Checking in and out of hospital on the same day. This trend—a growing phenomenon in America—requires fast-acting medications. This is one reason why Organon Teknika (Boxtel, the Netherlands) recently developed a new muscle relaxant. Marketed in the U.S. by Organon Inc., under the brand name Raplon®, the new drug’s principal characteristics are its fast onset and short duration of action.
In the world of surgery muscle relaxants are critical for operations carried out under general anesthesia and as a worldwide market leader in this area, Organon Teknika has a strong track record with these drugs. The business unit has previously launched three of them with success: Pavulon®, Norcuron® and Esmeron® (called Zemuron® in North America). Approval of Raplon was recently granted by the Food and Drug Administration (FDA) in the US, where sixty percent of all operations are carried out on an outpatient basis, which means that there is a real need for fast-acting drugs. “That’s why FDA approval was so important for us,” says Marc van Bekkum, manager Development Pharmaceuticals and project manager for Raplon. “The trend toward outpatient care will also increase in Europe. It lowers costs and improves efficiency.” Van Bekkum has high expectations for Raplon even though a similar fast-acting muscle relaxant is already on the market. This drug, succinylcholine, has been available since 1949, but has a number of potential side-effects such as malignant hyperthermia, caused by disturbances in the body’s temperature regulation. Also, succinylcholine can trigger cells to release potassium, which can lead to cardiac arrhythmias and cardiac arrest. Raplon doesn’t have these side effects. Raplon is the fourth muscle relaxant to be introduced onto the market by Organon Teknika since 1969. Pavulon was the first, followed by Norcuron in 1983. “After that, we developed Esmeron and introduced it in 1994. It has a number of advantages over Norcuron. Raplon is an additional muscle relaxant that the anesthesiologist may choose. It is unique that we have developed four products out of a series of compounds based on the same basic structure. Differences between these four products are the onset time and the duration of action.” Raplon has the shortest onset and duration of action. Esmeron, for example, works for 30 to 40 minutes, Raplon has a clinical duration of about 15 minutes.
‘Time to relax’ Raplon took six years to develop. “In 1993, the master plan for the project was written after the selection of the compound at the Organon research location in Newhouse, Scotland. Approximately 180 employees from Organon, Organon Inc., Diosynth and Organon Teknika worked intensively in worldwide teams to make Raplon a success. We used video conferencing a great deal and the marketing people were involved from the very beginning. Throughout the whole process we kept in close contact with the FDA,” says Van Bekkum. The 60,000 page final dossier consisted of European and American studies. June last year, when the dossier was ready to be submitted, a truck was hired to transport the 16 meter wide report to the FDA. “Everybody worked hard”, says Van Bekkum, “especially just before submitting the dossier for approval, which, by the way, took 14 months.” On the day that the dossier was submitted, he boarded a plane for America with 100 T-shirts printed with the slogan ‘Time to relax.’ Now that Raplon has received FDA approval, the most important development work has been completed. Van Bekkum clearly lead the project with pleasure. “In this experienced development team, you could compare my role to that of a passionate soccer midfielder, connecting and boosting the team. You want to do a good job, but also be fast. Therefore you have to know the limits of the game, you weigh the risks. In the end, we only had a three month delay since we started the project in 1993.” A dossier has also been submitted in Canada, and Europe will follow shortly. Approval in the Netherlands is expected in the second half of 2000. In Newhouse, work is already underway on a new series of compounds that may lead to even more effective muscle relaxants. “The ideal muscle relaxant is one that the anesthesiologist can turn on and off at a moment’s notice and that has no side effects. But who knows if such a drug can be created?” The strategy of the unit is also geared toward the other aspects of anesthesia such as sleep-inducing drugs and painkillers. Van Bekkum and his team are already working on a new project: pain management during operations. A new reason for him to have T-shirts made, this time with the text ‘No time to relax.’
Anesthesia and muscle relaxants Anesthesia has three pillars: ‘sleep’, pain management and muscle relaxation. Muscle relaxants have only been in use since 1942. Before that time a large amount of a sleep-inducing drug was administered to the patient with all the associated risks. The introduction of muscle relaxants made it possible to lower the dosage of other anesthetics, which considerably improved the safety of anesthesia for the patient. Relaxed muscles during surgical interventions are important for three reasons. It facilitates the insertion of a tube into the trachea. This tube serves a couple of functions, one of which is the connection to a respirator. Artificial respiration is made easier and safer. Thirdly, the muscle relaxation considerably improves the conditions under which the surgeon must work, and thereby also the safety for the patient. Muscle relaxants (also called neuromuscular blocking agents) are used in 75 percent of operations carried out under general anesthesia. In 60 percent of all operations, general anesthesia is used while 40 percent are carried out under local anesthesia. There are two types of muscle relaxants: depolarizing and non-depolarizing. Raplon is the first non-depolarizing muscle relaxant that combines both rapid onset with short duration for tracheal intubations and short surgical procedures. The drug causes paralysis by blocking a neurotransmitter called acetylcholine from binding to its receptor. There is no depolarization of the muscle fiber membrane (which does occur with the depolarizing muscle relaxant, succinylcholine) and therefore no muscle fasciculation. Curare, a naturally occurring paralyzing agent used on arrow heads by South American Indians to paralyze their prey (goes back to the 15th century), was the first muscle relaxant used in clinical practice (1942).