RESUMO
UNLABELLED: The efficacy and safety of weekly oral odanacatib (ODN) 50 mg for up to 8 years were assessed in postmenopausal women with low bone mineral density (BMD). Treatment with ODN for up to 8 years resulted in continued or maintained increases in BMD at multiple sites and was well tolerated. INTRODUCTION: ODN is a selective inhibitor of cathepsin K. In a 2-year phase 2b study (3/10/25/50 mg ODN once weekly [QW] or placebo) and extensions (50 mg ODN QW or placebo), ODN treatment for 5 years progressively increased BMD and decreased bone resorption markers in postmenopausal women with low BMD ( ClinicalTrials.gov NCT00112437). METHODS: In this prespecified interim analysis at year 8 of an additional 5-year extension (years 6 to 10), patients (n = 117) received open-label ODN 50 mg QW plus weekly vitamin D3 (5600 IU) and calcium supplementation as needed. Primary end points were lumbar spine BMD and safety. Patients were grouped by ODN exposure duration. RESULTS: Mean (95 % confidence interval [CI]) lumbar spine BMD changes from baseline were 4.6 % (2.4, 6.7; 3-year continuous ODN exposure), 12.9 % (8.1, 17.7; 5 years), 12.8 % (10.0, 15.7; 6 years), and 14.8 % (11.0, 18.6; 8 years). Similar patterns of results were observed for BMD of trochanter, femoral neck, and total hip versus baseline. Geometric mean changes from baseline to year 8 for bone resorption markers were approximately -50 % (uNTx/Cr) and -45 % (sCTx), respectively (all groups); bone formation markers remained near baseline levels. No osteonecrosis of the jaw, delayed fracture union, or morphea-like skin reactions were reported. CONCLUSIONS: Treatment with ODN for up to 8 years resulted in gains in BMD at multiple sites. Bone resorption markers remained reduced, with no significant change observed in bone formation markers. Treatment with ODN for up to 8 years was well tolerated.
Assuntos
Compostos de Bifenilo/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea , Osteoporose Pós-Menopausa/tratamento farmacológico , Idoso , Compostos de Bifenilo/administração & dosagem , Conservadores da Densidade Óssea/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Pós-MenopausaRESUMO
To study the significance of the increased activity of the kallikrein-kinin system described in patients with Bartter's syndrome, we investigated the pressor response to infused angiotensin II in four patients with the syndrome receiving no treatment and during the administration of aprotinin and of indomethacin. Five normal subjects served as controls. Aprotinin is a proteolytic enzyme that inhibits the formation of kinins by inhibiting plasma and glandular kallikrein. Indomethacin, a prostaglandin-synthesis inhibitor, can also inhibit the kallikrein-kinin system and normalizes vascular responsiveness to angiotensin II in Bartter's syndrome. All patients had increased urinary kallikrein and prostaglandin E2 concentrations. Aprotinin significantly decreased the dose of infused angiotensin II required to induce a 20 mm Hg increase in diastolic blood pressure, from 11 +/- 4 ng/kg/min to 7.0 +/- 2.0 ng/kg/min (mean +/- SD; p less than 0.05) in normal subjects and from 135 +/- 57 ng/kg/min to 70 +/- 26 ng/kg/min (p less than 0.05) in the patients with Bartter's syndrome, without significantly changing plasma renin activity, mean control blood pressure, or urinary prostaglandin E2 concentration. Indomethacin normalized the pressor response to angiotensin II in three patients who had been pretreated for 4 days (pressor dose, 10 ng/kg/min) but not in one patient who received a single oral dose of indomethacin 5 hours before the test. Our results suggest that inhibition of the kallikrein-kinin system alone accounts for approximately a 50% decrease in vascular resistance to the pressor effect of angiotensin II in Bartter's syndrome, while additional suppression of prostaglandins entirely normalizes the vascular response to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Síndrome de Bartter/fisiopatologia , Hiperaldosteronismo/fisiopatologia , Calicreínas/fisiologia , Cininas/fisiologia , Adulto , Angiotensina II , Aprotinina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Humanos , Indometacina/farmacologia , Masculino , Resistência Vascular/efeitos dos fármacosRESUMO
The variations in plasma levels of TSH, T4, T3, and rT3, during the pubertal period, were studied in 647 school students from the urban area of Santiago in Chile (47% males and 53% females) with ages ranging between 7.5 and 15 yr. The subjects were grouped by age in consecutive intervals of 6 months each, and pubertal development was determined in every subject. TSH showed a significant increase, reaching a peak in the 9- to 9.5-yr interval. The same was found for T3 and T4, which reached a peak by 10 and 11 yr. The T4/T3 ratio did not show any significant variation with age. After 9.5 yr, a decrease in rT3 and increase in the T4/rT3 ratio was found. The TSH peak preceded the onset of clinical pubertal development, while the T3 and T4 peaks coincided with this onset. The variations in rT3 suggest an increase of peripheral conversion of T4 to T3. These transient events, not described until now, could be termed thyroidarche and could have a significant effect on pubertal growth and development.
