Sitagliptin (Januvia)

Diabetes has been known since antiquity. In fact, the term “diabetes mellitus” comes from the Greek meaning “siphon and honey” due to the excess excretion (siphon or faucet) of hyperglycemic (sweetened, or honeyed) urine associated with diabetes. In ancient times, diabetes was mostly type I, which usually manifests acutely in the young, secondary to certain underlying insults (possibly infections) to the islet cells of the pancreas resulting in an absolute lack of insulin. Insulin was discovered by Banting and Best in 1921, and insulin injection has literally saved millions of lives since then. With the wondrous efficacy that insulin bestows, type I diabetes is largely controlled because type I diabetes is insulindependent. However, type II diabetes, a more prevalent form of diabetes, is not insulin-dependent. In ancient times, when nutrition was scarce and obesity was not prevalent, type II diabetes mellitus (T2DM) was extremely rare. Indeed, type II diabetes is a disease more frequently associated with maturity, obesity, and gradually increasing blood glucose concentrations, and it may be asymptomatic for some time, only discovered on routine glucose screening. In fact, with the increasing body weight of the general population of the developed world, type II diabetes is becoming an epidemic. Serious complications of diabetes include nephropathy (kidney diseases), neuropathy (nerve damage), and retinopathy (blindness). Diabetes is the most common cause of blindness and amputation in the elderly in the United States. Oral diabetes drugs are required for most type II diabetic patients. Diabetes drugs may be classified into four categories: (a) agents that augment the supply of insulin such as sulfonylureas; (b) agents that enhance the effectiveness of insulin such as biguanides and thiazolidinediones; (c) GLP agonists; and (d) DPP4 Inhibitors. The efficacy of all the antidiabetic drugs can be monitored by measuring glycosylated hemoglobin (HaA1c) as a long term marker of elevated blood glucose. The amount of HaA1c reflects the average level over the last 120 days, the life span of a red blood cell, and should remain below 7%.

Imatinib Mesylate (Gleevec)

Great strides had been made in the war against cancer with chemotherapy even before the emergence of protein kinase inhibitors. For instance, prior to vinblastine (1, Velban) became available in 1964 for the treatment of lymphoma, the diagnosis of Hodgkin’s disease (a cancer of the lymph nodes) was virtually a death sentence. Today there is a 90% chance of survival with the treatment by vinca alkaloids such as 1 and other chemotherapies. Similarly, when Sidney Farber discovered the effects of methotrexate (2, Trexall) on leukemia, it marked the beginning of the triumph over childhood leukemia. Following Barnett Rosenberg’s discovery of cisplatin (3, Platinol)’s effects on tumor cells in 1967, cisplatin and its analogs such as carboplatin (4, Paraplatin) and oxaliplatin (5, Eloxatin) contributed significantly in boosting the survival rate of patients with metastatic testicular cancer, ovarian tumors, and bladder cancer. Most significantly, breast cancer, a malady striking one in eight women, has been effectively managed via a plethora of treatments including surgery, radiation, and chemotherapies. The arsenal of chemotherapeutics for treating breast cancer includes SERMs such as tamoxifen (6) and raloxifene (7, Evista). Type I, II, and III aromatase inhibitors have now also been widely prescribed to combat breast cancers (more details may be found in chap. 4). Today, breast cancer is sometimes viewed as a chronic disease that can be managed, rather than a lethal disease. Despite the efficacy of the aforementioned chemotherapeutics, they kill cancer cells and normal cells with equal ferocity. (Some have compared chemotherapy to a “carpet bombing” strategy.) However, the reason these chemotherapies are effective is that cancer cells divide at much faster rate than normal cells; therefore, chemotherapies kill more malignant cells than healthy cells. Chemotherapies invariably come with significant side effects rooted. For example, hair follicle cells have a physiologically high mitosis rate; therefore, chemotherapies kill them faster than other healthy cells. In the same vein, other common side effects of chemotherapy include diarrhea (because ephithelial renewal is inhibited), bone marrow suppression (because granulopoiesis, thrombopoiesis, cytopoiesis, and erythropoiesis are inhibited), and lymph node damage (because of lymphocyte multiplication inhibition causes immune weakness).

