Blood Thinners: From Heparin to Plavix

Three types of blood cells exist in the human body: red blood cells, white blood cells, and platelets, in addition to plasma, which takes up 55 percent of the blood’s volume. Red blood cells take up approximately 45 percent of the blood’s volume. They transport oxygen from the lungs to other body parts. White cells defend us against bacterial and viral invasions. Platelets (less than 1 percent of the blood), the third type of blood cells, are sticky little cell fragments that are involved in helping the blood clot, a process known as coagulation. Without platelets (even though they constitute less than 1 percent of blood), our blood would not be able to clot, and we would have uncontrolled bleeding. However, formation of blood clots is a double-edged sword. Clots are beneficial because they heal cuts and wounds; blood clots in the bloodstream are harmful because they block coronary arteries, constrict vital oxygen supplies, and cause heart attacks and strokes, more and more frequent modern maladies as the baby boomers get older. Whenever the body is cut or injured and blood comes into contact with cells outside the bloodstream, a tissue factor on these cells encounters a particular protein within the blood, which triggers the clotting process. In the same vein, a series of other blood factors then come into action and amplify one another to quickly form a jelly-like blood clot. Blood clots form when an enzyme called thrombin marshals fibrin (a blood protein) and platelets (tiny cells that circulate in the blood) to coagulate at the site of an injury. Individuals with no ability to clot have a genetic condition called hemophilia; such people are also known as “bleeders.” Queen Victoria was hemophilic, and she passed on her genes to her many heirs who ruled Europe for over a century. This is why hemophilia is sometimes known as the royal disease. Symptoms of hemophilia manifest only in male offspring. People with hemophilia must periodically administer a clotting factor to their blood to prevent constant bleeding.

Antihistamines as Allergy Drugs

Most blockbusters have at least one thing in common—they are all widely prescribed to treat common illnesses such as hypertension, high cholesterol, pain, ulcers, and depression. Allergies are another malady that afflicts more and more Americans. To many, allergies are no longer an inconvenience but a major annoyance with constant sneezing and itching. For them, an allergy medicine is often needed to relieve the symptoms. As a consequence, many antihistamine allergy drugs, especially nonsedating antihistamines, have become blockbuster drugs. Allergies are the sixth leading cause of chronic illness in the United States. More than 50 million Americans have allergies and spend in excess of $18 billion a year on medical treatment. The word allergy was coined by Austrian pediatrician Clemens von Pirquet in 1906. According to his definition, allergy was manifest in cases of serum sickness, hay fever, sensitivities to mosquito bites and beestings, and various idiosyncratic food reactions, as well as in individuals who had been exposed to, or successfully immunized against, common infectious diseases such as diphtheria and tuberculosis. Today, the word allergy is broadly associated with allergic rhinitis, asthma, hay fever, and food allergies. Allergies are the malady of civilization. In ancient times, allergies like hay fever and food allergies were virtually nonexistent. The first report of a case of allergy did not appear until the 1870s in Europe. The beginning of the 20th century saw a sharp rise in allergies. Nowadays, hay fever is so prevalent in the United Kingdom, that there are 1.4 to 1.8 million students who are drowsy from taking antihistamines. U.K. educational authorities even schedule the exams away from the peak of pollen season. In the United States, hay fever is the number-one chronic disease. Until we learn how to turn off the genes responsible for hay fever and asthma, these afflictions will remain among the most irritating of our existence. During evolution, humans developed the immune system to fight the real danger of foreign invaders like bacteria and viruses. It turns out that the human body has two types of responses toward tissue damage or infection.

More Blockbuster Drugs for Ulcers: Prilosec, Nexium, and Other Proton-Pump Inhibitors

