Tuesday, March 24, 2015

parkinson's and drugs

You should take about 10 mg carbidopa with 12 tablets Mucuna Pruriens to prevent L-dopa from being metabolized in the periphery of the body, decreasing amount of Mucuna that is needed. See forum https://healthunlocked.com/parkinsonsmovement/posts/131620015/mucuna-purens-as-a-source-of-dopamine Carbidopa can also increase serotonin that comes from 5-HTP (wiki).

L-deprenyl (Selegiline) metabolizes to an amphetamine and is not otherwise sympathomimetic like drugs but not like green tea (sympathomimetic are drugs that look like neurotransmitters as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine, etc.

Rasagiline aka AGN1135 aka Azilect is preferred because it is not sympathomimetic and because of the lower dose is much less likely to cause a "cheese" reaction (conflict with tyramine in diet).  It is not their MOA-B inhibitory mechanism that prevents progression of the disease, but their "propargyl moiety". The S-optical isomer of rasagiline, TVP1022 and propargylamine are poor MOA inhibitors and yet have the same neuroprotection that results from "interaction of Bcl-2 family protein with PKC-dependent MAPkinase pathway."

Rasagiline side effects: nausea, vomiting, orthostatic hypotension, somnolence, hallucinations and dyskinesias are tolerable in most cases. Vomiting was noteable at 1 mg/day. "Do not take AZILECT® (rasagiline tablets) if you are taking meperidine as it could result in a serious reaction such as coma or death. Also, do not take AZILECT with tramadol, methadone, propoxyphene, dextromethorphan, St. John’s wort, or cyclobenzaprine. "

TV3326  (MAO-AB) is in phase 2 for AD and PD and antidepressant. It is an offshoot of rasagiline's S-isomer and carbamate cholinesterase inhibitor moiety to try to treat AD patients that also have PD and depression.

VK-28 is an BBB iron chelators. 

M-30 is a propargylamine (a rasagiline site) but is MAO-AB instead of rasagiline's selective irreversible (disables the protein) MAO-B inhibitors.  It is an iron-chelator. HLA-20 is in same class and also newest on the horizen. M-30 restores levels of the antiapoptotic protein Bcl-2 in mice (lactacystin  model) and iron-dependent hydroxyl radical generation. Both M30 and parent molecule VK28 showed behavioral improvements in mice (including MPTP model) ...  "M10 is another hydroxyquinoline derivative with radical scavenging and iron-chelating properties. It is a potent hydroxide scavenger and has been shown to be as effective as rasagiline in PC10 cell culture and inhibits lipid peroxidation with an IC50 value comparable to desferal "

"We determined that M-30 has a wide range of pharmacological activities, including prosurvival neurorescue effects reducing proapoptotic Bcl-2 family proteins, regulation of APP and A levels, and induction of neuronal differentiation. M-30 induced the outgrowth of neuritis, triggered cell cycle arrest in G0/G1 phase, and enhanced the expression of growth-associated protein 43 (GAP-43). This drug may improve the prognosis of PD and AD patients and exert disease-modifying effects by either delaying or preventing further neuronal loss by endogenously regulating NTFs, as suggested recently in clinical trials of early PD patients with rasagiline. "


ladostigil (TV-3, 326) acts as a reversible acetylcholinesterase and butyrylcholinesterase inhibitor, and an irreversible monoamine oxidase B inhibitor, and combines the mechanisms of action of older drugs like rivastigmine and rasagiline into a single molecule. In addition to its neuroprotective properties, ladostigil enhances the expression of neurotrophic factors like GDNF and BDNF, and may be capable of reversing some of the damage seen in neurodegenerative diseases via the induction of neurogenesis. Ladostigil also has antidepressant effects, and may be useful for treating comorbid depression and anxiety often seen in such diseases as well.  

PD drugs overview:

Overall sales for Parkinson’s disease drugs in seven major countries will decline slightly from US$2.7 billion in 2010 to US$2.6 billion in 2020 in France, Germany, Italy, Japan, Spain, the UK and US, according to a new report from research and advisory firm Decision Resources. The decline is attributed to key therapies losing patent protection and subsequent generics competition.

The key Parkinson’s disease therapies reported to lose patent protection by 2020 are Novartis/Orion Pharma’s Comtan/Comtess/Stalevo (carbidopa/levodopa/entacapone) and Teva/Lundbeck’s Azilect/Agilect (rasagiline).

The report also expects GlaxoSmithKline’s Requip (ropinirole) and Boehringer Ingelheim’s Mirapex/Mirapexin/Sifrol/BI-Sifrol (pramipexole) to face increasing generics competition
Sales in France, Germany, Italy, Japan, Spain, the UK and US will continue to be driven by the leading dopamine agonists, pramipexole and ropinirole, and by increasing use of the monoamine oxidase B (MAO-B) inhibitor Azilect/Agilect (rasagiline), as well as by the re-entry of UCB/Schwarz Pharma's Neupro/Leganto (rotigotine) to the US market and its wider use in Europe.
The report forecasts that despite some key current therapies experiencing increased uptake and the launch of three new agents by 2020, sales of current products and the market impact of emerging therapies will be offset by generic competition.
The three new therapies set to launch by 2020 are Impax Laboratories/GSK’s IPX-066, a reformulation of levodopa, the mainstay of Parkinson’s disease therapy, Merck Serono/Newron Pharmaceuticals’ MAO-B inhibitor safinamide and Kyowa Hakko Kirin’s adenosine A2A receptor inhibitor antagonist istradefylline.
IPX-066, and to a lesser extent safinamide, are expected to contribute moderately to market growth. Both drugs are expected to contend with established agents within the same respective drug classes (where generic alternatives exist) and which are commonly used in the patient populations targeted by the emerging therapies.
While the first-in-class agent istradefylline will benefit from use in the management of motor response complications arising from levodopa treatment, its overall impact will be modest as it is currently expected to launch only in Japan.
The report does not expect major changes in the treatment of Parkinson’s disease over the next 10 years, and generics growth of key Parkinson’s disease therapies is expected to ‘depress market growth’ by 2020. Decision Resources analyst Ms Nadja Rodovsky comments that ‘future therapies will need to clearly demonstrate superiority over current therapies to gain a competitive edge in this mature market’.


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