Former date rape drug reincarnated as answer to unmet medical needs

Just a quick post on an article that caught my eye: Jazz Pharmaceuticals of Palo Alto, CA, has announced that the US FDA has accepted their new drug application (NDA) filing for JZP-6, or sodium oxybate, for the treatment of pain and fatigue associated with fibromyalgia.
The NDA was based on positive outcomes of two, Phase III clinical trials – those randomized, placebo-controlled double-blind trials that serve as the gold standard for drug efficacy. The company expects an approval decision from FDA by October 2010.
Jazz has already garnered approval for sodium oxybate under the brand name Xyrem® for the treatment of daytime sleepiness in patients with narcolepsy. The company stresses, however, that the drug has not yet been approved for symptoms associated with fibromyalgia.
200px-4-hydroxybutanoic-acid.pngThe item of note here is that sodium oxybate is another name for the sodium salt of gamma-hydroxybutyrate or GHB, a sedative that resembles the inhibitory neurotransmitter GABA but also has its own receptors in the central nervous system. GHB was implicated as far back as the early 1990s on college campuses where young men who lacked any other redeeming qualities to attract women used it to dope the drinks of their dates.
But here we see the study of a drug of abuse giving rise to a useful pharmaceutical, first in narcolepsy and, soon perhaps, for fibromyalgia.
It is a paradox of pharmacology that a sedative like GHB would prevent excessive sleepiness or fatigue. But a similar paradox exists with the use of the stimulant methyphenidate in hyperactivity conditions.
Now that I’ve seen the business reports, I’ll turn to some of my CNS pharmacology colleagues to help explain the neurobiology.
However, this compound demonstrates to me the unanticipated benefits of funding research that aims to investigate drugs of abuse.
Beneficial therapeutic agents come when and where you may least expect them.

Did the patient fail the treatment or did we fail the patient?

While the coffee wasn’t quite ready this morning, I ventured to the Wall Street Journal health page at the Wall Street Journal, one of my frequent first-reads.
I was immediately intrigued by a short article from the excellent Jennifer Corbett Dooren about Roche-Genentech gaining US FDA approval for a new rheumatoid arthritis drug, Actemra.
Actemra (tocilizumab) is a monoclonal antibody that works via a novel mechanism of blocking the receptor for interleukin-6, a pro-inflammatory molecule called a cytokine. What is most important is that Actemra appears to work in patients who have not been helped by other existing drugs such as those like Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab) that block the effects of another cytokine called TNF-alpha.
Rheumatoid arthritis is not just joint aches and pains. It is a very serious disease that can cause not just pain but deformity and progressive disability. Rheumatoid arthritis afflicts 1.3 million people in the US.
But what caught my eye and generated my pre-caffeine ire was in the opening sentence, terminology used in clinical pharmacology and therapeutics, words that I admit to have even uttered myself:

WASHINGTON–The Food and Drug Administration Friday approved a new type of drug by Roche Holding AG’s Genentech unit to treat rheumatoid arthritis in patients who have failed other treatments. [emphasis mine]

I know that we use that phrase because it is seems less cumbersome than saying, “in patients whose disease has not responded to existing drugs.”
But saying that the patient failed the treatment makes it seems that the patient somehow bears responsibility for the lack of their disease to respond to the tools we currently have available. Yes, yes, I know – disease is essentially a patient’s own pathophysiology, where their own homeostatic mechanisms are awry or respond inappropriately to environmental changes or invading organisms.
But jeez, have you ever thought what it sounds like to a patient to hear that they failed the therapy? Could we possibly take any less responsibility for our failure to treat disease? Even if physicians want to use the word “fail” couldn’t they at least shift the blame to us basic scientists who’ve failed to come up with an alternative drug?
As I’m writing this and searching for literature on the medical psychology of using this term, I just realized why I am bothered. If we accept that medicine says, “the patient failed the treatment,” that’s one thing. What troubles me is that I just read the statement in the opening sentence of an article in a highly-regarded business publication crafted by a health and medicine writer whom I respect.
Don’t get me wrong. I’m all for personal responsibility in health. All of us could do a better job of watching what we eat, exercising more, not smoking, drinking alcohol in moderation – the big four factors that could make a greater impact on human disease than the next new wonder drug.
But just because a $10,000/year drug doesn’t work for me and my rheumatoid arthritis, does that really mean that “I failed the treatment?”
I know we’ve got some medical sociologists and psychologists out there reading – I’d be grateful for any commentary or direction to scholarly literature on why we continue to use the term, “the patient failed the treatment.”
One final note
As an amorphous descriptor, Big Pharma has certainly lost a lot of trust of the general public and the scientific community over the past several years from data cover-ups on drug-related deaths to ghostwriting of peer-reviewed journal articles, the latter of which was eloquently addressed by Orac last year. These practices are inexcusable and deserve strong punishment, especially where it is clear that loss of lives was a result of deceptive clinical data submission.
I’ve had the pleasure of training with many outstanding scientists who now work in the industry and, particularly in the field of pharmacology, have come to respect and learn from new colleagues who’ve chosen industrial careers. Several of these people are among the most ethical I know and, as with any other industry, are pained equally if not more by the scandalous cases.
So when good things happen, such as the approval of a new drug that has the potential to help people in pain for whom no other agent has helped, I like to acknowledge the efforts of those folks behind the work.
Let me offer my heartiest congratulations to colleagues at Roche and Genentech on this nail biter after having been asked for more data last year. Addressing these kinds of scientific and regulatory challenges gives me great respect for my colleagues at the bench and in the clinic who have worked to relieve human suffering from this debilitating disease.

