The stuff I do is really long. Determining if any of them really helps is really difficult. The strange stuff I've ordered from China so far is fisetin, apigenin, naringin, nobiletin, tangeretin, and hesperidin. I'm looking into a lot of others. I see good results for the others I've mentioned in a recent and a 9/15/2015 post about a-Syn, but I have not made confirmation of bioavailability and ordered them.
The non-food strange things I do are hanging upside down sometime with gravity boots (to increase head pressure to reduce inflammation that I suspect in my case), wearing a 250 watt infrared LED helmet I made that may help in some cases of dementia (not that I have that, I just do it for cortex health), and laying naked under 1000 watts of halogen work lights with side reflectors to simulate the beach without UV. The simulated beach seems to be greatly improving my mood, even if it not why my tremors recently reduced.
In terms of nutritional supplements in my stock, I have about 100. The following is my daily goal.
1 mg rasagiline
Vitamins D, E, A, B-complex, K. (2000 IU, 800 IU, 25,000 IU, B-100, 1 K pill)
Calcium, magnesium, zinc, MSM. (1000 mg, 400 mg, 60 mg, 4 g)
Fish oil, olive oil, canola oil. (3 g, 30 grams, double the recommendations)
Extracts: green tea, black tea, grape seed, ginseng. (2 pills each, 3x/day)
citrus: naringin, nobiletin, tangeretin, and hesperidin (1 g each 2x/day)
fisetin
apigenin
melatonin (13 mg at bedtime)
5-HTP (currently about to restart, 200 mg 2x/day)
6+ cups of coffee
8 mg nicotine in gum (like 4 cigarettes)
200 mg aspirin
1/2 beer 2x/day
Food for PD in men: strawberries, apples, blueberries.
For me seems to help: broccoli, kale, spinach, peas.
I am less consistent with the following: ALC, ALA, NAC, citicholine.
1.5 hour exercise with heart rate > 120 BPM.
No chocolate, milk, or stressful video games.
LED helmet and halogen light bed.
Lecithin
Everything I've listed has good evidence in animals models of PD or human epidemiological evidence, except for maybe calcium, vitamin K, MSM and a couple others. They might have support directly, but I have not researched them for PD.
Melatonin seems to have helped a lot in terms of my mood, and maybe 5-HTP too, if not reduced my tremors.
I have minor tremor in left thumb. It was starting in the other fingers and other hand before I recently increased my efforts in the above. My mood recently improved along with the reduced tremor. It could have been more exercise the preceding month, going from 30 min/day to 1.5 hour/day, the halogen bed or LED helmet, 5-HTP, melatonin, alcohol, the citrus stuff, vitamin E, fisetin, rasagiline more consistently, or MSM. These were the new things in the preceding month. Maybe there was more zinc, vit A, vit D, and magnesium.
Saturday, November 14, 2015
Friday, November 13, 2015
parkinson's: GM1 Ganglioside a cure?
Again and again, I accidentally come across some compound that seems to have profound effects for PD, and yet there is no one getting paid to tell us about it, so we never hear about unless it is through each other.
For example, here's a phase 2 trial completed 4 YEARS AGO for a compound shown in the 1980's to help PD and it shows patients having a REVERSAL of symptoms for as long as they got the 2/day injections. The patients were forced to stop taking it and began showing normal progression of PD in the 2 years since. It seems to be very expensive as it needs to be derived from animals, but it might be much cheaper if there was a larger need for it.
JS Schneider has been publishing on GM1 for decades
http://www.ncbi.nlm.nih.gov/pubmed/26099170 (2015, 40 patients)
the clinical trial:
https://clinicaltrials.gov/ct2/show/NCT00037830 (subcutaneous injection, 100 mg, 2 doses per day)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/ (2012, 77 patients)
http://www.ncbi.nlm.nih.gov/pubmed/20206941 (2010, 16 patients, end of 5 year study)
http://www.ncbi.nlm.nih.gov/pubmed/9633704 (1998, 45 patients)
http://www.ncbi.nlm.nih.gov/pubmed/7783880 (1995 worked in 10 patients)
http://www.ncbi.nlm.nih.gov/pubmed/1613817 (1992 in cats)
http://www.ncbi.nlm.nih.gov/pubmed/1350379 (1992, primates)
http://www.ncbi.nlm.nih.gov/pubmed/2568945 (1989 mice)
http://www.ncbi.nlm.nih.gov/pubmed/6141701 (1983, different researcher, rats)
making body generate GM1, worked a little, using sialidase from bacteria
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668049/
The link below is the first of 5 research papers in the 1980's showing its benefit for PD in animals. There are literally 100 natural compounds that have shown the same results in animals, although many of them will probably not reach the human brain, including the most powerful.
http://www.ncbi.nlm.nih.gov/pubmed/6141701
Three years ago GM1 was discussed on this web site:
https://healthunlocked.com/parkinsonsmovement/posts/631068/another-promising-find-again
And an interesting comment from one poster (3 years ago)
"In the last five years I have seen dozens of these studies. I never see where they actually go into treatment. I am receiving the same treatment I would have gotten twenty years ago. Seems odd."
Moreover, this natural compound may be the underlying reason nilotinib works. The tyrosine kinase inhibitors like nilotinib induce GM1 (see 2006 article http://www.jimmunol.org/content/176/2/864.long ). So it begs the question: exactly why are the researchers interested in leukemia's tyrosine kinase inhibitors in the first place? Did they or Novartis see the work on GM1 and say, hmmm, is there a pharmaceutical that can do this?
There are 61 papers with GM1 Ganglioside and Parkinson's in the abstract. Here's one of them:
"The nigral neurons of PD subjects that were severely deficient in GM1 showed subnormal levels of tyrosine phosphorylated RET. Also in PD brain, GM1 levels in the occipital cortex, a region of limited PD pathology, were significantly below age-matched controls, suggesting the possibility of systemic GM1 deficiency as a risk factor in PD. This would accord with our finding that mice with partial GM1 deficiency represent a faithful recapitulation of the human disease. Together with the previously demonstrated age-related decline of GM1 in human brain, this points to gradual development of subthreshold levels of GM1 in the brain of PD subjects below that required for effective GDNF signaling. This hypothesis offers a dramatically different explanation for the etiology of sporadic PD as a manifestation of acquired resistance to GDNF. "
http://www.ncbi.nlm.nih.gov/pubmed/25448159
There is a company trying to make this compounds available to people with PD and it seems like it already has FDA approval as an orphan drug, so it could be used off-label for Parkinson's.
http://www.glycoscienceresearch.com/2015/01/24/fda-pind-pre-investigatve-new-drug-application/
"The actual approval status is that the US FDA on December 3, 2012, designated GM-1 as an orphan drug in acute SCI treatment, and GM-1 is now in the US FDA IDE NDA (New Drug Application) and approval process."
"The authors of the letter go on to mention the renewed activity around GM-1 at the Federal Drug Administration (FDA). We were particularly encouraged and interested to hear about this, but upon searching the FDA site, we found only that the orphan drug designation had been given, but that, unfortunately, it was not approved for use in acute spinal cord injury (Figure 1).
"We then noted that the Sponsor for the application at the FDA was TRB Chemedica International S.A. and we wondered whether, if we wanted to use the drug “off-label” for acute spinal cord injury (as Geisler and Coleman are apparently suggesting), it would be available to us. In searching the site of this company that manufactures and sells drugs related to ophthalmology and joint diseases for any mention of GM-1, we found that it was listed in a history of the company back in the 1990s as a potential treatment for Parkinson’s Disease (Figure 2). Direct inquiries to the company on its availability yielded no response.