Assuntos
Puberdade/sangue , Tireotropina/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Adolescente , Criança , Chile , Creatina/urina , Feminino , Humanos , Iodo/urina , MasculinoRESUMO
We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.
Assuntos
Alendronato/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Absorciometria de Fóton , Idoso , Alendronato/efeitos adversos , Osso e Ossos/diagnóstico por imagem , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/patologia , Fatores de TempoRESUMO
We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.
Assuntos
Alendronato/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/prevenção & controle , Pós-Menopausa , Absorciometria de Fóton , Adulto , Alendronato/administração & dosagem , Colágeno/urina , Colágeno Tipo I , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Peptídeos/urina , PlacebosRESUMO
The function of the adrenal zona glomerulosa was studied in two pubertal siblings with the hypertensive virilizing form of congenital adrenal hyperplasia who had never been treated. Initially, their plasma 11-deoxycortisol and 11-deoxycorticosterone (DOC) levels were very high, PRA was suppressed, and plasma aldosterone and 18-hydroxycorticosterone (18-OHB) were undetectable. To selectively study zona glomerulosa function, the patients and five normal subjects were given dexamethasone (2 mg/day; thus suppressing zona fasciculata function), and their sodium intake was restricted to 10 mmol/day. After 3-5 days, the zona glomerulosa was stimulated with either angiotensin II or potassium chloride. The same protocol was repeated in the patients at various intervals up to 39 months after beginning maintenance therapy with dexamethasone (0.25 mg twice daily). PRA, plasma aldosterone, and 18-OHB remained low during the first 6 months of treatment. After the first year, PRA recovered, and the zona glomerulosa began to respond. Plasma aldosterone and 18-OHB levels reached normal basal and stimulated values in one of the patients after 2 yr of treatment, but remained subnormal after 39 months of treatment in the other patient. Both patients, however, had persistently elevated plasma DOC concentrations, suggesting slight but definite impairment of 11 beta-hydroxylation in the zona glomerulosa. We conclude that in spite of a severe and persistent 11 beta-/18-hydroxylation deficiency in the zona fasciculata, the zona glomerulosa can recover almost completely after prolonged treatment. Appropriate stimulation, however, discloses a minor 11 beta-hydroxylation impairment also in the zona glomerulosa. In addition, the lack of parallelism in zona glomerulosa 11 beta- and 18-hydroxylation of DOC provides evidence for the concept of different 18-hydroxylating systems in the adrenal cortex.
