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Archive → October, 2010

WSJ Feature on “The Other Chemistry”

Jeanne Whalen, a Wall Street Journal reporter based in London, had an article yesterday on the European aspects of a phenomenon we’ve been discussing here at Terra Sig since the beginning of the year: the adoption of academic chemistry to produce legal intoxicants that are just on this side of the law. Whalen spends the first half of her article talking with David Llewellyn, a middle-aged Scotsman in Belgium who works with a chemistry colleague to scour the literature for synthetic schemes and basic pharmacology to manufacture “legal highs.”

I’ve spoken before about Clemson University chemistry professor emeritus, John W. Huffman, and his cannabimimetic naphthoylindoles synthesized in the 1990s that are now creating a buzz, as it were, in the US in the form of herbal incense and synthetic marijuana products.

In Whalen’s article, Llewellyn is quoted as finding the work of Purdue University pharmacologist, Dr. David E. Nichols, as a particularly fruitful information source. Nichols, the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology in the Department of Medicinal Chemistry and Molecular Pharmacology in the College of Pharmacy is not particularly pleased:

“The drugs we make often end up on the black market, and it’s very troubling to me,” he says. Particularly worrying is that the drugs are rarely tested in humans before hitting the street. Random people sometimes write to him to ask for help in making certain chemicals, he says. He doesn’t reply out of caution.

“When people use this stuff chronically, on a weekly basis—suppose it produces liver cancer?” he asks. Also of concern are effects on the kidneys and bone marrow. Most of the designer drugs haven’t been tested in humans at all, let alone in large clinical trials. Dr. Nichols says he himself only ever carried out animal tests of the compounds that others are now copying and selling.

Whalen also speaks with St. George’s University of London toxicologist, Dr. John Ramsey, about his efforts to keep up a database from identification of street drugs as they appear.

It’s a fascinating article on an issue that chemists and law enforcement have been dealing with for decades.

Source: Jeanne Whalen (with Kersten Zhang), In Quest for ‘Legal High,’ Chemists Outfox Law, Wall Street Journal, 30 October 2010.

Hat-tip: Aaron Rowe via Twitter.

Extraordinary Opportunities: UNCF/Merck Science Initiative for African American Students

If you don’t get the hardcopy version of C&EN, you are likely to have missed the ad on pg. 36 (Oct 25) for a fantastic scholarship and fellowship opportunity benefiting African American undergrad, graduate students, and postdocs in the chemical or biological sciences.

The United Negro College Fund (UNCF) has partnered with Merck and the Merck Company Foundation to offer some comprehensive awards to create these unique awards. For example, the undergraduate award consists of scholarships up to $25,000 plus a paid internship at a Merck research facility. The graduate dissertation award is for up to $43,500 plus a $10,000 research and travel grant. The postdoc award consists of a fellowship of up to $92,000: $77K in salary for up to 24 months (but no more than $55K in one year) plus a $15,000 research and travel grant. Continue reading →

“Wining” about corked Tylenol

Lot number BCM155 of the 50-caplet product is affected by the October 18th recall.

Things have not been going very well for Johnson & Johnson’s McNeil Consumer Healthcare division with regard to their now-closed Fort Washington, PA, manufacturing facility. Last week, they issued another recall for 8-Hour Tylenol products due to a musty smell caused by trace quantities of 2,4,6-tribromoanisole (TBA).

wrote about J&J’s issues at this blog’s old home back in May when some of our comments were included in a ABC News report by Dan Childs after a recall of 43 different products due to problems with potency, microbial contamination, and particulate matter in liquid dosage formulations.

This past week’s story was covered extensively around the popular press but I was particularly taken by the article on TIME magazine’s Healthland site written last Wednesday by Meredith Melnick, a former fellow at Columbia University’s Digital Media program. In general, I’ve been really impressed with the quality of science writing at Healthland all around, a blog I’ve been following since an online writer friend, Maia Szalavitz, joined them.

Beyond the high quality of her writing, Melnick won points from me in discussing the chemistry of the TBA contamination.

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British Chemists Hacked Off By Government’s “Lazy Stereotype”

The Royal Society of Chemistry is not at all amused.