"It then appears that this renewed activity around the “actual approval status” does not afford the practitioner access to the drug, even if he/she wanted to use it off-label."
Currently only 2 grams per brain and 1 gram per day is needed:
Ovine GM1 ganglioside is currently produced from brain tissue supplied by GRI to Avanti Polar Lipids in Alabaster, Alabama. Ovine GM1 ganglioside is currently produced for research use only. Levels of GM1 ganglioside from brain are approximately 1.5 – 2.0 grams per brain. Levels in spinal cord and other tissues such as salivary gland, adrenal gland, liver, kidney spleen, intestinal mucosa and many others are significantly elevated and maximum yield per lambs is expected to approach 4 to 5 grams based on preliminary data.
http://www.glycoscienceresearch.com/exec-summary/
As a reminder, a "cure" for Parkinson's was discovered 20 years ago, with a safety study almost the same as this one:
http://www.ncbi.nlm.nih.gov/pubmed/7783880
It was known even in the 1980's but mad cow disease eliminated the cow-brain source of GM1.
This researcher JS Schneider keeps doing clinical trials (he has 235 papers, most on PD, about 27 on GM1), and the results are always the same: patients were better than at the start of the study for as long as they took it:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/
He first looked into it in 1989 in mice
http://www.jimmunol.org/content/176/2/864.long
The first research on this for PD was in rats in 1983....32 years ago!
http://www.ncbi.nlm.nih.gov/pubmed/6141701
The only reason GM1 is not available to us now is because it requires investment in flocks of sheep, so the pharmaceuticals were not interested. It will remain a problem because with genetically modified sheep, then can still only get 1 or 2 g per brain, and 0.2 gram is the daily dose used in the trials, 1 sheep brain per 10 days. There is a PhD vetenarian and his M.S. degreed wife who are licensing the raising of the genetically modified sheep, now over 4000 ewes:
http://www.glycoscienceresearch.com/about/
And here's the punch line: nilotinib may be working the same as GM1. Nilotinib's cousin imatinib "upregulates" GM1, so if GM1 is not available in enough quantity from the sheep, it can be combined with nilotinib to amplify it: "Inhibition of Bcr/Abl tyrosine kinase activity by imatinib induces a high surface expression of GM1"
http://www.jimmunol.org/content/176/2/864.long
For example, here's a phase 2 trial completed 4 YEARS AGO for a compound shown in the 1980's to help PD and it shows patients having a REVERSAL of symptoms for as long as they got the 2/day injections. The patients were forced to stop taking it and began showing normal progression of PD in the 2 years since. It seems to be very expensive as it needs to be derived from animals, but it might be much cheaper if there was a larger need for it.
JS Schneider has been publishing on GM1 for decades
http://www.ncbi.nlm.nih.gov/pubmed/26099170 (2015, 40 patients)
the clinical trial:
https://clinicaltrials.gov/ct2/show/NCT00037830 (subcutaneous injection, 100 mg, 2 doses per day)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/ (2012, 77 patients)
http://www.ncbi.nlm.nih.gov/pubmed/20206941 (2010, 16 patients, end of 5 year study)
http://www.ncbi.nlm.nih.gov/pubmed/9633704 (1998, 45 patients)
http://www.ncbi.nlm.nih.gov/pubmed/7783880 (1995 worked in 10 patients)
http://www.ncbi.nlm.nih.gov/pubmed/1613817 (1992 in cats)
http://www.ncbi.nlm.nih.gov/pubmed/1350379 (1992, primates)
http://www.ncbi.nlm.nih.gov/pubmed/2568945 (1989 mice)
http://www.ncbi.nlm.nih.gov/pubmed/6141701 (1983, different researcher, rats)
making body generate GM1, worked a little, using sialidase from bacteria
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668049/
The link below is the first of 5 research papers in the 1980's showing its benefit for PD in animals. There are literally 100 natural compounds that have shown the same results in animals, although many of them will probably not reach the human brain, including the most powerful.
http://www.ncbi.nlm.nih.gov/pubmed/6141701
Three years ago GM1 was discussed on this web site:
https://healthunlocked.com/parkinsonsmovement/posts/631068/another-promising-find-again
And an interesting comment from one poster (3 years ago)
"In the last five years I have seen dozens of these studies. I never see where they actually go into treatment. I am receiving the same treatment I would have gotten twenty years ago. Seems odd."
Moreover, this natural compound may be the underlying reason nilotinib works. The tyrosine kinase inhibitors like nilotinib induce GM1 (see 2006 article http://www.jimmunol.org/content/176/2/864.long ). So it begs the question: exactly why are the researchers interested in leukemia's tyrosine kinase inhibitors in the first place? Did they or Novartis see the work on GM1 and say, hmmm, is there a pharmaceutical that can do this?
There are 61 papers with GM1 Ganglioside and Parkinson's in the abstract. Here's one of them:
"The nigral neurons of PD subjects that were severely deficient in GM1 showed subnormal levels of tyrosine phosphorylated RET. Also in PD brain, GM1 levels in the occipital cortex, a region of limited PD pathology, were significantly below age-matched controls, suggesting the possibility of systemic GM1 deficiency as a risk factor in PD. This would accord with our finding that mice with partial GM1 deficiency represent a faithful recapitulation of the human disease. Together with the previously demonstrated age-related decline of GM1 in human brain, this points to gradual development of subthreshold levels of GM1 in the brain of PD subjects below that required for effective GDNF signaling. This hypothesis offers a dramatically different explanation for the etiology of sporadic PD as a manifestation of acquired resistance to GDNF. "
http://www.ncbi.nlm.nih.gov/pubmed/25448159
There is a company trying to make this compounds available to people with PD and it seems like it already has FDA approval as an orphan drug, so it could be used off-label for Parkinson's.
http://www.glycoscienceresearch.com/2015/01/24/fda-pind-pre-investigatve-new-drug-application/
"The actual approval status is that the US FDA on December 3, 2012, designated GM-1 as an orphan drug in acute SCI treatment, and GM-1 is now in the US FDA IDE NDA (New Drug Application) and approval process."
"The authors of the letter go on to mention the renewed activity around GM-1 at the Federal Drug Administration (FDA). We were particularly encouraged and interested to hear about this, but upon searching the FDA site, we found only that the orphan drug designation had been given, but that, unfortunately, it was not approved for use in acute spinal cord injury (Figure 1).
"We then noted that the Sponsor for the application at the FDA was TRB Chemedica International S.A. and we wondered whether, if we wanted to use the drug “off-label” for acute spinal cord injury (as Geisler and Coleman are apparently suggesting), it would be available to us. In searching the site of this company that manufactures and sells drugs related to ophthalmology and joint diseases for any mention of GM-1, we found that it was listed in a history of the company back in the 1990s as a potential treatment for Parkinson’s Disease (Figure 2). Direct inquiries to the company on its availability yielded no response.
"It then appears that this renewed activity around the “actual approval status” does not afford the practitioner access to the drug, even if he/she wanted to use it off-label."
