Parkinson's Disease: Nicotine Reduces Levodopa-induced Dyskinesias

http://www.sciencedaily.com/releases...1024093555.htm

ScienceDaily (Oct. 24, 2007) — The Parkinson's Institute and Clinical Center has announced research showing that intermittent nicotine treatment reduces medication-induced dyskinesias by as much as 50 percent in models of Parkinson's disease. Levodopa, the most common drug used to treat Parkinson's disease, is initially very effective.

However, long-term treatment often lessens efficacy and causes multiple complications, including abnormal involuntary movements, called dyskinesias. These uncontrolled movements of the head and limbs tend to worsen over time and can become as debilitating as Parkinson's disease itself.

Currently, there are only limited therapeutic options for dyskinesias, including reduction in levodopa dose, amantadine administration, and deep brain stimulation for a limited number of patients.

Most of the research on tobacco has focused on its detrimental health effects. Studies conducted over the last 40 years show that the incidence of Parkinson's disease is about 50 percent less in smokers than in the general population. Recent studies in experimental models suggest that the nicotine in smoke may be responsible for this neuroprotective effect.

In addition, this is the first research to show that nicotine may also reduce levodopa-induced dyskinesias. With an estimated 1.5 million Parkinson's disease patients in the United States, and levodopa being the top prescribed medication for Parkinson's disease, this study has far-reaching implications for the treatment of Parkinson's disease.

"Our hope is that this research represents a useful treatment strategy to reduce the dyskinesias that so many Parkinson's disease patients suffer, "said Dr. Maryka Quik of the Parkinson's Institute and Clinical Center in Sunnyvale. "Reducing the side effects of levodopa makes it a much more effective and long-term treatment."

Lead by senior research scientist, Maryka Quik, Ph.D., the research will be published in an upcoming issue of the Annals of Neurology.

Thanks Carolyn,
The report is right when it says dyskinesias are as disabling as the diease. After 16 years of levodopa, I suffer dreadfully from dyskinesia, which generally makes me perspire, my shirt gets soaked.
I recently read something about nicotine being detrimental, but did not save it. Just done a search and can't find it. However, I will try anything to reduce this problem. Unfortunately, I tried once before in the UK to buy nicotine patches after a similar report on nicotines benefits in slowing progression. Here, although it is not a prescription drug, pharmacists won't sell it to you, unless you can convince them you require it to reduce smoking. I suppose they don't want any legal problems if you use it for other purposes and it goes wrong. Maybe I was just unlucky in my choice of pharmacist.
I will try a different pharmacist and see if I can try again.
Thanks again
Ron

Brief Report
Worsening of motor performance in patients with Parkinson's disease following transdermal nicotine administration
http://www3.interscience.wiley.com/c...09386/ABSTRACT

Georg Ebersbach, Michael Stöck, Jörg Müller, Gregor Wenning, Jörg Wissel, Werner Poewe *
Department of Neurology, University Clinic Innsbruck, Innsbruck, Austria

*Correspondence to Werner Poewe, University Clinic Innsbruck, Dept. of Neurology, Anichstr. 35, 6020 Innsbruck, Austria

Funded by:
VERUM Foundation, Munich, Germany

Keywords
Parkinson's disease; Nicotine; Motor performance

Abstract
Nicotine has been reported to have positive effects on motor performance in patients with Parkinson's disease. In this study, motor performance was evaluated in 16 patients with idiopathic Parkinson's disease during a practical off-period using the motor part of the Unified Parkinson's Disease Rating Scale after 12 hours' exposure to a transdermal patch containing 35 mg nicotine or placebo. The study was performed using a double-blind crossover design. In contrast to previous reports, nicotine exposure was followed by a worsening of symptoms compared with placebo. A negative response to subthreshold dopaminergic stimulation, resulting from an inhibitory effect of low striatal dopamine concentrations acting on a subset of dopamine receptors, might possibly account for this finding.

