A full-page advertisement in the April 3, 1999 edition of the Washington Post announcing the merger of what had been Upjohn & Pharmacia with Monsanto inspired the first version of this account.  The new combine was to be known to the world simply as Pharmacia, The announcement, led to the suspicion at that time that the recombination would eventually lead to the disappearance of the names Searle, Upjohn, Adria and Farmitalia Carlo Erba.  The fact that these are the very names that formed part of my own identity over better than half my career as a research chemist made that ad particularly relevant. The announcement towards the end of 2002 that Pfizer had agreed to buy Pharmacia made it almost certain that the names would be relegated to the famous dustbin of history. A very sad story that appeared in C&E News in August 2003 confirmed this by chronicling the disappearance of drug finding research from Kalamazoo.

Back in 1955, when I got my degree, the chemistry departments of pharmaceutical companies represented the shining castle on the hill for the many synthetic organic chemists who opted for careers in industry.   Those laboratories offered the best chance to work on relatively complex molecules.  The goal of producing compounds aimed at alleviating disease added a somewhat altruistic motive to the simple desire to carry out what we considered engrossing chemistry.  This perception probably still obtains today even though the shape of the industry has undergone a massive change.  Back in the nineteen-fifties, the industry consisted of a few big companies and a host of smaller firms.  The former still exists in some form, though more often than not as part of some agglomeration with other firms, and not uncommonly under some other name.  Most of the smaller companies have disappeared with nary a trace.  This brief account traces the convoluted stories of the several companies with which I have been associated.

As a freshly minted Ph.D. I had the very good luck to get a job in the industry with what was then one of the upcoming smaller firms. That company, G. D. Searle, was a family owned concern located in Skokie, Illinois, a suburb of Chicago.  Like many other pharmaceutical firms it got its start by manufacturing standard recipes that had in earlier days been compounded by individual pharmacists.  Shortly after World War 2, the company apparently hit it big with some quite popular product.  The motion sickness remedy, Dramamine, was probably the drug that set Searle on the road to riches.

The Searle family, who had firm control of the company, some time in the late 1940′s or early 1950′s moved the company’s operations from its former location in Chicago to a newly built facility in Skokie.  The whole operation was, as a result, housed in a very impressive set of very contemporary, almost Bauhaus-like, white brick buildings.  These included a state-of-the-art manufacturing plant, a set of very well equipped laboratories and the obligatory headquarters office building.  The family also put up funds to staff a sizeable research operation.   The new Director of research, Al Raymond, chose to hire well-credentialled academicians to head up his major departments.  Biology for example was headed up Victor Drill then well known as the editor of the massive tome entitled “Drill’s Pharmacology”. The chemistry department’s Director was Byron Riegel who had had been full Professor in the Chemistry Department at neighboring Northwestern University before moving over to Searle.  Perhaps because of his background, Riegel set out to run a very collegial department in which all 20 or so chemists, most of whom had their Ph.D.’s, reported directly to him; there were no assistants in Chemical Research.  Riegel had taken what looked at the time like a rash gamble by devoting better than half the company’s chemical research to steroids.  There was fairly reliable hearsay to the effect that the Company had pursued a sizable effort just a few years earlier for producing cortisone by perfusing progesterone through columns of beef adrenal glands. One memento of this program consisted of a collection of carboys containing solutions of side fractions of as yet unidentified perfusion products.  They had apparently been saved in the hope of someday going back in the search for some miracle cure.  Searle was in the process of running through batch after batch in order to accumulate a goodly supply of the cortisone. They were holding off announcing its commercial availability until enough was on hand to meet the expected rush of customers. Just barely before that happened, the rival firm Upjohn announced its successful introduction of oxygen at the 11 position in progesterone by fermentation.  This would obviously lead to a much simpler and more economical route to cortisone. Searle pulled the plug on its effort when it became clear that the perfusion process could not possibly compete with the route that used fermentation as a key step for producing the drug.  An apocryphal story has it that one of the scientists who was let go when Searle closed out its perfusion project sent Al Raymond, the Director of Research, a very bloody beef adrenal slice, in an Intradepartmental mailing envelope.

