Rotigotine, sold under the brand name Neupro among others, is a
dopamine agonist
A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
of the non-
ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a variety of alkaloids, referred to as ergoline derivatives or ergoline alkaloids. Ergoline alkaloids, one being ergine, were initially characterized in ergot. Some of thes ...
class of medications indicated for the treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
and
restless legs syndrome
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...
.
It is formulated as a once-daily
transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. An advantage of a transdermal drug delivery route over other types of medicat ...
which provides a slow and constant supply of the drug over the course of 24 hours.
Like other dopamine agonists, rotigotine has been shown to possess
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
effects and may be useful in the treatment of
depression as well.
History
Initially developed at the
University of Groningen
The University of Groningen (abbreviated as UG; nl, Rijksuniversiteit Groningen, abbreviated as RUG) is a Public university#Continental Europe, public research university of more than 30,000 students in the city of Groningen (city), Groningen in ...
in 1985 as N-0437, Aderis Pharmaceuticals acquired rotigotine and continued development toward commercialization. In 1998, Aderis globally out-licensed rotigotine for development and commercialization to Schwarz Pharma, which firm was acquired by
UCB S.A. in 2006. Schwarz completed acquisition of full rights to rotigotine from Aderis as of 2005.
The drug was approved by the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) for use in Europe in 2006. In 2007, the Neupro patch was approved by the
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA). It became the first transdermal treatment of Parkinson's disease in the United States. In 2008, Schwarz Pharma recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. FDA also suspended its marketing authorization after crystal formation was noted in some patches. The patch was reformulated, and was reintroduced in the United States in 2012.
Rotigotine was authorized as a treatment for restless legs syndrome in August 2008.
Side effects
General
side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s for rotigotine may include
constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
,
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
,
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose.
Vomiting can be the result of ailments like Food-poisoning, foo ...
,
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
,
fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
,
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
,
somnolence
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 ...
,
confusion
In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion" , and
hallucination
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
s.
More serious complications can include
psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
and
impulse control disorder
Impulse-control disorder (ICD) is a class of psychiatric disorders characterized by impulsivity – failure to resist a temptation, an urge, or an impulse; or having the inability to not speak on a thought. Many psychiatric disorders feature imp ...
s like
hypersexuality
Hypersexuality is extremely frequent or suddenly increased libido. It is controversial whether it should be included as a clinical diagnosis used by mental healthcare professionals. Nymphomania and satyriasis were terms previously used for the c ...
,
punding
Punding is compulsive performance of repetitive, mechanical tasks, such as assembling and disassembling, collecting, or sorting household objects. The term was originally coined to describe complex prolonged, purposeless, and stereotyped behaviou ...
, and
pathological gambling
Problem gambling 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 gambling is ...
.
Mild adverse skin reactions at the patch application site may also occur.
Pharmacology
Rotigotine acts as a non-selective
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
D1,
D2,
D3, and, to a lesser extent,
D4 and
D5 receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s, with highest
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
for the D
3 receptor.
In terms of
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
, rotigotine has 10-fold selectivity for the D
3 receptor over the D
2, D
4, and D
5 receptors and 100-fold selectivity for the D
3 receptor over the D
1 receptor.
In functional studies however, rotigotine behaves as a
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of D
1, D
2, and D
3 with similar potencies (
EC50).
Its ability to activate both
D1-like and
D2-like receptors is similar to the case of
apomorphine
Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...
(which notably has greater
efficacy
Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a pragmatic clinical trial#Efficacy versu ...
in the treatment of Parkinson's disease than D
2-like-selective agonists but has suboptimal
pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
properties) and
pergolide
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...
but unlike
pramipexole
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
and
ropinirole
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. I ...
.
Rotigotine possesses the following ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
''
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
binding profile:
*
D1 receptor (K
i = 83 nM)
*
D2 receptor (K
i = 13.5 nM)
*
D3 receptor (K
i = 0.71 nM)
*
D4.2 receptor (K
i = 3.9 nM)
*
D4.4 receptor (K
i = 15 nM)
*
D4.7 receptor (K
i = 5.9 nM)
*
D5 receptor (K
i = 5.4 nM)
*
α1A-adrenergic receptor (K
i = 176 nM)
*
α1B-adrenergic receptor (K
i = 273 nM)
*
α2A-adrenergic receptor (K
i = 338 nM)
*
α2B-adrenergic receptor (K
i = 27 nM)
*
α2C-adrenergic receptor (K
i = 135 nM)
*
5-HT1A receptor (K
i = 30 nM)
*
5-HT7 receptor (K
i = 86 nM)
*
H1 receptor (K
i = 330 nM)
All affinities listed were assayed using
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
materials except that for α
2B-adrenergic which was done with
NG 108–15 cells. Rotigotine behaves as a
partial
Partial may refer to:
Mathematics
* Partial derivative, derivative with respect to one of several variables of a function, with the other variables held constant
** ∂, a symbol that can denote a partial derivative, sometimes pronounced "partial ...
or
full agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
(depending on the assay) at all dopamine receptors listed, as an
antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
at the α
2B-adrenergic receptor, and as a partial agonist at the 5-HT
1A receptor.
Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a
selective D
1-like (D
1, D
5) and D
2-like (D
2, D
3, D
4) receptor agonist, with its α
2B-adrenergic and 5-HT
1A activity also possibly having some minor relevance.
See also
*
Piribedil
Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.
...
*
Pramipexole
Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
*
Ropinirole
Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. I ...
References
External links
*
Rotigotine (SPM-962) - The First Once-a-Day Transdermal Patch to Treat Parkinson's Disease
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