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A Tribute to Dr. Paul A. J. Janssen: Entrepreneur Extraordinaire, Innovative Scientist, and Significant Contributor to Anesthesiology

Section Editor(s): Durieux, Marcel E.; Gin, TonyStanley, Theodore H. MD*; Egan, Talmage D. MD*; Van Aken, Hugo MD

doi: 10.1213/ane.0b013e3181605add
Anesthetic Pharmacology: Preclinical Pharmacology: Clinical Pharmacology: Special Article
Chinese Language Editions

Dr. Paul Janssen was the founder of Janssen Pharmaceutica and the developer of over 80 pharmaceutical compounds that proved useful in human, botanical, and veterinary medicine. He and his coworkers synthesized the fentanyl family of drugs, many other potent analgesics, droperidol, etomidate, and numerous other important medicines that were extremely useful in psychiatry, parasitology, gastroenterology, cardiology, virology, and immunology. Anesthesiology and medicine as a whole have benefited a great deal from his resourcefulness, creativity, and entrepreneurial spirit.

IMPLICATIONS: Few in the field of anesthesiology appreciate the sheer magnitude of Dr. Janssen’s numerous contributions to various fields in human, botanical, and veterinary medicine. From the invention and development of over 80 pharmaceutical compounds to his monumental merger of Janssen Pharmacuetica with Johnson and Johnson, Dr. Paul Janssen truly embodies what it means to be a productive scientist and an entrepreneur extraordinaire.

From the *Department of Anesthesiology, University of Utah, Salt Lake City, Utah; and †Department of Anesthesiology and Critical Care, Universitätsklinikum Münster, Albert-Schweitzer-Straβe, Münster, Germany.

Accepted for publication October 3, 2007.

Conflict of interest: None of the authors of this manuscript believe they have a conflict of interest with Janssen Pharmaceutica or the J&J Corporation.

Address correspondence and reprint requests to Theodore H. Stanley, MD, Department of Anesthesiology, University of Utah School of Medicine, 30 North 1900 East, 3C444 SOM, Salt Lake City, UT 84132. Address e-mail to theodore.stanley@hsc.utah.edu.

Dr. Paul Janssen, shown in Figure 1, the founder of Janssen Pharmaceutica and developer of over 80 pharmaceutical compounds (many of significant importance in modern anesthesiology practice) died unexpectedly while visiting Rome, Italy on November 11, 2003.1–4 Some senior members of our specialty are familiar with Janssen’s many contributions to anesthesiology and a few have had the pleasure of meeting and working with “Dr. Paul” on a number of occasions. Others, especially younger physicians in practice and those still in training, may have read or heard his name mentioned, but they are probably unaware of how he came to discover, synthesize and develop droperidol, etomidate, the fentanyl family of opioids and other analgesics. Few in our specialty appreciate the magnitude of Dr. Janssen’s numerous other contributions in allergy, psychiatry, parasitology, virology, immunology, fungal disease, gastroenterology, botanical disorders and veterinary medicine.

Figure 1

Figure 1

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His Early Years and His Father, Dr. Constant Janssen

Paul Adriaan Jan Janssen was born at midday on September 12, 1926 in his parents’ home.2,3 He was the first born of four children of Dr. Constant Janssen (a general practitioner in the Northern Belgium town of Turnhout) and Margriet Fleerackers. Paul’s father was one of four general practitioners who provided consultations, house calls, assisted in difficult deliveries (often in primitive conditions) and performed operations in patients’ homes (something that was normal for the time) 6 days a week in Turnhout and the surrounding area. Dr. C. Janssen was highly respected by his many patients but did not view his busy life as a family doctor as his only mission in life.3 He possessed, in those days, what is today called an “entrepreneurial spirit.” During an educational training period in pediatrics in Vienna in 1921, he met Ladistas Richter, the son of Gedeon Richter, a business man who managed a chemical and pharmaceutical company (Richter of Budapest, Hungary). The Richter Company had branches in several Western European Countries. Dr. C. Janssen contacted Gedeon Richter some years later and, in the early 1930s, began to import and sell the latter’s pharmaceutical products in Belgium, The Netherlands, and the Belgian Congo. These were not original therapeutic compounds but rather mainly tonics, stimulants, various vitamin preparations, and organic extracts. They were usually repackaged and sold under the N.V. Produkten Richter name. In 1938, Dr. C. Janssen’s medical product business had increased so much that he decided to terminate his practice of medicine and, with his wife as an assistant, devote himself entirely to the continued growth of his company. After purchasing an old factory and some adjoining houses in Turnhout, he began making and selling his own tonics and vitamin preparations as well as those of the Richter Company.

