Ten Drugs, Thomas Hager, 2019 - If you have been stumped by the pharma sector and need a place to start, there’s nothing better than this book. It covers the history of medicine from opium, its cultural, historic and economic impact - About how opium derivatives like morphine, heroin came about - how it led to first semi-synthetic drugs. The golden age of Pharma between 1930s and 1960s and how most modern Big Pharma started off as dye chem companies and birth of Organic chemistry. The birth of vaccines and antibiotics. An in-depth look at Monoclonal antibodies and the birth of Biotech. A skeptical look at statins and drugs in general. A historic perspective on the birth of the FDA and so on.
My notes -
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Avg American takes 2 pills/day over his lifetime - or around 50k pills on avg. $34b on OTC drugs and $270b on prescription drugs. 5% of world population contributes 50% of overall revenue
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People in the old days didn’t worry about cancer or heart disease because they barely lived long enough to get them
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Seige cycle - stage 1 - astonishing new drugs with widespread enthusiasm. stage 2 - news articles come up on dangers of wonder drug leading to alarm stage 3 - a more balanced view emerges
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Its a wonder that human beings discovered any natural drugs at all - considering only 5% of all plant species is edible to us - some famous remedies - mandrake root (stomach problems, cough, sleep issues), black hellebore (strong laxative), henbane (painkiller and sedative) and belladonna (sleep and eye problems), cannabis (numbing pain) and opium (pain reduction & euphoria)
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Sumerians (3400 BC) referred to opium poppy as “joy plant”. It traveled then on to Assyrians to Babylonians to Egyptians and then on to Europe. Alexander carried it with them in their conquests of Asia to India
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Al-chemie - filtration, distillation, sublimation and crystallisation was the Egyptian science of making medicine
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Opium has been part of all miracle remedies in the last several centuries - from Paracelsus’ laudanum in 1530 (Swiss-German), Sydenham’s laudanum in Britain (standard measure, to prevent overdosing), Dover’s powder, Quaker’s drops and Dr. Bates’ Pacific pills in 1700s, - it was used to treat everything from the snake bite to plague
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Opium was cheaper than gin and more widely available than tobacco in Britain in the 1900s. Doctors acted as sales agents for it. To feed the growing need, the East India Company started growing it in India and marketing it everywhere
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Chinese elite developed the tobacco habit - something they acquired in exchange to their porcelain and silk (British had nothing else of value to exchange). It became a strong addiction that it had to be banned by the emperor in 1632 and all addicts executed
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In the 1800s, the British discovered Chinese tea which built a large craze in England (just like tobacco in China). To fuel its purchase, they needed something other than tin, lead, cotton fabrics, watches, dried fish (which the emperor wasn’t impressed by) - and just as with tobacco, found opium as a good exchange since silver wasn’t abundant (this trade deficit thing has been around for centuries looks like)
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By 1832, 1/6th of British GNP was opium. Chinese govt. wanted to put a stop to it and Opium wars ensued. By 1840, large part of Chinese army was addicted to opium and were no match to British guns - the emperor ceded Hong Kong to the British along with access to ports and better trading terms. HK became world’s opium center. By 1888, 70% of adult males in China were addicted
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Opium spread from China to America with immigrants and gave birth to America’s drug subculture. The Chinese communist govt. outlawed cultivation of opium in 1950 and plowed the fields over and by 1960 it was wiped out of China
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Most opium addictions addictions were triggered by doctors who prescribed it for illness or injury
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Opium wasn’t one thing but many complex cocktail of alkaloids. The most potent of these was isolated and was found to be 10x more potent than opium - this gave birth to morphine
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Merck, the German pharma firm built its empire and fortune on the bedrock of morphine. This also fuelled what we today know as “Organic chemistry” (study of the molecules of life).
