Archive for the 'Pharmacology' category
Sorry folks, I'm swamped lately. Kept meaning to do something for Black History Month that was new but I haven't managed to get to it. So I'll repost this from a few years back. It originally appeared on the SB blog Feb 17, 2009.
sourcePercy Lavon Julian, Ph.D. (1899-1975) was a scientist who rose from humble beginnings, was trained and educated in an adverse cultural era and became a highly accomplished synthetic chemist and entrepreneur (Wikipedia; PubMed; ACS bio). From the American Chemical Society biography:
He was born in Montgomery, Alabama, on April 11, 1899, the son of a railway clerk and the grandson of slaves. From the beginning, he did well in school, but there was no public high school for African-Americans in Montgomery. Julian graduated from an all-black normal school inadequately prepared for college. Even so, in the fall of 1916, at the age of 17, he was accepted as a subfreshman at DePauw University in Greencastle, Indiana. This meant that in addition to his regular college courses he took remedial classes at a nearby high school. He also had to work in order to pay his college expenses. Nevertheless, he excelled. Julian was elected to Phi Beta Kappa and graduated with a B.A. degree in 1920 as valedictorian of his class.
A link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were "first in class", i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 "follower" drugs.
The review also focused mostly on small molecule drugs instead of "biologics" because of an assumption that the latter are all exclusively "target based" discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That's my formulation of what the authors term "target based screening" (which may include "molecular mechanism of action") discovery and "phenotypic screening" type of discovery. As they put it:
The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.
A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.
You will note that this is related to some comments I made previously about mouse models of depression.
The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:
For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome
and for target based approaches:
A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir
The authors even ventured to distinguish discovery approaches by disease area:
Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases
Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.
Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.
The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can't really go into the details but there are areas where my professional career is...affected, let us say...by the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:
at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.
Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.
in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.
Ultimately I think this review argues quite effectively for an "all hands on deck" approach to drug discovery but it can't help but come off as a strong caution to the folks that think that "smarter" (aka, "rational drug design") is the only solution. Yes, this points the finger at Francis Collins' big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480
Professor David E. Nichols is a legend for scientists who are interested in the behavioral pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, aka, 'Ecstasy'). If you look carefully at many of the earlier papers (and some not-so-early) you will see that people obtained their research supply of this drug from him. As well as much of their background knowledge from publications he has co-authored. He has also worked on a number of other compounds which manipulate dopaminergic and/or serotonergic neurotransmission, some of which are of great interest to those in the recreational user community who seek (ever and anon) new highs, particularly ones that might be similar to their favorite illicit drugs but that may not currently be controlled. Those who are interested in making money supplying the recreational consumer population are particularly interested in the latter, of course.
Professor Nichols has published a recent viewpoint in Nature in which he muses on the uses to which some of his work has been put:
A few weeks ago, a colleague sent me a link to an article in the Wall Street Journal. It described a "laboratory-adept European entrepreneur" and his chief chemist, who were mining the scientific literature to find ideas for new designer drugs — dubbed legal highs. I was particularly disturbed to see my name in the article, and that I had "been especially valuable" to their cause. I subsequently received e-mails saying I should stop my research, and that I was an embarrassment to my university.
I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people.
As with most scientists, I have little doubt. And ultimately, I agree with his observation that
There really is no way to change the way we publish things, although in one case we did decide not to study or publish on a molecule we knew to be very toxic. I guess you could call that self-censure. Although some of my results have been, shall we say, abused, one cannot know where research ultimately will lead. I strive to find positive things, and when my research is used for negative ends it upsets me.
It is unfortunate that Professor Nichols has been put in this position. Undoubtedly John Huffman of JWH-018 fame (one of the more popular synthetic full-agonist cannabinoids sprayed on herbal incense products) feels much the same about his own work. But I suppose this is the risk that is run with many lines of basic and pre-clinical work. Not just recreational drug use but even therapeutic use- after all off-label prescribing has to start somewhere. And individual health (or do I mean "health") practices such as high-dosing on blueberries or cranberries, various so-called "nutritional supplements", avoiding certain foods, exercise regimes, diets, etc may be based on no more than a single scientific paper, right?
So we should all feel some bit of Professor Nichols' pain, even if our own work hasn't been mis-used or over-interpreted...yet.
UPDATE: Thoughts from David Kroll over at the cenblog home of Terra Sigillata.
You may have heard a bit on your local news or perhaps read a piece in your local paper about quasi-legal synthetic marijuana products being sold in your local head shop as "incense". They come under a variety of brand names of which Spice and K2 may be most familiar. Very likely, the media bit you have seen was from some local politician or other trying to make some political hay over his or her concerns that this incense is ruining the lives of the constituency. All that hysteria for incense? Something else must be afoot, you are thinking...and you are quite correct.
Please join me in offering your congratulations to our good blog friend Scicurious of the Neurotopia blog. She has announced that the defense of her dissertation went brilliantly and she has been awarded her Ph.D.
