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Category → Adverse Reactions

The Case Of The Malodorous Metabolite

Over where I also write at Forbes.com, Matthew Herper, Senior Editor for Pharma and Healthcare, reported on GlaxoSmithKline’s NEJM clinical trial of darapladib in coronary artery disease. The drug had been developed as a small molecule, orally-formulated, subnanomolar inhibitor of lipoprotein-associated phospholipase A2.

Lp-PLA2 is associated with apolipoprotein B-containing lipoproteins, such as LDL and non-HDL particles, and is found in the necrotic center of atherosclerotic plaques. Formerly known as platlet-activating factor acetylhydrolase, the enzyme produces pro-apoptotic lysophosphatidylcholine and stimulates the synthesis and release of proinflammatory mediators such as IL-1 beta, IL-6, ICAM-1, and VCAM-1.

A meta-analysis of nearly 80,000 patients across 32 trials indicated that Lp-PLA2 was associated with a relative risk for coronary artery disease of 1.10 for each 1-standard deviation increase in activity, even when correcting for other influences. This magnitude of relative risk is similar to that for non-HDL cholesterol or systolic blood pressure.So, the enzyme seemed like a reasonable target for small-molecule inhibition.

Darapladib (SB-480848) emerged from screening for inhibitors and a synthesis campaign, each published in 2002 and 2003, and was selected for clinical trials. A study with 330 patients with coronary artery disease, The Integrated Biomarkers and Imaging Study-2 trial, showed that 12 months of darapladib (160 mg daily, p.o.) decreased the progression of atherosclerotic plaques that occurred in the placebo group, even when they were also receiving standard-of-care statin therapy.

Darapladib (SB-480848; N-[2-(diethylamino)ethyl]-2-(2-{[(4fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1 H-cyclopenta[d]pyrimidin-1-yl)-N-{[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide

Darapladib (SB-480848; N-[2-(diethylamino)ethyl]-2-(2-{[(4fluorophenyl)methyl]thio}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)-N-{[4’-(trifluoromethyl)-4-biphenylyl]methyl}acetamide

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Acetyl Fentanyl: Dangerous, Poorly-Named Street Drug

Acetyl fentanyl HCl, courtesy of Cayman Chemical Company. Click on the image to view the source page.

Acetyl fentanyl HCl, courtesy of Cayman Chemical Company. Click on the image to view the source page.

The U.S. Centers for Disease Control and Prevention has released a summary on a cluster of 14 deaths in Rhode Island earlier this year attributed to “acetyl fentanyl,” an analog of the potent, short-lived opioid used in pain management and outpatient anesthesia. The report, “Notes from the Field: Acetyl Fentanyl Overdose Fatalities — Rhode Island, March–May 2013,” appears in the August 30, 2013 issue of Morbidity and Mortality Weekly Report (MMWR).

The first 10 deaths were reported in the Providence Journal on May 13, 2013, leading CDC officials to join the team in the investigation. A total of 14 deaths were identified. Samples from the decedents gave positive ELISA results for fentanyl but GC/MS revealed an analog that authorities are calling acetyl fentanyl. A CDC health advisory released in June briefly details the chromatographic pattern and mass spectra.

Cayman Chemical Company, who offers the reference material, also calls it acetyl fentanyl, but offers desmethyl fentanyl as an alternative. The IUPAC name is N-​phenyl-​N-​[1-​(2-​phenylethyl)-​4-​piperidinyl]-​acetamide; fentanyl has a propionamide instead of the acetamide.

A CBC news story described a late April series of drug busts in Montreal that included seizure of a compound they called desmethyl fentanyl. The current MMWR release also links to an alert from the Pennsylvania Department of Drug and Alcohol Problems that reports 50 acetyl fentanyl deaths in the state this year, through June 27th (PDF).

Most curious is that the compound has not been described before as a recreational drug. It’s not available as a prescription drug anywhere in the world and is only a minor side product (0.04%) found in prescription fentanyl (DOI: 10.1016/j.jpba.2010.04.004).

