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(New page: {{BioPsy}} The combination of carbidopa and levodopa is used to treat Parkinson's disease and Dopa-Responsive Dystonia (DRD). This combination is sold under several brand ...)
 
 
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{{BioPsy}}
 
{{BioPsy}}
The combination of [[carbidopa]] and [[levodopa]] is used to treat [[Parkinson's disease]] and Dopa-Responsive [[Dystonia]] (DRD). This combination is sold under several brand names, including '''Sinemet®''', '''Parcopa®''', and '''Atamet®'''.
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{{Drugbox
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| verifiedrevid = 447382801
   
==External links==
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<!--Combo data-->
* [http://www.medsafe.govt.nz/profs/Datasheet/s/Sinemettab.htm Sinemet&reg; datasheet]
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| type = combo
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| component1 = Agonist
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| class1 = [[Levodopa]]
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| component2 = Enzyme inhibitor
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| class2 = [[Carbidopa]]
   
[[Category:Antiparkinsonian agents]]
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<!--Clinical data-->
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| tradename =
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| MedlinePlus = a601068
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| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
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| pregnancy_US = <!-- A / B / C / D / X -->
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| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
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| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
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| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
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| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
   
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<!--Identifiers-->
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| ATC_prefix = N04
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| ATC_suffix = BA02
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| PubChem = 104778
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| ChemSpiderID = 94585
   
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<!--Chemical data-->
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| smiles = O=C(O)[C@](NN)(C)Cc1cc(O)c(O)cc1.O=C(O)[C@@H](N)Cc1cc(O)c(O)cc1
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| InChI = 1/C10H14N2O4.C9H11NO4/c1-10(12-11,9(15)16)5-6-2-3-7(13)8(14)4-6;10-6(9(13)14)3-5-1-2-7(11)8(12)4-5/h2-4,12-14H,5,11H2,1H3,(H,15,16);1-2,4,6,11-12H,3,10H2,(H,13,14)/t10-;6-/m00/s1
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| InChIKey = IVTMXOXVAHXCHI-YXLMWLKOBF
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| StdInChI = 1S/C10H14N2O4.C9H11NO4/c1-10(12-11,9(15)16)5-6-2-3-7(13)8(14)4-6;10-6(9(13)14)3-5-1-2-7(11)8(12)4-5/h2-4,12-14H,5,11H2,1H3,(H,15,16);1-2,4,6,11-12H,3,10H2,(H,13,14)/t10-;6-/m00/s1
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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| StdInChIKey = IVTMXOXVAHXCHI-YXLMWLKOSA-N
  +
}}
   
