Droxidopa

drugbox
IUPAC_name = (2R,3S)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid


CAS_number = 23651-95-8
PubChem = 3171
C = 9 | H = 11 | N = 1 | O = 5
molecular_weight = 213.18734 g/mol
bioavailability = 90%
protein_binding = 50%
metabolism = hepatic
excretion = renal
elimination_half-life = 2-3 hours
legal_status = Rx-only (not yet approved in the US)
routes_of_administration = Oral

Droxidopa (L-threo DOPS, L-DOPS) is a synthetic amino acid precursor of the neurotransmitter and hormone norepinephrine (noradrenalin).

History

Droxidopa was developed by Sumitomo Pharmaceuticals for treatment of neurogenic orthostatic hypotension associated with various disorders including Multiple System Atrophy, Familial Amyloid Polyneuropathy, hemodialysis induced hypotension and Parkinson's Disease . The drug has been approved in Japan in these indications since 1989. Following a merger with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed the drug to Chelsea Therapeutics to develop and market the drug worldwide except in Japan, Korea, China and Taiwan.

Chelsea obtained Orphan Drug Status for droxidopa in the US for symptomatic neurogenic orthostatic hypotension associated with Parkinson’s Disease, Pure Autonomic Failure and Multiple System Atrophy and is currently in phase III trials.

Therapeutic Use

Droxidopa is a prodrug of norepinephrine used to increase the levels of norepinephrine in the body. It is metabolized by aromatic L-amino acid decarboxylase. Patients with neurogenic orthostatic hypotension have depleted levels of norepinephrine which leads to decreased blood pressure upon orthostatic challenge.cite journal | author=Robertson, David | title=The pathophysiology and diagnosis of orthostatic hypotension | journal=Clin Auton Res | year=2008 | volume=18 | issue= Supplement 1 | pages=2-7] Droxidopa works by increasing the levels of peripheral norepinephrine thus enabling the body to maintain blood pressure during standing.

Droxidopa can also cross the blood-brain barrier where it is converted to norepinephrine.cite journal | author=Goldstein, DS | title=L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug | journal=Cardiovasc Drug Rev | year=2006 | volume=24 | issue=3-4 | pages=189-203] Increased levels of norepinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral DOPA decarboxylase inhibitor (Carbidopa or benserazide) to increase CNS norepinephrine levels while maintaining peripheral levels.

Potential Indications

*Neurogenic orthostatic hypotension
*Intradialytic hypotension (IDH)
*Hypotension associated with Fibromyalgia and Chronic Fatigue Syndromecite journal | author=Crofford, LJ | title=Pain management in fibromyalgia | journal=Curr Opin Rheumatol | year=2008 | volume=20 | issue= 3 | pages=246-250]

Adverse Effects

With close to 20 years on the market, droxidopa has proven to have very few side effects of which most are mild. Patients have reported increased blood pressure, nausea and headache.cite journal | author=Mathias, Christopher J | title=L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension | journal=Clin Auton Res | year=2008 | volume=18 | issue= Supplement 1 | pages=25-29]

Clinical Trials

Droxidopa is currently being studied in phase III trials in the US, Canada, Australia and throughout Europe. Provided successful completion of the trials, droxidopa could be approved for the symptomatic neurogenic orthostatic hypotension indication in 2009. [ [http://clinicaltrials.gov/ct2/results?intr=%22Droxidopa%22 Search of: "Droxidopa" - List Results - ClinicalTrials.gov ] ]

A phase II trial in IDH is also underway.

References

External Links

* [http://Clinicaltrials.gov Clintrials.gov]
* [http://chelseatherapeutics.com/pipeline/droxidopa/droxidopa.html Chelsea Therapeutics]
* [http://www.mc.vanderbilt.edu/root/vumc.php?site=adc Vanderbilt Autonomic Dysfunction Center]