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Re: Ecstasy safely converted and prescribed? Larry Hoover

Posted by Dave001 on August 31, 2004, at 21:12:57

In reply to Re: Ecstasy safely converted and prescribed? Dave001, posted by Larry Hoover on August 31, 2004, at 10:48:57

> > > I appreciate the digression into uncertainties of estimate. There are always assumptions made in cross-species comparisons, of course. There are
> >
> > And thus the need to correct false assumptions, such as a 1:1 association with human metabolic rate. ;-)
>
> Indeed. Inter-species safety factors that I have worked with have been ten-fold, or hundred-fold, in different circumstances. We don't know that those safety factors are necessary. They arise from prudence. Overdosing a rat to produce neuronal damage is not generalizable, even with an a priori conversion factor. We're simpling being prudent.
>

True, though that's an issue not directly related to normalization for metabolic rate.

> > > also different ways to estimate HED (I assume yours is BW to the 2/3 power, rather than the metabolic parameter BW to the 3/4). Primate
> >
> > It is generally preferable to use standardized conversion factors which have demonstrated reasonable accuracy. Using generic formulas is usually is only advisable if the species is not listed or if the weight falls outside of the specified ranges.
>
> I was speaking to the EPA formulae for HED. The body area formula is the BW ^2/3 formula. I'd welcome another reference, for pharmacokinetic conversions, if you have one handy.
>

I'm assuming by BW you mean a ratio of animal to human weight; e.g., HED = animal dose * (animal weight/human weight)^2/3. Yeah, that is what I would go by in the absence of specific data for a given species, or if there is an extreme inner-species variation in weight.

Ah, here we go. I knew this had to be somewhere on their site. See <URL:http://www.fda.gov/cber/gdlns/dose.htm#v>; for dose conversion guidelines.

> > These are the methods used by drug companies when extrapolating from animal data to determine initial human doses.
>
> For phase one studies, which are later revised from empirical evidence. I'm sure there are variances from the 0.16 ratio, used a priori.
>
> > > studies are probably more applicable, and the same pattern is found as in the rats. I.e. only extremely high doses, or recurrent use without sufficient recovery time, lead to measurable neuronal damage or changes in neurotransmitter concentrations. Another variable to consider is antioxidant status, and I wonder if e.g. ravers aren't a little more likely to eat poorly?
> > >
> >
> > Quite possibly. I would imagine the body naturally kicks the production of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, etc., into full gear in the presence of such toxins.
>
> Perhaps, if nutrient stores are up to it. Antioxidants are sacrificial. They are consumed, so the physiological stress passes into distinct realms depending on antioxidant capacity at baseline. That was the conclusion of the authors of the rat study, that different outcomes are predicated by those thresholds of depletion.
>

True, though 'nutrient storage' is somewhat ambiguous in the context of enzymes which are endogenously produced "as needed" as opposed to dietary antioxidants. However, deficiencies of important enzyme cofactors could of course occur. The importance of age in regulating antioxidant defenses has been particularly impressive in many studies I've seen -- I mean to a much greater extant than one might expect.

Dave

> > > By no means was I suggesting the referenced article was conclusive, but merely suggestive. There is a toxic threshold, and the issue of exceeding that threshold is not clearly defined in humans.
> >
> > My comments were not intended to make any inference regarding the toxicity of MDMA.
> >
> > Dave
>
> Cool.
>
> Lar


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poster:Dave001 thread:383476
URL: http://www.dr-bob.org/babble/20040830/msgs/385023.html