Category → Miscellaneous
In this week’s issue, I look at the perceived exodus by pharma companies from neuroscience R&D. Between AstraZeneca’s recent cutbacks, the closure of Novartis’ neuroscience research facility in Basel, and earlier moves by GSK and Merck, industry watchers are understandably worried that the neuroscience pipeline will dry up.
One person who isn’t worried is Michael Ehlers, Pfizer’s chief scientific officer for neuroscience research. Ehlers came to Pfizer a year and a half ago from Duke, with the explicit mission to revamp how the company finds and develops drugs for brain diseases. The scientist is convinced that the field is ripe for new and better drugs, and that by staying in the game, Pfizer will be in a good position to capitalize on what he believes will be a healthy flow of new discoveries.
Many drug companies argue that the risk in neuroscience simply doesn’t justify the investment. The overarching sentiment is that the brain is still a black box: good targets are few and far between; clinical trials are long and unpredictable; regulatory approval is tough; and generic competition is plentiful. For many big pharma firms, the math just doesn’t add up.
“I personally don’t find that calculus to give you the total picture,” Ehlers says. Shifting resources away from neuroscience to focus on areas like oncology, where the environment looks favorable—clear clinical trial endpoints, the opportunity for fast-track approval, an easier chance for reimbursement from payors—only makes sense in the short term, Ehlers says. But that thinking “is short sighted as to where the fundamental state of biology is in neuroscience,” he says.
Why is Ehlers so encouraged about a field that so many are walking away from? He believes that neuroscience is poised to benefit from the kind of genetic links that generated so many targets—and eventually so many targeted-drugs—in oncology. “There is going to be kind of a revolution in the next five years—it’s not going to be tomorrow…but you have to think about that inflection of opportunity over the five-to-ten year time horizon.”
To take advantage of each new genetic clue, Ehlers has revamped Pfizer’s approach to neuroscience R&D. As this week’s story explains:
In the past, big pharma often gave its scientists a mandate to work in areas such as Alzheimer’s or schizophrenia, regardless of tractable drug targets. Now at Pfizer, Ehlers says, his team is “indication agnostic.” Any program that Pfizer undertakes must have a critical mass of biological knowledge—for example, human genetics, human phenotyping, and evidence of dysfunctional neurocircuits—to convince Ehlers it’s worth pursuing. “We start there,” he says. “That hasn’t always been the case.”
Moreover, Pfizer no longer relies on mouse models as predictors for responses in humans. “We’ve for the most part stopped all rodent behavior as a model for disease and are much more about what’s happening in the brain,” he says. Scientists measure human responses to prove experimentally that a drug works.
Pfizer’s goal, according to Ehlers, is to tackle fewer projects but have more confidence in their potential for success. The result should be a drug pipeline “rooted in something more than optimism.”
He cites Huntington’s disease as one area that, even before coming to Pfizer, he saw as a prime scientific opportunity. “You know the gene, you know a fair bit about what’s going on, you have a wealth of data, tons of models, a clear clinical course, and an identifiable patient population,” he says. “If we can’t deal with that, we’re in trouble.”
For those keeping track, yesterday’s layoffs at AstraZeneca add to an already substantial list of cuts in the pharma and biotech industries since the beginning of the year. By our tally, nearly 13,000 job cuts, many in R&D, have been announced so far–and we’re barely into February. Here’s where we’re at (and do let us know if we’ve missed any):
–AstraZeneca is chopping 7,300 jobs, including 2,200 R&D positions, by 2014. Neuroscience research is being revamped and focused on external partnerships; the company’s Montreal R&D site will be shuttered, and research activities ended at its Södertälje site in Sweden.
–Genzyme gave the pink slip to an unspecified number of R&D scientists this week. The layoffs come as Sanofi integrates its big biotech acquisition.
–Alnylam is trimming 61 jobs, or 33% of its workforce, in order to save roughly $20 million this year.
–BioSante Pharmaceuticals is shedding 25% of its staff, or 21 employees and contractors, after disappointing Phase III results for its female sexual dysfunction treatment LibiGel.
