Treatments of Parkinson's Disease
Encyclopedia
As Parkinson's disease is a chronic disorder, Treatment of Parkinson's Disease
requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.
While many medications treat Parkinson's, none actually reverse the effects of the disease or cure it. People with Parkinson's therefore often must take a variety of medications to manage the disease's symptoms. The Parkinson's Disease Foundation
(PDF) has a chart on its website that provides details about Parkinson's medications.
Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of Parkinson's Disease. However, none are yet on the market with specific approval to treat Parkinson's.
. Since motor symptoms are produced by a lack of dopamine in the substantia nigra the administration of L-DOPA temporarily diminishes the motor symptomatology.
Only 5-10% of L-DOPA crosses the blood-brain barrier
. The remaining is often metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea
, dyskinesia
s and stiffness. Carbidopa
and benserazide
are peripheral dopa decarboxylase inhibitor
s. They help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons and therefore reduce side effects. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa
(co-careldopa, trade names Sinemet, Parcopa, Atamet) and benserazide/levodopa
(co-beneldopa, trade name Madopar). Levodopa has also been related to a dopamine dysregulation syndrome
, which is a compulsive overuse of the medication, and punding.
There are controlled release
versions of Sinemet and Madopar that spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.
Tolcapone
inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa. It has been used to complement levodopa. However, due to its possible side effects such as liver failure, it's limited in its availability. A similar drug, entacapone
has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo
).
Levodopa results in a reduction in the endogenous formation of L-DOPA, and eventually becomes counterproductive. Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesia
s and fluctuations in the response to medication. When this occurs PD patients change fastly from stages with good response to medication and few symptoms ("on" state) to phases with no response to medication and important motor symptoms ("off" state). For this reason levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice. A former strategy to reduce motor complications was to withdraw patients from L-DOPA for some time. It is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome
. Most people will eventually need levodopa and later develop motor complications.
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.
It is critical that patients identify their on/off symptoms as early and with as much accuracy as possible. Your medical team will need accurate information to add additional therapies, shorten the time between doses, or suggest dietary or lifestyle changes. Patients experiencing on/off may wish to use a free on-line tool that graphs the vaccilations quickly and easily. The free on-line tool is available at www.datadrivenheatlh.org.
s in the brain have a similar effect to levodopa since they bind to dopaminergic post-synaptic receptors. Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD they are useful at reducing the off periods. Dopamine agonists include bromocriptine
, pergolide
, pramipexole
, ropinirole
, piribedil
, cabergoline
, apomorphine
, and lisuride
.
Agonists produce significant, although mild, side effects including somnolence
, hallucination
s, insomnia
, nausea
, and constipation
. Sometimes side effects appear even at a the minimal clinically efficacious dose, leading the physician to search for a different agonist or kind of drug. When compared with levodopa, while they delay motor complications they control worse symptoms. Nevertheless they are usually effective enough to manage symptoms in the initial years. They are also more expensive. Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects more common in older patients. All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter. Agonists at higher doses have also been related to a wide variety of impulse control disorders.
Apomorphine
, which is a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare it has been recommended that patients under apomorphine treatment should be closely monitored. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and primary caregiver
(often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules
. Apomorphine is also available in a more acute dose as an autoinjector
pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone
(an antiemetic).
s (Selegiline
and rasagiline
) increase the level of dopamine in the basal ganglia by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. Therefore reducing MAO-B results in higher quantities of L-DOPA in the striatum. Similarly to dopamine agonists, MAO-B inhibitors improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the first stages of the disease but produce more adverse effects and are less effective than levodopa. Evidence on their efficacy in the advanced stage is reduced although it points towards them being useful to reduce fluctuations between on and off periods. Although an initial study had as result that selegiline in combination with levodopa increased the risk of death this has been later disproven.
Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more notorious and potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be stomatitis
. Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
and anticholinergic
s may be useful as treatment of motor symptoms in early and late PD, but since quality of evidence on efficacy is reduced they are not first choice treatments. In addition to motor PD is accompanied by an ample range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of clozapine
for psychosis, cholinesterase inhibitors for dementia and modafinil
for day somnolence
.
A preliminary study indicates that taking the drug donepezil
(Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts levels of the neurotransmitter acetylcholine
, and is currently an approved therapy for the cognitive symptoms of Alzheimer's disease
. In the study, participants taking donepezil experienced falls half as often as those taking a placebo, and those who previously fell the most showed the most improvement.
