NEWS The Journal of Clinical Investigation The 2018 Lasker~DeBakey Clinical Medical Research Award recognizes John Baird Glen for the discovery of propofol

The Lasker~DeBakey Award for Clinical lism. Multiple administrations dramati- James, who thought it was worthwhile to Medical Research commends individu- cally increase patient recovery time and revisit ICI’s existing compound collection. als whose achievements have profoundly risk of adverse effects. Nonetheless, The older arsenal of compounds had advanced medicine. In 2018, the Albert thiopental remained the preferred agent been abandoned because of poor solubil- and Mary Lasker Foundation honors for anesthesia induction throughout the ity in water, a requirement for i.v. injection. John (Iain) Baird Glen, BVMS, PhD, for 1960s, combined with newer inhalational “It’s a bit of a catch-22 situation,” his contributions to the practice of anes- agents for maintenance. The search for explains Glen. “You need a lipid-soluble thesia. Glen (Figure 1) spearheaded the a compound that would enable total i.v. molecule to get it into the brain, but if you discovery and clinical development of anesthesia continued (3). have a lipid-soluble molecule, you can’t get the i.v. anesthetic propofol, which has it into aqueous solution.” been identified among anesthesiologists Glen’s discovery of propofol Auspiciously, the steroid anesthet- as the most transformative drug in their Iain Glen’s innovative career began with ics Glen had studied at the University of field (1), as well as the development of a his studies of veterinary medicine at the Glasgow had been formulated in a surfac- breakthrough infusion system that helped University of Glasgow. After graduating tant material known as Cremophor EL, standardize anesthetic delivery. Togeth- in 1963, he spent a year as a veterinary which made it possible to solubilize lipid er, propofol and its infusion system have surgeon at the University of Nairobi and molecules in an aqueous solution. Glen and remodeled expectations for the precision, returned with an interest in pursuing aca- James identified anesthetic activity in 2,6 safety, and tolerability of anesthesia. demic research rather than veterinary diethylphenol, but it was not sufficiently practice. In 1965, he accepted a lecturer potent or rapidly acting enough to compete The pursuit for total i.v. position in the Department of Small Ani- with thiopental. However, the observa- anesthesia mal Surgery at his alma mater, an oppor- tion turned their attention toward an array William Morton and others performed tunity that would also allow him to con- of similar hindered phenol compounds. the first documented surgeries on anes- duct research in veterinary medicine. To Among the first three compounds tested was thetized patients in the 1840s, and use facilitate his teaching role, he studied for 2,6 diisopropylphenol (propofol). Although of general anesthesia increased steadily the University of Glasgow Royal College the chemical effort continued until 1976 throughout the remainder of the century. of Veterinary Surgeons’ newly created spe- and evaluated 300 phenols in total, no com- Early methods relied almost exclusively cialty diploma in Veterinary Anesthesia. pound with superior properties to propofol on gaseous inhalational anesthetics such The training, which qualified him to teach was discovered. Over the duration of the as ether, chloroform, and nitrous oxide, the topic, also ultimately redirected his project, more than 3,000 candidates were which typically produced slow-onset lifelong research interests. tested for anesthetic activity. anesthesia, sluggish recovery of con- Glen became particularly interested sciousness, and — often — adverse post- in investigating several newly developed Early challenges operative effects (2). anesthesia agents, including the steroid Propofol and thiopental had similar ther- Anesthetics (i.v.) possessed an impor- mixture of alfaxalone and alfadolone and apeutic indices, but propofol was more tant advantage over inhalational methods: the sedatives xylazine and droperidol. potent and carried a much lower risk of they could provide a quicker onset of anes- Eventually, Glen changed the focus of his postoperative nausea. Due to its speedy thesia. John Lundy, of the Mayo Clinic, is PhD to studies on the pharmacology of metabolism, propofol also retained its credited with bringing the i.v. anesthetic injectable anesthetic agents. short recovery latency throughout repeat- sodium thiopental into clinical practice In 1972, Glen joined ICI Pharmaceu- ed dosing, which represented a clear in the 1930s. Injection (i.v.) of thiopental, ticals’ anesthetics research team, which advantage over thiopental (4). a highly potent barbiturate, was found to sought to identify a compound that matched Still, Glen tells the JCI, “It was quite a induce anesthesia rapidly and displayed a thiopental’s induction speed but improved struggle to convince the company that pro- favorable therapeutic index (3). upon its slow metabolism. Although ICI’s pofol was worth developing.” In spite of its advantages, thiopental chemists were producing new compounds ICI Pharmaceuticals’ forecasts for was not considered suitable for maintain- with structures that resembled known anes- propofol’s commercial potential were pes- ing anesthesia due to its sluggish metabo- thetics, Glen was paired with chemist Roger simistic, but Glen was convinced of the compound’s promise. “I had to go and speak to the technical Reference information: J Clin Invest. 2018;128(10):4198–4200. https://doi.org/10.1172/JCI124375. director and try to explain to him that this