Assuntos
Córtex Suprarrenal/fisiopatologia , Hiperplasia Suprarrenal Congênita/fisiopatologia , Hipertensão/complicações , 18-Hidroxicorticosterona/sangue , Adolescente , Córtex Suprarrenal/enzimologia , Hiperplasia Suprarrenal Congênita/complicações , Aldosterona/sangue , Angiotensina II , Criança , Cortodoxona/sangue , Citocromo P-450 CYP11B2 , Desoxicorticosterona/análogos & derivados , Desoxicorticosterona/sangue , Feminino , Humanos , Masculino , Cloreto de Potássio , Renina/sangue , Esteroide 11-beta-Hidroxilase/análise , Esteroide Hidroxilases/metabolismoRESUMO
Fractional distal chloride reabsorption was measured in 8 patients with Bartter's syndrome, 8 patients with comparable degrees of hypokalemia of different etiologies and 7 normal subjects during maximal diuresis induced by an intravenous infusion of 5% dextrose in water. A low fractional distal chloride reabsorption (0.55 +/- 0.01) was found only in patients with Bartter's syndrome, whose serum potassium concentrations ranged between 1.2 and 3.1 mEq/l. Non-Bartter's syndrome hypokalemic patients had serum potassium concentrations between 2.4 and 3.2 mEq/l (p NS when compared to patients with Bartter's syndrome) but their fractional distal chloride reabsorption was 0.88 +/- 0.33, significantly higher (p less than 0.001) than that of patients with Bartter's syndrome. Normokalemic control subjects had a fractional distal chloride reabsorption of 0.86 +/- 0.01, higher than patients with Bartter's syndrome (p less than 0.001) but not significantly different from patients with hypokalemia. These results suggest that there is no effect of serum potassium concentration on fractional distal reabsorption of chloride in man. Hypokalemia of a moderate to severe degree is not accompanied by obligatory renal chloride loss except in Bartter's syndrome. Chloruresis is a specific feature of Bartter's syndrome rather than an effect of hypokalemia.
Assuntos
Síndrome de Bartter/metabolismo , Cloretos/metabolismo , Hiperaldosteronismo/metabolismo , Hipopotassemia/metabolismo , Túbulos Renais/metabolismo , Alça do Néfron/metabolismo , Absorção , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Taxa de Filtração Glomerular , Humanos , Hipopotassemia/etiologia , Lactente , Masculino , Pessoa de Meia-Idade , Potássio/sangueRESUMO
To examine the effects of primary hyperparathyroidism separately from those of hypertension per se on blood pressure regulation in patients with primary hyperparathyroidism, we studied the pressor response to infused angiotensin II (AII) and to norepinephrine (NE) in 7 normotensive patients with primary hyperparathyroidism before and after surgical cure, and compared it to that observed in 10 subjects with idiopathic hypertension and 10 normal controls. While the subjects were on an ad libitum diet, we measured urinary and plasma electrolytes, creatinine, and plasma renin activity. Except for calcium, these values were not significantly different among the three groups. The blood pressure was measured basally and in response to graded doses of AII or of NE until a 20-mmHg increase in the diastolic blood pressure was reached ("pressor dose"). The pressor doses of AII and of NE were lower in the normotensive patients with primary hyperparathyroidism than in normal controls [4.6 +/- 2.0 vs. 7.3 +/- 3.5 ng/kg/min (p < 0.05) and 164 +/- 114 vs. 302 +/- 176 ng/kg/min (p < 0.05) respectively] and not significantly different from those found in idiopathic hypertension (3.1 +/- 1.2 and 137 +/- 95 ng/kg/min). When the patients with primary hyperparathyroidism were studied again between 2-6 months after surgical cure, their pressor doses of AII and of NE remained unchanged from their preoperative values (5.4 +/- 2.9 and 137 +/- 80 mg/kg/min). We conclude that the hyperparathyroid condition can disrupt the normal responsiveness to pressor agents even if the blood pressure remains within normal limits, and that this abnormality may persist after surgical cure.
