Thursday, February 17, 2005

Pipeline Update: Insomnia;
Implications for Basic Science

Yesterday, I did a CME program (Medscape, free registration required) on insomnia.  The program was sponsored by Pfizer and Neurocrine.  Neurocrine, as it turns out, is developing a new medication, indiplon, which Pfizer will market.  This sort of arrangement is common: a small company develops the drug, and then contracts with a big company to sell it.  Often, then, one of them will sponsor educational programs to promote awareness of the drug.  Because of FDA restrictions, they cannot actually advertise the drug before it is approved.  Therefore, they use the CME (Continuing Medical Education) channel to increase awareness of the product and develop some interest in the medical community.

These things generally are sponsored by unrestricted educational grants, which means that they cannot influence the content of the presentation or program.  It is an interesting exercise to look at them and see if any commercial bias is evident.  In this case, there wasn't any obvious bias.  There was a section on "Newer Compounds" that described four agents that are not on the market yet.  One of them, eszopiclone, has been approved in the US, and should be available soon.  The other three are in various stages of development.  The section on indiplon was a couple of sentences longer than the sections for the other three new products, but it appears to be accurate and objective.  Neurocrine has a web page describing the compound, for those who are interested.  One unique aspect to the marketing of indiplon is that they have come up with two formulations.  One is an immediate-release preparation, to be used for those with early or middle insomnia, but not early morning awakening.  They also have a modified-release preparation, for those with early morning awakening.  The MR releases some drug right away, to put the person to sleep, then another bolus later in the night.  Clever.

That, however, is not what really caught my attention.  There is another product in the pipeline, gaboxadol, that is a topic of interest.  Gaboxadol is being developed in Europe by a Danish company, Lundbeck

Chemical structure of gaboxadol

Gaboxadol is a peculiar CNS drug: it acts at nonsynaptic receptors.  It has a selective effect on GABA-A receptors, which is not terribly unusual these days, but the demonstration of activity upon receptors that are not located at a neuronal synapse is unusual.  I am hopeful that further investigation of this may lead to important discoveries about the fundamental principles of brain function. 

We've known for a while that the nerve cells in the brain sometimes have receptors in odd locations.  For example, some nerve cells that release norepinephrine have presynaptic receptors that are sensitive to serotonin.  We have no idea why they are there.  It is fortunate that they are; an antidepressant, mirtazapine, acts on those receptors.  Investigation of apparent anomalies such as these sometimes leads to important discoveries. 

Gaboxadol has another interesting property.  From the Medscape article:

Gaboxadol. Another GABA-A receptor agonist, THIP, or gaboxadol, has been given some attention in Europe as a possible treatment for insomnia. Gaboxadol is unique in that it acts at GABA receptors in nonsynaptic locations. These receptors have a high affinity for GABA, and desensitize slowly.[46,78] The pharmacologic and clinical properties of gaboxadol most likely reflect its potent effects at extrasynaptic GABA-A receptors insensitive to benzodiazepines and containing alpha(4)beta(3)delta subunits.[46,78] A study by Krogsgaard-Larsen and associates[78] of the effect of gaboxadol on human sleep patterns showed that the functional consequences of a directly acting agonist are distinctly different from those seen after administration of GABA-A receptor modulators, such as benzodiazepines.

Mathias and colleagues[79] investigated the influence of a single oral dose of 20 mg gaboxadol on postnap sleep (as a model of disturbed nocturnal sleep) in a randomized, placebo-controlled cross-over study in young, healthy subjects. The study authors noted that previous studies have demonstrated that gaboxadol increases both non-REM sleep and EEG delta activity within non-REM sleep in rats and slow-wave sleep (SWS) as well as low-frequency activity in the EEG within non-REM sleep in healthy humans under normal conditions. Compared with the placebo postnap night, gaboxadol tended to shorten sleep latency, significantly reduced intermittent wakefulness, lengthened total sleep time and SWS, enhanced delta and theta activity in the non-REM EEG, and improved subjective sleep quality.[79]

Not many drugs increase slow-wave sleep.  Slow-wave sleep is important, although frankly, its exact significance is still being investigated.  We know that it plays a role in the consolidation of memory, for example.  We also know that persons with fibromyalgia tend to have too little slow wave sleep.  Sodium oxybate (Xyrem) has been shown to increase slow wave sleep and reduce pain in fibromyalgia patients.  Xyrem has a high potential for abuse, so it can be prescribed only under a special program.  Gaboxadol probably will have a much lower potential for abuse.  If it also helps fibromyalgia patients, that would be an important advance. 