The German occupation of Belgium during World War II and the murder of Gedeon Richter by the Nazis toward the end of the war seriously interfered with the supply of Richter products to the small Belgian company and forced the family to increase the production of its own products. The new products were successful for many reasons, not the least of which was a huge demand for penicillin and sulfonamides (neither of which were developed by Richter nor Dr. C. Janssen, but both of which were sold by each of them after the war) in the post-war period.

By the end of the 1940s, Dr. C. Janssen’s little family business had grown to more than 70 employees. His wife Margriet, besides running the family home, and looking after Paul and his three siblings, played an important role in the business. She took care of all the office work and organized and supervised the entire production line, including quality control of the raw materials up to the dispatch of the finished products. Paul Janssen first became involved in some of the business in the 1940s. He developed a few products (Perdolan, Bronchosedal, and Rubalgan)a, some of which are still sold by Janssen today.

Paul Janssen was an excellent student and loved European football (soccer) and chess. Young Paul had his primary and secondary schooling at St. Josef College in Turnhout, which was one of the strictest Jesuit schools in Belgium at that time. He finished these studies in 1943 at the age of 16. Although many young Belgian males were forced to work as laborers in German factories during the last years of the war, Paul, with the help of his uncle Emiel Janssen, was able to secretly enroll in college at the Faculte‘ Notre Dame de la Paix in Namur, Belgium. At Notre Dame, 12 Jesuit teachers gave lessons in physics, biology, philosophy, and chemistry to <10 students without the knowledge of the occupying German powers. The courses were intense and stimulating to young Paul and, perhaps because of his exposure during his early years to his fathers business, he became excited and interested in the importance of chemistry in medicine. Combining the two sciences into what he called “medicinal chemistry” was an exciting and new frontier. After 2 yr at Notre Dame, Paul received his Bachelor of Natural Sciences degree (magna cum laude) and moved to Leuven, Belgium at the end of 1945 to study medicine at the Catholic University.1,2 As he started medical school, his interest in discovering and developing original new drugs was increasing. He also realized that the selling of vitamins and tonics and similar medicines in which no patent could be obtained was no longer viable for his father’s company. In addition, Paul became convinced that there must be a connection between the chemical structure of a pharmaceutical compound and its action in a patient’s body. This idea became the foundation for later research by Dr. Paul; that is, synthesizing chemical compounds with the objective of finding the relationship between their chemical structure and their pharmacological activity.

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Six Months in America

In 1948, during his second year at the Leuven Faculty of Medicine, Paul realized that in order to synthesize new drugs he had to first gain a better understanding of developments in world-wide research in chemistry and pharmacology. Therefore, he convinced his parents to allow him to take a leave of absence from medical school in order to visit the United States for an extended period. His objective was to attend courses as a part-time student and to visit a number of pharmaceutical companies. His parents provided him with a small amount of money but most of his finances came from playing competitive chess when he could find “pick-up” matches in the cities he visited in America.1

Upon arriving in the United States, Paul first visited Professor Harry Gold, a famous pharmacologist at Cornell Medical School in New York City. After his visit to New York, he studied with Edwin Cohn at Harvard and then attended a series of lectures by Carl Pfeiffer, a well-known pharmacologist at the University of Chicago. He spent the summer of 1948 in a biochemistry course at the California Institute of Technology in Pasadena. Between lectures in California he visited a number of pharmaceutical companies including Searle, Upjohn and Lederle to gain knowledge of contemporary pharmacological research.

Paul Janssen arrived back in Belgium in the autumn of 1948 for the year’s academic examinations, which he passed with honors, and then moved to Ghent University for his last 2 yr of practical medical training. Paul received his medical degree in 1951, again, magna cum laude. After graduation, the young Dr. Paul had a national military obligation. He accomplished this near Cologne in Germany. He had plenty of free time while in Cologne so he continued his studies in pharmacology and chemistry with Professor Dr. J. Schuller at the University of Cologne. He remained at Schuller’s laboratory until the end of 1952. Between 1951 and 1954, Dr. Paul had further periods of practical medical training in Paris, Vienna, and Heidelberg and made a number of study trips to Oxford, London, and Stockholm and a second visit to the United States.