Currently only 2 grams per brain and 1 gram per day is needed:
Ovine GM1 ganglioside is currently produced from brain tissue supplied by GRI to Avanti Polar Lipids in Alabaster, Alabama. Ovine GM1 ganglioside is currently produced for research use only. Levels of GM1 ganglioside from brain are approximately 1.5 – 2.0 grams per brain. Levels in spinal cord and other tissues such as salivary gland, adrenal gland, liver, kidney spleen, intestinal mucosa and many others are significantly elevated and maximum yield per lambs is expected to approach 4 to 5 grams based on preliminary data.
http://www.glycoscienceresearch.com/exec-summary/
As a reminder, a "cure" for Parkinson's was discovered 20 years ago, with a safety study almost the same as this one:
http://www.ncbi.nlm.nih.gov/pubmed/7783880
It was known even in the 1980's but mad cow disease eliminated the cow-brain source of GM1.
This researcher JS Schneider keeps doing clinical trials (he has 235 papers, most on PD, about 27 on GM1), and the results are always the same: patients were better than at the start of the study for as long as they took it:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532888/
He first looked into it in 1989 in mice
http://www.jimmunol.org/content/176/2/864.long
The first research on this for PD was in rats in 1983....32 years ago!
http://www.ncbi.nlm.nih.gov/pubmed/6141701
The only reason GM1 is not available to us now is because it requires investment in flocks of sheep, so the pharmaceuticals were not interested. It will remain a problem because with genetically modified sheep, then can still only get 1 or 2 g per brain, and 0.2 gram is the daily dose used in the trials, 1 sheep brain per 10 days. There is a PhD vetenarian and his M.S. degreed wife who are licensing the raising of the genetically modified sheep, now over 4000 ewes:
http://www.glycoscienceresearch.com/about/
And here's the punch line: nilotinib may be working the same as GM1. Nilotinib's cousin imatinib "upregulates" GM1, so if GM1 is not available in enough quantity from the sheep, it can be combined with nilotinib to amplify it: "Inhibition of Bcr/Abl tyrosine kinase activity by imatinib induces a high surface expression of GM1"
http://www.jimmunol.org/content/176/2/864.long
Monday, November 9, 2015
parkinson's: baicalein bioavailability, not good
The following does not address "oxidized" baicalein which was the most potent at dis-aggregating a-Syn. I do not know if the oxidized form (a quinone) is "bioavailable" to the brain.
My summary: very effective as B against a-Syn and easily crosses BBB, but it seems to be absorbed only 15% and is immediately converted to BG for transport to the liver. No info on BG effect on a-Syn. Definitely a possibility if BG works on a-Syn, but it is double the m.w. of B.
Baicalin (m.w. 446) (aka BG aka baicalein 7-O-glucuronide) is the primary metabolite of Baicalein (m.w. 270), but there is no research on its health effects. But it appears to be absorbed less than Baicalein.
Baicalein was shown in 2004 to have an incredible ability to revert a-Syn aggregations, especially in its oxidized form.
http://www.ncbi.nlm.nih.gov/pubmed/15096521
peperine, curcumin, and (-)-epicatechin (a catechin isomer) increase bioavailability (absorption) and P and C prevent glucuronation of baicalein. Catechins are in teas, grapes, apples, lentils, and black-eyed peas
http://www.ncbi.nlm.nih.gov/pubmed/21906668
easily penetrated blood brain barrier in rats, especially if it was not allowed to undergo metabolism by P-glycoprotein which was inhibited by cyclosporin A (an immunosuppressant for transplants) which doubled concentration in brain. Without cycloA, 60 mg/kg injected resulted in 1.5 ng/ml (5 nM) at 30 min and about half as much at 60 minutes (rapid elimination) and half as much if 30 mg/kg. Was 3 times higher in blood verses brain tissue.
http://www.ncbi.nlm.nih.gov/pubmed/12466241
Monkeys given 50 to 500 mg/kg got 13 to 26% of it into blood. ('bioavailable" means percent of oral compared to I.V.)
http://www.ncbi.nlm.nih.gov/pubmed/22245084
"glycosylation (not glucuronation) increased the bioavailability of baicalein by helping to protect this vital molecule from chemical or enzymatic oxidation." [keep in mind the oxidized form is more effective]
http://www.ncbi.nlm.nih.gov/pubmed/25446915
traditional concoction with "x grams of baicalein" had same bioavailability as concentrated powder of "x grams", FULL TEXT
http://www.ncbi.nlm.nih.gov/pubmed/23258986
Sulfation and P450 mediated hydroxylation of B were much less significant than glucuronidation (UDP-glucuronosyltranferase (UGT) in the extensive liver and intestinal first-pass glucuronidation )Three metabolites of B namely baicalein 7-O-glucuronide (BG) [the main one], the isomer of baicalein 7-O-glucuronide (BG'), and baicalein sulfate were found.
http://www.ncbi.nlm.nih.gov/pubmed/17109214
soya lecithin best for nanoparticle delivery for myricetin, 3x higher
http://www.ncbi.nlm.nih.gov/pubmed/25445518
LCN increases B 4x in mice
http://www.ncbi.nlm.nih.gov/pubmed/24028326
doubling the dose from 2.5 to 5 mg/kg (injection) saturared rat ability to make conjugated forms, resulting in 8 uM after 3 minutes instead of 1.5 uM. Initial concentration was about 70 uM, so pure form drops RAPIDLY. See figure 4. The conjugated forms go just as quickly to the bile. 10 uM appears by my calculation to be 10% of dose assuming 270 m.w., 500 g rats with 50 ml blood.
http://www.ncbi.nlm.nih.gov/pubmed/21607811/
baicalein may block some CYP3A liver enzymes (like peperine)
=================
Good overall view, seems to exaggerate lack of bioavailability (most of his references are cited above):
My summary: very effective as B against a-Syn and easily crosses BBB, but it seems to be absorbed only 15% and is immediately converted to BG for transport to the liver. No info on BG effect on a-Syn. Definitely a possibility if BG works on a-Syn, but it is double the m.w. of B.
Baicalin (m.w. 446) (aka BG aka baicalein 7-O-glucuronide) is the primary metabolite of Baicalein (m.w. 270), but there is no research on its health effects. But it appears to be absorbed less than Baicalein.
Baicalein was shown in 2004 to have an incredible ability to revert a-Syn aggregations, especially in its oxidized form.
http://www.ncbi.nlm.nih.gov/pubmed/15096521
peperine, curcumin, and (-)-epicatechin (a catechin isomer) increase bioavailability (absorption) and P and C prevent glucuronation of baicalein. Catechins are in teas, grapes, apples, lentils, and black-eyed peas
http://www.ncbi.nlm.nih.gov/pubmed/21906668
easily penetrated blood brain barrier in rats, especially if it was not allowed to undergo metabolism by P-glycoprotein which was inhibited by cyclosporin A (an immunosuppressant for transplants) which doubled concentration in brain. Without cycloA, 60 mg/kg injected resulted in 1.5 ng/ml (5 nM) at 30 min and about half as much at 60 minutes (rapid elimination) and half as much if 30 mg/kg. Was 3 times higher in blood verses brain tissue.
http://www.ncbi.nlm.nih.gov/pubmed/12466241
Monkeys given 50 to 500 mg/kg got 13 to 26% of it into blood. ('bioavailable" means percent of oral compared to I.V.)
http://www.ncbi.nlm.nih.gov/pubmed/22245084
"glycosylation (not glucuronation) increased the bioavailability of baicalein by helping to protect this vital molecule from chemical or enzymatic oxidation." [keep in mind the oxidized form is more effective]
http://www.ncbi.nlm.nih.gov/pubmed/25446915
traditional concoction with "x grams of baicalein" had same bioavailability as concentrated powder of "x grams", FULL TEXT
http://www.ncbi.nlm.nih.gov/pubmed/23258986
Sulfation and P450 mediated hydroxylation of B were much less significant than glucuronidation (UDP-glucuronosyltranferase (UGT) in the extensive liver and intestinal first-pass glucuronidation )Three metabolites of B namely baicalein 7-O-glucuronide (BG) [the main one], the isomer of baicalein 7-O-glucuronide (BG'), and baicalein sulfate were found.
