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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: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline

« The Hydrogen Wave Function, Imaged | Main | Update on Bexarotene for Alzheimer's »

May 29, 2013

Sulfa Side Effects, Decades Later

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Posted by Derek

You'd think that by now we'd know all there is to know about the side effects of sulfa drugs, wouldn't you? These were the top-flight antibiotics about 80 years ago, remember, and they've been in use (in one form or another) ever since. But some people have had pronounced CNS side effects from their use, and it's never been clear why.

Until now, that is. Here's a new paper in Science that shows that this class of drugs inhibits the synthesis of tetrahydrobiopterin, an essential cofactor for a number of hydroxylase and reductase enzymes. And that in turn interferes with neurotransmitter levels, specifically dopamine and serotonin. The specific culprit here seems to be sepiapterin reductase (SPR). Here's a summary at C&E News.

This just goes to show you how much there is to know, even about things that have been around forever (by drug industry standards). And every time something like this comes up, I wonder what else there is that we haven't uncovered yet. . .

Comments (17) + TrackBacks (0) | Category: Infectious Diseases | Toxicology


COMMENTS

1. nitrosonium on May 29, 2013 10:51 AM writes...

THB is also cofactor in NO synthase

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2. MDA Student on May 29, 2013 12:06 PM writes...

If the polypharm of a drug is missed, odds are its going to be missed in grandfathered/GRAS drugs.

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3. luysii on May 29, 2013 12:52 PM writes...

For 3 more examples of the unexpected actions of drugs, including two drugs that were rationally designed to attack a specific disease, please see

https://luysii.wordpress.com/2013/05/29/why-drug-discovery-is-so-hard-reason-22b-drugs-arent-always-doing-the-things-we-think-they-are/

This is one of the things that makes drug discovery so hard -- we don't fully understand the system we're trying to influence. This leads to frustration, loss of money, and the shedding of chemists by big pharma.

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4. Mimer on May 29, 2013 2:19 PM writes...

Derek, should we as drug researchers adapt to the already overwhelming use by the medical community of "antibiotics" for all anti-infectives, including synthetic antibacterials? I don't think so but I'm afraid that the fight is already lost. True antibiotic researchers, however, still cling to the correct use, i.e. "Antibiotics may be informally defined as the subgroup of anti-infectives that are derived from bacterial sources and are used to treat bacterial infections".

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5. darwinsdog on May 29, 2013 2:39 PM writes...

A nice piece of work but still just a hypothesis since there is a big jump to make from in vitro catecholamine synthesis inhib. and concluding that is the cause of various CNS effects (I would make that bet but add that at such high micromolar levels of these drugs there could be many enzymes inhibited and contributing to the polypharmacology and this is just one possible example). Appropriately, the paper doesn't reach beyond the observation. That won't stop some in-over-their-head of research from putting the sulfonamide group on a black-list.

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6. Am I Lloyd peptide on May 29, 2013 3:45 PM writes...

#3 luysii; You don't always need to fully understand the system you are trying to influence (although it helps). Many drugs have been and will continue to be discovered by phenotypic screening.

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7. luysii on May 29, 2013 5:03 PM writes...

#6 Am I Lloyd peptide -- agree -- but wouldn't it be nice if we understand the system better? I have to think that drug development would be more fruitful.

What I find so interesting about two of the three examples I gave, is that in both, discovery was based on an understanding of what we were trying to treat, the drugs had the desired effect on the targeted system, but even then they are also doing something else (which may be equally important for their therapeutic effect).

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8. IBD Sufferer on May 29, 2013 6:47 PM writes...

There's a bunch of us IBD/Colitis/Crohn's patients who still suck down several large tablets of sulfasalazine every day. Is that form of sulfa part of the problem?

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9. jbosch on May 30, 2013 8:04 AM writes...

#7 luysii: but wouldn't it be nice if we understand the system better? I have to think that drug development would be more fruitful.

That's what I think too. However there's a whole generation of people stuck in the phenotypic screening mode as being the de facto standard for drug discovery, calling it "the proven technique" in contrast to more modern approaches.

You guys are all pretty smart out there, is anybody aware of a publication which examines drugs developed and approved say before 1990-2000 and drugs that came later ?
What I expect to see is a shift in techniques for drug discovery in the later developed drugs. In particular more driven by either biochemistry of a given system or structural knowledge aka crystal structure of protein X versus classical phenotypic whole cell screening.

Any thoughts ?

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10. dave w on May 30, 2013 1:27 PM writes...

Re #4... with respect to defining "antibiotics" as the "subgroup of anti-infectives that are derived from bacterial sources and are used to treat bacterial infections" - doesn't this overlook the fact that many are derived from fungal sources, rather than bateria per se? (Is it any less imprecise to include fungi in with "bacteria" than it is to include the sulfa substances in the "antibiotics"?)