That close brush with disaster did not, happily for Searle, result in abandonment of all work on steroids.  By the mid-1955, close to half the chemists, eight individuals spent all their time on steroids. Fields of investigation ranged from highly substituted corticosteroids to the simpler steroid sex-hormones. The latter was in part spurred by the belief that progesterone would provide the basis for a contraceptive drug. Progesterone itself was not active when taken by mouth; a derivative that overcame that shortcoming was a clear goal for steroid. Frank Colton, who had been by then been at Searle for about six years, had quite early suspected the potential of the so-called 19-nor steroids as orally active hormonal drugs.  The steroid with the jaw-breaking name 17-ethynyl-17-hydroxy-estr-5(10)-ene which came out of Frank’s lab eminently met the goal. This compound later to be better known by its generic name ethynodrel or the subsequent trade name, Enovid went on to become the world’s first marketed oral contraceptive. The fact that Searle that Carl Djerassi and his colleagues at Syntex produced and patented the very closely related compound norethindrone, at virtually the same time has led to long running contention as to the inventorship of the first oral contraceptive.

Enovid actually came on the market in 1960 as a drug for treating menstrual irregularities; approval as an oral contraceptive followed within a year or so.  As the very first drug in its class it was a runaway commercial success that kept Searle in the black for many a year.  The cash generated by sales of this pioneering compound and closely related follow-on derivatives allowed Searle to expand its research program to the point where this matched that of some of the major companies.  They were however not again to have a real blockbuster to match Enovid for many a decade.  

The Searle toxicology program was, by the way, the focus of a major scandal sometime in the early 1970′s that had a profound effect on the whole industry.  A routine audit by FDA of some data that they had submitted to support a New Drug Application revealed major problems.  Data on given animals for would for example disappear and then later reappear at strange intervals.  The upshot was an in-depth FDA audit that gave Searle and the industry in general a black eye.  When a group of us from Upjohn had occasion to visit the Searle labs in 1973 we had a hard time finding a place to park since half of the Visitor slots were marked “Reserved for FDA”. By the same token we noted that a set of permanent picture ID badges were kept at the reception desk for FDA personnel.  Similar sloppy and possibly dishonest conduct was also found by audits of some contract toxicology labs.  FDA as a result promulgated as set of guidelines entitled Good Laboratory Practices (GLP).  These guidelines, which had the force of regulations, set forth how studies were to be conducted as well as how records need be kept in minute detail.

Searle was not, however, to survive as such.  In 1985 the company was acquired by Monsanto when the latter decided to try its luck in pharmaceuticals.  Its luck would turn out to be outstanding with the discovery of the first cyclooxgenase-2 inhibitors.  At this writing Celebrex is the second or third largest selling prescription drug in the US.  It is still strange however to read about Searle of Chesterfield, Missouri instead of Skokie, Illinois; this St. Louis suburb being Monsanto’s headquarters.

The next company, Upjohn, shared many characteristics with Searle, in that it too was still largely controlled by the founding family.  The firm had its start in 1885 when a physician in Kalamazoo devised a method for manufacturing pills that would actually disintegrate in the stomach and then dissolve.  The company logo for many years consisted of a thumb in the process of crushing a pill.  This was to draw the distinction with the many competing products that could be actually hammered into a wooden board without coming apart.  Over the coming decades the company grew by providing a full line of the then-standard products.  It first big push in the 1940s consisted of a line of vitamins.  By the 1950s the company had grown to many times the size of Searle.  In 1951 they built a massive new manufacturing facility in Portage, Michigan just south of the city of Kalamazoo.  The buildings that had previously housed downtown manufacturing complex were then remodeled as laboratories for the mushrooming research effort.  This company too had gotten into steroid research quite early.  They had even gone so far as to set up a stable in order to do some pilot runs on extracting conjugated estrogens from the urine of pregnant mares.  Upjohn seems to never have followed up on this as a potential product. Ayerst on the other hand exploited very similar technology to come up with Premarin. This product is still one of the mainstays of American Home Products, the firm that eventually swallowed Ayerst. American Home Products quite recently renamed itself Wyeth after one of its constituent firms.  This was not to be the last gold mine overlooked by Upjohn management.  Meanwhile, in the late 1940s Kendall and Hench at the Mayo Clinic had discovered the dramatic anti-inflammatory activity of cortisone.  This set off a heated race among the major pharmaceutical labs to find a practical method for synthesizing these compounds since they occurred in animals in only very low concentrations.  The main hurdle that needed to be overcome was the introduction of an oxygen atom at the 11 position of a steroid; no steroids from plant sources had that crucial substituent. We have already visited Searle’s ruinously expensive solution to that problem.  Upjohn was to be luckier: In 1952 a group of Upjohn scientists announced that they had successfully introduced the required atom by fermenting progesterone in the presence of a mold.  After some a few years of subsequent intensive research by a sizeable group of chemists the firm came on the market with cortisone and cortisol.  The same group of chemists then went on to produce a sizeable number of analogues which were much more potent than the parent molecule; a number of these in fact became a marketed drug.  An unintended consequence of this success lay in the fact that steroid chemists had come to dominate the chemistry effort. Well over half of the Chemical Research Department staff devoted their entire effort to steroids.  The chemists who worked in the more traditional areas of medicinal chemistry were perceived as lacking that special éclat.