The introduction of clozapine
(Clozaril) represents a breakthrough in the treatment of psychotic symptoms of PD. Prior to its introduction, treatment of psychotic symptoms relied on reduction of dopamine therapy or treatment with first generation antipsychotics, all of which worsened motor function. Other atypical antipsychotic
s useful in treatment include quetiapine
(Seroquel), ziprasidone
(Geodon), aripiprazole
(Abilify), and paliperidone
(Invega). Clozapine is believed to have the highest efficacy and lowest risk of extrapyramidal side effect.
Treating PD with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.
Less than 10% of PD sufferers qualify as suitable candidates for a surgical response. There are three different mechanisms of surgical response for PD: ablative surgery
, (the irreversible burning or freezing of brain tissue
) stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery.
Target areas for DBS or lesions include the thalamus
, the globus pallidus
(the lesion technique being called pallidotomy
) or the subthalamic nucleus
.
symptoms.
Because it is difficult to accurately measure the amount of tissue to be destroyed, it is not uncommon for tremor
s to persist through multiple courses of surgery since tissue is irreversibly damaged and removed and it is safer to test smaller areas of tissue to prevent serious complications, such as a stroke
or paralysis
.
(DBS) is presently the most used method of surgical treatment, although other surgical therapies exist and are also effective. DBS employs three hardware components: a neurostimulator
, also called an implanted pulse generator (IPG), which generates electrical impulses used to modulate neural activity, a lead wire which directs the impulses to a number of metallic electrode
s towards the tip of the lead near the stimulation target, and an extension wire that connects the lead to the IPG. The IPG, which is battery-powered and encased in titanium, is traditionally implanted under the collarbone, and is connected by the subcutaneous extension to the lead, which extends from outside the skull under the scalp down into the brain to the target of stimulation. The entire three component system is sometimes referred to as a brain pacemaker
, as the system operates on many of the same principles as medical cardiac pacing
.
DBS is recommended to PD patients without important neuropsychiatric contraindication
s who suffer motor fluctuations and tremor badly controlled by medication, or to those who are intolerant to medication.
DBS is effective in suppressing symptoms of PD, especially tremor. A recent clinical study led to recommendations on identifying which Parkinson's patients are most likely to benefit from DBS.
and gastroparesis
(food remaining in the stomach for a longer period of time than normal). A balanced diet is recommended to help improve digestion. Diet should include high-fiber
foods and plenty of water. Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, competing between them for access. When taken together the consequences of such competition is a reduced effectiveness of the drug. Therefore when levodopa is introduced excessive proteins are discouraged, while in advanced stages additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins levodopa is recommended to be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch and are usually taken at dinner. As the disease advances dysphagia
may appear. In such cases specific measures include the use of thickening agent
s for liquid intake, special postures when eating and gastrostomy
in the worst cases.
and/or therapy
can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Exercise may also improve constipation. One of the most widely practiced treatment for speech disorders associated with Parkinson's disease is the Lee Silverman Voice Treatment
(LSVT), which focuses on increasing vocal loudness and has an intensive approach of one month. Speech therapy and specifically LSVT may improve voice and speech function. Occupational therapy
(OT) aims to promote health and quality of life by helping people with the disease to participate in as many activities of their daily living as possible. There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.
is often required in the final stages of the disease, often when dopaminergic treatments have become ineffective. The aim of palliative care is to achieve the maximum quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative are; caring for patients at home while adequate care can be given there; reducing or withdrawing dopaminergic drug intake to reduce drug side effects and complications; preventing pressure ulcers by management of pressure areas of inactive patients; facilitating the patient's end of life decisions for the patient as well as involved friends and relatives.
s have been proposed as possible treatments; however there is no evidence that vitamin
or food additive
s improve symptoms. There is not enough evidence to suggest that acupuncture
, and practice of qigong
or t'ai chi have any effect on symptoms. Fava
and velvet beans are natural sources of L-DOPA and are taken by many people with PD. While they have shown some effectiveness, their intake is not free of risks. Life threatening adverse reactions have been described, such as the neuroleptic malignant syndrome
. It has been suggested that faecal transplants may have a beneficial impact on symptoms.
alkaloid
s obtained from the plant of the belladona were described during 19th century by Charcot
, Erb and others. Modern surgery for tremor, consisting of the lesioning of some of the basal ganglia structures was first tried in 1939, and was improved over the following 20 years. Before this date surgery consisted in lesioning the corticospinal pathway with paralysis
instead of tremor as result. Anticholinergics and surgery were the only treaments until the arrival of levodopa, which reduced their use dramatically.