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The race in org. chem. led to isolating other alkaloids from opium - leading to codeine (used in cough syrups), thebaine, noscapine, papaverine, narcotine, narceine etc. More alkaloids were later found in other plants - cocaine, nicotine, caffeine, strychnine, quinine, atropine from coca, tobacco, coffee, nux vomica and cinchona bark
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Treatment for varicose veins led to discovery of syringe - made for delivery of morphine to the veins. American Civil War used morphine shot intravenously for treatment of the wounded. Per capita usage of opiates tripled post war due to addiction leading to America’s first opiate crisis
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Smallpox is the biggest infectious disease by mortality - even more than the black plague. People who got it once never got it again and could nurse the afflicted (led to vaccines). Today there hasn’t been a case since 1970s.
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Smallpox vaccine was first discovered by Turkish doctors and carried over to England by Lady Mary who had her son inoculated with powdered scab and pus
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Lady Mary’s account wasn’t accepted by British doctors and to establish it, orphans were used for the first “clinical trials” (tests on prisoners and orphans were considered acceptable in those days). This reduced mortality rate from 1 in 4 to 1 in 50 (still that 1 in 50 was enough for birth of what we today know as ‘antivaccers”)
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British docs were against smallpox vaccine (of Turkish origin) as it was bad for their business of laxatives, bloodletting and special diets (today’s Ayurveda unfortunately is right here)
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Vaccination comes from vacca - latin for “cow” after vaccination for cowpox. Jenner takes credit for this, though smallpox vaccine existed prior from Turkey and even cowpox vaccine was discovered by a farmer - but Jenner did the experiments and convinced people - in science credit goes to the man who convinces than to the man who discovers
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Vaccines recover upkeep every few years. Smallpox having been eradicated we dont get inoculated anymore (stopped in ‘71). A lab leak of the virus made news in 1978 - the outbreak was controlled and all stocks of the virus around the world were destroyed
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Today vaccines are available for flu, herpes, shingles and several other conditions which are left to the patient to decide. Some like diphtheria and tetanus are mandated due to seriousness of illness
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The organic chemicals in living tissue were thought to possess a vital spark (around Mary Shelley’s Frankenstein - 1800s). It took the synthesis of Urea by Wohler in the lab to disprove it in 1832. Wohler’s friend Liebig figured plants required Nitrogen, Phosphorous and Potassium and in general how fertilisers work (father of Ag chem)
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Liebig (Lie big?) realised there’s no vital spark and it was all just chemical processes. He started making lot of interesting new chemicals - one of them chloral hydrate did not exist in any form in the world until he synthesised it. Its fumes could knock a person unconscious - we know it today as chloroform. It found it use in 1869 as sleeping aid and for soothing patients before surgery.
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Chloral (Chloroform) was used until 1905 in mental hospitals until better barbiturates were synthesised followed by early forms of today’s tranquillisers and antipsychotics. Chloral kicked off the trend of tinkering with molecules and synthesising drugs as medicines that could match of exceed natural drugs which gave birth to today’s Big Pharma
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Bayer company and several others converted coal tar into valuable synthetic dyes - everybody made lots of money with these colors used in fabrics (1890s). The method was similar to morphine from opium - separating the compounds and experimenting was applied to other natural materials to find their essence and to alter it
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Willow bark was used to treat fevers - Bayer managed to separate the active compound in it and attached an acetyl group, the new compound was even better at treating fevers - marketed as Bayer’s Aspirin. The same method of attaching acetyl group to Morphine yielded the wonder drug - Bayer’s Heroin (5x stronger than morphine - which was 10x stronger than opium). Heroin was marketed as less addictive to morphine addicts though it was way more addictive
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All the dye companies became pharma companies after Bayer’s success with Aspirin and Heroin (moving from dyes and chemicals to pharma seems to be natural progression - as with PI and Aarti)
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Opiates vs Opiods - opiates are derived from opium while opioids are synthesised (today’s painkillers like oxycontin).
