41 replies to this topic

[Karomesis]

I was under the impression that dosing is to correlate with animals which means I dose at 134mg per day. I have looked up in vain ANY study most of which were co-authored by ames what the dosing would be. Paul on morelife indicates that he takes it with a powder mix of 9 trillion others in his morning cocktail. CAn anyone else here offer some light on my quandry? [cry]

[FunkOdyssey]

This is part of the problem with being on the cutting edge... not much guidance available. I hope some knowledgeable people contribute on this thread, as I'm interested myself.

Relentless Improvement is selling it, so there must be some people around here using it.

[nbourbaki]

I take it. First as part of Paul's group and now again since Relentless started selling it. I'm about 80kg and I take 50mg BID which in aggregate is a little less than what Paul currently takes. There is little literature to base the dosing. I would start with a smaller daily intake and work my way up.

[motf]

I take it.  First as part of Paul's group and now again since Relentless started selling it.  I'm about 80kg and I take 50mg BID which in aggregate is a little less than what Paul currently takes.  There is little literature to base the dosing.  I would start with a smaller daily intake and work my way up.

What effects do you notice from this dose? And do these differ from your expectations? Any cognative effects at all? Or noticable lowering of blood sugar?

[Karomesis]

nbourbaki, so you dose at half of what paul doses? I am roughly 90kg, should I go with 60mg per day and work up from there?

Also, have you heard of the muscular dystrophy drug that supposed to hit the market soon? It works by inhibiting the expression of myostatin which limits muscle mass.

funkodyssey, I hear what you're saying about cutting edge, Some of the stuff I am going to take are still in trials/experimental stages ,so I am left to my own devices as to extrapolating from mus musculus or the current studies.

[nbourbaki]

50mg BID would total 100mg per day at 80kgs that would be 1.25 mg per kg. Paul is 63kg and is taking 108mg which works out to 1.71mg per kg. So a little less than Paul.

I find that I have more energy and recover faster from physical exertion. When ski season starts I up the dose to 75mg BID for a total of 150mg per day. This season that dosing allowed me at 51 to ski 6 days in a row in Utah last December. Before NtBHA I couldn't ski 4 days in a row.

This is an experimental drug, so I started at 30mg a day and worked my way up over the course of three months. I didn't add any new supplement during this time to make sure I'd recognized any negative effect. After three month I took a full physical to make sure nothing was going too wrong. My blood sugar stayed about the same. My C-Reative protein dropped but that's about the only change I saw in my blood work.

[nbourbaki]

Oh, almost forgot. Relentless is taking both NtBHA and PBN off their site after today. If you are interested, you better get your order in.

[Karomesis]

if you don't mind me asking, what your C- reactive at currently?


I ordered 20g a week ago from pete. [thumb] should last me till sep/oct.


there are a couple of heavyhitters poised to come out of the woodwork soon, I also hear pfizer is going all in with a statin that they say will reduce LDL by 50-60% [:o] [:o] so much for artheresclerosis. [lol] elixr is currently testing a SIRt1 drug on mammals. And metaphore is in phase lll clinicals with one of their SOD mimetics M40403.

[syr_]

elixr is currently testing a SIRt1 drug on mammals.

Uhm, this is VERY interesting

[nbourbaki]

51 years old. C-Reactive, Quant 0.3 mg/L Range 0.0-4.9

[FunkOdyssey]

Wow, that's excellent for 51 years old. Mine is 0.2mg/L at age 25 with moderate supplementation.

[nbourbaki]

Wow, that's excellent for 51 years old. Mine is 0.2mg/L at age 25 with moderate supplementation.

I'll have new blood work done in June. I'm hoping I can improve on the 0.3mg/L.

[karitas]

where do you get these test done?

[FunkOdyssey]

You can order them through www.lef.org, but they can get expensive. I am fortunate to have a forward thinking doctor that works with me to order tests and get them paid for by my insurance. That takes some clever work on the doctor's part depending on how often and wide-ranging your blood tests are.

[nbourbaki]

where do you get these test done?

A combination of LEF when they have their sale on blood tests and my GP. It's going to be more difficult to get the CRP test with my GP since my low reading would indicate I don't have a problem there. I would highly recommend that you get blood work done if you start taking something like NtBHA.

