PHARMA HISTORY III

Drug disasters - DES

Tragically, most modern drug disasters have been associated with therapies delivered to pregnant women. In 1938, the British scientist, Edward Dodds (1899-1973), discovered a synthetic oestrogen hormone called diethylstilboestrol (DES). It was prescribed to pregnant women believed to be at risk of miscarriages. An estimated 5-10 million women in Europe and America took the drug between 1938-1971 when it was banned for use in pregnancy because of an association with a rare cancer of the vagina and cervix in their daughters. The risks of `DES daughters' developing this cancer were estimated to be 1 in 10,000. However, both DES daughters and sons were found to have a higher than average incidence of other abnormalities of the reproductive system.

Drug disasters - thalidomide

Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.

Drug disasters - thalidomide

Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.

By 2000, thalidomide was available in Britain only on a `named patient' basis.

Thalidomide - the aftermath

The thalidomide tragedy resulted in more stringent testing of drugs, and extensive clinical trials prior to the launch of a new product. Typically, a prescribed only medication (POM) requires evaluation for toxicity and effects on fertility. If the drug is to administered to women of child-bearing age, it must also be tested for potential foetal malformation (teratogenicity). All toxicity studies are carried out in animals. Toxicity tests are followed by Phase I studies, usually on healthy human volunteers, sometimes patients. These determine common side effects. Phase II and III studies investigate efficacy on 1000-2000 patients, and also look for adverse reactions. These are early clinical trials. The time span between the beginning of Phase I and the end of Phase III may be as long as 5 years.

The Medicines Control Agency (MCA) in Britain, and the Food and Drug Administration (FDA) in the US, act both as regulatory bodies and licensing authorities. In Britain, by the 1980s, all newly licensed drugs were identified with a black triangle. In addition, the `Yellow Card' system was introduced in 1964 so that doctors could report adverse reactions to new and established drugs directly to the Committee on Safety of Medicines. By 1989, the annual number of reports was about 20,000. In the United Kingdom and Europe, only medically confirmed suspected adverse reactions were reported to regulatory authorities. In the United States, reports by patients, nurses and pharmacists were given similar consideration to those made by doctors. Pharmaceutical companies also began to establish drug surveillance units which monitored reports of adverse reactions to their products on a worldwide basis.

National Poisons Information Service

The doctors of ancient Greece believed that all substances were potentially poisonous. The only thing which distinguished a poison from a remedy was the dosage. By the 19th century, this was an accepted fact and the investigation of poisons became known as toxicology. During the 1960s, the Department of Health in Britain, established a Poisons Information Service. This gave doctors 24-hour telephone access to expert advice on the diagnosis, treatment, and management of patients who may have been poisoned. The term `poison' covered a wide range of substances including drugs, plants, household products, and snake venom. By 2000, there were 6 regional poisons centres and one national centre for complex cases. As well as answering telephone queries, these units also supported toxicology laboratories which analysed samples from cases of suspected poisoning.

This work was important not only to the medical profession but also to police, industry, and the legal profession. The American Association of Poison Control Centers offers a similar service in the United States. The European Association of Poisons Centres and Clinical Toxicologists was established in 1964 to advance knowledge and understanding of the diagnosis and treatment of all forms of poisoning.

Pharmacy comes of age

The American doctor of the late 19th century was said to get by with calomel (a mercury compound used as a purgative), opium, quinine, buchu (a diuretic), ipecac (an emetic), and Dover's powder (an opium preparation). The therapeutic range of the British general practitioner was little different. The therapeutic revolution of the second half of the 20th century changed everything. Restrictive legislation on medicines sold over the counter was first passed in Britain in 1860 when prescription-only drugs came into being. In 1948, when the National Health Service was established, a general practitioner's average prescription costs were 72 pence per patient a year. Fifty years later, this had risen to œ90 per patient a year. In 1988, there were 106 pharmaceutical companies manufacturing prescribed-only medications, and 147 supplying over-the-counter products. Gone were the days when aspirin simply meant `acetylsalicylic acid'.

A British general practitioner in 1991 could choose between 15 different brands of aspirin, 30 brands of paracetamol, 29 brands of contraceptive pill, 29 brands of insulin, and 21 brands of penicillin antibiotics. The manufacture of `me-too' drugs became a phenomenon of the late 20th century as pharmaceutical companies played around with molecules in order to come up with a variation on a theme. If the end result turned out to be a `me-too', the packaging could make or break the product. The retail pharmacist became the local drugs `expert' and acted as an important intermediary between doctor and patient. In July 2000, the British government published its NHS Plan which included new roles for community pharmacists.

