Clinical Aspects Of Dopaminergic Therapy
The clinical benefit of levodopa has not been doubted since its description and is still the most effective symptomatic drug for PD . Current therapeutic approaches rely upon levodopa and dopamine agonists. Levodopa, the precursor of dopamine moves across the BBB and combines with the peripherally-acting decarboxylase inhibitors such as benserazid and carbidopa to ensure its bioavailability in the CNS and thereby its clinical effectiveness in patients . However, it does not relieve other disabling symptoms of PD possibly derived from alterations in other neurotransmitter systems, such as cholinergic, noradrenergic, and serotonergic systems . Furthermore, several classifications of PD subtypes were created with the need of an individual and/or combined strategy to pharmacotherapy during the course of the disease.
Levodopa In The Treatment Of Parkinson’s
Levodopa is a common drug administered during the progressive stages of PD. L-dopa is considered a prodrug, meaning it is not activated until after it crosses the blood brain barrier via active transport. The primary use of Levodopa is to restore depleted levels of dopamine at the presynaptic terminal of the substantia nigra, which restores functional movement. This replacement can relieve symptoms of PD, such as freezing and rigidity. If a tolerance is built up to L-dopa, or adverse motor effects become present with this drug alone, partner drugs Benserazide and Carbidopa can be supplemented to prevent the further premature breakdown in the periphery.
Optimal oral dosing of LD-CD is typically between 97.5 mg-390 mg for a single dose, and 25mg-100mg bi-daily/tri-daily for either sustained release or immediate release. The volume of distribution is typically around 28.5 L and the plasma half-life clearance is 1.8 hours. Therefore, frequent dosage is required. The renal clearance of L-dopa is approximately 72 ml/min.
References:
Lack Of Dopaminergic Neurons In Parkinsons Disease
Then, almost 50 years later, Hornykiewicz and his collaborator Ehringer found that dopamine content was significantly reduced in specific parts of the brain of deceased Parkinsons patients. Knowing Guggenheims works, Hornykiewicz initiated the first therapy attempts with L-dopa in Parkinsons patients, hoping that L-dopa could overcome the blood-brain barrier. He published his results in 1961 together with the neurologist Birkmayer, highlighting the significant improvement in akinesis characterized by the loss of the ability to create muscular movement in Parkinsons disease patients after L-Dopa administration and its longer-lasting effects.
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Study Could Explain Why Parkinson’s Drug Improves Then Diminishes Quality Of Life
by University of California, Irvine
A team of University of California, Irvine researchers has discovered a possible reason why L-dopa, the front-line drug for treating Parkinson’s disease, loses efficacy and causes dyskinesiainvoluntary, erratic muscle movements of the patient’s face, arms, legs and torsoas treatment progresses.
“Paradoxically, the exact therapy that improved the quality of life for tens of thousands of Parkinson’s patients is the one that contributes to the rapid decline in quality of life over time,” said the study’s co-corresponding author Amal Alachkar, Ph.D., associate professor of teaching in UCI’s Department of Pharmaceutical Sciences. “L-dopa has been shown to accelerate disease progression through neural mechanisms that are not very well understood.”
Findings from the study were recently published in ACS Chemical Neuroscience.
L-dopa and other pharmacological treatments for Parkinson’s are designed to replace the lost dopamine caused by the degeneration of nerve cells in the brain. Although dopamine can’t cross the blood-brain barrier, which lets substances such as water and oxygen pass into the brain, L-dopa can, and it’s used to treat the disease’s motor symptoms. However, 99 percent of L-dopa is metabolized outside the brain, so it’s administered in combination with an enzyme inhibitor to increase the amount of the dose that reaches the brain to 5 to 10 percent and to prevent side effects such as nausea and heart problems.
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How Can Levodopa Treat Parkinsons Disease
A host of symptoms are associated with Parkinsons disease , such as slow movement, loss of dexterity, tremors, rigidity, and freezing gait, in addition to other motor and cognitive deficits. There is no cure for Parkinsons disease, but levodopa a natural precursor of dopamine is the most common treatment. It can, however, easily enter the brain and send signals to the brain, unlike dopamine.