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Tall claims and abuse of cocaine, cannabis, barbiturates, ether and nitrous oxide led to birth of the Food and Drug Act of 1906. Physicians had to register and keep a record of every transaction involving opium, morphine or cocaine. Physicians prescribed less - opium shipments plummeted from 42k tons in 1906 to 8k tons in 1934
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Unable to get a legal dose from doctors after the Harrison act, illegal drug trade started booming and exists to this day. After Bayer stopped marketing heroin, criminals made it from morphine or even opium and heroin being a powder was easier to transport
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Heroin is a semi-synthetic drug (acetyl attachment to morphine isolated from natural opium). Several other semi-synthetic opiates were synthesised to be less addictive than heroin - codeine tweaked to make hydrocodone (mixed with acetaminophen to make vicodin), hydromorphone (Dilaudid), oxycodone (Oxycontin) - all were addictive (Purdue pharma and Oxycontin - read ‘Empire of Pain’)
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Completely synthetic drugs were tried which had no roots to opium - like fentanyl and carfentanil - but without exception these were addictive (Search fentanyl on X)
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Medicine in 1930s did not have antibiotics - pneumonia, cholera, diphtheria, tuberculosis, meningitis and several others were rampant epidemics. Antibiotics alone have extended human life by 10 years
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Paul Ehrlich at Bayer was experimenting with dyes - methylene blue in particular and found that it attached to nerves but not muscles - he found similar dyes that attached only to bacteria - why not use it to attach poison and kill bacteria? Thus was born Salvarsan which was arsenic attached to a dye that attached to bacteria. It worked to stop syphilis but was toxic and worked only for Syphilis (first antibiotic)
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Drugs which were effective against bacteria ‘in vivo’ (in a petri dish) were metabolised and ineffective or outright toxic to humans. Azo dyes were marginally effective against bacteria - Bayer modified these to cure Strep infections. The drug suddenly stopped working in mice (resistance - but unknown at the time). Attaching a sulphur containing chain made the azo dye work again (sulfanilamide or sulfa drugs)
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Sulfa drugs worked at every dose level against strep infections, in every form without serious side effects but because these (the sulfa bit which did all the work) had already existed, Bayer could not patent it. So they did not release the drug as they could not make money off it - until Roosevelt’s son FDR Jr. had to be cured of a Strep infection
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Sulfa drugs were all over the place - for pneumonia, meningitis, gonorrhea - cheap to make, they were ubiquitous - by 1937 American drug firms were making 10 tons per week of sulfa drugs and nurses were walking around and handing them over like aspirin (leading to resistance)
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Elixir Sulfanilamide, sulfa-drug made for kids contaminated with diethyline glycol used in antifreeze (used to dissolve the sulfa) led to death of 73 kids and subsequently to passing of FDA Act that drugs be proved safe and all active ingredients be listed on labels (until then FDA was a small unit that oversaw false claims and misuse of drugs under Dept. of Agri)
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Penicillin was discovered around same time in 1928 when mold contaminated samples of bacteria had clear zones around mold where bacteria wouldn’t grow. It was more effective and broader (syphilis and anthrax) than sulfa drugs. Other molds then yielded streptomycin, neomycin, tetracycline and scores of others (one new pathway found leads to scores of other drugs is the story of pharma discovery)
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Antibiotics work against bacterial infections but not viruses (vaccines do) or parasites (malaria)
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Disease causing bacteria have a way of creating chemicals that can neutralise antibiotics or find ways to disguise themselves leading to antibiotic resistance - misuse of sulfa drugs was first known case of it. Having gone out of usage Sulfa drugs are today found to be effective as resistance to it has dropped
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Surgical shock - patient’s blood pressure would drop, breath grow shallow and heart would start racing while on the surgical table - due to fear and anxiety causing flood of adrenaline and other such molecules released in small quantities
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Artificial hibernation to induce ataraxia (tranquil state free from stress and anxiety while at same time strong and virtuous) was needed to prevent surgical shock - led to cocktail of chemicals (RP-4560) from atropine, procaine, curare, opiods and sleeping drugs, antihistamines (histamines were released in response to injury or allergy)