Assuntos
Hiperparatireoidismo/fisiopatologia , Hipertensão/fisiopatologia , Adulto , Idoso , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cálcio/sangue , Feminino , Humanos , Hiperparatireoidismo/sangue , Hiperparatireoidismo/complicações , Hipertensão/sangue , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Estudos ProspectivosRESUMO
Intracellular calcium has been reported to be increased in essential hypertension, and thought to play a role in its genesis through facilitation of vascular smooth muscle contraction. Since hypertension is more prevalent in primary hyperparathyroidism, intracellular calcium may also be increased in this condition. To investigate whether the hyperparathyroid condition, i.e., hypercalcemia and increased PTH per se, could be associated with high intracellular calcium, we measured intracellular calcium in platelets with the Quin-2 AM fluorometric method in 11 normotensive patients with primary hyperparathyroidism, 15 patients with essential hypertension, and 18 normal controls, all matched for age and sex. We repeated the measurements in 9 of the hyperparathyroid patients after successful surgery. We found that intracellular calcium was higher in normotensive patients with primary hyperparathyroidism than in normal controls (198 +/- 24 vs 113 +/- 11 nM, p < 0.05), but lower than in patients with essential hypertension (198 +/- 24 vs 286 +/- 38 nM, p < 0.05). Successful removal of a parathyroid adenoma decreased intracellular calcium from 215 +/- 22 to 116 +/- 19 nM, (p < 0.01). In the patients with primary hyperparathyroidism, intracellular calcium was strongly correlated with the levels of PTH (r = 0.87, p < 0.01), but not with the total serum calcium levels (r = 0.04, NS). The decrease in intracellular calcium after parathyroidectomy was also strongly correlated with the decrease in PTH (r = 0.84, P < 0.01), but not with the decrease in total serum calcium (r = 0.16, NS). In the patients with essential hypertension, intracellular calcium correlated well with systolic (r = 0.69, p < 0.01), diastolic (r = 0.76, p < 0.01) and especially mean arterial pressure (r = 0.86, P < 0.01). There was no correlation between blood pressure and intracellular calcium in the patients with primary hyperparathyroidism. We conclude that normotensive patients with primary hyperparathyroidism, as well as patients with essential hypertension, can have increased concentrations of intracellular calcium in platelets. The correction of the hyperparathyroid condition normalizes intracellular calcium concentration. The close correlation between PTH and intracellular calcium suggests that PTH may act as a ionophore for calcium entry into cells. Whether the increased levels of intracellular calcium may reflect a pre-hypertensive condition in normotensive patients with primary hyperparathyroidism remains to be determined.
Assuntos
Pressão Sanguínea/fisiologia , Cálcio/sangue , Hiperparatireoidismo/sangue , Hiperparatireoidismo/fisiopatologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Adenoma/sangue , Adenoma/fisiopatologia , Adenoma/cirurgia , Plaquetas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Espectrometria de Fluorescência , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/fisiopatologia , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
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 +/- 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
Pós-Menopausa/sangue , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Vitamina D/sangue , Idoso , Biomarcadores/sangue , Densidade Óssea/fisiologia , Chile/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Deficiência de Vitamina D/epidemiologiaRESUMO
A patient with cerebral dysrhythmia and fever of unexplained origin for 2 years is described. She had elevated and nonsuppressible levels of urinary 17-hydroxycorticosteroids but no clinical features of hypercortisolism. Treatment with valproate sodium corrected all the abnormalities. It is postulated that cerebral dysrhythmia can affect the hypothalamic mechanisms of body temperature and regulation of adrenocorticotropic hormone levels.
Assuntos
Encéfalo/fisiopatologia , Síndrome de Cushing/tratamento farmacológico , Febre de Causa Desconhecida/tratamento farmacológico , Ácido Valproico/uso terapêutico , Adulto , Síndrome de Cushing/fisiopatologia , Eletroencefalografia , Feminino , Febre de Causa Desconhecida/fisiopatologia , HumanosRESUMO
We report a man in whom a 15 cm. renal tumor was excised at the age of 49. The pathological examination showed a clear cell carcinoma. Five years later, he presented with headache, vomiting and unilateral palpebral ptosis. Imaging studies showed a sellar tumor with pituitary apoplexy. The tumor was excised and the pathological study disclosed a clear cell tumor, positive for vimentin, cytokeratins AE1 and AE3 and immunohistochemically negative for LH, TSH, ACTH and GH. Considering the similar histopathological features, it was considered as a metastasis of the renal tumor. The patient was supplemented with thyroid, adrenal and gonadal hormones. Seven years later, he presented a new tumor in the remaining kidney, that corresponded to a cystic papillary renal cell carcinoma. Afterwards, he presented a transitional urinary bladder tumor. Mortality associated to renal cell tumors is 90% at 5 years, and pituitary metastases are extraordinarily uncommon.
Assuntos
Adenocarcinoma de Células Claras/secundário , Carcinoma de Células Renais/secundário , Neoplasias Renais/patologia , Apoplexia Hipofisária/etiologia , Neoplasias Hipofisárias/secundário , Adenocarcinoma de Células Claras/cirurgia , Carcinoma de Células Renais/cirurgia , Seguimentos , Humanos , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Apoplexia Hipofisária/patologia , Apoplexia Hipofisária/cirurgia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgiaRESUMO
OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.