Levodopa
was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century. It entered clinical practice in 1967, and the first large study reporting improvements in people with Parkinson's disease resulting from treatment with levodopa was published in 1968. Levodopa brought about a revolution in the management of PD. By the late 1980s deep brain stimulation
emerged as a possible treatment, and it was approved for clinical use by the FDA
in 1997.
s of the disease, and the potential usefulness of gene therapy, stem cell
s transplants and neuroprotective agents.
MPPP
brought to light MPTP
as a cause of parkinsonian symptoms. Other predominant toxin-based models employ the insecticide rotenone
, the herbicide paraquat
and the fungicide maneb
. Models based on toxins are most commonly used in primate
s. Transgenic rodent
models also exist.
to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme
which helps to manage PD symptoms or protects the brain from further damage. As of 2010 there are four clinical trials using gene therapy in PD. There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.
therapy is based on the idea that certain neuron
s that produces dopamine
and are susceptible to premature degeneration
and cell death can be protected by the introduction of neuroprotective pharmaceuticals. This protection can occur before any symptoms manifest based on genetic risk, and also during early or late-stage PD when other treatments have ceased their impact due to the progression of the disease. Accordingly, neuroprotective therapy seeks to delay the introduction of levodopa.
Several molecules have been proposed as potential treatments. However none of them has been conclusively demonstrated to reduce degeneration. Agents currently under investigation include anti-apoptotic
s (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase
inhibitors (selegiline
, rasagiline
), promitochondrials (coenzyme Q10, creatine
), calcium channel blocker
s (isradipine
) and growth factor
s (GDNF). Preclinical research also targets alpha-synuclein
.
) inhibitors
.
metabolite
s caused by selegiline, another promising treatment is in MAO B propargyl
amine inhibitor rasagiline
(N-propargyl-1-R-aminoindan, Azilect((R))). The oral bioavailability
of rasagiline is 35%, it reaches T(max) after 0.5–1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism
primarily by cytochrome
P450 type 1A2 (CYP1A2). Rasagiline
is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5–1 mg once-daily as adjunctive to levodopa in advanced PD patients.
, porcine
, carotid
or retina
l tissues have been used in cell transplants for PD patients.
Although there was initial evidence of mesencephalic
dopamine-producing cell transplants being beneficial, the best constructed studies up to date indicate that cell transplants have no effect. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonia
s. Stem cell
s transplants are a main research recent target: they are easy to manipulate and when transplanted into the brains of rodent
s and monkey
s cells survive and improve behavioral abnormalities of the animals. Nevertheless use of fetal stem cells is controversial
. Some have proposed that such controversy may be overcome with the use of induced pluripotent stem cell
s from adults.
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.
While many medications treat Parkinson's, none actually reverse the effects of the disease or cure it. People with Parkinson's therefore often must take a variety of medications to manage the disease's symptoms. The Parkinson's Disease Foundation
Parkinson's Disease Foundation
The Parkinson's Disease Foundation is a leading national presence in the United States in Parkinson's disease research, education and public advocacy. PDF funds scientific research to find the causes of and a cure for Parkinson's...
(PDF) has a chart on its website that provides details about Parkinson's medications.
Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of Parkinson's Disease. However, none are yet on the market with specific approval to treat Parkinson's.
Pharmacologic
The main families of drugs useful for treating motor symptoms are Levodopa, dopamine agonists and MAO-B inhibitors. The most commonly used treatment approach varies depending on the disease stage. Two phases are usually distinguished: an initial phase in which the individual with PD has already developed some disability for which he needs pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side-effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of causing the onset of dyskinesias to be retarded. In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also have to be controlled. When medications are not enough to control symptoms surgery and deep brain stimulation can be of use.Levodopa
Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years. L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylaseAromatic L-amino acid decarboxylase
Aromatic L-amino acid decarboxylase is a lyase enzyme.-Reactions:It catalyzes several different decarboxylation reactions:* L-DOPA to dopamine - a neurotransmitter* 5-HTP to serotonin - also a neurotransmitter...
. Since motor symptoms are produced by a lack of dopamine in the substantia nigra the administration of L-DOPA temporarily diminishes the motor symptomatology.
