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L-DOPS
Systematic (IUPAC) name
(2R,3S)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Identifiers
CAS number 23651-95-8
ATC code none
PubChem 3171
Chemical data
Formula C 9H11NO5  
Mol. mass 213.18734 g/mol
Pharmacokinetic data
Bioavailability 90%
Metabolism hepatic
Half life 1.5 hours
Excretion renal
Therapeutic considerations
Pregnancy cat.  ?
Legal status Rx-only (not yet approved in the US)
Routes Oral

L-DOPS (L-threo-dihydr oxyphenylserine; Droxidopa; SM-5688) is a psychoactive drug and synthetic amino acid precursor which acts as a prodrug to the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline).[1] Unlike norepinephrine and epinephrine themselves, L-DOPS is capable of crossing the protective blood-brain barrier (BBB).[1]

Contents

Indications

History

L-DOPS was developed by Sumitomo Pharmaceuticals under the trade name Droxidopa for the treatment of hypotension, including NOH,[2] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asian areas for these indications since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharma licensed L-DOPS to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan.

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Clinical Trials

Though L-DOPS has been used in Japan and Southeast Asia already for some time, it is also currently in clinical trials at the phase III point in the United States (U.S.), Canada, Australia, and throughout Europe. Provided L-DOPS successfully completes clinical trials, it could be approved for the treatment of NOH as early as 2009.[4] Additionally, phase II clinical trials for IDH are also underway. Chelsea Therapeutics obtained orphan drug status (ODS) for L-DOPS in the U.S. for NOH, and that of which associated with PD, PAF, and MSA, and is the pharmaceutical company developing it in that country.

Pharmacology

L-DOPS is a prodrug of norepinephrine and epinephrine used to increase the concentrations of these neurotransmitters in the body and brain.[1] It is metabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine and epinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.[5] L-DOPS works by increasing the levels of norepinephrine and epinephrine in the peripheral nervous system (PNS), which induces tachycardia or increased heart rate and hypertension or increased blood pressure, thus enabling the body to maintain blood flow upon and while standing.

L-DOPS can also cross the blood-brain barrier (BBB) where it is converted to norepinephrine and epinephrine from within the brain.[1] Increased levels of norepinephrine and epinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. L-DOPS can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) or DOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine and epinephrine concentrations while maintaining peripheral levels.

Side Effects

With close to 20 years on the market, L-DOPS has proven to have very few side effects of which most are mild. Patients have reported tachycardia, hypertension, nausea and vomiting, and headache or migraine.[2]

See also

  • D-DOPA (Dextrodopa)
  • L-DOPA (Levodopa; Sinemet, Parcopa, Atamet, Stalevo, Madopar, Prolopa, etc)
  • Methyldopa (Aldomet, Apo-Methyldopa, Dopamet, Novomedopa, etc)
  • Dopamine (Intropan, Inovan, Revivan, Rivimine, Dopastat, Dynatra, etc)
  • Norepinephrine (Noradrenaline; Levophed, etc)
  • Epinephrine (Adrenaline; Adrenalin, EpiPed, Twinject, etc)

References

  1. ^ a b c d Goldstein, DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovasc Drug Rev 24 (3-4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x.  
  2. ^ a b c Mathias, Christopher J (2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z.  
  3. ^ Crofford, LJ (2008). "Pain management in fibromyalgia". Curr Opin Rheumatol 20 (3): 246–250. doi:10.1097/BOR.0b013e3282fb0268.  
  4. ^ Search of: "Droxidopa" - List Results - ClinicalTrials.gov
  5. ^ Robertson, David (2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0.  

External links


Droxidopa
Systematic (IUPAC) name
(2R,3S)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Identifiers
CAS number 23651-95-8
ATC code none
PubChem 3171
Chemical data
Formula C9H11NO5 
Mol. mass 213.18734 g/mol
Pharmacokinetic data
Bioavailability 90%
Metabolism hepatic
Half life 1.5 hours
Excretion renal
Therapeutic considerations
Pregnancy cat.

?

Legal status

Rx-only (not yet approved in the US)

Routes Oral

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

Contents

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.[1] 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.[2] 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 Syndrome[3]

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.[4]

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.[5]

A phase II trial in IDH is also underway.

References

  1. Robertson, David (2008). "The pathophysiology and diagnosis of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0. 
  2. Goldstein, DS (2006). "L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug". Cardiovasc Drug Rev 24 (3-4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. 
  3. Crofford, LJ (2008). "Pain management in fibromyalgia". Curr Opin Rheumatol 20 (3): 246–250. doi:10.1097/BOR.0b013e3282fb0268. 
  4. Mathias, Christopher J (2008). "L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension". Clin Auton Res 18 (Supplement 1): 25–29. doi:10.1007/s10286-007-1005-z. 
  5. Search of: "Droxidopa" - List Results - ClinicalTrials.gov

External links

Template:Dopaminergic agents


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