  +
'''Carbidopa/levodopa''' (sometimes referred to as '''levocarb''') is the combination of [[carbidopa]] and [[levodopa]] and is used to treat [[Parkinson's disease]]<ref name="pmid17078781"/> and [[dopamine-responsive dystonia]] (DRD). It is sold under several brand names, including '''Sinemet''', '''Parcopa''', '''Atamet''', and '''Apo-Levocarb'''. The generic name under the [[British Approved Name]] system is '''Co-careldopa'''.
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== Benefits of the combination drug ==
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Levodopa is converted to [[dopamine]] via the action of a naturally occurring [[enzyme]] called [[DOPA decarboxylase]]. This occurs both in the peripheral circulation and in the [[central nervous system]] after levodopa has crossed the [[blood brain barrier]]. Activation of central dopamine receptors improves the symptoms of Parkinson's disease; however, activation of peripheral dopamine receptors causes nausea and vomiting. For this reason levodopa is usually administered in combination with a [[DOPA decarboxylase inhibitor|DOPA decarboxylase inhibitor (DDCI)]], in this case carbidopa, which is very polar (and charged at physiologic pH) and cannot cross the blood brain barrier, however prevents peripheral conversion of levodopa to dopamine and thereby reduces the unwanted peripheral side effects of levodopa. Use of carbidopa also increases the quantity of levodopa in the bloodstream that is available to enter the brain.
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==History==
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In 1960 the Austrian biochemist [[Oleh Hornykiewicz]], while at the [[University of Vienna]], examined results of autopsies of patients who had died with Parkinson's disease. He suggested that the disease was associated with, or caused by, a reduction in the levels of dopamine in the [[basal ganglia]] of the brain. Since dopamine itself did not enter the brain, he tried treating twenty patients with a [[racemic mixture]] of [[L-DOPA|dihydroxyphenylalanine]] (DOPA), which could enter the brain and be converted there to dopamine by the action of DOPA decarboxylase. His results were positive, as were those of another trial in Montreal run by [[André Barbeau]]. Unfortunately, other investigators were unable to replicate these early results, and the use of DOPA remained in question until 1967, when [[George Cotzias]] at the [[Brookhaven National Laboratories]] in Upton, New York, used megadoses of DOPA, up to 16&nbsp;grams per day. Not long after these results became known, Curt Porter at [[Merck & Co.|Merck]] showed that L-DOPA was the active [[stereoisomer]], thus reducing the effective dose to half.<ref name=Scriabine/>
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With L-DOPA identified as the active form, Alfred Pletscher and his colleagues at [[Hoffman-LaRoche]] synthesized [[benserazide]], an inhibitor of DOPA decarboxylase, which further reduced the required dose. A drug combining L-DOPA with benserazide was marketed under the brand name of Madopar. Independent work was carried out by Victor Lotti at Merck in West Point, Pennsylvania. Merck had already synthesized and patented carbidopa, another dopa decarboxylase inhibitor in 1962, and in 1971 Lotti showed that the use of the L-form of carbidopa, further reduced the therapeutic dose of L-DOPA into the range of 1 to 2&nbsp;grams per day. The combination of L-carbidopa and L-DOPA was marketed under the brand name of Sinemet.<ref name=Scriabine/>
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In 1991 the manufacture and sale of Sinemet was taken over by a new joint venture, Dupont Merck Pharmaceutical Company. That same year approvals for a sustained release formulation (Sinemet CR) which could be taken less frequently were also obtained.<ref name=Dupont/> [[DuPont|Dupont]] purchased Merck's share in the joint venture in 1998 and began operating the company as Dupont Pharmaceuticals (later Dupont Pharma), but Merck continued to manufacture the drug for Dupont.<ref name=listingdrugs/> Starting in late 2009 and continuing into 2011 Merck stopped manufacturing the drug while awaiting regulatory approvals due to a change in the supplier of the active ingredient. This resulted in shortages of the brand name products Sinemet and Sinemet CR, although alternative generic versions were still available.<ref name=Bibmomma/>
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== See also ==
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* [[Carbidopa]]
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* [[Levodopa]]
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* [[Stalevo]] in combination with [[entacapone]]
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== References ==
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<references>
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<ref name="pmid17078781">{{cite journal |author=Nyholm D |title=Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson's disease |journal=Expert Review of Neurotherapeutics |volume=6 |issue=10 |pages=1403–11 |year=2006 |month=October |pmid=17078781 |doi=10.1586/14737175.6.10.1403 |url=http://www.future-drugs.com/doi/abs/10.1586/14737175.6.10.1403?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov}}</ref>
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<ref name=Scriabine>Scriabine, Alexander (1999). "Discovery and Development of Major Drugs Currently in Use", pp. 222&ndash;223 in ''Pharmaceutical Innovation: Revolutionizing Human Health'', edited by Ralph Landau, Basil Achilladelis, and Alexander Scriabine. Philadelphia: Chemical Heritage Press. ISBN 978-0-941901-21-5.</ref>
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<ref name=Dupont>[http://www2.dupont.com/Heritage/en_US/related_topics/sinemet.html Sinemet] at Dupont Heritage.</ref>
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<ref name=listingdrugs>[http://www.listingdrugs.com/drugs/SINEMET.HTM SINEMET] at listingdrugs.com</ref>
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<ref name=Bibmomma>[http://bibmomma.wordpress.com/2010/09/01/letter-from-merck-about-sinemet-shortage/ Letter From MERCK About SINEMET Shortage] at Bibmomma's Blog – Reflections of an early onset Parkinson's patient.</ref>
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</references>
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== External links ==
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* [http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601068.html Levodopa and Carbidopa] at MedlinePlus Drug Information
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* [http://www.merckfrosst.ca/mfcl/en/corporate/products/sinemet_cr.html Sinemet CR product information] at Merck Frosst Canada
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* [http://www.medsafe.govt.nz/profs/Datasheet/s/Sinemettab.htm Sinemet datasheet]{{Dead link|date=May 2012}}
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{{Antiparkinson}}
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{{Dopaminergics}}
   
 
[[Category:Antiparkinsonian agents]]
 
[[Category:Antiparkinsonian agents]]
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[[Category:Combination drugs]]
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{{enWP|Carbidopa/levodopa}}
 
{{enWP|Carbidopa/levodopa}}

Latest revision as of 23:12, September 11, 2012

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Carbidopa/levodopa chemical structure
Carbidopa/levodopa

{{{IUPAC_name}}}
IUPAC name
CAS number
{{{CAS_number}}}
ATC code

N04BA02

PubChem
104778
DrugBank
{{{DrugBank}}}
Chemical formula {{{chemical_formula}}}
Molecular weight {{{molecular_weight}}}
Bioavailability {{{bioavailability}}}
Metabolism {{{metabolism}}}
Elimination half-life {{{elimination_half-life}}}
Excretion {{{excretion}}}
Pregnancy category {{{pregnancy_category}}}
Legal status {{{legal_status}}}
Routes of administration {{{routes_of_administration}}}


Carbidopa/levodopa (sometimes referred to as levocarb) is the combination of carbidopa and levodopa and is used to treat Parkinson's disease[1] and dopamine-responsive dystonia (DRD). It is sold under several brand names, including Sinemet, Parcopa, Atamet, and Apo-Levocarb. The generic name under the British Approved Name system is Co-careldopa.