This is a wonderful accomplishment and I do hope she is in the midst of enjoying the moment in the company of friends, colleagues and significant others. As many of my readers know, graduate school can be a hard and soul-crushing experience at times. Unfortunately, our business still delights in a "school of hard knocks" approach at certain stages of training. It is testament to grit, smarts, determination, desire and beyond all else a burning need to find stuff out when someone is finally admitted to the Tribe of doctoral scientists.
For those of you who read both of our blogs, it should not be surprising that I operate in related and overlapping subfields of biomedical science with Scicurious. On this more personal note, I am overjoyed that such a highly promising young scientist has made it over this particular hurdle into the field. I am familiar with her doctoral work and it is impressive. Findings that will have sustained impact on her areas of investigation and ones that seem to me to have a great many implications for much broader areas of science.
Reading through the lines, as it were, I am also impressed that Sci has received what I consider to be some of the best, if not easiest, training if you want to eventually head your own laboratory. And that is the training of having to learn some pretty hard scientific approaches on your own hook, trouble shoot, refine and make them pump out data. It may be a bit of a bias of mine but I am far more impressed by a grad student or postdoc who had to build up a research capacity that was not the heart of the training PI's lab than I am by an arm's length list of papers coming from a "slot-into-the-machine-and-churn-it-out" trainee.
This is not just me talking, either. I hope I am not stepping too far out of line to observe that Sci has been on a great number of postdoctoral interviews with extremely well-respected laboratories and has received many offers. I am unsurprised by this- if there was a logical fit with my lab I would have been giving the hard sell myself. But it adds a little perspective to my comments- this is not just blogger homeslicery talking here. As it was, I had a lot of fun trying to pimp out a few of my peers to Sci, trying to get her to go work with them. I look forward to seeing where Sci lands in her next career step and I anticipate many more scientific accomplishments are on the horizon.
If you haven't done so already I urge you to wander over to Neurotopia and leave her a congratulatory comment.
[ Please welcome our guest blogger, who identifies as robin, just your average everyday neuropharmacologist. -DM ]
One of the most important yet overlooked tasks of the average pharmacologist is dissolving drugs into solution. Those of you who work with things that don't have to cross the blood-brain barrier probably have a generally easier time dissolving shit than those of us who prefer to study CNS-active compounds. For those of us who play with compounds that are hydrophobic enough to cross the blood-brain barrier, I can testify that those range from fairly easy to major suck to put into an aqueous solution.
A 19-year-old man was found dead in Boulder on Tuesday morning, and authorities suspect poppy tea as the cause.
If so, it would be the second death in five months of a young person in Boulder who drank opium tea, police said.
Jeffrey Joseph Bohan, a 2008 graduate of Fairview High School in Boulder, drank the powerful psychoactive brew with his older brother about midnight, authorities said.
His brother found him unresponsive at 6 a.m. in a home
Abel Pharmboy had written some comments about that first death of a young man in Boulder. In the first post, Able overviewed a bit of the history of the medicinal (and recreational) preparation of products from the opium poppy.
The sad fact is that we've known for over 200 years that this is a bad idea: based upon growing conditions, harvest time, and extraction method, the resulting concoction can provide an extremely variable dose of these compounds. Used medicinally as one of the strongest analgesics ("painkillers") we know, in higher doses the opiates can impart a warming sense of euphoria but, at even higher doses, suppresses the respiratory control center of the brain stem, resulting in death.
Abel also mentioned a website created by a father of yet another kid who overdosed on poppy tea. The point of Poppy Seed Tea Can Kill is, quite obviously, to educate people on the risks of home-brewed poppy tea. It includes a redacted version of the drug panels run on his son postmortem which is a great thing. I wish all the parents / closest relative of the folks who die from "Ecstasy" would do similar- this kind of information goes a long way toward addressing controversy over what did and did not kill the individual.
At any rate, it is very sad that this seeming fad in recreational drug use is resulting in fatalities. It seems that it is doing so almost entirely because the dose is so hard to control / appreciate under the typical use circumstances. Perhaps publicizing this hypothesis widely would go a long way toward harm reduction by inducing a bit of caution in the user population. I can hope, anyway.
See, now this is the problem with trying to make complex scientific points relatively simple. They never are. Biology and physiology are complicated and thus we end up minimizing or overlooking important aspects at times. Luckily in the blogosphere someone is usually all over it.
Abel Pharmboy responded to my recent post on a paper comparing MDMA pharmacokinetics between humans and one of the animal models which has generated the most specific and controversial data as a real pharmacologist should:
Getting back to other differences even within a given species is that the initial, non-conjugative metabolism of MDMA is mediated by CYP2D6, a notoriously polymorphic enzyme. In humans, there are significant interethnic differences in 2D6 activity: ~75 allelic variations that are grouped into four phenotypes: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). (nice free full-text review, albeit in the oncology setting, by CYP clinical pharm guru David Flockhart and colleagues.)
So, if there is toxicity in humans, it is important to consider whether the parent MDMA or any number of its metabolites are neurotoxic and whether there are correlations of toxicity with individuals any of the four phenotypes. As if that is not complicated enough, the methylenedioxy group (the MD of MDMA) is notorious for mechanism-based inhibition of P450 activities and I'm having trouble thinking of whether this would be have more or less influence on a poor or ultra-rapid metabolizing individual.
Hammer meet head of nail.