In 1959 Upjohn was clearly a world leader in the field of steroid.  The company was also quite successful in terms of sales and profits; its sales and income led to its being regularly ranked among the ten biggest pharmaceutical firms.  The company had gone public not long before.  A rather complimentary article in Fortune magazine, marking the occasion was part of the recruiting package.  Management had up to that time been very paternalistic and took great pride in the fact that they had not laid off any employees during the Depression.  The article interestingly noted an apocryphal saying that Upjohn was “a country club with working privileges”.  Success seemed to follow upon success in those years.  Sometime in the middle 1950s they launched, Orinase, which was world’s first antidiabetic drug.  It should however be noted that this was a product licensed from the German company, Hoechst. The analogue Tolinase that was a very close variant first synthesized in Kalamazoo followed within a few years.  Management also supported a very sizeable program aimed at developing new antibiotics.  This resulted in the structurally unique drug lincomycin, first isolated from an organism obtained in a soil sample from Lincoln, Nebraska.  A much improved semisynthetic cousin clindamycin followed within a few years.

 Sometime in the early sixties the company seemed to hit a bad patch financially with the result that hiring in research was suspended for four to five years. Other interesting portends of future problems could have been noticed by those equipped with good crystal balls.  Upjohn for example was very late in developing an oral contraceptive in spite of the fact that the company was one of the two or three major players in the field of steroid research.  This was supposedly due to a ruling from top management that pregnancy was not a disease and thus not a proper target for pharmaceutical intervention.  The product they did finally put on the market, Provest, never took an important share of the market possibly due to lack of aggressive promotion. The overall direction of research was dictated by the top management philosophy that decreed that the company would steer clear of what they called me-too products.  Instead they held that the chemical structures of Upjohn product candidates should bear no visible relation to competitors’ drugs. This had a very direct effect on their position in the field of antibiotics.  By the middle 1960s the very massive screening effort the company devoted to the search for new antibiotics was yielding fewer and fewer results; the pipeline for new drugs in this class was essentially dry.  This was coincidentally the very time that 6-aminopenicillanic (6-APA) acid became readily available from commercial sources. Other research centers started intensive programs on developing semi-synthetic penicillins based on 6-APA. The response of Upjohn’s research management was to assign a group of antibiotic chemists to a six-month program to prepare 6-APA derivatives.  They unsurprisingly failed to come up with a drug candidate. The mandated time frame conveniently overlooked the fact that it probably takes that long just to learn how to handle these delicate molecules.  The upshot was that no significant new antibiotics were to be launched under the Upjohn name for the remainder of the twentieth century.  .

The program on the synthesis of analogues of cortisone was producing a series of ever more potent molecules.  It was however becoming evident that the newer analogues quite simply showed increases in only milligram potency.   The pattern of side effects that these newer compounds elicited in various test systems was virtually exactly the same as that of cortisone itself.  This put very much of a damper on the hope of finding new drugs that would show a mythic “split”; that is an increase in anti-inflammatory activity and a decrease in the potentially serious side effects these drugs show on long term administration.