[trh001]

We can probably get a rough idea of what Paul W is up to given the reference below:

http://bmsr.usc.edu/...bs/dzd/3862.pdf

In it, the authors describe the non-linear relationship between species (mice, rate, rhesus) weight and clearance rate for a drug. This is, as I understand it, typical in scale up, though clearance rates are tricky and can vary from the straight regression line in figure 4 (note the log/log scale on the graph). We'll assume the scale up for NtBHA models the same across species. The unknown we're trying to estimate is clearance for human.

This *may* not be a good assumption, if, for example, metabolism by mice in the liver, alternative clearance via the kidney, or uptake via the GI tract, are not as modeled. Still, it'll give us a rough idea. I assumed 70kg for human. I'm not sure what the authors used, but it's close enough for a test.

The authors generate two coefficients from their regression line, and provide a model one can use based upon these, to estimate clearance.

CL (ml/min) = A(wt)^B

"A" was estimated to = 6.46
"B" was estimated to = 0.9
Wt = weight in kg for the species under consideration

Mice typically weigh in at 20g. [http://www.informati...e_facts3.shtml]

So, our 70kg human clearance would be: A(70)^B = 296 ml/min
Our mouse clearance is A(20/1000)^B = 0.191 ml/min.

As a percentage of body weight (a surrogate estimate for total body fluid volume)
we have clearance at 4.22% of body weight in humans, and 9.55% of body weight in the mouse, or ca. 2.26 fold higher percent clearance.

This means we'd want about 2.26-fold less drug on a mg/kg basis in humans than in mice, I believe. So, the study that Paul cites on his site (and one of two I could find, this being the more recent, see below) shows a 5mg/kg dose in mice.

This would mean the equivalent estimated dose (using our model, which may be wrong for the reasons cited above, but a model is a good start in lieu of human studies) for humans would be 5/2.26 or about 2.21mg/kg, or a dose of 63*2.21 = 139mg for Paul.

This estimate based on our model of 139mg is pretty close to what he's taking (108mg), so perhaps this is the sort of logic he's used to arrive at the dose. Generally it's a good idea to use such a model when one has no recourse but to extrapolate from animal studies.

----------
Carcinogenesis. 2004 Aug;25(8):1435-42. Epub 2004 Mar 11. Related Articles, Links


The use of N-t-butyl hydroxylamine for radioprotection in cultured cells and mice.

Lee JH, Kim IS, Park JW.

Department of Biochemistry, College of Natural Sciences and College of Medicine, Kyungpook National University, Taegu 702-701, Korea.

Exposure of cells to ionizing radiation leads to formation of reactive oxygen species (ROS) that are associated with radiation-induced cytotoxicity. Therefore, compounds that scavenge ROS may confer radioprotective effects. Recently, it has been shown that the decomposition product of the spin-trapping agent alpha-phenyl-N-t-butylnitrone (PBN), N-t-butyl hydroxylamine (NtBHA), mimics PBN and is much more potent in delaying ROS-associated senescence. We investigated the protective role of NtBHA against ionizing radiation in U937 cells and mice. Viability and cellular oxidative damage reflected by lipid peroxidation, oxidative DNA damage and protein oxidation were significantly lower in the cells treated with NtBHA when the cells were exposed to ionizing radiation. The modulation of cellular redox status was more pronounced in control cells compared with NtBHA-treated cells. The ionizing radiation-induced mitochondrial damage reflected by the altered mitochondrial permeability transition, the increase in the accumulation of ROS and the reduction of ATP production was significantly higher in control cells compared with NtBHA-treated cells. NtBHA administration before irradiation at 5 mg/kg daily for 2 weeks provided substantial protection against killing and oxidative damage to mice exposed to whole-body irradiation. These data indicate that NtBHA may have great application potential as a new class of in vivo, non-sulfur containing radiation protector.

[trh001]

Btw, when you plug a number in to the above model,

1) it would need to be from a study that uses one of the animals known to fall on the metabolic log-log linear fit (mouse, rat, or rhesus monkey)

2) you probably want to use a study that has a chronic dosing intended to look at a range of efficacy for some target effect you're interested in, and then pick the lowest efficacious dose that the authors cite. Don't use a dose from a deliberately high dose toxicity study, or a high dose metabolic mapping study, as these don't tell you anything about your drug of interest wrt efficacy, and they tend to be very, very large doses to ensure that a result is seen in a short time.