Only 5-10% of L-DOPA crosses the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. The remaining is often metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
s and stiffness. Carbidopa
Carbidopa
Carbidopa is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa.- Pharmacology :...
and benserazide
Benserazide
Benserazide is a peripherally-acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood-brain barrier.- Indications :...
are peripheral dopa decarboxylase inhibitor
Dopa decarboxylase inhibitor
An aromatic L-amino acid decarboxylase inhibitor is a drug which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase ....
s. They help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons and therefore reduce side effects. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa
Carbidopa/levodopa
Carbidopa/levodopa is the combination of carbidopa and levodopa and is used to treat Parkinson's disease and dopamine-responsive dystonia . It is sold under several brand names, including Sinemet, Parcopa, and Atamet...
(co-careldopa, trade names Sinemet, Parcopa, Atamet) and benserazide/levodopa
Benserazide
Benserazide is a peripherally-acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood-brain barrier.- Indications :...
(co-beneldopa, trade name Madopar). Levodopa has also been related to a dopamine dysregulation syndrome
Dopamine dysregulation syndrome
Dopamine dysregulation syndrome , sometimes known as hedonistic homeostatic dysregulation in Parkinson's disease, is a dysfunction of the reward system in subjects with Parkinson's disease due to a long exposure to dopamine replacement therapy...
, which is a compulsive overuse of the medication, and punding.
There are controlled release
Slow-release
Slow-release is a strategy in material science in which a chemical compound is introduced into a system at a reduced speed. Slow-release is applied in fertilizers, pesticides and drugs....
versions of Sinemet and Madopar that spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.
Tolcapone
Tolcapone
Tolcapone is a drug that inhibits the enzyme catechol-O-methyl transferase . - Uses :Tolcapone is used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa medication.- Chemistry :...
inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa. It has been used to complement levodopa. However, due to its possible side effects such as liver failure, it's limited in its availability. A similar drug, entacapone
Entacapone
Entacapone is a drug that functions as a catechol-O-methyl transferase inhibitor. It is used in the treatment of Parkinson's disease....
has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo
Stalevo
Stalevo is an anti-parkinsonian dopaminergic combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease...
).
Levodopa results in a reduction in the endogenous formation of L-DOPA, and eventually becomes counterproductive. Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
s and fluctuations in the response to medication. When this occurs PD patients change fastly from stages with good response to medication and few symptoms ("on" state) to phases with no response to medication and important motor symptoms ("off" state). For this reason levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice. A former strategy to reduce motor complications was to withdraw patients from L-DOPA for some time. It is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
. Most people will eventually need levodopa and later develop motor complications.
The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.
It is critical that patients identify their on/off symptoms as early and with as much accuracy as possible. Your medical team will need accurate information to add additional therapies, shorten the time between doses, or suggest dietary or lifestyle changes. Patients experiencing on/off may wish to use a free on-line tool that graphs the vaccilations quickly and easily. The free on-line tool is available at www.datadrivenheatlh.org.
Dopamine agonists
Dopamine agonistDopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
s in the brain have a similar effect to levodopa since they bind to dopaminergic post-synaptic receptors. Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. When used in late PD they are useful at reducing the off periods. Dopamine agonists include bromocriptine
Bromocriptine
Bromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...
, pergolide
Pergolide
Pergolide is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease....
, pramipexole
Pramipexole
Pramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease and restless legs syndrome...
, ropinirole
Ropinirole
Ropinirole is a non-ergoline dopamine agonist. It is manufactured by GlaxoSmithKline , Cipla and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease...
, piribedil
Piribedil
Piribedil is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist...
, cabergoline
Cabergoline
Cabergoline , an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph cells...
, apomorphine
Apomorphine
Apomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...
, and lisuride
Lisuride
Lisuride is an antiparkinson agent of the iso-ergoline class, chemically related to the dopaminergic ergoline Parkinson's drugs. Lisuride is described as free base and as hydrogen maleate salt.Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks...
.
Agonists produce significant, although mild, side effects including somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, and constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
. Sometimes side effects appear even at a the minimal clinically efficacious dose, leading the physician to search for a different agonist or kind of drug. When compared with levodopa, while they delay motor complications they control worse symptoms. Nevertheless they are usually effective enough to manage symptoms in the initial years. They are also more expensive. Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects more common in older patients. All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter. Agonists at higher doses have also been related to a wide variety of impulse control disorders.
Apomorphine
Apomorphine
Apomorphine is a non-selective dopamine agonist which activates both D1-like and D2-like receptors, with some preference for the latter subtypes. It is historically a morphine decomposition product by boiling with concentrated acid, hence the -morphine suffix...
