Dr. Leng, a CA-2 research track resident at the University of California, San Francisco, is a budding physician-scientist and an avid surfer, tennis player, and utter amateur at golf.
A Story About the Discovery of Dexmedetomidine
By Kun Leng, MD, PhD
An interview with Mervyn Maze, MB, CHB
“Chance favors the prepared mind.”
— Louis Pasteur
As a junior anesthesia resident and budding physician-scientist at UCSF, I often pause to marvel at the historical artifacts showcased in our department’s hallways (for example, vials of curare). I would also listen wide-eyed to the stories that the older attendings would tell of how anesthesia was done “back then”—before propofol, before pulse-ox… In comparison to my imagination of the past, the way anesthesia is delivered today seems like an otherworldly utopia. Our patients are safe, and we are comfortable. Our job to protect patients, though not easy, is facilitated with the panoply of effective and safe drugs at our disposal in a neatly arranged tray. How did we get here from “back then”? What is the story behind each drug in the tray? Who were the heroes of the past who have won us our peace today?
The hero and mentor of mine whom I would like to honor here is Dr. Mervyn Maze, and the story I would like to retell is about how he discovered the sedative-hypnotic properties of dexmedetomidine.
Dr. Maze was born in South Africa and obtained his medical degree from the University of Cape Town in 1970. He then left apartheid-era South Africa and trained in internal medicine at the Royal Free Hospital in London. Looking to distinguish himself as a rising academician, he chose to pursue postdoctoral research at Stanford University, where he pivoted to a new clinical field—anesthesiology. He focused his research on investigating the mechanisms of anesthetic action.
At the time, it was known that modulation of adrenergic signaling in the brain affected the potency of volatile anesthetics. Dr. Ted Eger (together with a promising research resident Dr. Ronald Miller) had shown that depletion of norepinephrine centrally but not peripherally reduced the MAC of halothane.1 The distinction between alpha-1 vs alpha-2 adrenergic receptors was also beginning to be understood,2 and it was not known which one modulated anesthetic depth. Based on this body of knowledge, Dr. Maze set out on a path to prove that central noradrenergic neurotransmission controlled anesthetic depth, requiring agents that potently and specifically modulated the activity of alpha-1 vs alpha-2 receptors.
Clonidine was one such compound, but it was not selective or potent enough for Dr. Maze’s purposes. In a serendipitous encounter while visiting one of his postoperative patients, Dr. Maze met a Stanford-trained psychiatrist, Dr. John Csernansky, who told him about a compound he had acquired from a visiting research pharmacologist. The pharmacologist was Dr. Risto Lammintausta, who hailed from the Finnish pharmaceutical company Farmos. The compound didn’t do much for Dr. Csernansky’s research pursuits on serotonin, but he was happy to connect Dr. Maze with Dr. Lammintausta.
Dr. Maze followed up on this lead and secured a sample of the compound, which was called medetomidine. Having already done a series of experiments on a different compound of the same class, he was able to move forward with testing quickly. The experiment went something like this: a canine subject was anesthetized with halothane, and increasing amounts of medetomidine were injected while halothane was weaned, until, to everyone’s surprise, the halothane was completely turned off, and the dog was still asleep! (And to everyone’s relief, not dead.) The eureka moment, as Dr. Maze recalls, was when his research team then administered yohimbine, an alpha-2 antagonist, and the dog immediately woke up and bolted off the table. This was when he realized that medetomidine itself was a sedative-hypnotic that acted through alpha-2 agonism.
As chance would have it, by this time in 1987, Farmos had already moved on to separate medetomidine, a racemic mixture, into its enantiomers. However, Farmos chose to carry on its clinical investigations with the racemic mixture. Dr. Maze secured the pure enantiomers from Farmos and then went on to demonstrate that it was exclusively the D enantiomer which exhibited sedative-hypnotic properties, thus discovering dexmedetomidine as we know it today.3 This novel and inventive finding motivated him and Stanford to file successfully a use patent application for dexmedetomidine as a sedative-hypnotic. Subsequently, Farmos acquired the patent from Stanford for a sum of $250,000, which Stanford graciously allocated to Dr. Maze’s research laboratory. (This princely sum is dwarfed by greater than $1 billion in sales of dexmedetomidine in 2024!)
The use patent for dexmedetomidine would eventually be licensed by Abbott Laboratories, which tried to recruit Dr. Maze as a consultant to translate dexmedetomidine into anesthetic practice. Not wanting to be seen as a salesman peddling his drug, he refused compensation while facilitating dexmedetomidine’s clinical development. The road from Dr. Maze’s eureka moment in the lab in 1987 to dexmedetomidine winning market authorization in the United States in 1999 was long and tortuous, too long to tell in full here. But one anecdote stands out.
Dr. Maze was involved in the early human subject testing for dexmedetomidine, which meant recruiting young healthy residents to be instrumented to the hilt with invasive monitors (such as an arterial line, middle cerebral artery doppler, and pulmonary artery catheter!) while being infused with increasing amounts of dexmedetomidine. As he recalls it, one subject was a young anesthesia resident whose newly pregnant wife implored him not to participate in the experiment, as that Saturday was to be his first weekend day off for three weekends. To everyone’s horror during the experiment, the resident experienced a 12-second asystolic period while receiving dexmedetomidine (!), at which point Dr. Maze asked the research nurse to administer a dose of glycopyrrolate through the PA catheter. Fortunately, everything ended up being fine. In fact, after awakening, the resident recalled Dr. Maze asking for the glycopyrrolate while he was in asystole! Mervyn jokes that this was his second eureka moment when he realized that it was possible to complete anesthesia residency without cerebral perfusion. The stories of the past give us hope and courage for the future. Although the field of anesthesia has come a long way, there remain many challenges ahead, and we cannot rest on our laurels. How can we as a field maintain the vigor of our research? What drugs will we discover next?