The then-Director of Research, David Weisblatt, had gotten to know the Swedish chemist Sune Bergstrom as he had done his graduate work in the same field. The two had apparently stayed in touch over the ensuing years.  In early 1961 Sune got in touch with his friend to let him know that he was on track of an extremely potent hormone-like compound.  This substance which was first isolated from human semen was named prostaglandin after its putative origin in the prostate.  This looked like the answer to a maiden’s prayer to the steroid chemists. Prostaglandin seemed to hold out the promise of a new class of hormonal compounds that would serve as the basis of potent new drugs.  It had the further attraction of being composed solely of carbon, hydrogen and oxygen, an attribute that seemed to make it amenable to the same sorts of manipulations with which steroid chemists were most familiar.  The program on prostaglandin (still singular) started quite modestly with the assignment of a single chemist (me) to work on it half time.  Within six months it was clear that there was more than one prostaglandin and that the problem would require far more manpower than originally believed.  Suffice it to say, since this is not a history of prostaglandin research, that at its peak in the mid to late 1970′s, the program involved well over two dozen Upjohn scientists in various disciplines.  This seemed to be matched by the discovery of a new prostaglandin (by now plural several times over) every other year or so.  Instead of being hormones however, the prostaglandins turned out to be compounds released by tissue injury.  Very few drugs have come from this massive effort at Upjohn or corresponding programs at other research labs.

The main negative impact of the prostaglandin program did not lie entirely in its lack of success.  That is pretty much the fate of the majority of pharmaceutical research.  The research fields that Upjohn overlooked because of this intense focus on a single class of compounds had a much more telling effect.  It can be argued that, as a result, too little attention was devoted to the more traditional areas of medicinal chemistry. The relatively easy field of beta-blockers, for example, was ignored because the pharmacologist in the area was allowed to carry the day by stating that he would study those as potential drugs only “when I understand how they work”. Well over a dozen beta-blockers from other firms were on the market before their mechanism of action was elucidated.

A couple of drugs that came out of a very effective licensing program and what must be considered the once forbidden area of me-too research meant that the effect of the company’s research philosophy was not seen immediately.  The first of these was Motrin.  Someone in the licensing department had recognized the fact that the British company Boots had a drug with great potential in ibuprofen.  Upjohn licensed the drug at a very early development stage and carried out the major portion of the clinical trials required for approval by FDA.   As the first of the non-steroid anti-inflammatory agents (NSAID) since aspirin the drug proved a runaway success almost from the moment it was approved.  There was actually very soon a real crisis in finding sources for the compound ibuprofen since Upjohn’s in-house synthesis plant could not keep up with demand.  It was discovered, ironically, that this drug and all the other NSAIDs actually work by suppressing the prostaglandins associated with inflammation.

After the introduction of its antidiabetic drug Tolinase, which was based in the licensed Orinase, Upjohn devoted only a minimal chemical effort to this field.  Hoechst, who had licensed Orinase to Upjohn in the first place, on the other hand quite obviously kept a major program going in this area.  This resulted in a series of compounds that showed potencies that were orders of magnitude better than that of the parent drug.  This made it possible for patients to take tablets that were much smaller than the relatively large Orinase dosages.  Upjohn did manage to license one of these drugs from its German originator.  This oral anti-diabetic agent, glyburide, was launched under the imaginative name of Micronase in the middle 1970s.

The other two products kept the company in business by way of new market entries were due to a decision by Manager of the CNS unit to allow his chemists to indulge in some hitherto taboo me-too research.  By making some clever modifications on the structure of the by then well established drug Vallium they were able to come up with a couple of very potent new drugs that seemed to show a somewhat different profile than its parent.  One of these, alprazolam, Xanax was promoted as a more potent tranquilizer.  The other, triazolam, gained widespread use as a sleeping pill.  It also gained considerable notoriety under the trademark Halcion.  

    There matters stood when I left Kalamazoo in late 1976 and was no longer privy to the inner workings of Upjohn Research and Development.  

