PHARMA HISTORY II

Physic gardens - gathering world medicines

*Aristotle (384-322 BCE), the Greek natural philosopher and tutor of *Alexander the Great (reigned 336-323 BCE), created a botanic garden which was tended by Theophrastus of Eresos (370-285 BCE). Theophrastus's botanical lectures in the Lyceum included descriptions of the plants seen by his pupil's armies as they travelled through India and the Persian Gulf. The spread of Christianity throughout Europe from the beginning of the 4th century resulted in a proliferation of monasteries, which became the centres of organised learning. Monks often tended the sick and grew medicinal plants in dedicated physic gardens. Some of these plants were imported, and Benedictine monks were largely responsible for bringing Roman horticultural techniques from Italy to the rest of Europe.

The first British and European universities grew out of the monastic schools. These initially instructed scholars for vocations in the Church, but by the 14th century they were training students for the professions of law and medicine. In the medical faculties, it was important to teach students how to distinguish the many plants used in remedies and the idea arose of growing them side by side in a systematic way. The discovery of America in the late 15th century provided a further impulse towards the creation of large, formal physic gardens whose purpose was to gather plants from all over the world.

Physic gardens - the recreation of Eden

In 1543, a physic garden was established at the University of Pisa, Italy, under the guidance of Luca Ghini (1490-1556), Professor of Botany at Bologna. He had already created his own private garden at Bologna and invented the `herbarium', portable bound volumes of dried, pressed, and labelled plant specimens which botanists carried on field trips. Two other Italian universities, Florence and Padua, founded physic gardens in 1545. Plants were labelled and arranged in formal beds. At Padua, an attempt was made to divide the garden into 4 sections representing the flora of Europe, Africa, America, and Asia. Other gardens emulated this idea. The garden at Padua also contained statues of Aesculapius, *Hippocrates, *Galen, and Mithridates. In 1587, a physic garden was established at Leiden University in the Netherlands.

This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. By the end of the 16th century, there were physic gardens at the important medical universities of Heidelberg in Germany and Montpellier in France. Montpellier cultivated an outstanding collection of alpine plants. The first physic garden in England was established by the Earl of Danby ( 1573-1649) at Oxford in 1621. His wish was to improve the teaching of medicine at the university. Its first curator, Jacob Bobart (1600-1680), was appointed in 1642. He encouraged botanists travelling to remote parts of the world to contribute to the garden's collection.
The Chelsea Physic Garden

The Chelsea Physic Garden, a 3.5 acre site originally on the banks of the River Thames, was founded in 1673 by the Worshipful Society of Apothecaries of London for the botanical instruction of their members and apprentices. Chelsea was then a rural area so it was important for the apothecaries to select a riverside site since students could visit the garden by boat. The first exchange visits began in 1683 when Paul Hermann, Professor of Botany at Leiden University in Holland, visited Chelsea to exchange plants and seeds with John Watts, the Gardener. At that time, Chelsea had an underfloor-heated glasshouse, probably the first in the world. In 1722, the physician, Sir Hans Sloane (1660-1753), who had studied at the garden and subsequently purchased the Manor of Chelsea, leased the Physic Garden to the Society of Apothecaries for œ5 a year in perpetuity on condition that it always be maintained as a physic garden.

The terms of the lease required that 50 plant specimens a year be donated to the Royal Society (of which Sloane was president) until 2000 had been received. By 1796, the total had reached 3750. In 1736, the great Swedish botanist, Carl *Linnaeus (1707-1778) visited Chelsea during the tenure of Philip Miller, Gardener from 1722-1771. Miller was eventually persuaded to adopt Linnaeus' binomial nomenclature in the 8th edition of his Gardeners' dictionary, one of the first encyclopaedias of horticulture. During these years, Chelsea sent *cotton seeds to Georgia, the newly founded English colony in America where cotton became the staple crop. In return, Miller received seeds of new species. Sir Joseph *Banks (1743-1820, who also helped develop the Royal Botanic Gardens at Kew), donated seeds from his travels around the world with Captain James Cook (1728-1729).
The rise of chemical medicines

The 18th century was marked by the growing respectability of iatrochemistry (chemistry applied to medicine), which had gradually become popular after the death of Paracelsus (1493-1541) who had considered disease to be an imbalance in the human body of the chemical elements, mercury, sulphur, and salt. The work of British chemist, Robert *Boyle (1627-1691) in the 17th century put the preparation of chemical compounds on a more scientific basis. Research into how the body worked (physiology) helped provide a foundation for the science of drug action. Swiss physician, Albrecht von Haller (1708-1777) studied the effects of alcohol, silver nitrate, antimony chloride, and other chemicals, on animal tissues which helped formulate his theory of muscle excitability. He contributed a preface to the Pharmacopoeia Helvetica (1771).

