Duodopa
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Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications
carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...
and
levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...
. It is primarily used to manage the symptoms of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, but it does not slow down the disease or stop it from getting worse. It is taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
. It can take two to three weeks of treatment before benefits are seen. Each dose then begins working in about ten minutes to two hours with a duration of effect of about five hours. Common side effects include movement problems and nausea. More serious side effects include depression,
low blood pressure with standing Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...
, sudden onset of sleepiness,
psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, and increased risk-taking behavior. Carbidopa prevents the breakdown of levodopa outside the brain. In the brain, levodopa is broken down into
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
, its active form. Carbidopa also helps prevent some of the nausea which levodopa causes. It is on the
World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2022, it was the 278th most commonly prescribed medication in the United States, with more than 700,000 prescriptions.


Medical uses


Parkinson's disease

It is primarily used to improve the symptoms of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
but does not change the course of the disease. It can take two to three weeks of treatment before benefits are seen. Each dose then begins working in about ten minutes to two hours depending on the formulation, with a duration of effect of about five hours. A formulation that can be given in an intra-
intestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
pump, known as Duodopa, is being developed.


Other

Other uses include for
dopamine-responsive dystonia Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years (variable start age). Characteristic symptoms are increased m ...
(DRD) and
restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...
. Using carbidopa/levodopa may lead to augmentation syndrome, with increasing persistence of restless legs syndrome, and increasing severity. There is tentative evidence that it is useful in
amblyopia Amblyopia, also called lazy eye, is a disorder of sight in which the brain fails to fully process input from one eye and over time favors the other eye. It results in decreased vision in an eye that typically appears normal in other aspects. Amb ...
when used with other treatments.


Side effects

Common side effects include
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
,
drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
,
blurred vision Blurred vision is an ocular symptom where vision becomes less precise and there is added difficulty to resolve fine details. Temporary blurred vision may involve dry eyes, eye infections, alcohol poisoning, hypoglycemia, or low blood pressur ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
,
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
,
dry mouth Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...
, low appetite,
heartburn Heartburn is a burning sensation felt behind the breastbone. It is a symptom that is commonly linked to acid reflux and is often triggered by food, particularly fatty, sugary, spicy, chocolate, citrus, onion-based and tomato-based products. Ly ...
, diarrhea, constipation, frequent sneezing, nasal congestion,
flu-like symptoms Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss ...
, cough, muscle pain, numbness,
paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
, sleep disturbances, skin rash, itching, or headache. Less common, but more serious, side effects can include very frequent blinking or twitching of the eyes,
fainting Syncope , commonly known as fainting or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...
, mood changes (e.g., depression), confusion,
hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s,
delusion A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
s, thoughts of suicide,
compulsive behavior Compulsive behavior (or compulsion) is defined as performing an action persistently and repetitively. Compulsive behaviors could be an attempt to make obsessions go away. Compulsive behaviors are a need to reduce apprehension caused by internal ...
(e.g.,
compulsive gambling Problem gambling, ludopathy, or ludomania is repetitive gambling behavior despite harm and negative consequences. Problem gambling may be diagnosed as a mental disorder according to DSM-5 if certain diagnostic criteria are met. Pathological ga ...
),
hypersexuality Hypersexuality is a proposed medical condition said to cause unwanted or excessive sexual arousal, causing people to engage in or think about sexual activity to a point of distress or impairment., according to the website of ''Psychology Toda ...
, worsening of involuntary movements or
spasm A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ, such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a musc ...
s, or other movement problems.


Mechanism of action

Levodopa is converted to
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
via the action of a naturally occurring
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
called
DOPA decarboxylase Aromatic L-amino acid decarboxylase (AADC or AAAD), also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme (), located in region 7p12.2-p12.1. Mechanism The enzyme uses pyri ...
. This occurs both in the peripheral circulation and in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
after levodopa has crossed the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
. 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.


History

In 1960, the Austrian biochemist Oleh Hornykiewicz, while at the
University of Vienna The University of Vienna (, ) is a public university, public research university in Vienna, Austria. Founded by Rudolf IV, Duke of Austria, Duke Rudolph IV in 1365, it is the oldest university in the German-speaking world and among the largest ...
, 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 The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
of the brain. Since dopamine itself did not enter the brain, he tried treating twenty patients with a
racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
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 In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
, thus reducing the effective dose to half. With L-DOPA identified as the active form, Alfred Pletscher and his colleagues at Hoffman-LaRoche synthesized
benserazide Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is on the World Health Organization's List of Essential Medicines. Medical use ...
, 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. The combination of L-carbidopa and L-DOPA was marketed under the brand name of Sinemet.


Society and culture


Economics

It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.


Names

The generic name under the BAN system is Co-careldopa. It is sold under several brand names, including Sinemet ( Merck Sharp & Dohme Limited), Pharmacopa, Atamet, Apo-Levocarb, Duodopa, Kinson, and Pharmacopa, among others. Extended-release formulations are sold as Rytary and Sinemet-CR. An extended-release enteral solution is sold as Duopa.


Shortages

In 1991, Merck licensed the rights to the manufacture and sale of Sinemet to a newly created 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.
DuPont Dupont, DuPont, Du Pont, duPont, or du Pont may refer to: People * Dupont (surname) Dupont, also spelled as DuPont, duPont, Du Pont, or du Pont is a French surname meaning "of the bridge", historically indicating that the holder of the surname re ...
purchased Merck's share in the joint venture in 1998 and began operating the company as DuPont Pharmaceuticals (DuPont Pharma), but Merck continued to manufacture the drug for DuPont. 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.


References

{{DEFAULTSORT:Carbidopa Levodopa Antiparkinsonian agents Combination psychiatric drugs Drugs developed by AbbVie Drugs developed by Merck & Co. Monoamine precursors Wikipedia medicine articles ready to translate World Health Organization essential medicines