    My next employer, Mead Johnson, had quite an interesting history in its own right.  The company was founded around the turn of the century by D. Mead Johnson.  This man was actually the third Johnson of the family that founded the pharmaceutical firm Johnson and Johnson.  He broke away about the turn of the century to start a company that specialized in infant nutrition; Pablum was probably his first product.  He eventually moved the firm to Evansville in southern Indiana to get closer to the sources of the grain and milk that formed the basis for his products.  Not long after the end of World War 2, Mead Johnson management, like that of other small companies, decided to try to move into the field of prescription pharmaceuticals.  This would hopefully get them into a larger playing field than the niche market in which they were so successful.  They chose the then-standard approaches that meant setting up a research lab and looking for licensing candidates.  The first real hit was ironically yet another nutritional product.  Sometime in the late 1960s Mead Johnson’s Nutrition Division came up with the diet food Metracal by modifying one of their infant formulas.  The product quickly became a wild runaway success.  It was so successful that it was said that rumors circulated around the company that each employee was to be awarded a free VW beetle!

    The unexpected riches from Metracal led Mead Johnson management to beef up the research department to the point where it came close to the size of one would expect to find in one of the major pharmaceutical firms.  The chemistry department alone numbered at least 60 individuals in its heyday in 1974.  The controlling share of the stock was at that time held by another D. Mead Johnson, a direct descendant of the company’s founder.  He apparently deemed the time ripe to look for a merger or acquisition, spurred no doubt by the increased value of his firm as well the then-prevailing merger mania. This was about the same time that Parke Davis merged with Warner Lambert.   The outcome was the merger between Mead Johnson and Bristol Myers.  The latter was a firm with a very different ethos specializing mostly in over the counter drugs and household products.   The research-based part of the company comprised Bristol Labs in Syracuse, New York.  Their research staff was smaller than that of Mead Johnson’s. No conflict in research goals was expected since they specialized in antibiotics and Mead Johnson had no programs in that area.  Bristol Myers real strength lay in its aggressive marketing and very strong International Division.

    D. Mead Johnson’s involvement in the merged company did not last very long.  A completely unauthenticated account has it that he believed that he and a friend held enough stock in the merged company to give them a significant voice on the Bristol Myers Board of Directors.  When he went to his first meeting of that Board he of course traveled by company jet.  Mead Johnson had a fleet of three of these to make up for the fact the Evansville was well off the beaten track; a judgement to which I will personally attest.  To D. Mead’s dismay it became very clear that he and his friend would have little to say about how Bristol Myers was run.  To add insult to injury an apocryphal story has the Board instructing him to return to Evansville by commercial airline, leaving the jet in New York for corporate use; and oh yes, send the other two as well.  The story continues with him selling off every share of Bristol Myers as soon as he could.

    In any event, the merged companies operated separately for a number of years since there was still some concern about antitrust matters in those simpler years.  (The same was apparently also true for Parke Davis and Warner Lambert).  This all changed in 1973 or thereabouts when Bristol Myers management decided to cash in on the savings from the merger by rationalizing operations.  Corporate management mandated that each division’s research budget should reflect its dollar sales in pharmaceuticals.  He did this by imposing an internal tax on drug sales. The funds raised by this tax would then be reapportioned by a corporate level committee in response to detailed research proposals submitted by the Bristol Labs and Mead Johnson research management.  The International Division held the whip hand because it contributed heavily to the research fund and exercised a large voice in its apportionment between Evansville and Syracuse since it had only a rudimentary research division of its own. Almost needless to say, Mead Johnson’s pharmaceutical sales came nowhere near the level needed to support its sizeable research operation.  The result was a bloodbath in late 1974 or early 1975 in which staff was drastically reduced.  The chemistry department for example was halved to 30 individuals; most of the so-called excess staff was simply shown the door though a few persons were kept on elsewhere in the company.  After a very short respite the same department was cut back to 22 in 1977.  By the time I left in 1980 Bristol Myers was still rent by fierce competition for research dollars between Evansville and Syracuse.

 It was not until the late 1980′s that Bristol Myers bowed to the inevitable and set up a corporate central pharmaceutical research lab.  This was at neither of the formerly contending sites in Evansville or Syracuse but at a brand new campus in Wallingford, Connecticut.  Most of the departments were then moved there as well as some selected employees.  This was not quite the end of that particular tale since Bristol Myers merged with Squibb a few years later.