The definition might be perhaps better stated as "derived from microbial sources..."

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11. hcc biochemist on May 30, 2013 5:06 PM writes...

As a biochemist, with personal experience of the CNS effects of a sulfa drug, it brought me great joy to read a possible molecular mechanism, thanks for highlighting the paper.

IBD sufferer, yes one of the drugs tested was sulfasalazine, although CNS side effects with this drug are very rare, they can happen and this paper gives at least one reason why this might be the case.

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12. Cellbio on May 30, 2013 9:59 PM writes...

jbosch,

You overstate the case, quite a bit. Phenotypic screening is not prevalent now. Some folks, like me for instance, argue that to ignore it in favor of pursuing only target based HTS campaigns is foolish, given the early days of drug discovery success rates compared to today. A good logical argument does not say that phenotypic screening is the only way to go, and neither does it say we should not use modern approaches. In fact, the use of newly developed techniques and instrumentation opens the door to phenotypic screening being much more powerful than prior days when the core apparatus, tissue baths, was produced by a skilled glass blower.

In addition, an inescapable part of drug discovery that everyone needs to digest is that once you get to preclinical and clinical work, drug discovery is phenotypic. Animal models are phenotypic (though myopic), most of toxicology is phenotypic, even if observed through a microscope in sections, and clinical measures of efficacy and adverse events are phenotypic.

This leads me to conclude, that no matter what start a program gets, target-based or phenotypic, early phenotypic measures make sense. While it is a neat story to find out later that an efficacious drug has broader pharmacology than first appreciated, this is a rarer outcome than terminations due to unintended pharmacology in tox or early clinical trials.

So, rather than think of this as a new stuck generation eschewing the modern, think of us as folks who think the modern target based drug discovery effort displaced core skills and we are paying the price in failing pipelines. If that core skill, pharmacology, is rebranded as phenotypic screening, or system biology, or integrative biology, it may be so because it is also being reborn with new methodologies and data mining capabilities that revitalize old school pharmacology.

No matter the terms applied, success comes from properly moving the 'system' from a pathological state. I am quite convinced that what we learn about the system both creates drug discovery opportunities and tail chasing exercises, with more of the later in my experience. It appears to me that knowing more makes us feel better about our failures, because at least we could articulate a fact filled rationale.

The rational falls apart quickly when whole sets of compounds with nearly identical profiles from a med chem effort are profiled in broad fashion, and one sees extensive diversity of pharmacology. Everyone I know who has seen this in a program converts to this idea of a 'new' approach to drug discovery that uses the principles of cellular pharmacology at a scale now enabled by technology.

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13. Erebus on May 31, 2013 1:14 AM writes...

Does this imply, as I suspect, that tetrahydrobiopterin administration could prevent or ameliorate sulfa-drug side effects? THB is already approved by the FDA as "Kuvan" -- so this might represent some interesting commercial opportunities.

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14. molecular game on May 31, 2013 2:06 AM writes...

#4: Etymology subtopic! What you are probably clinging to is the antibiotic definition given by Waksman (1941, published in 1947) and precised by #10. Interestingly, this definition takes its root from the term "antibiote" coined by Vuillemin in 1889 for any organism “displaying a toxic or deleterious action on another organism for the benefit of its own”. Since then however, science has evolved a lot and the situation has become murkier:
- antibiotics from microbial origin can be produced synthetically (eg chloramphenicol). Would you still call the man-made chloramphenicol "antibiotic"?
- many useful antibacterial compounds have been derived from synthetic modification of natural antibiotic (macrolide, b-lactams...). Where do you draw the line, not necessarily knowing if what the chemist modifies has not been already produced by nature?
- To complicate the situation even more, some "made-made" synthetic compounds used as antibacterials have later on been described as secondary metabolites produced "naturally" in human neutrophils (hypochlorous acid!)
>>> So in doubt, the antibiotic definition has been been, rightfully IMHO, extended to ANY antibacterial compound, synthetically and/or naturally made.

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15. Paul on May 31, 2013 7:50 AM writes...

#13: I don't think the molecule crosses the blood brain barrier very well.

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16. Erebus on May 31, 2013 1:30 PM writes...

It does seem to cross the BBB to some extent. (Fiege B, Ballhausen D, Kierat L, et al. Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. Mol Genet Metab. 2004;81(1):45-51.)

...And, in any case, many of the really serious CNS-related side effects from sulfa drugs are peripheral -- like neuritis and spinal cord myelin degeneration.

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17. HTSguy on June 6, 2013 10:41 AM writes...

#16: The spinal cord is inside of the BBB and is part of the CNS.

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