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Published Entries

DISCOVERING A PROLACTIN INHIBITOR IN HUMANS

– a story of more than just a scientific effort

The first trial of bromocriptine in man:
A personal historical note

by Peter M. Lutterbeck, M.D. and
Ethan Taub, M.D. Dept. of Neurosurgery, Klinik Im Park

Abstract

The senior author (PML) is the first human being who ever took bromocriptine. In the late 1960’s, as a young physician in the research division of the Sandoz Pharmaceutical Company, he learned of newly developed ergot alkaloids with anti-fertility properties, which were considered potential commercial rivals to the hormonal contraceptives then (as now) in use. One such compound, CB-154 (later named bromocriptine), was found to have an anti-prolactin effect in animals. It was structurally similar to apomorphine, a known dopaminergic agonist. He proposed studying its clinical effect in certain prolactin- and dopamine-related conditions, particularly galactorrhea and Parkinson’s disease. His superiors rejected the idea as a long shot, irrelevant to the goal of creating new anti-fertility drugs, and transferred him to another division of the company. He kept hold of the idea till an encounter with a gynecologist treating patients with galactorrhea gave him an adequate patient group for a small-scale clinical trial. First, drug safety was tested semi-secretly on one person: the author himself. As there was no ill effect, he obtained informed consent from three patients with severe galactorrhea and gave them CB-154, with good results in all three. The initial publication in the British Medical Journal (1971) was followed by further studies confirming the effectiveness of the drug.

These studies would have been impossible if human experimentation had been regulated as strictly in 1970 as it is today. This story shows that tenacity and a certain disregard for one’s superiors can be very helpful in scientific research.

Historical note

Those who think unconventionally are likely to be disparaged or even ridiculed, and pain and frustration may result. But it is worth defying such obstacles if one has a creative idea to pursue. Tenacity and good luck, which largely consists of being in the right place at the right time, can bring such efforts to success.

The senior author (PML) attended medical school in Basel, Switzerland, in the 1960’s, and then did an internship and residency in pathology in the U.S.A. He returned to Basel in 1968 to take a research position at the Sandoz Pharmaceutical Company. Despite his inexperience in pharmacology, he was asked to set up a neuroendocrine screening laboratory in the pharmacology department. His immediate superior was a prominent zoologist who was well versed in the physiology of the animal species with which the company was working.

Technical assistants helped set up the laboratory and showed him how to handle the animals and familiarized him with the drugs that were then the major focus of interest at Sandoz, namely, the ergot alkaoids. The main task was to explore the effect of these substances on fertility. There was already evidence that they prevented implantation of the fertilized ovum in the uterine wall. It could be readily demonstrated in rats that these compounds interfered in a dose-dependent manner with normal pregnancy, as well as with pseudo-pregnancy induced by psychotropic drugs.

A possible anti-fertility effect of orally administered ergocornine (a prototype ergot alkaloid) in humans had been studied previously by groups in Japan and Yugoslavia, but with inconclusive findings: a few women had become pregnant despite taking ergocornine, but there were no data showing that the drug had really been absorbed. These studies convinced no one that ergocornine could be a commercially viable contraceptive agent. But the Japanese study1 did yield an interesting finding, on which the investigators themselves had no further comment: a few days after ergocornine ingestion, there was a consistent, 3- to 7-fold surge in urinary estrogen levels. Pituitary luteinizing hormone, LH, was not measured.

The company’s neuroendocrine laboratory studied a new ergot alkaloid called CB-154 (bromoergocryptine, bromocriptine), which had no activity in experimental animals when given orally, but turned out to have a far more potent anti-fertility effect than other ergot alkaloids when given parenterally, and seemed devoid of other pharmacologic activity. But what was its mechanism of action? The experts, both in and outside the company, thought it interfered with pituitary prolactin, but prolactin had no known effect in the initiation or maintenance of human pregnancy. Our novice researcher was able to show, in line with the Japanese clinical results on ergocornine, that a surge of estrogen levels preceded the drug’s anti-fertility effect. Perhaps CB-154 not only acted similarly to prolactin inhibiting factor (PIF), but also caused pituitary LH release and thus, indirectly, the release of estrogen from the ovaries. (PIF, of course, would later be identified as dopamine.)

There was then only a cumbersome bioassay available for prolactin. He repeatedly proposed using LH and estrogen assays to study the effect of CB-154, but, given the lack of in-house expertise for such assays, the company decided to put its resources to other uses. This was perhaps an understandable decision at the time.
With this avenue of laboratory research apparently closed off, He tried to think of a clinical condition in which to test the anti-prolactin effect of CB-154. The obvious choice was non-puerperal galactorrhea (NPG). A test of CB-154 as an inhibitor of post-partum lactation, a normal condition, would also have been worthwhile, but there were insufficient data on its safety or stability to justify giving it to normal volunteers. No tablet or capsule formulation existed, as it was only available as bulk material for parenteral use in laboratory animals. Needless to say, there was no drug assay of any kind, hot or cold.

