and one more time....


New pharmacologic horizons in the treatment of Parkinson disease.
Neurology 2006, Oct 10,67 (7 Supl 2) S 30-8

Bonuccelli U, Del Dotto P.

Department of Neuroscience, University of Pisa, Italy. u.bonuccelli@med.unipi.it

Many of the motoric features that define Parkinson's disease (PD) result primarily from the loss of dopaminergic neurons of the substantia nigra. l-dopa remains at present the most powerful symptomatic drug for the treatment of this condition. However, motor complications of chronic l-dopa treatment have emerged as a major limitation of this therapy. Slowing or delaying the progression of the disease with neuroprotective therapies may delay the need for l-dopa. In the past few years, novel insight into the pathogenetic mechanisms of neurodegeneration in PD has been provided. Mitochondrial function deficiency, increased oxidative stress, apoptosis, excitotoxicity, and inflammation are part of the processes that ultimately result in neurodegeneration. Drugs that are now under clinical scrutiny as neuroprotectant include molecules that combine one or more of the following properties: (1) monoamine oxidase inhibition (rasagiline, safinamide); (2) mitochondrial enhancement (coenzyme Q10, creatine); (3) antiapoptotic activity; (4) anti-inflammatory activity; (5) protein aggregation inhibition; (6) neurotrophic activity. In advanced Parkinson's disease, the combination of disease progression and l-dopa therapy leads to the development of motor response complications, particularly wearing off, on off, dyskinesias and dystonias. The nonphysiologic pulsatile stimulation of striatal dopamine receptors, produced by the currently available dopaminergic drugs, may trigger a dysregulation of many neurotransmitter systems within the basal ganglia, mainly localized on medium spiny striatal neurons. These include alterations of glutamatergic, serotonergic, adrenergic and adenosine A(2A) receptors. Novel strategies for pharmacological intervention with nondopaminergic treatments hold the promise of providing effective control or reversal of motor response complications. Of particular interest are NMDA and AMPA antagonists or drugs acting on 5-HT subtype 2A, alpha2-adrenergic, and adenosine A(2) receptors. Future strategies may also target pre- and postsynaptic components that regulate firing pattern of basal ganglia neurons, such as synaptic vesicle proteins, nonsynaptic gap junction communication mechanisms, or signal transduction systems that modulate the phosphorylation state of glutamatergic receptors.

PMID: 17030738 [PubMed - in process]

Hi, there is an FDA drug being used by many people with MS but a few with PD, myself included. It is low dose naltrexone, LDN, I have been taking it now for 28 months along with low doses of Sinemet and Mirapex. I was able to cut back on my Sinemet by 2/3rds to 1x 25/100. My problem was tremor. It's gone for now, I don't think I've progressed. LDN is supposed to stop the progression of many diseases. There are research papers that seem to support the claims made by the developer of LDN, Dr. Bernard Bihari.
http://www.lowdosenaltrexone.org/index.htm
Ashley

From a NIH paper, naloxone and naltrexone are similar.
"The purpose of this study was to identify two neuroprotective compounds with a similar bimodal dose response, to discern whether the neuroprotective characteristics of each compound could converge into a single mechanism, and through this process, to elucidate a common femtomolar site of action.

Parkinson’s disease (PD) is characterized by the specific and progressive death of dopaminergic neurons in the substantia nigra (SN); other neuronal cell types are much less affected. Recent reports have linked inflammation to neurodegenerative disease, where microglia, cells of myeloid lineage responsible for innate immunity in the brain, are considered to be the major cell type underlying the inflammation-mediated neurotoxicity (7 8 9) . The activation of microglia is a complex process involving the release of several soluble proinflammatory factors [tumor necrosis factor {alpha} (TNF-{alpha}), PGE2, IL-1] and free radicals (nitric oxide, superoxide) (7) . Current replacement therapy with L-dopa is able to alleviate disease symptoms, but is unable to alter the disease course. Thus, therapeutic interventions designed to inhibit the microglial inflammatory response offer hope for attenuation of the neurodegenerative disease process. The current anti-inflammatory treatments available, including steroids and nonsteroidal anti-inflammatory drugs, are limited by the ability to influence only a small portion of the microglial response (10) . Thus, identification of compounds acting on novel targets to inhibit the release of a wide range of proinflammatory factors from overactivated microglia is of paramount importance. In the ensuing study, we report that femtomolar concentrations of naloxone and the peptide fragment glycine-glycine-phenylalanine (GGF) attenuate a broad spectrum of the microglia inflammatory response (reactive oxygen species (ROS) and proinflammatory factors) and are neuroprotective with extremely potent efficacy through the inhibition of microglial NADPH oxidase."

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

Thank you for posting this and what i am about to say is in no way a comment on that (or maybe you posted it for the reasons below - not sure what your intro line refers to) - my beef is with the status quo in industry and research in general. Also, this is pretty much off the cuff so might be a little less clear and organized than it could be.

I love the way motor complications are presented as if they just popped up a few months or even years ago - as opposed to the reality, which is that they have been glaringly evident since before levodopa went on the market in 1970, and this "effort" to fix them has been underway for just as long, i.e., some 36 years. and if you have ever just poked around on Pubmed, you will know that articles like this pop up regularly - and most of what they present is nothing new - but it is presented, like motor complications, as if it is breaking news.