Addiction - how it began

The concept of `addiction' or `substance abuse' as a social evil was largely a 20th century creation although the `medicalisation' of intoxication began in the 18th century. Throughout history, psychoactive substances have played a major role in ritual, recreation, medical treatment, and pain relief. The ancient Egyptians used opium to stop children crying and send them to sleep. The Roman emperor, *Marcus Aurelius (CE 121-180) began each day with a portion dissolved in wine, prescribed by his physician, *Galen (CE 129-c. 200/216). Both the Greeks and the Romans enjoyed wine and beer, often to excess. Hemp was used in ancient India, Mesopotamia, Egypt, western Europe, and Britain. Coca leaves were chewed by Andean Indians from the third century BCE. Its use was a court privilege as well as a religious observance.

It was also an important source of revenue during Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cacao (cocoa) was used as a stimulant by the *Aztecs of Mexico, coffee was discovered in Arabia sometime after the 10th century, and tea belonged to China. Tobacco had long been known to *American Indians when Europeans began colonisation of the New World in the 16th century. Spain and Portugal became the first countries to introduce tobacco smoking (initially, for medicinal purposes) but most other countries followed by about 1600. At first, the Spanish *Inquisition considered tobacco smoking to be a mark of possession since only Satan could confer upon humans the power to exhale smoke through the mouth.

Addiction - creating the alcoholic

Drunkenness commanded the attention of religious authorities throughout the Middle Ages but was scarcely mentioned in medical writing except to warn against the use of drink to relieve melancholia. In 1684, the English physician, Thomas Willis (1621-1675), suggested that habitual drunkenness resulted in `stupidity' but physicians frequently prescribed wine, beer, and spirits as medicines. The 18th century was particularly renowned for its excesses, and habitual drunkenness came to be seen as a disease. The American physician, Benjamin Rush (1745-1813), concocted a rum and tartar emetic which he used as aversion therapy for men who preferred the tavern to domestic society. Doctors began to associate drink with insanity. The term `delirium tremens' (DTs) was first used in 1813 by English physician, Thomas Sutton.

An episode of DTs was sufficient reason for admission to a lunatic asylum and there was a common belief that habitual drunkenness resulted in dementia. A study of 668 men admitted to a London lunatic asylum between 1880-1920 revealed that `drink' was considered a cause of insanity in 22% of cases. There were no admissions associated with opium or other drugs. Drunkenness officially achieved disease status in 1852 when Swedish physician, Magnus Huss (1807-1890) introduced the term ` chronic alcoholism'. In England, Charles Mercier and Henry Maudsley (1835-1918) classified alcoholic insanity as a distinct disease. Alcoholism was also seen as a social evil and there began a movement in Britain and America to establish `inebriate reformatories' for habitual drunkards. In England, the Reverend Harold Nelson Burden (1860-1930) and his wife, Kate (c.1856-1919) established 617 homes by 1907.

Addiction - opium

Opium was the most important and powerful drug in the doctor's bag. The English physician, Thomas Sydenham (1624-1689), formulated 'Sydenham's Laudanum' which was opium diluted in Malaga wine with saffron, cinnamon, and cloves. Both he and the Dutch physician, Hermann Boerhaave (1668-1738) maintained that opium was a gift from God to alleviate the sufferings of man. Physicians were divided on the relationship between opiates and insanity. The English physician, Thomas Willis (1621-1675) believed that opium dulled the mind although he recommended it as a remedy against insanity. Between 1814-1818, opium accounted for one third of all export trade from Bengal in British India to China and the East Indies. It was known to be habit-forming but until the 19th century, there was no culture of 'drug abuse' to heap shame or secrecy on users.

Opium was used regularly by monarchs, writers, poets, and artists, not only as a 'recreational' drug but also to ease pain or relieve the symptoms of chronic disease. Thus, the English poet, John Keats (1795-1821), used it to treat his tuberculosis, and Elizabeth Barrett Browning (1806-1861) swallowed laudanum (opium dissolved in spirits) to suppress the agony of an injured spine. In England, at mid-19th century, it could be bought from any chemist, druggist, or grocer for one penny an ounce. A palatable opium mixture, given to children, was Godfrey's cordial which contained opium, sweet treacle, water and spices. During the 1860s, a Manchester druggist was selling half a gallon a week. Other brands were called Steedman's Powder and Atkinson's Royal Infants Preservative.