Some persons are interested in the pharmaceutical pipeline, so they can rush out and buy stock in companies that are likely to introduce a successful new drug.  Personally, I don't care about that.  I wouldn't buy stock on that basis, because it would be a conflict of interest: it could affect my prescribing pattern, which would not be right.  Rather, the reason I am interesting in drug development is that it can potentially teach us about how the brain works.  Gaboxadol acts on nonsynaptic receptors, and increases slow-wave sleep.  Understanding the role of nonsynaptic receptors could lead to a much greater understanding of the functional organization of the brain.  Understanding the relationship between sleep patterns and disease could help us understand, not only the brain, but the fundamentals of how various body systems interact in health and disease:
Sleep, cytokines and immune function
Sleep Med Rev. 1999 Sep;3(3):219-28
Dickstein JB, Moldofsky H.

Bi-directional communication pathways exist between the brain and the cytokine-immune-endocrine systems. The hypothalamic-pituitary axis, the efferent neuronal hypothalamus-autonomic nervous system axis, and the direct drainage of macromolecules from the brain into the blood and the lymphatic system provide a network by which the sleeping/waking brain influence bodily functions. Similarly, changes in cytokine levels in the periphery modulate the central nervous system either directly or via the vagal nerve and influence the sleeping/waking brain. In humans, circadian nocturnal sleep-daytime wakefulness is associated with changes in peripheral cytokines, cellular immune functions, and endocrines. Progesterone levels influence sleep and cellular immune functions during the menstrual cycle. The interaction between the circadian sleeping/waking brain and the cytokine-immune-endocrine system are integral to preserving homeostasis. Disorganization or loss of sleep disrupts the harmonious integration of the circadian cytokine-immune-endocrine system. However, the mechanisms of circadian sleep/wakefulness-related cytokine-immune-endocrine functions in host defence against disease remain to be determined.
"The mechanisms remain to be determined."  We hear that a lot.  I am hopeful, though, that the interplay between basic science research, and applied research by pharmaceutical companies, will lead to: "Now we finally understand the mechanism."

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Tuesday, February 15, 2005

Changes in the Drug Safety Landscape

The New York Times today has two articles about changes at the FDA.  One mentions that the Agency has a new commissioner.  The second informs us that the FDA is creating anew board to monitor drug safety.  Also the New England Journal of Medicine published today was a set of early-release articles about the safety concerns that have arisen regarding Cox-2 inhibitors (Vioxx, Bextra, Celebrex).  The articles are on the NEJM website now, and will be printed in the 3/17/2005 issue. 

The Cox-2 story has attracted a lot of attention, and I am not sure I have anything to add to the volumes written already.  However, the Corpus Callosum is all about connections, and the two topics -- the changes at the FDA, and the Cox-2 story -- are indeed connected.  The top job at the FDA has been vacant for a long time, possibly because not a lot of people actually want the job right now.  And the creation of a new drug safety board is a direct response to the public concern about the Cox-2 inhibitors, among other recent and brewing matters.  However, the Bush Administration does not have good record when it comes to addressing matters of public safety.  Do the current efforts exceed our expectations, or do they fall short?

