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Norepinephrine precursor therapy in neurogenic orthostatic hypotension.
Circulation. 2003 Aug 12; 108(6):724-8.Circ

Abstract

BACKGROUND

In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture.

METHODS AND RESULTS

We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients

CONCLUSIONS

Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system.

Authors+Show Affiliations

Kaufmann H
Mount Sinai School of Medicine, Box 1052, New York, NY 10029, USA. Horacio.Kaufmann@mssm.edu
Saadia D
No affiliation info available
Voustianiouk A
No affiliation info available
Goldstein DS
No affiliation info available
Holmes C
No affiliation info available
Yahr MD
No affiliation info available
Nardin R
No affiliation info available
Freeman R
No affiliation info available

MeSH

Administration, OralAgedAntiparkinson AgentsAromatic-L-Amino-Acid DecarboxylasesBlood PressureCarbidopaCross-Over StudiesDouble-Blind MethodDroxidopaFemaleHemodynamicsHumansHypotension, OrthostaticMaleMiddle AgedNeurodegenerative DiseasesNorepinephrinePostureSingle-Blind MethodTreatment Outcome

Pub Type(s)

Clinical Trial
Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12885750

Clinical Trial Links

A Two Part Study (306A/306B) to Assess Droxidopa in Treatment of NOH in Patients With Parkinson's Disease
Droxidopa in Treating Patients With Neurogenic Hypotension
Dose Response to the Norepinephrine Precursor Droxidopa in Hypotensive Individuals With Spinal Cord Injury

Citation

Kaufmann, Horacio, et al. "Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension." Circulation, vol. 108, no. 6, 2003, pp. 724-8.
Kaufmann H, Saadia D, Voustianiouk A, et al. Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003;108(6):724-8.
Kaufmann, H., Saadia, D., Voustianiouk, A., Goldstein, D. S., Holmes, C., Yahr, M. D., Nardin, R., & Freeman, R. (2003). Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation, 108(6), 724-8.
Kaufmann H, et al. Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension. Circulation. 2003 Aug 12;108(6):724-8. PubMed PMID: 12885750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Norepinephrine precursor therapy in neurogenic orthostatic hypotension. AU - Kaufmann,Horacio, AU - Saadia,Daniela, AU - Voustianiouk,Andrei, AU - Goldstein,David S, AU - Holmes,Courtney, AU - Yahr,Melvin D, AU - Nardin,Rachel, AU - Freeman,Roy, Y1 - 2003/07/28/ PY - 2003/7/30/pubmed PY - 2003/9/18/medline PY - 2003/7/30/entrez SP - 724 EP - 8 JF - Circulation JO - Circulation VL - 108 IS - 6 N2 - BACKGROUND: In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. METHODS AND RESULTS: We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients CONCLUSIONS: Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/12885750/Norepinephrine_precursor_therapy_in_neurogenic_orthostatic_hypotension_ DB - PRIME DP - Unbound Medicine ER -