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Dairyland Rat Poison

Dairyland Rat Poison container made
for the Wisconsin Pharmacal Co.
of Milwaukee, 1955-1965.

(Museum object #1999.143.34)

The same substance that can save your life can also kill you. This is emphatically the case for the compound dicumarol, developed in the agricultural chemistry laboratory of University of Wisconsin professor Karl Paul Link. As an anticoagulant, it can prevent life-threatening blood clots and strokes, but a variant is also the most commonly used rat poison in the world, and an active ingredient in the Dairyland Rat Poison featured here. How this seemingly contradictory compound was developed is a story of drama, insight, and most of all, the persistence of a team of scientists working for more than two decades.

Dairyland Rat Poison is one of many brand names applied to the compound commonly known as Warfarin, which was developed largely under Link's supervision and patented in 1948. This Dairyland Rat Poison container was made between 1955 and 1965 for the Wisconsin Pharmacal Co. of Milwaukee, one of the many companies to license the patent. Founded in 1896, Wisconsin Pharmacal developed as a typical regional drug manufacturer, compounding its own remedies from supplies of raw ingredients. Before the industry assumed its modern, research-driven, capital-intensive form, the average pharmaceutical company more closely resembled a hardware store, offering a broad range of house and garden chemicals. In the 1950s and early 1960s, it was not unusual for a drug company to also market household poisons.

The saga of Warfarin began in the winter of 1933, when distraught farmer Ed Carlson arrived in Link's lab with a can of blood that refused to clot and a load of spoiled clover hay. The farmer's herd was being decimated by "sweet clover disease," which produces uncontrolled bleeding in cattle. The disease is caused by moldy or improperly cured clover, and the only practical treatment was to switch feed sources immediately. If caught in time, cattle could recover with no detectable long-term effects, but replacing their entire feed supply was financially impossible for many Depression-strapped farmers.

Link set out to identify the hemorrhagic agent (or HA) in the spoiled clover. He faced two primary tasks: first, to extract and isolate the chemical components of spoiled clover, and second, to test each compound on animals to see if it provoked the bleeding disease. With a talented crew of graduate students, Link spent six years on these tasks. His team bred and cared for a population of genetically similar test rabbits and established procedures, standards and test protocols, in addition to performing the countless hours of bench work to extract the compounds. In June 1939, Link's assistant Harold Campbell finally succeeded in isolating the HA. The compound, C19H12O6, was produced by the metabolic action of various molds on coumarin, the substance that gives fresh-cut clover its sweet smell.

The potential medical usefulness of a controllable anticoagulant was clear, and the team set about identifying the molecular structure of the HA, developing a method of synthesizing it in the lab, and verifying the synthetic compound's identity via animal tests. C.F. Huebner and Mark Stahmann overcame these challenges by the spring of 1940, establishing the compound as 3,3'-methylene-bis (4-hydroxy-coumarin). This compound was tested on human patients that year and was patented under the trade name dicumarol in 1941. Link's team continued to study the scope of dicumarol's physiological effects on different animal species under different conditions. Because so many factors (diet, cumulative dosage, other medications, etc.) influenced the intensity of the drug's effects, and because the role of vitamin K in reversing its effects was not fully appreciated outside Link's lab, the medical community came to consider dicumarol a useful but dangerous drug, apt to provoke uncontrolled bleeding in patients.

Recuperating from a recurrence of tuberculosis in 1945-1946, Link reviewed the research on dicumarol and read up on rodent control. If the substance could cause cows to bleed to death, why not rats? His team had tested dicumarol as a rat poison in 1942, but had concluded it would not be very effective, largely due to the high vitamin K content of a typical rodent's diet. But Link also knew that his lab had produced more than 100 related 4-hydroxycoumarin compounds, most of which had not been fully evaluated. He instructed his crew to test the anticoagulant properties of each one. By 1947 they had identified two synthetic coumarin derivatives, called numbers 42 and 63, which were more powerful than dicumarol. At Stahmann's insistence, the team filed a patent application through the Wisconsin Alumni Research Foundation (WARF) , for use of compound 42 as a rodenticide. It was trade named Warfarin in the Foundation's honor.

Warfarin was effective, did not cause bait shyness, and was remarkably safe for other animals when administered in rat-sized doses. It quickly became a success when it was released as a rodenticide in 1948. Despite its identification as a rat poison, Link saw clinical advantages of Warfarin over its predecessor dicumarol, and concluded that a water-soluble sodium salt of Warfarin would be the ideal way to administer the new drug. In the early 1950s, Link's lab developed the method for producing this compound in commercial quantities. The result was a second generation blood thinner, trade named Coumadin. Compared to its predecessor, Coumadin was 5 to 10 times more potent; faster acting; had essentially the same absorption rates given orally, intravenously, rectally or by injection. Overdoses could be corrected by vitamin K. By the mid-1950s, Coumadin had become the medical anticoagulant of choice.

UW scientists continued to improve Warfarin as a rodenticide as well. They developed an improved formula, called Prolin, by adding sulfaquinoxaline, a bactericide that inhibits the body's production of vitamin K. This container of Dairyland Rat Poison uses the Prolin formula.

Known for his iconoclastic personality and volatile temper, Karl Paul Link was also an inspiring classroom teacher as well as a keen scientist. It is hard to say what results he may have imagined in 1933, but his work on coumarin compounds became a classic example of persistent, insightful scientists turning fundamental research into practical benefits.

[Sources: Link, Karl Paul. "The Discovery of Dicumarol and its Sequels" in "Circulation" vol. 19 (January, 1959), available online at http://circ.ahajournals.org; Link, Karl Paul. The Anticoagulant from Spoiled Sweet Clover Hay (Madison, WI, 1944), reprinted from the Harvey Lectures series, 39, 1943-1944, pp. 162-216; Karl Paul Link's papers are held at the UW Archives, Harold Campbell oral history available online in the UW Library Catalog.]

DBD


Posted on June 26, 2008

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