The Drug Hunters

by Donald R Kirsch

  Since the formation of blood-pressure-increasing angiotensin II is regulated by ACE, any compound that inhibits ACE will also block the formation of angiotensin II and might serve as a treatment for high blood pressure.

  189: It was so profitable, in fact, that it made more money for Squibb than the rest of its drug portfolio combined: By 1985, there were multiple classes of antihypertensive therapies. The three most popular were the thiazide diuretics, the beta blockers, and the ACE inhibitors. The seemingly bottomless appetite for antihypertensive drugs led Pfizer to pursue a new class of antihypertensive. In 1985, scientists at the Pfizer laboratories in Sandwich, England, began studying a signaling molecule called cyclic GMP (cGMP) that was known to participate in multiple physiological pathways that controlled blood pressure. Even better, there appeared to be a well-established strategy for increasing cGMP levels: inhibiting the enzymes that degrade cGMP, enzymes called phosphodiesterases.

  As Pfizer began searching for phosphodiesterase inhibitors, a trio of scientists announced their groundbreaking discovery that nitric oxide, a type of gas, served as a signaling molecule in the body. (This discovery would earn the scientists the 1998 Nobel Prize in medicine.) This finding had special implications for the treatment of angina pectoris, a form of chest pain produced by insufficient oxygen to the heart muscle. Ever since the nineteenth century, nitroglycerin was widely used to treat angina, but nobody knew how it worked. But now scientists realized that nitroglycerin released nitric oxide, which in turn caused blood vessels to dilate and supply more oxygen to the heart. Why did this matter to the Pfizer drug hunters? Because the second messenger for the action of nitric oxide turned out to be cGMP.

  The Pfizer team in Sandwich switched their objective. They continued searching for a phosphodiesterase inhibitor that increased cGMP, but the goal was to develop a drug to treat angina pectoris instead of high blood pressure. In 1989, they finally found the right molecule: UK-92-480, which they later named sildenafil. In 1991, sildenafil entered clinical trials for angina … and the drug turned out to be a complete bust. It was not meaningfully better than nitroglycerin, the angina drug that had been discovered more than a century earlier and was available widely and cheaply.

  However, a few of the scientists became intrigued by one of the side effects reported by the subjects of the clinical trials. Many of the male patients got erections.

  At the time, there was very little in the way of treatment for erectile dysfunction. (In fact, the very phrase “erectile dysfunction” was not in widespread use.) Some physicians recommended a collection of pumps and constriction devices to aid with erections, although these were obviously not highly conducive to romance. There was a single approved drug for erectile dysfunction, alprostadil, but it had to be injected directly into the penis with a syringe or—even worse—pellets of the drug had to be shoved down the urethra of the penis. There were also prosthetic devices that needed to be surgically implanted. Thus, Pfizer concluded, there might be a very large market for a simple pill that helped men get erections.

  Pfizer set up clinical trials for sildenafil as a treatment for erections. Almost nine out of ten of the male subjects (87.7 percent) stated that sildenafil improved their erections. An even larger majority wanted to continue using the drug. But perhaps most revealing was the feedback from the subjects. One wrote: “Before I took part in the study I was heavily depressed. I was continually arguing with my wife and generally making life hell for her and my children…. [E]ntering the study saved our family from much grief…. [I]t probably saved my marriage and possibly my life.”

  Another participant stated: “[T]he drug has proved very effective in enabling me to engage in sexual activity… despite my age (91) I am able to function as well as men many years my junior.”

  Pfizer filed the sildenafil application with the FDA in September 1997. The product was assigned for priority review and approval was announced on March 27, 1998. In 1998, Pfizer began selling its new drug, which it dubbed Viagra. Between 1998 and 2008, Pfizer reported $26 billion in total global sales of Viagra.

  Chapter 11: The Pill: Drug Hunters Striking Gold outside of Big Pharma

  216: Rock gathered together fifty female volunteers from his fertility laboratory and began giving them the three versions of the progesterone: The three versions were norethisterone (from Russell Marker’s Syntex) and noretynodrel and norethandrolone (both made by Searle). In December of 1954, Rock began the first studies of the ovulation-suppressing potential of five 50 mg doses of the three oral progestins for three months (for twenty-one days per cycle; he administered the medication on days five through twenty-five followed by pill-free days in order to produce withdrawal bleeding). At 5 mg doses, norethisterone and noretynodrel—and norethandrolone at all doses—successfully suppressed ovulation, but they also caused breakthrough bleeding. At 10 mg or higher doses, norethisterone and noretynodrel suppressed ovulation without breakthrough bleeding and led to a 14 percent pregnancy rate during the following five months. Pincus and Rock selected Searle’s noretynodrel for the contraceptive trials in Puerto Rico.