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Receiving His PhD

In the early 1950s, Paul Janssen became friendly with Professor Dr. Corneille Heymans who directed the Institute of Pharmacology and Therapeutics of the University of Ghent in Belgium. Professor Heymans won the Nobel Prize in medicine in 1938 for the discovery of the reflex-ogenic role of the cardio-aortic and carotid sinus areas in the regulation of respiration. Dr. Heymans was a scientist who Dr. Paul admired and with whom he loved to work. He regularly visited Professor Heymans and was a part-time assistant at the institute between 1950 and 1956. In 1956, Dr. Janssen received a degree in Chemical Pharmacology with a thesis entitled “On the pharmacology of a series of propylamines” from the University of Ghent.

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Starting His Own Company

While it would have been logical for Dr. Paul to join Dr. Heymans at the Institute in Ghent or to join any number of academic institutes or Universities in Belgium or Western Europe in the mid 1950s, he never aspired to an academic career. Instead, early in 1953, he decided that the time had come for him to begin the achievement of his childhood dream, the establishment of a completely independent research company, capable of surviving and expanding on the income from its own research results. The principal reason behind his decision was not financial profit but rather the irresistible urge to prove that he could do it. He understood that he had to produce medically important compounds as quickly as possible. They had to be valuable and he needed to secure patents. He could then license them to larger companies and with the income thus generated, recruit new associates and repeat the process again and again. This was clearly an ambitious goal for the young scientist who was only 27-yr-old and had very modest resources at his disposal.

Paul Janssen’s friends and associates did not believe an independent, self-financing research laboratory was a wise idea, considering the financial demands and high risk of failure in the pharmaceutical business. Nonetheless, Paul began the project, encouraged by his parents. His father (according to Dr. Paul) provided Paul the third floor of his company’s building, for his first research laboratory. His father also gave him a grant (50,000 Belgian francs, approximately $1000 and probably the equivalent of $5000–$7000 in today’s purchasing power) to begin his work. Years later, when quizzed about whether he needed more financial support after his father’s initial grant, Paul always indicated the royalties secured from licensing his early compounds were all that were necessary (T. Stanley, personal communication).

After funding his laboratory in 1953, Paul Janssen hired a secretary (Andre Janssen [unrelated to Paul] who remained a secretary and confidant for over 40 yr), a bookkeeper from his father’s firm, and a few scientific coworkers and began the job of synthesizing new compounds. Many of the first individuals Dr. Paul hired were not university graduates but, in his words “… they all had common sense, a desire to work hard, trusted him and had inquisitive minds that were continually searching for innovation.” One of the early objectives of the small group of scientists was trying to understand how chemical compounds produced their actions in animals. Once they had an idea of the mechanism by which a compound acted, their objective was to intelligently manipulate the compound’s structure to improve or enhance its biological effects.

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The First Compounds

One of Dr. Paul’s early interests was reducing the occurrence of painful muscular spasms in a number of organs. The fifth new compound synthesized in the new laboratory, ambucetamide (Neomeritine), a uterine antispasmodic, was successfully introduced in the clinic in Belgium in 1955 and is still marketed today in some countries as an effective drug for the relief of menstrual pain. Initially, Dr. Paul and his team performed simple screening tests using in vitro and in vivo animal models of the day. Time was vital. Interesting new compounds needed to be patented and evaluated using the few resources available as quickly as possible. After basic screening tests, Dr. Paul sent most of his first compounds to Dr. David K. de Jongh, a Dutch physician in Amsterdam who, like Dr. Janssen, had studied for a time with Professor Heymans at Ghent. Dr. de Jongh had equipment for undertaking more extensive pharmacological modeling and research, which helped to determine the new compounds’ medicinal activity and value as new drugs. Dr. de Jongh differentiated Dr. Janssen’s compounds by giving them an R number (from Richter). Assigning new compounds, R numbers never changed and by 1956 (3 yr after starting the synthesis of new compounds) more than 1100 new compounds had been created. The 100,000th R number was reached in 1993 and 147,000th R compound was synthesized in 2001.

The second important compound created by the Janssen research team was R79, isopropamide iodide, an atropine-like substance which was launched in 1955 and is still a component of a number of Janssen pharmaceutical products. This compound was licensed to Smith, Kline and French of Philadelphia for sale in the United States under the brand names Combid and Darbid. The success of those products and two other compounds, dextromoramide (R875) and diphenoxylate (R1132) synthesized in 1955 and 1956, respectively, were very important for the ultimate success of the Janssen research team. Dextromoramide (Palfium) launched in Europe, but never in the United States, was not so important for its commercial success but, rather, because it was significantly more potent than morphine and for awhile was the most potent opioid available in the world for clinical use. In those days, being able to synthesize the most potent opioid provided Dr. Paul Janssen with a certain amount of academic recognition.

