Starting article on "hormesis"
Hoping this is a reasonable approach
One of the first thing that hormesis brings to mind is type-0 and type-1 pharmacokinetics, especially drug (or toxin) clearance. Obviously simplified, zero-order kinetics has a basic model that the excretion process has infinite capacity, while first-order kinetics has a saturation point. More precisely, zero-order kinetics asssume a constant absolute rate of clearance, while first-order clearance assumes a constant fraction of the total body concentraion over time.
Such effects are at the high-end range of dose-effect mechanisms.
At a low end -- thinking of infection rather than drugs -- in biohazard mitigation and biological warfare work, there is a well-established "minimum infective concentration" (often expressed as the 50th percentile). Tularemia, for example, can establish disease with only a few cells, where more dangerous agents require a considerably larger concenntration.
Howard C. Berkowitz 12:32, 1 October 2008 (CDT)
- Interesting, Howard. Will give this some thought, and check 'hormesis' references to see if anyone touches on the subject.--Anthony.Sebastian 16:51, 12 October 2008 (UTC)
Michaelis-Menten work relevant here?
Is this an area that should be in this discussion? Howard C. Berkowitz 13:08, 1 October 2008 (CDT)
- Howard, how would you approach this? Would Briggs-Haldane kinetics serve better? Hope you will elaborate. --Anthony.Sebastian 16:51, 12 October 2008 (UTC)
- I've worked less with Briggs-Haldane, but isn't there a significant range in which they both apply? ? Briggs-Haldane appears to be an extension. When talking about the general issues of hormesis, is the difference really significant, or could many hormetic effects be explained by competitive inhibition of enough receptors to block the present effect of some toxic substance at constant concentration? (see note below about another possible mechanism)
- Let me answer directly, and also a little indirectly. Michaelis-Menten is about competitive inhibition. Assume chemical X is a toxin, even naturally produced. Further, there are cellular X-receptors, and there is a minimum trigger number of X-receptors that will cause an undesirable effect.
- If chemical Y competes for X-receptors, and the quantity of X does not increase, the physiological effect of X is blocked. Receptor blocking (or interfering in the pathway that creates the substance for which the receptor is sensitized) is common to many effective drugs.
- By receptor blocking, there actually are a number of places that the hormetic substance could work, such as being a presynaptic reuptake agonist or antagonist.
- Howard, very interesting, and I see your point. I think discussing suggested mechanisms of hormesis should come soon in the developing article, as ideas about mechanism will make reader undestanding of the phenomenon a lot easier. You have thought deeper on this than I have, but I will try to catch up.
- Re Briggs-Haldane vs. Michaelis-Menten, I wrote the following in the article on J. B. S. Haldane. Not exactly my area of expertise, so feel free to correct:
- Early on (1925), at Cambridge University, Haldane applied his early-acquired and life-long passion for mathematical analysis of biological chemistry to the field of enzymology. Enzymologists study the behavior of enzymes, the protein catalysts that accelerate biochemical reactions in living cells without themselves getting consumed in the reactions. Among other studies, enzymologists generate schematic and mathematical models of the many different kinds of biochemical reactions catalyzed by enzymes. With a colleague, George E. Briggs, Haldane presented a theoretical analysis of enzyme catalyzed reactions that could account for quantitative measurements of the rates of many of such reactions ('enzyme kinetics'). Briggs and Haldane used a different reaction equation and a more generally applicable assumption about the process of enzyme catalyzed reactions compared to the earlier model presented by Michaelis and Menten — specifically, they presented the mathematics of quasi-steady-state relationship of the enzyme-substrate complex whereas Michaelis and Menten analyzed the reactions at equilibrium. The Briggs-Haldane analysis remains the standard approach to enzymatic reaction ‘kinetics’, and has set a foundation for, and stimulated, the further developments in that field up to the 21st century.
- --Anthony.Sebastian 01:27, 13 October 2008 (UTC)
- Briggs GE, Haldane JBS. (1925) A note on the kinetics of enzyme reactions. Biochem J 19:338-339
- They end the paper: “It may be remarked that with this modification of their [earlier] theory, Michaelis and Menten's analysis of the effects of the products of the reaction, or other substances which combine with the enzyme, still holds good.”