–Takeda is axing 2,800 jobs, or 9% of its workforce, following its acquisition of Swiss drugmaker Nycomed. The bulk of the layoffs, which cut across R&D, commercial, operations, and administrative positions, will occur in Europe.
–Novartis unveiled plans to shed some 1,960 positions in the U.S. as it braces for generic competition for Diovan, a blood pressure medicine that brought in more than $6 billion in 2010, and an expected drop in demand for its renin inhibitor Rasilez following questions about the drug’s safety.
–Human Genome Sciences said it would cut 150 jobs, or about 14% of its workforce, in a move that affects manufacturing, R&D, and administrative activities.
–Xoma is shedding 84 workers, or 34% of its staff, as it shifts to outsourcing late-stage and commercial manufacturing, as well as some research.
–SkyePharma is cutting 20% of the 101 employees at its site in Muttenz, Switzerland.
–Sanofi plans to layoff 100 workers at its Monteal site as part of an overhaul of its Canadian operations.
–J&J will trim 126 workers as it closes its Monreal R&D center.
AstraZeneca wielded a heavy ax to its workforce today as it prepares for tougher times ahead. The British-Swedish drugmaker is chopping 7,300 jobs, including 2,200 R&D positions, in hopes of achieving $1.6 billion in annual cost savings by 2014.
This is the third round of major cutbacks at AstraZeneca. In 2010, the company announced plans to slash 8,000 jobs over four years, a move that added to the elimination of 15,000 jobs between 2007 and 2009. This specific round girds against an onslaught of generic competition for key products and accounts for several disappointments in the company’s late-stage pipeline. In the coming months, the company will lose patent protection in various markets for the anti-psychotic Seroquel IR, the anti-cholesterol drug Crestor, and the blood thinner Atacand. Meanwhile, AstraZeneca’s late-stage pipeline has faltered. The recent setbacks (adding to earlier ones) include ending development of the PARP inhibitor olaparib, which prompted it to take a $285 million charge; a failed Phase III trial for the antidepressant TC-5214; and a thumbs down from FDA last month for dapagliflozin, a Type II diabetes drug being developed with Bristol-Myers Squibb.
R&D has taken a heavy hit in each round of cuts. During the Q&A session following AstraZeneca’s earnings presentation, one analyst said his back of the envelope calculations suggest the company will have shed 7,600 R&D jobs between 2006 and 2014. Based on comments by AstraZeneca’s R&D chief Martin Mackay, small molecule research has born the brunt of those cuts. He noted that headcount in biologics research has grown, and pointed out that biologics now account for 40% of the company’s early-stage pipeline (candidates in studies earlier than Phase II), up from 15-20% in recent years.
The latest R&D revamp will be primarily focused on AstraZeneca’s neuroscience activities, where the risk of investment is seen as particularly high. “It’s a really tough area,” Mackay said. “The industry hasn’t produced enough and we haven’t produced enough.”
The challenge was highlighted in November, when TC-5214, an anti-depressant being developed by Targacept and AstraZeneca, failed to show benefit in a Phase III trial. The bad news came as a surprise, as TC-5214 had demonstrated strong efficacy in smaller trials. Three other Phase III trials are underway, but analysts are skeptical that the program can be salvaged. “Prospects appear grim,” Leerink Swann analyst Joshua Schimmer said in a note last month.
AstraZeneca is creating a small team of 40 to 50 scientists that will work with external partners in academia and industry to discover and develop neuroscience drugs. The adoption of this new strategy means that the company’s Montreal R&D facility will be shuttered, and it will end R&D at its Södertälje site in Sweden.
AstraZeneca’s overhaul of its neuroscience activities is the latest in what appears to be a big pharma exodus from internal central nervous system R&D. In December, Novartis said it would close its neuroscience research facility in Basel, Switzerland, and GlaxoSmithKline two years ago decided to end research in certain central nervous system areas, such as depression and pain.
Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points:
1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout. And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring.