, which is a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare it has been recommended that patients under apomorphine treatment should be closely monitored. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and primary caregiver
Primary caregiver
A primary caregiver is the person who takes primary responsibility for someone who cannot care fully for themselves. It may be a family member, a medical professional or another trained professional. Depending on culture there may be other members of the family engaged in care. This concept is very...
(often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules
Nodule (medicine)
For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure....
. Apomorphine is also available in a more acute dose as an autoinjector
Autoinjector
An autoinjector is a medical device designed to deliver a single dose of a particular drug....
pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone
Domperidone
Domperidone is an antidopaminergic drug, developed by Janssen Pharmaceutica, and used orally, rectally or intravenously, generally to suppress nausea and vomiting, or as a prokinetic agent...
(an antiemetic).
MAO-B inhibitors
MAO-B inhibitorMonoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s (Selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
and rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
) increase the level of dopamine in the basal ganglia by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. Therefore reducing MAO-B results in higher quantities of L-DOPA in the striatum. Similarly to dopamine agonists, MAO-B inhibitors improve motor symptoms and delay the need of taking levodopa when used as monotherapy in the first stages of the disease but produce more adverse effects and are less effective than levodopa. Evidence on their efficacy in the advanced stage is reduced although it points towards them being useful to reduce fluctuations between on and off periods. Although an initial study had as result that selegiline in combination with levodopa increased the risk of death this has been later disproven.
Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more notorious and potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
. Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
Other drugs
There is some indication that other drugs such as amantadineAmantadine
Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
s may be useful as treatment of motor symptoms in early and late PD, but since quality of evidence on efficacy is reduced they are not first choice treatments. In addition to motor PD is accompanied by an ample range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
for psychosis, cholinesterase inhibitors for dementia and modafinil
Modafinil
Modafinil is an analeptic drug manufactured by Cephalon, and is approved by the U.S. Food and Drug Administration for the treatment of narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea...
for day somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
.
A preliminary study indicates that taking the drug donepezil
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
(Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts levels of the neurotransmitter acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, and is currently an approved therapy for the cognitive symptoms of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
. In the study, participants taking donepezil experienced falls half as often as those taking a placebo, and those who previously fell the most showed the most improvement.
The introduction of clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
(Clozaril) represents a breakthrough in the treatment of psychotic symptoms of PD. Prior to its introduction, treatment of psychotic symptoms relied on reduction of dopamine therapy or treatment with first generation antipsychotics, all of which worsened motor function. Other atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s useful in treatment include quetiapine
Quetiapine
Quetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
(Seroquel), ziprasidone
Ziprasidone
Ziprasidone was the fifth atypical antipsychotic to gain FDA approval . In the United States, Ziprasidone is Food and Drug Administration approved for the treatment of schizophrenia, and the intramuscular injection form of ziprasidone is approved for acute agitation in schizophrenic patients...
(Geodon), aripiprazole
Aripiprazole
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
(Abilify), and paliperidone
Paliperidone
Paliperidone , also known as 9-hydroxyrisperidone, is an atypical antipsychotic developed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing...
(Invega). Clozapine is believed to have the highest efficacy and lowest risk of extrapyramidal side effect.
Surgical
Less than 10% of PD sufferers qualify as suitable candidates for a surgical response. There are three different mechanisms of surgical response for PD: ablative surgery
Ablation
Ablation is removal of material from the surface of an object by vaporization, chipping, or other erosive processes. This occurs in spaceflight during ascent and atmospheric reentry, glaciology, medicine, and passive fire protection.-Spaceflight:...
, (the irreversible burning or freezing of brain tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
) stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery.
Target areas for DBS or lesions include the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, the globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
(the lesion technique being called pallidotomy
Pallidotomy
Pallidotomy is a procedure where a tiny electrical probe is placed in the globus pallidus , which is then heated to 80 degrees celsius for 60 seconds, to destroy a small area of brain cells...
) or the subthalamic nucleus
Subthalamic nucleus
The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...
.
Ablation
Ablative surgery locates and destroys the part of the brain that is associated with the neurologicalNeurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
symptoms.
Because it is difficult to accurately measure the amount of tissue to be destroyed, it is not uncommon for tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
s to persist through multiple courses of surgery since tissue is irreversibly damaged and removed and it is safer to test smaller areas of tissue to prevent serious complications, such as a stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
.