Clopidogrel Bisulfate (Plavix)

Three types of blood cells exist in the human body: red blood cells, white blood cells, and platelets. Red blood cells, 45% of the blood, transport oxygen from the lungs to other body parts. White cells, less than 1% of the blood, defend us against bacterial and viral invasions. Platelets, also less than 1% of the blood (55% of the remaining blood is plasma), are small cell fragments that are involved in helping the blood clot, a process known as blood coagulation. Coagulation takes place when the enzyme thrombin elicits platelets and fibrin, a blood protein. Without platelets, coagulation at the site of an injury does not occur and uncontrolled bleeding ensues. Individuals with no ability to clot have a genetic condition called hemophilia. These individuals must periodically administer a clotting factor to their blood to prevent constant bleeding. Conversely, thrombosis, the formation of blood clots inside blood vessels, can block coronary arteries and constrict vital oxygen supplies, resulting in a heart attack or stroke. Coronary thrombosis is a life-threatening blood clot in the artery. Deep-vein thrombosis (DVT) is commonly associated with long-distance air travel, when passengers are confined to cramped spaces for many hours. In contrast with thrombosis, in which the clot is stationary, embolus is when an object such as a clot migrates from one part of the body through blood circulation and causes blockage. A pulmonary embolism occurs when emboli travel to the lungs. Approximately 90% of heart attacks and 80% of strokes are caused by blood clots, which kill some 200,000 hospital patients in the US each year. Anticoagulants (blood thinners) are the drugs of choice to prevent and treat both thrombosis and embolism. To date, heparin, warfarin, and aspirin have all been widely used as blood thinners to prevent blood clots from forming. Heparin is one of the oldest medicines still in widespread clinical use. Heparin was extracted in 1916 by Jay McLean from dog’s liver in the laboratories of William Howell at the Johns Hopkins University.

Amlodipine (Novasc)

Hypertension (high blood pressure) is estimated to afflict 1 billion individuals worldwide and is a major risk factor for stroke, coronary artery disease, heart failure, and end-stage renal disease. The first class of drugs to treat hypertension was the mercurial diuretics, discovered by Alfred Vogl in 1919 in Vienna. Diuretics, by removing fluid from the body, reduce the pressure on the heart. Mercurial diuretics revolutionized the treatment of congestive heart failure resulting from severe edema and were the primary treatment until the late 1950s, when thiazide diuretics emerged. In 1957, Merck chemist Frederick C. Novello prepared chlorothiazide (2, Diuril), a potent diuretic that does not cause elevation of bicarbonate excretion, an undesired side effect associated with mercurial diuretics. Shortly after chlorothiazide’s (2) success, George deStevens at Ciba reduced a double bond on chlorothiazide (2) to a single bond to give hydrochlorothiazide (3, HydroDiuril) which was 10-fold more potent than the prototype 2. Hydrochlorothiazide was introduced to medical practice in 1959 and within a short time became the drug of choice for the treatment of mild hypertension. One of the liabilities of these drugs is thiazide diuretic-induced hyperglycemia. As early as 1948, Raymond P. Ahlquist at the Medical College of Georgia speculated that there were two types of adrenergic receptors (adrenoceptors in short), which he termed α-adrenoceptor and β-adrenoceptor, that are 7-transmembraned protein as GPCR. In 1957, Irwin H. Slater and C. E. Powell at Eli Lilly prepared dichloroisoprenaline (DCI, 4), the dichloro analog of isoprenaline; it was later found to be the first selective β-adrenoreceptor blocking reagent, also known as a β-blocker. However, DCI was not further pursued as a drug candidate because it had a marked undesirable stimulant effect on the heart, an intrinsic sympathomimetic action (ISA). Beginning in 1958, James Black at Imperial Chemical Industries (ICI) led a team to look for β-blockers that were devoid of the stimulant effect on the heart. In 1962, the first selective β-adrenoreceptor inhibitor pronethalol (5) was discovered but was withdrawn from further development when it was found to cause thymic tumors in mice.

Sofosbuvir (Sovaldi)