2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project. He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work.
3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis.
4. Sirtuins, and “Stuff I Won’t Work With – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the Science wrap-up at years’ end. Derek also left us with a tantalizing tidbit for 2012 – the long-awaited “Things I Won’t Work With” book may finally be coming out!
5. Active Antibacterial Development – In the middle of 2011, several high-profile and deadly bacterial infections (Germany, Colorado, among others) shined a spotlight on those companies developing novel antibacterials. We explored front -line antibiotics for nasty Gram-negative E.coli, saw FDA approval for Optimer’s new drug Fidiclir (fidaxomicin) show promise against C. difficile and watched Anacor’s boron-based therapeutics advance into clinical testing for acne, and a multi-year BARDA grant awarded to GSK and Anacor to develop antibacterials against bioterrorism microorganisms like Y. pestis.
6. Obesity, Diabetes, and IBS – Drugs for metabolic disorders have been well-represented in Haystack coverage since 2010. Both Carmen and See Arr Oh explored the vagaries of Zafgen’s ZGN-433 structure, as the Contrave failure threatened to sink obesity drug development around the industry. Diabetes drugs tackled some novel mechanisms and moved a lot of therapies forward, such as Pfizer’s SGLT2 inhibitors, and Takeda’s pancreatic GPCR agonist. Ironwood and Forest, meanwhile, scored an NDA for their macrocyclic peptide drug, linaclotide.
7. The Medicine Show: Pharma’s Creativity Conundrum – In this piece from October, after Steve Jobs’ passing, Forbes columnist Matt Herper both eulogizes Jobs and confronts a real ideological break between computer designers and drug developers. His emphasis? In biology and medical fields, “magical thinking” does not always fix situations as it might in computer development.
We hope you’ve enjoyed wading through the dense forest of drug development with Carmen, Aaron, Lisa, and See Arr Oh this past year. We here at The Haystack wish you a prosperous and healthy 2012, and we invite you to come back for more posts in the New Year!
Last month, I wrote a post on amide formation, that humble but useful tool in the medicinal chemistry arsenal, for CENtral Science’s “Your Favorite Reaction” blog carnival. Today, CENtral Science’s own pharmacologist-in-residence David Kroll has compiled a must-read guide to all the entries in the carnival, and I was pleased to see a few more entries that might pique medicinal chemists’ interest. I was especially psyched to see entries from bloggers with whose writing I wasn’t familiar.
FDA has given the regulatory nod to crizotinib, Pfizer’s ALK inhibitor that has proven very effective in the small portion of the population whose lung cancer is driven by the protein.
Pfizer says the drug, to be sold under the brand name Xalkori, will cost $9,600 per month, and it will provide assistance so that patient co-pays will not exceed $100. It’s the first in a handful of new drugs Pfizer is counting on to help offset the sales drain when the patent expires this fall on its blockbuster cholesterol drug Lipitor.
The approval is notable as the second drug/diagnostic combo to get the FDA green light in recent weeks—Plexxikon/Roche’s melanoma treatment Zelboraf is the other.
Also notable? We call the compound an ALK-inhibitor, but scientists didn’t start out looking for an ALK-inhibitor. Work on crizotinib originated at Sugen, a South San Francisco-based biotech first bought by Pharmacia, which was later acquired by Pfizer. Sugen chemists were intent on finding a molecule that blocked c-Met, a protein implicated in tumor metastasis. They had already struck upon a promising amino pyridine scaffold by the time their activities were moved into Pfizer’s La Jolla site, where lead optimization took place.
An optimized molecule, billed as a c-Met inhibitor, was put into clinical trials. Then, as we wrote last year, scientific discovery and serendipity converged to change the course of the drug’s development:
Researchers led by Hiroyuki Mano, a professor of functional genomics at Japan’s Jichi Medical University, found that when a certain chromosome inverted, a fusion occurred in lung cancer cells between the echinoderm microtubule-associated proteinlike 4 (EML4) gene and the ALK gene. The researchers found that the fusion caused tumor formation in mice. A subsequent test determined that about 7% of lung cancer patients had this fusion gene. In a paper published in Nature, the researchers concluded that ALK would make a good drug target (Nature 2007, 448, 561).
