Parkinson's Disease Tulip


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Old 12-16-2006, 04:29 PM #1
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Default Anti-convulsant Zonisamide (Zonegram) helps PD

I think I posted about this before, but it's worth a repost. Zonegram is also good for nerve pain, like neurontin, another anticonvulsant:

Zonisamide has beneficial effects on Parkinson's disease patients

Miho Murata

Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Neuroscience Research
Volume 41, Issue 4 , 21 December 2001,


Abstract

Zonisamide (ZNS) is a generally well tolerated anticonvulsant that has beneficial effects on Parkinson's disease (PD). ZNS (300 mg/day) given to a patient with PD who incidentally had convulsive attacks, ameliorated the attacks and, surprisingly, his parkinsonian symptoms.

We, therefore, carried out an open trial of ZNS on nine patients with PD. Patients were given 50–200 mg/day ZNS in addition to their anti-PD drugs.

Seven clearly showed lessening of symptoms, especially wearing-off. We speculate that long lasting activation of dopamine synthesis by ZNS ameliorates parkinsonian symptoms, in particular wearing-off.

FULL ARTICLE:

http://www.sciencedirect.com/science...171309c05523b2

FROM ANOTHER ARTICLE:

"Recently, the clinical and experimental studies have suggested some new indications for ZNS administration, as mania, neuropathic pain, Parkinson's disease or migraine prophylaxis. Nowadays, it is also well established that ZNS exerts neuroprotective properties."

http://www.if-pan.krakow.pl/pjp/pdf/2003/5_683.pdf
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Old 12-16-2006, 04:33 PM #2
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: No To Shinkei. 2003 Aug;55(8):685-9.
Effect of zonisamide on resting tremor resistant to antiparkinsonian medication

Department of Neurology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8510, Japan.

The antiparkinsonian effect of zonisamide (ZNS), an antiepileptic agent, has been reported. Generally, resting tremor of patients with Parkinson's disease is not the main therapeutic target in this disease. However, depending on the social situation of the patient, the amelioration of the tremor may be necessary.

In this study, we examined the effect of ZNS on tremor in nine patients who desired amelioration of their tremor. Except for tremor, they seemed to be under optimal therapeutic condition based on their daily activities. By the add-on administration of ZNS, the degree of tremor was reduced in seven out of nine patients (p < 0.0017).

Although one patient felt sleepiness and two patients had a transient loss of appetite, all the patients tolerated the eight-week ZNS administration period.

The final dose of ZNS was 100 mg/day in the majority of the patients. Although the mechanism of the antitremulous effect of ZNS is not yet clear, other than the enhancement of dopaminergic transmission, some specific action of the drug on tremor may exist. A more detailed random examination should be carried out.

PMID: 13677302 [PubMed - indexed for MEDLINE]
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Old 12-16-2006, 04:39 PM #3
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Novel Therapeutic Effects of the Anti-Convulsant, Zonisamide, on Parkinson's Disease

Author: Murata, M.1

Source: Current Pharmaceutical Design, Volume 10, Number 6, February 2004, pp. 687-693(7)


Abstract:
We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically.

An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off.

Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years.

Nation-wide double-blind controlled study confirmed that the small dose (50mg / day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein.

ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system.

Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca++ channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

****************************
The therapy of wearing-off
Nippon Rinsho. 2004 Sep;62(9):1716-9.

* Murata M.

Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry.

Wearing-off, predictable end of dose deterioration, is one of the major problems of long-term levodopa treatment for Parkinson's disease. The mechanisms of wearing-off are (1) loss of striatal dopamine storage, (2) change in the peripheral pharmacokinetics of levodopa and (3) modification of dopamine receptors. The main therapeutic strategy for wearing-off is continuous stimulation of dopamine system.

For this purpose, we increase frequency of levodopa doses and use long half-life dopamine agonist(continuous stimulation of dopamine receptors), COMT inhibitor and MAOB inhibitor (prolongation of the half-life of levodopa and dopamine), and zonisamide (long-term increase of dopamine synthesis).

PMID: 15462390 [PubMed - indexed for MEDLINE]

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Old 12-16-2006, 04:56 PM #4
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In reading about the anti-pain effects of anti-convulsive drugs, I found a pain article that said that anti-depressants are also effective pain killers, and not just neuropathic pain.

I began taking a tricyclic, doxepin, to help me with joint and muscle pain, and it does help me alot, and also helps me sleep well. It was being studied at the time as a treatment for chronic fatigue syndrome. I've been taking it for about 20 years and am afraid to stop it, so azilect isn't an option for me now.