Adria Laboratories, located in Columbus, Ohio, which was my next venue, had arguably the most convoluted story of them all. The creation of Adria starts with the fact that by the 1970s almost every one of the major U.S. chemical companies had at one time or another stuck its foot into the pharmaceutical waters.  The enormous returns from the sale of what they perceived to be essentially pure chemicals presented too good a target to pass up.  They were also certainly not unaware of the fact that most of the major pharmaceutical firms in Europe, such as for example ICI, Hoechst and CIBA,  had started as divisions of large chemical firms.  It is of note, by the way, that these have by now spun off their pharmaceutical divisions. The new firms are now separate companies with impenetrable names constructed by computers.  None of the U.S. companies with the exception of Lederle, whose parent company was the chemical company Cyanamid, had managed to make the transition by the 1960′s.  This track record did not deter Hercules, a company that got its start as one of the segments split from Du Pont when the powder trust was dismantled in the 1920s.  Rather than start from a scratch, Hercules management in the 1970′s decided to proceed by way of a joint venture with a firm that had an ongoing pharmaceutical division.  The Italian giant, Montedison, itself the product of a merger between Edison, Italia and Montecatini, with which Hercules already had some other ongoing joint ventures, providentially owned the greater portion of a world wide pharmaceutical firm based in Milan.  A portion, because about 25% of the stock in company, Farmitalia Carlo Erba, was traded on the Milan stock exchange.  This firm, known to initiates by its acronym FICE, had been formed within the past decade by the merger of the drug manufacturers Farmitalia and Carlo Erba.  Hercules contributed some $25 million to the joint venture while Montedison, gave them nine drug candidates in late stages of development.  This was not quite the same as giving the fledgling products because none had yet been approved by the U.S. FDA.

The drug that gave the company its start was an antitumor antibiotic Adriamycin,
also known by its generic name doxorubcin.  The U.S. National Cancer Institute had by that time accumulated a large amount of clinical data that pointed to the fact that this would be a successful chemotherapy agent.  FDA approval was the granted while the new company was still located in temporary quarters in the Hercules building in downtown Wilmington, Delaware.  Not too long after this product was approved, management decided to name the company Adria after that product.  They could not have then possibly foreseen, based on sales of then available chemotherapy agents that this would become the company’s dominant product.  Sales did however start briskly enough to convince the powers that be that the time had come to acquire all the appurtenances of a pharmaceutical company including research labs, a manufacturing plant and offices.

    Possibly in order to stave off future misunderstandings, the Adria Board of Directors included an equal number of representatives from Hercules and Montedison.  This finely balanced structure in effect gave the president of Adria a carte blanche since neither side could muster a majority in cases where his decision favored on side or the other.  His selection of a permanent site for Adria may be a case in point.

    The choice for a location for Adria interestingly again comes back to the itch felt by American chemical companies to acquire a foothold in pharmaceuticals.  The Warren-Teed Company in Columbus, Ohio was one of the small drug houses that eked out a living by marketing a line of products that comprised mostly over-the-counter remedies.  The company did have a few prescription products the most prominent of which comprised several controlled release potassium supplements.  They were bought out some time, probably in the 1960′s, by the chemical and polymer manufacturer Rohm and Haas.  As was so often the case, Rohm and Haas management lost faith in pharmaceuticals when no new large miracle drugs had come out by the end of a decade.  They essentially closed down the research department and moved the few staff whom they did not dismiss outright to their corporate facility back east.  They may have also closed the plant.

    Adria management bought Warren-Teed lock stock and barrel.  They also paid for good will and some of their drug candidates.  For this, they got a rather antiquated manufacturing plant in downtown Columbus and a set of lab buildings on the edge of a cornfield in suburban Dublin, Ohio.   The purchase price incidentally included the cornfield.  The original owner of the company, a Mr. Warren, was said to have been something of an animal fancier.  Most of the buildings at the research site had consequently started life as stables and/or pens.  More or less adequate laboratories had been shoehorned into the shells at a later date.  The whole assemblage was connected by enclosed passageways and fronted by a reasonably modern one-story office cum cafeteria facility that probably dated to the Rohm & Haas incarnation.   They managed to lease a very chic office building for not far from the labs. This had been built and briefly occupied as corporate headquarters by the Midwest distributor for Volkswagen.  The quite large room that was used for bigger meetings was unfortunately located right next door to what had been a VW garage.  Memories from important large meeting, including those of the Adria Board of Directors, are strongly associated with a distinct scent of gasoline and automobile exhaust.