As it happened, Pfizer had just learned it had an ALK inhibitor on its hands. The company and Massachusetts General Hospital had evaluated results from large biochemical and cell-based screens to see whether crizotinib was hitting targets other than c-Met, says James Christensen, director of translational research in Pfizer’s oncology unit. Upon characterizing the hits, the collaborators found that it was blocking ALK’s activity.
Better, crizotinib was just as good at blocking ALK as it was at shutting down c-Met. Pfizer scientists believe the dual activity is due to a similarity in a residue on each protein. Specifically, both c-Met and ALK have a particular tyrosine within one of the three phosphorylation sites, called the activation loop, which seems to be responsible for the compound’s activity.
All in all, pretty cool science that has translated into a very promising treatment for some lung cancer patients.
Vernalis shares shot up today after Novartis gave a shout out to AUY922, which blocks a molecular chaperone called Hsp90, in a discussion of its second-quarter results. The Swiss pharma major identified AUY922 in a list of potential blockbusters, a distinction that may seem ambitious to those who have been watching compound after compound targeting Hsp90, which helps stabilize stressed-out proteins, crash and burn.
So what makes the Vernalis drug so interesting? We took a look at the field back in 2007, and at the time it was clear the Vernalis compound differed from most of the other drugs in or poised to enter clinical studies. The first and second-generation Hsp90 inhibitors were all based on geldanamycin, an antibiotic found in soil microorganisms. On its own, the natural product is a poor drug candidate—a quinine moiety renders it highly reactive and highly insoluble. Much of the early discovery work was focused on engineering out those issues, leading to drug candidates from Kosan Bioscience (bought by Bristol-Myers Squibb in 2008, work on the Hsp90 drug, however, seems dead in the water), Conforma Therapeutics (bought by Biogen Idec in 2006, after which the Hsp90 compound was put on the backburner), and Infinity Pharmaceuticals.
But, as we wrote, Vernalis sidestepped geldanamycin altogether:
Vernalis deployed fragment-based drug discovery technology to find low-molecular-weight compounds with a weak binding affinity for Hsp90. Guided by X-ray crystal structures of prospective compounds bound to Hsp90, company researchers optimized the compounds into leads. The end result is a range of drugs that do not all fall under the geldanamycin umbrella.
That’s the structure piece, but another piece of the puzzle is that researchers appear to be figuring out how best to use these compounds. On their own, Hsp90 inhibitors have shown limited to no therapeutic benefit. “It is abundantly clear that with rare exceptions we did not see a lot of single agent activity” with Hsp90 inhibitors, Julian Adams, president of R&D at Infinity, told me last month at the ASCO annual meeting. The lack of activity might have been predicted, he adds, given that it was known that blocking Hsp90 only activated another protein-folding chaperone called Hsp70.
Indeed, evidence is emerging that Hsp90 inhibitors could find use in combinations with other targeted agents and for specific patient populations. Infinity did a deep dive into the data gathered from a Phase I trial combining Infinity’s lead Hsp90 inhibitor retaspimycin and Taxotere in lung cancer patients. The result: signs of strong activity in people with the ALK mutation (the target of Pfizer’s lung cancer drug crizotinib), in heavy smokers, and in people who carried the normal KRas gene.
There is also interest in combining Hsp90 inhibitors with Jak2 inhibitors, like ruxolitinib, conveniently being developed by Novartis and Incyte to treat rare blood disorders. Last fall, Memorial Sloan Kettering scientists showed that Jak2 is a very unstable protein, and blocking Hsp90, which ostensibly helps keep Jak2 pieced together, in combination could improve therapeutic outcomes.
Novartis is recruiting for a slew of clinical trials looking at the effect of combining AUY922 with other targeted agents. It’s early days for AUY922, which is still in Phase II trials. If all goes well, Novartis expects to file for regulatory approval for the compound in 2015.
