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. We tested whether CAR attenuates L-DOPS conversion to norepinephrine (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 L-DOPS with CAR, ENT, or placebo on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol (DHPG), dihydroxymandelic acid (DHMA)) were measured. L-DOPS+ENT increased systolic pressure, but L-DOPS+CAR did not. The peak increase in plasma NE after L-DOPS averaged less than 1/15,000th that in L-DOPS itself 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 et al., J Clin Pharmacol 2011;51:66-74). We found that L-DOPS used in the above study was contaminated with a trace amount of the toxic catecholaldehyde dihydroxyphenylacetaldehyde (DOPA)L and that after L-DOPS ingestion DOPAL was detected in plasma of humans. Because of the deuterium isotope effect, which stabilizes the alpha carbon-nitrogen bond of catecholamines such as NE, deuterated L-DOPS would be expected to be more potent and less toxic than non-deuterated L-DOPS. We developed assay methodology for measuring dihydroxyphenylglycolaldehyde (DOPEGAL), the aldehyde produced from oxidative deamination of NE, and showed that deuterated NE is less susceptible to conversion to deuterated DOPEGAL than non-deuterated NE is to conversion to non-deuterated DOPEGAL. This finding confirms the deuterium isotope effect. A patent is pending for deuterated L-DOPS. 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. As 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 was infused i.v. at doses titrated individually to maintain blood pressure during head-up tilt at increasing angles from horizontal. We found that i.v. NE infusion temporarily eliminates OH (Goldstein et al., Clin Auton Res (in press)).
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