“Complementary and alternative medicine (CAM)” is not a single “thing”

I just had a chance to check in on a triad of posts by Prof Janet Stemwedel at Adventures in Ethics and Science (1, 2, 3) on the ethical issues of the conduct of studies, particularly clinical trials, supported by the US NIH’s National Center for Complementary and Alternative Medicine (NCCAM).
For background, NCCAM was originally established for political, not scientific reasons, as the NIH Office of Alternative Medicine in October 1991. It received a token budget of $2 million at the time. They still only get $120-ish million; modest by NIH standards as compared, say, with the 2007 NCI budget of about $4.8 billion. But that $120-125 million is pretty significant in that it could fund about 60 independent researchers and their laboratory groups for five full years.
How was alternative medicine defined then? Primarily as folk and cultural modalities not incorporated into conventional Western medicine but used and promoted for disease treatment or prevention without statistically-defined efficacy and safety. The net was cast very wide, from “energy therapies” that defy the basic tenets of physics to herbal medicines that have given rise to 25% of prescription medicines.
Hence, CAM is not one modality. It is a term used to describe a wide spectrum of health-promoting approaches that have not been evaluated previously under rigorous, controlled basic or clinical science standards.
CAM is a terrible term. It is NOT medicine. Modalities proven to work are medicine. Modalities that don’t work are not medicine. There is no complement to medicine. Medicine is medicine. There is no integrative medicine, either. Medicine already takes advantage of all modalities: surgical, pharmacological, radiological, physical, psychological, nutritional – if a clear benefit can be offered to a patient that outweighs the risk.
So-called integrative medicine gurus have adopted proven, preventive medicine techniques – diet, exercise, meditation, yoga – and have used them 1) to justify that “CAM” works and 2) that the efficacy of these approaches justifies study and implementation of approaches that have absolutely no scientific basis.
Oh yeah, often with substantive personal financial benefit.

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Cancer research funding: not just a bunch of self-serving whining

Our quick post yesterday cited Jonathan Alter’s Newsweek essay this week on the sad state of cancer research funding in the context of Hamilton Jordan’s recent death and Ted Kennedy’s recent glioblastoma diagnosis. Like many areas of US federal research funding, cancer research support has been flat under the Bush administration and, in fact, declined in real dollars since 2004.
But when one hears a federally-funded researcher like me whining about this situation, one might think I am solely acting in a self-serving fashion, caring only about the preservation of my career and that of my trainees – the next generation of cancer researchers.
Well, Marilyn Chase has a short piece on page 3 of this morning’s Wall Street Journal that raises another issue about cancer research funding that should concern all citizens and their loved ones with cancer:

Dr. Davidson, a professor of oncology at Johns Hopkins University in Baltimore, said the situation has led to a curtailment of research into breast cancer, melanoma, sarcoma and pediatric cancer.

