the other a non-written code of medical conduct that we call professionalism has emerged. Internationally, several institutions have attempted to define medical professionalism, to identify its components and to describe behaviors against its principles. The values of professionalism are transmitted mainly through the observation of exemplary conduct and by the installation of a culture of good professional practice in medical schools, considering the peculiarities of each particular discipline. In a Catholic university, professionalism acquires transcendence as a manifestation of love for one’s neighbor within an anthropology that has its origin, significance and transcendence in the person of Christ.


Assuntos
Educação Médica , Competência Profissional
3.
N Engl J Med ; 350(12): 1189-99, 2004 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-15028823

RESUMO

BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. METHODS: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. RESULTS: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.


Assuntos
Alendronato/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Alendronato/efeitos adversos , Alendronato/farmacologia , Estatura/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/prevenção & controle , Humanos , Pessoa de Meia-Idade , Radiografia , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controle , Fatores de Tempo
4.
Rev. méd. Chile ; 130(2): 167-172, feb. 2002. tab, graf
Artigo em Espanhol | LILACS | ID: lil-313179

RESUMO

Background: Anti thyroglobulin antibodies are present in 25 percent of patients treated for a differentiated thyroid cancer, invalidating thyroglobulin determination. Those patients subjected to total thyroidectomy and free of disease, should reduce the production of these antibodies, due to the lack of antigenic stimulus. Therefore, anti thyroglobulin antibodies could be useful to detect early relapses. Aim: To assess the relationship between anti thyroglobulin antibodies and the evolution of the disease in patients treated for thyroid cancer. Material and methods: Retrospective analysis of 26 patients treated for thyroid cancer with positive anti thyroglobulin antibodies, followed for three years. These were divided in those with or without lymphocytic thyroiditis (19 and 7 respectively). Results: At the first year of follow up, anti thyroglobulin antibody concentration was 401ñ94.9 UI/ml (xñsem) in patients with thyroiditis and 38.9ñ8.9 UI/ml in those without thyroiditis (p < 0.005). During the three years of follow up, no differences in anti thyroglobulin antibodies were observed between patients with or without tumor relapse. Conclusions: Concentration of anti thyroglobulin antibodies was higher in patients with thyroiditis and did not differentiate patients with tumor relapse


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Tireoglobulina , Neoplasias da Glândula Tireoide , Tireoidite , Tireoidite Autoimune , Seguimentos , Recidiva Local de Neoplasia , Formação de Anticorpos/imunologia , Biomarcadores Tumorais/isolamento & purificação , Testes de Função Tireóidea
5.
Rev. méd. Chile ; 129(8): 849-852, ago. 2001. tab, graf
Artigo em Espanhol | LILACS | ID: lil-300144

RESUMO

Background: Low vitamin D levels are a risk factor for osteoporosis. In the Northern hemisphere, a high frequency of low vitamin D levels has been detected. The correction of this deficit is associated with a lower fracture risk. Aim: To measure serum vitamin D levels in postmenopausal women with low bone mineral density. Material and methods: 25-hydroxyvitamin D levels were measured in 40 postmenopausal women aged 50 to 74 years old, with a spine bone mineral density of less than 2 standard deviation of the values for young individuals. Serum calcium, phosphorus and calcium dietary intake were also measured. Results: Mean serum 25-hydroxyvitamin D levels were 32.2 ñ 12.5 ng/ml. No correlation between vitamin D levels and other measured variables was observed. Using a cutoff value of 15 ng/ml, two women had low 25-hydroxyvitamin D levels. Conclusion: In this sample of postmenopausal women, vitamin D deficiency was infrequent


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Deficiência de Vitamina D , Pós-Menopausa , Desmineralização Patológica Óssea/etiologia , Deficiência de Vitamina D , Calcifediol , Cálcio da Dieta , Densitometria , Osteoporose Pós-Menopausa/etiologia
6.
Rev. méd. Chile ; 129(3): 295-8, mar. 2001. ilus
Artigo em Espanhol | LILACS | ID: lil-286865

RESUMO

The association of hyperprolactinemia over 100 ng/ml and a pituitary adenoma is usually diagnostic of prolactinoma. However type 3 pituitary adenomas can occur with similar serum prolactin values. We report a 31 years old woman that consulted due to headache and photopsiae. She had a serum prolactin level of 148 ng/ml and imaging studies showed a solid tumor that occupied the selar region and most of the left temporal fossa. The tumor was partially resected and the patient recovered her lost visual field. Light microscopy showed an acidophilic and in part chromophobe adenoma. Immuno-histochemistry was positive for prolactin and growth hormone. Electron microscopy disclosed features of a silent type 3 adenoma such as big cells with cytoplasmic prolongations, pleomorphic nuclei and a greatly developed rough endoplasmic reticulum


Assuntos
Humanos , Feminino , Adulto , Neoplasias Hipofisárias/ultraestrutura , Hiperprolactinemia/patologia , Adenoma/ultraestrutura , Prolactina/sangue , Campos Visuais , Diagnóstico Diferencial
7.
Rev. méd. Chile ; 128(1): 17-26, ene. 2000. graf
Artigo em Espanhol | LILACS | ID: lil-258083

RESUMO

An 11-year old girl was seen in 1981 with hypokalemia, low renin, low aldosterone, and severe hypertension. A medical adrenalectomy with dexamethasone and aminoglutethimide, and the blockade of mineralocorticoid receptors with spironolactone improved her condition, but the blockade of glucocorticoid receptors with RU-486 worsened it. An aldosterone infusion induced no changes. A sister was born in 1982 with similar findings. Both patients had an impaired ability to convert cortisol to cortisone after an oral load of 200 mg cortisol. In urine, an elevated ratio for metabolites of cortisol to metabolites of cortisone was found. These data suggested a defect in the activity of renal 11ß-hydroxysteroid dehydrogenase. Both parents were asymptomatic, phenotypically normal and non-consanguineous. Their urinary metabolites of cortisol and cortisone were normal before and after stimulation with ACTH. However, the mother reached a peak plasma cortisone concentration 3 SD below the mean reached by normal subjects after an oral 200-mg cortisol load, a fact that suggests that this test could be used to detect heterozygotes. The genetic studies revealed a homozygous mutation on exon 3 of the HSD11K gene, which by substituting TGC for CGC changes Arg 213 for Cys and induces a loss of 84 percent of the enzymatic activity in transfected cells. Both unrelated parents had the same heterozygous mutation. Both patients have been treated with dexamethasone but have also required spironolactone. The older sister has also required high doses of nifedipine to lower her blood pressure. After 19 years of follow-up, the older sister has become normotensive and normokalemic under therapy, and reached a final height of 140 cm at age 17. The younger sister has increased her mean blood pressure at a rate of 1 mm Hg per year, in spite of treatment. Her final height is 143.5 cm


Assuntos
Humanos , Masculino , Feminino , Adulto , Adolescente , Hidroxiesteroide Desidrogenases/deficiência , Mineralocorticoides , Hipertensão/congênito , Espironolactona/administração & dosagem , Cortisona/sangue , Dexametasona/administração & dosagem , Hidrocortisona/sangue , Nifedipino/administração & dosagem , Mifepristona/administração & dosagem , Aldosterona/administração & dosagem
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