http://www.ncbi.nlm.nih.gov/pubmed/17109214
soya lecithin best for nanoparticle delivery for myricetin, 3x higher
http://www.ncbi.nlm.nih.gov/pubmed/25445518
LCN increases B 4x in mice
http://www.ncbi.nlm.nih.gov/pubmed/24028326
doubling the dose from 2.5 to 5 mg/kg (injection) saturared rat ability to make conjugated forms, resulting in 8 uM after 3 minutes instead of 1.5 uM. Initial concentration was about 70 uM, so pure form drops RAPIDLY. See figure 4. The conjugated forms go just as quickly to the bile. 10 uM appears by my calculation to be 10% of dose assuming 270 m.w., 500 g rats with 50 ml blood.
http://www.ncbi.nlm.nih.gov/pubmed/21607811/
baicalein may block some CYP3A liver enzymes (like peperine)
=================
Good overall view, seems to exaggerate lack of bioavailability (most of his references are cited above):
Baicalin belongs to Class IV of Biopharmaceutical Classification System (BCS) due to the extremely low hydrophilicity (solubility 0.052 mg/mL in water) and lipophilicity (Papp = 0.037×10−6 cm/s) [18]. Baicalein is highly permeable (Papp = 1.7×10−5 cm/s) but poorly water soluble, which is classified as a Class II compound according to BCS [19,20]. The poor solubility results in both baicalin and baicalein very low bioavailability [21]. Extensive studies have been conducted to explore the in vivo processes of these two drugs. The serum profiles and pharmacokinetics of orally administered baicalein and baicalin were compared. Baicalin was absorbed more slowly and had lower Cmax than baicalein [22]. There exists wide complicated biotransformation of baicalin and baicalein in vivo (Figure 2). As a natural glycoside, baicalin possesses more favorable aqueous solubility than baicalein. However, baicalin is difficult to be absorbed as its parent form due to the poor lipophilicity. When baicalin was orally administered, only a small portion was absorbed as its original form by the body, and most was hydrolyzed to baicalein by intestinal bacterial [23]. The recovered baicalein was then extensively subjected to Phase 2 metabolism, and glucuronides and/or sulfates of baicalein were exclusively presented in the plasma. Notably, the circulating baicalin is not the administered parent drug but one of the conjugated metabolites of baicalein after oral administration of baicalin. The circulating baicalin reenters the gastrointestinal tract via the biliary excretion mechanism [24]and undergoes enterohepatic circulation [21]. After oral administration of baicalein, it is subjected to the extensive first-pass metabolism in liver and small intestine [25,26], and therefore, glucuronides/sulfates of baicalein including baicalin are predominant in the plasma [22]. The biotransformation of baicalin and baicalein and the enterohepatic circulation of baicalin can keep a balance in the systemic levels. With the oral administration of baicalin and baicalein, dominantly circulating in the plasma are the glucuronides/sulfates of baicalein, and therefore, the conjugated metabolites are actually responsible for the in vivo effects. Because baicalin itself is one of the conjugated metabolites after oral administration of baicalin or baicalein, the activity of baicalin reported in in vitro studies can only partially explain the in vivo effects of baicalin and baicalein [22].
A sound knowledge of the pharmacokinetic characteristics of baicalin and baicalein enables scientists to further optimize use of these agents. Various formulations have been developed to improve the oral bioavailability of baicalin and baicalein. Baicalein nanocrystal [27], baicalein-hydroxypropyl-β-cyclodextrin inclusion complex [28], baicalein self-microemulsifying drug delivery system [29], and baicalein solid dispersion [30]have been developed to improve dissolution and oral bioavailability of baicalein. Some nano-based formulations such as solid nanocrystals [31], nanoemulsions [32], and solid lipid nanoparticles [33]have been designed for increasing baicalin's solubility and absorption rate and improving its oral bioavailability. Besides, change administration route of baicalein may be employed to avoid the first-pass effect of the gastrointestinal tract or liver and enhance its bioavailability. For example, pulmonary administration of baicalein nanocrystal can obtain similar pharmacokinetic parameters to intravenous injection of baicalein solution [27].
Saturday, November 7, 2015
Parkinson's: Compound LIST
I need to research the following:
uridine
saffron: (crosses human BBB and 2 other studies for PD in mice)
http://www.ncbi.nlm.nih.gov/pubmed/25163440
http://www.ncbi.nlm.nih.gov/pubmed/25713594
possibly low on other hormones: vasopresin, norepinephrin, TSH
Tauroursodeoxycholic acid (TUDCA)
inositol (scyllo-inositol, raises uric acid?)
rifampicin ( antibacterial for leprosy who did not get PD. upregulates HSP GRP78)
thioredoxin reductase activates thioredoxin and 1 form of it depends on selenocysteine. It upregulates hsp GRP78, IRE1α, TRAF2, JNK, caspase-12, and CHOP
metformin is an ancient "increase lifespan" drug for type 2 diabetes that reduces glucose in absorption, liver, and blood (like calorie restriction?) It binds to a-syn without letting misfold. It help in PD models of mice.
ritalin binds to a-syn in a way that locks it but does not let it misfold.
ritalin and metformin: http://www.ncbi.nlm.nih.gov/pubmed/26378986
"Several polyphenols, phenothiazines, porphyrins, polyene macrolides, and Congo red and its derivatives, BSB and FSB, inhibited α-synuclein filament assembly with IC50 values in the low micromolar range. Many compounds that inhibited α-synuclein assembly were also found to inhibit the formation of Aβ and tau filaments."
=== possibly harmful compounds reported===
milk, chocolate, creatine with caffiene, DHA in fish oil, niacin, manganese of course
I'm going to order the following plant extracts in bulk from China as powders and mix them for storage and later mixing in drinks.
I'll dump the powders in a 5 gallon bucket, shake, bottle, and label according to FDA. I'm already taking about 2/3 of them. Let me know if I'm missing anything. I take 1 tablespoon of the powder twice a day mixed in a juice/wine.
The dose simulates the animal and test tube research. Doses are between 200 mg and 2000 mg daily doses, but usually 500 mg to 1000 mg twice a day. So it's the equivalent of 30 pills per day, replaced by 2 bad-tasting drinks.