  Chapter 12: Mystery Cures: Discovering Drugs through Blind Luck

  232: most members of the psychiatric establishment believed there could never be a drug to treat these disorders: Woody Allen includes a classic joke in his film Annie Hall:

  It reminds me of that old joke—you know, a guy walks into a psychiatrist’s office and says, hey doc, my brother’s crazy! He thinks he’s a chicken. Then the doc says, why don’t you turn him in? Then the guy says, I would but I need the eggs. I guess that’s how I feel about relationships. They’re totally crazy, irrational, and absurd, but we keep going through it because we need the eggs.

  Modern psychiatry has put extensive effort into distinguishing between mental illness and poor judgment. It’s not easy, but there are two words for crazy used by German Jews that nicely capture the distinction: meschugge and verrückt. A middle-aged man, happily married for more than thirty years, suddenly becomes infatuated with his twenty-something secretary and starts an affair. His wife learns of it and demands a divorce. The man is immediately full of regret and apologizes, but the wife, feeling betrayed, refuses to reconcile. This is meschugge. In another case, a man hears his middle-aged brother has not been showing up for work and his neighbors report they have not seen him in days. The man enters his brother’s home to find out what’s going on and discovers him hiding under his bed, screaming and eating bugs. This is verrückt.

  From a pharmacology perspective, most—if not all—psychiatric medications in current use are pretty poor drugs. In general, to proceed with the discovery of a new drug one needs either a validated pharmacological target or, lacking that, an animal model of the disease that can be used to test candidate drug compounds. The big problem with psychiatric disorders is that we still know very little about their physiological basis and can only guess at the neurochemical imbalances that underlie these diseases. Complicating matters even further is the fact that we cannot reproduce mental disorders in laboratory animals. How do we know for sure if an animal is feeling suicidal, suffering from hallucinations, or having disturbing thoughts? And how would we know if a drug is mitigating these abnormal thoughts and feelings?

  236: The success of chlorpromazine also marked the beginning of the end for psychoanalysis: The widespread adoption of the first antipsychotic drugs soon led to the closing of mental hospitals around the country, a public health phenomenon known as deinstitutionalization. It was no longer necessary to warehouse the incurable mentally ill, since antipsychotic drugs enabled them to live within the community. Nevertheless, these drugs are highly imperfect medicines. Deinstitutionalization had the undesired and unintended effect of expelling many individuals whose psychotic disorders were only partially treated by drugs, or, even in cases where patients responded very well to antipsychotic drugs, many of these patients would stop taking their medication, especially since these drugs have many unpleasant side effects. Cons
equently, many deinstitutionalized patients have ended up in prison, which has now become the institution holding the highest number of mentally ill individuals. A 2011 New England Journal of Medicine article reports that the prevalence of mental health disorders among jail inmates is thirty times higher than in the general population. Jailing sick people is not an acceptable solution, and hopefully the discovery of new and more effective medicines will eventually settle this disturbing medical problem.

  Conclusion: The Future of the Drug Hunter: The Chevy Volt and the Lone Ranger

  250: More severely, in 2016, a painkiller drug trial in France killed one man and critically injured five others: Another tragic case: in 2006, TeGenero Immuno Therapeutics started clinical trials in London on TGN1412, a new drug that had been developed to treat leukemia and rheumatoid arthritis. It worked by modulating the human immune system. The drug was given to six healthy male volunteers at a tiny fraction of the dose that had previously been demonstrated to be safe in monkeys (one five-hundredth, or 0.2 percent). Within four hours all six men were gravely ill. They suffered catastrophic organ failure resulting from a “cytokine storm,” which produces a massive flood of active immune cells and fluids. Four of the volunteers ended up in critical condition and almost died. Although all six volunteers eventually recovered, they may face a variety of immunological diseases later in life.

  The British equivalent of the FDA, the Healthcare Products Regulatory Agency or MHRA, investigated the incident and found no evidence of fraud or malfeasance. TeGenero appeared to have honestly disclosed all their data to the regulatory authorities and followed the appropriate testing protocols. In response to the disaster there was a reevaluation of MHRA protocols. Consequently, the regulations for conducting clinical trials in Britain have been stiffened.