    Adria never did have an overall Vice President or even Director of Research.  Instead, the Directors for Biology, Medical Research and Pharmaceutical Sciences reported directly to the president.  His lack of hands-on experience in the trenches led to some strange adventures.  These were prompted by the fact that Adria was totally dependent on FICE for its supply of its bread and butter drug, Adriamycin.  The Italians as a result managed to double-dip by this circumstance: they made their first profit in selling the drug to Adria and a second one from their half of Adria’s net.   This provoked Adria to spend appreciable sums of money in grants to any academic who even whispered that he was working on a synthesis for doxorubicin or some of its analogues.  Thus was intended to dependence on FICE for drug supplies by this stratagem. It did however reflect lack of appreciation of the difficulties involved in such an endeavor.  It is of note that starting material for doxorubicin is still obtained by fermentation some thirty years later.

    Company sales were on a steady and remarkable upswing from at least 1980, when I came aboard until the winter of 1983.  The weekly analyses at the Management Committee meetings made it clear that this was due almost entirely to Adriamycin.  There was even talk of using a linear regression model to predict sales.  The linear regression curve hit a very sudden plateau that winter.  The VP for marketing at first attributed this to the very severe winter weather.  The coming of spring showed that the demand for chemotherapy was not weather related or for that matter unlimited.  

The other products more or less held their own.  Only two of the portfolio of nine drugs contributed by FICE showed much promise of being approved.  They both came to rather unfortunate ends.  The first to be approved, ceruletide, was a CCK like peptide that caused the gall bladder to contract and could thus be used to monitor that organ.  A far less invasive procedure involving sonography came into common use at the same time and pretty much shut off demand for the quite expensive drug.    The NSAID indoprofen was supposed to seal the success of Adria by getting the firm into a more general market.  A series of adverse effect reports from the UK caused the Brits to halt usage in that country.  The finding of tumors in a long-term carcinogenicity trial conducted in-house at Adria sealed the fate of this drug in 1984.  This was ironically an unnecessary study because data was already available that showed a clean bill of health from a duplicate trial on indoprofen carried out by a contract lab.  Two drug candidates acquired with the purchase of Warren-Teed rounded out the portfolio. Bentiromide is a clever little compound that could be used to assess pancreatic function; it was approved by FDA in about 1983 and may still achieve some modest sales under the trade name Chymex.  The final hope lay in tripamide, a compound licensed from the Japanese company Esai.  This rip-off of the diuretic indapamide was being tested by Adria for its activity as a first stage anti-hypertensive agent.  It too died as a result of long term carcinogencity trials. This was probably a blessing in disguise since it would have competed against a host of well established and much cheaper compounds in the same class to say nothing of the series of new truly innovative anti-hypertensive drugs just then coming on the scene.

By late 1983, Hercules was probably having serious second thoughts about this joint venture in pharmaceuticals, particularly as the ten-year term of the joint venture contract was about to expire.  The subtle signs were there had we but known where to look.  Joint Adria-FICE research meetings in 1980 tended to be quite plush affairs complete with meals in multiple star restaurants and chauffeured cars; Fiats but still chauffeured.  These got more down to earth with time to the point where we were picked up at Malpensa in a minivan for the January, 1984 meetings.

The moment of truth came in late March of that year with a small article in the business pages of the New York Times announcing the formation of a new company that was to be owned by Montedison and Hercules.  The name of this new firm, Erbamont, incorporated the “mont” syllable that was obligatory as a pre- or suffix for all companies associated with Montedison.  This new entity was to incorporate all of FICE, Adria, an early biotech outfit in Minneapolis called Kallestad and a custom synthesis lab called of all things, Lark.  The complex ownership scheme reflected the fact that dollar poor Montedison could not simply pay off Hercules for its half interest in the original joint venture.  Montedison, as I recall, retained about 50% of the stock in Erbamont; Hercules got about 20% in stock.  The rest went on the NYSE with proceeds presumably going to Hercules.