List of nutrients to be included in my next batch, not a-Syn blockers
=================
fisetin (strawberries)
apigenin (chamomile, parsley, celery, and in bee products, an MAO-AB inhibitor)
nobiletin (from citrus, may not include if the taste is too bad)
hesperidin (citrus, etc, very common)
Heptamethoxyflavone HMF (citrus)
citicoline (helps memory in AD, dopamine receptors, is bioavailable, neuroprotective, hormones (TSH, GH, TSH)
a-Syn blockers to be included (bioavailability possible but not known by me):
=======
naringin (the grapefruit bitterness)
gallic acid (from nutgall, black tea, teas, grapes, berries)
myricetin (bayberry bark)
morin (guava, osage)
Nordihydroguaiaretic acid
Genistein (ginseng) (possibly because it is like nobiletin: a TKI)
cuminaldehyde (cumin)
quercetin (apples)
a-Syn non-supplment blockers
========
exercise? HSP GRP78?
nilotinib (pharmaceutical, primarily by increasing AMPK)
rasagiline? (pharmaceutical)
methylene blue (common chemical, not completely safe)
4-phenyl butyrate (BPA)
rapamycin (immuno-suppressant for organ transplant)
Rifampicin (anti-bacterial for tuberc & leprosy, upregulates HSP GRP78)
Considering:
==========
inosine (raises urate, should not take too much, raises activity of other compounds)
Tangeretin (tangerine, very expensive but requires only 1/5 as much as others)
alpha-lipoic acid
acetyl-L-carnitine
NAC
creatine (this can make PD worse when taken with caffeine)
CoQ10
black tea extract (in case gallic acid is the not the primary benefit)
rutin (like quercetin)
peperine (for increasing bioavailability of some, hot taste will be tough to swallow straight)
Works or may work in PD and advisable in my opinion and not listed above included:
===========
Best evidence: nicotine (causes temporary imbalance and nausea), vitamins A, B's, D, E, fish oil, omega 3's from canola or flax, zinc, magnesium, melatonin, caffeine, 5-HTP, an NSAID like aspirin or ibuprofen, ellagic acid in olive and canola oil.
Whole extracts or foods: blueberry, apple, strawberry, teas, grape seed, beer, sardines.
Others with possibility: Co-Q10, theanine, selenium. Less evidence for: Mucuna pruriens, fava/broad beans, Bacopa monnieri, Gotu Kola, Ashwagandha. Bioavailable? PQQ, resveratrol, curcumin.
Not part of my a-Syn blockers/breakers listed above due to questions about bioavailability
==============
baicalein (skullcap flower, oxidized this breaks up existing a-Syn possibly like no other, seems completely unable to make it past liver to brain)
berberine (not strongly bioavailable, but can be helped with verapamil)
rosmarinc acid blocks a-Syn aggregation, but does not appear to be bioavailable.
resveratrol
curcuminoids
palmitoylethanolamide (PEA) is not orally bioavailable. (increases neurosteroidgenisis, affects cannaboid receptors, reduces inflammation and pain, improves mouse model for PD "Our results indicate that the PEA is neuroprotective even when administered once the insult has been initiated." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422290/)
Pharmaceuticals useful in PD:
===========
L-DOPA, rasagiline, Ritalin, SSRI anti-depressants and wellbutrin (norepinephrine), synthetic triterpenoids, statins, ferriprox (iron chelator for PD), Nilotinib/Bafetinib/Dasanitib ($100,000 per year). Rifampicin is used in tuberculosis and leprosy and is an a-Syn blocker. Sirolimus (rapamycin) has been investigated a lot for PD and shows strong effects in animals, 150 pubmed articles. No trials in humans that I saw. It is an immunosupressant used in organ transplant, has a lot of research like mice lifespan extension and cancer cause and cure. It's derivative tacrolimus could also be important, 5 articles. Trichostatin A , an epigenetic repairer, has been used in mice to negate distant (non-contact) mothering and been used in PD.
Toxic stuff
=========
possibly iron, chocolate, definitely milk (men only?), creatine when taken with caffiene, amphetamines, manganese, possibly high dose vitamin C, possibly DHA
Warnings about drug interactions (not complete). These will amplify or reduce effects of some drugs by affecting liver enzymes. See the links for which pharmaceuticals are affected. This is more important than "grapefruit" interactions because the doses I want to take are very very high compared to grapefruit.
=================
some compounds require CYP3A4 for oxidation in order to activate the compound, so inhibiting it may also decrease some compounds. But these compounds NEEDING CYP3A4 will still go by the name "substrate" in Wikipedia which otherwise means they are degraded by it. Also "inhibitors" are also blocked by it because they are "occupied" instead of making it to the bloodstream.
quercetin: https://en.wikipedia.org/wiki/CYP2C8
piperine, curcumin, baicalein, milk thistle, grapefruit juice: https://en.wikipedia.org/wiki/CYP3A4
quercetin, naringin, naringenin, hesperitin: https://en.wikipedia.org/wiki/CYP1A2 and https://en.wikipedia.org/wiki/CYP3A4
apigenin: https://en.wikipedia.org/wiki/CYP2C9
tangeretin, nobiletin: SULT1A1
quercetin, naringin: SULT1A3 which increases beta(2) agonists (asthma)
quercetin upregulates the CYP3A4 enzyme, so taking it several days can lessen the effect of compounds trying to get past CYP3A4.
Taking peperine, curcumin, naringin, and baicalein at same time can amplify each other.
Blocking CYP1A2 increases rasagiline
http://www.ncbi.nlm.nih.gov/pubmed/26530401
myricetin: vegetables, fruits, nuts, berries, tea, and is also found in red wine. Structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the same functions as these other members of the flavonol class of flavonoids
references to FULL text articles:
http://www.ncbi.nlm.nih.gov/pubmed/22634381
http://www.ncbi.nlm.nih.gov/pubmed/18258594
http://www.ncbi.nlm.nih.gov/pubmed/21443877
rasagiline, methylene blue, BPA, baicalein
http://www.sciencedirect.com/science/article/pii/S0925443911002250
nicotine
http://www.ncbi.nlm.nih.gov/pubmed/12815102 (full)
nicotine and caffeine
http://www.ncbi.nlm.nih.gov/pubmed/25081642
Grape Seed Extract (gallic acid)
http://www.ncbi.nlm.nih.gov/pubmed/24157371
http://www.ncbi.nlm.nih.gov/pubmed/19221432 (full)
http://www.ncbi.nlm.nih.gov/pubmed/20653511
naringin and rutin
http://www.ncbi.nlm.nih.gov/pubmed/22331747
tangeretin (tangeritin)
http://www.ncbi.nlm.nih.gov/pubmed/23112876
ginseng
http://www.ncbi.nlm.nih.gov/pubmed/24316034
ellagic acid
http://www.ncbi.nlm.nih.gov/pubmed/25247703
heat shock proteins (hot baths and exercise)
http://www.ncbi.nlm.nih.gov/pubmed/15992180
notes:
citrulline: could not find support for it.
========================
UPDATED POST
This is an update of a previous post. The number of compounds that help in the test tube or mice is overwhelming. Unfortunately, there is not a standard test to determine which ones erach the human brain and thereby works the best. But this long list gives a lot of hope for PD: there are many different ways a-Syn misfolding can be prevented, reversed, and cleared out of the cell, so a combination of the right ones would not be a waste, but synergistic.
Previous article:
https://healthunlocked.com/parkinsonsmovement/posts/132541563/compounds-that-prevent-a-syn-misfolding
Here are new ones to add to the list:
===========
nicotine & caffeine ( http://www.ncbi.nlm.nih.gov/pubmed/25081642 )
ritalin
metformin (relatively safe and old anti-diabetic medicine)
rifampicin (anti-bacterial)
trehalose (like glucose, found in mushrooms http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496693/ )
This last one has 28 articles on it that mention PD, and it's the most recent one I've found. It makes me wonder how many more are out there.