Diphenoxylate was ultimately licensed to Searle in the United States. Luck played and impressive part in the licensing deal. One of Jack Searle’s (the Chief Executive Officer of Searle) relatives was suffering from a severe attack of diarrhea which was rapidly cured by taking diphenoxylate (later called Lomotil). Soon after this episode, Searle acquired the rights to the drug and launched it in the United States. Lomotil was also in the medical kit of the Apollo astronauts and taken in their spacecraft to the moon.

In the late 1950s, Dr. Paul merged his laboratory business with his father’s company to form Janssen Pharmaceutica with Paul as President and Director of Research. Paul Janssen’s mother gradually retired from the business at the end of the 1950s, but his father remained active until his death in April, 1970. At his death, Dr. C. Janssen was the Chairman of the Board of Directors of Janssen Pharmaceutica. The synthesis of haloperidol (Hadol) in 1958, the first antipsychotic that allowed patients to be treated at home instead of in a psychiatric institution, and fentanyl (again the most potent opioid of its day) in 1960, began to get the attention of the giants of the pharmaceutical industry.

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The Merger with Johnson & Johnson

In the late 1950s, Johnson & Johnson (J&J), the huge international conglomerate of health care companies, was scouting to buy a pharmacological research company with a bright future. In 1959, it purchased the American company, McNeil Laboratories and a small Swiss company entitled Cilog Chemic. In late 1957, J&J made an initial contact with Dr. Paul. The courtship continued over the next few years and was consummated on July 17, 1961. Under the terms of the contract, the Janssen family of companies (there were by 1961, Janssen subsidiaries in the Netherlands and Germany as well as three companies within Belgium) merged within J&J for an exchange of a block of shares of J&J stock.

Despite the merger, Dr. Paul was fiercely independent. J&J, in its wisdom, recognized the value of Dr. Paul’s independence and the tremendous potential of his still young company. Dr. Paul was given a formal guarantee that his Belgian company would be permitted to retain its own identity and independence within the international group at J&J. For Paul Janssen, the merger with J&J was sort of a life insurance contract. As he mentioned numerous times, “I have always been convinced that we needed an American anchor. It’s not only a huge market, the most important in the world, but it is also the best place to make yourself known to the world. A drug that doesn’t make it in America will never become an international blockbuster.”1,2

The merger with J&J provided Janssen with financial security, interactions with many wise individuals within the J&J family of companies and undoubtedly numerous other advantages of which only he was fully aware.

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The Discovery and Development of Fentanyl and the Fentanyl Family of Analgesics

At the beginning of Paul Janssen’s research in 1953, morphine (Fig. 2) was the standard analgesic for the relief of pain. As a medical student, Dr. Paul had learned about pethidene (meperidine) (Fig. 2) a new atropine-like antispasmodic/antidiarrheal drug that had been introduced into European medicine in 1939.1 Clinical experience indicated meperidine was a morphine-like analgesic although much less potent. Dr. Paul recognized that meperidine had a piperidine ring (Fig. 2) within its structure, like morphine. He and his colleagues believed that the piperidine ring was the most important chemical structure in morphine and meperidine that produced analgesia. He was also attracted to begin working with meperidine, as the parent molecule in the production of newer compounds, rather than morphine, because it was much less complex a molecule and thus easier to manipulate.1 His strategy was to find new molecules that were more powerful and specific analgesics and antidiarrheals than either morphine or meperidine and which he hoped would have fewer unwanted side effects.5,6

