Treatment of Catecholamine-Related Disorders

L-DOPS目前正在美国进行临床试验，以治疗发生在帕金森病中的OH。辅助性抗帕金森病药物可能与L-DOPS相互作用。其中一种药物是卡比多巴(CAR)，一种L芳香氨基酸脱羧酶抑制剂，常规与治疗帕金森病的左旋多巴联合使用。CAR阻止了左旋多巴在大脑外向多巴胺的转化，从而增加了左旋多巴向中枢神经系统的输送，同时防止了由于左旋多巴在大脑外产生的多巴胺的副作用而引起的恶心。CAR还应干扰L-DOPS向去甲肾上腺素(NE)的转化。我们测试了CAR是否减弱了L-DOPS向NE的转换，并阻断了L-DOPS的升压效应。儿茶酚-O-甲基转移酶抑制剂恩塔卡彭(ENT，Comtan)也用于帕金森病的治疗，通过干扰左旋多巴在脑外的酶促分解来增加左旋多巴的疗效和作用时间。ENT对L-DOPS代谢有干扰作用，但对升压作用有增强作用。自主神经衰竭患者在不同的时间服用L多糖400 mg和安慰剂200 mg，CAR或ENT。测定血浆L-DOPS、去甲肾上腺素及去氨基去甲肾上腺素代谢产物(二羟基苯甘醇、二羟基扁桃酸)。L-DOPS+聚乳酸和L-DOPS+耳鼻咽喉管给药后3h的收缩压升高幅度分别为27.8和24.9 mm Hg。L-DOPS+CAR没有增加压力。血浆去甲肾上腺素升高峰值平均不到L-DOPS组的1/15000，不到DHPG+DHMA组的1/35。CAR预防和ENT增强血浆DHPG和DHMA对L-DOPS的反应。根据这些发现，我们得出结论，服用L-DOPS后，血浆NE水平没有升高到足以升高血压的程度。相反，对L DOPS的升压反应似乎反映了神经外产生的NE，它逃避广泛的酶去氨化和O-甲基化，并在到达体循环之前引起血管收缩(Goldstein DS，Holmes C，Sewell L，Pechnik S，Kopin Ij)。卡比多巴和恩塔卡彭对去甲肾上腺素前体药物L-DOPS代谢命运的影响。J Clin Pharmacol 2011；51：66-74)。 二羟基苯乙醛(DOPAL)是多巴胺的一种有毒代谢物，由胞质中的多巴胺在单胺氧化酶的催化下氧化脱胺而成。结果发现，本研究中使用的L DOPS被微量DOPAL污染，摄入L DOPS后，人体血浆中检测到DOPAL。13例受试者口服L多糖多糖片400 mg。分别于用药前、用药后1、2、3、6、24、48h采集手臂静脉血，测定血浆中L多糖核酸、去甲肾上腺素和多糖胺的水平。L-DOPS中DOPAL的含量为0.01%。服药6小时后，所有受试者手臂静脉血浆中均可检出多巴酚丁胺(P&lt；0.0001)。DOPAL平均浓度为L-DOPS的0.03%。血浆DOPAL与L DOPS呈正相关(r=1.00)。血浆DOPAL较基线平均增加4倍以上。在2例PD患者中，DOPAL在基线时检测到，并在L DOPS后增加了75倍。我们得出结论，商业化的L DOPS被微量的DOPAL污染(Holmes C，Whittaker N，Goldstein DS)。去甲肾上腺素前体药物L多酚对二羟基苯乙醛的污染。Clin Chem 2010；56：832-838)。这种剂量的DOPAL是否会产生神经毒性作用是不太可能的，但也是未知的。 慢性自主神经衰竭(CAF)患者通常有致残性直立性低血压(OH)。在这种情况下，OH是由于压力感受性反射缺陷导致交感神经释放NE所致。在单纯自主神经衰竭(PAF)或帕金森病(PD)和OH患者中，心脏和心外去甲肾上腺素能神经支配加剧了压力感受性反射衰竭的影响。CAF患者的OH通常与仰卧位高血压有关，这可能是严重的，而治疗OH的药物会恶化仰卧位高血压。因此，OH合并仰卧位高血压是一项艰巨的治疗挑战。这项研究是开发假体压力感受器系统的第一步，该系统可以在直立位期间保持血压，而不会恶化仰卧位高血压。PAF或PD+OH患者静注去甲肾上腺素。在单独滴定的剂量，以保持血压在头部向上倾斜，从水平角度增加。血压直接通过动脉内导管持续监测。由于去神经超敏的现象，我们预计，与交感去甲肾上腺素能去神经相关的OH患者，如PAF和PD，应该特别对静脉注射有反应。不能。到目前为止，我们已经研究了2名PAF患者，发现我们可以通过滴定NE输注暂时消除他们的OH。

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.