The NYT article about the new commissioner, Dr. Lester M. Crawford, informs us that he is a veterinarian with a PhD in pharmacology.  He has experience in government, academia, and in the food industry.  Reviews of his selection have been mixed:
"By rewarding Mr. Crawford for buckling under political pressure, President Bush is showing his true colors once again," said Nancy Keenan, president of Naral Pro-Choice America, an abortion rights group. "In this administration, keeping far-right activists happy is the most important thing."
Frankly, I'm not sure that Dr. Crawford views this new job as a "reward."  Nor am I sure that NARAL has the expertise to make an informed judgment on this topic.  Other reviewed were mixed, or positive:
Not all consumer groups agreed. "He's not my ideal candidate, but the devil you know is better than the one you don't," said Dr. Michael F. Jacobson, executive director of the Center for Science in the Public Interest, a frequent critic of the government and the food industry.
Senator Edward M. Kennedy, the Massachusetts Democrat whose opposition could have proved troublesome, said, "Dr. Crawford has had a long association with the F.D.A. and is intimately familiar with the issues facing the agency."
My concern is not about the man, since I frankly don't know the guy, and as far as I know, he appears to be qualified.  At least he's willing to do it, despite the fact that he undoubtedly will face intense scrutiny and frequent criticism, no matter what he does.  Rather, my concern is about the new drug safety board. 

One of the editorials in the NEJM (subscription required for full text) states:
COX-2 Inhibitors -- Lessons in Drug Safety
Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D.
February 15, 2005

[...] We believe that to protect the public, Congress needs to provide the FDA with the necessary authority and also to create an independent Center for Drug Safety with new authority and funding.  Civil penalties should be commensurate with drug sales.  Provisional approval and regular repeated review would provide opportunities to reevaluate risk and benefit.  In addition, congressional oversight of the FDA would afford an important forum for the public discussion of drug safety.  [...]
However, the new board, as currently conceptualized, will not be independent, there is no provision for direct congressional oversight, appears to have no new authority, and there is not sufficient funding:
F.D.A. to Establish Group to Monitor Approved Medicines

WASHINGTON, Feb. 15 - Responding to widespread criticism that government oversight of drug safety problems is inadequate, the Food and Drug Administration announced today that it is creating an independent drug-safety board.

Dr. Lester Crawford, the F.D.A.'s acting commissioner, said that the board would be made up of scientists from several government departments as well as the chairmen of the F.D.A.'s independent advisory boards.

When drug controversies erupt, the board will examine the science involved and decide how the agency should respond and what to tell patients. [...]

Dr. Crawford, who is being nominated by President Bush to head the agency, acknowledged that its present system for monitoring unexpected and sometimes lethal drug reactions is a passive system.

"We need an active system," he said.

The announcements drew muted praise from drug-safety advocates and academics. Advocates have been calling for a more muscular drug-safety agency that would be entirely independent of the F.D.A. or at least independent of the agency's drug review division. The new board will not be completely independent of either.

In addition, academics note that creating an active drug reaction surveillance system could cost tens of millions of dollars each year. So far, there is no money in the agency's budget for such an expense. [...]
Creating a separate agency would be politically unpopular, in these days of budget cutting and supposedly smaller government.  The last major restructuring of the FDA included a provision for partial funding from the drug industry.  That seemed like a good idea at the time, since it took some burden off of taxpayers.  Now, however, it is one factor that has been implicated in the creation of the more recent controversies.  Having an independent review board would enable the FDA to  receive funding from industry, but eliminate or reduce the worry about conflict of interest. 

The NEJM editorial by Drs. Psaty and Furberg mentions that the new board should have real authority.  This should include the ability to mandate remedial action by industry.  Currently, the FDA negotiates with industry about any proposed changes.  Of course, the companies come to these negotiations armed with reams of data and carefully-crafted arguments, often the result of lengthy, costly preparations by a small army of experts.  To counter that, the FDA has few harried scientists, understaffed, with limited financial resources.  In that context, negotiation is not very effective.  They need legal authority.  The editorial mentions several areas specifically.  These include the ability to change product labels, mandate physician or patient education, limit or ban certain advertising campaigns, modify approved uses of medications, or to restrict the use of medication to certain subgroups of patients.  Perhaps most importantly, they need authority to mandate the completion of post-marketing surveillance studies. 