In discussing the chemistry of “legal highs” earlier this week, I was reminded of a dust-up last month in the UK following the launch of a government anti-drug campaign to warn young people that “legal” intoxicants are not necessarily “safe.”

At issue was the Home Office’s “Crazy Chemist” campaign:

Featuring an eye catching and menacing scientist, the campaign conveys the unscrupulous nature of people who create and sell substances with little concern for the health of those who consume them.

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Mephedrone in the U.S.

The methcathinones, such as mephedrone (above), are based on the amphetamine structure with the exception of the ketone. Although more polar and with less propensity to cross the blood-brain-barrier, the additional 4-methyl substitution enhances lipophilicity.

In a news item last week, two young men found dead in Hillsborough Raleigh, North Carolina, were described by police as having been taking the recreational drug, mephedrone. Known to chemists as 2-methylamino-1-p-tolylpropan-1-one, 4-methylmethcathinone (4-MMC), or 4-methylephedrone, the compound is a semi-synthetic derivative of the natural product cathinone found in the shrub, Catha edulis – better known as khat.

My blogging colleague and substance abuse expert, DrugMonkey, has had an extensive series of posts on mephedrone since it became widely-used – and now outlawed – in much of Europe. Like amphetamine, these compounds are believed to enhance the release of dopamine in the brain but surprisingly little pharmacology is available in the literature. A PubMed search for “mephedrone” currently returns about two dozen papers that speak mostly to legality and use trends.

Natural products have always figured prominently among drugs of abuse – alkaloids with central nervous system penetration have been used as intoxicants since ancient times and remain popular today.

To stay ahead of drug enforcement regulatory authorities, clandestine chemists have endeavored to scour the scientific literature for old synthetic schemes – preferably in non-English journals – to make chemical analogs to create legal highs. In the US, the response of the Drug Enforcement Agency (DEA), was to promote within the Controlled Substances Act the Federal Analogue Act of 1986 that made illegal any “analog” of a known Schedule I substance (for those outside the US, Schedule I compounds are those forbidden for any medical use). In fact, the paper most often cited online for the first mephedrone synthesis is Bulletin de la Societé Chimique de France 1929;45: 284–286.

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“The current phenomenon of ‘bloggers’ should be of serious concern to scientists”

In his October 12 Analytical Chemistry editorial, “Science Blogs and Caveat Emptor,” Editor-in-Chief Royce Murray submits that “the current phenomenon of “bloggers” should be of serious concern to scientists.

I agree.

I’m concerned that not enough scientists are bloggers.

Dr. Royce Murray has had a remarkable career in chemistry with over 440 publications and a h-index of 87, having trained 72 Ph.D. students, 16 master’s students, and 58 postdoctoral fellows, 45 of whom who have gone on to university faculty positions. The American Chemical Society just held a symposium in his honor at the recent annual meeting in Boston in marking 50 years since his first faculty appointment. That a scientist of his stature and influence holds negative views of science blogs is deserving of today’s discussion.

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BMJ meta-analysis: Reboxetine “an ineffective and potentially harmful antidepressant”

Reboxetine, racemic mixture.

Thanks to Ben Goldacre and Vaughan Bell, I learned this morning of an interesting paper in British Medical Journal that analyzed substantial unpublished data from Pfizer on their norephinephrine reuptake inhibitor antidepressant, reboxetine. Sold in Europe as a pair of enantiomers under the trade name Edronax, reboxetine’s US application was rejected by the FDA in 2001 for “lack of compelling evidence of efficacy.”

The authors, all from the Institute for Quality and Efficiency in Healthcare in Köln, Germany, requested from Pfizer all unpublished clinical data on the antidepressant from trials comparing its efficacy and safety to either placebo or active SSRI drugs. (The institute is better known by the acronym, IQWiG, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG).) An accompanying analysis of the article discusses the role of the IQWiG.

ResearchBlogging.orgThe paper stemmed from a report the Institute had conducted in 2009 for the German Federal Joint Committee (G-BA) for efficacy and safety of reboxetine, mirtazepine, and bupropion given acutely, generally eight to ten weeks. Both Essex Pharma and GSK provided IQWiG investigators with all unpublished data for the analysis of the latter two drugs but Pfizer had not (PDF, English translation).