  TeGenero filed for bankruptcy in late 2006.

  Bibliography and Suggested Readings

  Introduction: The Pharmaceutical Library of Babel

  Ötzi the ice man

  Fowler, Brenda. Iceman: Uncovering the Life and Times of a Prehistoric Man Found in an Alpine Glacier. Chicago: University of Chicago Press, 2001.

  Rapamycin—Suren Sehgal

  Loria, Kevin. “A Rogue Doctor Saved a Potential Miracle Drug by Storing Samples in His Home after Being Told to Throw Them Away.” Business Insider, February 20, 2015.

  Sehgal, S. N. “Sirolimus: Its Discovery, Biological Properties, and Mechanism of Action.” Transplant Procedures. 35 (3 Suppl.) (2003): 7S–14S.

  Seto, B. “Rapamycin and mTOR: A Serendipitous Discovery and Implications for Breast Cancer.” Clinical and Translational Medicine 1 (2012): 1–29.

  Cost of FDA-approved drug

  DiMasi, J. A., H. G. Grabowski, and R. W. Hansen. “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs.” Boston: Tufts Center for the Study of Drug Development, November 18, 2014. http://csdd.tufts.edu/news/complete_story/cost_study_press_event_webcast, retrieved January 4, 2016.

  Emanuel, Ezekiel J. “Spending More Doesn’t Make Us Healthier.” New York Times, October 27, 2011.

  “Research and Development in the Pharmaceutical Industry, A CBO Study.” October 2006, https://www.cbo.gov/sites/default/files/109th-congress-2005-2006/reports/10-02-drugr-d.pdf, retrieved January 27, 2016.

  Vagelos, P. R. “Are Prescription Prices Too High?,” Science 252 (1991): 1080–4.

  Possible shapes and charge distributions for compounds circa 500 daltons = 3 x 1062

  Bohacek, R. S., et al. “The Art and Practice of Structure-based Drug Design: A Molecular Modeling Perspective.” Med. Res. Rev. 16 (1996): 3–50.

  Library of Babel

  Borges, Jorge Luis. The Library of Babel. Boston: David R. Godine, 2000.

  Lipitor acts upon HMG-CoA reductase, the protein controlling the rate of cholesterol synthesis; penicillin shuts down peptidoglycan transpeptidase

  Bruton, L., et al. Chapter 31, “Drug Therapy for Hypercholesterolemia and Dyslipidemia.” In Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill Education/Medical (12th edition), 2011.

  ———. Chapter 53, “Penicillins, Cephalosporins, and Other β-Lactam Antibiotics.” In Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill Education/Medical (12th edition), 2011.

  Chloroform discovery

  Dunn, P. M. “Sir James Young Simpson (1811–1870) and Obstetric Anesthesia.” Archives of Disease in Childhood, Fetal and Neonatal Edition 86 (2002): F207–9.

  Gordon, H. Laing. Sir James Young Simpson and Chloroform (1811–1870). New York: Minerva Group, 2002.

  Drug discovery

  Ravina, Enrique. The Evolution of Drug Discovery. Weinheim, Germany: Wiley-Verlag Helvetica Chimica, 2011.

  Sneader, Walter. Drug Discovery: A History. Hoboken, NJ: John Wiley and Sons, 2005.

  Chapter 1: So Easy a Caveman Can Do It: The Unlikely Origins of Drug Hunting

  Opium

  Booth, Martin. Opium: A History. London: St. Martin’s Griffin, 2013.

  Brownstein, M. J. “A Brief History of Opiates, Opioid Peptides, and Opioid Receptors,” Proceedings of the National Academy of Science USA 90 (1993): 5391–3.

  Goldberg, Jeff. Flowers in the Blood: The Story of Opium. New York: Skyhorse Publishing, 2014.

  Hodgson, Barbara. Opium: A Portrait of the Heavenly Demon. Vancouver: Greystone Books, 2004.

  Paracelsus and opium (laudanum)

  Hodgson, Barbara. In the Arms of Morpheus: The Tragic History of Morphine, Laudanum and Patent Medicines. Richmond Hill: Firefly Books, 2001.

  Paregoric

  Boyd, E. M., and M. L. MacLachan. “The Expectorant Action of Paregoric.” Canadian Medical Association Journal 50 (1944): 338–44.

  Dover’s Powder and Alexander Selkirk

  Alleyel, Richard. “Mystery of Alexander Selkirk, the Real Robinson Crusoe, Solved.” Daily Telegraph, October 30, 2008.

