Category Archives: TB

Psychotropic Serendipities

Serendipities abound in history of medicine, in our own time no less than in the past.  In the 15 years that followed the end of World War II, a period of special interest to me, the discovery of what we now consider modern psychiatric (or psychotropic) drugs is a striking case in point.

Researchers in the final years of the war and immediately thereafter were hardly looking for psychotropics.  They were looking for other things:  improved antihistamines; preservatives that would permit penicillin to hold up during transport to troops in Europe and Asia; and the development of antibiotics effective against penicillin-resistant microorganisms like the tubercle bacilli that caused tuberculosis.

When Frank Berger, a Czechoslovakian bacteriologist, fled to England in 1939, he gained work as as a refugee camp physician.  Then, in 1943, he was hired by a government laboratory in London and joined in the work that engaged so many British scientists of the time:  the purification and industrial production of penicillin.  Berger’s particular assignment was the search for a penicillin preservative; he was especially interested in finding an agent that would prevent the breakdown of penicillin by gram-negative bacteria (penicillinase) during shipment.  And with the synthesis of mephenesin in 1945, he achieved success – and then some.  Mephenesin not only preserved penicillin, but, in small-scale animal trials on toxicity begun at the end of 1951, it revealed something else:  On injection into mice, rats, and guinea pigs, the preservative produced deep muscle relaxation, a sleep-like state that Berger described in 1946 as “tranquillization.”[1]

Berger emigrated to the United States in 1947, and after a brief stint at the University of Rochester Medical School, became Director of Laboratories at Carter-Wallace in Cranbury, New Jersey.  There, joined by the chemist Bernard Ludwig, he developed a more potent and slowly metabolizing form of mephenesin.  The drug was meprobamate, the first minor tranquilizer, for which a patent was finally granted in 1955.  Released by Carter-Wallace as Miltown and by Wyeth (a licensee) as Equanil, it took the American market by storm.  In 1956, it leaped from less than 1% to nearly 70% of new tranquilizer prescriptions; in1957 more than 35 million prescriptions were sold, the equivalent of one per second. Meprobamate single-handedly transformed American medicine by transmuting the everyday stresses and strains of Everyman (and Everywoman) into pharmacologically treatable anxiety.  For general practitioners in particular it was a godsend.  “If generalists could not psychoanalyze their troubled patients,” the historian David Herzberg has observed, “they could at least ease worries with a pill, possibly preventing a minor condition from worsening into serious mental illness.”[2]  Not bad for a penicillin preservative.

In 1952, at the very time Berger was observing the “tranquillization” of small rodents injected with meprobamate,  Henri-Marie Laborit, a French naval surgeon working at the Val de Grâce military hospital outside Paris, published his first article on the usefulness of chlorpromazine (CPZ), a chlorinated form of the antihistamine Promazine, in surgical practice.  Laborit, who was working on the development of “artificial hibernation” as an anesthetic technique, found that the drug not only calmed surgical patients prior to the administration of anesthesia, but also prevented them from lapsing into shock during and after their operations.  The drug had been synthesized by the Rhône-Poulenc chemist Paul Charpentier at the end of 1951. Charpentier was searching for an improved antihistamine, but he quickly saw the drug’s possible usefulness as a potentiator of general anesthesia,[3] which indeed it proved to be.

Impressed with the drug’s effectiveness (in combination with other drugs as a “lytic cocktail”) in inducing relaxation – what he termed “euphoric quietude” – and in preventing shock, Laborit encouraged his colleague Joseph Hamon to try it on psychiatric patients.  It was subsequently taken up by the French psychiatrists Jean Delay and Pierre Deniker, who tried it on psychiatric patients at the Sainte-Anne mental hospital in Paris.  In six journal articles published in the spring and summer of 1952, they reported encouraging results, characterizing their patients’ slowing down of motor activity and emotional indifference as “neuroleptic syndrome” (from the Greek “that take the nerve”).  Thus was born, in retrospect, the first major tranquilizer, a drug far more effective than its predecessors (including morphine and scopolamine in combination) in controlling extreme agitation and relieving psychotic delusions and hallucinations.[4]