Yes it would cost money.  Remember, though, that we are spending over a billion dollars a week fighting an unnecessary war, in an adventure that is costing more American lives than it ever will save.  In that perspective, spending tens of millions of dollars per year, to save thousands -- maybe tens of thousands -- of lives, looks like a pretty good deal.

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Sunday, February 13, 2005

Traditional Wisdom

You know what they say: He who hesitates, is lost.  Those same people say: Look before you leap.  So what should we do?  If you hesitate, you loose; if you don't hesitate, you loose. 

The great thing about conventional wisdom is that it is free.  All you have to do is sit in an easy chair somewhere and think about it. 

Plain old common sense tells us that humans are too complex to have come into existence via evolution.  After all, where would the first biologically-significant molecules come from?  Outer space?

Actually, yes.  Radio astronomers have detected signals from aldehydes, important precursors for prebiotic chemistry, in outer space.  26,000 light-years away, to be exact, in an area known as Sagittarius B2.
"The detection of the two new aldehydes, which are related by a common chemical pathway called hydrogen addition, demonstrates that evolution to more complex species occurs routinely in interstellar clouds and that a relatively simple mechanism may build large molecules out of smaller ones. The GBT [ Robert C. Byrd Green Bank Telescope] is now a key instrument in exploring chemical evolution in space," said Hollis.
Traditional wisdom also tells us that bacteria will loose their resistance to antibiotics, if allowed to grow long enough in the absence of antibiotics.  Sometimes, that's because the mechanism for antibiotic resistance take energy for the bacteria, and if there is no need to expend that energy, the organism will stop doing it.  Even if the structural changes needed for antibiotic resistance do not require energy, the structure cannot be the optimum for the organism.  That's because, if it were optimum, the organism already would have been making the structure that way. 

Actually, no.  The scenarios described above are the ones that are most likely to be true, in a typical situation.  But there is no guarantee that they will be true in all cases.  Certainly, though, antibiotic-resistant organisms can't possibly be hardier than their non-resistant precursors, can they?

Actually, yes.  Veterinary microbiologists have discovered that antibiotic-resistant bacteria can outcompete strains that are not resistant to antibiotics, even if grown in the absence of antibiotics. 
Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure
Naidan Luo, Sonia Pereira, Orhan Sahin , Jun Lin, Shouxiong Huang, Linda Michel, and Qijing Zhang
PNAS | January 18, 2005 | vol. 102 | no. 3 | 541-546

Campylobacter jejuni, a major foodborne human pathogen, has become increasingly resistant to fluoroquinolone (FQ) antimicrobials. By using clonally related isolates and genetically defined mutants, we determined the fitness of FQ-resistant Campylobacter in chicken (a natural host and a major reservoir for C. jejuni) in the absence of antibiotic selection pressure. When monoinoculated into the host, FQ-resistant and FQ-susceptible Campylobacter displayed similar levels of colonization and persistence in the absence of FQ antimicrobials. The prolonged colonization in chickens did not result in loss of the FQ resistance and the resistance-conferring point mutation (C257 -> T) in the gyrA gene. Strikingly, when coinoculated into chickens, the FQ-resistant Campylobacter isolates outcompeted the majority of the FQ-susceptible strains, indicating that the resistant Campylobacter was biologically fit in the chicken host. The fitness advantage was not due to compensatory mutations in the genes targeted by FQ and was linked directly to the single point mutation in gyrA, which confers on Campylobacter a high-level resistance to FQ antimicrobials. In certain genetic backgrounds, the same point mutation entailed a biological cost on Campylobacter, as evidenced by its inability to compete with the FQ-susceptible Campylobacter. These findings provide a previously undescribed demonstration of the profound effect of a resistance-conferring point mutation in gyrA on the fitness of a major foodborne pathogen in its natural host and suggest that the rapid emergence of FQ-resistant Campylobacter on a worldwide scale may be attributable partly to the enhanced fitness of the FQ-resistant isolates.
Conventional wisdom is great, unless you really want to know the truth.  If you do want to know the truth, you have to do the experiment.  Conventional wisdom doesn't cost anything, and it is worth every penny.

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