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  Providing resources and ideas for therapies and medical developments for Parkinson's disease:

 

FDA Approved Parkinson's Drug Treatments:

The following are a list of drugs used to treat the symptoms of Parkinson's disease, primarily the tremors often refered to as "Motor Fluctuations". The most popular treatments are the Levodopa based drugs blended with Carbidopa to improve longevity of the drug in one's system. Levodopa can be also be complimented with a Dopamine Agnost, a COMT inhibitor or a MAO inhibitor medication. The drugs effects are often refered to as "On time" where the drugs take effect vs "Off time" when the drug effects are wearing off and less effective.

Drugs are refered to by their "corporate brand name" and by their "generic name".

Levodopa:

Levodopa is combined with other drugs like Carbidopa to improve half life, absorption and efficacy. Carbidopa prevents the conversion of Levodopa into dompamine while in the blood stream so that levodopa can make the journey to the brain for conversion where it is needed. When high doses are taken, the peak medication levels of Levodopa may produce involuntary movements known as dyskinesia. Another condition is dystonia, when your muscles continuously contract (cramping), which may cause parts of your body to twist. This leads to repetitive movements or abnormal postures (for example curling of the toes or turning of the foot or ankle) and can cause great pain and discomfort. Both dyskinesia and dystonia often occur at peak doses.

Levodopa has the ability to cross the blood-brain-barrier to reach the aflicted nigral dopaminergic neurones. Levodopa is the precursor used by the body to generate dopamine within the nigral neurons in the brain (by a reaction with aromatic amino acid decarboxylase - ACC), which then acts as a neurotransmitter.
Various versions of Levodopa based drugs exist. Here are the top five:

  • Sinemet: also available in a Sinemet "Controlled Release" (CR) version.
    Studies have shown that patients on Levodopa have a higher risk (2 to approximately 6 times higher) of developing melanoma. ref FDA: page 6
    Side effects can include halucinations, diskenesia, dystonia and sudden onsets of sleep.
  • Rytary: a carbidopa and levodopa based oral medication
  • Stalevo: a carbidopa, levodopa and entacapone based oral medication
  • Duopa: a gel formulation which is slowly and continuously pumped through a tube inserted surgically through the stomach into your intestine to smoothly delivers medication.
  • Inbrijia: inhaled levodopa. Can be used up to 5 times a day. Low rate of diskinesia. Quick acting - improved motor scores after 30 minutes.
    Side effects: cough, upper respiratory tract infection, nausea, discolored sputum. Dangerous side effects if taken with MAO inhibitors.

Tip: drink lots of water with every dose to help push it along from the stomach to the first part of the intestine when it can be absorbed. Levodopa does not get absorbed in the stomach (ref).

Also see Mid Stride - probably the best resource on carbidopa/levodopa drugs.

Levodopa Side Effects and Risks:
Carbidopa-Levodopa

Dopamine Agonists:

In general medical terms, an agonist is a drug which can combine with a receptor on a cell to produce a physiologic reaction typical of a naturally occurring substance. The drug acts along a normal and natural pathway.

A dopamine agonist acts like dopamine by performing the same communications neurotransmitter function in the brain. This class of drug may have bad withdrawal effects. Side effects include hallucinations and excessive daytime sleepiness. Levodopa is often added if the patient's symptoms are not being controlled adequately. Dopamine agonists are effective in prevention and treatment of motor complications. Often the initial drug of choice in young and biologically fit older patients.

  • Pramipexole (Mirapex): used alone or with Levodopa. Reduces risk of dyskinesia but more addictive than traditional carbidopa-levodopa and may induce drowsiness.
    Also see: Mirapex vs. carbidopa-levodopa
  • Ropinirole (Requip): has escalation of dosage issues, Reduces risk of dyskinesia with long term use
  • Neupro (Rotigotine): transdermal patch
    Also see the phase 1 trial NCT02055274 intramuscular injection version of this drug
  • Apokyn, Ixense, Spontane, Uprima (Apomorphine): also a treatment for opiod addiction. Used to reduce L-DOPA dosing. Injected. Check drug interactions.
  • Kynmobi (Sublingual apomorphine): strip placed under tongue. Apomorphine activates both D₂-like and, to a much lesser extent, D₁-like receptors.

COMT (catechol-O-methyltransferase) Inhibitors:

COMT (catechol-O-methyltransferase) is an enzyme which degrades dopamine. Drugs listed here are used to block COMT so that dopamine is retained. Used with Levodopa to make it more effective by inhibiting the break-down of dopamine.