Also, neuroprotective would be great, but do you see how it is presented only as a means to *delay* the need for pharmaceuticals? Why not *preclude* the need for pharmaceuticals? and why is it that we feel the *need* to delay the use? because the current set up doesn't work, that's why, and they know it, but it is the most lucrative for industry, having this base product that is in such need of bandaids that there is infinite capacity for growth in the selling of old and inventing of new bandaids.

I don't know if folks are aware of how entrenched the current set up is, in which several big pharmaceutical companies that make/market levodopa products also make the adjuncts that are supposed to fix the problems levodopa causes. Take Novartis, for example. Novartis markets Stalevo, levodopa/carbidopa/entacapone, which is manufactured by Orion, which has made entacapone, a COMT-inhibitor, since 1999.

Novartis owns 33% of Roche, which introduced the first two levodopa products ever back in the early 70's, one of which it definitely still makes - Roche Pharma funded and undertook a study in 1999 that found that their levodopa productt was even better with a COMT-inhibitor.

Novartis also makes bromocriptine.

Novartis' generic arm, Sandoz, makes, at the least, carbidopa/levodopa, amantadine (good for dyskinesias), amytriptyline (which i believe has an anti-cholinergic effect), and bromocriptine.

If you look at the product labeling for Stalevo, you will see that there is a 75% higher incidence of dyskinesias with levodopa/carbidopa/entacapone (they didn't actually test the single pill (containing all three drugs) form) - amantadine often helps alleviate dyskinesias.

Novartis appears to have sponsored the most recent Levodopa Consensus Conference (it issued the press release, at least), which took place either in Paris or a small, exclusive ski village in Switzerland (there have been two of these conferences - i can't remember which was where) and, surprise surprise, 30 of the top experts in the field agreed (unlike at the first levodopa consensus conference) that no one has proved the levodopa is toxic in vivo (its toxicity to dopaminergice neurons in vitro is not even debated), as if dyskinesias weren't proof enough, and that it remains "the gold standard."

Novartis has also paid for numerous Continuing Medical Education courses with titles like "The Future of Levodopa Therapy for Parkinson's Disease," that concludes with a plug for Stalevo ("The concurrent use of levodopa/carbidopa plus entacapone is now facilitated by the availability of a levodopa/carbidopa/entacapone combination product") including recommended dosages.

The above article does not require disclosures, but if you search around a little, you will find info like this about Robert A. Hauser, MD, one of the authors of the above course:

"Robert A. Hauser, MD, MBA, has disclosed that he has served as an investigator and on the advisory boards and speakers bureaus for Roche Laboratories, GlaxoSmithKline, Athena Neurosciences, Pfizer/Pharmacia, Medtronic, Novartis, Teva Pharmaceuticals, and Somerset Pharmaceuticals. He has also served as a consultant for Roche Laboratories, Somerset Pharmaceuticals, Merck (Germany), and Kyowa. He has also served on the Advisory Board of Watson Laboratories and as an investigator for Kyowa. Dr. Hauser has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity."

Roche, Novartis, Merck, Teva (or its generic arm, Ivax - could be both) and perhaps Somerset and Watson (don't have my notes with me) all make levodopa products, as does Novartis' generic arm. Kyowa is currently conducting clinical trials on a compound testing to see how well it manages motor complications. Medtronic, of course, is DBS, the *ultimate* "fix" for motor complications.

it is abundantly clear to me that industry has *zero* incentive to shake up the status quo by inventing a symptomtatic therapy that actually *works,* and the reference above to motor complications "having emerged" is, in my opinion, far from accidental - industry and researchers on its payroll intentionally perpetuate the impression that a) the problems have only recently made themselves known, and b) there are myriad "new" possibilities on the horizon - the problems are *not* new, most of the possibilities are not new, and levodopa is *still* broken, and that is the most lucrative set up for industry - always room for another adjunct, just don't threaten the foundation, levodopa, with a drug that actually works, cuz if you do, there goes your infinite capacity for growth in the adjunct realm.

at some point soon, i will be finishing an article on this subject.

Hi Boann, I have begun to think that the big drug companies only want to research or trial new drugs that will have a big payoff. Maybe years from now there will be an actual "cure" for PD. But meanwhile, those of us who have PD continue to progress, some faster then others. Because I was told I had MS four years ago, I searched the net for MS treatments. I came across The LDN website where most of the users of low dose naltrexone have MS. Many claim it works better than the very powerful and expensive MS drugs they had been taking. I got an Rx for LDN 28 months ago and noticed some improvements in my balance. They changed my Dx to PD four months later and I began Sinemet which fixed my tremor. I have reduced my Sinemet by 2/3rds, maybe because 3 a day was more than I needed but I don't see my self getting worse. I hope taking LDN is keeping me from progressing.
The research papers I posted previously show to me that, independant of the anecdotal LDN claims, there is scientific reason to believe that there are now FDA approved drugs like naltrexone and dextromethorphan (cough syrrup) that could stop progression of PD. They exist now, are very cheap and so the drug companies can't make any money on them since they would have to show in expensive trials that they work for PD and then would not be able to claim them as their own invention.
My hope is that LDN will keep PD at bay indefinately and I won't need any miracle drug besides 1x Sinemet. Time will tell.
There was someone from the other site who said he was taking another opioid receptor antagonist, dextromethorphan (cough syrrup), instead of LDN and was doing ok. Would like to here from him.

http://www.ncbi.nlm.nih.gov/entrez/q...&dopt=Abstract

Regards, Ashley

dear boann,
this is an excellent sumation!!
BRAVO!!