But only in retrospect.  At the time of the preliminary trials, the primary application of chlorpromazine remained unclear.  Rhône-Poulenc conducted clinical trials for a number of applications of the drug: to induce “hibernation” during surgery; as an anesthetic; as an antinausea drug (antiemetic) for seasickness; as a treatment for, respectively, burns, stress, infections, obesity,  Parkinson’s disease, and epilepsy.  When Smith, Kline, & French became the American licensee of the drug in early 1953, it planned to market it to American surgeons and psychiatrists alike, and it also took pains to license the drug as an antiemetic.  Only at the end of 1953 did it recognize the primary psychiatric use of the drug, which it released in May, 1954 as Thorazine.

Of course, the birth of modern antibiotic therapy begins with penicillin – the first of the wartime “miracle drugs.” And a miracle drug it was, with an antibacterial spectrum that encompassed strep and staph infections, pneumonia, syphilis and gonorrhea.  But the foregoing infections were all caused by gram-positive bacteria.  Penicillin did not touch the kind of gram-negative bacteria that caused tuberculosis.

The first wonder drug effective against TB was streptomycin, an actinomyces (a soil-dwelling, anaerobic bacteria) discovered by Salman Waksman and his doctoral student Albert Schatz at the Rutgers Agricultural Experiment Station in 1943.  Eight years later, in 1951, chemists working at Bayer Laboratories in Wuppertal, Germany, at Hoffman-La Roche in Basel, Switzerland, and at the Squibb Institute for Medical Research in New Brunswick, New Jersey simultaneously discovered a drug that was not only more effective in treating TB than streptomycin; it was also easier to administer and less likely to have serious side effects.  It was isoniazid, the final wonder drug in the war against TB.  In combination with streptomycin, it was more effective than either drug alone and  less likely to elicit treatment-resistant strains of the tubercle bacilli.

But here’s the thing:  A side-effect of isoniazid was its mood-elevating (or, in the lingo of the day, “psycho-stimulative”) effect.  Researchers conducting trials at Baylor University, the University of Minnesota, and Spain’s University of Cordoba reached the same conclusion:  The mood-elevating effect of isoniazid treatment among TB patients pointed to psychiatry as the primary site of its use.  Back in New York, Nathan Kline, an assistant professor of psychiatry at Columbia’s College of Physicians and Surgeons, learned about the “psycho-stimulative” effect of isoniazid from a report about animal experiments conducted at the Warner-Lambert Research Laboratories in Morris Plains, New Jersey.  Shortly thereafter, he began his own trial of isoniazid with patients at Rockland State Hospital in Orangeburg, New York, and published a report of his findings in 1957.

A year later the drug was brought to market as an antitubercular agent (Marsilid), even though it had been given to over 400,000 depressed patients by that time.  Its improved successor drug, iproniazid, was withdrawn from the U.S. market in 1961 owing to an alleged linkage to jaundice and kidney damage.  But isoniazid retains its place of honor among psychotropic serendipities:  It was the first of the monoamine oxidase inhibitors (MAOIs), potent antidepressants of which contemporary formulations (Marplan, Nardil) are used to treat atypical depressions, i.e., depressions refractory to newer and more benign antidepressants like the omnipresent SSRIs.[5]

Nathan Kline was likewise at hand to steer another ostensibly nonpsychotropic drug into psychiatric usage.  In 1952, reports of Rauwolfia serpentine, a plant root used in  India for hypertension (high blood pressure), snakebite, and “insanity,” reached the West and led to interest in the root’s potential as an antihypertensive.  A year later, chemists at the New Jersey headquarters of the Swiss pharmaceutical firm Ciba (later Ciba-Geigy and now Novartis) isolated an active salt, reserpine, from the root, and Kline, ever ready with the mental patients at Rockland State Hospital, obtained a sample to try on the hospital’s depressed patients.

