In 1956, two different sulfonylureas were brought to market in Germany under the trade names Nadisan and Rastinon. American pharmaceutical companies in the postwar period had been seeking to establish business relations with the remnants of German pharmaceutical giants weakened by the war and partition of Germany. Upjohn (based in Kalamazoo until its purchase by Pharmacia in the 1990s) made deals with Hoechst, maker of Rastinon. The result was a cross-licensing agreement which produced Orinase. Upjohn stood to open up a whole new arena of treatment for diabetes, one with a built-in and sustainable market, i.e. patient population. Just as two German companies brought sulfonylureas to market within the same year, Upjohn discovered Eli Lilly had begun clinical trials for carbutamide, another oral hypoglycemic. Upjohn pushed for large-scale clinical trials from 1955–1957, enrolling over 5,000 patients at multiple sites. Upjohns formulation was preferred when the Lilly formulation demonstrated evidence of toxicity in parallel trials at the Joslin Clinic. Lilly pulled carbutamide and halted development, leaving the field open for Upjohn to market its new treatment. In 1956, Upjohn filed for approval from the Food and Drug Administration. Jeremy A. Greene found the applications size – 10,580 pages in 23 volumes with 5,786 cases reports – was necessary to "render visible the relatively small improvements provided in less severe forms of diabetes." Indeed, Orinase was marketed by Upjohn not as a cure-all for all diabetics, but specifically as a treatment that was "not an oral insulin" and "did not work in all diabetics".
Tolbutamide is a first-generation potassium channel blocker, sulfonylurea oral hypoglycemic medication. This drug may be used in the management of type 2 diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas. It is not routinely used due to a higher incidence of adverse effects compared to newer, second-generation sulfonylureas, such as Glibenclamide. It generally has a short duration of action due to its rapid metabolism, so is safe for use in older people. It was discovered in 1956. Side effects
Hypoglycemia
Weight gain
Hypersensitivity: cross-allergicity with sulfonamides
Drug interactions (especially first-generation drugs): Increased hypoglycemia with cimetidine, insulin, salicylates, and sulfonamidesSalicylates displace tolbutamide from its binding site on plasma binding proteins which lead to increase in free tolbutamide concentration, thus hypoglycemic shock. History
Orinase was developed by Upjohn Co. at a time when the primary medical treatment for diabetes was insulin injections. Eli Lilly had a lock on the market for insulin production at the time. Orinase, like other treatments for drugs detected by so-called paraclinical signs rather than clinically observable signs or patient-reported symptoms, benefitted from an increased sensitivity and availability of blood glucose testing. Milton Moskowitz (editor in 1961 of Drug and Cosmetic Industry) claimed the introduction of Orinase, "expanded the total market by bringing under medical care diabetics who were formerly not treated." It did this by changing the mindset about diabetes even more than insulin had.