Here are the previous list of "supplements" that help:
=============
naringin (the grapefruit bitterness)
gallic acid (from nutgall, black tea, teas, grapes, berries)
myricetin (bayberry bark)
morin (guava, osage)
Nordihydroguaiaretic acid
Genistein (ginseng) (possibly because it is like nobiletin: a TKI)
cuminaldehyde (cumin)
quercetin (apples)
tangeretin (expensive, from tangerine peel)
olive oil (ellagic acid)
EGCG (green tea extract)
Ginkgolide B (ginkgo)
pharmaceutical-like a-Syn protectors:
=============
nilotinib (pharmaceutical, primarily by increasing AMPK)
rasagiline (pharmaceutical)
methylene blue (common chemical, not completely safe)
4-phenyl butyrate (BPA)
rapamycin (immuno-suppressant for organ transplant)
reduces a-Syn misfolding but probably not bioavailable:
==============
baicalein (skullcap flower, oxidized this breaks up existing a-Syn possibly like no other, seems completely unable to make it past liver to brain)
berberine (not strongly bioavailable, but can be helped with verapamil)
rosmarinc acid blocks a-Syn aggregation, but does not appear to be bioavailable.
resveratrol
curcuminoids
palmitoylethanolamide (PEA)
In a sense, kind of a-Syn misfolding reducers:
=============
exercise (increases heat-shock proteins and ATP energy 24 hr/day)
alcohol (increases ATP energy increases ATP energy for clearance)
water (staying hydrated, dehydration increases a-Syn misfolding)
correcting underlying diabetes (increases ATP energy for clearance)
Reminder of the AD-toxic foods:
=========
possibly iron, chocolate, definitely milk (men only?), creatine when taken with caffiene, amphetamines, manganese, possibly high dose vitamin C, possibly DHA in fish oil
uridine
saffron: (crosses human BBB and 2 other studies for PD in mice)
http://www.ncbi.nlm.nih.gov/pubmed/25163440
http://www.ncbi.nlm.nih.gov/pubmed/25713594
possibly low on other hormones: vasopresin, norepinephrin, TSH
Tauroursodeoxycholic acid (TUDCA)
inositol (scyllo-inositol, raises uric acid?)
rifampicin ( antibacterial for leprosy who did not get PD. upregulates HSP GRP78)
thioredoxin reductase activates thioredoxin and 1 form of it depends on selenocysteine. It upregulates hsp GRP78, IRE1α, TRAF2, JNK, caspase-12, and CHOP
trehalose is a glucose-like sugar used by insects for flynig because it generates more energy. less sweet than gluscose. It also helps cells survive dehydration and helps stabilize a-syn folding at low concentrations.
http://www.ncbi.nlm.nih.gov/pubmed/?term=PMC4496693
It may be broken down too much by trehalase in the GI tract and those missing this enzyme have problems like those missing lactase. http://www.hc-sc.gc.ca/fn-an/gmf-agm/appro/nf-an119decdoc-eng.php
Tyrosine deficiency (amino acid)metformin is an ancient "increase lifespan" drug for type 2 diabetes that reduces glucose in absorption, liver, and blood (like calorie restriction?) It binds to a-syn without letting misfold. It help in PD models of mice.
ritalin binds to a-syn in a way that locks it but does not let it misfold.
ritalin and metformin: http://www.ncbi.nlm.nih.gov/pubmed/26378986
"Several polyphenols, phenothiazines, porphyrins, polyene macrolides, and Congo red and its derivatives, BSB and FSB, inhibited α-synuclein filament assembly with IC50 values in the low micromolar range. Many compounds that inhibited α-synuclein assembly were also found to inhibit the formation of Aβ and tau filaments."
=== possibly harmful compounds reported===
milk, chocolate, creatine with caffiene, DHA in fish oil, niacin, manganese of course
I'm going to order the following plant extracts in bulk from China as powders and mix them for storage and later mixing in drinks.
I'll dump the powders in a 5 gallon bucket, shake, bottle, and label according to FDA. I'm already taking about 2/3 of them. Let me know if I'm missing anything. I take 1 tablespoon of the powder twice a day mixed in a juice/wine.
The dose simulates the animal and test tube research. Doses are between 200 mg and 2000 mg daily doses, but usually 500 mg to 1000 mg twice a day. So it's the equivalent of 30 pills per day, replaced by 2 bad-tasting drinks.
List of nutrients to be included in my next batch, not a-Syn blockers
=================
fisetin (strawberries)
apigenin (chamomile, parsley, celery, and in bee products, an MAO-AB inhibitor)
nobiletin (from citrus, may not include if the taste is too bad)
hesperidin (citrus, etc, very common)
Heptamethoxyflavone HMF (citrus)
citicoline (helps memory in AD, dopamine receptors, is bioavailable, neuroprotective, hormones (TSH, GH, TSH)
a-Syn blockers to be included (bioavailability possible but not known by me):
=======
naringin (the grapefruit bitterness)
gallic acid (from nutgall, black tea, teas, grapes, berries)
myricetin (bayberry bark)
morin (guava, osage)
Nordihydroguaiaretic acid
Genistein (ginseng) (possibly because it is like nobiletin: a TKI)
cuminaldehyde (cumin)
quercetin (apples)
a-Syn non-supplment blockers
========
exercise? HSP GRP78?
nilotinib (pharmaceutical, primarily by increasing AMPK)
rasagiline? (pharmaceutical)
methylene blue (common chemical, not completely safe)
4-phenyl butyrate (BPA)
rapamycin (immuno-suppressant for organ transplant)
Rifampicin (anti-bacterial for tuberc & leprosy, upregulates HSP GRP78)
Considering:
==========
inosine (raises urate, should not take too much, raises activity of other compounds)
Tangeretin (tangerine, very expensive but requires only 1/5 as much as others)
alpha-lipoic acid
acetyl-L-carnitine
NAC
creatine (this can make PD worse when taken with caffeine)
CoQ10
black tea extract (in case gallic acid is the not the primary benefit)
rutin (like quercetin)
peperine (for increasing bioavailability of some, hot taste will be tough to swallow straight)
Works or may work in PD and advisable in my opinion and not listed above included:
===========
Best evidence: nicotine (causes temporary imbalance and nausea), vitamins A, B's, D, E, fish oil, omega 3's from canola or flax, zinc, magnesium, melatonin, caffeine, 5-HTP, an NSAID like aspirin or ibuprofen, ellagic acid in olive and canola oil.
Whole extracts or foods: blueberry, apple, strawberry, teas, grape seed, beer, sardines.
Others with possibility: Co-Q10, theanine, selenium. Less evidence for: Mucuna pruriens, fava/broad beans, Bacopa monnieri, Gotu Kola, Ashwagandha. Bioavailable? PQQ, resveratrol, curcumin.
Not part of my a-Syn blockers/breakers listed above due to questions about bioavailability
==============
baicalein (skullcap flower, oxidized this breaks up existing a-Syn possibly like no other, seems completely unable to make it past liver to brain)
berberine (not strongly bioavailable, but can be helped with verapamil)
rosmarinc acid blocks a-Syn aggregation, but does not appear to be bioavailable.
resveratrol
curcuminoids
palmitoylethanolamide (PEA) is not orally bioavailable. (increases neurosteroidgenisis, affects cannaboid receptors, reduces inflammation and pain, improves mouse model for PD "Our results indicate that the PEA is neuroprotective even when administered once the insult has been initiated." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422290/)
Pharmaceuticals useful in PD:
===========
L-DOPA, rasagiline, Ritalin, SSRI anti-depressants and wellbutrin (norepinephrine), synthetic triterpenoids, statins, ferriprox (iron chelator for PD), Nilotinib/Bafetinib/Dasanitib ($100,000 per year). Rifampicin is used in tuberculosis and leprosy and is an a-Syn blocker. Sirolimus (rapamycin) has been investigated a lot for PD and shows strong effects in animals, 150 pubmed articles. No trials in humans that I saw. It is an immunosupressant used in organ transplant, has a lot of research like mice lifespan extension and cancer cause and cure. It's derivative tacrolimus could also be important, 5 articles. Trichostatin A , an epigenetic repairer, has been used in mice to negate distant (non-contact) mothering and been used in PD.