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RP-4560 found its way outside of usage for surgical shock to treatment of neurotics, psychotics, depressives, schizophrenics, catatonics - in general extensive usage in mental asylum (Betlehem hospital or Bedlam). It was a miracle drug for treatment of schizophrenia as it dissolved delirium and hallucinations. It did so many things that Rhone-Poulenc didn’t know how to market it - a nervous system modifier, narcotic, hypnotic, sedative, painkiller, anti-nausea, anaesthetic - all in one. It was marketed as Megaphen in France and Largactil in UK - chlorpromazine or CPZ to physicians (first Anti-psychotic leading to today’s Seroquel, Abilify and Zyprexa and birth of psychopharmacology)
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Rhone-Poulenc sold rights of CPZ to Smith, Kline & French (SKF) (first licensing deal?) to market it in US (Thorazine). SKF filed it for treatment of nausea and vomiting - once deemed safe, physicians began prescribing it for mental health (first off-label usage?). Patient who hadn’t spoken in 30 yrs after WW-I were cured by Thorazine (truly miracle drug). By 1955, Thorazine alone accounted for 1/3rd of SKF’s sales. Revenues 6x between 1953 and 1970 (
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5% of mental hospital budgets was CPZ. Patients in mental asylum patients started going down for first time in history. Freudian psychotherapists junked CPZ (like bricklayers shunning concrete or doctors shunning vaccine earlier in these notes). Giant asylums were torn down and turned to luxury hotels
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Miltown, for treating minor anxiety (martini in a pill) was a minor tranquilizer. Several others followed like Librium and Valium which were popular among celebrities (Rolling Stones’ song Mother’s Little Helper) in the 60s and 70s
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A cure for TB led to iproniazid. A strange side-effect of it was a cure for depression. Led to a class of antidepressant medicines like Prozac and others that became popular in the 80s and 90s
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Seroquel, Abilify and Zyprexa, the second gen anti-psychotics are similar to CPZ and affect neurotransmitters but have lower risk of tardive diskensia and are prescribed for PTSD in veterans, eating disorders in children, anxiety and agitation in elderly (and other such made up illnesses) and not just to severely ill mental patients there by expanding the market and making these bestselling class of drugs
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1930s to 1960s - the golden age of pharmaceutical development (WW-II fuelled medical research). From a dozen proven remedies, it had exploded to over 2000. Many of today’s Big Pharma giants prospered in this period. Antibiotics, antipsychotics, antihistamines, anticoagulants, anti-epilepsy drugs, anti-cancer drugs, hormones, diuretics, sedatives, painkillers - all bloomed in this period - mostly through serendipity
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Golden age expanded Sulfa drugs to 12 classes of antibiotics. In the last 50, only 2 new classes have been added and no money is going into it which is tragic given the growth of resistance to existing drugs (Expensive research and small payback from single use as compared to blockbuster drugs with repeat usage)
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The contraceptive pill (”The Pill”) was the outcome of Rockefeller foundation’s research on social control grounded in natural, medial and social sciences. Sex would turn from conception to recreation. Haberlandt, the grandfather of the Pill would commit suicide caught in crossfire of moral, ethical and political ideas of the time
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In 1930s, the structure of progesterone (led to the Pill), alongside other sex hormones like testosterone and estradiol were understood - all related with 5 or 6 sides carbon rings, part of family of steroids
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Comstockery (using anti-vice Comstock laws from 1873 used to suppress obscene literature) was used to ban sale of contraceptives in 30 states (selling a pill could land $1000 fine)
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Progesterone was yielded in small amounts from sacrificing lot of cows, sheep and other animals so was very expensive. It would get digested in the stomach and not enter bloodstream - so these hurdles had to be overcome. The first one was overcome from a yam found in mexico which yielded 6 pounds of progesterone from 10 tons of root. A synthetic form, called progestin was created to alter it to enter bloodstream when given orally
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Enovid (The Pill) was marketed as a control for menstruation and not for preventing pregnancy to overcome Comstock laws (by 1967, 13 million women had used it. Today over 100 million have)
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Enovid empowered women to choose the life they wanted once they could control pregnancy - female lawyers rose from 5% in 1970 to 30% in 2000. physicians from 9% to 30% and so on. Age of first marriage for women went up (accidental pregnancies prevented)
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Pfizer research stumbled upon a drug to prevent erectile dysfunction when they were working a drug to prevent angina (reduced blood flow from heart). The drug that could open blood vessels to make blood flow more easily led to Viagra (Vigor + Niagara - approved in 1998) - $2b in sales per year as 30k prescriptions were written per day in 100 countries (peaked in 2012 - patent expired in 2020 and generics today have eroded value to $1b or so).