So will an Hsp90 inhibitor finally make it to market? Detractors? Supporters? Speak up in the comments!
Former Pfizer R&D head John LaMattina created a minor stir yesterday with comments he made to Reuters suggesting his old employer might one day regret its deep research cuts. The Reuters story touched off a dialogue on Twitter amongst reporters, pharma industry watchers, and LaMattina himself about the whether Pfizer—and more generally, big pharma—could justify their historical levels of R&D spending based on a rather pitiful return on investment. After all, shouldn’t pharma try to exercise some fiscal restraint given the slowdown in new drug approvals, not to mention how few of the new drugs that reach the market actually originated in their labs? Many seemed to agree with the sentiment from biotech executive @Michael_Gilman: “It’s not how much you got, it’s how you use it.”
Still, its hard not to wonder whether there’s a middle ground to be reached in the industry’s cuts. LaMattina notes that Pfizer’s cuts will bring its percentage of R&D spending for 2012 down to 10 to 11% of its expected revenue for the year. That’s a rather precipitous drop from the 20% of sales drug firms used to reinvest into their research engines.
Forbes reporter Matt Herper (@MatthewHerper) asked LaMattina whether it would be wiser to come up with solutions to the productivity problem before returning to those historical levels of R&D investment: “Isn’t there something to the idea, I think of it as Viehbacher’s [CEO of Sanofi], that one should at least cut spend until one finds a fix?”
Another valid point. LaMattina (@John_LaMattina) countered with: “Fully agree with demanding more evidence; that’s why you need to do both; that’s why you need a strong R&D budget.”
Pharma certainly is experimenting with fixes to its productivity problem. Pfizer, for example, is banking on its new academic network to accelerate translational medicine, and do so more cheaply. The company also announced today that it would spin-off or sell its animal health and nutrition assets, a move designed to shift its focus back to its prescription medicines business. Meanwhile, GlaxoSmithKline, Sanofi, and AstraZeneca have all revamped the structure of their research organizations to empower scientists to do more of the decision-making, their way of trying to replicate, internally, both the incentives and pressures that scientists at a biotech feel to justify investment in their programs. (teaser: for more on those efforts, see Monday’s issue of C&EN)
The problem seems to be that its going to be years for the industry to fully understand whether all these experiments are worthwhile. Clearly, companies need to do something to get better at R&D. But as LaMattina points out in the Reuters article, there’s also a risk of figuring out too late that cutting spending so deeply was a mistake.
So what do you think readers? Is there a middle ground? Or is cutting to the bone the way to go?
Merck’s R&D head Peter Kim has often discussed the excitement at the company on the day in late 2009 that its acquisition of Schering-Plough closed and the curtain shielding the two organization’s pipelines from one another was drawn. Kim himself spent hours in front of a computer, gleefully filing through the database of compounds now under his watch.
But in today’s rough R&D climate, pharma companies simply can’t afford to do everything and anything. Almost as soon as the pipelines were combined, Merck also had to file through all its compounds and decide which to shed. Though Merck has not specified a number for how many programs it is cutting overall, the pipeline reorganization is said to be substantial. At the BIO annual meeting, held last week in DC, I sat down with Meeta Chatterjee, Merck & Co.’s head of global outlicensing and asset management, to chat about how Merck is going about finding new homes for those compounds.
The first step in the process was charging every therapeutic franchise head with prioritizing their portfolios. While some companies, such as GlaxoSmithKline and Pfizer, have cut entire therapeutic areas, Merck chose to weed out programs from across its entire organization, Chatterjee says.
The end result was a long list of molecules across all phases of development, and even some at the lead optimization stage, suddenly up for grabs. The list included some that, due to clauses in partnering agreements, had to be returned to a biotech company (see here for how biotechs are grappling with those newly returned assets); others that would be sold outright; and some assets that Merck hoped to keep ties to through a partnership that would include an option to buy back the program down the road after some of the development risk had been removed. Last, a handful of compounds were simply shelved because they showed signs of toxicity in early studies.