Swedish pharmacist, Carl Wilhelm *Scheele (1742-1786), and French chemist, Antoine Laurent *Lavoisier (1743-1794), developed chemical methods of purifying the active principles of crude drugs by crystallisation. Experiments on animals by the French investigators, Xavier Bichat (1771-1802) and François Magendie (1783-1855), enabled the effects of potent drugs to be measured. Popular mineral-based drugs included mercury which was the favoured treatment for syphilis, and calomel, a mercury compound used as a purgative. Antimony was favoured as a febrifuge (for reducing fevers). Patented by Dr Robert James as `Dr James's Fever Powders', it was given unconventional publicity in the children's story, Goody Two-Shoes, published by James' agent, John Newbery (1713-1767). The heroine's father died because he was seized with a fever in a locality where `Dr James's Fever Powders' were not available.

Quackery was entrepreneurial medicine writ large and its practitioners medically unqualified. Some were itinerant traders, doing the rounds of fairs, circuses, and markets. Others, such as the Scottish empiric, James Graham (1745-1794), who had worked the American circuits, were `big names' with ostentatious premises. Graham's Temple of Health opened in Pall Mall, London, in 1780. The entrance fee was 6 guineas, a phenomenal sum. Clients were lectured on sexual rejuvenation, during which a scantily clad `Hebe Vestina, Rosy Goddess of Health and Hymen' would rise through a trap door to distribute bottles of `aethereal balm'. Hebe Vestina, was supposedly played by Emma Lyon, who became more famous as Lady *Hamilton (1761-1815), the mistress of Lord *Nelson (1758-1805).

A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. Another wealthy empiric was Joanna Stephens (d. 1774) whose successful remedy for dissolving bladder stones (very common at the time) was purchased by Parliament for œ5000. The Reverend Stephen *Hales (1677-1761), awarded the Royal Society's *Copley Medal in 1739 for his analysis of bladder stones, investigated her secret formula. Of all the ingredients, he believed that it was the lye used in soap making, and lime from eggshells which dissolved the stones.

Quack medicines

Quack medicines were often claimed to cure conditions untreatable by doctors including cancer, the pox (syphilis), tuberculosis, ageing, or impotence. Nevertheless, some empirical nostrums were as effective as any prescribed by doctors. Husson's Eau médicinale, a widely advertised gout remedy, contained colchicum, an alkaloid of the Meadow saffron (Colchicum autumnale), particularly effective for pain and inflammation in acute gout. Quack cures generally came in fancy packaging, accompanied by flashy advertising, mail order, free gifts, special offers, endorsement by famous names, and money-back-guarantees. They were an important part of the national economy, particularly in Britain where empirics from the Continent could purchase royal privileges to practise, and all quack medicines were subject to stamp duty.

Britain's philosophy of free trade viewed quackery with lenience although it did not have the same freedom in other European countries, particularly France which attempted to limit empirical remedies and charlatan practice through the Société Royale de M‚dicine. By the end of the 18th century, however, as the medical and pharmaceutical professions became organised and regulated, quacks and other `alternative' practitioners began to be pushed out of the medical marketplace.

New drugs for old

As the range of new drugs increased, medication gradually became more central to healing, doctors claimed a superior knowledge of medicines over quacks or self-prescribers, and pharmacy became organised into guilds and companies. There arose a new professional group of manufacturing druggists like the London chemist, Thomas Corbyn (1711-1791), who traded with Europe and the Americas, and supplied wholesale medicines to hospitals and the colonies. Whilst the Leiden Pharmacopoeia Leodiensis (1741) listed oil of earthworms amongst its remedies, the fifth edition of the London Pharmacopoeia (1746) omitted spider's webs, human fat, moss from human skulls, and unicorn's horn. Wood-lice, pearls, bezoars, vipers, coral, and theriac were, nevertheless, retained.

In 1745, the English physician, William Heberden (1710-1801), censured the continuing use of theriac, and by the sixth edition in 1788, most of these had disappeared. New drugs and compounds included aconite, castor oil, magnesia, ether, tartrate of iron, oxide of zinc, sarsaparilla, paregoric (liquid opium), and various patent preparations including Dr James's Fever Powders (contained antimony), Dover's powder (an opium mixture), and Huxham's tincture. In 1763, it was discovered that the bark of the English willow tree (Salix species), reduced fevers in a similar manner to the expensive imported remedy, cinchona (Peruvian bark).

Digitalis - foxglove tea

Foxglove tea, prepared from the leaves of the foxglove (Digitalis purpurea), was an English folk remedy for treating swollen hands, legs, and feet. William Withering (1741-1799), a physician working in Birmingham, learned about it from a country woman in Shropshire and a carpenter in Oxford. Being an ardent medical botanist, he made a study of the foxglove during 1775-1785 and published his findings in 1785. He recognised that it increased the flow of urine, reduced dropsy (excess body fluid), and had a powerful action on the heart. As digitalis, the drug appeared in the London Pharmacopoeia of 1809. Nevertheless, its use in dropsy declined possibly because dropsy due to heart failure was not easy to distinguish from dropsy due to kidney disease. The circulation of the blood was known because it had been discovered by William *Harvey (1578-1657) in the 1620s, but its role in transporting water was not.