Received: 19 August 1998; Revised: 31 March 1999; Accepted: 12 July 1999

Drugs Aging. 1997 Sep ;11 (3):206-28 9303280 [Cited: 2]

Nicotinic system involvement in Alzheimer's and Parkinson's diseases. Implications for therapeutics.

[My paper] P A Newhouse , A Potter , E D Levin

Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.

Mesh-terms: Alzheimer Disease, drug therapy; Alzheimer Disease, etiology; Alzheimer Disease, metabolism; Animals; Cognition Disorders, metabolism; Cognition, drug effects; Combined Modality Therapy; Disease Models, Animal; Human; Nicotine, pharmacology; Nicotine, therapeutic use; Nicotinic Agonists, pharmacology; Nicotinic Agonists, therapeutic use; Nicotinic Antagonists, pharmacology; Nicotinic Antagonists, therapeutic use; Parkinson Disease, drug therapy; Parkinson Disease, etiology; Parkinson Disease, metabolism; Receptors, Nicotinic, drug effects; Receptors, Nicotinic, metabolism; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.;

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Psychopharmacology (Berl). 1999 Apr ;143 (2):158-65 10326778 [Cited: 2]
Four-week nicotine skin patch treatment effects on cognitive performance in Alzheimer's disease.
[My paper] H K White , E D Levin
RATIONALE: Acute nicotine injections have been found to improve attentional performance in patients with Alzheimer's disease (AD), but little is known about chronic nicotine effects. OBJECTIVE: The present study was undertaken to evaluate the clinical and neuropsychological effects of chronic transdermal nicotine in Alzheimer's disease subjects over a 4-week period. METHODS: The double-blind, placebo controlled, cross-over study consisted of two 4-week periods separated by a 2-week washout period. Patients wore the nicotine patch (Nicotrol) for 16 h a day at the following doses: 5 mg/day during week 1, 10 mg/day during weeks 2 and 3 and 5 mg/day during week 4. The eight subjects had mild to moderate AD and were otherwise healthy. RESULTS: Nicotine significantly improved attentional performance as measured by the Conners' continuous performance test (CPT). There was a significant reduction in errors of omission on the CPT which continued throughout the period of chronic nicotine administration. The variability of hit reaction time (reaction time for correct responses) on the CPT was also significantly reduced by chronic nicotine. Nicotine did not improve performance on other tests measuring motor and memory function. CONCLUSIONS: The sustained improvement in attention found in this study with nicotine dermal patches is encouraging. However, the lack of detected effects of nicotine treatment on other cognitive and behavioral domains in this study leaves questions concerning the clinical impact of nicotinic treatment in Alzheimer's disease. The modest size of this study limited statistical power which may have been needed to detect more subtle but clinically significant cognitive effects. Higher doses of nicotine, other nicotinic ligands or combination treatment of nicotine with other therapies may be efficacious for producing broader therapeutic effects.
Mesh-terms: Administration, Cutaneous; Aged; Aged, 80 and over; Alzheimer Disease, drug therapy; Alzheimer Disease, psychology; Attention, drug effects; Cognition, drug effects; Female; Human; Male; Memory, drug effects; Middle Aged; Nicotine, administration & dosage; Nicotine, therapeutic use; Nicotinic Agonists, administration & dosage; Nicotinic Agonists, therapeutic use; Psychomotor Performance, drug effects; Treatment Outcome;

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Widespread Decrease of Nicotinic Acetylcholine Receptors in Parkinson's Disease

