Treatment of Catecholamine-Related Disorders

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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.