Effect of Pyridoxamine in Oxalate excretion in Stone Disease and Hyperoxaluria

吡哆胺对结石病和高草酸尿症草酸盐排泄的影响

• 批准号: 7282663
• 负责人: Jon I Scheinman
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282663
• 关键词: Adult; Age; Anabolism; Animals; Blood; Calcium Oxalate; Calculi; Characteristics; Chemicals; Clinic; Clinical Trials, Other; Complex; Crossover Design; Development; Diet Monitoring; Disease; Dose; Double-Blind Method; Drug Metabolic Detoxication; Equilibrium; Excretory function; Generations; Glyoxylates; Goals; Hepatocyte; Hereditary Disease; Human; Hyperoxaluria; In Vitro; Intake; Kidney Calculi; Kidney Diseases; Kidney Failure; Malignant - descriptor; Mass Spectrum Analysis; Modeling; Monitor; Mutation; Nature; Nephrocalcinosis; Nephrolithiasis; Orphan Disease; Oxalates; Patients; Personal Satisfaction; Pharmacological Treatment; Physiological; Placebo Control; Plasma; Population; Predisposing Factor; Prevalence; Primary Hyperoxaluria; Process; Production; Public Health; Purpose; Pyridoxamine; Rate; Rattus; Recurrence; Relative (related person); Research Personnel; Risk; Risk Factors; Serum; Source; Testing; Transplantation; United States; Urine; Vitamin B6; absorption; adduct; animal data; base; calcification; calcium phosphate; diabetic; glycolaldehyde; glyoxylate; human subject; improved; in vivo; peroxisome; prevent; programs; research study; response; urinary

DESCRIPTION (provided by applicant): Kidney stone disease is frequent, and increasing, and has an unacceptable recurrence rate. Most stones are made of calcium oxalate (CaOx), and urinary oxalate is a major risk factor. There is not yet an effective treatment for stone disease that can target urinary oxalate. Our long-term goal is to find a way to prevent stone formation in common idiopathic stone disease, and kidney calcification in the rare but most malignant form of stone disease, primary hyperoxaluria (PH). Pyridoxamine (PM) is a derivative of vitamin B6 that is present in small amounts in normal humans. Its chemical nature allows it to trap the precursors of oxalate biosynthesis (glyoxylate and glycolaldehyde). This process is well demonstrated in vitro. In our preliminary animal data, we showed (1) that PM can significantly lower oxalate excretion in normal and hyperoxaluric rats; and (2) that PM can dramatically decrease the development of CaOx calcification in these hyperoxaluric rats. Other clinical trials have shown that pyridoxamine is non-toxic in humans. We propose that PM will reduce human oxalate synthesis that occurs primarily in the detoxification compartment of liver cells (the peroxisome) in humans. This will decrease oxalate excretion, and therefore reduce a risk factor for kidney stone formation. The primary goal of the proposed study is to show that it is feasible to reduce urinary oxalate excretion in humans by using PM. The Specific Aims of the study will be (1) to evaluate PM treatment in people with kidney stones without hyperoxaluria. This is a placebo- controlled, double-blinded, crossover design. We expect to find that urinary oxalate will be reduced while other factors will not change. Therefore, the supersaturation state, which strongly influences stone formation, will be significantly improved. Patients from stone clinics are available for this study and are highly motivated to participate. (2) We will also study patients with Primary Hyperoxaluria (PH), a genetic disease that usually results in kidney failure at an early age. Here, we will explore the feasibility of lowering the massive oxalate generation derived from endogenous synthesis. If it is successful, PM will offer the first significant non-transplant treatment for this frequently fatal disease. To directly test the model of PM action we also plan (3) to characterize the way that PM forms complexes with the precursors of oxalate, glyoxylate and glycolaldehyde, in urine and serum of these patients. The public health implications of this study are in its contributions to preventing common kidney stone disease, and preventing kidney failure in an orphan disease, Primary Hyperoxaluria.

描述（由申请人提供）：肾结石疾病是常见的，并增加，并具有不可接受的复发率。大多数结石由草酸钙（CaOx）组成，尿草酸盐是一个主要的风险因素。目前还没有一种针对尿草酸盐的结石病的有效治疗方法。我们的长期目标是找到一种方法来预防常见的特发性结石病的结石形成，以及罕见但最恶性的结石病原发性高尿酸（PH）的肾脏钙化。吡哆胺（PM）是维生素B6的衍生物，在正常人体中存在少量。其化学性质允许其捕获草酸盐生物合成的前体（乙醛酸和乙醇醛）。这一过程在体外得到了很好的证明。在我们的初步动物数据中，我们表明（1）PM可以显着降低正常和高尿酸大鼠的草酸排泄;（2）PM可以显着减少这些高尿酸大鼠中CaOx钙化的发展。其他临床试验表明，吡哆胺对人体无毒。我们建议，PM将减少人体草酸盐的合成，主要发生在人体肝细胞（过氧化物酶体）的解毒室。这将减少草酸盐排泄，从而降低肾结石形成的风险因素。这项研究的主要目的是证明使用PM减少人体尿草酸排泄是可行的。本研究的具体目的是（1）评价无高尿酸血症的肾结石患者的PM治疗。这是一项安慰剂对照、双盲、交叉设计。我们期望发现尿草酸盐会减少，而其他因素不会改变。因此，将显著改善强烈影响结石形成的过饱和状态。来自结石诊所的患者可参与本研究，并且参与的积极性很高。(2)我们还将研究原发性高尿酸血症（PH）患者，这是一种遗传性疾病，通常在早期导致肾衰竭。在这里，我们将探讨降低大量的草酸产生来自内源性合成的可行性。如果成功，PM将为这种经常致命的疾病提供第一个重要的非移植治疗。为了直接测试PM作用的模型，我们还计划（3）表征PM在这些患者的尿液和血清中与草酸盐、乙醛酸盐和乙醇醛的前体形成复合物的方式。本研究的公共卫生意义在于其对预防常见肾结石疾病和预防孤儿疾病原发性高尿酸肾衰竭的贡献。