NAME THAT DRUG
BY KIMBERLY SAMANO, PHD, QUEST DIAGNOSTICS Lifting the Veil on Drugs in Disguise T
he discovery of penicillin in 1928 by Sir Alexander Fleming in England and its initial clinical use
in 1941 by United States (U.S.) research- ers Florey, Heatley and Abraham are thought to be among the most important pharmaceutical breakthroughs of the 20th century. Penicillin’s availability increased during World War II, as it was made com- mercially available by the collaborative efforts of scientists from the US Depart- ment of Agriculture, Abbott, Lederle, Merck, Pfizer and Squibb (now Bristol- Meyers Squibb). However, due to limited initially-available quantities, mortality from pneumonia, rheumatic fever, syphi- lis and other common bacterial infec- tions remained quite common. This is because antibiotic regimens require on- going treatment over a period of days or weeks, and the clearance of penicillin was too rapid to maintain therapeutic levels in infected patients. Consequently, it was not unheard of for urine to be collected from those being treated with penicillin with the aim of extracting the drug from the urine for re-administration. To overcome the problem of rapid
clearance from the body, research efforts were directed towards the identification of a safe treatment, which would physi- ologically slow the excretion of peni- cillin, effectively increasing its plasma half-life. After scientists optimized the synthesis and purification of penicil- lin, co-administration of this month’s mystery drug with the antibiotic greatly improved treatment efficacy. Addition- ally, the discovery and development of this drug in the 1940s by the late Dr. Beyer of Merck pharmaceuticals proved to be the first successful therapy for gout. This drug was also found to be a urico- suric and has been used clinically since
60 datia focus
1952. It works by inhibiting the reuptake of uric acid in the kidneys, thus promot- ing its excretion in urine and decreas- ing build-up in the body. After studies determined its mechanism of action, this drug was exploited for its ability to delay urine clearance rates across various drugs classes with diverse pharmacologi- cal functions (e.g. salicylates, antibiotics, antivirals and glucuronide metabolites of certain performance enhancing drugs, among others). In the spring of 1987, the International
Olympic Committee’s (IOC) Medical Commission alerted the IOC accredited laboratories to the use of this drug by athletes attempting to cheat on their urine drug tests. While testing for this substance occurred during the 1987 Pan American Games in Indianapolis and sev- eral athletes were found to have this drug in their urine, no sanctions occurred as the drug was not formally on the IOC’s list of banned (prohibited) substances until January of 1988. Although this drug has genuine therapeutic applications, it also serves as a masking agent for certain prohibited substances encountered in athletic and performance-enhancing drug (anti-doping) testing. This drug is not scheduled under the Controlled Substances Act, but it is currently banned by the IOC and the World Anti-Doping Agency (WADA) and is included on the WADA 2014 Prohibited List as a mask- ing agent. First gaining notoriety in the late 1980s, while infrequent, its use is still detected in anti-doping testing, as South African cyclist Daryl Impey was withdrawn from the 2014 Tour de France after testing positive for this drug. This drug is administered orally and
can typically be found as a 500 milligram, yellow, oblong tablet or capsule, with rec-
ommended adult doses of up to 2 grams (g) per day for the treatment of gout and gouty arthritis. Single doses of 1–2 g are prescribed when taken in conjunc- tion with antibiotics for the treatment of sexually transmitted diseases such as gonorrhea. Significantly higher doses are required for this drug to be used illegiti- mately as a masking agent. Te drug exhibits a dose-dependent
half-life of 2–12 hours, with maximum plasma concentrations observed 2–4 hours aſter a single 500 mg dose. Tis drug is well-tolerated in most individuals, but side effects include headache, upset stomach, dizziness, nausea and vomiting. As a sulfonamide drug, mild to severe hypersensitivity reactions are observed in approximately 2–4 percent of patients. Overdose is characterized by central nervous system (CNS) stimulation, convulsions and death from respiratory depression. Approximately 80–90 percent of this month’s mystery drug is excreted as in the form of inactive metabolites formed by oxidation, n-dealkylation and glucuro- nide conjugate reactions which can be detected in urine for as long as 96 hours aſter administration. Specimen handling and preparation
may be important, as studies have shown that the major glucuronide metabolite will rapidly degrade in alkaline conditions in both serum and urine. Laboratory analysis for anti-doping purposes is traditionally conducted by gas chromatography mass spectrometry (GC/MS) as a part of the testing panel for anabolic agents. This month’s drug is probenecid, taken
orally as Benemid(e), Benuryl [UK], Procid, Probalan or in combination with colchicine, an anti-inflammatory agent, as Colbenemid or Proben-C. ❚
winter 2015
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