Kline’s results were encouraging.  In short order, he was touting  reserpine as an “effective sedative for use in mental hospitals,” a finding reaffirmed later that year at a symposium at Ciba’s American headquarters in Summit, New Jersey, where staff pharmacologist F. F. Yonkman first used the term “tranquilizer” to characterize the drug’s mixture of sedation and well-being.[6]  As a major tranquilizer, reserpine never caught on like chlorpromazine, even though, throughout the 1950s, it “was far more frequently mentioned in the scientific literature than chlorpromazine.”[7]

So there we have it: the birth of modern psychopharmacology in the postwar era from research into penicillin preservatives, antihistamines, antibiotics, and antihypertensives.  Of course, serendipities operate in both directions:  drugs initially released as psychotropics sometimes fail miserably, only to find their worth outside of psychiatry.  We need only remember the history of thalidomide, released by the German firm Chemie Grűnenthal in 1957 as a sedative effective in treating anxiety, tension states, insomnia, and nausea.  This psychotropic found its initial market among pregnant women who took the drug to relieve first-trimester morning sickness.  Unbeknown to the drug manufacturer, the drug crossed the placental barrier and, tragically, compromised the pregnancies of many of these women.  Users of thalidomide delivered grossly deformed infants with truncated limbs, “flipper” babies, around 10,000 in all in Europe and Japan.  Only 40% of these infants survived.

This sad episode is well-known among historians, as is the heroic resistance of the FDA’s Frances Kelsey, who in 1960 fought off pressure from FDA administrators and executives at Richardson-Merrell, the American distributor, to release the drug in the U.S.  Less well known, perhaps, is the relicensing of the drug by the the FDA in 1998 (as Thalomid) for a totally nonpsychotropic usage: the treatment of certain complications of leprosy.  Prescribed off-label, it also proved helpful in treating AIDS wasting syndrome.  And beginning in the 2000s, it was used in combination with another drug, dexamethasone, to treat multiple myeloma (a cancer of the plasma cells). It received FDA approval as an anticancer agent in 2006.[8]

Seen thusly, serendipities are often rescue operations, the retrieving and reevaluating of long-abandoned industrial chemicals and of medications deemed inadequate for their intended purpose.  Small wonder that Librium, the first of the benzodiazepine class of minor tranquilizers, the drug that replaced meprobamate as the GP’s drug of choice in 1960, began its life as a new dye (benzheptoxidiazine) synthetized by the German chemists K. von Auwers and F. von Meyenburg in 1891. In the 1930s the Polish-American chemist Leo Sternbach returned to the chemical and synthesized related compounds in the continuing search for new “dyestuffs.”  Then, 20 years later, Sternbach, now a chemist at Hoffmann-La Roche in Nutley, New Jersey, returned to these compounds one final time to see if any of them might have psychiatric applications.  He found nothing of promise, but seven years later, in 1957, a coworker undertook a spring cleaning of the lab and found a variant that Sternbach had missed.  It turned out to be Librium.[9]  All hail to the resourceful minds that return to the dyes of yesteryear in search of the psychotropics of tomorrow – and to those who clean their labs with eyes wide open.

______________________

[1] F. M. Berger & W. Bradley, “The pharmacological properties of α:β dihdroxy (2-methylphenoxy)-γ- propane (Myanesin),” Brit. J. Pharmacol. Chemother., 1:265-272, 1946, at p. 265.

[2] D. Herzberg, Happy Pills in America: From Miltown to Prozac (Baltimore: Johns Hopkins, 2009), p. 35.  Cf. A. Tone, The Age of Anxiety: A History of America’s Turbulent Affair with Tranquilizers  (NY:  Basic Books, 2009), pp. 90-91.

[3] P. Charpentier, et al., “Recherches sur les diméthylaminopropyl –N phénothiazines substituées,” Comptes Rendus de l’Académie des Sciences, 235:59-60, 1952.