In a lengthy discussion on Twitter last night and this morning with Chemjobber, SeeArrOh, and others, I initially asked whether acetic anhydride could have been used to acetylate fentanyl, thinking — without looking at the structure — that it was truly acetylated. I found later that fentanyl is made from 4-anilino-N-phenethylpiperidine (ANPP) using either propionyl chloride or propionic anhydride. Hence, acetyl fentanyl could be made by reacting ANPP with either acetyl chloride or acetic anhydride (That’s the extent of my synthetic expertise, Dear Reader.).

The major problem with acetyl fentanyl — or fentanyl for that matter — is its high potency relative to natural opioids like morphine or the more potent synthetic, heroin. As a result, the CDC recommends that emergency rooms and other facilities providing substance misuse care services stock up on the opiate receptor antagonist naloxone in anticipation of an increase in overdoses across North America.

But it looks like we’re stuck with acetyl fentanyl as the name. Any thoughts?

Making People Hate Chemistry on Halloween

Actual Twitter profile picture of the contributing editor at Gizmodo.

Thanks to a tip from ChemBark et al., here is the most “insanely irresponsible” promotion of hazardous chemistry demos that I’ve seen. Written by Gizmodo Contributing Editor Eric Limer, the post draws from books by author William Gurstelle (Backyard Ballistics, Absinthe & Flamethrowers).

On one hand, Gurstelle has done much to promote scientific curiosity among the public. That’s a good thing. Plus, Gurstelle has safety glasses in his promo picture. But Limer takes some of Gurstelle’s ideas out of context and suggests that they be used to scare or harm others.

Thankfully, many commenters have gone over to Gizmodo to register their disapproval but the post remains up. I understand from his profile and website that Limer lives in an area hit by Hurricane Sandy but I encourage him to take down his hurtful post as soon as is feasible.

Quirky is fun and interesting and people can find this information elsewhere with a little work. But promoting it at a major geek site is a Bad Idea.

Legislation to protect men from PDE5 inhibitors

Ohio State Senator Nina Turner. Credit: Official website.

I’ve been rather quiet here as of late, Dear Reader. Between my new day job and trying to finish my book chapter on natural toxins while fighting an overall bout of writer’s block, these pages have been devoid of pixels.

But I couldn’t resist posting this news that came across my screen from various sources:

State Senator Nina Turner (D-Cleveland) announced legislation today that would protect men in Ohio from the risks of PDE-5 inhibitors, drugs commonly used to treat symptoms of impotence.  Turner’s legislation would include provisions to document that the symptoms are not psychological in nature, and would guide men to make the right decision for their bodies. Physicians would be required to obtain a second opinion from a psychological professional to verify that a patient has a true medical malady before the medication could be prescribed.

“The men in our lives, including members of the General Assembly, generously devote time to fundamental female reproductive issues—the least we can do is return the favor,” Senator Turner said. “It is crucial that we take the appropriate steps to shelter vulnerable men from the potential side effects of these drugs.”

No, this is not from The Onion.

This is a press release from State Senator Turner’s website.

And the closer:

“We must advocate for the traditional family, protect the sanctity of procreation, and ensure that all men using PDE-5 inhibitors are healthy, stable, and educated about their options—including celibacy as a viable life choice. This legislation will do just that.”


The State Senator is my new hero.


Four Loko for Locos

Well, that was fast. After a year-long investigation of pre-made, highly-caffeinated alcoholic beverages, the US FDA today warned four companies to go decaf.

The U.S. Food and Drug Administration today warned four companies that the caffeine added to their malt alcoholic beverages is an “unsafe food additive” and said that further action, including seizure of their products, is possible under federal law.