Forgot to add that doxepin is good vs itching, too, and I had a problem of being itchy (having nothing to do with dry skin!), a neurological kind of itching. I take four doses throughout the day instead of one dose at night. It has antihistamine properties. Substance P may be the cause of my itching: (Vol. 286, Issue 3, 1140-1145, September 1998
Substance P Induction of Itch-Associated Response Mediated by Cutaneous NK1 Tachykinin Receptors in Mice).

Way back then, when I first had fibromyalgia symptoms, I also had raynaud's syndrome along with discoid lupus, an autoimmune disorder. It's interesting the people with fibromyalgia have high level of substance P in their cerebral spinal fluid. And substance P is low in PD brains. And high in spinal fluid of very depressed people. Anyway, this article suggests that substance P may be the cause of raynaud's which I hadn't read before:

Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis.

In 30 patients with diagnosed fibromyalgia, the CSF level of immunoreactive substance P (SP) was investigated. Compared to normal values (9.6 +/- 3.2 fmol/ml), all the patients had elevated CSF levels of SP (36.1 +/- 2.7 fmol/ml, range 16.5-79.1 fmol/ml). Anamnestic information from the patients revealed that 53.3% had Raynaud/Raynaud-like phenomenon localized in the fingers, the toes or both. Although SP levels did not differ significantly in patients with or without the Raynaud phenomenon, elevated activity may be present in the peripheral branches of SP neurons which could be responsible for the last (rubor) phase of the triphasic Raynaud's phenomenon. ...

****************

Also found this interesting:

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome.

Levels of substance P were determined in the cerebrospinal fluid (CSF) in 15 patients with chronic fatigue syndrome (CFS). All values were within normal range. This is in contrast to fibromyalgia (FM). The majority of patients with FM have increased substance P values in the CSF. The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

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Old 12-16-2006, 09:56 PM #5
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Loss of brainstem serotonin- and substance P-containing neurons in Parkinson's disease

G.M. Halliday

Abstract

Using postmortem immunohistochemical analysis, we have identified degeneration of several different neuronal cell groups in the brainstem of patients dying with idiopathic Parkinson's disease.

We report the first chemically identified loss of presumed serotonin neurons in the median raphe nucleus of the pons and of substance P-containing preganglionic neurons in the dorsal motor vagal nucleus.

This evidence is concordant with other evidence that the primary neuropathological process is not confined either to a single pathway or to neurons containing a particular transmitter. Rather it appears that Parkinson's disease affects several clases of neurons in localized areas of the brainstem.

http://www.sciencedirect.com/science...4e988e9b565366

**************

"Specific lower brainstem nuclei are consistently and strikingly affected in PD, with the Lewy body pathology primarily confined to noncatecholaminergic neurons. Lewy body degeneration of the dorsal vagal nucleus affects noncatecholaminergic large motor neurons but spares melanized cells.[43-45] Substance P-containing neurons within the dorsal vagal nucleus are most depleted, with 77% neuronal loss[40][46]; in contrast, nearby tyrosine hydroxylase-immunoreactive neurons are almost spared (<5% reduction).[46] Others have also reported nearly complete sparing of catecholaminergic neurons within the medulla.[47][48] The noncatecholaminergic lateral medullary reticular nucleus is severely affected in PD,[49][50] with 85% loss of the substance P-containing neurons.[40]"

From:


http://www3.interscience.wiley.com/c...299/HTMLSTARTW

Glial-cell-line-derived neurotrophic factor (GDNF) enhances biosynthesis of substance P in striatal neurons in vitro


http://www.springerlink.com/content/dbhblrl3g3r1wecd/

A GOOD REVIEW ARTICLE ABOUT SUBSTANCE P:

http://medschool1.mc.vanderbilt.edu/...ncePReview.pdf

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Old 12-18-2006, 10:20 AM #6
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I tried Zonegram last year, made my ears ring ... nothing else.

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Old 01-02-2007, 09:39 PM #7
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There's a new article about zonegram:

http://www.forbes.com/forbeslife/hea...out600520.html

Unfortunately, it's in the sulfur drug family, and I'm allergic to sulfur antibiotics so my doctor won't prescribe this. I was wondering if I should switch from Neurontin to this, but I guess I can't.

Anyone else try this drug? Does it help with bradykinesia?

Oh, Neurotonin (gabapentin) helps with PD, too:

1: Am J Med. 1997 Jan;102(1):60-6.Click here to read Links
Gabapentin for parkinsonism: a double-blind, placebo-controlled, crossover trial.