[4] On the discovery and early uses of chlorpromazine, see D. Healy, The Creation of Psychopharmacology (Cambridge: Harvard, 2002), pp. 77-101; F. Lopez-Munoz, et al., “History of the discovery and clinical introduction of chlorpromazine,”  Ann. Clin. Psychiat., 17:113-135, 2005; and T. A. Ban, “Fifty years chlorpromazine:  a historical perspective,” Neuropsychiat. Dis. & Treat., 3:495-500, 2007.

[5] On the development and marketing of isoniazid,  see H. F. Dowling, Fighting Infection: Conquests of the Twentieth Century (Cambridge: Harvard, 1977), p. 168; F. Ryan, The Forgotten Plague: How the Battle Against Tuberculosis was Won and Lost (Boston:  Little, Brown, 1992), p. 363; F. López-Munoz, et al., “On the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics,” J. Clinical Psychopharm., 28:1-4, 2008; and Tone, Age of Anxiety, pp. 128-29.

[6] E. S. Valenstein, Blaming the Brain: The Truth about Drugs and Mental Health  (NY:  Free Press, 1998), p. 69; D. Healy, The Antidepressant Era (Cambridge: Harvard, 1997),  pp. 59-70;  D. Healy, Creation of Psychopharmacology, pp. 103-05.

[7] Healy, Creation of Psychopharmacology, p. 106.

[8] P. J. Hilts provides a readable overview of the thalidomide crisis in Protecting America’s Health:  The FDA, Business, and One Hundred Years of Regulation (NY:  Knopf, 2003), pp. 144-65.  On the subsequent relicensing of thalidomide for the treatment of leprosy in 1998 and its extensive off-label use, see S. Timmermans & M. Berg, The Gold Standard:  The Challenge of Evidence-Based Medicine and Standardization in Health Care. (Phila: Temple University Press, 2003), pp. 188-92.

[9] On the discovery of Librium, see Valenstein, Blaming the Brain, pp. 54-56; A. Tone,“Listening to the past: history, psychiatry, and anxiety,” Canad. J. Psychiat,, 50:373-380, 2005, at p. 377; and Tone, Age of Anxiety, pp. 126-40.

Copyright © 2014 by Paul E. Stepansky.  All rights reserved.

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The Costs of Medical Progress

When historians of medicine introduce students to the transformation of acute, life-threatening, often terminal illness into long-term, manageable, chronic illness – a major aspect of 20th-century medicine – they immediately turn to diabetes.  There is Diabetes B.I. (diabetes before insulin) and diabetes in the Common Era, i.e., Diabetes A.I. (diabetes after insulin).  Before Frederick Banting, who knew next to nothing about the complex pathophysiology of diabetes, isolated insulin in his Toronto laboratory in 1922, juvenile diabetes was a death sentence; its young victims were consigned to starvation diets and early deaths.  Now, in the Common Era, young diabetics grow into mature diabetics and type II diabetics live to become old diabetics.  Life-long management of what has become a chronic disease will take them through a dizzying array of testing supplies, meters, pumps, and short- and long-term insulins.  It will also put them at risk for the onerous sequelae of long-term diabetes:  kidney failure, neuropathy, retinopathy, and amputation of lower extremities.  Of course all the associated conditions of adult diabetes can be managed more or less well, with their own technologically driven treatments (e.g., hemodialysis for kidney failure) and long-term medications.

The chronicity of diabetes is both a blessing and curse.  Chris Feudtner, the author of the outstanding study of its transformation, characterizes it as a “cyclical transmuted disease” that no longer has a stable “natural” history. “Defying any simple synopsis,” he writes, “the metamorphosis of diabetes wrought by insulin, like a Greek myth of rebirth turned ironic and macabre, has led patients to fates both blessed and baleful.”[1]  He simply means that what he terms the “miraculous therapy” of insulin only prolongs life at the expense of serious long-term problems that did not exist, that could not exist, before the availability of insulin.  So depending on the patient, insulin signifies a partial victory or a foredoomed victory, but even in the best of cases, to borrow the title of Feudtner’s book, a victory that is “bittersweet.”