In 1835, a French physician, J-B Bouillaud, noted that digitalis slowed the heart beat. He administered it by blistering the chest over the heart (precordium) and covering the area with powdered drug. He described its effect as `an opium for the heart'. In 1873, FT Roberts found that digitalis relieved the symptoms of palpitations caused by disease of the heart's mitral valve (usually a result of rheumatic fever which was common at that time). In 1908, the English general practitioner, James Mackenzie (1853-1925), published his 10-year study of the heart's rhythm in health and disease. He showed that digitalis was valuable when heart failure was due to the excessive pumping action of the ventricles (the main pumping chambers of the heart) which exhausted the heart. It slowed the heart rate and allowed the ventricles to fill with blood before they contracted. He noted that `the effect of the drug was at times phenomenal'.

Homeopathy

In 1796, the German physician, Samuel Hahnemann (1755-1843), published his system of treating disease which he named `homeopathy' from the Greek, homoios, meaning similar. Hahnemann conceived the idea for homeopathy after translating a work on medicines by Scottish physician, William Cullen (1710-1790). He believed that Cullen's ideas on the action of drugs was vague. From his self-experimentation with cinchona, the remedy for intermittent fever, he concluded that the drug caused the same symptoms as the illness, and worked by mobilising and redirecting the body's vital forces to overpower and suppress it. Physicians, therefore, needed to use a medicine which induced artificial disease, a principle he called similia similibus curantur or `like cures like'.

Hahnemann contrasted this with the principle of opposites, contraria contrariis curantur, employed by most physicians in their aim to rid the body of so-called `morbid' substances which they associated with the cause of disease. He called this type of therapy, `allopathic', from the Greek àllos, meaning different. He believed that allopathic medicines created new, artificial diseases alongside the original illness which made the patient worse and more incurable. Physicians then piled on larger and stronger doses of medicines, often mixing a considerable number of drugs. These sometimes resulted in temporary suppression of the symptoms or illness which then had to be kept at bay with larger and more frequent doses. Hahnemann used the example of the pain-killer, morphine, to prove this point. Sometimes, it was the medicine and not the disease which eventually killed the patient.

Pharmacy, pharmacology, and toxicology

The emerging professions of pharmacy and pharmacology combined the skills of apothecaries, botanists, chemists, and physiologists. In 1806, a German apothecary's assistant, Friedrich Sertürner (1783-1841), isolated morphine from opium. This was one of the first `alkaloids', so-called because they were drugs which formed salts with acids (like inorganic salts). The French physiologist, François Magendie (1783-1855) collaborated with pharmacist, Pierre Joseph Pelletier (1788-1842) to study the effects of poisonous plants. They isolated the substance in ipecacuanha which caused vomiting, and named it emetine. From the seeds of the Indian tree, Strychnos nux-vomica, they prepared strychnine, a poison which caused convulsions, but in minute doses was a popular ingredient of `tonic' medicines.

Between 1817-1821, Pelletier and Joseph Bienaimé Caventou (1793-1877) isolated a range of alkaloids including veratrine from hellebore, caffeine from coffee beans, and quinine from cinchona. Many European medicines depended on natural products from the tropical regions of the world. Cinchona plantations were established in Dutch Java and British India during the mid-19th century. In India, there were important botanic gardens at Calcutta (1793), Saharanpur (1818), Darjeeling, and Mussoorie which grew medicinal plants such as belladonna, digitalis, senna, and valerian. The first university department of pharmacology was established at Dorpat (now Tartu, Estonia) under Rudolf Buchheim (1820-1879) who had been trained at Leipzig.

Kill or cure

The ancient Egyptians used opium to stop children crying and send them to sleep. It was still being used for the same purpose at mid-19th century and could be bought from any chemist or druggist for one penny an ounce. A more palatable version 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. Arsenic, from the Greek word `arsenikon' meaning `potent', was used by the Greeks and Romans as a treatment for cleaning wounds and ulcers. It was also used as a poison by the Roman emperor, Nero (CE 15-68), and the notorious 15th century *Borgia family of Italy. During the 18th century, arsenic was favoured as a remedy for ague, headaches, blood disorders, and rheumatism.

Patent medicines which contained arsenic, such as Thomas Wilson's `ague drops', and Fowler's Solution, remained popular through the 19th century. Nevertheless, doctors and apothecaries became increasingly concerned about the ready availability of potentially lethal substances. In the medical hierarchy, apothecaries were the forerunners of general practitioners and prescribed medicines for illnesses which they themselves had diagnosed. Chemists and druggists, on the other hand, were retail and wholesale pharmacists who often indulged in fierce undercutting of apothecaries' prices. The publicity given to `spectacular' poisonings emphasised the significant role played by chemists and druggists in the sale of poisons. Between 1839-1849, 70 people in England were convicted of murder by poisoning but others certainly got away with it.

Opium - a gift from God

Opium, extracted from the poppy (Papaver somniferum), was known to the Minoans and Egyptians in about 1300 BCE. In Egypt, one of its uses was to quieten a crying child. The Greek physician, *Galen (CE 129-c. 216), prescribed opium for the emperor, *Marcus Aurelius (CE 121-180), although he was apparently aware of its addictive properties. The Swiss physician, Paracelsus (1493-1541) invented a secret remedy which he named laudanum, which was probably opium dissolved in wine. In terms of its pain-relieving properties, opium was arguably the most important and powerful drug in the doctor's bag. In England, 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.