The companies receiving Warning Letters and their products are:

• Charge Beverages Corp.: Core High Gravity HG, Core High Gravity HG Orange, and Lemon Lime Core Spiked
• New Century Brewing Co., LLC: Moonshot
• Phusion Projects, LLC (doing business as Drink Four Brewing Co.): Four Loko
• United Brands Company Inc.: Joose and Max

FDA’s action follows a scientific review by the Agency.  FDA examined the published peer-reviewed literature on the co-consumption of caffeine and alcohol, consulted with experts in the fields of toxicology, neuropharmacology, emergency medicine, and epidemiology, and reviewed information provided by product manufacturers.  FDA also performed its own independent laboratory analysis of these products.

“FDA does not find support for the claim that the addition of caffeine to these  alcoholic beverages is ‘generally recognized as safe,’ which is the legal standard,” said Dr. Joshua M. Sharfstein, Principal Deputy Commissioner.  “To the contrary, there is evidence that the combinations of caffeine and alcohol in these products pose a public health concern.”

Experts have raised concerns that caffeine can mask some of the sensory cues individuals might normally rely on to determine their level of intoxication.  The FDA said peer-reviewed studies suggest that the consumption of beverages containing added caffeine and alcohol is associated with risky behaviors that may lead to hazardous and life-threatening situations.


That last paragraph was what I focused upon in my post over the weekend that was stimulated by a frontpage Raleigh News & Observer article by higher ed reporter, Eric Ferreri (@campus_notes). Large amounts of caffeine taken with a 23.5 ounce beverage containing 12% (v/v) ethanol deceives the drinker into thinking they are less drunk than their motor skills or blood alcohol concentration would reveal. I’m not one for a nanny state but this is in a nutshell is the threat to public health with highly-caffeinated alcoholic beverages.

A couple of my dear Twitter followers were having sport with me today about these products and some asked why FDA is acting on these products but not the practice of mixing vodka and Red Bull or whiskey with coffee. The major reason is that these are prepared food products (I’d also add that Four Loko has four times the caffeine as a typical Red Bull).

From the FDA’s Q&A today:

Under what authority is FDA issuing these Warning Letters?

FDA is issuing the four Warning Letters under its authority to implement the Federal Food, Drug, and Cosmetic Act (the FFDCA).  Under the FFDCA, a substance added to food (such as caffeine added to an alcoholic beverage) is deemed an “unsafe food additive” and is unlawful unless its particular use has been approved by FDA, is the subject of a prior sanction, or is generally recognized as safe (GRAS).  A food that contains an unsafe food additive is deemed adulterated under Section 402(a)(2) of the FFDCA [21 U.S.C. 342(a)(2)]; adulterated foods are subject to agency enforcement actions, including seizure.

The FDA has only listed caffeine as GRAS as an ingredient for use in cola-type beverages in concentrations of no greater than 200 parts per million. There is no food additive regulation that permits the addition of caffeine, at any level, to an alcoholic beverage. Based on the information FDA has reviewed, the agency does not consider the use of caffeine in the products listed above to be GRAS.

What puzzles me is that most of the public and media concern has been with regard to the caffeine with little discussion of the alcohol content. As I noted over the weekend, one can of Four Loko is approximately the same volume and alcohol content as an entire bottle of wine (or 4+ decent beers.). In fact, the folks at BuzzFeed got it wrong yesterday when they offered their own recipe for homebrewed Four Loko: Five watermelon Jolly Rancher candies, a caffeine pill, a can of Sprite, a can of Monster Energy Drink, and a 40 oz bottle of St. Ides malt liquor. St. Ides is 8.3% ABV and when diluted out with the soda and energy drink, you’ve got about 68 oz of 4.9% ABV swill.

BuzzFeed friends and readers: You’d still have to drink 58 oz of this loathsome assault on humanity to equal the amount of alcohol in a single 23.5 oz can of Four Loko. This fact alone should make apparent to even defenders of Red Bull and vodka that this stuff is, uh, roughly four crazy drinks.

Four. Crazy. Drinks.

I finally get it.

So now, assuming the companies respond to their FDA warning letters, we’ll simply have products in the cooler that are insipid, fruit-flavored beverages with 12% alcohol.