It is the same story whenever new technologies and new medications override an otherwise grim prognosis.  Beginning in the early 1930s, we put polio patients (many of whom were kids) with paralyzed intercostal muscles of the diaphragm into the newly invented Iron Lung.[2]  The machine’s electrically driven blowers created negative pressure inside the tank that made the kids breathe.  They could relax and stop struggling for air, though they required intensive, around-the-clock nursing care.[3]  Many survived but spent months or years, occasionally even lifetimes, in Iron Lungs.  Most regained enough lung capacity to leave their steel tombs (or were they nurturing wombs?) and graduated to a panoply of mechanical polio aids: wheelchairs, braces, and crutches galore.  An industry of rehab facilities (like FDR’s fabled Warm Springs Resort in Georgia) sprouted up to help patients regain as much function as possible.

Beginning in 1941, the National Foundation for Infantile Paralysis (NFIP), founded by FDR and his friend Basil O’Connor in 1937, footed the bill for the manufacture of Iron Lungs and then distributed them via regional centers to communities where they were needed.   The Lungs, it turned out, were foundation-affordable devices, and it was unseemly, even Un-American, to worry about the cost of hospitalization and nursing care for the predominantly young, middle-class white patients who temporarily resided in them, still less about the costs of post-Iron Lung mechanical appliances and rehab personnel that helped get them back on their feet.[4]  To be sure, African American polio victims were unwelcome at tony resort-like facilities like Warm Springs, but the NFIP, awash in largesse, made a grant of $161,350 to Tuskegee Institute’s Hospital so that it could build and equip its own 35-bed “infantile paralysis center for Negroes.”[5]

Things got financially dicey for the NFIP only when Iron Lung success stories, disseminated through print media, led to overuse.  Parents read the stories and implored doctors to give their stricken children the benefit of this life-saving invention – even when their children had a form of polio (usually bulbar polio) in the face of which the mechanical marvel was useless.  And what pediatrician, moved by the desperation of loving parents beholding a child gasping for breath, would deny them the small peace afforded by use of the machine and the around-the-clock nursing care it entailed?

The cost of medical progress is rarely the cost of this or that technology for this or that disease.  No, the cost corresponds to cascading “chronicities” that pull multiple technologies and treatment regimens into one gigantic flow.  We see this development clearly in the development and refinement of hemodialysis for kidney failure.  Dialysis machines only became life-extenders in 1960, when Belding Scribner, working at the University of Washington Medical School, perfected the design of a surgically implanted Teflon cannula and  shunt through which the machine’s tubing could be attached, week after week, month after month, year after year.  But throughout the 60s, dialysis machines were in such short supply that treatment had to be rationed:  Local medical societies and medical centers formed “Who Shall Live” committees to decide who would receive dialysis and who not.  Public uproar followed, fanned by the newly formed National Association of Patients on Hemodialysis, most of whose members, be it noted, were white, educated, professional men.

In 1972, Congress responded to the pressure and decided to fund all treatment for end-stage renal disease (ESRD) through Section 2991 of the Social Security Act.  Dialysis, after all, was envisioned as long-term treatment for only a handful of appropriate patients, and in 1973 only 10,000 people received the treatment at a government cost of $229 million.  But things did not go as planned.  In 1990, the 10,000 had grown to 150,000 and their treatment cost the government $3 billion.  And in 2011, the 150,000 had grown to 400,000 people and drained the Social Security Fund of $20 billion.

What happened?  Medical progress happened.  Dialysis technology was not static; it was refined and became available to sicker, more debilitated patients who encompassed an ever-broadening socioeconomic swath of the population with ESRD.  Improved cardiac care, drawing on its own innovative technologies, enabled cardiac patients to live long enough to go into kidney failure and receive dialysis.  Ditto for diabetes, where improved long-term management extended the diabetic lifespan to the stage of kidney failure and dialysis.  The result:  Dialysis became mainstream and its costs  spiraled onward and upward.  A second booster engine propelled dialysis-related healthcare costs still higher, as ESRD patients now lived long enough to become cardiac patients and/or insulin-dependent diabetics, with the costs attendant to managing those chronic conditions.