  • Opicapone (Ongentys): extends effectiveness of Carbidopa-Levodopa (Sinemet) "on" time by about an hour. Common side effects are dyskinesia, constipation, increased blood creatine kinase, hypotension/syncope, and decreased weight.
    Dosage: once daily
    Side effects: dyskinesia, constipation, hypotension/syncope, weight decrease
  • Comtan (entacapone): extends effectiveness of Carbidopa-Levodopa by inhibiting COMT from breaking it down
  • Tasmar (Tolcapone): demonstrated significant liver toxicity (hepatotoxicity), which has led to its suspension

MAO (Monoamine oxidase) Inhibitors:

(early treatment) therapeutic agents for panic disorder and social phobia. Targets MAO-B thus affecting dopaminergic neurons. MAO-B is a protein which enables the break-down of excess dopamine thus inhibiting MAO-B allows for more dopamine to be available thus helping Parkinson's patients. MAO-B is also a participant in the production of GABA in astrocytes (nutritional bridge between the blood supply and neurons) which is involved in stress and neurotransmitter inhibition leading to dormant neurons. Thus a MAO-B inhibitor reduces GABA, stress and neurotransmitter inhibition. Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAO inhibitors and are considered to be a safer alternative (ref). MAO-A is also known to affect carcinogenesis.

  • Eldepryl (selegiline): also treats depression. Makes low dosage Levodopa more effective by preventing the dopamine from being destroyed. Lower dosage of Levodopa avoids its side effects. Can be used alone to delay Carbidopa-Levodopa treatment by about a year Also used as an anti-depressant. Deprenyl is another name for this drug.
  • Azilect, Azipron (rasagiline): Teva. Used in early and moderate Parkinson’s to reduce motor fluctuations. May cause hallucinations and psychotic-like behavior.
    Phase 1 drug trial results: NCT01879748 (2013)
  • Xadago (safinamide): FDA approved 2017 for treatment of "off" periods. Used with levodopa and carbidopa.

Rho-kinase inhibitors:

  • Fasudil: Rho-kinase inhibitor and vasodilator. Fasudil, considerably lowered α-synuclein aggregation in an H4 cell culture model. More typically used to treat ALS.

A2A Receptor Antagonists:

The Adenosine A2A receptor has been shown to interact with Dopamine receptor D2. The Adenosine receptor A2A can be used to decreases activity in the Dopamine D2 receptors thus affecting dopamin flow.

  • Istradefylline (Nourianz): oral medication to reduce "off" time by approximately 0.73 hours.
    Side effects: dyskinesia

Dyskinesia Treatements:

Used to treat the side effects of high doses of levodopa.

  • Amantadine ER (extended-release) (Gocovri, Symadine, Symmetrel): increases dopamine release and blocks dopamine reuptake. A weak antagonist of the NMDA-type glutamate receptor (anesthesia effects) and can cause dizziness, and hallucinations. Origionally developed and FDA approved as an anti-viral drug as a prophylactice agent against Asian influenza.
    Dosage: once nightly
    Side effects include dry mouth , nausea, decreased appetite, insomnia, orthostatic hypotension, constipation, visual hallucinations.
  • Pridopidine (Huntexil): is a dopamine stabilizer that interacts with dopamine D3, adrenergic α2C and serotoninergic 5-HT1A receptors. Primarily used as a drug to treat Huntington's disease.

Other:

  • Nuplazid (pimavanserin): treatment for Parkinson's related hallucinations and delusions associated with dementia related psychosis
  • Symadine, Symmetrel, Gocovri, Osmolex ER (Amantadine): used together with Levodopa based medicines to treat the symptoms of levodopa-induced dyskinesia.
  • Cogentin (Benztropine): used together with other medicines to treat the symptoms of Parkinson's disease (muscle spasms, stiffness, tremors, poor muscle control). Cogentin is an Anticholinergic which is used to restore the balance between the two brain chemicals, dopamine and acetylcholine, by reducing the amount of acetylcholine. Benztropine may cause weakness or the inability to move particular muscle groups, especially in large doses. Can impare memory and thinking and therefore rarely prescribed today. Hallucinations have been reported.

Avoid:

Medications To Be Avoided Or Used With Caution in Parkinson’s Disease

Pros:
  • Carbidopa-Levodopa based drugs have a long track record of reducing tremors in Parkinson's patients.

Cons:
  • Carbidopa-Levodopa based drugs only mask symptoms, do not change the rate of progression of the disease, nor do they cure Parkinson's and they have bad side effects.