Viruses are humanity’s invisible enemy. They wreak daily havoc by causing the flu, measles, rabies, hepatitis, smallpox, polio, and even human immunodeficiency virus (HIV). Although viruses have existed on the earth much longer than humans, it was not until in 1892 when the concept of virus took root when Chamberland experimented with viruses using the Pasteur–Chamberland filter. Solid evidence emerged when tobacco mosaic virus (TMV) crystal was isolated in 1935. However, human ingenuity afforded successful measures to combat viruses long before 1892. For instance, Jenner successfully pioneered a vaccination for preventing smallpox in 1796, nearly one hundred years before Chamberland’s exploits and before Pasteur developed the first vaccination for rabies in 1885. The scourge of polio has been nearly wiped out thanks to Salk’s inactivated polio vaccine (IPV) available since 1954 and Sabin’s oral poliovirus vaccine (OPV) popularized in 1960. The 1951 the Nobel Prize in Physiology or Medicine was awarded to Theiler for his contributions to yellow fever vaccines. In terms of small molecule antiviral drugs, the nucleoside iododeoxyuridine (IDU, 2), a simple analog of thymidine (3), was first synthesized and used as an antiviral drug in 1959 by Prusoff. Unfortunately, due to its systemic cardiotoxicities, IDU is now only used topically to treat herpes simplex keratitis. A similar antiviral nucleoside, trifluorothymidine (TFT, Viroptic, 4), is less toxic than 2, and is also primarily used topically in eyes to kill the herpes simplex virus (HSV). Under the leadership of future Nobel laureate Elion, Burroughs Wellcome introduced the nucleoside analog acyclovir (Zovirax, 5) in 1978 for the treatment of HSV infection.3 While not the first antiviral agent on the market, Zovirax (5) was the first small molecule drug to be widely used to control a viral infection. Introduction of valacyclovir (Valtrex, 6), a prodrug of Zovirax (5) with higher oral bioavailability, afforded the patient a more convenient regimen because it does not have to be taken as frequently as the parent drug Zovirax (5).

Esomeprazole (Nexium)

Gastric acid, hydrochloric acid (HCl), is essential to our digestion. It helps break down proteins, fats, and starches in our food into nutrients such as amino acids and carbohydrates that our body can absorb. Alas, there can be too much of a good thing. Too much secretion of gastric acid for too long can cause heartburn or acid reflux, also known as gastroesophageal reflux disease (GERD). In addition, having too much gastric acid for too long will damage the mucosa of the stomach and may cause ulcer and even stomach cancers! While the exact pathogenesis of ulcers is not known, theories abound. It is still a popular belief that ulcer is caused by stress. Thirty years ago, the discovery of Helicobacter pylori demonstrated that the bacterium contributes to gastritis and peptic ulcers. Regardless of the root of stomach ulcers, they are closely associated with excessive secretion of gastric acid, so that was what early ulcer drugs intended to treat. Dozens of antacids are on the market to neutralize excess HCl: For instance, Mylanta and Maalox contain Al(OH)3 and Mg(OH)2. Tums contains CaCO3. Alka-Seltzer contains NaHCO3 (baking soda). However, antacids only treat the symptoms of excessive acid secretion, and are therefore only effective as a short-term treatment. A better therapy would treat the causation of excessive acid secretion. Histamine-2 receptor antagonists work by blocking the receptors that are responsible for excessive acid secretion: the histamine- 2 receptors. As a consequence, they are more efficacious and have fewer adverse effects in comparison to conventional antacids. The fact that histamine stimulates gastric acid secretion in the stomach was first observed by Popielski in the 1920s. Popielski studied under Pavlov, who won the Nobel Prize (for Physiology or Medicine) in 1904 for his studies in digestive system, but who is now better known for his classical dog-conditioning experiments. As an independent researcher at the University of Kraków, Popielski discovered that histamine was a stimulant of gastric glands, and acted directly without the involvement of vagal nerves. After injecting histamine subcutaneously into gastric fistulas in dogs, Popielski observed copious gastric acid secretion and extremely high acidity in the dogs’ stomachs.

Olanzapine (Zyprexa)

Schizophrenia is a devastating mental disorder, inflicting 1.1% of the population over the age of 18, which translates to 51 million people worldwide including 2.2 million people in the United States. Schizophrenia strikes men and women at different ages; the average onset age is 18 for men and 25 for women. Schizophrenia is characterized by positive symptoms such as delusions, hallucinations, and disorganized speech/behavior and negative symptoms including apathy, withdrawal, lack of pleasure, and impaired attention. While it might be relatively easy to treat positive symptoms with antipsychotics, negative symptoms are more difficult to treat. Other symptoms include depressive/anxious symptoms and aggressive symptoms such as hostility, verbal and physical abusiveness, and impulsivity. Because of schizophrenia’s complexity, it is challenging to find therapeutics that are both efficacious and safe, especially considering that the patient has to take them for a prolonged period of time. In ancient times, an “insane” person was often thought to be possessed by the devil, or he was being punished by God for his sins. As a consequence, beating, bleeding, starvation, hot- and cold-water shock treatment, restraint, and incarceration were widely practiced on mental patients, which only worsened their conditions. In 1927, Austrian neurologist Julius Wagner von Jauregg invented the fever shock treatment, introducing malaria in psychotics. Egaz Moniz invented the lobotomy to “introduce an organic syndrome” for the treatment of schizophrenia; both men won the Nobel Prize (for Physiology or Medicine). Today, neither malaria introduction nor lobotomy is still in use. Although there is still a certain stigma attached to mental illnesses, we have now amassed a tremendous amount of knowledge with regard to the genetic, biochemical, and environmental impacts on the human brain. Psychopharmacological drugs such as olanzapine (Zyprexa, 1) have significantly contributed to managing and understanding mental diseases including schizophrenia. Before chlorpromazine (2) became available in 1962, early treatments for schizophrenia included prolonged narcosis, known as “narcosis for psychosis.” Meanwhile, history also saw the use of excruciating treatments such as electroshock and shock introduced by fever, methiazole, and insulin.