It became increasingly apparent even before the item appeared in the Times that some important changes were on the way that involved closer ties with Farmitalia. The takeover was finalized in the summer of 1984 when Erbamont management took over. The Adria President as well as the heads of Biological Sciences and Pharmaceutical sciences let to “pursue other interests. These departures were prompted in no small part by the fact that their staffs and resources were dwarfed by their counterparts in Milano.

Later details get vague they were seen via the public media and hearsay.  Hercules did sell its part of Erbamont in fairly short order.  Montedison itself underwent considerable further turmoil.  The Feranti interests in Italy eventually bought it out.  

By 1989 I left the private sector and joined the National Cancer Institute. Three of my colleagues at the Institute’s Drug Synthesis and Chemistry Branch had spent a good many years at Squibb, a well-respected pharmaceutical company.  A phone call one morning early in the 1990′s had them all agog: the merger of Squibb with Bristol Myers had just been announced.  This one seemed to make some sense since these were then both these firms were of a size that could have been raided.  It also combined Bristol Myers strength in marketing with Squibb’s far superior research organization.  Over the next several years in fact Bristol Myers research managers were eased out by those from Squibb.  

Mergers then started to strike closer to home.

By late 1992 I had transferred to the Pharmaceutical Resources Branch (PRB) and was responsible among other things for Developmental Therapeutics Program’s parenteral dosage form manufacturing contracts.  The larger of these involved Ben Venue Laboratories in the Cleveland area; a company with which I had become familiar while at Adria.  The other contract was with none other than Adria!  This part of the company had however not yet existed in my days in Columbus.  This branch interestingly actually traced its ancestry back to Ben Venue.  After a high-ranking executive in that company, had a falling out with the owner, he started his own small parenteral manufacturing firm in Albuquerque called Summa.  In the meantime by the late 1980s, Adria management seems to have prevailed on Erbamont to manufacture the dosage form of some of their oncology drugs, including I think Adriamycin, in this country.  This led to the purchase of Summa, which might have been having some financial problems.  After a year or so on the job in PRB, I got a call one day from Albuquerque informing me that Erbamont, and with it Adria, had just been acquired by the Swedish firm, Pharmacia.  The next several months thus saw the Adria logo inexorably displaced by Pharmacia’s on all their reports and communications.  It was sad but of minor import since four years  with Adria left had no financial and little emotional stake in the company.

Three months later in 1995 a small item in the Washington Post announced the merger of Pharmacia with Upjohn.  The fact of the merger was not too surprising since Upjohn had been in play for some time.  It size made it a plum ripe for picking though its lack of success in bringing new products to market and seemingly dry pipeline must have acted as a deterrent to potential buyers.  Neither Pharmacia nor its Erbamont components, on the other hand, were themselves producing any exciting new drugs.  The merger very much gave the impression of the marriage of two weak partners.  A recent news report in fact included an allusion of a rough start for the merged firm.  

That part of ring was closed a few years ago in 200 with the merger of the company then know as “Pharmacia and Upjohn” with Monsanto. The announcement included the information that the new merged giant would be simply called Pharmacia.  The names, G.D. Searle and Company, the Upjohn Company and Adria Laboratories that had appeared over the years on my paychecks will presumably disappear except to possibly identify some specialized products.

Yet another, and probably final, chapter was added to this saga in late 2002. The purchase of Pharmacia by the already inflated Pfizer provides the coda to this convoluted story. The merger was contingent on Pharmacia spinning off the non-pharmaceutical part of Monsanto or in other words keeping only Searle, which duly happened. My retirement check will, one of these days then, probably carry the Pfizer logo. This closes a circle, in some ways, because people at Pfizer were quite eager to hire me in 1959. This was spurred by a glowing unsolicited recommendation from EJ Corey who was already one of their consultants.

Sometime early this year, a small item appeared in Chemistry & Engineering News that noted that Pfizer was reorganizing and consolidating research at its now very numerous labs. The news did not sound very promising for Upjohn research in Kalamazoo, though the brief article was not very specific. A full page article that appeared in C&EN in 2003 definitively closes out Upjohn research. The prestige that came from research on prostaglandins was obviously not enough to keep the outfit in business.