“A hundred Phase I and Phase II clinical trials have been postponed, and the number of people able to participate in clinical trials has been reduced by 3,000,”
she said. [my emphasis]

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When medical experimental therapeutics gets co-opted as complementary and alternative medicine (CAM)

Sorry to get to this so late but I wanted to weigh on an excellent post from my cancer blogging colleague, Orac, the other day on the investigation of CAM therapies in cancer. The post covers a lot of ground, as expected from any of Orac’s exhaustive missives, but I wanted to focus on the comparison and contracts between NIH’s National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Cancer Complementary and Alternative Medicine within the National Cancer Institute (NCI-OCCAM).
I am on record as a strong critic of NCCAM but a supporter of NCI’s OCCAM in that the latter is much more committed to real science and issues of cancer patients being preyed upon by unscrupulous marketers. I would argue that each NIH Institute would best have a division like OCCAM to focus on the most widely used alternative therapies within each disease area and dismantle NCCAM.
One of Orac’s commenters, factician, commented that she might swallow her ethics and apply for some of this NCCAM funding:

It makes me more than a little bit angry to know that if I were dishonest or incompetent, that I would have an easier time getting money applying to the NCCAM.

But contrary to what you might think, NCCAM funding is not easy money at all. Looking at the NIH IC rankings for FY2007, overall funding success % (not percentiles, which are much lower) is barely 11% for NCCAM while it is about twice that for NCI, NIDDK, etc. In fact, many superb investigators are quite surprised when their NCCAM-directed grants get shitcanned.

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Science Based Medicine: a superb new group blog

I’m very excited to announce to Terra Sig readers the kickoff of a new group blog called Science Based Medicine. Yes, it may sound odd that one would need to preface “Medicine” with the qualifier, “Science-Based,” but therein lies the goal of this new resource from its mission statement:

Safe and effective health care is critical to to everyone’s quality of life; so much so that it is generally considered a basic human right. The best method for determining which interventions and health products are safe and effective is, without question, good science. Therefore it is in everyone’s best interest for health care to be systematically evaluated by the best science available. . .
. . .And yet there are numerous and powerful influences in society that strongly appose the scientific basis of medicine. Driven by some combination of ideology or the desire for profit they wish to eliminate standards of science in health care, or (often under the guise of “health care freedom”) create a double standard in which unscientific methods and products can thrive unchecked.

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Snake Oil Science sounds like a great read

A former research director for a complementary and alternative medicine program at a major academic medical center has just released a book that I must get my hands on. I just learned about “Snake Oil Science” by R. Barker Bausell from a Jerry Adler article in the current issue of Newsweek (10 Dec 2007).
To set the proper context, med bloggers like Orac, Dr. R.W., Panda Bear, MD, Sid Schwab, and we here at Terra Sig have been increasingly expressing concern about the seemingly uncritical integration of alternative medicine programs into some of North America’s most respected medical schools and academic medical centers. (Orac’s recent post is a particularly excellent resource in that it aggregates links to those centers.).

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Children’s Cold Medicine Controversy

Perhaps you’ve stumbled on this post late at night while tending to a child suffering from a cold.
Well, I’ve been reading a fair bit lately about the 18-19 October meeting of the FDA’s joint meeting of their Nonprescription Drug and Pediatric Advisory Committees, trying to make sense about calls to restrict or prohibit the use of cough and cold medicines in children under age 6. There is so much material on the subject that I have hesitated to post on the issue until I received the following e-mail from an old friend, fellow scientist and parent, North of 49:

Okay, so I’m writing to you to in order to prod you to open up a discussion on Terra Sig about the FDA recommendation that cough and cold medicines not be administered to kids. As a pharmacologist, what are your thoughts on this? What about as a parent?
According to the FDA’s own report, only 11 [efficacy] studies (in humans) have been done on these compounds, and even they admit that many of these were scientifically flawed. Yet, the FDA panel voted (13-9) to recommend stopping the use of cough and cold meds for kids [aged 2 to 5 yrs]. My feeling is that this is likely because of the deaths that have resulted from their improper use – A quick check, however, reveals that since 1969, 123 kids have died. This sounds like a lot, but when you calculate the number of doses that must have been given in the 38 yr time period, and the fact that (according to the FDA) a number of deaths were the result of parental error (either overdose of using multiple meds with similar active ingredients), it seems to me (as a humble physiologist) that your chances of being struck by lightning are higher if the meds are used properly – In fact, your chance of being struck (and killed) by lightning are approximately 20-fold higher – In the USA every year, 73 people die after being struck by lightning!!! (source)
Damn you Mother Nature!! Perhaps the FDA will recommend that we never go outside.
Also, the odds of death by a spoonful of medicine don’t even come close to the matching the odds of what we would (rationally) consider highly, highly improbable events:
Odds of fatally slipping in bath or shower: 2,232 to 1
Odds of getting away with murder: 2 to 1
Odds of dating a supermodel: 88,000 to 1
Odds of being on plane with a drunken pilot: 117 to 1
Chance that Earth will experience a catastrophic collision with an asteroid in the next 100 years: 1 in 5,000
(source)
Please guide us in this important discussion, o wise one.