Duloxetine Hydrochloride (Cymbalta)

“To live is to suffer, to survive is to find some meaning in the suffering.” Nietzsche’s words ring true to many. Depression is romanticized at times due to its association with poets and artists, but in reality depression, especially major depressive disorder (MDD), can be debilitating. There are two types of depression: MDD and bipolar, also known as manic–depressive illness. Severe changes in mood is the primary clinical manifestation of both disorders. MDD presents as feelings of intense sadness and despair with little drive for either socialization or communication; physical changes such as insomnia, anorexia, and sexual dysfunction can also occur. Mania is manifested by excessive elation, irritability, insomnia, hyperactivity, and impaired judgment. It may afflict as much as 1% of the population. MDD is among the most common psychiatric disorders in humans, affecting up to 10% of men and 20% of women over the course of their lives. Among those affected, 28% experience a moderate degree of functional impairment, while 59% experience severe reductions in their normal functional ability. About 19 million Americans suffer from depression per year. In terms of disease burden, MDD ranks as the fourth most costly illness in the world, with estimated annual costs of depression in the US amounting to approximately $43.7 billion. While we all agree that depression exists, we do not all agree on the causes of depression. The exact causes of depression are not definitively known. However, in the 1950s, it was observed that in addition to its other pharmacological properties, reserpine (a Rauwolfia alkaloid) induced a depressive state in normal patients and also depleted levels of neurotransmitters such as norepinephrine (NE) and serotonin (5-HT). This observation and others led to the hypothesis that the biological basis of major mood disorders may include abnormal monoamine neurotransmission. Substances such as NE, serotonin, and dopamine (DA) mediate neurotransmission. These substances are released from presynaptic neurons, cross the synaptic gap, and interact with receptors on the postsynaptic cells. The synthesis, transmission, and processing of these neurotransmitters provide a number of points of intervention through which a pharmacological agent may affect transmission.

Atorvastatin Calcium (Lipitor)

To the human body, cholesterol (2) is a Janus-faced molecule. On the one hand, it is an indispensable building block for life—about 23% of total body cholesterol resides in the brain, making up one-tenth of the solid substance of the brain. Red blood cell membranes are also rich in cholesterol, which helps stabilize the cell membranes and protect cells. Furthermore, cholesterol is also the precursor of hormones such as progesterone, testosterone, estrogen, and cortisol. On the other hand, cholesterol helps plaque buildup, which constricts or blocks arteries, leading to angina, heart attack, stroke, and many other cardiovascular diseases. To date, the experimental, genetic, and epidemiologic evidence all point to escalating cholesterol levels as a major risk factor for cardiovascular diseases. Other major risk factors include obesity, diabetes, hypertension, smoking, and inactive lifestyle. Depending on different water-soluble carriers, cholesterol could have starkly opposing effects on the heart. Cholesterol in low-density lipoprotein (LDL), often known as “bad” cholesterol, is the fundamental carrier of blood cholesterol to body cells. It can slowly build up in the walls of the arteries feeding the brain and heart and can form plaques. In contrast, cholesterol in high-density lipoprotein (HDL), frequently dubbed “good” cholesterol, is a carrier that takes cholesterol away from the arteries and brings it to the liver, where it can be removed from circulation by metabolism. The higher the levels of HDL, the better. In general, women have higher levels of HDL, which may explain why women have longer life expectations than men. Their higher levels of estrogen are somehow correlated to higher HDL-cholesterol levels. Many attempts have been made to lower cholesterol levels. In the 1950s and 1960s, estrogen was tried but was quickly abandoned because it caused feminizing side effects on men. Thyroid hormone also had unacceptable side effects, such as trembling. Resins such as cholestyramine were used as bile acid sequestrants, or bile acid binding resins. The approach was not popular in patients because they were difficult to swallow—literally.