The company management was wholly uninterested in a trial of the type he suggested, as no market existed for a prolactin inhibitor, and NPG was a rare disorder with no commercial potential. When he speculated that CB-154 might also turn out to inhibit the secretion of other pituitary hormones, such as growth hormone, he was met with further derision and told the market was too small. He also suggested using CB-154 against Parkinson’s disease, as its chemical similarity to apomorphine, and its being a derivative of lysergic acid, both raised the possibility of dopaminergic activity. Finally, he tried to stir up interest in the drug by theorizing that it could be used to treat “post-pill” amenorrhea, in case it indeed turned out to induce LH release. But all to no avail; permission to test the drug was denied.

In the 1960’s, it should be remembered, drug companies mainly produced “me-too” drugs, i.e., spin-offs of successful drugs that were already on the market. The chemical development group at Sandoz had a deserved reputation for excellence, and a number of their ergot alkaloids were in widespread clinical use. But the company, at least in this case, lacked the imagination to go out into wholly uncharted waters and test unfamiliar substances against exotic or poorly understood diseases.

Senior management began to notice his frustration as repeated requests to test CB-154 kept being rejected. Finally, the head of research offered to transfer him to a new in-house department of clinical therapeutics. He accepted, went to the USA for 6 months to learn how such units worked, and returned to Switzerland to join the team. He was fortunate to have Dr. Jack Pryor as his superior, an open-minded English nephrologist who was willing to do exploratory studies in man that might not have been allowed under the regulations then prevailing in the U.K. and the U.S.A. At that time, human experimentation with drugs was essentially unregulated in Switzerland.

The department of clinical therapeutics turned out to have only minor projects on its agenda, and Dr. Pryor gave our novice the green light to study CB-154, though he could not allocate any time or funds to the project. He decided to pursue it in his vacation time. Recalling a lecture he had heard on abnormal lactation states by Professor R. Wenner, chief of gynecology at the district hospital near Basel, he contacted him, and he told him he had a dozen or so patients with intractable NPG, some of whom were psychologically in a desperate condition. The professor agreed to let him perform his proposed trial of CB-154, even though the agent’s pharmacological properties, including its toxicity in animals, were essentially unknown. There was then no Institutional Review Board or governmental human experimentation committee to contend with, so he simply obtained informed consent from the patients and went ahead.

He first performed a preliminary “study” on the safety of CB-154 in man, by taking himself as the sole subject. He had a pharmacist help him make up 5 mg capsules of the drug by hand and then took one a day for three days, without any noticeable effect. His secretary, who was also a nurse, monitored his vital signs and found no change. Other than Dr. Pryor, no one else at the company knew what he was doing.

The clinical study was performed on an outpatient basis and began with three women with intractable NPG, to whom he gave 1 mg of CB-154 three times daily (reasoning that he had already tolerated a higher dose himself, so this would presumably be safe). Routine laboratory tests were performed, and the vital signs were checked, a few hours after each patient began taking the drug. No one involved in the study, neither the patients nor the investigators, received any compensation for taking part.

The most severely affected of the three patients telephoned him at home four days after she had begun taking CB-154. It was a Sunday evening. She was delighted to report that she had stopped lactating and her breasts had become smaller by at least one-third. She had also started to menstruate again, for the first time in six years. The other two patients obtained a similar benefit, with cessation of previously intractable galactorrhea. He reported these results internally, and went on to publish them in the British Medical Journal.2 . The NPG study group later grew to include 14 patients. Meanwhile, he also set up a double-blind study comparing CB-154 with standard estrogen therapy and placebo for the suppression of puerperal lactation. The positive findings of that study were published in the BMJ as well.3

These two papers found their way slowly into print, because the general level of interest in bromocriptine was low or essentially non-existent at that time. By the time they were published, he had already left Sandoz. Further studies of the other clinical uses of the drug, along the lines he had suggested, were carried out without his participation. As he had speculated, bromocriptine turned out to be useful in the treatment of acromegaly, Parkinson’s disease, and a variety of non-ovulatory conditions. The drug enjoyed a remarkable financial success that spurred a good deal of further research on neuroendocrine mechanisms.

It bears pointing out, without bitterness, that credit for the “discovery” of bromocriptine was later taken by the very individuals who had impeded his earlier efforts to study it. As is well known, the misattribution of credit is far from rare in the history of science. But the more important lesson of this story is that established research institutes should always be open to the proposals of younger scientists who have not yet become prejudiced by preconceived thinking. In the pharmaceutical industry and elsewhere, many promising avenues of research remain unexplored, and many interesting observations are disregarded, simply because of institutional resistance to unconventional ideas. In such an environment, a newcomer can make a difference only if he is willing to paddle against the stream. And, as in his case, a dose of good luck often helps.

References

1.Koi H. Clinical studies on the action of ergocornine in women. Keio J Med (Japan) 15 (4):197-212, 1966.
2.Lutterbeck PM, Pryor JS, Varga L, Wenner R. Treatment of non-puerperal galactorrhea with an ergot alkaloid. Brit Med J 3:228-229, 1971.
3.Varga L, Lutterbeck PM, Pryor JS, Wenner R, Erb H. Suppression of puerperal lactation with an ergot alkaloid: a double-blind study. Brit Med J 2:743-744, 1972.

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