25,26(OH)2D3: EFFECT ON METABOLISM OF 1,25(OH)2D

这项研究的长期目标是评估临床 25，26-二羟基维生素D(25，26(OH)2D3)治疗糖尿病的疗效观察 原发性甲状旁腺功能亢进症等高钙血症状态， 结节病、淋巴瘤引起的高钙血症和吸收 高钙尿症。具体目标是1)确定 25，26(OH)2D3的最佳剂量和剂量长度 小鼠血清1，25-二羟基维生素D(1，25(OH)2D)的降低 2)探讨25，26(OH)2D3的作用机制。 在动物模型中介导血清1，25(OH)2D的降低； 3)评价25，26(OH)2D3给药的效果 对于各种疾病状态的患者，其特征是高 循环1，25，(OH)2D浓度和高钙血症， 高钙尿症，或两者兼而有之。 初步调查显示，药理学 25，26(OH)2D3的量具有独特的能力显著地 降低1，25(OH)2D的循环浓度， 维生素D的生理活性形式，同时展示 它本身的生物活性很少或没有。这一观察结果将是 通过给予不同剂量的25， 26(OH)2D3给大鼠不同时间间隔和测量 血清1，25，(OH)2D。然后，研究将扩展到犬类。 检查是通过什么机制(即新陈代谢增加 清除、合成减少或两者兼而有之)25，26(OH)2D3促进 血清1，25(OH)2D浓度降低。这将是 通过注射微量剂量的放射性物质1来完成， 25(OH)2D3给狗，前后适当25，26(OH)2D3 给药，并量化血浆中放射性的消失。 从这些研究来看，不能手术的患者 甲状旁腺机能亢进症、结节病、淋巴瘤 高钙血症和吸收性高钙尿症将被纳入 综合临床研究中心，并进行基本的 恒定代谢状态下钙稳态的评价 25、26(OH)2D3给药前后的饮食。如果有正当理由， 评估1，25(OH)2D3清除率和合成率可以 也可以获得。这些研究可能表明，药理学 25，26(OH)2D3的用量可有效降低1，25，(OH)2D 集中于手术(如原发性甲状旁腺功能亢进症)， 或药物治疗，如类固醇(如结节病或淋巴瘤) 禁忌。肾结石患者的类似研究 疾病应披露应披露维生素的真实程度-- 肠钙吸收在吸收中的D依赖性 高钙尿症。

The long term objective of this study is to assess the clinical efficacy of 25, 26-dihydroxyvitamin D (25, 26(OH)2D3) in treating hypercalcitriolemic states such as primary hyperparathyroidism, sarcoidosis, lymphoma induced hypercalcemia and absorptive hypercalciuria. The specific aims are 1) to determine the optimum dose and length of dosing of 25, 26(OH)2D3 to maximize reduction of serum 1, 25-dihydroxyvitamin D (1, 25(OH)2D) in an animal model; 2) to determine the mechanism of 25, 26(OH)2D3- mediated reduction of serum 1, 25(OH)2D in an animal model; and 3) to evaluate the effectiveness of 25, 26(OH)2D3 administration to patients with various disease states characterized by high circulating 1, 25,(OH)2D concentrations and hypercalcemia, hypercalciuria, or both. Preliminary investigations have disclosed that pharmacologic amounts of 25, 26(OH)2D3 have a unique ability to significantly reduce the circulating concentration of 1, 25(OH)2D, the physiologically active form of vitamin D, while demonstrating little or no biological activity of its own. This observation will be further investigated by administering various doses of 25, 26(OH)2D3 to rats for different intervals of time and measuring serum 1, 25,(OH)2D. Studies will then be extended to the canine to examine by what mechanism (i.e., increased metabolic clearance, decreased synthesis or both ) 25, 26(OH)2D3 promotes a reduction in serum 1, 25(OH)2D concentration. This will be accomplished by administering a trace dose of radioactive 1, 25(OH)2D3 to dogs, before and after appropriate 25, 26(OH)2D3 dosing, and quantifying the plasma disappearance of radioactivity. Form these studies, patients with inoperative primary hyperparathyroidism, sarcoidosis, lymphoma-induced hypercalcemia and absorptive hypercalciuria will be admitted to the General Clinical Research Center and undergo a basic evaluation of calcium homeostasis while on a constant metabolic diet before and after 25, 26(OH)2D3 dosing. If warranted, assessment of 1, 25(OH)2D3 clearance and synthetic rates can also be obtained. These studies may indicate that pharmacologic amounts of 25, 26(OH)2D3 are effective in lowering 1, 25,(OH)2D concentration where surgery (e.g. primary hyperparathyroidism), or drug therapy such as steroids (e.g. sarcoidosis or lymphoma) is contraindicated. Similar studies in patients with renal stone disease should disclose should disclose the true extent of vitamin- d dependency of intestinal calcium absorption in absorptive hypercalciuria.