Opium - the Opium Wars

The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.

Opium - the Opium Wars

The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.

In 1839, the Peking government tried to enforce the opium ban to which the British responded by defending the principle of `free trade'. In the ensuing `Opium War' (1840-1842), the port of Canton was bombarded, and China was forced to surrender. Under the treaty of Nanking, Canton, Shanghai and 3 other ports were once again opened to trade, and China ceded the island of Hong Kong to the British. The Second Opium War (1857-1860) resulted in further losses of Chinese sovereignty and the country was opened to foreign residents and Christian missionaries. By 1895, however, China was producing 85% of its internal demand for opium, and by 1906, it was estimated that 13.5 million Chinese, or 27% of the adult males, smoked opium. In that year, the Chinese Government forbad the consumption of opium and the cultivation of the opium poppy in China.

John Bell & Co, a London chemist

In 1798, John Bell opened his chemist and druggist shop at number 338 Oxford Street, in the heart of London's West End. Behind its plate glass windows were the trademark symbols of the retail chemist - glowing glass bottles filled with yellow, red, and blue liquid. Bell's was a high-class establishment with its own laboratory on the premises and a full staff of counter assistants, servants, porters, and errand boys. It sold not only to the public, but dispensed medicines from physicians' prescriptions as well as supplying drugs and chemicals to hospitals and dispensaries. Like many successful chemists and druggists of the time, the Bell family were *Quakers with a wide network of Quaker Friends and business associates. As non-conformists, Quakers were barred from holding public office or entering the established universities, so they trained and apprenticed their own.

Bell's shop became a private school of pharmacy not only for indentured apprentices but also for medical students training to be surgeon-apothecaries. The Apothecaries Act (1815) required the Society of Apothecaries to set a qualifying examination for surgeon-apothecaries who later became known as general practitioners. It was the first government attempt to establish a standard of professional medical education. Nevertheless, many people continued to seek advice from chemists, often because they could not afford to pay doctors' or apothecaries' fees, and patent medicines were generally cheaper than prescription drugs. Large establishments like Bell's would supply medicine chests, veterinary supplies, spectacles, leeches, pills, powders, liniments, lotions, bandages, drops, gargles, and plasters.

Jacob Bell and the Pharmaceutical Society

During the first half of the 19th century, the medical profession made concerted efforts to raise its professional status. At the same time, there was a growing interest in drug analysis and the effects of drugs on the body. This gave retail chemists and druggists the impetus to prove themselves as skilled practitioners rather than be labelled shop-keepers. The first journal for druggists, The Chemist, was launched in January 1840, by which time John Bell's son, Jacob (1810-1859), was a partner in John Bell & Co although he had long abandoned the Quaker speech and dress. In February 1841, government drafted a Bill which would bring chemists and druggists under the control of apothecaries and make over-the-counter prescribing illegal. Fines of œ20 were inflicted on druggists who flouted this ruling.

On 17 March, Bell met with a group of retail chemists and formed the Pharmaceutical Society which by September had 450 members. The Society was open to all bone-fide chemists and druggists but it was envisaged that, in the future, none would be admitted without a qualifying examination. By May 1842, the Society's membership was just under 2000 and in 1843, it received a Royal charter, becoming the Royal Pharmaceutical Society. The Pharmaceutical Times was launched in 1846, and Peter Squire (1798-1884), who owned a shop near the Bell's, became the first chemist and druggist to replace an apothecary in supplying medicines to the Royal Family.

Jacob Bell and the Pharmacy Act

Jacob Bell (1810-1859), of John Bell & Co, moved in high circles. A talented artist himself, he was a fervent patron of the arts, and commissioned William Powell *Frith (1819-1909) to paint Derby Day which was completed in 1858. Bell also found all the models for the painting. He was a very close friend of Sir Edwin *Landseer (1802-1873), Queen Victoria's favourite painter, and best known for his animal subjects. For Shoeing, exhibited at the Royal Academy in 1844, Jacob supplied his mare, `Old Betty', his bloodhound, `Laura', and even his farrier. The model for The Sleeping Bloodhound was an animal which had died after falling from a parapet at John Bell's house in Wandsworth. By the late 1840s, Jacob realised that the pharmaceutical industry could only be regulated through an Act of Parliament.

Unable to find a Member of Parliament willing to take up his cause, Jacob decided to enter Parliament himself, although as a non-conformist, he stood little chance of being elected. However, in 1850, the Member of Parliament for St Albans in Hertfordshire, died, and Jacob was informed that most of the electorate would be willing to sell their votes, as they regularly did. Accordingly, he spent œ2500 in securing his seat as a Liberal MP and beat his opponent by 276 votes. Jacob worked feverishly to push his private member's Pharmacy Bill through Parliament and succeeded by the skin of his teeth. On 2 February 1852, the St Albans Bribery Commission published its findings against Jacob, and on 3 May the Borough of St Albans was disenfranchised. He remained in the House of Commons until July when Parliament was dissolved after the fall of the Liberal government.

