RTI scientists solving forensic, designer drug mysteries
Sep09

RTI scientists solving forensic, designer drug mysteries

Catching up on my reading this Sunday morning, I'm beaming with pride on the collective accomplishments and coverage of some old friends and colleagues. Kerstin Nordstrom, a AAAS Mass Media Fellow with the Raleigh News & Observer, had a nice story on 3 September about the work of Dr. Peter Stout at RTI International. You old-timers will know this non-profit entity as Research Triangle Institute, home to the discoveries of Taxol and camptothecin by Wall and Wani and colleagues. Kerstin, or Dr. Nordstrom I should say as she holds a PhD in physics, interviews RTI's Dr. Peter Stout on the institute's forensic analytical chemistry capabilities with regard to the "designer drug" industry. Yes, here we go again with my long-running commentary on the "synthetic marijuana," "herbal incense," "plant food," and "bath salts" products that have recently taken a direct hit from "Operation Log Jam," a coordinated, federal operation to shut down the industry. In my post on the federal takedown, I referred to a paper by Stout's RTI colleagues where mass defect filtering was used to identify unknown analogs of known illegal compounds, particularly the JWH group of cannabimimetic naphthoylindoles (Anal. Chem., DOI:10.1021/ac300509h). (Addendum: That paper was also covered nicely in the 15 June C&EN by Erika Gebel.) Coincidentally, both Kerstin and Peter are dear to me - hence the following disclosures before singing the praises of the article: Peter earned his Ph.D. in molecular toxicology from Dr. Jim Ruth's lab at my former home, the Department of Pharmaceutical Sciences at the University of Colorado Denver's Skaggs School of Pharmacy. My time at RTI's Natural Products Laboratory (2002-2008) overlapped with Peter's hiring. As an aside, I had not known Peter was hired until he saw a cart outside of my laboratory with my name and hunted me down, guessing there weren't many Krolls in biochemical pharmacology. An equally lighthearted observation is that Peter has almost completely shaved his head as long as I've know him; I'm certain that's a coincidence with his dissertation research project, "Mechanisms of Drug Disposition into Hair." Disclosure #2: Kerstin is a fellow graduate of the 2011 Santa Fe Science Writing Workshop and serendipitously ended up here in the Triangle for her AAAS Mass Media Fellowship. What I like about the story is how both of them describe analytical techniques in relatively approachable language: Kerstin on HPLC: For liquid chromatography, an unknown chemical is pushed through a pipe. The pipe is filled with tiny silica particles – 1 to 10 micrometers in size – that attract some molecules and repel others. Each chemical has a different attraction, and so some, attracted to the grains, go slower than...

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How Do You Like Your Caffeine?
Mar08

How Do You Like Your Caffeine?

Inhaled or oral? Natural or synthetic? Two interesting reports came across the interwebs over the last couple of days. Earlier this week, the US Food and Drug Administration issued a warning letter (press release) to makers of Aeroshot brand of inhaled caffeine. No, it's not an asthma medicine (although oral theophylline is). It's billed as a non-caloric caffeine delivery system, 100 mg per hit. That's roughly the amount in two 12 fl oz/355 mL cans of Mountain Dew or one gulp more than a 8.4 fl oz/250 mL can of Red Bull energy drink. However, the company claims that only 15-25 mg are delivered - perhaps half the amount in a Coca-Cola. The FDA has concerns about the dual promotion of the product for swallowing and inhalation, the relative safety of inhaled caffeine, and the potential for children and adolescents to use the product in combination with alcohol. The company's FAQ specifically notes that the product is not marketed for use in children. Readers will recall that Four Loko caffeinated alcohol drinks were withdrawn from the market in late 2010 and replaced with alcohol-only versions. On another front, Analytical Chemistry published a paper by a group led by Maik Jochmann at Essen, Germany on an isotopic ratio method for determining whether caffeine in a consumer product is derived from plants or synthetically. While public demand for naturally-caffeinated products doesn't seem to be especially a big deal in the US, the FDA only requires listing of caffeine content for products with added synthetic caffeine. (Note: I only just found out this afternoon that C&EN Online had covered this paper back on February 29th. My apologies to all for not linking to it. That report is here.) The authors show here that 13C ratios can indeed be used to determine the source of caffeine. In general, 13C represents 1.11% of Earth's carbon. However, plants incorporate less 13C in making caffeine via C3 carbon fixation from atmospheric carbon dioxide. I'm still a bit unclear as to whether the method can determine the difference between naturally-occurring caffeine from products spiked with purified, plant-derived caffeine (I don't think so). In the paper, I learned something new and of relevance to the American South (where I live): the international standard for 13C/12C ratios is Vienna Pee Dee Belemnite (VPDB). In 1957, the late Scripps Institution of Oceanography geochemist Harmon Craig, defined terrestrial carbon isotope ratios from a fossilized cephalopod in the Pee Dee limestone formation of South Carolina. Although none of the original specimen remains, secondary standards are now used for calculations. To complete our history lesson, you should know that the Pee Dee River...