Toxic stuff
=========
possibly iron, chocolate, definitely milk (men only?), creatine when taken with caffiene, amphetamines, manganese, possibly high dose vitamin C, possibly DHA
Warnings about drug interactions (not complete). These will amplify or reduce effects of some drugs by affecting liver enzymes. See the links for which pharmaceuticals are affected. This is more important than "grapefruit" interactions because the doses I want to take are very very high compared to grapefruit.
=================
some compounds require CYP3A4 for oxidation in order to activate the compound, so inhibiting it may also decrease some compounds. But these compounds NEEDING CYP3A4 will still go by the name "substrate" in Wikipedia which otherwise means they are degraded by it. Also "inhibitors" are also blocked by it because they are "occupied" instead of making it to the bloodstream.
quercetin: https://en.wikipedia.org/wiki/CYP2C8
piperine, curcumin, baicalein, milk thistle, grapefruit juice: https://en.wikipedia.org/wiki/CYP3A4
quercetin, naringin, naringenin, hesperitin: https://en.wikipedia.org/wiki/CYP1A2 and https://en.wikipedia.org/wiki/CYP3A4
apigenin: https://en.wikipedia.org/wiki/CYP2C9
tangeretin, nobiletin: SULT1A1
quercetin, naringin: SULT1A3 which increases beta(2) agonists (asthma)
quercetin upregulates the CYP3A4 enzyme, so taking it several days can lessen the effect of compounds trying to get past CYP3A4.
Taking peperine, curcumin, naringin, and baicalein at same time can amplify each other.
Blocking CYP1A2 increases rasagiline
http://www.ncbi.nlm.nih.gov/pubmed/26530401
myricetin: vegetables, fruits, nuts, berries, tea, and is also found in red wine. Structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the same functions as these other members of the flavonol class of flavonoids
references to FULL text articles:
http://www.ncbi.nlm.nih.gov/pubmed/22634381
http://www.ncbi.nlm.nih.gov/pubmed/18258594
http://www.ncbi.nlm.nih.gov/pubmed/21443877
rasagiline, methylene blue, BPA, baicalein
http://www.sciencedirect.com/science/article/pii/S0925443911002250
nicotine
http://www.ncbi.nlm.nih.gov/pubmed/12815102 (full)
nicotine and caffeine
http://www.ncbi.nlm.nih.gov/pubmed/25081642
Grape Seed Extract (gallic acid)
http://www.ncbi.nlm.nih.gov/pubmed/24157371
http://www.ncbi.nlm.nih.gov/pubmed/19221432 (full)
http://www.ncbi.nlm.nih.gov/pubmed/20653511
naringin and rutin
http://www.ncbi.nlm.nih.gov/pubmed/22331747
tangeretin (tangeritin)
http://www.ncbi.nlm.nih.gov/pubmed/23112876
ginseng
http://www.ncbi.nlm.nih.gov/pubmed/24316034
ellagic acid
http://www.ncbi.nlm.nih.gov/pubmed/25247703
heat shock proteins (hot baths and exercise)
http://www.ncbi.nlm.nih.gov/pubmed/15992180
notes:
citrulline: could not find support for it.
========================
UPDATED POST
This is an update of a previous post. The number of compounds that help in the test tube or mice is overwhelming. Unfortunately, there is not a standard test to determine which ones erach the human brain and thereby works the best. But this long list gives a lot of hope for PD: there are many different ways a-Syn misfolding can be prevented, reversed, and cleared out of the cell, so a combination of the right ones would not be a waste, but synergistic.
Previous article:
https://healthunlocked.com/parkinsonsmovement/posts/132541563/compounds-that-prevent-a-syn-misfolding
Here are new ones to add to the list:
===========
nicotine & caffeine ( http://www.ncbi.nlm.nih.gov/pubmed/25081642 )
ritalin
metformin (relatively safe and old anti-diabetic medicine)
rifampicin (anti-bacterial)
trehalose (like glucose, found in mushrooms http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496693/ )
This last one has 28 articles on it that mention PD, and it's the most recent one I've found. It makes me wonder how many more are out there.
Here are the previous list of "supplements" that help:
=============
naringin (the grapefruit bitterness)
gallic acid (from nutgall, black tea, teas, grapes, berries)
myricetin (bayberry bark)
morin (guava, osage)
Nordihydroguaiaretic acid
Genistein (ginseng) (possibly because it is like nobiletin: a TKI)
cuminaldehyde (cumin)
quercetin (apples)
tangeretin (expensive, from tangerine peel)
olive oil (ellagic acid)
EGCG (green tea extract)
Ginkgolide B (ginkgo)
pharmaceutical-like a-Syn protectors:
=============
nilotinib (pharmaceutical, primarily by increasing AMPK)
rasagiline (pharmaceutical)
methylene blue (common chemical, not completely safe)
4-phenyl butyrate (BPA)
rapamycin (immuno-suppressant for organ transplant)
reduces a-Syn misfolding but probably not bioavailable:
==============
baicalein (skullcap flower, oxidized this breaks up existing a-Syn possibly like no other, seems completely unable to make it past liver to brain)
berberine (not strongly bioavailable, but can be helped with verapamil)
rosmarinc acid blocks a-Syn aggregation, but does not appear to be bioavailable.
resveratrol
curcuminoids
palmitoylethanolamide (PEA)
In a sense, kind of a-Syn misfolding reducers:
=============
exercise (increases heat-shock proteins and ATP energy 24 hr/day)
alcohol (increases ATP energy increases ATP energy for clearance)
water (staying hydrated, dehydration increases a-Syn misfolding)
correcting underlying diabetes (increases ATP energy for clearance)
Reminder of the AD-toxic foods:
=========
possibly iron, chocolate, definitely milk (men only?), creatine when taken with caffiene, amphetamines, manganese, possibly high dose vitamin C, possibly DHA in fish oil
Friday, November 6, 2015
Parkinson's: my tremor reduced
Morning: 11/6/2015:
My tremor suddenly reduced 8 days ago (11/29/2015) during alcohol testing and I need to document the changes to my regimen that may have caused it. It typically reduced suddenly 30 minutes after drinking an alcoholic beverage. After a day of doing this and a couple of days of mixing a little with my citrus compounds (naringin, nobiletin, tangeretin, hesperidin) the tremor did not return nearly as bad as it used to be.
Mood is also MUCH better. Holding mp3 player on my bike handle with "good" hand is no longer showing a tremor either, like it started doing 3 months ago.
These are the things I started right before the tremor stopped. These are in order of best guess. "Previous" means days before the tremor stopped.
halogen light bed, 1000 W, 30 min/day, no water blocking heat.
MSM (not best guess, but correct timing and potential).
alcohol triggering my body to keep glucose levels more even...tremor comes back when I am low on calories and stressed from exercise.
melatonin previous 2 weeks.
LED helmet, 20 min/day previous 3 days.
5-HTP previous 4 days (stopped 2 days ago).