PD and neurorehabilitation specialist Giuseppe Frazzitta at the Moriggia-Pelascini Hospital in Italy describes levodopa as the best drug for rigidity and bradykinesia in PD. It is ineffective for parkinsonism symptoms of tremors and slowness of movement. When symptoms of gait and posture dysfunction begin to develop, levodopa no longer proves effective. In rare cases, levodopa may worsen these symptoms and have an adverse affect on cognitive function.
In some patients with typical parkinsonism who are resistant to levodopa, physicians who may use drugs with differential half-lives, as well as different methods of administration, such as intramuscular or nasal administration, may be able to help them. A nasal delivery system increases absorption of the drug into the bloodstream, allowing it to reach the brain quicker since the drug is not absorbed through the intestines. One possible option is an intramuscular injection of apomorphine . Apomorphine is a fast-acting, short-lived medication.
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Levodopa Responses Across All Subjects
Across all subjects, regional flow significantly increased in midbrain and anterior cingulate cortex yet significantly decreased in the right lateral inferior parietal cortex . The midbrain region was very large, extending from the upper pons to just below the thalami, covering the entire midbrain and bilateral subthalamic nuclei . The anterior cingulate and right lateral inferior parietal regions were comparatively restricted . There were no significant differences between groups in baseline, on levodopa blood flow or change in blood flow. All groups demonstrated a significant change in blood flow .
Figure 5
Means for baseline and on levodopa blood flow in midbrain, anterior cingulate, and right parietal for control group , levodopa naive PD group , and treated PD group . These three regions showed significant change in blood flow with levodopa over all subjects and within each group there were no differences between groups at baseline, on levodopa or in the change in blood flow after levodopa administration.
The Dorsal Vagus Nerve And Parkinson’s Disease
a number of otherwise vital biochemical reactions in our brains and bodies can go awry. We may stop producing healthy levels of particular enzymes, peptides, hormones and neurotransmitters, or make too much of these, or else stop being able to remove toxic by-products, that are necessarily created as part of the chemical steps in the creation and degradation of these substances, fast enough.
For example, our bodies may become depleted of specific chemicals called co-factors, required for proper functioning of detoxification biochemistry, lacking now perhaps due to long years of overburden exposure to ingested or internally created personal poisons. We have already explored an example of this which arises as part of Dopamine biochemistry, whereby the metabolic steps in the breakdown of this neurotransmitter creates a toxic aldehyde called DOPAL.
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What Are The Most Common Medicines Used To Treat Pd
Sinemet®
Levodopa is the most commonly prescribed and most effective medicine for controlling the symptoms of PD, particularly bradykinesia and rigidity.
Levodopa is a chemical found naturally in our brains. When given as a medicine, it is transported to the nerve cells in the brain that produce dopamine. It is then converted into dopamine for the nerve cells to use as a neurotransmitter.
Sinemet is made up of levodopa and another drug called carbidopa. Levodopa enters the brain and is converted to dopamine while carbidopa prevents or lessens many of the side effects of levodopa, such as nausea, vomiting, and occasional heart rhythm disturbances. It is generally recommended that patients take Sinemet on an empty stomach, at least ½ hour before or one hour after meals.
There are two forms of Sinemet: controlled-release or immediate-release Sinemet. Controlled-release Sinemet and immediate-release Sinemet are equally effective in treating the symptoms of PD, but some people prefer the controlled release version. Ask your doctor which approach is best for you.
Dopamine agonists
Dopamine agonists are medicines that activate the dopamine receptor. They mimic or copy the function of dopamine in the brain.
Parlodel®, Requip®, and Mirapex® are all dopamine agonists. These medicines might be taken alone or in combination with Sinemet. Generally, dopamine agonists are prescribed first and levodopa is added if the patient’s symptoms cannot be controlled sufficiently.