* Olson WL,
* Gruenthal M,
* Mueller ME,
* Olson WH.

Department of Neurology, University of Louisville, Kentucky 40292, USA.

PURPOSE: Gabapentin is a recently available anticonvulsant whose mechanism of action remains unknown. We suspected efficacy from serendipitous observations of gabapentin in patients with parkinsonism. This led us to a double-blind, placebo-controlled, crossover trial.

PATIENTS AND METHODS: We administered gabapentin in a placebo-controlled, double-blind, crossover trial to 19 subjects with advanced parkinsonism. We measured the effect of placebo and gabapentin on subjects' symptoms with the Unified Parkinson's Disease Rating Scale, the Webster Scale, and the Hoehn and Yahr Scale. We assessed tremor with surface-recorded electromyography.

RESULTS: Total Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo (P = 0.0005). Likewise, activities of daily living and examination subscore of the Unified Parkinson's Disease Rating Scale improved with gabapentin compared with placebo but did not achieve statistical significance. Webster Scale showed improvement but neither Hoehn and Yahr Scale nor Webster Scale changes reached statistical significance.

Tremor as measured by the Unified Parkinson's Disease Rating Scale improved with gabapentin but the use of the root mean square of the rectified electromyography as a measure of tremor activity was not statistically significant.

CONCLUSIONS: This study demonstrates that gabapentin improves rigidity, bradykinesia, and tremor of parkinsonism including both Parkinson's disease and Parkinson's syndrome. The rigidity and bradykinesia of parkinsonism improve on the drug even when the effects of gabapentin on tremor are discounted.

******************

I just raised my gabapentin dose, but it's still a very low dose. I need to raise it more (for nerve pain). Maybe it will help me with other symptoms.
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Old 01-03-2007, 10:35 AM #8
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Hi ZuchiniFlower,
I think I beat you by 5 hours on this one!!!
I posted the story under
http://neurotalk.psychcentral.com/sh...ad.php?t=10130
See "A New Treatment"

It isn't that new, I find I had written down the structural formula in 2002, which tallies with one of your references of 2001.
The formula is not like any other beneficial compound. I have compiled a large list of the formulae of every compound that improves the symptoms of PD, to see if I can spot a particular chemical grouping which occurs in many of them. However, no real progress yet, no re-occurence of a particular group in significant numbers.
Keep up the good work!!
Regards
Ron
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Old 01-03-2007, 05:09 PM #9
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Hi Ron,

It seems there are a variety to drug targets in PD. It's all too complex for me without studying hard, and I'd rather read Darkly Dreaming Dexter!

Here's the discussion from the article I posted about gabapentin (I'm not sure if it's accessible to the general public):

Discussion

It has been long recognized that degeneration of the substantia nigra is a causative factor for Parkinson's disease[12] related to loss of dopaminergic supply to the striatum and that levodopa given to patients with parkinsonism is metabolized to dopamine with beneficial effect on the symptoms.[13]

To date the principal treatments of parkinsonism have been oriented to dopaminergic supply.[14] It is known that dopamine from the substantia nigra acting at the striatum[15] results in an inhibitory cascade that is GABAergic from caudate, putamen, and globus pallidus externa.[16]

Gabapentin, (1-aminomethyl)-1-cyclohexaneacetic acid, was synthesized as a structural analogue of GABA.[17] However, gabapentin does not act at GABAA, GABAB,[18] or GABAC[19] receptors, is not metabolized into GABA or a GABA agonist,[20] does not inhibit GABA uptake[21] nor degradation by GABA-transaminase,[22] but it is known to be a competitive inhibitor of branched-chain amino acid aminotransferase and stimulates the activity of glutamate dehydrogenase.[22]

It is known that gabapentin increases brain GABA,[23, 24] enhances the release of GABA from rat neostriatum,[25] and inhibits monoaminergic release from the striatum, but not acetylcholinergic release from the striatum.[26]

Further, gabapentin does not act at benzodiazepine, glutamate, glycine, Image-methyl-d-aspartate receptors,[27] nor does it influence sodium or calcium channels.[28, 29] It is not a substrate for any of the enzyme systems involved in the synthesis or catabolism of GABA.[22]

In neurons, the gabapentin-binding site[30] is associated with Image-neutral amino acid transporter[31] on cell bodies.[32]

We chose a dose of 400 mg three times a day because we noted that a dose of 300 mg three times a day in other patients with parkinsonism has little or no effect. The 11-day washout period was chosen because in a companion study[33] we noted that subjects with spinal cord injury did not return to baseline for at least a week after cessation of gabapentin despite a half life (t1/2) of 4 to 6 hours.[34]

In this trial, 400 mg gabapentin administered TID improved the total Unified Parkinson's Disease Rating Scale score, suggesting that gabapentin exerts an effect on the symptoms and signs of parkinsonism.

