SUMMARY One of the major roles of a medicinal chemist is to synthesize pharmaceutical drug agents that provide positive therapeutic responses in alleviating pain, sickness, and/or curing alignments and diseases for the great good of humanity. To ensure that the general population receives the best medicines available, regulatory agencies such as the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) provide pharmacovigilance or the monitoring of safety and acceptance of new drug treatments. While these governing bodies are empowered to warrant final approval in releasing medicines to the consumer, certain approved therapies were shown to be more toxic that efficacious. Here, we provide two case studies (1) Thalidomide and (2) Baycol®, two drugs produced in the last fifty years, approved by regulatory agencies and administered to patients were irreversible toxic side effects had occurred to the individual or to their offspring.
While we’d like to think that all prescription medicines are safe because of FDA and EMEA approval, this is not always the case. Every time a patient is administered a new chemical entity (NCE) or biologic, he is putting his health into the hands of the pharmaceutical industry. Despite modern technology, the best scientists, and billions of dollars the industry has at its disposal, a patient’s safety may be taken for granted.
Currently, pharmaceutical companies perform preliminary research necessary to develop new drugs. If a drug successfully completes a series of clinical trials, it then goes to the FDA or EMEA for approval, pending further trials if necessary. These Agencies will approve drugs by weighing the potential harm of the medication against its potential benefits. Once the drug is approved a post-marketing program is put in place, monitoring the drug for unexpected adverse events. This program alerts the Agencies to potential threats to the public health.
Regardless of how stringent this system is, the Journal of the American Medical Association reported that 20% of all new drugs treatments are found to have serious or irreversible toxicological damage that have not been discovered or have been undisclosed at the time of drug approval. In addition, they reported that in the last 25 years, 16 drugs have been recalled because of serious side effects (source http://www.adrugrecall.com).
Thalidomide and Baycol® are just two cases studies out of the 20% reported drug treatments were irreversible toxic damage has occurred on mammalian systems (human). Could these tragedies been prevent and are drug companies and regulatory agencies continuing to fulfill their ethic duty in providing safety to the patient for the pharmaceutical agents that they manufacturer and approve? Here is the story of Thalidomide and Baycol®.
Thalidomide Thalidomide appeared on the market in Germany on October 1, 1957 and was claimed to be a safe and effective sleeping pill. Soon it became the drug of choice to help pregnant women combat the symptoms associated with morning sickness. Shortly afterwards doctors began to notice that some patients developed “peripheral neuritis” a condition that caused tingling and loss of sensation in the limbs. In some people this side effect was irreversible (“Extraordinary”).
Even after clinical trials, there was no evidence that thalidomide was teratogenic -a drug that could penetrate the placenta of pregnant women and cause malformations of the embryo or fetus-. But in 1961, Widukind Lenz and William McBride independently accumulated evidence that the drug, caused an enormous increase in a previously rare syndrome of congenital anomalies. The most noticeable of these anomalies was phocomelia, a condition in which the long bones of the limbs are absent (amelia) or severely deficient (peromelia), thus causing the resulting appendage to resemble a seal flipper. There was also a risk of other problems such as, deafness, small or missing eyes, paralysis of the face, kidney abnormality, and mental retardation (“Thalidomide”).
Over 7000 affected infants were born to women who took this drug, and a woman needed only one tablet to produced children with all four limbs deformed (Lenz, 1966). Other abnormalities induced by the ingestion of thalidomide included heart defects, absence of the external ears, and malformed intestines. The drug was withdrawn from the market in November, 1961.
When Baycol, a member of a class of cholesterol lowering drugs that are commonly referred to as statins, was approved for use in the U.S. in 1997, it appeared to be a potentially lifesaving drug with few side effects. It had been tested on more than 3,000 patients, and no serious problems had turned up.
While all statins have been associated with very rare reports of rhabdomyolysis, cases of fatal rhabdomyolysis in association with the use of Baycol were reported significantly more frequently than for other approved statins.
Problems with Baycol had become apparent by December 1999, more than two years after it went on the market, because several reports of deaths from rhabdomyolysis had come in. The FDA and the drug's maker cooperated in warning patients and doctors how to avoid the trouble. Doctors were advised not to start patients on the highest dose available and not to give patients both cerivastatin and Lopid, or gemfibrozil, a nonstatin drug that lowers blood triglyceride levels and cholesterol. Patients taking both seemed more likely to develop muscle problems, doctors were told. A little over a year later, a second warning was sent to doctors. But reports of deaths linked to Baycol continued to come in.
On August 8, 2001, Baycol also known by the generic name cerivastatin, was taken off the market. Its manufacturer, the German company Bayer Health Care, took that step after 31 patients on the drug had died and the cases cast suspicion on Baycol.
The deaths were caused by a disorder called rhabdomyolysis, in which muscle cells break down releasing the contents of muscle cells into the bloodstream flooding the kidneys with masses of cellular waste. Death occurs if the kidneys are overwhelmed and shut down. Symptoms of rhabdomyolysis include muscle pain, weakness, tenderness, malaise, fever, dark urine, nausea, and vomiting. The pain may involve specific groups of muscles or may be generalized throughout the body.
Most frequently the involved muscle groups are the calves and lower back; however, some patients report no symptoms of muscle injury. In rare cases the muscle injury is so severe that patients develop renal failure and other organ failure, which can be fatal.
CHEMICAL STRUCTURE AND CHARACTERISTICS Table 1 lists some general characteristics for thalidomide and Baycol®. Figure 1&2 display the chemical structures for both compounds. All information was obtained from the Physicians Desk Reference (PDR) http://www.pdr.net/HomePage_template.jsp.