In the first half of the 19th century, British physician William Prout conclusively showed that gastric juice contains hydrochloric acid. U.S. Army officer William Beaumont examined the physiological control mechanism of gastric acid secretion by studying Alexis St. Martin’s chronic gastric fistula that had resulted from a gunshot wound in the 1820s. Gastric acid is essential to digest protein and emulsify fats. It breaks down food so it can go on to the small intestine where nutrients are absorbed. Low levels of gastric acid can contribute to a myriad of discomforts and diseases. On the other hand, too much of a good thing is bad. High levels of gastric acid often result in heartburn and ulcers. Heartburn is a symptom produced by reflux when digesting food and gastric acid passes back up into the esophagus through the sphincter muscle at the top of the stomach. It is also known as GERD, for gastroesophageal reflux disease. If reflux occurs often and the body fails to sufficiently clear the acidic mixture back into the stomach, the tissue of the esophagus can be damaged, and that is when ulcers develop. Forty million Americans experience heartburn two days a week, and 60 million have it at least once a month. The disorder costs an estimated $10 billion in the United States, counting visits to doctors and hospitals, medications, and time lost from work, according to the American Gastroenterology Association. Before the emergence of Tagamet and Zantac as H2 histamine-receptor blockers for the treatment of heartburn and ulcers, numerous medicines were available, but none were satisfactory. For over a century, heartburn sufferers had been taking over-the-counter (OTC) antacid products such as Alka-Seltzer, Maalox, Mylanta, Pepto-Bismol, Rolaids, and Tums. Most of them contain simple inorganic bases as the principal active ingredients. Americans alone spend approximately $1 billion a year on these antacids, which bring relief within minutes and work by neutralizing the stomach acid that causes heartburn.

Reflections

Most blockbusters have at least one thing in common—they are widely prescribed to treat a common illness, such as hypertension, high cholesterol, pain, ulcers, allergies, and depression. The larger the potential patient population, the higher the likelihood for a drug to become a blockbuster. Obviously, the drug has to be effective. If it does not work, or works only marginally, the average patient is not going to be enthusiastic about taking it. However, efficacy alone is not good enough. For instance, the old tricyclic antidepressants worked if patients finished the full course of treatment. Unfortunately, they were nonselective, hitting many targets. As a consequence, they were so toxic and replete with side effects that only a fraction of patients (less than 20 percent) were able to tolerate them until completion of a treatment course. In contrast, the newer selective serotonin reuptake inhibitors (SSRIs) are more selective and thus possess fewer side effects. As a result, SSRIs like Prozac, Zoloft, Paxil, Wellbutrin, and revolutionized the treatment of depression. Similarly, atypical antipsychotics such as Zyprexa, Geodon, and others Abilify helped schizophrenia patients tremendously. These drugs transformed debilitating diseases into treatable chronic illnesses. Most psychiatric patients these days do not need to be institutionalized as they were half a century ago. A drug with good efficacy and a high safety profile treating a widespread disease does not necessarily sell itself, however. Direct advertisements to consumers and a strong sales force are essential to create and sustain the popularity of a drug. Blockbuster drugs save lives and support a vibrant pharmaceutical industry. What do we, as a society, do to ensure their sustainability? While realizing that there is no single prescription for this problem, one could certainly begin by talking about patent reform. The current patent system is antiquated as far as innovative drugs are concerned. Decades ago, 17 years of patent life was somewhat adequate for drug companies to recoup their investments in R&D because the life cycle from discovery to marketing at the time was relatively short and the cost was lower. Today’s drug R&D is a completely new ball game.

Beginning of an Era: The First Blockbuster Drug, Tagamet

Tagamet emerged as the first blockbuster drug when its sales exceeded $1 billion in 1986, three years after its introduction to the market. An anti–peptic ulcer drug, Tagamet was discovered by James W. Black and his colleagues at Smith Kline & French’s (SK&F) British subsidiary in Welwyn Garden City. Before Tagamet, SK&F was a little-known U.S. drug firm in Philadelphia. After Tagamet, SK&F became one of the largest pharmaceutical companies in the world. The history of Tagamet is one of the most extraordinary in the annals of medicine. It is a saga of a drug that almost escaped detection because the research efforts that began in 1964 did not seem to produce results within the first 11 years! Smith Kline started as a humble drug store in Philadelphia in 1830. During the American Civil War, Smith Kline was founded as a small apothecary by two physicians, John K. Smith and John Gilbert on North Second Street. Not only was Philadelphia the birthplace of the United States of America, it was also the cradle of American pharmacy. Wyeth, McNeil, Rorer, and Warner-Lambert all trace their origins to small drug stores established there during the Civil War. In the 1880s, Mahlon N. Kline led the company into research and manufacturing of its own products. In 1891, it absorbed French, Richards & Co. founded by Harry B. French, creating Smith Kline & French. After its establishment, the company slowly expanded its inventory. By the 1920s, it had some 15,000 products ranging from aspirin to liniment. Their Eskay’s Albumenized Food was highly popular as a digestible food for infants and the disabled. Later, the company did very well with Eskay’s Tablets for Seasickness. Its specialty, Eskay’s Neurophosphates, a nerve tonic, soothed millions of people at home and abroad. In 1929, Smith Kline & French Laboratories was created to devote itself solely to research and development (R&D). During the Great Depression year of 1936, the company stepped up its efforts in R&D (in a recent contrast, many pharmaceutical companies stepped down their R&D investments during the last recession of 2008).