Figure 2

Figure 2

The Janssen research team realized that meperidine was only about one-tenth as potent as morphine and decided that it was such a poor analgesic because it could not easily penetrate into the central nervous system. They concluded meperidine was too hydrophilic or water soluble and believed that they needed to synthesize a more fat soluble meperidine derivative. In order to do this, the Janssen chemists first replaced the methyl (CH3) group attached to the N of piperidine at the extreme left of the meperidine molecule (Fig. 2) with an additional benzene ring. This meperidine derivative was more lipid soluble and had stronger analgesic action, presumably because of better penetration of the blood–brain barrier. The chemists knew that more than increased fat solubility was required for greater analgesic potency. The compound would also have to bind with a receptor (the μ receptor had, at the time, not yet been identified but the concept of a pain receptor was well known). In considering the binding of the new compounds with a pain receptor the chemists then added a C=O in combination with two CH2 groups between the left benzene and piperidine rings of the first new compound and came up with R951 (Fig. 3). R951 showed a still greater increase in analgesic potency. The addition of still another CH2 group between the left benzene and piperidine rings, R1187 (Fig. 3) resulted in a compound with less analgesia than R951. However in 1957, phenoperidine, R1406 (Fig. 3) was synthesized. Changing the C=O group attached to the left benzene ring in R951 to a C–OH group in R1406 resulted in a dramatic increase in potency. Phenoperidine was more than 25 times the potency of morphine. It was also, at the time of its synthesis, the most potent opioid in the world. Phenoperidine was introduced into many European countries, but not the United States, as a potent, fast onset of action, short-lasting analgesic for anesthetic use. It is still available in many of the countries into which it was introduced.1

Figure 3

Figure 3

Dr. Paul and his research team continued experimenting in the late 1950s with new molecules related to phenoperidine.5,6 When they reduced the distance between the piperidine ring and the benzene ring on the left side of phenoperidine to –CH2–CH2–, incorporated a N between the piperidine ring and benzene ring on the right side of phenoperidine, and changed the SYMBOLattached to the piperidine ring in phenoperidine to a SYMBOLand moved it to the N between the piperidine and right-sided benzene ring, they came up with fentanyl (Fig. 4).1,7 Fentanyl was first synthesized in 1960 and was being used in a number of European countries 3 yr later. The research team was not finished synthesizing new fentanyl derivatives and over the next 16 yr created many additional compounds.8–11 The most successful and useful of these were sufentanil (first synthesized in 1974 and introduced in Europe in 1979 and the United Sates in 1985), alfentanil (first synthesized in 1976 and introduced into Europe in 1983 and the United States in 1987) and carfentanil (first synthesized in 1974, and introduced in veterinary medicine in 1986) (Fig. 4, Table 1).1,8–11

Symbol

Symbol

Symbol

Symbol

Figure 4

Figure 4

Table 1

Table 1

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Fentanyl’s FDA Approval

One interesting and historically important contact that Dr. Paul Janssen made after the merger with J&J was with Robert McNeil, the founder of NcNeill Laboratories which was purchased by J&J in 1959. In the middle of the 1960s Janssen launched fentanyl and droperidol as independent drugs in Europe. Anesthesiologists in most European countries were pleased with both drugs used separately and in some practices together, and both drugs were enjoying success and becoming quite popular.7,12,13 Unfortunately, the Janssen Company was having difficulty getting fentanyl through the Food and Drug Administration (FDA) approval process in the United States. One strong opponent to the approval of fentanyl was Dr. Robert Dripps, the distinguished professor of anesthesiology at the University of Pennsylvania in Philadelphia, Pennsylvania. Dr. Dripps felt that fentanyl was too potent, and caused rigidity. This, he thought, would result in many patients needing to be tracheally intubated and would lead to many abuse problems. Through Robert McNeill, who knew Dr. Dripps, Dr. Paul was introduced to Dr. Dripps and began a dialog and negotiation that ultimately convinced Dr. Dripps to lessen his opposition to fentanyl’s approval. The compromise was that fentanyl would only be approved in combination with droperidol. As a result, when fentanyl was approved by the FDA in 1968, clinicians could only get it combined with droperidol in a ratio of 50:1 droperidol to fentanyl. The combination was called Innovar in the United States and thalamonal in other countries.

The 50:1 ratio came about after Paul consulted with Dr. George de Castro, a wise and experienced clinician. Dr. de Castro worked in Brussels and tested, in patients, all of Janssen’s IV analgesics, hypnotics, sedatives, and similar compounds. This work occurred after extensive animal testing in the Janssen laboratories but before the drugs were studied by other clinicians in the human trials of the day. Dr. de Castro often used fentanyl in combination with droperidol in a neurolept-analgesia technique that was somewhat popular in some Western European countries in the early to mid 1960s.12,13 George de Castro calculated what his usual mixture of fentanyl to droperidol was in his clinical practice. It turned out to be approximately 50:1 droperidol to fentanyl. This ratio was suggested by Dr. Janssen to Dr. Dripps. Both of them knew that droperidol produced a “bad high” if taken as a recreational drug and both believed that the mixture of droperidol and fentanyl would likely minimize its abuse potential. The FDA agreed and Innovar was approved for use in the United States early in 1968 (personal communication P. Janssen and T. Stanley).