Deep Brain Stimulation
Deep brain stimulationDeep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
(DBS) is presently the most used method of surgical treatment, although other surgical therapies exist and are also effective. DBS employs three hardware components: a neurostimulator
Neurostimulator
In medical technology a neurostimulator, also called an implanted pulse generator is a battery powered device designed to deliver electrical stimulation to the brain.-Applications and use:...
, also called an implanted pulse generator (IPG), which generates electrical impulses used to modulate neural activity, a lead wire which directs the impulses to a number of metallic electrode
Electrode
An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit...
s towards the tip of the lead near the stimulation target, and an extension wire that connects the lead to the IPG. The IPG, which is battery-powered and encased in titanium, is traditionally implanted under the collarbone, and is connected by the subcutaneous extension to the lead, which extends from outside the skull under the scalp down into the brain to the target of stimulation. The entire three component system is sometimes referred to as a brain pacemaker
Brain pacemaker
"Brain pacemakers" are used to treat people who suffer from epilepsy, Parkinson's disease, major depression and other diseases. The pacemaker is a medical device that is implanted into the brain to send electrical signals into the tissue. Depending on the area of the brain that is targeted, the...
, as the system operates on many of the same principles as medical cardiac pacing
Artificial pacemaker
A pacemaker is a medical device that uses electrical impulses, delivered by electrodes contacting the heart muscles, to regulate the beating of the heart...
.
DBS is recommended to PD patients without important neuropsychiatric contraindication
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
s who suffer motor fluctuations and tremor badly controlled by medication, or to those who are intolerant to medication.
DBS is effective in suppressing symptoms of PD, especially tremor. A recent clinical study led to recommendations on identifying which Parkinson's patients are most likely to benefit from DBS.
Diet
Muscles and nerves that control the digestive process may be affected by PD, therefore, it is common to experience constipationConstipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
and gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
(food remaining in the stomach for a longer period of time than normal). A balanced diet is recommended to help improve digestion. Diet should include high-fiber
Dietary fiber
Dietary fiber, dietary fibre, or sometimes roughage is the indigestible portion of plant foods having two main components:* soluble fiber that is readily fermented in the colon into gases and physiologically active byproducts, and* insoluble fiber that is metabolically inert, absorbing water as it...
foods and plenty of water. Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, competing between them for access. When taken together the consequences of such competition is a reduced effectiveness of the drug. Therefore when levodopa is introduced excessive proteins are discouraged, while in advanced stages additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins levodopa is recommended to be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch and are usually taken at dinner. As the disease advances dysphagia
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
may appear. In such cases specific measures include the use of thickening agent
Thickening agent
Thickening agents, or thickeners, is the term applied to substances which increase the viscosity of a solution or liquid/solid mixture without substantially modifying its other properties; although most frequently applied to foods where the target property is taste, the term also is applicable to...
s for liquid intake, special postures when eating and gastrostomy
Gastrostomy
Gastrostomy refers to a surgical opening into the stomach. Creation of an artificial external opening into the stomach for nutritional support or gastrointestinal compression....
in the worst cases.
Rehabilitation
There is partial evidence that speech or mobility problems can improve with rehabilitation although studies are scarce and of low quality. Regular physical exercisePhysical exercise
Physical exercise is any bodily activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons including strengthening muscles and the cardiovascular system, honing athletic skills, weight loss or maintenance, as well as for the purpose of...
and/or therapy
Physical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Exercise may also improve constipation. One of the most widely practiced treatment for speech disorders associated with Parkinson's disease is the Lee Silverman Voice Treatment
Lee Silverman voice treatment
The Lee Silverman voice treatment is one of the most widely practiced treatment for speech disorders associated with Parkinson's disease . It focuses on increasing vocal loudness and has an intensive approach of one month. Speech therapy and specifically LSVT may improve voice and speech function...
(LSVT), which focuses on increasing vocal loudness and has an intensive approach of one month. Speech therapy and specifically LSVT may improve voice and speech function. Occupational therapy
Occupational therapy
Occupational therapy is a discipline that aims to promote health by enabling people to perform meaningful and purposeful activities. Occupational therapists work with individuals who suffer from a mentally, physically, developmentally, and/or emotionally disabling condition by utilizing treatments...
(OT) aims to promote health and quality of life by helping people with the disease to participate in as many activities of their daily living as possible. There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.