Medicines from plants and coal

By the mid-19th century, chemists had isolated the active principles from many plants used in medicine. These included codeine (1832) and papaverine (1850) from the opium poppy (Papaver somniferum); aconitine from aconite or common monkshood (Aconitum napellus); atropine from deadly nightshade (Atropa bella-donna); colchicine from the Autumn crocus or meadow saffron (Colchicum Autumnale); hyoscyamine from henbane (Hyoscyamus niger); daturine from thornapple (Datura stramonium); and cocaine from coca (Erythroxylum species). Newly discovered soporifics included ether, chloroform, and nitrous oxide.

Another important raw material was coal. In 1825, the English chemist, Michael *Faraday (1791-1867), isolated benzene from coal tar which was produced commercially as a fuel. Industrial chemists investigated coal tar for medicinal compounds and developed the analgesics, phenacetin and paracetamol. In the 1850s, another English chemist, William Henry *Perkins (1838-1907), attempted to synthesise quinine from coal tar but instead, produced the first synthetic dye, mauvein (mauve). This not only established the synthetic dyestuffs industry but was an important milestone on the road to antimicrobial medicines, antiseptics, and tissue stains for microscope specimens.

Rise of the pharmaceutical industry

In 1858, ER Squibb opened a laboratory to supply medicines to the United States army, and went on to manufacture chloroform and ether. Parke, Davis & Company was founded in 1867, and Eli Lilly in 1876. In 1880, Burroughs Wellcome brought mass-produced, machine-made tablets to England from America, and the German company, Merck, opened an American division in 1891. In 1763, it had been discovered that the bark of the English willow tree (Salix species) reduced fevers in a similar manner to cinchona. After the extraction of quinine from cinchona, chemists looked for the active principle in willow. Salicin (which is converted to salicylic acid in the body) was isolated in 1830, and salicylic acid synthesised in 1852. For many years, it was used as a treatment for rheumatic diseases until the German pharmaceutical company, Bayer, produced acetylsalicylic acid in 1899. It was given the trade name Aspirin and became the world's most popular drug.

Bayer sold Aspirin in a double package with heroin, a morphine-derived substance isolated in 1883. Heroin was so called because of its energetic properties which supposedly calmed all fears, stopped coughs (including those of tuberculosis), and cured morphine addiction. The sleeping potion, chloral hydrate, was introduced in 1869, but soon found to be addictive. It was followed in 1888 by an even more potent drug called sulfonal. In 1903, Bayer produced its first barbiturate, `Veronal', which was followed by `Luminal' in 1912. These were all habit-forming drugs. Once the structure of a drug was identified, the chemistry could be manipulated to produce compounds which had more effective or safer properties. The local anaesthetic, `Novocain' or procaine, synthesised in 1899, was modelled on cocaine but was less hazardous and had a simpler chemical structure.

Bromides

Bromide of potassium was first used during the 1850s to control `hysterical' epilepsy in young women. The English physician, Sir Charles Locock (1799-1875), conceived the idea of its use in this way from a German report which suggested that it caused temporary impotence in men. Since hysteria was believed to be related to sexual disorders (the Greek word hystera means `womb'), the remedy seemed appropriate. It was found to be successful and for some years was confined to use in women who suffered epileptic fits during menstruation. Other physicians preferred to continue with an old remedy, tincture of henbane. The popularity of bromide of potassium rose during the 1860s when physician Samuel Wilks (1824-1911) used it successfully in patients with general paralysis of the insane (syphilis affecting the brain). These patients suffered uncontrollable seizures during the late stage of their disease.

Eventually, by the mid-1870s, it came to be used in all types of epilepsy. It proved so successful that the National Hospital for Paralysis and Epilepsy in London (now the National Hospital for Neurology and Neurosurgery) used 2.5 tons of bromide a year. Unfortunately, its side effects included severe skin rashes and abscesses. Bromide of potassium remained the mainstay of treatment for epilepsy until 1912 when the barbiturate sedative, phenobarbital (Luminal), was introduced. Nevertheless, by 1915, the National Hospital was still using 1.5 tons of bromide a year.

The dried leaves of the coca (Erythroxylum species) bush were chewed by native *American Indians in the Andes from the third century BCE. When the *conquistadors discovered the *Inca Empire of Peru in the 1530s, the use of coca was a court privilege as well as a religious observance. Priests chewed coca during religious ceremonies in order to appease the gods, and the leaves were burned to produce sacred smoke at sacrifices. Coca was an important source of revenue during the period of Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an anti-depressant. 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. Having experienced its numbing sensation in the mouth, he suggested to his friend, Carl Koller (1857-1944), an eye surgeon, that it might be used as a local anaesthetic in the eye. Koller tried this successfully in 1884 and it was thereafter taken up by ophthalmologists throughout the world. In the same year, the American surgeon, William Stewart Halsted (1852-1922), who had spent time in Vienna, began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. In the course of his experiments he became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency.