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Large Doses of Opioids

In December 1969, an important study was published by Lowenstein et al.14 This study demonstrated that large doses of morphine would produce unconsciousness and extremely stable cardiovascular dynamics before, during, and after open heart surgical procedures in severely ill patients with valvular heart disease. Large-dose morphine anesthesia became popular as an anesthetic technique in very sick patients having heart surgery within a year or so after the publication of Lowenstein et al.’s paper. However, a short time later, problems with awareness, severe hypertension during surgery and other issues called into question the desirability of using large doses of morphine for anesthesia in physically fit patients, such as those undergoing the new coronary artery bypass operation.15 This led to many studies in animals evaluating large-dose fentanyl as an alternative opioid anesthetic and later large doses of fentanyl for cardiac anesthesia in patients.16 The success of fentanyl in these patients resulted in a dramatic increase in the sales of fentanyl as it was going “off patent.” Indeed, the sales of fentanyl in the United States increased 10-fold the first year the drug was off patent. Rarely does this kind of an increase in sales occur with any drug going off patent, much less an opioid that was, at least at that time, only used in the perioperative period by anesthesiologists and their associates.

The marked increase in fentanyl sales spurred Dr. Paul and the Janssen Company to develop sufentanil, alfentanil, and etomidate in the early 1980s and a little later transdermal fentanyl in a patch called Duragesic in partnership with the Alza Company. All four drugs were approved by the FDA and became useful products for anesthesiologists and pain physicians. Only Duragesic came close to being a blockbuster. In 2004, sales of Duragesic topped $2 billion world wide.

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Dr. Paul as a Mentor

Over his lifetime, Dr. Paul Janssen not only had a plan for developing promising chemical substances but also a talent for recognizing and stimulating outstanding colleagues. When the Belgian Congo declared its independence in the late 1950s, he recruited more than 24 pharmacologists, neurologists, parasitologists, veterinarians, and others who had been working for many years in the tropics of the Congo but were forced to return to Belgium by the new leaders of the country which became Zaire. Many (Bob Marsboom, Carlos Niemegeers, Denis Theinportm, Jan van Aitsem, Jan van Nueten, and Oscar Vanparys are a few of the better-known names from a long line of distinguished scientists who came out of Africa) became world experts in their respected fields and contributed hugely to the knowledge base of the Janssen company. A growing number of university graduates also came to work at Janssen Pharmacuetica starting in the late 1950s to swell the ranks of the 30 or so original researchers in the little town of Beerse, Belgium (where the company was located by 1957). These individuals greatly expanded the many contacts that Dr. Paul had already established with Dr. Corneille Heymans, Dr. J. Schuller, Dr. David de Jongh, and numerous others in the scientific and medical communities and throughout the pharmaceutical industry. This resulted in increased communication and frequently collaborative research with the likes of P.J. Carpenter, N.B. Eddy, G. de Castro, R. Reneman, J. Cruel, T. Savage, B.G. Eazzard, G.M. Hall, J.J. Rouby, K.C. Wong, C.C. Hug, D. Stanski, F.G. Hayden, G.N. Tytgat, E. Panconesi, M. Tubiana, and dozens of others in Europe and the United States in a variety of medical and scientific disciplines. Within the walls of the expanding company, many younger scientists grew into well-known experts in pharmacology, parasitology, dermatology, and pyschiatric, cardiovascular, allergic, gastrointestinal, fungal and veterinary diseases and their pharmacological treatment. The names of J.E. Leysen, A.U. Colpaert, J.A. Jorgeneau, K.H. Schellekens, C. van Der Eycken, A.H.M. Raeymaekers, P.J.A. Demoen, R. Xhonneux, H. von Den Bossche, F.M. Lenaerts, F.J. Verbruggen, A.U. Heykonts, A. Wauguier, W. Soudijn, A. Wouters, M. Borgers, the recruits from the Congo (those mentioned above and others) and still others who came to work in Beerse became world authorities. This happened because Dr. Paul motivated them and they studied the tens of thousands of molecules synthesized by the Janssen chemists, published hundreds of articles in the world’s basic and clinical science literature, and appeared in hundreds to thousands of scientific meetings and gatherings worldwide. By the year 2002, Dr. Paul had himself published over 870 articles in the world’s scientific literature. Thousands of additional articles were published without his name on them by his friends, coworkers and colleagues within and outside of the company.