Symmetrel®
Discussion And Concluding Remarks
Pharmacological treatment of LID is a major challenge in PD patients. First, LID is a complex clinical phenomenon characterized by a combination of choreic and dystonic abnormal movements in different body parts, with specific features linked to each L-dopa cycle. A significant limitation in many clinical trials is that LID assessment has often been based on patient self-assessment diaries. However, PD patients may not be completely aware of LID, and therefore data collected through self-assessment questionnaires may be biased.139 An important step to overcome this limitation has been the introduction and validation of the UDysRS, a new LID rating scale that is now increasingly used in clinical trials. UDysRS, indeed, has four parts and part III and IV consist in the objective evaluation by the researcher of LID severity and related disability, thus excluding possible biases due to the patients subjective perceptions. Importantly, the objective sections of UDysRS have demonstrated high internal consistency and good inter- and intra-rater reliability.111 However, because different pathophysiological substrates possibly underlie dyskinesia, the drugs tested for LID treatment may be effective for only a specific type of dyskinesia . Finding the right drug for LID is also problematic since LID pathophysiology is complex and may involve several neurochemical pathways and neurophysiological mechanisms.
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When Tom Was Put On Levodopa He Thought It Wonderful Because His Symptoms Went Away He Didn’t
And so I went when, when I went to the doctor and said, What on earths going on? And I had since then Id also developed this slight tremor in my right hand. He said, Well its probably, a central tremor or trapped nerve or something like that. And anyway, then it got a bit worse and then I was, I was recommended to go to a neurologist. And the neurologist had a look at me and gave me some pills. And he said, Come back and tell me if these work.
This is about, about sort of, nine months after my, my not being able to finish the, the postcard. And, and he said, Take these pills. And the pills worked. Magically the tremors stopped and I thought this is wonderful. And so I went back to the neurologist and I said, Yes everythings fine now. The pills have, the pills have worked. And far from looking happy about this he looked rather, rather grave and he said, I think youd better go to another neurologist.
Books And Movies Based On The Incephalitis Lethargica Epidemic:
Awakenings by Oliver Sack in 1973
Oliver Sacks published a non-fiction book called Awakenings in 1973. Sacks chronicles his efforts to help these patients in the Bronx, New York, at the Beth Abraham Hospital . L-DOPA was used in the treatment.
1990s Hollywood movie Awakenings based on the book by Oliver Sack
Adapted from Oliver Sackss 1973 memoir of the same name, Awakenings is a 1990 American drama film. In this film, Robin Williams plays the role of Dr. Malcolm Sayer, a fictional character based on Sacks. It was his discovery of the drug L-Dopa that led to his discovery of its beneficial effects. His treatment plans include catatonic patients who survived encephalitis lethargica, which was prevalent from 1917 to 1928. The patients are woken up by Leonard Lowe and must adapt to a new time and new life after decades of sleep. A total of three Oscar nominations have been given to this film.
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Common Drugs For Parkinson’s Disease
Levodopa and carbidopa . Levodopa is the most commonly prescribed medicine for Parkinsonâs. Itâs also the best at controlling the symptoms of the condition, particularly slow movements and stiff, rigid body parts.
Levodopa works when your brain cells change it into dopamine. Thatâs a chemical the brain uses to send signals that help you move your body. People with Parkinsonâs donât have enough dopamine in their brains to control their movements.
Sinemet is a mix of levodopa and another drug called carbidopa. Carbidopa makes the levodopa work better, so you can take less of it. That prevents many common side effects of levodopa, such as nausea, vomiting, and irregular heart rhythms.
Sinemet has the fewest short-term side effects, compared with other Parkinsonâs medications. But it does raise your odds for some long-term problems, such as involuntary movements. An inhalable powder form of levodopa and the tablet istradefylline have been approved for those experiencing OFF periods, OFF periods can happen when Parkinsonâs symptoms return during periods between scheduled doses of levodopa/carbidopa.
People who take levodopa for 3-5 years may eventually have restlessness, confusion, or unusual movements within a few hours of taking the medicine. Changes in the amount or timing of your dose will usually prevent these side effects.
Dopamine agonists. These drugs act like dopamine in the brain. They include pramipexole , rotigotine , and ropinirole , .
