2018 Lasker~DeBakey Clinical Medical Research Award

Discovery and development of propofol, a widely used anesthetic

For the discovery and development of propofol, a chemical whose rapid action and freedom from residual effects have made it the most widely used agent for induction of anesthesia in patients throughout the world

The 2018 Lasker~DeBakey Clinical Medical Research Award honors John B. (Iain) Glen (retired from AstraZeneca), who discovered and developed propofol, a chemical whose rapid action and freedom from residual effects have made it the most widely used agent for induction of anesthesia in patients throughout the world. In 2016, the World Health Organization deemed propofol an “essential medicine” and at the time of that decision, more than 190 million people had received the drug.

Anesthetic aim

In 1972, Glen joined Imperial Chemistry Industries (ICI; through mergers, ICI eventually became AstraZeneca) to help find new short-acting intravenous anesthetics. Eventually he took charge of the enterprise. The type of drug he sought—an induction agent—is used to sedate people so they can then tolerate inhaled anesthetics that maintain unconsciousness for long procedures. Administration of these gases through a mask can cause discomfort, and some of them can provoke an initial feeling of suffocation.

The gold standard induction agent at the time was called thiopentone, which induced anesthesia quickly, but had limitations. Most prominent among them, it builds up in the body, so repeated use during surgery would cause patients to remain unconscious long afterward. Glen’s team wanted to find a medication that possesses the anesthetic power of thiopentone, but allows rapid recovery. In addition to serving as a new induction agent, such a drug might maintain sedation and thus provide an injected alternative to inhaled anesthetics. The group also aimed to reduce common unpleasant after-effects of anesthesia such as nausea and vomiting.

Glen and the ICI team not only had to identify an active ingredient, they also had to find a delivery vehicle for it. This challenge posed a formidable barrier and almost toppled the project at several junctures. To gain access to the brain, anesthetics must be lipid soluble, but to achieve compatibility with blood, they must be presented in an aqueous solution for injection. Soon after Glen’s arrival at ICI, a different anesthetic entered the market; it was dissolved in an ethoxylated castor oil preparation that allowed an aqueous formulation to be achieved. The application of this material with a clinically useful anesthetic presented the possibility of testing a bank of previously synthesized lipid-soluble chemicals that ICI had stored in its compound collection.

Awakening a promising candidate

ICI chemist Roger James chose a number of compounds from the collection, and Glen began screening them in mice. In 1973, he demonstrated that one of these chemicals, propofol (chemical name, 2, 6-diisopropylphenol; trade name, Diprivan®), showed anesthetic promise in a battery of animal tests. In mice, it was 1.8 times as strong as thiopentone—and it matched standard agents in producing a rapid onset of effect. It did not cause the muscle twitching and tremors that plagued many anesthetics, and it could be combined safely with a variety of other drugs typically used for sedation.

Crucially, the compound did not accumulate in the body, even after multiple injections. Glen gave doses that induced short periods of sleep and repeated them each time the animals regained consciousness. The first injection of propofol or thiopentone knocked them out for four-to-five minutes. Ten doses of propofol lengthened that time only slightly—to about 15 minutes. In contrast, four doses of thiopentone rendered the animals unconscious for more than three hours. Subsequent tests of balance showed that the mice recovered quickly from propofol, without the significant hangover effect observed with thiopentone treatment.

Dissolving the problem

ICI launched clinical trials and gathered data on more than 1000 patients. Propofol delivered its anesthetic effects smoothly and safely, and people recovered quickly, with minimal grogginess, nausea, or other lingering unpleasantness.

Despite these positive results, the delivery substance triggered a life-threatening reaction in several individuals, and the trials were halted. The formulation challenges and other setbacks—including dosage issues and pain on injection in some circumstances—were dampening enthusiasm at ICI for the drug. Glen continued to champion the program within the company, and he kept it alive.

The company’s scientists had long wondered whether they could design an emulsion—a suspension of tiny oil droplets dispersed in a liquid—to carry propofol, but technology for producing such a material initially failed to produce sufficiently small particles. Improved emulsion-manufacturing methods allowed Glen, in collaboration with ICI pharmaceutical chemists, to identify constituents with acceptable biological and pharmacological attributes. This project culminated in a soybean oil-based emulsion formulation in which propofol bestowed its anesthetic benefits on animals without serious side effects.

Potent anesthetic: The isopropyl side groups (blue) of propofol’s chemical structure (left) are essential for the anesthetic activity and advantageous side effect profile of the drug. The soybean-derived formulation is a white liquid (right), which has inspired its nickname, Milk of Amnesia.

A global success

The soybean emulsion formulation performed well in people. Results from almost 1500 individuals treated with this version of propofol reflected the safety and efficacy findings obtained previously with the agent—minus the life-threatening reaction. In 1986, the drug received regulatory approval in the UK. Thirteen years had elapsed between its discovery and launch. US FDA approval followed in 1989, and it is now approved in more than 90 countries.