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develop computer algorithms for optimal anesthetic administration, and Glen saw a new opportunity to improve propofol’s application in the surgical setting. He organized a meeting between research groups from all over the world to deter- mine whether ICI should develop a model- driven device for propofol. “At the end of that meeting, I was con- vinced that target-controlled infusion, or TCI as it’s called, would make the adoption of maintenance of intravenous anesthesia easier. It took me another couple of years to convince ICI to begin development in that area,” he says. Working with Gavin Kenney and Mar- tin White, Glen oversaw the development and clinical evaluation of a TCI system that relied on propofol’s pharmacokinet- ics to safely induce and maintain anesthe- Figure 1. Iain Glen, recipient of the Lasker~DeBakey Award for Clinical Medicine Research. Image credit: Flora Lichtman. sia. The Diprifusor TCI module could be installed in any compatible commercially available syringe pump, ensuring consis- was not just another thiopental. This was a ber one meeting when, by 5 votes to 4, we tent performance across surgical settings drug which could be used much more wide- decided to continue development. There (6). Coordinated commercial marketing of ly because of its rapid metabolism,” he says. was a need to fight for the drug to that Diprivan and Diprifusor began 1996, and He convinced the company that pro- extent because it wasn’t widely supported both remain in wide use globally. pofol could be appropriate for a greater by all parties in the development team.” variety of therapeutic applications than Faced with waning company enthusi- The legacy of Glen’s thiopental, including maintenance of anes- asm, Glen was an advocate for propofol’s innovations thesia, sedation in intensive care patients, improved emulsion formulation. Iain Glen’s predictions for propofol’s wide- and sedation in conjunction with regional Glen transferred from research to spread applications were correct: Today, or local anesthetic techniques. the medical affairs department in 1983 to propofol remains the preferred anesthetic In initial trials, propofol was solubi- assist Ron Stark and Katie Hopkins in the in numerous diverse medical procedures. lized with Cremophor EL, but the formu- clinical evaluation of the emulsion formu- Though he notes that the drug has draw- lation was not ideal. Glen and colleagues lation. He was particularly interested in backs — it can cause injection-site pain in conducted a series of experiments impli- advancing propofol’s use for maintenance some patients, and the original emulsion cating Cremophor EL as responsible for of anesthesia in specialized patient groups formulation was susceptible to bacte- the anaphylactoid reactions associated in whom inhalational anesthesia was par- rial contamination — Glen is pleased with with alfaxalone, alfadolone, and other ticularly inconvenient or life-threatening, propofol’s success. agents. They subsequently spent 2 years including patients undergoing operations “It’s a credit to the drug. As far as the searching for an alternative surfactant for- on the head, neck, or airway and those sus- quality of recovery is concerned, I think it’s mulation suitable for clinical use before ceptible to malignant hyperthermia. fantastic that patients who experience pro- shifting their focus to emulsions. Ulti- The ensuing clinical trials were suc- pofol anesthesia do actually see the differ- mately, they developed a soybean oil for- cessful, and propofol entered the United ence if they have had an earlier anesthetic mulation to emulsify propofol and render Kingdom’s clinical market as Diprivan in with thiopentone,” he says. the product fit for clinical trials (5). 1986. By this time, commercially avail- Glen is also optimistic that propofol able technologies made it possible to con- will produce further advancements in Clinical development of duct the continuous, real-time physiologic anesthetic practice. The Diprifusor system propofol monitoring that is now standard during was never approved in the United States, Clinical trials had initially been performed anesthesia and recovery periods. Phar- but he is hopeful that a commensurate in Belgium with the Cremophor EL–based macokinetic modeling, which had been device may make it to market now that pro- formulation. The results were somewhat employed with increasing precision since pofol is available as a generic drug. Ongo- chaotic, plagued by inconsistent adminis- the 1960s, was also refining the guidelines ing research into the drug’s pharmacoki- tration and inadequate records. for dosing patients safely and effectively. netics, specifically in pediatric patients, “Some of the early results really were Academic researchers were begin- continues to improve anesthetic methods quite confusing,” Glen says. “I can remem- ning to utilize pharmacokinetic models to and patient outcomes (7).

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Glen says that receiving the Lasker~ actualizing innovations that have dramati- Anaesthesia. Oxford, United Kingdom: Oxford DeBakey award is a “huge honor and a cally improved general anesthesia for the University Press; 2013. great surprise. I believe serendipity played millions of patients who undergo surgery 3. Corssen G. John S. Lundy: Father of intravenous anesthesia. In: Rupreht J, van Lieburg MJ, Lee a role in the initial discovery. I knew what I each year. For these transformative con- JA, Erdmann W, eds. Anaesthesia. Berlin, Heidel- was looking for, and it was largely a matter tributions to anesthesiology, the Lasker berg, Germany: Springer; 1985. of persevering and overcoming a number Foundation presents Dr. Iain Glen with the 4. Glen JB. Animal studies of the anaesthetic of barriers to get the drug to the market. 2018 Lasker~DeBakey Award for Clinical activity of ICI 35 868. Br J Anaesth. 1980;52(8):731–742. It’s the drug really, I think, that deserves Medicine Research. 5. Glen JB, Hunter SC. Pharmacology of an emul- the award.” sion formulation of ICI 35 868. Br J Anaesth. In propofol, Glen recognized an Elyse Dankoski 1984;56(6):617–626. agent whose properties were capable of 6. Glen JB. The development of ‘Diprifusor’: a TCI revolutionizing anesthetic practice. His 1. Bateman BT, Kesselheim AS. Propofol as a system for propofol. Anaesthesia. 1998; transformative drug in anesthesia: insights 53(suppl 1):13–21. persistent push for propofol’s clinical from key early investigators. Drug Discov Today. 7. Mahmoud M, Mason KP. Recent advances development and expansion into multiple 2015;20(8):1012–1017. in intravenous anesthesia and anesthetics. therapeutic indications were critical to 2. Webster NR, Galley HF, eds. Landmark Papers in F1000Res. 2018;7(F1000 Faculty Rev):470.

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