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Was Demi Moore smoking synthetic marijuana?
Jan28

Was Demi Moore smoking synthetic marijuana?

My substance abuser writer and researcher friend DrugMonkey (@drugmonkeyblog) just tweeted a CNN story suggesting that actress Demi Moore may have suffered adverse reactions after smoking a synthetic cannabimimetic product: A woman called 911 soliciting help for actress Demi Moore, whom she said was "convulsing" and "burning up" after "smoking something," according to a recording of the call obtained Friday from the Los Angeles Fire Department. [. . .] "She smoked something -- it's not marijuana, but it's similar to incense. And she seems to be having convulsions of some sort." Reports of tremors and seizures have been accumulating in association with synthetic marijuana products. These products are generally composed of an herbal material that is spiked with one or more synthetic compounds that act at cannabinoid CB1 receptors. The "burning up" described by the 911 caller in the story would be consistent with some reports of serotonin-like syndrome associated with synthetic marijuana use. The US Drug Enforcement Agency is currently regulating some of the psychoactive compounds as Schedule I substances, illegal for use or sale as they are deemed as having no medical value. Individual states have also issued bans on compounds containing even more related compounds in these products. However, marketers have been skirting laws by using compounds not expressly deemed illegal in state or federal statutes. Moreover, analytical crime laboratories across the nation have suffered extensive budget cuts making it difficult to keep up with the demands in determinig which products are illicit. On a personal note, the synthetic marijuana story that DrugMonkey, dr_leigh, and I have been writing about for two years is growing increasingly disturbing. I just received my second reader email in three months from a father whose son shot himself to death while allegedly addicted to synthetic marijuana products. We've been in touch with the US DEA to inquire as to whether similar cases are currently under investigation. Just as DrugMonkey wrote awhile back (I have to find the post), adverse drug effects with celebrities are usually required before aggressive government action is taken against illicit drugs (death of University of Maryland basketball player Len Bias from cocaine and a congenital cardiac...

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FDA Withdraws Avastin Approval for Breast Cancer
Nov18

FDA Withdraws Avastin Approval for Breast Cancer

  As reported around the wires today, US FDA Commissioner Dr. Margaret A. Hamburg formally revoked the accelerated approval of the antiangiogenic drug Avastin (bevacizumab) for breast cancer treatment. Avastin is a humanized mouse antibody that binds and inactivates the vascular endothelial growth factor VEGF-A, a mediator of blood vessel growth. Andrew Pollack at The New York Times does a nice job condensing this episode for us. The highlights are that Avastin was approved based on the surrogate endpoint of progression-free survival in metastatic breast cancer, meaning that it appeared to increase the time from treatment to return of the growth of cancer metastases. However, the true endpoint is long-term patient survival. There, subsequent studies showed that Avastin had no benefit. Moreover, Avastin also use appears to increase the risk of hemorrhage and bowel perforation. These are potentially life-threatening side effects and are considered too great of a risk when no statistical benefit of survival or quality of life are apparent. Of course, there are cases of individual patients who have benefited from Avastin and many questions remain for them. In the 69-page ruling made available today (PDF), Dr. Hamburg includes a well-articulated Q&A for patients and their caregivers. I doubt seriously that the full text of this section will be published in the mainstream media, although Pollack does provide the hyperlink. I found this quite valuable as someone who cares about family and friends with breast cancer. But the text also provides an espeically close look at the rationale behind the US drug approval process. As this rich information is buried in a 69-page federal document, I wanted to provide this text here for ease of reading by those concerned about this ruling. This following statement is from US FDA Commissioner Dr. Margaret Hamburg. The full text is in the public domain and can be accessed here.   I. AN EXPLANATION FOR PATIENTS AND THOSE WHO SUPPORT THEM This document, which lays out the basis for my decision, has several purposes. It is an explanation, for physicians, scientists, patients and the public in general, of the data available on the metastatic breast cancer indication for Avastin and of FDA's evaluation of those data. It also describes how FDA has applied the law and its regulations in making the decision to withdraw the approval for that indication. I know I speak on behalf of the many physicians that have been involved with this issue here at the Food and Drug Administration and elsewhere in saying that we encourage patients and those who support them, to ask hard questions and to demand explanations concerning the drugs that are recommended to...