Germ theory and magic bullets

The relationship between basic research in the medical sciences and the development of drugs was symbiotic. The French physiologist, Claude Bernard (1813-1878), showed that drugs did not act uniformly all over the body but at specific sites. For example, the paralysis caused by curare, the arrow poison used by South American Indians, was due to its effect on specialised tissue called the neuromuscular junction. Paul Ehrlich (1854-1914) of Germany, and the British physiologist, John Newport Langley (1852-1925), took this one stage further. Ehrlich investigated the dyes used for staining microscope specimens and noted how particular dyes fixed to specific types of tissue. He proposed that drugs acted on body organs by similar fixation and believed that they would not work unless they were fixed. He called this the `side chain theory'. Langley identified specialised sites of action in organs and nervous tissue.

These concepts developed into the `receptor' theory, which was used to explain the interaction of drugs with cells in all manner of living tissues. Ehrlich conceived the idea of the `magic bullet' whereby drugs might be produced which always found their way to the target. The most important targets discovered in the late 19th century were microorganisms. In France, Louis Pasteur (1822-1895) conceived of the germ theory of disease whereby minute living organisms (microbes) invaded the body. The German bacteriologist, Robert Koch (1843-1910), was the first to implicate bacteria in a disease, anthrax (1876), and went on to discover the organisms responsible for tuberculosis (1882) and cholera (1884). Between 1879-1900, the organisms responsible for major infectious diseases were discovered at the rate of one a year.

Hormones

Drug research was influenced by the increasing understanding of the body's complex nature. In 1883, the Swiss surgeon, Theodor Kocher (1841-1917), noted that patients whose thyroid glands had been removed because of goitre usually died. In animals it was found that death could be prevented by grafting a portion of thyroid gland into the abdomen. Research showed that the thyroid and other glands secreted substances or `chemical messengers' into the bloodstream which acted on distant organs and were essential to the overall function of the body. In 1905, the English physiologists, William Bayliss (1860-1924) and Ernest Starling (1866-1927), named these secretions `hormones' from the Greek word meaning `to excite'. As hormones were synthesised, they became important replacement drugs to treat deficiency of a natural secretion.

Adrenaline, isolated from adrenal glands in 1895, was the first hormone to be chemically isolated (1901). More than 30 corticosteroids were then isolated from the adrenals by researchers such as Tadeus Reichstein (b. 1897) of Switzerland, and the Americans Edward Kendall (1886-1972), and Philip Hench (1890-1965) who pioneered anti-inflammatory treatment with the corticosteroid, cortisone. All 3 won a Nobel Prize in 1950. Kendall also isolated thyroxine from the thyroid gland (1915). Testicular and ovarian hormones, isolated during the 1920s, included testosterone, oestrin, progesterone, oestriol, oestrone, and oestradiol. By 1928, Selmar Ascheim (1878-1979) and Bernhard Zondek (1891-1967) in Berlin, had developed a reliable pregnancy test based on levels of pregnancy hormones in urine.

Neuro-transmitters

The discovery of hormones as `chemical messengers' which relayed information from one part of the body to another prompted research into other kinds of messenger systems. During the 1920s, the Austrian pharmacologist, Otto Loewi (1873-1961), showed that chemical substances were released at nerve endings (hence their alternative name of neurotransmitters) which stimulated or inhibited other nerve cells, muscles, or glands. He and the British physiologist, Sir Henry Hallett Dale (1875-1968), identified one of these chemical or neuro-transmitters as acetylcholine. They shared a Nobel Prize in 1936. Another, noradrenaline, was identified by Ulf von Euler (1905-1983) from Sweden who was awarded a Nobel Prize in 1970.

The discovery of transmitters helped explain the action of certain drugs such as atropine (from Deadly nightshade), curare (the arrow poison from Strychnos toxifera), and eserine (from dried seeds of Physostigma venenosum). These drugs either stimulated or paralysed nerves and muscles. The synthesis of drugs which imitated transmitter activity included those for the treatment of Parkinson's disease, Huntington's chorea, anxiety and depression, eye disorders, gastric disorders, nausea and vomiting. In 1942, the Americans, HR Griffith (1894-1985) and GE Johnson, were the first to use curare as a muscle relaxant during surgery which made it easier for surgeons to operate on the abdomen.

Salvarsan - a treatment for syphilis

In 1905, Fritz Schaudinn (1871-1906) and Erich Hoffmann (1868-1959) in Germany discovered the micro-organism (Treponema pallidum) which caused syphilis. Since the arrival of syphilis in Europe following Christopher *Columbus' (1451-1506) voyage to the Americas, the most important therapy for the disease had been mercury. Patients treated with large doses of mercury often developed mercury poisoning, the symptoms of which included copious salivation (believed to remove the syphilitic poison from the body), loosening of the teeth, and softening of the bones. In 1909, the German immunologist, Paul Ehrlich (1854-1915), and his Japanese colleague, Sahachiro Hata (1873-1938), synthesised a `magic bullet' to seek out and destroy the treponema.