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Quality of life drugs is where the big money is as usage is repetitive - since they are taken indefinitely and profit will roll in for decades. The definition of Erectile Dysfunction became wider and were prescribed to older men as well (why Ozempic is so wonderful as a product and is so similar to Viagra on many aspects - socially, culturally, economically. Pushed me to look at Shaily that makes pens used to delivery GLP-1 drugs)
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Viagra was covered in insurance but birth control pills were not (strange)
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Viagra has serious pricing power - launched at $7 per pill in the 2000s to $50 today (generic sildenafil available for $2 as it fell off patent cliff)
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Drug discovery today takes 2 decades of research and half a billion dollars of investment (the push for to invest in Wockhardt with 2 decade research almost completely written off just as it was coming to fruition)
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Best way to make a long-lasting blockbuster is to make sure it doesn’t cure anything or merely treats symptoms so that it can be taken endlessly (Viagra, Ozempic, Lipitor, Celebrex)
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Merepethedine (Demerol) was discovered by accident at Hoechst when they were looking for a drug to cure muscle spasms. It not only killed pain but it makes its users feel energised. Due to abuse potential, it doesn’t get prescribed anymore
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Amidon (methadone) was made by Hoechst after Pethidine while looking for something less addictive. It wasnt much of a painkiller and had unpleasant effects and could be taken orally so ended up being used as treatment for heroin addicts (Methodone clinics)
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Paul Janssen while stripping the essence of opioids found the piperidine ring (the enchanted ring) was present in all of these compounds. He wanted to synthesize something more powerful than morphine that was fat-soluble (to get across cell membranes) - this led to pheoperidine (used today as general anesthetic - its 25x more powerful than morphine)
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Janssen and team synthesised a molecule 100x powerful than morphine (Fentanyl) - currently the most powerful opioid on the planet
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Our brain has receptors for opioids from poppy seeds not by accident - but because endorphins which are natural opioids produced by the body use those receptors. Receptors are turned on by agonists - morphine, heroin, oxycodone and fentanyl are agonists (GLP-1 agonists in Ozempic and Wegovy makes better sense now)
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Just like agonists which attach to receptors, there are also antagonists which attach and block receptors without switching them on - Naloxone (Narcan) is used to treat drug addicts by muscling off opioids from the receptors (leading to a trip crash for the addict)
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America consumes 15x as many opiates as Austria, Germany and Italy combined and only 20% are taken for medical reasons (80% of world’s opioids are consumed by US). Its a $10b per year business.
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Drug companies working on discovery work with physicians and scientists can influence published papers and ensure information gets into the right journals (while I suspected this, turns out this practice is quite rampant)
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Oxycontin addicts take to heroin as its cheaper on the street at $10 as compared to Oxycontin’s $30-$100 levels. Unwillingness to bear pain and bias towards finding a pill for every problem makes America’s opioid epidemic a peculiar American problem
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Statins are amazing drugs that lower the amount of cholesterol. Most of them are now off-patent and cheap. But the way they are prescribed for everyone above 55 is perhaps overdone
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Cholesterol is absolutely essential for the body and liver produces 3/4th of it (rest comes from food) what it needs to make Vitamin-D to bile acids
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A drug made by a blue-green mold found in rice (similar to Penicillium) blocked body’s ability to make its own cholesterol by shutting down an enzyme (HMG-CoA reductase). Not only it reduced production, it also increased cholesterol uptake by cells - a one-two punch - leading to the first statins
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High-fat diets lead to high serum cholesterol levels (Total measure of LDL or bad chol. and HDL or good cholesterol) which increase risk of heart disease was the assumption. But the actual relation between dietary fat, serum cholesterol and heart disease is more complex and subtle. People with low cholesterol sometimes get heart disease and high cholesterol sometimes never do - but it is a risk factor - one among many (so high chol. causing heart disease isn’t like a germ causing an infection - a single cause)
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One culprit per disease mindset comes from wanting to find the culprit so we can find a medicine to stop it
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Merck got the first statin (lovastatin) to the market (Mevacor). Then simvastatin (Zocor), pravastatin (Pravachol), atorvastatin (Lipitor), fluvastatin (Lescol) and rosuvastation (Crestor) came into the market
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Worries about cholesterol fed the market for statins and research on statins fed the worries about cholesterol. (Statins help high-risk but moderate-risk cases are oversold on it)
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Interest in a medical condition seems to develop in tandem with the development of its drug. The drug transforms a bodily state into a treatment category and then a disease category (Like how ADHD transformed from a behavioural problem in schools to a treatable disease)
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Definition of “high cholesterol” has constantly kept moving downward (To sell statins). Lipitor alone has sold $120b between ‘96 and ‘11.
