Treatment of Catecholamine-Related Disorders

儿茶酚胺相关疾病的治疗

• 批准号: 8342295
• 负责人: David Goldstein
• 金额: $ 22.41万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8342295
• 关键词: Accounting; Acids; Adverse effects; Aromatic Amino Acids; Attenuated; Autonomic Dysfunction; Baroreflex; Biological Assay; Blood; Blood Circulation; Blood Pressure; Brain; Carbidopa; Cardiac; Cardiology; Cardiovascular system; Catechol O-Methyltransferase; Catecholamines; Catheters; Chronic; Clinical Trials; Deamination; Denervation; Development; Disease; Dopamine; Dose; Endocrinology; Epinephrine; Failure; Functional disorder; Head; Hour; Human; Hypertension; Infusion procedures; Ingestion; Integrative Medicine; Levodopa; Measures; Mediating; Metabolic; Metabolism; Methylation; Monitor; Monoamine Oxidase; Movement Disorders; Nausea; Nerve; Neuraxis; Neurology; Neurons; New York; Norepinephrine; Novartis brand of entacapone; Orthostasis; Orthostatic Hypotension; Parkinson Disease; Parkinsonian Disorders; Patients; Pharmaceutical Preparations; Placebos; Plasma; Pressoreceptors; Printing; Prodrugs; Prosthesis; Psychiatry; Pure Autonomic Failures; Sampling; Sympathetic Nervous System; System; Systolic Pressure; Testing; Therapeutic; Time; Venous; arm; decarboxylase inhibitor; entacapone; inhibitor/antagonist; nerve supply; neurotoxic; nigrostriatal system; noradrenergic; pressure; prevent; putamen; response; vasoconstriction

L-DOPS is undergoing clinical trials in the US for treatment of OH such as occurs in PD. Adjunctive anti-Parkinsonian drugs might interact with L-DOPS. One such drug is carbidopa (CAR), an L-aromatic amino-acid decarboxylase inhibitor that used routinely in combination with therapeutic levodopa in PD. CAR blocks conversion of levodopa to dopamine outside the brain and consequently increases levodopa delivery to the central nervous system, while preventing nausea as a side effect of dopamine produced from levodopa outside the brain. CAR should also interfere with conversion of L-DOPS to norepinephrine (NE). We tested whether CAR attenuates L-DOPS conversion to NE and blocks L-DOPSs pressor effect. The catechol-O-methyltransferase inhibitor entacapone (ENT, Comtan) is also used in PD treatment, to increase the effects and duration of action of levodopa by interfering with enzymatic breakdown of levodopa outside the brain. ENT should interfere with L-DOPS metabolism but augment the pressor effect. Autonomic failure patients took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol (DHPG), dihydroxymandelic acid (DHMA)) were measured. L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 8 and 24 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE averaged less than 1/15,000th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS. From these findings we concluded that after L-DOPS administration plasma NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem instead to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation (Goldstein DS, Holmes C, Sewell L, Pechnik S, Kopin IJ. Effects of carbidopa and entacapone on the metabolic fate of the norepinephrine pro-drug L-DOPS. J Clin Pharmacol 2011;51:66-74). Dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, is produced by oxidative deamination of cytosolic dopamine catalyzed by monoamine oxidase. We found that L-DOPS used in the above study was contaminated with a trace amount of DOPAL and that after L-DOPS ingestion DOPAL was detected in plasma of humans. Thirteen subjects took 400 mg L-DOPS orally. Arm venous blood was sampled at baseline and at 1, 2, 3, 6, 24, and 48 hours after drug administration, for assays of plasma L-DOPS, NE, and DOPAL levels. L-DOPS contained 0.01% DOPAL. At 6 hours of L-DOPS ingestion, all subjects had detectable DOPAL in arm venous plasma (p<0.0001). The mean DOPAL concentration averaged 0.03% that of L-DOPS. Plasma DOPAL correlated with plasma L-DOPS (r=1.00). The mean increment in plasma DOPAL from baseline was more than 4 times that of NE. In 2 patients with PD, DOPAL was detected in plasma at baseline and increased by 75-fold after L-DOPS. We concluded that commercially available L-DOPS is contaminated with a trace amount of DOPAL (Holmes C, Whittaker N, Goldstein DS. Contamination of the norepinephrine pro-drug L-DOPS by dihydroxyphenylacetaldehyde. Clin Chem 2010;56:832-838). Whether this amount of DOPAL exerts neurotoxic effects is unlikely but also is unknown. Patients with chronic autonomic failure (CAF) often have disabling orthostatic hypotension (OH). OH in this setting results from deficient baroreflex-mediated release of NE from sympathetic nerves. In patients with pure autonomic failure (PAF) or Parkinson disease (PD) and OH, cardiac and extra-cardiac noradrenergic denervation exacerbates effects of baroreflex failure. OH in CAF patients is often associated with supine hypertension, which can be severe, and drugs to treat OH worsen supine hypertension. Therefore, the combination of OH with supine hypertension poses a difficult therapeutic challenge. This study is a first step toward development of a prosthetic baroreceptor system to maintain blood pressure during orthostasis without worsening supine hypertension. In patients with PAF or PD+OH NE is infused i.v. at doses titrated individually to maintain blood pressure during head-up tilt at increasing angles from horizontal. Blood pressure is monitored continuously directly via an intra-arterial catheter. Because of the phenomenon of denervation supersensitivity, we anticipate that patients with OH associated with sympathetic noradrenergic denervation, as in PAF and PD, should be especially responsive to i.v. NE. To date we have studied 2 PAF patients and found that we could eliminate their OH temporarily by titrated NE infusion.