Glutamate Receptor Antagonists And Modulators
ADX48621 or dipraglurant is a negative allosteric modulator of the metabotropic glutamate 5 receptor developed by Addex Therapeutics. Its antidyskinetic properties had already been tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model.108 A Phase II randomized, double-blind, placebo-controlled study on 76 participants testing dose escalation from 50 mg once daily to 100 mg three times a day showed that dipraglurant was safe and well tolerated and determined a statistically significant improvement at day 14 in peak-dose dyskinesia as measured by the modified Abnormal Involuntary Movement Scale . However, a strong placebo response at day 28 resulted in significance being lost.109 A phase IIb/III pivotal clinical trial on 140 PD patients with LID that was postponed due to the Covid-19 pandemic is scheduled to start at the end of 2020 and will use the UDysRS instead of the mAIMS to measure efficacy of the primary endpoint. Concerning these two scales, the mAIMS focuses on anatomical distribution and severity of dyskinesia whereas the UDysRS combines both patient-based and objective evaluation of dyskinesia severity and related disability.110,111 The UDysRS was shown to be more sensitive to treatment effects and less prone to placebo responses than mAIMS.112
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Levodopa In The Treatment Of Parkinson’s Disease: Current Status And New Developments
Article type: Review Article
Authors: Salat, David | Tolosa, Eduardo
Affiliations: Universitat Autònoma de Barcelona, Barcelona, Spain | Parkinson’s Disease and Movement Disorders Unit, Neurology Service, Hospital ClÃnic, University of Barcelona Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona, Spain
Note: Correspondence to: Eduardo Tolosa MD, FRCP, Neurology Service, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona 080036, Spain. Tel.: +34 93 227 57 85 Fax: +34 93 227 57 83 E-mail:
Keywords: Levodopa/carbidopa, Parkinson’s disease, wearing-off, dyskinesia, entacapone
DOI: 10.3233/JPD-130186
Journal: Journal of Parkinson’s Disease, vol. 3, no. 3, pp. 255-269, 2013
Abstract
Studies Of Ochratoxin A
David then suggested I looked up Malassezia and L-Dopa.
“Malassezia is a genus of fungi, naturally found on the skin surfaces of many animals, including humans. Allergy tests for this fungus are available.”
Moreover,
“Investigations show that the Malassezia species causing most skin disease in humans, including the most common cause of dandruff and seborrhoeic dermatitis. As the fungus requires fat to grow, it is most common in areas with many sebaceous glands: on the scalp, face, and upper part of the body. When the fungus grows too rapidly, the natural renewal of cells is disturbed, and dandruff appears with itching .”
This is interesting, because such skin issues are very prevalent in Parkinson’s Disease. Indeed, David makes one more extremely important connection. Malassezia feeds on L-Dopa,
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Complications Of Levodopa Therapy
Although treatment with levodopa was shown to improve the symptoms of PD, it became apparent in the late 1960s that many patients who responded to levodopa also developed motor fluctuations and dyskinesias . Between 40 and 75% of patients developed these complications after 46 years of levodopa therapy . More recently, it has been recognized that both motor and nonmotor symptoms can fluctuate in association with the clinical duration of benefit of levodopa .
The development of dyskinesias is also hypothesized to relate in large measure to postsynaptic mechanisms. In healthy individuals, dopamine receptors in the striatum are generally tonically innervated, and pulsatile stimulation from levodopa-derived dopamine may induce downstream changes that alter the function of basal ganglionic neurons . Pulsatile administration of short-acting dopamine agonists induces more dyskinesia than administration of the same agonist in a continuous fashion . Similarly, continuous administration of levodopa has been associated with a reduction in dyskinesia . Following elucidation of the continuous dopaminergic stimulation concept, research has focused on attempting to provide more sustained dopamine concentrations in the CNS.
Learnings From Black Urine Disease
I believe that some of the disruptions due to prolonged Dorsal Vagus activation may resemble or mimic genetically inherited problems, and I feel it is worth exploring what we can learn from these.
When I started using a urination bottle as a practical way to make going to the bathroom easier, less stressful and less messy while in an “off” state, I noticed that although my urine was quite clear at the time of passing water, frequently in the morning the little bit which was left in the bottom of the bottle would have turned dark brown or even black overnight . I emphasise here the changing of the color in the air-exposed bottle, some hours after passing perfectly clear wee, and not just coming out dark in the first place, which may be due to quite different reasons .
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