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Dubious research from 80s and 90s blamed dietary fats which pushed people towards grains and sugars that led to diabetes which is a risk factor for heart disease
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Reducing LDL below 90 made no change to risk. Below 70 levels, it in fact increased the risk. Smoking, family history, diet and exercise played just as large a role as cholesterol levels in heart disease. Drug companies talk about relative risk which inflates numbers like 33% but absolute risk is reduced only by 1% in taking statins (classic statistical fudging that ignores conditional probability). Statins are in stage 2 of Seige cycle (critical review)
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Monoclonal antibodies - mono for one and clonal for copies - so copies of a single antibody (WBC). A large and growing family of precise and safe drugs. They all end with -mab. Infliximab (Remicade) for autoimmune diseases, bevacizumab (Avastin) for cancer treatment, trastuzumab (Herceptin) for breast cancer, tiruzimab (Rituxan) for cancer and adalimumab (Humira) for inflammation (top blockbuster drug) - all are clones of white blood cells
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Antibody-producing white blood cells (B cells) when switched on can pump out millions of antibody molecules per minute. There are billions of B cells so it can potentially cater to billion different types of antibodies. These antibodies are essentially proteins - big and complicated molecules far bigger than traditional drugs produced in the golden age of pharma, which are now called “small molecules”
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The tailoring bit of the antibody comes from using mice myeloma cells and normal cells that produce antibody for a specific target in the lab (hybridoma). These hybridoma cells could then be cloned making the same pure antibody. Unlike a vaccine that takes time to produce response, monoclonal antibodies work instantaneously (Milstein and Kohler didn’t patent it and gave away the process for free, kicking off a monoclonal gold rush and the biotech industry)
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First MAB was approved in 1984 was 2/3rd human and 1/3rd mouse and sometimes had immune reactions to the mice part - today monoclonals are entirely human
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Monoclonals are expensive to make and they can’t get inside of cells and they dont get across the blood-brain barrier. Was the fastest growing segment by 2006 and there were 30 MABs in the market in 2008 ($140b by 2024 - Humira alone does $21b today. A year’s treatment with Humira could cost $50k - A wall of patents kept its revenues secure until ‘23. Today there are biosimilars (generic version of biologicals like monoclonal antibodies) available for Humira)
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New trends in pharma - Shift from chemicals (small molecules) to biologicals - shift away from chemical drug discovery of the golden age to precise targeted antibodies - lab designed enzymes - digital drugs with sensors in drugs that can track consumption - drug discovery at the level of huge proteins with computers, a move from in vivo to in silico - crowdsourced drug development - personalised medicine - new adjuvants to existing vaccines (like Wockhardt’s cefepime-zidebactam) - repurposing, like in the case of Abilify which has secured 24 new approved uses
I loved this book as much, if not more than the Attention merchants, because both of them go back a 100 years or more while trying to cover a sector and in the process we learn about how things came about the way they are today, the people and processes that were involved. This adds a depth that cannot be gleaned by reading articles or any other shallow source. Well-researched books like this on an industry go a long way in getting a great understanding on the lay of the land. 11/10
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