L-DOP正在美国接受临床试验，以治疗OH，例如PD中发生的。辅助性抗原药物可能会与L dop相互作用。一种这样的药物是Carbidopa（CAR），一种L-氨基酸脱羧酶抑制剂，该抑制剂通常与PD中的治疗性左旋多巴结合使用。 CAR阻止了左旋多巴向大脑外多巴胺的转化，因此增加了左旋多巴到中枢神经系统的递送，同时防止恶心为大脑外左旋多巴产生的多巴胺的副作用。汽车还应干扰L-DOP转换为去甲肾上腺素（NE）。我们测试了汽车是否会减弱l-底部转换为NE并阻止L-Dops施加效应。 Catechol-O-甲基转移酶抑制剂Entacapone（ENT，COMTAN）也用于PD处理中，以通过干扰大脑外左旋多巴的酶促分解来增加左旋多巴的作用和作用持续时间。 ENT应干扰L-Dops代谢，但会增强压力效应。自主衰竭患者在不同的日子上服用了400毫克的L型dop，用200毫克的安慰剂（PLA），汽车或ENT服用。测量了血浆L-DOP，NE和脱氨酸的NE代谢产物（二羟基苯基乙醇（DHPG），二羟基甲丙酸（DHMA））。 L-Dops+PLA和L-DOP+ENT同样增加了收缩压（3小时时27 8和24 9 mm Hg）。 l-Dops+汽车没有增加压力。血浆NE的峰值增加平均小于1/15,000的峰值，而L-DOP中的峰值峰值则小于DHPG+DHMA中的1/35峰值。汽车阻止了等离子DHPG和DHMA对L型dop的响应。 从这些发现中，我们得出的结论是，在L型施用后，血浆NE水平不足以增加血压。相反，对L型折件的反应似乎反映了NE的外交产生，从而避免了广泛的酶促脱氨基和O-甲基化，并在达到系统性循环之前引起血管收缩（Goldstein DS，Holmes C，Sewell L，Sewell L，Pechnik S，Pechnik S，Pechnik S，Kopin ij。 l-Dops。 二羟基苯基乙醛（多巴胺）是多巴胺的有毒代谢产物，是通过单胺氧化酶催化的胞质多巴胺的氧化脱氨酸产生的。我们发现，上述研究中使用的L dop被痕量的多巴尔污染，并且在人类血浆中检测到L dops摄入多巴巴。 13名受试者口服400毫克L型。在药物给药后的1、2、3、6、24和48小时以1、2、3、6、24和48小时的速度进行静脉血，以进行血浆L-DOP，NE和多巴巴水平的测定。 L型型含有0.01％的多体。在6小时摄入的L型插入时，所有受试者在手臂静脉血浆中均可检测到多巴多（p <0.0001）。平均多巴尔浓度平均为0.03％的L型型。等离子体的血浆与血浆L dop相关（r = 1.00）。基线的血浆多巴巴的平均增量是NE的4倍以上。在2例PD患者中，在基线时在血浆中检测到多巴巴，在L dop后增加了75倍。我们得出的结论是，市售的L-Dop被痕量的多巴巴污染（Holmes C，Whittaker N，Goldstein DS。二羟基苯基苯基甲醛对去甲肾上腺素Pro-Drug L-Dop的污染。这种数量的多巴尔是否发挥神经毒性作用是不可能的，但尚不清楚。 慢性自主衰竭（CAF）的患者通常患有处置性低血压（OH）。哦，在这种情况下，由于不足的压力反射介导的NE从交感神经中释放出来。在纯自主衰竭（PAF）或帕金森氏病（PD）的患者中，哦，心脏和心外甲肾上腺素能神经神经膜的影响加剧了压力反射衰竭的影响。 OH在CAF中，患者通常与仰卧高血压有关，这可能是严重的，并且可以治疗OH恶化的仰卧高血压。因此，OH与仰卧高血压的组合构成了艰巨的治疗挑战。这项研究是开发假体压力感受器系统以维持直立性血压的第一步，而不会加剧仰卧高血压。在PAF或PD+OH NE的患者中，注入了静脉注射。以滴定的剂量单独滴定，以保持头部倾斜期间的血压，以从水平的角度提高。血压通过动脉内导管直接直接监测。由于去神经超敏反应的现象，我们预计与PAF和PD中的OH相关的OH患者应该特别反应i.v. NE。迄今为止，我们研究了2名PAF患者，发现我们可以通过滴定的NE输注来暂时消除其OH。