Having said that, the study I used above where 5mg/kg was used, didn't do a "dose-response" -- it was a single dose. Therefore, it's quite possible that, say, 1mg/kg would have yielded satisfactory results as well, suggesting this dose is more than is needed to achieve some effect. As new studies come about in the literature showing efficacy for a target (in this case it was protection from whole body irradiation -- pretty severe) that is more reasonable, it may suggest that lower doses can be used.

What would be good would be an array of metrics under normal mouse aging. I'll see if I can find a mouse aging study with PBN (parent molecule) or NtBHA. This would be a better study to find doses to extrapolate from.

[trh001]

Of additional note is that clearance on average for people is just that, there may be:

1) differences between men and women

2) there are definite differences as one ages (reduced clearance)

3) there are definite differences if one has liver damage (assuming a liver clearance mechanism) or if one drinks heavily and induces liver enzyme expression which could result in higher clearance.

All of the above suggests that getting blood work done, over time, is a good one, though, one can't be sure what one might be looking for since one is not monitoring for the drug directly (unless you pay someone to do HPLC on your blood in an assay to look at tbHA, which is possible if you know a chemist and can provide him/her with a sample to use as a standard for the HPLC...but not likely).

So, as a rule of thumb, I'd make sure your liver is healthy via the normal blood studies one gets, and cross one's fingers. This really goes for any supplement that could potentially become toxic as liver/kidney function fails as one grows older, say. For example, I take magnesium at 800mg per day, but someone with impaired kidney function might not be able to take that much without gradual buildup in blood and tissues and consequential toxicity.

[trh001]

if you don't mind me asking, what your C- reactive at currently?


I ordered 20g a week ago from pete. [thumb] should last me till sep/oct.


there are a couple of heavyhitters poised to come out of the woodwork soon, I also hear pfizer is going all in with a statin that they say will reduce LDL by 50-60% [:o]  [:o] so much for artheresclerosis. [lol]  elixr is currently testing a SIRt1 drug on mammals. And metaphore is in phase lll  clinicals with one of their SOD mimetics M40403.

Ordered from same supplier -- have you received your order yet and do you get a confirmation of any sort prior to that? Gave him email address and fax number, but no response, yet. it's only be 3 days, though.

[Michael]

All:

In extrapolating from human to human studies, the accepted practice is to adjust the dose using Kleiber's allometric metabolic scaling law, which is that metabolic rate in mammals (and thus a remarkable range of stuff governed thereby, including the toxic and biologically effective doses of bioactive compounds, and even lifespan) scales to the negative one-quarter power of mass. This is at least partly the result of surface-to-volume ratio. A few references on this:

Rucker R, Storms D. Interspecies comparisons of micronutrient requirements: metabolic vs. absolute body size. J Nutr. 2002 Oct;132(10):2999-3000.

Gillooly JF, Brown JH, West GB, Savage VM, Charnov EL. Effects of size and temperature on metabolic rate. Science. 2001 Sep 21;293(5538):2248-51.

Mordenti J. Dosage regimen design for pharmaceutical studies conducted in animals. J Pharm Sci. 1986 Sep;75(9):852-7.

Mordenti J. Man versus beast: pharmacokinetic scaling in mammals. J Pharm Sci. 1986 Nov;75(11):1028-40.

Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE. Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep. 1966 May;50(4):219-44.

Kleiber M: The Fire of Life. An Introduction to Animal Energetics. New York: Wiley; 1961.

[Cribbed]: Kleiber M: Body size and metabolism. Hilgardia 1932, 6:315-353.

So, eg, to scale a dose on an interspecies basis, you go: [Directly-extrapolated dose] * [(Human weight/Rodent weight)[to the exponent -0.25]].

For the RLA doses from the Hagen/Ames studies (I have this in notes -- see the recently-posted link to my CR Society Conference supplement presentation), but unfortunately nt WHICH specific study; they're all in the same ballpark, however):

0.2% or 0.1% (wt/wt) R(+) in AIN93M diet; 13.1 g food /day; body weight 415.5 g. 13100 [mg food] * {between 0.0002 and 0.0001 [mg RLA/mg food]} / 0.4155 kg rat) = 31.5 - 73 mg R(+)-LA/kg rat. For a 70 kg human, this is 2207-4414 mg. Adjusting for metabolic scaling: [Extrapolated dose] * [(70 kg/0.4155 kg)-0.25] = 612.6 - 1225.2 mg R(+)-LA.


