DNP - Soon to get Approved for Fat Loss in a Country Near You
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Most of us are aware of the recent push to develop "weight-loss" drugs that will help thin out the obese western population. The ones that are currently being used, the GLP-1's, do so through less than perfect means.
Many are aware of the recently discovered BAM-15, which has been studied in rodents as being protective against various metabolic conditions and stressors.
There is, however, to my knowledge, not a single human study using BAM-15, even though it is available on the black market.
What will be of interest to the members of this forum, however, is that Rivus Pharmaceuticals has developed an orally available prodrug to DNP they call HU6 (that's right - it converts to DNP). It has been studied in humans to significantly reduce liver fat associated with obesity and metabolic syndrome.
https://www.thelancet.com/journals/langas/article/PIIS2468-1253(23)00198-X/abstract
In fact, a Phase II trial has already been completed in which various doses were administered that closely mirror the underground doses of DNP to achieve weight loss. Liver fat reductions were significant and there were no deaths or serious adverse events.
Only a matter of time before Big Pharma slaps a new label on good old DNP, which since the '20's was used to lean out the fatties.
DNP
HU6
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@jamezb46 Seems to have alot of side effects, including cardiac ones.
"In those treated with HU6, flushing (19 [32%] participants), diarrhoea (15 [25%] participants), and palpitations (seven [12%] participants) were the most frequently reported TEAEs "
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True, I wouldn't use it myself. It should have similar safety profile to DNP itself. The innovation is that the conversion to DNP is slow which means there is more of a "controlled burn" than with DNP itself
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@jamezb46 Surely, given the 72 hour half life (iirc), the steady state concentration would be the same eventually?
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Do you have a reference for the human half life of 72 hours for oral administration?
According to the below report by the CDC, DNP given orally to dogs does not accumulate.
"The time course of plasma concentrations of 2,4-DNP following oral administration to dogs (one per
dose) at 5, 12.5, or 25 mg/kg gave no evidence of a trend towards higher plasma levels with continued
daily dosing (Kaiser 1964). Hence, 2,4-DNP did not appear to accumulate."https://www.atsdr.cdc.gov/toxprofiles/tp64-c3.pdf
Likewise,
"The half-time for
absorption of 2,4-DNP following gavage administration of a single 22.5 mg/kg dose to mice was
0.5 hours based on serum concentrations of 2,4-DNP measured 1, 3, 6, 12, and 24 hours after dosing
(Robert and Hagardom 1983). Similarly, peak plasma concentrations occurred within the first 0.5–
2 hours of gavage doses up to 22.5 mg/kg in mice (Robert and Hagardom 1985) or 25 mg/kg/day in rats
(Perry et al. 2015a,b), and within the first 0.5–4 hours of oral doses up to 125 mg/kg in dogs (Kaiser
1964) "So, oral DNP does indeed seem to be rapidly absorbed.
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@jamezb46 Not 72 hours, that was off the top of my head. But there seems to be so much variance of reportedhalve lives
https://pmc.ncbi.nlm.nih.gov/articles/PMC4534549/#sec9
"The elimination half-life (t 1/2) of 2,4-DNP was (88.78±14.66) h in the routine HP group, while the t 1/2 was only (54.58±12.92) h in the intensive HP group. The t 1/2 of 2,4-DNP in the intensive HP group was apparently shorter than that in the routine HP group, with statistical significance (t=4.535, P=0.001)."
But the FDA says: "The elimination half-lives for the terminal phase were estimated at 10.3 hours for 2,4-DNP, 46.2 hours for 2-amino-4-nitrophenol, and 25.7 hours for 4-amino-2-nitrophenol."
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It definetley does accumalate though, which is why deaths are never instant - at least to my knowledge - so it must have quite a long half life.
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@alfredoolivas said in DNP - Soon to get Approved for Fat Loss in a Country Near You:
It definetley does accumalate though, which is why deaths are never instant - at least to my knowledge - so it must have quite a long half life.
Yes, we must not be deceived by short plasma half-lifes when in fact it accumulates within cells and tissues. Iirc of DNP fatalities they also showed increasing skin and tissue discoloration (yellow, as the DNP powder) and could die several days after their last dose. Giving a prodrug should simply extend that to even greater lengths?
It's reall not at all controllable by acute countermeasures. Wouldn't take it. -
Well, the study I linked showed no serious adverse events and certainly no deaths after 61 days at 450 mg per day of HU6.
If you look at the molecular structure of HU6, it's clear that for every one molecule of HU6, there is one molecule of DNP.
The Dinitrobenzene moiety on the lower left obviously can convert to DNP when the C-O bond is broken
I assume for the rest of my argument that the 5 carbon ring on the upper right is not pharmacologically active, though that clearly need not be true. If it is pharmacologically active, then the equivalent dose would be even higher than what I estimate below.
We can try to calculate the molecular weight of the moiety attached to the core DinitroBenzene molecule to calculate an equivalent dose of DNP.
Molecular weight of DiNitroBenzene core of HU6 = 6(12) + 2(14) + 4(16) + 16 = 180d
Molecular weight of moiety attached = 12 + 3(12) + 2(14) + 14 + 2(16) + 1 = 123d
=> Overall weight = 303d => fraction of weight that is converted to DNP (assuming perfect enzymatic conversion) = 0.6
=> Assuming 80% conversion = 0.47
So, 0.6 to 0.47 of the 450 mg dose is converted to active DNP, given the 80% efficiency assumption (which is arbitrary) = 450(0.47) - 450(0.6) = 213mg - 267mg DNP equivalent from the highest tested dose = 450 mg.
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@CrumblingCookie said in DNP - Soon to get Approved for Fat Loss in a Country Near You:
@alfredoolivas said in DNP - Soon to get Approved for Fat Loss in a Country Near You:
It definetley does accumalate though, which is why deaths are never instant - at least to my knowledge - so it must have quite a long half life.
Yes, we must not be deceived by short plasma half-lifes when in fact it accumulates within cells and tissues. Iirc of DNP fatalities they also showed increasing skin and tissue discoloration (yellow, as the DNP powder) and could die several days after their last dose. Giving a prodrug should simply extend that to even greater lengths?
It's reall not at all controllable by acute countermeasures. Wouldn't take it.If it does indeed accumulate, then wouldn't you see long lasting effects due to that accumulation? Or to put it another way, doesn't it mean you could just take one dose and be done until it clears your system?
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@alfredoolivas The question is whether those metabolites:
2-amino-4-nitrophenol and 4-amino-2-nitrophenol
are uncouplers or not.
At least the 4-amino variant appears not to be an uncoupler, nor does injecting it into rodents seem to cause cancer (see pages 6-9 below)
https://oehha.ca.gov/sites/default/files/media/downloads/proposition-65/chemicals/4am2ntro.pdf
The 2-amino variant appeared to decrease BW slightly only in male rats, was modestly toxic at very high doses to the kidneys, but is probably not carcinogenic. So, I doubt it is an uncoupler.
Therefore, it seems that those two metabolites are not uncouplers. If they were, we would have seen evidence of uncoupling in the rat models.
So, their long half-life is irrelevant as to the active life of DNP.
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@engineer I don't think any uncoupling agent does accumulate. Certainly the 2 and 4 amino metabolites I mentioned are not uncouplers.
The yellow color could be because of those metabolites, which themselves are yellow but are not uncouplers.
