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Extra Dakka in Drugs | Qualia Computing

Extra Dakka in Drugs | Qualia Computing

2023-11-12 21:05:05

By Sarah Constantin (weblog – 1, 2)

The More Dakka story is widespread in drugs. You do an intervention; the illness doesn’t get higher, or will get solely marginally higher; the analysis literature concludes it doesn’t work; no one tries doing MORE of that intervention, however when someone simply raises the dose excessive sufficient, it does work.

Examples:

a.) Chemotherapy didn’t work on most cancers till medical doctors made cocktails of medicine, raised the dose so excessive it might kill you, after which mitigated the unwanted side effects with prednisone and intermittent dosing schedules. If they simply used a secure day by day dose of a single chemotherapeutic agent, they’d have concluded chemo didn’t work.

Prednisone-2D-skeletal

Prednisone

b.) Mild remedy barely works for SAD; two internet-famous folks have independently found that REALLY BRIGHT mild remedy fully fixes SAD.

c.) The instance within the put up is about allopurinol. Allopurinol prevents gout assaults by decreasing uric acid. “In research, [allopurinol] improved [uric acid] linearly with dosage. Research noticed that sick sufferers whose [uric acid] reached wholesome ranges skilled full remission. The therapy was absolutely secure. Nobody tried growing the dose sufficient to cut back [uric acid] to wholesome ranges.

d.) The usual therapy for hypothyroidism is thyroid hormone. Folks with “subclinical hypothyroidism”– folks whose thyroid hormone ranges are decrease than common, however nonetheless above the cutoff for hypothyroid, and nonetheless endure from precisely the identical signs as hypothyroid–, ALSO profit from thyroid hormone remedy. It’s not commonplace of care but, although.

e.) I imagine some vitamin deficiencies, don’t bear in mind which precisely, are the identical means; there’s an official cutoff for “poor” however folks barely above that cutoff nonetheless have signs and nonetheless expertise symptom reduction from supplementation.

f.) Same deal with HIV. Virus has a replication fee & a clearance fee; its replication fee can be its mutation fee; an antiviral drug can increase the clearance fee above the replication fee, which is able to make the inhabitants drop exponentially, but when there’s just one drug the virus can have an opportunity to evolve to be resistant earlier than the inhabitants drops low sufficient to be undetectable. And it is a easy differential equation you could calculate years earlier than what the medicine even are. One drug: demise. Two medicine: demise. Three or extra medicine: survival.

Fortunately David Ho was a physicist and thought of it this fashion, so when the antiviral medicine got here out he was prepared to check them in cocktails.

So “single antibiotics don’t work for power Lyme however cocktails do and this wasn’t realized for many years” isn’t an unprecedented story. It may prove that means.

I guess that is one thing that has a extra formal and correct phrasing, however: if there’s an exponential-growth dynamic (like in a malignant most cancers or an an infection) the place you’re making an attempt to kill the exponentially-growing inhabitants, and if there’s a dose-response relationship the place larger dose = extra killing, then you’ve a bifurcation level within the final result as t -> infinity, the place a dose under that time means the enemy takes over and the affected person dies and a dose above that time means “the enemy is killed sooner than it might probably reproduce and so dies out in the long term.” And in precept you’ll be able to calculate this cutoff if the dose-response relationship, as Ho did.

And individually, there’s a security threshold; is the minimal efficient dose secure or unsafe? With chemotherapy, the minimal efficient dose is UNSAFE, which is why they should get intelligent with methods to present you doses excessive sufficient to kill you whereas retaining you alive anyway. (Or “discover a higher drug”, however no one has discovered a cytotoxic drug with strictly higher tolerability/effectiveness tradeoffs for the reason that 1960’s.)

That is kinda the way you get a steady/analog system to present you discrete outcomes: bifurcation factors! Works in gene regulation too. “This regulatory gene activates that gene’s transcription” – properly, what’s truly occurring is a steady scalar, a fee of transcription and a fee of clearance, however as a result of exponential features are concerned you get bifurcations in “steady-state” outcomes over the several-hour timescales wanted to get to “this cell has tons of mRNAs for that gene or it’s actually empty of them”.

Techniques biology is cool, it explains the maths that will get you from a statistical-chemistry mannequin of the cell (as a bag of molecules that stumble upon one another and have a chance of interplay) to a tinkertoy mannequin you could deal with like a graph. (Gene regulatory networks, protein-protein interplay networks, neuron networks, and many others.)



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