Additional clinical trials led to tremendous expansion of propofol’s applications—in children, for example, and for “maintenance” anesthesia in surgery and critical care settings. That long-term use has proved especially valuable in intensive care units, where it can keep people from fighting mechanical ventilation. The drug can relax an individual who then receives a local painkiller—or one who is undergoing a procedure such as a colonoscopy or bronchoscopy. Because recovery from propofol is rapid, it is especially well suited for outpatient clinics. People can go home clearheaded and free of wooziness soon after their procedures, which increases willingness to undergo ambulatory surgery.

Propofol’s use in maintenance anesthesia was initially limited because giving repeated injections was unattractive, and suitable equipment for continuous administration was not available. In particular, existing pumps could not deliver the medicine rapidly enough. Glen established a collaboration with a commercial manufacturer, Ohmeda Company, and the resulting apparatus has served as a prototype for a new generation of devices.

Subsequently, he advanced deployment of a technology eventually known as target-controlled infusion for propofol. In real time, a computer, programmed with a pharmacokinetic model that describes how the body handles the drug, calculates the amount needed to achieve a particular concentration in the blood or brain, and adjusts infusion rates accordingly. This method produces more predictable outcomes than can be achieved with manual oversight alone and facilitates subtle regulation of anesthetic depth. Glen persuaded his company to launch a target-controlled infusion program and the resulting system is now available in most countries, although not the US. In some areas, it is used extensively to deliver propofol for prolonged periods.

Through his vision and persistence over more than twenty years, Glen ushered into the world’s medical arsenal a powerful and versatile anesthetic that acts quickly and produces minimal side effects. Clinicians routinely deploy it in operating rooms, intensive care units, emergency departments, and outpatient clinics—and it has dramatically eased and expanded ambulatory procedures. Propofol is now the standard intravenous anesthetic induction agent in the US and the world, and it has made a vast range of operations and medical tests comfortable and acceptable for people across the globe.

by Evelyn Strauss

Key publications of John Baird Glen

Glen, J.B., Davies, G.E., Thompson, D.S., Scarth, S.C., and Thompson, A.V. (1979). An animal model for the investigation of adverse responses to i.v. anaesthetic agents and their solvents. Br. J. Anaesth. 51, 819-827.

James, R., and Glen, J.B. (1980). Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents. J. Med. Chem. 23, 1350-1357.

Glen, J.B. (1980). Animal studies of the anaesthetic activity of ICI 35868. Br. J. Anaesth. 52, 731-742.

Glen, J.B., and Hunter, S.C. (1984). Pharmacology of an emulsion formulation of ICI35868. British J. Anaesth. 56, 617-626.

Stark, R.D., Binks, S.M., Dutka, V.N., O’Connor, K.M., Amstein, M.J., and Glen, J.B. (1985). A review of the safety and tolerance of propofol (‘Diprivan’). Postgrad. Med. J. 3,152-156.

Coetzee, J.F., Glen, J.B., Wium, C.A., and Boshoff, L. (1995). Pharmacokinetic model selection for target controlled infusions of propofol. Anesthesiology. 82, 1328-1345.

Glen, J.B. (2017). The development and regulation of commercial devices for the administration of drugs by target controlled infusion, Chapter 2. In Total Intravenous Anesthesia and Target Controlled Infusions: A Comprehensive Global Anthology. Edited by A.R. Absalom, and K.P. Mason, Springer International Publishing AG, Cham, Switzerland, pp. 9-29.

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Jury

2018 Lasker Medical Research Awards Jury

Seated, left to right: Xiaowei Zhuang, Harvard University ● J. Michael Bishop, University of California, San Francisco ● Lucy Shapiro, Stanford University ● Joseph Goldstein, Chair of the Jury, University of Texas Southwestern Medical Center ● Robert Horvitz, Massachusetts Institute of Technology ● Erin O’Shea, Howard Hughes Medical Institute ● Paul Nurse, Francis Crick Institute

Standing, left to right: K. Christopher Garcia, Stanford University ● Jeffrey Friedman, Rockefeller University ● Marc Tessier-Lavigne, Stanford University ● Dan Littman, NYU Langone Medical Center ● Jeremy Nathans, Johns Hopkins School of Medicine ● Charles Sawyers, Memorial Sloan-Kettering Cancer Center ● Bruce Stillman, Cold Spring Harbor Laboratory ● Richard Locksley, University of California, San Francisco ● Craig Thompson, Memorial Sloan-Kettering Cancer Center ● Laurie Glimcher, Dana-Farber Cancer Institute ● Richard Lifton, Rockefeller University ● James Rothman, Yale University ● Harold Varmus, Weill Cornell Medical College ● Michael Brown, University of Texas Southwestern Medical Center ● Christopher Walsh, Harvard University

Not pictured: Titia de Lange, Rockefeller University