1 can green peas/day consistently beginning that day until today but now stopping today.
blueberries w/ 1 apple beginning that day but now stopping today.
started 800 IU vitamin E per day about 2 weeks before it stopped.
started doing more black tea extract, GTE, and ginseng about 2 weeks before it stopped.
hung upside down for about 4 days in a row before it stopped.
started mixing alcohol with my citrus concentrate and upped my dosage. (naringin, tangeretin, nobiletin, hesperidin, strawberry extract, tangerine extract, blueberry extract)
There was a cold right after the alcohol so there was more
Vit A
vit D
zicam
Things that I began or started more consistently about 1 month before the tremors stopped
exercise
rasagiline
fisetin
magnesium
zinc
ginseng
My tremor suddenly reduced 8 days ago (11/29/2015) during alcohol testing and I need to document the changes to my regimen that may have caused it. It typically reduced suddenly 30 minutes after drinking an alcoholic beverage. After a day of doing this and a couple of days of mixing a little with my citrus compounds (naringin, nobiletin, tangeretin, hesperidin) the tremor did not return nearly as bad as it used to be.
Mood is also MUCH better. Holding mp3 player on my bike handle with "good" hand is no longer showing a tremor either, like it started doing 3 months ago.
These are the things I started right before the tremor stopped. These are in order of best guess. "Previous" means days before the tremor stopped.
halogen light bed, 1000 W, 30 min/day, no water blocking heat.
MSM (not best guess, but correct timing and potential).
alcohol triggering my body to keep glucose levels more even...tremor comes back when I am low on calories and stressed from exercise.
melatonin previous 2 weeks.
LED helmet, 20 min/day previous 3 days.
5-HTP previous 4 days (stopped 2 days ago).
1 can green peas/day consistently beginning that day until today but now stopping today.
blueberries w/ 1 apple beginning that day but now stopping today.
started 800 IU vitamin E per day about 2 weeks before it stopped.
started doing more black tea extract, GTE, and ginseng about 2 weeks before it stopped.
hung upside down for about 4 days in a row before it stopped.
started mixing alcohol with my citrus concentrate and upped my dosage. (naringin, tangeretin, nobiletin, hesperidin, strawberry extract, tangerine extract, blueberry extract)
There was a cold right after the alcohol so there was more
Vit A
vit D
zicam
Things that I began or started more consistently about 1 month before the tremors stopped
exercise
rasagiline
fisetin
magnesium
zinc
ginseng
parkinson's: cuminaldehyde (from cumin) against a-syn misfolding
That's a really good find because the molecular weight of cuminaldehyde is only 148, which is a lot less than all these other compounds that are able to cross the blood-brain barrier, so it should cross. Now the question is does it make it through the intestines and past the liver's glucuronation/sulfuronation? It is oxidized by one of the liver's P450 enzymes, but I do not know which one so I do not know if grapefruit or peperine could block it's degradation. It does not appear anyone knows if it can make it past the liver and therefore to the brain.
A way to take a guess about its bioavailability and even brain-availability is to look at what traditional medicine says. Especially if it has noticeable mental effects. "Āyurveda and Siddha regard jeeraka [Cuminum cyminum ] as having a bitter taste with a hot property, capable of removing vāta and kapha doṣas but causing pitta. It is dry, astringent, appetising, digestive, strengthening, light for digestion, good for the eyes and an aphrodisiac. It is used in the treatment of indigestion, dysentery, enlarged spleen, flatulence and vomiting."
Here's the paper :
http://www.ncbi.nlm.nih.gov/pubmed/26351865
It's about 1% in light colored cumin seed and half as much in black cumin. It's the ingredient that gives cumin its flavor. It's about 30% in cumin essential oil. It's the primary aldehyde.
It is not available as a supplement. It would take 2 heaping teaspoons cumin to get 100 mg cuminaldehyde which is minimum dose for most of these supplements, except for nicotine (people getting only 50 mg from a pack a day are strongly protected against PD, although 3 packs in one study wa a lot better). 6 cups of coffee is better than 3 cups and that's 600 mg of caffeine. The response in animals is almost always dose-dependent. You can't just take a supplement. It has to be in a strong dose.
It also prevents oxidation of L-DOPA, is antidiabetic, and protects against superoxide oxidation.
http://www.ncbi.nlm.nih.gov/pubmed/11513710
http://www.ncbi.nlm.nih.gov/pubmed/14759731
http://www.ncbi.nlm.nih.gov/pubmed/8394839
http://www.ncbi.nlm.nih.gov/pubmed/15796577
A way to take a guess about its bioavailability and even brain-availability is to look at what traditional medicine says. Especially if it has noticeable mental effects. "Āyurveda and Siddha regard jeeraka [Cuminum cyminum ] as having a bitter taste with a hot property, capable of removing vāta and kapha doṣas but causing pitta. It is dry, astringent, appetising, digestive, strengthening, light for digestion, good for the eyes and an aphrodisiac. It is used in the treatment of indigestion, dysentery, enlarged spleen, flatulence and vomiting."
Here's the paper :
http://www.ncbi.nlm.nih.gov/pubmed/26351865
It's about 1% in light colored cumin seed and half as much in black cumin. It's the ingredient that gives cumin its flavor. It's about 30% in cumin essential oil. It's the primary aldehyde.
It is not available as a supplement. It would take 2 heaping teaspoons cumin to get 100 mg cuminaldehyde which is minimum dose for most of these supplements, except for nicotine (people getting only 50 mg from a pack a day are strongly protected against PD, although 3 packs in one study wa a lot better). 6 cups of coffee is better than 3 cups and that's 600 mg of caffeine. The response in animals is almost always dose-dependent. You can't just take a supplement. It has to be in a strong dose.
It also prevents oxidation of L-DOPA, is antidiabetic, and protects against superoxide oxidation.
http://www.ncbi.nlm.nih.gov/pubmed/11513710
http://www.ncbi.nlm.nih.gov/pubmed/14759731
http://www.ncbi.nlm.nih.gov/pubmed/8394839
http://www.ncbi.nlm.nih.gov/pubmed/15796577
Thursday, November 5, 2015
Mechanical and Electrical Analogy: deriving of mass from charges, posted to talk page in wikipedia
I would love to see a theoretical physics discussion of the origin of the analogy between electrical and mechanical components. On the surface, you could say we find it easy to think in terms of linear systems, so we think of components that act linearly. This leads directly to the same simple differential equations for different systems, especially when conservation of energy is a natural focal point for optimizing engineering applications. The most natural of the possible analogies is the impedance analogy which is the one most commonly used and first cited in the Wikipedia article. The reason for this is that charge in electrical components is simply replaced with meters in the mechanical components. There are no other changes. Capacitors allow charge to build up for a fixed dielectric distance and the analogous spring allows meters to build up for a fixed number of charges (which are the source of resisting compression). For small compressions and non-saturating amounts of charge, both are linear. The same direct relation exists for inductors and mass: inductance (magnetism) from a classical view (pre-quantum) is a relativistic effect of charge build up per unit length, not a thing unto itself. See Schwartz, Feynman, and Wikipedia. For small changes, it is again linear so V=L*di/dt instead of having to resort to full-blown relativistic equations. So it seems mass could be viewed from a pre-quantum perspective as the relativistic effect of (quark?) charges being brought closer together as a result of length contraction. Again, it's linear for small changes in velocity so F=ma instead full-blown relativistic calculations. In short, linear electrical components control charge/length where length is held constant by the component, and mechanical systems do the same but hold the charge constant and allow lengths to change. This is simple enough that there should be some references out there that delve into the source of the analogies and thereby allow it to be included in the article.
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