The Law is widely accepted and used, but is not completely uncontroversial -- eg, some say that the true relationship is the negative one-third; see:

1: Agutter PS, Wheatley DN.
Metabolic scaling: consensus or controversy?
Theor Biol Med Model. 2004 Nov 16;1(1):13.
PMID: 15546492 [PubMed - as supplied by publisher]
http://www.tbiomed.c...1/1/13#IDAIVZDZ

trh001: We can probably get a rough idea of what Paul W is up to given the reference below:

[1:  Holleran JL, Parise RA, Joseph E, Eiseman JL, Covey JM, Glaze ER, Lyubimov AV, Chen YF, D'Argenio DZ, Egorin MJ.
Plasma pharmacokinetics, oral bioavailability, and interspecies scaling of the DNA methyltransferase inhibitor, zebularine.
Clin Cancer Res. 2005 May 15;11(10):3862-8.
PMID: 15897587 [PubMed - indexed for MEDLINE]]
http://bmsr.usc.edu/...bs/dzd/3862.pdf

In it, the authors describe the non-linear relationship between species (mice, rate, rhesus) weight and clearance rate for a drug. This is, as I understand it, typical in scale up, though clearance rates are tricky and can vary from the straight regression line in figure 4 (note the log/log scale on the graph). We'll assume the scale up for NtBHA models the same across species. The unknown we're trying to estimate is clearance for human.

This *may* not be a good assumption, if, for example, metabolism by mice in the liver, alternative clearance via the kidney, or uptake via the GI tract, are not as modeled.

Right: clearance rate is only one contributor to the total pharmacokinetic profile of the drug, and also you want to look at peak serum level, etc -- and as well, it's not just unlikely, but certainly not the case that the same clearance profile is going to hold across many compounds, because the mechanisms of clearance will vary wildly; so extrapolating from zebularine to carnosine, NtBHA, etc, and from clearnace rate to total pharmacokinetic profile and dosing required is really not going to lead to reliable conclusions.

-Michael

[trh001]

Since this isn't the CR listserv, I can thank Michael (by his preferred name) profusely, and publicly, for providing correction, guidance, and excellent references. Cheers to all. Tim

[rfarris]

Ok, I'm ready to cap up my NtBHA (and PBN). Does anyone know what volume 100mg of those would be? Or, more useful, which size caps would be 100mg, approximately?

Without knowing the density, I can't calculate the cap size. I know that I can get almost 800mg of piracetam in 00 caps, but only about 400mg of cinnamon. Can I get 100mg of the spin traps in size 2 caps? 3? 1?

Thanks!

[FunkOdyssey]

Why don't you just:

1) Weigh an empty size 2 cap

2) Fill it with spin trap

3) Weigh filled cap

4) Subtract weight of empty cap to determine how much spin trap fits in size 2 cap

5) Repeat for other cap sizes as needed

[rfarris]

Because I only have 00 caps. If someone whom had already capped some spin traps shared the size with me, I would order the appropriate cap today.

[stellar]

Oh, almost forgot. Relentless is taking both NtBHA and PBN off their site after today. If you are interested, you better get your order in.

Why?

[nbourbaki]

Ok, I'm ready to cap up my NtBHA (and PBN).  Does anyone know what volume 100mg of those would be?  Or, more useful, which size caps would be 100mg, approximately?

Without knowing the density, I can't calculate the cap size.  I know that I can get almost 800mg of piracetam in 00 caps, but only about 400mg of cinnamon.  Can I get 100mg of the spin traps in size 2 caps?  3?  1?

Thanks!

You really can't estimate by volume. If your over by 100mg of piracetam, no big deal. Far less is known about NtBHA and PBN. I measure each cap twice for accuracy.

[rfarris]

Would you mind telling me which size cap you're using?

[rfarris]

Ok, I have to guess that no one is actually capping spin traps. I ordered some #2 caps and will report back with my results. I suspect that the #2 is small, but I'd rather have to take two or three caps instead of half of one.

[Karomesis]

have you received your order yet and do you get a confirmation of any sort prior to that? Gave him email address and fax number, but no response, yet. it's only be 3 days, though.

hell yeah, pete runs a tight ship at relentless. I did recieve a confirm e-mail and it was here in 2 days [:o] [:o] Beats any other supplier I have done business with. [thumb] The guy sends thank you cards with fine art on them, who else does anything even remotely similar?

[syr_]

The guy sends thank you cards with fine art on them, who else does anything even remotely similar?

I got 3 christmas cards from supplement companies/shops last christmas