Palliative care
Palliative carePalliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...
is often required in the final stages of the disease, often when dopaminergic treatments have become ineffective. The aim of palliative care is to achieve the maximum quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative are; caring for patients at home while adequate care can be given there; reducing or withdrawing dopaminergic drug intake to reduce drug side effects and complications; preventing pressure ulcers by management of pressure areas of inactive patients; facilitating the patient's end of life decisions for the patient as well as involved friends and relatives.
Other treatments
Repetitive transcranial magnetic stimulation improves temporarilly levodopa induced dyskinesias. Its full usefulness in PD is an open research field. Different nutrientNutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...
s have been proposed as possible treatments; however there is no evidence that vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
or food additive
Food additive
Food additives are substances added to food to preserve flavor or enhance its taste and appearance.Some additives have been used for centuries; for example, preserving food by pickling , salting, as with bacon, preserving sweets or using sulfur dioxide as in some wines...
s improve symptoms. There is not enough evidence to suggest that acupuncture
Acupuncture
Acupuncture is a type of alternative medicine that treats patients by insertion and manipulation of solid, generally thin needles in the body....
, and practice of qigong
Qigong
Qigong or chi kung is a practice of aligning breath, movement, and awareness for exercise, healing, and meditation...
or t'ai chi have any effect on symptoms. Fava
Mucuna pruriens
Mucuna pruriens is a tropical legume known as velvet bean or cowitch and by other common names , found in Africa, India and the Caribbean. The plant is infamous for its extreme itchiness produced on contact, particularly with the young foliage and the seed pods...
and velvet beans are natural sources of L-DOPA and are taken by many people with PD. While they have shown some effectiveness, their intake is not free of risks. Life threatening adverse reactions have been described, such as the neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
. It has been suggested that faecal transplants may have a beneficial impact on symptoms.
History
The positive albeit modest effects of anticholinergicAnticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
s obtained from the plant of the belladona were described during 19th century by Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...
, Erb and others. Modern surgery for tremor, consisting of the lesioning of some of the basal ganglia structures was first tried in 1939, and was improved over the following 20 years. Before this date surgery consisted in lesioning the corticospinal pathway with paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
instead of tremor as result. Anticholinergics and surgery were the only treaments until the arrival of levodopa, which reduced their use dramatically.
Levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century. It entered clinical practice in 1967, and the first large study reporting improvements in people with Parkinson's disease resulting from treatment with levodopa was published in 1968. Levodopa brought about a revolution in the management of PD. By the late 1980s deep brain stimulation
Deep brain stimulation
Deep brain stimulation is a surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain...
emerged as a possible treatment, and it was approved for clinical use by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1997.
Research directions
There are no new PD treatments expected in the short time, however several lines of research are active for new treatments. Such research directions include the search of new animal modelAnimal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s of the disease, and the potential usefulness of gene therapy, stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s transplants and neuroprotective agents.
Animal models
The tragedy of a group of drug addicts in California in the early 1980s who consumed a contaminated and illicitly produced batch of the synthetic opiateOpiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
MPPP
MPPP
1-Methyl-4-phenyl-4-propionoxypiperidine or Desmethylprodine is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. It is not used in clinical practice, but has been illegally manufactured for recreational drug use...
brought to light MPTP
MPTP
MPTP is a neurotoxin precursor to MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain...
as a cause of parkinsonian symptoms. Other predominant toxin-based models employ the insecticide rotenone
Rotenone
Rotenone is an odorless chemical that is used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots and stems of several plants such as the jicama vine plant...
, the herbicide paraquat
Paraquat
Paraquat is the trade name for N,N′-dimethyl-4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals...
and the fungicide maneb
Maneb
Maneb is a foliate fungicide and is a polymeric complex of manganese with the ethylene bis anionic ligand. It was included in a biocide ban proposed by the Swedish Chemicals Agency and approved by the European Parliament on January 13, 2009....
. Models based on toxins are most commonly used in primate
Primate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s. Transgenic rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
models also exist.
Gene therapy
Gene therapy is currently under investigation. It involves the use of a non-infectious virusVirus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which helps to manage PD symptoms or protects the brain from further damage. As of 2010 there are four clinical trials using gene therapy in PD. There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.