In addition to recognizing talented scientists, Paul Janssen was unique in building the research of his company around his people, not the other way around. He gave all his coworkers the greatest possible latitude in their area of expertise, while he determined the general direction it would go. He acted firmly but also with great respect for the qualities of his associates. He had the talent of being able to stimulate and encourage them by continually nurturing their hopes.

Because of all of the above, success came rapidly to the Janssen company and in huge bundles. At the time of the merger with J&J, there were 377 employees and a few Janssen affiliated companies in Germany, Holland, the Belgian Congob, Jordanb and Egyptb. By the end of 1992, the Janssen company had 34 foreign affiliates and more than 11,000 employees worldwide selling the more than 80 pharmaceutical compounds it had developed for human, plant, and animal diseases. The drugs developed by Dr. Paul and his scientists included compounds for infestations by fungi and worms, all sorts of mental illnesses, cardiovascular disease, allergies, and gastrointestinal disorders as well as pain and anesthesiology. Besides the fentanyl family of drugs (alfentanil, fentanyl, and sufentanil for humans and carfentanil for wild animals) and etomidate, droperidol, and Innovar, the most well known drugs produced by Janssen are noted in Table 2.

Table 2

Table 2

Table 2

Table 2

At the time of Paul Janssen’s death, the sales of the Janssen division of J&J totaled more that $9 billion a year, approximately 25% of the $36 billion of sales of the entire J&J conglomerate in 2003. After relinquishing responsibility of the day-to-day decisions at the Janssen company in Belgium, Dr. Paul remained active as Director of the Janssen Research Foundation’s Center for Molecular Design and during the last year of his life was overseeing the development of a new series of compounds (one of which was in Phase II clinical studies) for the treatment of Acquired Immune Deficiency Syndrome.

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Dr. Paul’s Recognition, His Other Contributions and the Secret of his Success

Paul Janssen was a gifted, many-faceted scientist with a great dislike for bureaucracy “because it needlessly wastes a lot of time and suffocates creativity.” He considered himself lucky because as he said, “I was born at the right moment, because 10 years later the realization of my dream (forming his own company) would have been impossible.” He also considered himself “to have had a lot of luck in the choice of his associates and that he was rarely sick.”

The scientific and workplace opportunities Janssen Pharmaceutica provided to young scientists in the Benelux countries, parts of Germany, northern France and even England and the economic impact that the more than 30 Janssen companies had all over the world is hard to measure but is enormous. Politicians, royalty of numerous countries, as well as scientists and business leaders from all over were constant visitors to the company in north central Belgium. Dr. Janssen was an advisor to numerous politicians in Belgium and the Netherlands, was a consultant to upper management of the J&J Corporation and many of the J&J family of companies, frequently appeared on radio and television in Belgium to discuss the medical questions of the day and even played the piano publicly with world class pianists and other musicians. He traveled extensively throughout Europe, the United States (at times as often as monthly), Australia, China, and all over North and South America.

Dr. Paul received more than 35 scientific awards and assignments (Table 3) and 22 honorary doctorates, (Table 4).2 The honorary doctorates were not only in medicine but also natural science, veterinary medicine, pharmacy, and philosophy. In 1992, alone he was awarded four honorary doctorates. In 1993, he became the first foreigner to receive a pharmaceutical honorary doctorate in China. Despite all the awards and honors he received, Dr. Paul never wished to take all the credit for himself. When the title of baron was conferred on him in 1990 in Belgium, he indicated that the award was really recognition of the hard work and achievements of all his associates at the Janssen company over the years.

Table 3

Table 3

Table 4

Table 4

Sir James Black, Emeritus Professor of Pharmacology in the Department of Analytical Pharmacology of the Kings College of London, who was a competitor of Dr. Paul’s when he started his career at Imperial Chemical Industries in England in the late 1950s and became his close friend and admirer in later years, suggested that the reason why Dr. Paul Janssen “was the most prolific drug inventor of all time” was related to many skills.4 These included exceptional managerial talents in leading, motivating, and rewarding his large research and development group; extraordinary negotiating and deal-making skills in the marketplace; and an incredible inventiveness which included (whenever he started a project) a conception in his head of a chemical starting place or “lead” molecule (with appropriate bioassays). Dr. Janssen also possessed foresight of how this molecule would provide clinical utility and also how he might change the lead molecule and create additional analogues to possibly develop still better molecules. The iterative synthesis, bioassay evaluation, and test and feed back process would gradually build a picture of structure-activity relations. This became a Darwinian evolution of newer more effective compounds. The whole process had to be driven by intense concentration and extreme commitment to allow the evolving complex picture to be clear in his mind so that timely judgments could be made as to when to continue a line of chemical thought and when to change direction. In Black’s opinion, Paul Janssen’s intense concentration and passionate commitment were unique to the pharmaceutical industry.

