San Diego Inventor’s Drug Discovery is Nothing to Laugh (or Cry) About

9/4/09

[Corrected 9/4/09, 12:25 am. See below.]

Avanir Pharmaceuticals (NASDAQ: AVNR) announcement last month that its drug DMQ reduced involuntary fits of laughter and crying in neurological patients came as welcome news to San Diego scientist Richard A. Smith.

It was Smith who made the serendipitous discovery more than a decade ago that DMQ—a combination of two longtime generic drugs—could prevent unwanted emotional reactions in patients with neurodegenerative conditions.

Smith invented dextromethorphan/quinidine, or DMQ, as a possible treatment for amyotrophic lateral sclerosis, an incurable illness also known as Lou Gehrig’s disease. Smith and other scientists at the time thought that the active ingredient—dextromethorphan—might slow the destruction of brain pathways that regulate muscles throughout the body.

[Clarifies an earlier version to explain that Smith noticed the effects of dextromethorphan in an early patient safety trial, and conducted a second study with 12 ALS patients. We regret the error.]

Smith combined dextromethorphan with quinidine, a heart drug that prolongs the effect of dextromethorphan, and gave the drug to ALS patients in an early trial designed to assess the safety of DMQ. Smith did not expect the drug to produce a noticeable effect in the small, early study, but he was wrong.

Although the drug had done nothing to alter the course of their illness, patients told Smith their condition had improved. Grateful patients said DMQ freed them from the uncontrollable bouts of tears and laughter that afflict an estimated 50 percent of people with ALS. Intrigued, Smith conducted a second study in 12 patients to confirm the drug’s effect. This unexpected discovery led to Avanir’s development program for the condition, called pseudobulbar affect.

Drug development seldom follows a straight line, and sometimes the unanticipated outcomes are the ones that matter most. After discovering that an experimental HIV drug reduced uric acid blood levels, San Diego’s Ardea Biosciences (NASDAQ: RDEA) decided to instead develop the drug for gout. Allergan, (NYSE: AGN) a drug company located north of San Diego in Irvine, noticed a glaucoma drug spurred eyelash growth, so it repurposed the medication as an aesthetic treatment.

The active ingredient in DMQ has been used in over-the-counter cough medicine for more than 40 years. Scientists like Smith became interested in dextromethorphan during the 1980s, when a team from Stanford University discovered it had activity in the brain. Because most people quickly metabolize dextromethorphan, Smith combined it with quinidine, which was known to inhibit the breakdown of drugs in the body.

Smith, director of San Diego’s Center for Neurologic Study, said he was simply following the science where it led him.

That’s the hallmark of an inventor, says Avanir CEO Keith Katkin. “Some people look at the data and see obstacles. Others go through and see a bigger picture emerging,” Katkin said.

Smith said patients told him that DMQ changed their lives. One patient said that before receiving DMQ her emotions were so out of control that she laughed relentlessly during her mother’s funeral. Another patient had a laughing fit when she saw a neighbor’s dead cat. Smith said these accounts make his work “remarkably satisfying.”

Smith, a consultant to Avanir for 11 years until 2006, has continued to study DMQ. He believes the drug relieves neuropathic pain, an indication Avanir plans to pursue. He also thinks DMQ may one day prove useful against itching related to eczema, and other conditions he is not ready to talk about. Avanir, which is located across the San Diego County border in Orange County’s Aliso Viejo, CA, expects to seek FDA approval of the drug for pseudobulbar affect next year.

Denise Gellene is a former Los Angeles Times science writer and regular contributor to Xconomy. You can reach her at dgellene@xconomy.com Follow @

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  • http://sdbn.org Mary Canady

    Excellent post! Great tie in to Ardea.

    Mary Canady