In addition, subjects taking gabapentin manifested improvement in their Unified Parkinson's Disease Rating Scale activities of daily living subscore over placebo therapy, documenting a benefit on the subjective symptoms of Parkinsonism. Because gabapentin has been anecdotally reported to benefit patients with essential tremor,[10] we elected to look at gabapentin effects on parkinsonism tremor.

Of interest, even when those measures of tremor in the Unified Parkinson's Disease Rating Scale were removed from analysis, the total Scale scores still demonstrated a significant response to drug. Heretofore, this improvement in nontremor signs and symptoms of parkinsonism has been observed only with administration of dopamine receptor agonists.

These study results are the first evidence of significant treatment benefit by an agent having no known cholinergic or dopaminergic effect in parkinsonism. However, since all subjects were taking at least one dopaminergic agent, we cannot rule out a synergistic effect between gabapentin and the concurrent dopaminergic drug(s).

The failure of gabapentin to demonstrate a statistically significant effect on the examination scale of the Unified Parkinson's Disease Rating Scale may be due to the design of the trial itself. The last dose of drug, placebo or gabapentin, was noon of the day of evaluation, and the evaluation was between 4 PM and 6 PM, about 4 to 6 hours after the dose.

Gabapentin t1/2 is 4 to 6 hours, which suggests that subjects may have waning of effect. Thus, gabapentin likely affects the examination subscale of the Unified Parkinson's Disease Rating Scale, but to document this the evaluation should occur 1 to 3 hours after the dose, not 4 or more hours afterward.

We were interested in the possible effects of gabapentin on parkinsonism tremor, so we analyzed a number of measures of this effect. Three items in the Unified Parkinson's Disease Rating Scale (16, 20, and 21) and one item in the Webster scale (6) measure tremor effects. Tremor activity in the electromyography can be recorded with surface electrodes. While there seemed to be some improvement in each of these measures when subjects took gabapentin, none of the effects reached statistical significance.

All subjects had advanced parkinsonism, at least Hoehn and Yahr stage 2.5. Fourteen subjects had response fluctuations to their prescribed dopaminergic agents, but we collected “off” and “on” time activities of daily living data in only 7 subjects. Because meaningful results could not be obtained, we did not analyze our data for “off” or “on” effects.

The brevity of the study limited risks that may accrue in long-term treatment with antiparkinsonism medications.[35, 36, 37, 38] It also restricts conclusions regarding long-term efficacy and tolerability. Since parkinsonism is a lifelong illness once manifest, an investigation of long-term effects is needed. We have observed that some patients have received continued undiminished benefit from gabapentin for more than a year.

Although the mechanism of action of gabapentin still remains elusive, it seems to increase brain GABA,[24] including striatal GABA,[23] and to increase GABA release and acetylcholine release while reducing other monoaminergic release.[26]

Gabapentin also doubles postsynaptic GABA potentials, an effect blocked by GABAA-receptor inhibition.[39] GABAA receptors are known to be prominent in the striatum, globus pallidus interna, and substantia nigra reticulata[40] whereas GABAB receptors are more commonly seen in the substantia nigra compacta.[41] All of the GABA receptors are expressed in the thalamus.

Since parkinsonism is associated with relatively increased function of the indirect inhibitory GABAergic pathway, improvement in the condition may result from stimulation of GABAA receptors with the immediate feedback to inhibit further GABA release.[25] Alternatively, if the striatal indirect GABAergic pathway is involved, action of GABA on the globus pallidus interna and substantia nigra reticulata will decrease inhibition of target thalamic neurons and increase mobility.


Since striatal GABA-mediated postsynaptic inhibitory activity is an action in concert with the action of the dopamine on the striatum in the indirect pathway,[42] this may explain the effect of gabapentin on parkinsonism. Regardless, additional work to elucidate the mechanism of action of gabapentin as an adjunctive medicine in parkinsonism needs to be done.

One final note of caution seems pertinent. While this study did not analyze the effect of gabapentin on specific forms of parkinsonism, we have observed that 5 of 6 patients with progressive supranuclear palsy, who had not been subjects of this study, had worsening of their disease when given gabapentin, becoming bedfast (Hoehn and Yahr stage 5). Fortunately, this is a reversible effect on stopping the gabapentin. This observation suggests that not all forms of parkinsonism will benefit from gabapentin.
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