Chatterjee’s task is daunting. “Merck did some out-licensing in the past, but there was never a dedicated group, and the number of out-licensing deals were nowhere near what we were being asked to do,” Chatterjee says.
And given the sensitive nature of pharma research, finding partners is not as simple as handing out a spreadsheet of what’s available. “It’s almost reverse competitive intelligence,” Chatterjee says, adding that her group has “had to be judicious” in how information is shared.
Almost as soon as Merck said it was reevaluating its pipeline, a slew of companies and venture capital firms came forward to express interest in assets, she says. “We’ve been approached by everyone.” After the team put together full data packages on every program on the chopping block, they filtered through the requests and tried to find the right matches. In fewer cases, her team has sought to identify a partner that might be interested in a program.
Since completing the data packages on the compounds in December, Chatterjee’s group has done a few small deals, and hopes to complete a few more this year.
(An homage to Terra Sigillata; it might normally be covered on his beat.)
Astute readers of the New York Times may have noticed a front-page article from a few weeks back, highlighting a new late-night snack: Lazy Cakes. Taking a cue, perhaps, from the substance-laced brownies popular in the late ‘60s, these brownies pack a decidedly sleepy secret: each contains a “proprietary calming blend” of ingredients, chief among which is melatonin.
Melatonin is a hormone usually secreted by the pineal gland (a pinecone-shaped gland located just above the cerebellum) in humans and other mammals, in response to dark surroundings. (Note: Although they sound similar, melatonin should not be confused for melanin, the skin pigment formed by sunlight exposure) In mammals, melatonin induces the circadian rhythms associated with sleep, affects the onset of puberty and may help regulate DNA transcription.1,2 Biologically derived from tryptophan, the amino acid and purported suspect of the Thanksgiving “turkey coma”, melatonin has been shown clinically to have benefits for memory loss, in addition to antioxidant potential. Melatonin capsules have been sold over-the-counter for insomnia and jet lag since the 1980s.
Technically speaking, the product is labeled a dietary supplement, and as such skirts regulation by the FDA. One valid concern are possible interactions that melatonin, like other supplements, could have with prescription drugs, a topic addressed both by Terra Sig and C&E News. More controversy over the soporific snacks springs from their colored packaging and wide availability. This intrepid blogger ventured out into the wild to recover a sample for analysis. The packaging, upfront, has a distinctly comic-book appeal: purple and green swirls, a trippy logo evoking That ‘70s Show, and a cartoon brownie mascot leaned back for a snooze. The brownie itself is compact, and has quite a bit of heft for your average baked good. The back of the wrapper evokes language usually associated with cigarette labeling: multiple tiny lines of serious text stating Recommended for Adults Only, and Do Not Drive or Operate Heavy Machinery.
The “calming blend” also includes valerian root, which is commonly found in teas and herbal supplements. Containing sugar-decorated polycyclic lactones called iridoids, as well as valerenic acid3 derivatives, the extracts have been shown clinically to reduce anxiety and relieve insomnia.4 Passion flower extract brings a dose of alkaloids into the bedtime mix; well-known sleep inducers opium and morphine are part of this general molecular family. The other ingredients, however, seem to just be along for the ride: current “superfruits” goji berry and açai, with the old Vitamin C standby of rose hips.
For my part, I don’t believe that a baked good packing a pharmaceutical punch should be sold in colorful wrappers, next to the candy bars. However, having experienced my share of late-night grad school anxiety, I can’t blame someone for wanting a good solid nap, any way they can.
1. Fox, Stuart Ira. Human Physiology, Sixth Ed. Boston: WCB / McGraw Hill, 1999. pp. 289, 315.
2. Merck & Co., Inc. The Merck Index, 13th Ed. New Jersey, 2001. p. 5841
3. Ramharter, J.; Mulzer, J. Org. Lett. 2009, 11, 1151-1153.
4. NIH Dietary Supplement Fact Sheet: Valerian. 2008. Downloaded from http://ods.od.nih.gov