Benefits of the combination drug Edit

Levodopa is converted to dopamine via the action of a naturally occurring enzyme called DOPA decarboxylase. This occurs both in the peripheral circulation and in the central nervous system after levodopa has crossed the blood brain barrier. Activation of central dopamine receptors improves the symptoms of Parkinson's disease; however, activation of peripheral dopamine receptors causes nausea and vomiting. For this reason levodopa is usually administered in combination with a DOPA decarboxylase inhibitor (DDCI), in this case carbidopa, which is very polar (and charged at physiologic pH) and cannot cross the blood brain barrier, however prevents peripheral conversion of levodopa to dopamine and thereby reduces the unwanted peripheral side effects of levodopa. Use of carbidopa also increases the quantity of levodopa in the bloodstream that is available to enter the brain.

HistoryEdit

In 1960 the Austrian biochemist Oleh Hornykiewicz, while at the University of Vienna, examined results of autopsies of patients who had died with Parkinson's disease. He suggested that the disease was associated with, or caused by, a reduction in the levels of dopamine in the basal ganglia of the brain. Since dopamine itself did not enter the brain, he tried treating twenty patients with a racemic mixture of dihydroxyphenylalanine (DOPA), which could enter the brain and be converted there to dopamine by the action of DOPA decarboxylase. His results were positive, as were those of another trial in Montreal run by André Barbeau. Unfortunately, other investigators were unable to replicate these early results, and the use of DOPA remained in question until 1967, when George Cotzias at the Brookhaven National Laboratories in Upton, New York, used megadoses of DOPA, up to 16 grams per day. Not long after these results became known, Curt Porter at Merck showed that L-DOPA was the active stereoisomer, thus reducing the effective dose to half.[2]

With L-DOPA identified as the active form, Alfred Pletscher and his colleagues at Hoffman-LaRoche synthesized benserazide, an inhibitor of DOPA decarboxylase, which further reduced the required dose. A drug combining L-DOPA with benserazide was marketed under the brand name of Madopar. Independent work was carried out by Victor Lotti at Merck in West Point, Pennsylvania. Merck had already synthesized and patented carbidopa, another dopa decarboxylase inhibitor in 1962, and in 1971 Lotti showed that the use of the L-form of carbidopa, further reduced the therapeutic dose of L-DOPA into the range of 1 to 2 grams per day. The combination of L-carbidopa and L-DOPA was marketed under the brand name of Sinemet.[2]

In 1991 the manufacture and sale of Sinemet was taken over by a new joint venture, Dupont Merck Pharmaceutical Company. That same year approvals for a sustained release formulation (Sinemet CR) which could be taken less frequently were also obtained.[3] Dupont purchased Merck's share in the joint venture in 1998 and began operating the company as Dupont Pharmaceuticals (later Dupont Pharma), but Merck continued to manufacture the drug for Dupont.[4] Starting in late 2009 and continuing into 2011 Merck stopped manufacturing the drug while awaiting regulatory approvals due to a change in the supplier of the active ingredient. This resulted in shortages of the brand name products Sinemet and Sinemet CR, although alternative generic versions were still available.[5]

See also Edit

References Edit

  1. Nyholm D (October 2006). Enteral levodopa/carbidopa gel infusion for the treatment of motor fluctuations and dyskinesias in advanced Parkinson's disease. Expert Review of Neurotherapeutics 6 (10): 1403–11.
  2. 2.0 2.1 Scriabine, Alexander (1999). "Discovery and Development of Major Drugs Currently in Use", pp. 222–223 in Pharmaceutical Innovation: Revolutionizing Human Health, edited by Ralph Landau, Basil Achilladelis, and Alexander Scriabine. Philadelphia: Chemical Heritage Press. ISBN 978-0-941901-21-5.
  3. Sinemet at Dupont Heritage.
  4. SINEMET at listingdrugs.com
  5. Letter From MERCK About SINEMET Shortage at Bibmomma's Blog – Reflections of an early onset Parkinson's patient.

External links Edit



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