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PubMed

Post-mortem studies have demonstrated a substantial loss of nicotinic receptors in Parkinson's disease (PD), which may be at least partially responsible for some of the cognitive, motoric, and behavioral deficits seen in this disorder. Epidemiologic studies have suggested that cigarette smoking is a strong negative risk factor for the development of PD. We have previously shown that blockade of central nicotinic receptors produces cognitive impairment in areas of new learning, short-term memory, and psychomotor slowing with increasing dose sensitivity with age and disease. Studies of acute stimulation of nicotinic receptors in Alzheimer's disease with nicotine and the novel agonist ABT-418 in our laboratory and others have shown improvements in several measures of cognitive function. Prior studies of the effects of nicotine in PD have suggested some improvements in clinical symptomatology. We have begun quantitative studies of both acute and chronic nicotine in PD to assess both cognitive and motor effects. Fifteen (15) nondemented subjects (age 66 +/- 5.3; M/F = 11/4) with early to moderate PD (mean Hoehn-Yahr stage = 1.77; MMSE = 28.6) received a dose-ranging study of intravenous nicotine up to 1.25 microg/kg/min, followed by chronic administration of nicotine by transdermal patch with doses ranging up to 14 mg per day for 2 weeks. Testing occurred both during drug administration and up to 2 months after drug cessation to look for prolonged effects. Preliminary analysis shows improvements after acute nicotine in several areas of cognitive performance, particularly measures such as reaction time, central processing speed, and decreased tracking error. Improvements in attention and semantic retrieval were not seen. After chronic nicotine, improvements were seen in several motor measures suggesting improved extrapyramidal functioning. This appeared to be sustained for up to 1 month after drug. The treatment was well tolerated. Nicotinic stimulation may have promise for improving both cognitive and motor aspects of Parkinson's disease.

Early parkinson's detection, 1995

In article <3ns1ch$qgi at xmission.xmission.com>, lee writes:

>"I have some questions about Parkinson's disease, both for personal and
>family reasons. Apparently, for many years before a patient manifests
>clinically-detectable symptoms, there are frequently complaints (general
>loss of fine-motor coordination, non-specific chest pains, etc.) which go undiagnosed and continue to worsen until the clinical symptoms (e.g.
>shaking) appear. Is there any reason to believe that a patient with
>preclinical complaints might respond favorably to L-Dopa, as a
>nonexpensive and early probe for dopaminergic dysfunction?"
>
>"Any thoughts are appreciated."
>
>Lee
>
"Be very careful about taking L-DOPA without close medical supervision. It
is not an innocuous drug and an overdose would be both unpleasant and
dangerous, with multiple systemic and central effects. One possible test
for early niagrostriatal loss is to see if the person has an intolerance
for nicotine. This has not, to my knowledge, been tested rigorously but
here is the basis for the suggestion. One interesting result that came out
of several epidemiological surveys in the 1980's is a strong negative
correlation between smoking (tobacco) and Parkinson's disease. People who
have Parkinson's disease don't smoke and usually have a history of not
smoking for some years before the onset of the disease. This should not be
interpreted to mean that smoking causes Parkinson's disease. Rather, this
surprising negative correlation may reflect the fact that the cholinergic
neurotransmitter system plays a major role in compensating for subclinical
lesions of the niagrostriatal system. Any disruption of the cholinergic
system by nicotine may result in under- or overcompensation and this may
explain why people with Parkinson's disease don't tend to smoke. Of
course, people may have nicotine intolerance for many other reasons and so
the results may not necessarily indicate early preclinical Parkinson's
disease."

I am convinced that nicotine is one of the reasons I don't have Parkinson's right now. (http://www.lindborglabs.com/AboutHeid.htm)

And as a long time user, I have to say that the experiment using 35mg patches over 12 hours most likely overdosed the patients. I've been smoking a pack a day for 30 years and I couldn't have handled that high a dose. When I use patches (I have to when I visit my mother) I get the 21mg and cut it in half and take it off after dinner. I will be interested to see the new study and if they did dosage dependent analysis.

PWP also lose orexin cells in their hypothalamus.

It may be the orexin function(alertness) that nicotine stimulates/mimics.


Nicotine Up-Regulates Expression of Orexin and Its Receptors in Rat Brain

Activation of orexin neurons by acute nicotine

Hypocretin and Nicotine Excite the Same Thalamocortical Synapses in Prefrontal Cortex: Correlation with Improved Attention in Rat