Conquest of Pain: Analgesics: From Morphine to Lyrica

To live is to endure pain has been understood by almost everybody who is mature enough to gain some philosophical perspective on life. C’est la vie! as the French would say. Indeed, pain existed before the dawn of humanity—some research suggests that even plants respond to pain. According to ancient Greek myth, Prometheus stole fire from Olympus to give it to mortals. Zeus punished him by chaining him to a rock and having a great eagle feast on his liver daily, inflicting unbearable agony. Zeus also sent Pandora to Earth, unleashing pain (one of the items in Pandora’s box) and many evils as a vengeance to mankind. Without an understanding of pain, our ancestors resorted to many measures to ease pain; some were successful to some extent, and some were completely futile. Witches and shamans were sought out to exorcise pain from the body. From a psychological perspective, they might be effective for some believers. The hypnotizing technique reached its crescendo in the 18th century in France when Monsieur Anton Mesmer “mesmerized” many French citizens, liberating them from their pains. As civilization progressed, alcohol became more and more a universal painkiller after it was observed that drunkards were oblivious to pain. Chinese surgeon Hua Tuo (115–205 ad) gave his patients an effervescent powder (possibly cannabis) in wine that produced numbness and insensibility before surgical operations. Another ancient invention in Chinese medicine was the use of acupuncture to ease pain. Acupuncture, now an increasingly popular treatment for persistent as well as intermittent pain, is thought to work by increasing the release of endorphins, chemicals that block pain signals from reaching the brain. A recent survey by the National Institute of Health (NIH) indicated that acupuncture showed efficacy in adult postoperative pain, chemotherapy nausea and vomiting, and postoperative dental pain. There is no doubt that acupuncture works for some patients’ minor pain, through either physiological or psychological means, or both. or both. During the hype of the Great Culture Revolution (1966–1976), it was even claimed that major operations were carried out using acupuncture without any other anesthetics.

Before the Age of Blockbuster Drugs

Blockbuster drugs are drugs with annual sales over $1 billion these days. As a testimony of changing times, a blockbuster drug was defined as a drug with more than $500 million in annual sales just a decade ago! While these blockbuster drugs save millions of lives and improve the quality of life for millions of others, pharmaceutical companies make considerable profit. In turn, drug makers then spend a tremendous amount of money on research and development of new blockbuster drugs, looking for new ones that will sustain the “life cycle” for the health of both patients (physical and mental) and the drug companies themselves (financial). Pharmaceutical companies are sometimes known as “merchants of life.” Indeed, their products affect people’s lives in many positive ways. But make no mistake; the drug industry is a for-profit entity, responsible to its shareholders. It must make a profit to survive. This is the contradiction of the pharmaceutical industry. However, things were not always like this until the last few decades. The first antihistamine (the substance that counteracts the effects of histamine; see chapter 4 for more details) was discovered by French pharmacologist Daniel Bovet in 1937. Between 1937 and 1941, Bovet conducted more than 3,000 experiments to find the chemical formulas upon which most of the antihistamines now prescribed are based. Antihistamines are effective in treating allergic reactions. His discovery led to development of the first antihistamine drug, diphenhydramine (Antergan), for treating allergies in 1942, but it did not reach the market because of toxicity issues. In 1944, another one of Bovet’s discoveries, pyrilamine (Neoantergan), was produced as a drug. He did not patent it and did not make a penny out of his important discovery. Not all was lost, however; Bovet won the Nobel Prize in Physiology or Medicine in 1957. General Robert Wood Johnson (1845–1910), one of the three brothers who founded Johnson & Johnson, wrote a credo that codified the company’s socially responsible approach to conducting business.