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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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October 18, 2011

Cyclodextrin's Day in the Sun

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Posted by Derek

Under the "Who'da thought?" category, put this news about cyclodextrin. For those outside the field, that's a ring of glucose molecules, strung end to end like a necklace. (Three-dimensionally, it's a lot more like a thick-cut onion ring - see that link for a picture). The most common form, beta-cyclodextrin, has seven glucoses. That structure gives it some interesting properties - the polar hydroxy groups are mostly around the edges and outside surface, while the inside is more friendly to less water-soluble molecules. It's a longtime additive in drug formulations for just that purpose - there are many, many examples known of molecules that fit into the middle of a cyclodextrin in aqueous solution.

But as this story at the Wall Street Journal shows, it's not inert. A group studying possible therapies for Niemann-Pick C disease (a defect in cholesterol storage and handling) was going about this the usual way - one group of animals was getting the proposed therapy, while the other was just getting the drug vehicle. But this time, the vehicle group showed equivalent improvement to the drug-treatment group.

Now, most of the time that happens when neither of them worked; that'll give you equivalence all right. But in this case, both groups showed real improvement. Further study showed that the cyclodextrin derivative used in the dosing vehicle was the active agent. And that's doubly surprising, since one of the big effects seen was on cholesterol accumulation in the central neurons of the rodents. It's hard to imagine that a molecule as big (and as polar-surfaced) as cyclodextrin could cross into the brain, but it's also hard to see how you could have these effects without that happening. It's still an open question - see that PLoS One paper link for a series of hypotheses. One way or another, this will provide a lot of leads and new understanding in this field:

Although the means by which CD exerts its beneficial effects in NPC disease are not understood, the outcome of CD treatment is clearly remarkable. It leads to delay in onset of clinical signs, a significant increase in lifespan, a reduction in cholesterol and ganglioside accumulation in neurons, reduced neurodegeneration, and normalization of markers for both autophagy and neuro-inflammation. Understanding the mechanism of action for CD will not only provide key insights into the cholesterol and GSL dysregulatory events in NPC disease and related disorders, but may also lead to a better understanding of homeostatic regulation of these molecules within normal neurons. Furthermore, elucidating the role of CD in amelioration of NPC disease will likely assist in development of new therapeutic options for this and other fatal lysosomal disorders.

Meanwhile, the key role of cholesterol in the envelope of HIV has led to the use of cyclodextrin as a possible antiretroviral. This looks like a very fortunate intersection of a wide-ranging, important biomolecule (cholesterol) with a widely studied, well-tolerated complexing agent for it (cyclodextrin). It'll be fun to watch how all this plays out. . .

Comments (16) + TrackBacks (0) | Category: Biological News | Infectious Diseases | The Central Nervous System | Toxicology


1. Cyberax on October 18, 2011 12:18 PM writes...

I imagine that meeting:

"Gentlemen, we have two news: the good one and the bad one. The good one is that we've found an active component. The bad one is that this component is the placebo we've used"

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2. luysii on October 18, 2011 12:23 PM writes...

This is exactly the way valproic acid (Depakene, Depakote), an extremely useful anticonvulsant in the 70s - 90s era, was found. To get into the brain, an orally administered molecule must be quite lipid soluble as, like it or not, our brains are mostly fat. So molecules to be tested had to be put into a lipid solvent. Depakote (4 carboxy heptane) was the solvent. Everything seemed to work, and someone had the brains to do the control.

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3. hobglobulin on October 18, 2011 12:25 PM writes...

Calando Pharmaceuticals uses a cyclodextrin-based delivery system for siRNA.

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4. SteveM on October 18, 2011 12:48 PM writes...

Football coaching legend Ara Parsigian lost 3 grandchildren to Niemann-Pick, so he set up a research foundation.

Must be a brutal disease. Hope this interesting discovery is meaningful.

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5. pete on October 18, 2011 12:55 PM writes...

So, maybe we've finally arrived at that long fabled orally available / pleasant tasting (*sugar!*) / triple-strength PLACEBO

[Very cool story - hope it can translate into human Niemann-Pick patients]

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6. simpl on October 18, 2011 12:57 PM writes...

reminds me of DMSO testing positive for hair growth (written up in the google fringe) With DMSO being a useful solvent for in-vivo tests, how many labs stumbled across this?. I don't know who discovered this first, but I di remember a derivative being tested in the 90's in phase I. It was abandoned as some patients smelt too strongly.

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7. wather on October 18, 2011 1:25 PM writes...

...."the Wall Steet Journal"....that well- established, well-refereed scientic journal.....

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8. Pete on October 18, 2011 3:19 PM writes...

I've taken a quick look at the article on the screen and may well be missing something. It looked like the cyclodextrin was injected. I tend to think of cyclodextrins as a means to increase oral absorption although this may reflect the fact that I've only rarely worked on projects where we were looking for an injectable drug. It would have been very interesting if they'd been able to get some blood levels of the cyclodextrin. Also cyclodextrins come in different sizes and it'd be very interesting to see if the size of the cyclodextrin is a factor.

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9. Anonymous on October 18, 2011 6:31 PM writes...

Score one for the supramolecular chemists. Not to mention we've had an aerosol cure the whole time!

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10. gippgig on October 18, 2011 10:39 PM writes...

Now, does CD also do these things in normal animals?

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11. NJBiologist on October 19, 2011 11:08 AM writes...

@5 pete--No, unfortunately the oral bioavailabiltiy of cyclodextrins approaches zero: they break down in stomach acid.

@10 gippgig--That's been reported, although I can't seem to find the reference in my pile here at work....

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12. see what fits in my big ring on October 19, 2011 1:19 PM writes...

This is similar to the story of the discovery of Bridion (Sugammadex) which is a cyclodextrin based drug. Discovered by Organon chemists in the former Merck site in Scotland. Their reward? Merck shut it down.

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13. gippgig on October 19, 2011 1:41 PM writes...

Has anyone investigated the inositol analog of CD? It should be resistant to acid hydrolysis. Of course, since it's a different compound it could be toxic (and would probably be harder to make too).

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14. Brett on October 19, 2011 10:14 PM writes...

I'm a member of one of the labs involved in the research. Yes, the size of the cyclodextrin does matter. It's specific to beta-cyclodextrin, which also happens to be the best at binding cholesterol. Presumably what it's doing is removing excess cholesterol before the cholesterol can have its lipotoxic effects, which is also likely why it has to be delivered so frequently to have an effect.

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15. pete on October 20, 2011 3:13 PM writes...

@11 NJBiologist
Noted (bummer) -- Contest for appropriate candidate is back on

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16. Chris Hempel on October 23, 2011 2:12 PM writes...

Thanks Derek for reposting the WSJ article. I am the Mom treating my twins with both intravenous and intrathecal cyclodextrin (HPbCD) -- my twins have had over 25 injections into their spines so the cyclodextrin can reach their brains. I have lots of data on this compound on my website and what we are doing with -

We have filed for orphan drug designations with both the FDA and EMA and received the designation from both agencies.

Also, all anyone has to do is look at the HIV data from over years ago -- cyclodextrin kills the HIV virus.

Research by the Dietschy Lab at UT Southwestern you will see they are completley arresting the progressive neurological condition by putting cyclodextrin (HPbCD) into the brain of the mice.

Niemann Pick Type C is a genetic cholesterol disease -- the NPC1 gene controls human cholesterol metabolism at the cellular level.

The gene controls viral entry into the cell with both HIV and Ebola (and likely many other viruses).

I have told my twins are immune to getting HIV and Ebola -- they can't be infected because of this NPC1 gene defect.

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