The drug was an arsenic compound which they named `Salvarsan' (salvation through arsenic) although it was also called `606' because it was the 606th arsenical which they had synthesised. Salvarsan was marketed by the German pharmaceutical company, Hoechst, which sent 65,000 free samples to doctors all over the world. Intravenous infusions of salvarsan were used with mercury rubs, but later it was used with bismuth. The minimum duration of treatment was 18 months. In 1908, Ehrlich won a Nobel Prize for salvarsan which became the most important treatment for syphilis until the discovery of penicillin. During the First World War, it was used to treat infected soldiers. A saying amongst them was that `606' was the treatment for syphilis but a bullet from a `303' was the cure!

A red dye kills germs

In 1935, Gerhard Domagk (1895-1964), research director at the German chemical company, IG Farbenindustrie, discovered that a bright red dye called Prontosil was effective in the treatment of streptococcal infection. When Prontosil was analysed by J Tréfouël (1897-1977) at the Pasteur Institute, Paris, it was discovered that the compound split into 2 parts in the body. Only one of the parts, later called sulphanilimide, was effective against the streptococcus bacteria. In fact, sulphanilimide had been synthesised in 1908 by Paul Gelmo at IG Farbenindustrie who found that it enhanced the colour-fastness of synthetic dyes. Seven years later, it was re-discovered by Charles Heidelberger in America who established that it killed bacteria in the test tube but was too toxic to be used on humans. It, therefore, remained as a dye ingredient for the next 20 years.

When sulphanilimide was finally produced as a drug during the mid-1930s, it was used on a group of patients with puerperal fever at Queen Charlotte's Maternity Hospital, London. It reduced the mortality rate from 20% to 4.7% and was hailed as a `miracle drug'. Sulphanilimide was a bacteriostatic compound and worked by preventing bacteria from reproducing. This allowed the body's natural defences to mobilise against the invading organism. Other sulpha drugs were soon synthesised which proved effective against pneumococcal infections. In Britain, the drug company, May & Baker, produced sulphapyridine which cured Winston *Churchill's (1874-1965) pneumonia at a critical stage of the Second World War.

Penicillin - Alexander Fleming

During the First World War, the Scottish bacteriologist, Alexander *Fleming (1881-1955) and his boss, Sir Almroth Wright (1861-1947), spent time in France investigating wounds and resistance to infection. They observed that the strong antiseptics used to clean wounds, which were largely based on Joseph *Lister's (1827-1912) carbolic acid, killed the body's natural defence mechanisms (leucocytes or white blood cells) faster than they killed bacteria. However, it was August 1928 before Fleming, returning from holiday to his laboratory at St Mary's Hospital, London, discovered that a mould had appeared on a culture dish containing staphylococci bacteria, the organisms responsible for boils, abscesses, and pneumonia. The staphylococci had been destroyed by the mould which he identified as a Penicillium species (Penicillium notatum).

Fleming discovered that Penicillium killed bacteria but was non-toxic to leucocytes. Using the simple procedures available at St Mary's, he was unable to concentrate the substance which he called `penicillin' because it was very unstable and easily destroyed. Although he tried it on a few patients with some success, he did not pursue his research because he was, in fact, working in a laboratory which produced vaccines and was not specifically interested in the mode of action of penicillin.

Penicillin - Florey and Chain

In 1938, Ernst Chain (1906-1979), a biochemist who had fled to England from Hitler's purge of German Jewish scientists, began working on penicillin at Oxford University. His boss was Professor Howard Florey (1898-1968). Chain began to purify penicillin out of scientific interest and not because he thought it would have any practical application. However, by May 1940, the Oxford team found that they had isolated a very powerful drug which was effective, not only against staphylococci bacteria but also against streptococci. In order to produce enough penicillin to try it on a patient, they were forced to grow it in milk churns, lemonade bottles, bedpans and a bath tub. Their first patient was a policeman dying of septicaemia following a scratch while pruning his roses. Even his urine was collected to recycle the drug. He improved remarkably after the fourth day but then the penicillin ran out and he died.

Florey and Chain then approached British pharmaceutical companies to take over production but the Second World War had just begun and they were all too busy supplying drugs for the war effort. In July 1941, the Oxford team turned to the United States where, in Peoria, Illinois, the Northern Regional Research Laboratory of the US Department of Agriculture, added a by-product from a corn milling process to the penicillin culture medium and increased the drug yield 10 times. Meanwhile, moulds from all over the world were sent to Peoria in the hope of finding others which would increase the yield even more. A local woman, Mary Hunt, contributed a mouldy cantaloupe bought from a fruit market. This proved so successful that the yield was doubled again. By 1943, British pharmaceutical companies had joined the mass-production of penicillin, and Florey showed that its treatment of war wounds was phenomenally successful.