Addiction - creating addicts

In 1898, the German pharmaceutical company, Bayer, launched a `safer' derivative of morphine which they named heroin because of its stimulant properties. Heroin was advertised as a `cure' for morphine and opium addiction. When Bayer introduced Aspirin in 1899, it was sold in a double package with heroin. Between 1911-1914, England exported 40 tons of morphine, and Germany 10 tons of heroin, to China and the Far East in an attempt to rehabilitate the estimated 13.5 million Chinese (27% of all adult males) who were addicted to opium, largely through British exports from India. From the mid-20th century, a synthetic drug called methadone which resembled morphine, was being used to rehabilitate heroin addicts. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an antidepressant.

In 1876, Sir Clifford Allbutt (1836-1925), later Regius Professor of Medicine at Cambridge University, took coca leaves on a walking tour of the Alps. The Austrian neurologist, Sigmund Freud (1856-1939), began a research project on cocaine which included self-experimentation. In the same year, the American surgeon, William Stewart Halsted (1852-1922), began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. He became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency. By the 1890s, there were more than 100 beverages containing coca extracts or pure cocaine. In 1885, JS Pemberton, an American druggist, registered `Coca-Cola', which contained cocaine, cola nuts (a source of caffeine), and citrus juices.

Addiction - controlling drugs

The identification, by chemical analysis, of the active principle in psychoactive substances, often heightened their appeal. Peyote, an hallucinogenic plant used for centuries in Mexico, achieved new popularity after 1888 when its active principle, mescaline, was isolated. Afficionados were Irish poet, William Butler Yeats (1865-1939), American dramatist, Eugene O'Neill (1888-1953), and English physician, Henry Havelock Ellis (1859-1939). The cause of addiction to drugs and alcohol was related to weakness of character rather than substance availability so there was little incentive to regulate supply. In any case, about 65% of morphine addicts at the end of the 19th century were health professionals and their relatives who had access to any number of psychoactive drugs.

These included chloroform and ether, first used as anaesthetics during the 1840s but soon acquiring a following amongst the poor of Europe because they were cheaper than alcohol. The French writer, Guy de Maupassant (1850-1893) was an ether addict. By the beginning of the 20th century, doctors, pharmacists, politicians, and reformers in the United States, Britain, and Europe, were suggesting that drugs could be destructive unless dispensed by qualified health professionals. Doctors and psychiatrists defined an `addict type' and addiction was defined as a disease. In the United States, the Pure Food and Drug Act (1906) created the Food and Drug Administration (FDA) to regulate manufacture and sale of medicines. The Act also ended the availability of over-the-counter narcotics.

Addiction - controlling people

In Britain, the Dangerous Drugs Act (1920) was an attempt to control the supply of cocaine and opiates by making them available only through a doctor's prescription. Gradually, other drugs such as the barbiturates, developed during the early 20th century, came under the `controlled' list. Cannabis was made illegal in 1928. The Misuse of Drugs Act (1971) classified controlled drugs into 3 classes with the opioids in Class A, and benzodiazepines in Class C. Cannabis and codeine were slotted into Class B. In 1973, doctors were required to report suspected drug addicts to the Chief Medical Officer at the Home Office. Medical practitioners required a special licence issued by the Home Secretary to prescribe certain drugs to addicts. The Misuse of Drugs Regulations (1985) created 5 schedules of drugs, each of which had a set of regulations governing (amongst other things) supply, possession, and prescribing.

People using drugs listed in Schedules 2 and 3 were not allowed to travel abroad with more than 15 days supply without a licence. In the United States, the term `drug addiction' appeared in the 1934 American Psychiatric Association's diagnostic handbook, and 3 years later, the Marijuana Tax Act, illegalised cannabis. In 1971, President Richard Nixon (1913-1994) declared drug abuse to be `Public Enemy No 1'. His `war on drugs' campaign led to the arrest, during the 1980s, of 300,000 Americans a year on cannabis charges. The campaign against smoking was not so vociferous, and legislation was slow to be enacted. In 1950, epidemiologists, Richard Doll (b. 1912) and Austin Bradford Hill (1897-1991) published a report in the British Medical Journal entitled `Smoking and carcinoma of the lung'. Six years later, they showed that lung cancer deaths among doctors who smoked 25 or more cigarettes a day were 20 times higher than non-smokers.