The final, and perhaps greatest, talent that Paul Janssen possessed was his creativity. He had, as most successful inventors do, the good judgment to know when the invention (in this case, the new drug) was right for the purpose. Good judgment comes from experience, imagination, and a special kind of intuition.4,17 Dr. Paul had all of these in spades. It is sad that, for all the good Paul Janssen’s enormous pharmaceutical success brought to the people of the world, he never received the Nobel Prize, although he was nominated several times.

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SUMMARY

Dr. Paul Janssen was surely a scientist of great historical significance to clinical pharmacology and to anesthesiology in particular. From humble beginnings, he forged a path of innovative thinking and creativity that has had a huge impact on the quality of human life and the practice of anesthesia. Dr. Paul’s important legacy was recently honored by the creation of the Dr. Paul J. Janssen Award for Distinguished Contributions to Anesthetic Pharmacology given by the International Society for Anesthetic Pharmacology. The specialty of anesthesia has been fortunate to have had such a talented and energetic man interested in our therapeutic area. Dr. Paul’s influence in anesthesia truly runs deep.

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REFERENCES

1. Schwartz H. Breakthrough: the discovery of modern medicine at Janssen. Morris Plains: Skyline Publishing Group; 1990
2. Collier D. Dr. Paul. In Corporate Communications, Janssen Pharmaceutica, Turnhoutsweg 30 B-2340, Beerse, Belgium; 1992
3. Collier D. Dr. Constant Janssen. In Corporate Communications, Janssen Pharmacuetica, Turnhoutsweg 30, B-2340 Beerse, Belgium; 1996
4. Black J. A Personal Perspective on Dr. Paul Janssen. J Med Chem 2005;48:1687–8
5. Janssen PAJ, Eddy NB. Compounds related to pethidine-IV new general chemical methods of increasing the analgesic activity of pethidine. J Medicinal Pharma Chem 1960;2:31–45
6. Janssen PAJ. A review of the chemical features associated with strong morphine-like activity. Br J Anaesth 1962;34:260–8
7. Janssen PAJ, Niemegeers CJE, Dony JGH. The inhibitory effect of fentanyl and other morphine like analgesics on the warm water induced tail withdrawal reflex in rats. Arzneimittel-Forschung 1963;13:502–7
8. Niemegeers CJE, Schellekens JHL, van Bever WFM, Janssen PAJ. Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs. Arzneimittel-Forsching 1976;26:1551–6
9. van Bever WFM, Niemegeers CJE, Schellekens KHL, Janssen PAJ. N-(4-substituted-1-(2-arylethyl)-4-piperidinyl)-N-phenyl-propanamides, a Novel Series of Extremely Potent Analgesics with unusually High Safety Margin. Arzneimittel-Forschung 1976;26:1548–51
10. de Castro J, van de Water A, Wouters A, Xhonneux R, Reneman R, Kay B. Comparative study of cardiovascular, neurological, and metabolic side effects of eight narcotics in dogs. Acta Anaesthesiolog Belg 1979;30:5–99
11. Niemegeers CJE, Janssen PAJ. Alfentanil (R39209)-a particularly short acting intravenous narcotic analgesic in rats. Drug Development Research 1981;1:83–8
12. Nilsson E, Janssen PAJ. Neurolept-analgesia- an alternative to general anesthesia. Acta Anaesth Scand. 1961;5:73–84
13. de Castro J, Mundeleer R. Anesthesia sans barbituratiques: la neurolept analgesie. Anesth Analg (Paris) 1959;16:1022–56
14. Lowenstein E, Hallowell P, Levene FH, Daggett WM, Austen WG, Laver MB. Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 1969;281:1389–93
15. Lowenstein E. Morphine anesthesia—a perspective. Anesthesiology 1971;35:563–5
16. Stanley TH, Webster LR. Anesthetic requirements and cardiovascular effects of fentanyl-oxygen in man. Anesth Analg 1978;57:411–16
17. Broers H. Inventor for life: the story of W.J. Kolff, father of artificial organs. Kampen, The Netherlands: B&V Media; 2006

aThese also were not original therapeutic drugs but rather generally available substances or mixtures of substances and organic extracts which may have provided analgesia, bronchodilation and improved muscle blood flow, respectively.
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bThe headquarters of these companies were in Belgium.
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