Currently, there is no cure for Parkinson’s disease, as the cause of the disease is still unknown. Neither drugs nor surgeries can stop or delay the progression of Parkinson’s disease, but there are a variety of treatments that can compensate for the lack of dopamine. Few of the drugs that alleviate the symptoms of Parkinson's disease include, levodopa/ carbidopa, Comtan and Stalevo (Table 1). The type of drugs can be generally classified as dopamine-replacement drugs or dopamine agonist drugs.
Drugs
Dopamine-Replacement
The main ingredient in the dopamine-replacement drugs is levodopa (L-dopa). Levodopa, which is taken orally, travels through the circulatory system until it reaches the brain, where it crosses the blood-brain barrier. Levodopa is then synthesized into dopamine in the basal ganglia. For the drug to diffuse across the blood-brain barrier, levodopa needs to be converted after it crosses the blood-brain barrier because dopamine cannot diffuse through this tight barrier (Figure 1). If the patient were to consume only levodopa, aromatic-L-amino-acid decarboxylase (DOPA Decarboxylase or DDC) would biosynthesize the majority of levodopa into dopamine before the drug passes the blood-brain barrier, which also causes a great deal of nausea for the patient. By taking levodopa along with carbidopa, DDC is inhibited in the digestive tract, and levodopa retains its form until it reaches the brain. Also, carbidopa allows a lower dose of levodopa, which reduces the side effects, such as nausea.
Sinemet is a drug that contains both levodopa and carbidopa. Side effects include nausea, vomiting, diarrhea, lightheadedness and dizziness, and sleepiness. Entacapone (Comtan) is often taken with Sinemet. Similar to carbidopa, it inhibits an enzyme called catechol-O-methyltransferase (COMT), which degrades levodopa to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD), a molecule that cannot cross the blood-brain barrier. The side effects of Comtan include diarrhea, confusion and hallucinations. Stalevo is a drug that contains the ingredients of the previous two drugs levodopa, carbidopa and entacapone.
Dopamine Agonist
Dopamine agonists mimic the function of dopamine by activating the dopamine receptor. Pramipexole (Mirapex) and Ropinirole (Requip) are used in treatment of early stages of Parkinson's disease. Mirapex and Requip can also be used with levodopa. Side effects may include hallucinations or confusion, involuntary movements, drowsiness, nausea, vomiting and swelling of the legs. Apokyn is injected subcutaneously (under the skin) as an acute or rescue therapy to treat off episodes in patients who undergo on-off fluctuations. It is usually used along with other drugs. Side effects include nausea and vomiting, daytime sleepiness, sudden uncontrolled movements, dizziness and low blood pressure.
Other drugs include amantadine, selegiline (L-deprenyl) and anticholinergics, such as Artane and Cogentin.
Other drugs include amantadine, selegiline (L-deprenyl) and anticholinergics, such as Artane and Cogentin.
Limitations of Current Therapies
Current therapies have limited effect on postural and gait disturbances, and also, there are not many options for treating non-motor complications, such as autonomic dysfunction, urinary urgency and cognitive impairment. Common side effects after long periods of levodopa administration include on-off fluctuations, dyskinesia and wearing off. On-off fluctuations occur as the patient's body becomes used to levodopa. As can be in the video below, patients with this symptom go through rapid cycles of on-off periods, where during "on" periods, the patient walks in a relatively stable fashion. In contrast, during "off" periods, the patient's movements become severely impaired. Dyskinesia, continuous uncontrollable tremors, occurs as the patient's drug dosage reaches its maximum. In popular culture, many people may have recognized dyskinesia from the actor Michael J. Fox. Side effects of dopamine agonists include impulse control disorder in addition to the ones mentioned above.
Novel Treatment
Duodopa
In order to solve the problem of on-off fluctuations, the Abbott Laboratories developed a novel technique of delivering the drug combination of levodopa and carbidopa. The main issue with the previous techniques was that after around five years of consumption of the drugs, the duration of the effectiveness of the drugs began to diminish substantially. As it is important to keep the drug plasma level below the minimal toxic concentration (MTC), solely increasing the dose of the drug would not help the patient (Figure 2). Duodopa is a surgically implanted, intra-intestinal pump that allows a controlled release of the drug, as can be seen in the paper by Nyholm and Aquilonius (Figure 3). An analogy of the device would be the insulin pump. It is not yet commercially available, but Phase III stage studies are currently being performed (Figure 4-6).
Deep Brain Stimulation (DBS)
Similar to Duodopa, deep brain stimulation (DBS) is surgically inserted into the patient to reduce on-off fluctuations and dyskinesia, but instead of administering drugs, it stimulates the brain. The device is composed of four electrodes, a neurostimulator and an extension. Depending on the symptom of the patient, the electrode can stimulate the thalamus, the subthalamic nucleus or the internal globus pallidus.