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K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance
Nov14

K2 Synthetic Marijuana: Heart Attacks, Suicides, and Surveillance

Sixteen-year-old boys having heart attacks. Blog reports of deaths and suicides. And a little known chemistry and public health resource mobilized to identify "legal highs." The chemical and biological phenomenon that is "synthetic marijuana" continued to develop over the last week as we learn more about these products from the medical and public health communities. Most notably, pediatric cardiologists reported in the journal Pediatrics on three cases of Texas teenagers who experienced myocardial infarctions - heart attacks - after using a synthetic marijuana product (DOI: 10.1542/peds.2010-3823). (Many thanks to Dr. Ivan Oransky, Executive Editor at Reuters Health, for providing us with primary information after their own excellent report by Frederik Joelving). Brief background Sold under names like K2 or Spice as "incense" or "potpourri" and labeled as "not intended for human consumption," these products are laced with one or more synthetic psychoactive compounds that were published in 1990s work studying structure-activity relationships on cannabinoid receptors. The vast majority of the synthetic work was done in the laboratory of Dr. John W. Huffman, now professor emeritus of the Department of Chemistry at Clemson University, with his compounds know by "JWH-" nomenclature. The US Drug Enforcement Agency secured emergency prohibition of five of these compounds late last year, spurring "legal highs" manufacturers to reformulate second-generation Spice products containing related compounds not explicitly designated as illegal. Although the DEA does have the authority to prosecute sale and possession of these analogs, such action is rare. To learn more, we've put together a compilation of our synthetic marijuana posts for the reader's further reference. Adolescent heart attacks In this week's advance Pediatrics publication, the three cases - all in 16-year-old boys - were seen at the UT-Southwestern Medical Center in Dallas within three months of one another. The common presentation was a 3- to 7-day history of chest pain with myocardial infarction confirmed by electrocardiographic and biochemical endpoints (ST elevation in the inferolateral leads and substantial increases in cardiac troponin-I released into the bloodstream). As you might predict, heart attacks are extremely rare in otherwise healthy 16-year-olds. But marijuana itself is known to cause cardiac effects, with rare cases of myocardial infarction. In the discussion of the Pediatrics report, Dr. Arshid Mir and colleagues describe literature extending back to 1979 (DOI: 10.3109/15563657909010604) on the increased risk of cardiac disturbances, including myocardial infarction, within the first hour of marijuana use. Increased heart rate is a well-recognized effect of marijuana that is mediated by increased sympathetic nervous system outflow to the heart. This 1976 paper in Circulation describes how the majority of this tachycardia can be prevented by premedication with the non-selective beta-blocker, propranolol. But what about...

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Intravenous Milk Thistle for Mushroom Poisoning
Nov03

Intravenous Milk Thistle for Mushroom Poisoning

Apologies to readers for the radio silence - a heavier-than-usual load at the day job has been compounded by what I hope is not a prelude to a similar, serious bout of pneumonia I had almost two years ago. In the meantime, I wanted to share with you a chemistry-relevant post I wrote for my monthly gig at Science-Based Medicine on 28 October 2011. The comments there evolved into a mouth-watering discussion of culinary mushrooms. Enjoy! If you've been fortunate to live in the parts of the US that were soggier than usually as of late - or unfortunate enough to have had flooding from hurricanes and tropical storms - then you've be noticing a tremendous burst of mushrooms. For mycologists - mushroom enthusiasts - there are two classic chestnuts: "There are old mushroom collectors and bold mushrooms collectors, but there are no old, bold mushroom collectors." Or, in a more concise Croatian proverb, "All mushrooms are edible, but some only once." As such, this is the time of year that emergency rooms and regional poison centers begin to see a burst in poisonings from mushroom ingestion, due primarily to amateur misidentification of the fruiting bodies. Just this past week, Jason McClure at Medscape Oncology News (free reg req'd) wrote about the unusual bloom of mushrooms in the northeastern US and the concomitant bloom of mushroom poisonings this fall. But "mushroom poisoning" is an imprecise diagnosis for the ER physician. The constellation of symptoms caused by toxic mushrooms is as diverse as the colors and shapes of these wonders of nature. From another Medscape article on emergency management of mushroom poisoning by Dr. Rania Habal from the Emergency Medicine department of NYU: Mushrooms are best classified by the physiologic and clinical effects of their poisons. The traditional time-based classification of mushrooms into an early/low toxicity group and a delayed/high toxicity group may be inadequate. Additionally, many mushroom syndromes develop soon after ingestion. For example, most of the neurotoxic syndromes, the Coprinus syndrome (ie, concomitant ingestion of alcohol and coprine), the immunoallergic and immunohemolytic syndromes, and most of the GI intoxications occur within the first 6 hours after ingestion. Ingestions most likely to require intensive medical care involve mushrooms that contain cytotoxic substances such as amatoxin, gyromitrin, and orellanine. Mushrooms that contain involutin may cause a life-threatening immune-mediated hemolysis with hemoglobinuria and renal failure. Inhalation of spores of Lycoperdon species may result in bronchoalveolitis and respiratory failure that requires mechanical ventilation. Mushrooms that contain the GI irritants psilocybin, ibotenic acid, muscimol, and muscarine may cause critical illness in specific groups of people (eg, young persons, elderly persons). Hallucinogenic mushrooms may...

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