- Tzafriri AR, Edelman ER. (2004) The total quasi-steady-state approximation is valid for reversible enzyme kinetics. Journal of Theoretical Biology 226 (3):303-313]
- Pedersena MG, Bersani AM, and Bersani E. (2007) The total quasi-steady-state approximation for fully competitive enzyme reactions. Bull.Math.Biol. 69 (1):433-457 PMID 16850351
A slightly different but not completely unrelated issue: could a hormetic dose of Z still be sufficient to activate or suppress an excretion pathway, such as one of the cytochrome P-450 variants
- Good thinking. Surely. --Anthony.Sebastian 01:27, 13 October 2008 (UTC)
Interesting study that may or may not be relevant
With the disclaimer that I am suffering from coffee deprivation, I ran across http://www.medicine.ox.ac.uk/bandolier/booth/painpag/Chronrev/Other/amifibro.html. It's an interesting although small study, but does deserve followup, since the lower dose (both still well below the antidepressant dose) was more effective than the higher, although it appears there was a period after which neither was effective.
It presents a number of questions that may or may not be within the scope of hormesis. Might the effect have been prolonged either with a lower starting dose, or (just a hunch) if the 25mg were put into a time-release form? Let me try to describe something I really should draw. If the ascii art doesn't make sense, I'll try to fix my scanner (cats think of it as a great resting place, but it quits when there's too much weight on it).
There's no controversy, in pharmacology, that there are subtherapeutic, therapeutic, and toxic levels of a drug. We are now finding, however, that some drugs have qualitatively different effects at different dosage levels, such as atypical antidepressants. I can't put my hands on the paper I want, but there's evidence venlafaxine (Effexor) has a dose-dependent relationship with three different neurotransmitter systems: norepinephrine, serotonin, and dopamine. Some psychiatrists suggest that the reason for raising the dose isn't to increase the level of the first, but to get to affecting the second or third. Would it be fair to say that the dosage needed to affect norepinephrine but not serotonin and dopamine is hormetic?
With administration of a conventional oral medication, time zerom,the blood level rises until it hits a peak level. Assuming zero-order kinetics, which is reasonable in a low-dose situation such as here:
................. | | | <---Peak level of higher-dose drug . 2nd NT activated | | - ................ | | - - | <---Peak level of lower-dose drug . 1st NT activated - - | ................. | _ | - - | 0 0 0 0 0 0 0 0 0 0 1 1 1 0 1 2 3 4 5 6 7 8 9 0 1 2
In other words, the hormetic zone is that level that activates the first, but not the second, neurotransmitter. By giving a larger dose in the hope of extending effects, the second, which is detrimental, is activated. A slow-release variant, however, might hold the blood level in the "hormetic zone" for a longer period.
Amitriptyline, the drug in the paper I mentioned, is a post-synaptic inhibitor of catechol-O-methyltransferase, which breaks down both NE and ST. I don't know if there are any level-dependent effects on COMT, such that a low dose might be more selective. Since there have been some studies suggesting that people with fibromyalgia may have low peripheral serotonin levels, if amitriptyline only potentiated serotonin in a low dose, AND that's the fibromyalgia mechanism, the low-dose effect might be explainable.
A very different area, but that might tie in somewhere, are drugs, such as theophylline, whose clearance is a function of diurnal cycles. An idealized regimen for theophylline gives it twice daily, but not q12h. The times have to be optimized for each patient. Howard C. Berkowitz 18:02, 19 October 2008 (UTC)
Calabrese and clarity
To be honest, I had to reread the quote several times. Might I suggest some rephrasing, perhaps using "therapeutic index" as the base concept and then discussing variation?
Perhaps I'm reading something not there, but I have a sense that there is a suggestion that controlled use of toxic doses is inherently wrong. A trivial example would be the surgical use of neuromuscular blocking agents, which certainly would kill a patient not on a ventilator. A more complex situation would be the technique of leucovorin rescue following high-dose antifolate drugs such as methotrexate. Do the proponents of hormesis fundamentally object to all toxicity, or just toxicity that may have unpredictable effects, such as tumor activation? Howard C. Berkowitz 22:10, 15 November 2008 (UTC)
Wonderful stuff as always - my copy edits- as always keep or discard at will.Gareth Leng 14:14, 7 January 2009 (UTC)