Parents of kids with rare disease found a promising drug | Hacker News Reader

Parents of kids with rare disease found a promising drug

arstechnica.com

74 pointsshawndumas20 comments

> Typical treatments include statins and other cholesterol-lowering drugs, which are not always effective, particularly when patients don’t adhere to doctor-prescribed, low-cholesterol diets.

Must an otherwise good article perpetuate the tired bullshit about dietary cholesterol.

A piece of white bread topped with sugary jam (optionally on top of margarine) is a low-cholesterol snack.

Just because cholesterol shows up from what you ate doesn't mean that, say, statins aren't working; maybe you're just throwing off the method by which their effectiveness is indirectly gauged.

Please provide sources that dietary cholesterol has no impact.

See e.g. http://chriskresser.com/the-diet-heart-myth-cholesterol-and-... and the references therein.

Also, read https://en.wikipedia.org/wiki/Phytosterol#Cholesterol_loweri...

Dietary cholesterol seems to have a minor (~10%) impact on serum cholesterol levels, and no impact on CVD or all cause mortality. And this has been known (and ignored) IIRC for about 40 years now. Cholesterol is a symptom of problems, not their cause.

Note, however, that this is regarding a typical human. There are rare genetic diseases in which cholesterol itself is the culprit. I have no knowledge of this specific disease, but it might be one of them.

I know it doesn't have an impact in healthy people, but what about people with hypercholesterolemia?

I don't know if it is the case, but it sounds plausible that the drugs that regulate endogenous production like statins would only be effective in the absence of an external supply (since they don't affect the way cholesterolemia is regulated).

Expanding on this:

Cholesterol is a key culprit in atherosclerosis, not just a marker. It accumulates in the walls of blood vessels in the form of fibro-fatty plaques that are responsible for angina, infarctus, stroke etc.

The reason why it accumulates has not been completely elucidated (related to endothelium stress, caused by toxins like tobacco and bacteria that break in into the blood because of gingivitis).

The higher the level of cholesterol (especially LDL [†]) in the blood, the more plaque forms and the more one is at risk of consequences (plaque formation is rate-limited by cholesterolemia (blood cholesterol levels)).

Cholesterolemia in physiological conditions is independent of intake. If the body is in demand, the liver will synthetise cholesterol de novo in the absence of dieatary intake.

I don't think we know at this point what drives the demand, but we've developed drugs that work well on the innner supply end, namely statins, that block the production of cholesterol by the liver. They are, however, ineffective if you eat boatloads of cholesterol.

----

† Recent findings seem to show that HDL is not in itself protective, and that high levels of HDL (that are correlated with fewer complications) may be a passive marker of another protective process.

My father and I both have hdl levels that are 2 to 3 times higher then our ldl. We both also have Gilberts syndrome so I was hypothesising that it might be related but have not been able to find any research. Do you have links to these recent finding around the processes causing high hdl?

No link, but an experimental drug that moderately lowers LDL and dramatically raises HDL was recently abandoned after clinical trials showed no health benefits.

EDIT: H => L. hrrmm...

I heard that there are several phenotypes when it comes to dietary cholesterol. In people with normal cholesterol, dietary intake doesn't really matter, but in people with high cholesterol it does make a difference.

Yeah, it's so frustrating to read this tired regurgitation of the same old debunked info. The body uses cholesterol to repair lesions in artery walls. The lesions are the root problem, not the cholesterol, which is the body's only fix.

This is amazing. The unfortunate thing though is that the effectiveness of cyclodextrin on NPC (versus atherosclerosis) might not hold up to scrutiny - I remember the NPC finding when it first came out almost a decade ago (worked in a lab that was interested in NPC) but more recent experiments have thrown the result into question.

It's kind of strange that this hasn't been proposed before - when you buy cholesterol for scientific experiments, it's often encapsulated in cyclodextrin, that product has been around for a while.

[edit:] found this http://www.tandfonline.com/doi/abs/10.1080/10717540050120205... so someone has investigated it before, at least.

Article certainly piques my curiosity, unfortunately the paywall it's behind impedes getting the whole story. How often have we seen "breakthroughs" fail to live up to expectations, in this case not yet enough info to have any idea how it's likely to turn out.

An interesting side-note here is that cholesterol itself has "detergent-like" properties similar to the cyclodextrin agent. That is, both molecules have hydrophilic and hydrophobic ends, which enables stabilizing lipid droplets floating in an aqueous medium like the bloodstream. I suppose cyclodextrin properties will vary with molecular weight and conformation, but never would have guessed it would have the basic characteristics described.

Always amazes me where discoveries come from, goes to show it isn't always high-cost, specialized research that leads the way.

Beware surrogates. An apropos bit of news from a few days ago: http://www.nytimes.com/2016/04/04/health/dashing-hopes-study... http://blogs.sciencemag.org/pipeline/archives/2016/04/04/cet...

Cyclodextrin may be useful for Niemann-Pick disease, where the cholesterol itself is the immediate proximate cause of the problem, but if it's already clinically-approved and has been used, where are the heart attack correlations?

> but if it's already clinically-approved and has been used, where are the heart attack correlations?

This is what I'd like to know. I'm not a formulation chemist, but we should see differing outcomes related to different formulations. Maybe someone switched to PEG and saw worse outcomes for this reason?

I'd also be interested to see what happens with different substitutions on CD.

> but if it's already clinically-approved and has been used, where are the heart attack correlations?

I read is as being used currently, but the "breakthrough" being administration through IV. I'm not sure if that's correct, was just my interpretation.

Fantastically little information provided, yet it's called a "breakthrough!!".

How is the drug dosed? If it's oral, then I'm not surprised. It probably traps the cholesterol in the mouse-model diet before it can even be absorbed.

FTA:

    They found cyclodextrin and initially tried using it in
    oral doses, which is known to be safe. However, the 
    chemical couldn’t effectively reach the brain that way.
    The couple made headlines with their tireless efforts to
    get drug companies, the FDA, and doctors to let them try
    out intravenous treatments of cyclodextrin for their
    twins—and they won. Regular treatments gradually
    improved—although didn’t cure—the twins’ conditions.
    Cyclodextrin is now in clinical trials to treat other
    kids with NPC.

This interesting approach just raises more questions than it answers; experiments with sample size n=1 being run by non-medically trained individuals are unorthodox and generally suspect in the modern medical climate.

here's another experiment for you that I've run on myself:

When I consume products that contain wheat, I feel sick. When I don't, I feel fine. Sample size n=1, and I am not medically trained. What conclusions, if any, do you think I can draw from my experience?

Clearly, I need to stop eating wheat.

I don't know, did you control for placebo effects? Did you verify there isn't something else in those products that makes you feel sick?

Science is hard. Control experiments are key.

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