The retrieval of previously unpublished trials was hampered by the fact that during preparation of the preliminary health technology assessment report, the manufacturer of reboxetine did not provide a complete list of unpublished trials as requested by IQWiG. Secondary publications clearly indicated that further potentially relevant unpublished trials existed. As the preliminary report showed that reboxetine had been tested in at least 16 trials including about 4600 patients, but data on almost two thirds of these patients were not accessible, the institute initially concluded that no meaningful assessment of reboxetine was possible.

After the publication of the preliminary report, the manufacturer decided to cooperate and provided most of the missing data (one venlafaxine controlled trial was not available as a full publication).

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Nobel Prize in Chemistry 2010: Remembering Mizoroki

This year, a chemistry prize for the chemists!

I’m having to catch a plane but wanted to drop a quick note about this morning’s prize announcement. Steve Ritter, Carmen Drahl, Elizabeth Wilson and others have written extensively at C&EN about Pd-catalyzed cross-couplings and the work of Richard Heck, Ei-ichi Negishi, and Akira Suzuki.

In going through the archives this morning, I was drawn to Carmen’s excellent article on named reactions where she discussed the Mizoroki-Heck reaction, but was struck by a letter that followed on June 21:

I congratulate Carmen Drahl on her article on named chemical reactions, and especially for choosing a dramatic case: the Mizoroki-Heck reaction (C&EN, May 17, page 31). Both inventors had a cruel personal bend in their respective careers despite glamorous success and acclamation from the chemical community.

Tsutomu Mizoroki succumbed to pancreatic cancer only nine years after his breakthrough discovery of the palladium-catalyzed reaction. Richard F. Heck, despite an excellent publication record in ACS journals, lost funding, doesn’t have a single entry in PubMed, and is relegated to the eternal waiting list for the Nobel Prize. I fully agree with Victor A. Snieckus that Heck’s nomination for the Nobel Prize is overdue, also in remembrance of Mizoroki.

Raffaello Masciadri
Münchenstein, Switzerland

Of these two points, Carmen wrote:

Heck retired to Florida with his wife, Soccoro, in 1989 after having difficulty securing funding for his research. These days, he calls Soccoro’s native Philippines home. “I’m not doing any chemistry anymore, but I think I’ve done my share,” he says.

Asked what he thinks about the terms “Heck reaction” and “Mizoroki-Heck reaction,” he says he doesn’t have strong feelings either way. Mizoroki arrived at the reaction first, but “I wasn’t too far behind,” Heck says. Mizoroki didn’t follow up on the reaction or seem to recognize its value, he adds.

“Unfortunately, Mizoroki died quite young, before he could do much chemistry with palladium,” Heck says. “Maybe if he’d lived, it might’ve been called the Mizoroki reaction instead.”

So, just as we remember the late Patrick Steptoe for his work with Robert Edwards for this year’s prize in Physiology or Medicine, we should also remember the contributions of Dr. Mizoroki.

“A chemist today would be hard-pressed to find an area that this reaction hasn’t touched, from pharmaceuticals to materials and beyond,” wrote Carmen.

UPDATE: I also missed that Carmen gave us the backstory on her interview with Heck and search for Mizoroki on The Haystack blog back in May.

Avandia repercussions: Anyone need some contract drug manufacturing?

The pride of Zebulon, NC.

Putting on my Chamber of Commerce hat today, I bring you a story from the local North Carolina press about the GlaxoSmithKline manufacturing plant in Zebulon, just down the road apiece from the state capital.

Zebulon is home to the Carolina Mudcats, the Double-A minor league baseball farm team for the Cincinnati Reds. But among asthmatics like me, Zebulon is better known as the source of the GSK Advair Diskus – and about 20 other GSK drugs distributed in North America.

Turns out that the Avandia ruling, discussed here at The Haystack by Lisa Jarvis, has shut down manufacture of that drug in Zebulon, creating some excess capacity for contract drug manufacturing.

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