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Marine Chemical Ecology: Therapeutic Natural Products from the Sea

In a post the other day, we noted that the semi-synthetic natural product, ixabepilone, approved for advanced breast cancer was derived from a soil bacterium. Colleague PharmCanuck reminded us that the soil is not a new source for drugs: the anthracyclines, daunorubicin and doxorubicin, are derived from a strain of Streptomyces found growing on a 13th century castle along the Adriatic Sea (hence the brand name for doxorubicin, Adriamycin). Amazingly, Adriamycin remains a foundation of many breast cancer chemo regimens more than 30 years after its approval.
While we speak here quite often about plants or terrestrial microorganisms as drug sources, we tend to shortchange marine creatures and marine microorganisms. In fact, a rather old anti-leukemia drug, cytosine arabinoside (ara-C, cytarabine), was first inspired by compounds isolated from Cryptotheca crypta, a Pacific sponge – and I don’t mean Kato Kaelin.

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Another botanical clinical trial doomed to failure from day 1

This post appeared originally on 8 Feb 2006 at the old site for this blog. A frequent reader and commenter, Joe, suggested that I repost it here as it illustrates many common problems with clinical trials of botanical medicines.
You’d think the funding folks would learn at the NIH National Center for Complementary and Alternative Medicine (NCCAM). But, not as evidenced by the report in tomorrow’s New England Journal of Medicine detailing the lack of efficacy of saw palmetto (Serenoa repens) extract in the treatment of benign prostatic hypertrophy.
Yet another well-designed double-blind, placebo-controlled trial has been doomed to failure by inadequate chemical characteriztion of the study material. Political pressure to produce a postive clinical result has bypassed the normal path of pre-requisite basic science studies, casting a shadow on what may still be a useful herbal medicine.
About 2.5 million US men use extracts of berries from saw palmetto, a low-lying, scrubby palm native to the coastal southeast from South Carolina to Florida that can also be found in southern California. A couple of small clinical trials, covered in this Cochrane review, had intimated that saw palmetto extracts can improve urinary flow in men with enlarged prostate glands, with efficacy similar to the prescription drug finasteride. Finasteride, sold in the US as Proscar, inhibits an enzyme called 5-alpha-reductase that converts testosterone to its more active form, dihydrotestosterone. As a result, finasteride has been associated with a greater incidence of sexual side effects (mostly ejaculatory disturbances) relative to saw palmetto as detailed in this meta-analysis.
No one knows for sure how saw palmetto is thought to work. Some reports suggest that it too is a 5-alpha-reductase inhibitor, but then wouldn’t it be expected to produce the same sexual side effects as finasteride? No evidence exists either to suggest that saw palmetto might act as a alpha-1A adrenergic receptor antagonist, like another prescription drug, tamulosin.
In fact, no one knows the precise chemical compound(s) in saw palmetto extract that reduces prostate swelling. How then could a major US funding agency approve the conduct of a clinical trial when there was no possible way to chemically characterize the study agent? If you don’t know what to look for, how do you know it’s there?
Well, an advisory panel for NCCAM thinks they know. Cited in the paper was that while there are no widely-accepted guidelines on the content of saw palmetto extracts, a number of authorities have recommended that extract contain 80-95% fatty acids or 85-95% fatty acids and >0.2% sterols. Why no requirements for the presence of specific compounds with real, IUPAC names?…because no one knows the identity of the active components of this herbal extract. Would you be willing to invest what was probably $2-4 million in a clinical trial of this extract?
Not me, and certainly not with US taxpayer’s money. The scientific approach would be, minimally, to design an in vitro model for markers of prostatic hypertrophy (not exactly my area of expertise) and then chemically fractionate saw palmetto extracts to find the one, two, or ten chemical compounds that had effects on these endpoints. Then, you might want to try some simple metabolism experiments (and perhaps a phase I clinical trial where these pharmacokinetic parameters are assessed before anyone in their right mind would jump full bore into a phase III efficacy trial) to be sure that any of these compounds might make it to bloodstream and the prostate in concentrations consistent with these effects when patients are given a certain dose. After all, we catabolize fatty acids for energy and the liver’s cytochrome P450 drug metabolizing enzymes are likely to have first evolved to destroy plant sterols we encounter in our diet.

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