Neuroprotective treatments
Investigations on neuroprotection are at the forefront of PD research. While still theoretical, neuroprotectiveNeuroprotection
Neuroprotection within the nervous system protects neurons from apoptosis or degeneration, for example following a brain injury or as a result of chronic neurodegenerative diseases....
therapy is based on the idea that certain neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s that produces dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and are susceptible to premature degeneration
Degeneration
The idea of degeneration had significant influence on science, art and politics from the 1850s to the 1950s. The social theory developed consequently from Charles Darwin's Theory of Evolution...
and cell death can be protected by the introduction of neuroprotective pharmaceuticals. This protection can occur before any symptoms manifest based on genetic risk, and also during early or late-stage PD when other treatments have ceased their impact due to the progression of the disease. Accordingly, neuroprotective therapy seeks to delay the introduction of levodopa.
Several molecules have been proposed as potential treatments. However none of them has been conclusively demonstrated to reduce degeneration. Agents currently under investigation include anti-apoptotic
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
s (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase
Monoamine oxidase
L-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
inhibitors (selegiline
Selegiline
Selegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
, rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
), promitochondrials (coenzyme Q10, creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
), calcium channel blocker
Calcium channel blocker
A calcium channel blocker is a chemical that disrupts the movement of calcium through calcium channels.CCB drugs devised to target neurons are used as antiepileptics. However, the most widespread clinical usage of calcium channel blockers is to decrease blood pressure in patients with...
s (isradipine
Isradipine
Isradipine is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack...
) and growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s (GDNF). Preclinical research also targets alpha-synuclein
Alpha-synuclein
Alpha-synuclein is a protein that, in humans, is encoded by the SNCA gene. An alpha-synuclein fragment, known as the non-Abeta component of Alzheimer's disease amyloid, originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the...
.
Selegiline
Selegiline is used to help control the symptoms of Parkinson's disease in people whom are taking levodopa and carbidopa combination (Sinemet). Selegiline may help people with Parkinson's disease by... stopping the effects of levodopa/carbidopa from wearing off, and increasing the length of time that levodopa/carbidopa will continue to control symptoms. Selegiline is in a group of medications called monoamine oxidase type B (MAO-BMonoamine oxidase B
Monoamine oxidase B, also known as MAOB, is a protein that in humans is encoded by the MAOB gene.The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the mitochondrial outer membrane...
) inhibitors
Reaction inhibitor
A reaction inhibitor is a substance that decreases the rate of, or prevents, a chemical reaction.-Inhibition of a catalyst:An inhibitor can reduce the effectiveness of a catalyst in a catalysed reaction...
.
Rasagiline
In response to potentially toxic amphetamineAmphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
s caused by selegiline, another promising treatment is in MAO B propargyl
Propargyl
In organic chemistry, propargyl is an alkyl functional group of 2-propynyl with the structure HC≡C−CH2−, derived from the alkyne propyne.The term propargylic refers to a saturated position on a molecular framework next to an alkynyl group...
amine inhibitor rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
(N-propargyl-1-R-aminoindan, Azilect((R))). The oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of rasagiline is 35%, it reaches T(max) after 0.5–1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
primarily by cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450 type 1A2 (CYP1A2). Rasagiline
Rasagiline
Rasagiline is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen....
is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5–1 mg once-daily as adjunctive to levodopa in advanced PD patients.
Neural transplantation
Since early in the eighties fetalFetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
, porcine
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
, carotid
Common carotid artery
In human anatomy, the common carotid artery is an artery that supplies the head and neck with oxygenated blood; it divides in the neck to form the external and internal carotid arteries. - Structure :...
or retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l tissues have been used in cell transplants for PD patients.
Although there was initial evidence of mesencephalic
Mesencephalon
The midbrain or mesencephalon is a portion of the central nervous system associated with vision, hearing, motor control, sleep/wake, arousal , and temperature regulation....
dopamine-producing cell transplants being beneficial, the best constructed studies up to date indicate that cell transplants have no effect. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
s. Stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s transplants are a main research recent target: they are easy to manipulate and when transplanted into the brains of rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
s and monkey
Monkey
A monkey is a primate, either an Old World monkey or a New World monkey. There are about 260 known living species of monkey. Many are arboreal, although there are species that live primarily on the ground, such as baboons. Monkeys are generally considered to be intelligent. Unlike apes, monkeys...
s cells survive and improve behavioral abnormalities of the animals. Nevertheless use of fetal stem cells is controversial
Stem cell controversy
The stem cell controversy is the ethical debate primarily concerning the creation, treatment, and destruction of human embryos incident to research involving embryonic stem cells. Not all stem cell research involves the creation, use, or destruction of human embryos...
. Some have proposed that such controversy may be overcome with the use of induced pluripotent stem cell
Induced pluripotent stem cell
Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of specific genes....
s from adults.