With the shift to chronic disease, the historian Charles Rosenberg has observed, “we no longer die of old age but of a chronic disease that has been managed for years or decades and runs its course.”[6] To which I add a critical proviso:  Chronic disease rarely runs its course in glorious pathophysiological isolation.  All but inevitably, it pulls other chronic diseases into the running.  Newly emergent chronic disease is collateral damage attendant to chronic disease long-established and well-managed.  Chronicities cluster; discrete treatment technologies leach together; medication needs multiply.

This claim does not minimize the inordinate impact – physical, emotional, and financial – of a single disease.  Look at AIDS/HIV, a “single” entity that brings into its orbit all the derivative illnesses associated with “wasting disease.”  But the larger historical dynamic is at work even with AIDS.  If you live with the retrovirus, you are at much greater risk of contracting TB, since the very immune cells destroyed by the virus enable the body to fight the TB bacterium.  So we behold a resurgence of TB, especially in developing nations, because of HIV infection.[7]  And because AIDS/HIV is increasingly a chronic condition, we need to treat disproportionate numbers of HIV-infected patients for TB.  They have become AIDS/HIV patients and TB patients.  Worldwide, TB is the leading cause of death among persons with HIV infection.

Here in microcosm is one aspect of our health care crisis.  Viewed historically, it is a crisis of success that corresponds to a superabundance of long-term multi-disease management tools and ever-increasing clinical skill in devising and implementing complicated multidrug regimens.  We cannot escape the crisis brought on by these developments, nor should we want to.  The crisis, after all, is the financial result of a century and a half of life-extending medical progress.  We cannot go backwards.  How then do we go forward?  The key rests in the qualifier one aspect.  American health care is organismic; it is  a huge octopus with specialized tentacles that simultaneously sustain and toxify different levels of the system.  To remediate the financial crisis we must range across these levels in search of more radical systemic solutions.


[1]C. Feudtner, Bittersweet: Diabetes, Insulin, and the Transformation of Illness (Chapel Hill: University of North Carolina Press, 2003), p. 36.

[2] My remarks on the development and impact of the Iron Lung and homodialysis, respectively, lean on D. J. Rothman, Beginnings Count: The Technological Imperative in American Health Care (NY: Oxford University Press, 1997). For an unsettling account of the historical circumstances and market forces that have undermined the promise of dialysis in America, see Robin Fields, “’God help you. You’re on dialysis’,” The Atlantic, 306:82-92, December, 2010. The article is online at   http://www.theatlantic.com/magazine/archive/2010/12/-8220-god-help-you-you-39-re-on-dialysis-8221/8308/.

[3] L. M. Dunphy, “’The Steel Cocoon’: Tales of the Nurses and Patients of the Iron Lung, 1929-1955,” Nursing History Review, 9:3-33, 2001.

[4] D. J. Wilson, “Braces, Wheelchairs, and Iron Lungs: The Paralyzed Body and the Machinery of Rehabilitation in the Polio Epidemics,” Journal of Medical Humanities, 26:173-190, 2005.

[5] See S. E. Mawdsley, “’Dancing on Eggs’: Charles H. Bynum, Racial Politics, and the National Foundation for Infantile Paralysis, 1938-1954,” Bull. Hist. Med., 84:217-247, 2010.

[6] C. Rosenberg, “The Art of Medicine: Managed Fear,” Lancet, 373:802-803, 2009.  Quoted at p. 803.

[7] F. Ryan, The Forgotten Plague: How the Battle Against Tuberculosis was Won and Lost  (Boston:  Little, Brown, 1992), pp. 395-398, 401, 417.

Copyright © 2012 by Paul E. Stepansky.  All rights reserved.