  Bruce, J. S., and M. S. Bruce. “Alexander Selkirk: The Real Robinson Crusoe.” The Explorers Journal, Spring 1993.

  “Dr. Thomas Dover, Therapeutist and Buccaneer.” Journal of the American Medical Association, February 29, 1896, 435.

  Kraske, Robert, and Andrew Parker. Marooned: The Strange but True Adventures of Alexander Selkirk, the Real Robinson Crusoe. Boston: Clarion Books 2005.

  Leslie, Edward E. “On a Piece of Stone: Alexander Selkirk on Greater Land.” In Desperate Journeys, Abandoned Souls: True Stories of Castaways and Other Survivors. New York: Mariner Books 1998.

  Osler, W. “Thomas Dover, M. B. (of Dover’s Powder), Physician and Buccaneer.” Academy of Medicine 82 (2007): 880–1.

  Phear, D. N. “Thomas Dover 1662–1742; Physician, Privateering Captain, and Inventor of Dover’s Powder.” Journal of the History of Medicine and Allied Sciences 2 (1954) 139–56.

  Selcraig, B. “The Real Robinson Crusoe.” Smithsonian Magazine, July 2005.

  Heroin and Bayer

  Bruton et al. Chapter 18, “Opioids, Analgesia, and Pain Management.” In Goodman and Gilman’s The Pharmacological Basis of Therapeutics, New York: McGraw-Hill Education/Medical (12th edition), 2011.

  Chemical Heritage Foundation Felix Hoffmann Biography, http://www.chemheritage.org/discover/online-resources/chemistry-in-history/themes/pharmaceuticals/relieving-symptoms/hoffmann.aspx, retrieved December 22, 2015.

  Edwards, Jim. “Yes, Bayer Promoted Heroin for Children—Here Are the Ads That Prove It.” Business Insider, November 17, 2011.

  Scott, I. “Heroin: A Hundred Year Habit.” History Today, vol. 48, 1998.

  http://www.historytoday.com/ian-scott/heroin-hundred-year-habit, retrieved January 27, 2016.

  Sneader, W. “The Discovery of Heroin.” Lancet, 352 (1998): 1697–9.

  Sears Roebuck catalog heroin

  Buxton, Julia. The Political Economy of Narcotics. London: Zed Books, 2013.

  Endorphin receptor story

  Terenius, L. “Endogenous Peptides and Analgesia.” Annual Review of P
harmacology and Toxicology 18 (1978): 189–204.

  Increase in THC in marijuana

  Hellerman, C., “Is Super Weed, Super Bad?” CNN. http://www.cnn.com/2013/08/09/health/weed-potency-levels/, retrieved December 23, 2015.

  Walton, A.G. “New Study Shows How Marijuana’s Potency Has Changed Over Time.” Forbes, March 23, 2015. http://www.forbes.com/sites/alicegwalton/2015/03/23/pot-evolution-how-the-makeup-of-marijuana-has-changed-over-time/, retrieved December 23, 2015.

  SCN9A (Nav1.7)

  Drews, J., et al. “Drug Discovery: A Historical Perspective.” Science 287 (2000): 1960-4.

  King, G. F., and L. Vetter. “No Gain, No Pain: NaV1.7 as an Analgesic Target,” ACS Chemical Neuroscience 5 (2014): 749–51.

  Pina, A. S., et al. “An Historical Overview of Drug Discovery Methods.” Molecular Biology 572 (2009): 3–12.

  Chapter 2: Countess Chinchón’s Cure: The Library of Botanical Medicine

  Valerius Cordus, biography and discovery of ether

  Arbor, Agnes. “Herbals, Their Origin and Evolution: A Chapter in the History of Botany, 1470–1670.” Seattle: Amazon Digital Services, Inc., 1912.

  Leaky, C. D. “Valerius Cordus and the Discovery of Ether.” Isis 7 (1926): 14–24.

  Sprague, T. A., and M. S. Sprague. “The Herbal of Valerius Cordus.” Journal of the Linnean Society of London.52 (1939): 1–113.

  Chinchona—history

  Bruce-Chwatt, L. J. “Three Hundred and Fifty Years of the Peruvian Fever Bark.” British Medical Journal (Clinical Research Edition) 296 (1988): 1486–7.

  Butler A. R., et al. “A Brief History of Malaria Chemotherapy.” J R College of Physicians Edinborough 40 (2010): 172–7.