Penicillin - creation of a legend

In 1945, Florey, Chain and Fleming were awarded a Nobel Prize for their discovery and production of the world's first antibiotic. Florey was created a baronet and the other two received knighthoods. In the aftermath of the war, there was much resentment in Britain regarding the `theft' of penicillin by the United States. The government was accused of `handing over' the manufacture of the antibiotic instead of taking control of a British invention. Even worse was the idea that the British manufacturers of penicillin would be forced to pay royalties to American pharmaceutical companies since they held all the patents for its production. Antagonism also developed between Fleming's team at St Mary's Hospital, London, and Florey and Chain at Oxford who considered that Fleming's glorification as the discoverer of the century's miracle drug was inappropriate.

In 1945, St Mary's Hospital launched an appeal to pay for post-war modernisation. A display entitled, `The Exhibition of Penicillin and Modern Medicine' was prepared for a visit by Queen Elizabeth (b. 1900, now Elizabeth, the Queen Mother) in June 1945. Afterwards, the exhibition toured south and south west England in a train loaned by the Great Western Railway. It stopped at 20 stations and was seen by 70,000 people. In 1944, Imperial Chemical Industries (ICI), one of the manufacturers of penicillin in Britain, launched a film about its discovery which `starred' Fleming, Chain, and Florey, and was shown at a cinema in central London. The film was perceived by its promoters as `a vital piece of national prestige propaganda'. When the National Health Service was formed in 1948, its first annual expenditure for drugs was œ17.5 millions which was œ6 millions higher than expected.

More antibiotics

The development of penicillin by Alexander Fleming (1881-1955), Ernst Chain (1906-1979), and Howard Florey (1898-1968), prompted the search for other antibiotics. In 1945, after penicillin had been introduced into medicine, an Italian professor, Giuseppi Brotzu, isolated a mould of Cephalosporium from a sewage outfall in Sardinia. He sent a specimen to Florey at Oxford University where it was discovered to contain a new penicillin, penicillin N. In 1953, penicillin N was found to contain another substance called cephalosporin C which was useful against staphylococci bacteria that had become resistant to penicillin. In 1964, the pharmaceutical company, Glaxo, introduced the first cephalosporin antibiotic into Britain. Second and third generation cephalosporins followed in 1978 and 1983 respectively.

In 1944, a Russian-American microbiologist, Selman Waksman (1888-1973), discovered a soil-based fungus called Streptomyces griseus from which the antibiotic, streptomycin, was isolated. Streptomycin proved effective against the bacillus causing tuberculosis (Mycobacterium tuberculosis) although the bacillus soon became resistant. The first ever clinical controlled trial was designed to establish the effectiveness of streptomycin in tuberculosis by comparing patients who received the drug with those who did not, and so acted as a `control' group. The trial was organised in 1948 by Austin Bradford Hill (1897-1991) at the Medical Research Council in Britain. In 1950, he and Richard Doll (b.1912) published their report implicating another drug, tobacco, with lung cancer.

Antibiotics to treat cancer

An important group of antibiotics, discovered during the 1950s, were found to stop cell division in cancer cells. These cytotoxic (meaning toxic to cells) antibiotics helped initiate the chemotherapeutic revolution. Mitomycin was discovered in 1956, and others followed. By the 1980s, the most commonly used cytotoxic antibiotics in Britain were doxorubicin (used to treat acute leukaemia, lymphomas, and a variety of solid tumours), actinomycin D (principally used to treat cancers in children), bleomycin (lymphomas and solid tumours), and mitomycin (stomach and breast cancer). By the year 2000, daunorubicin was being used to treat Kaposi's sarcoma, a rare skin cancer associated with Acquired Immune Deficiency Syndrome (AIDS), and mitoxantrone had been introduced for breast cancer.

However, it was well established that prolonged use of cytotoxic antibiotics resulted in cancer cells becoming resistant in the same way that bacteria became resistant to anti-bacterial drugs.

A pill for every ill

After the Second World War, the drugs industry initiated a therapeutic revolution. Important anti-bacterial research was soon joined by research into anti-viral substances, and then a whole range of compounds that regulate or adjust the body's defences. The hunt for drugs to kill viruses was complicated by the fact that these organisms take up residence within infected cells and become encoded into their genetic material. Vaccines for viral infections were being developed during the late 1940s. Polio vaccines were available in 1955 and 1960, measles in 1963, and a triple vaccine for measles, mumps and rubella (MMR) was launched in 1988. The anti-viral drugs, acylovir (herpes virus), ganciclovir (cytomegalovirus), and zidovudine (HIV virus) were also produced during the 1980s.

In 1960, the Australian scientist, Frank Macfarlane Burnet (1899-1985), and Peter Medawar (1915-1987) in Britain, won a Nobel Prize for their work on rejection in organ transplantation. This research led to the development of important immunosuppressant drugs such as azathioprine and cyclosporin without which kidney, heart, and liver transplants would not have progressed. The concept of peptic ulcer disease which many doctors believed was related to stress, resulted in a plethora of therapeutic agents including antacids, reflux suppressants, anti-flatulents, anti-spasmodics, H2 receptor blockers, proton pump inhibitors, cytoprotectants, and prostaglandin analogues. Treatment was often maintained for years until researchers in the 1990s discovered that a bacterium, Helicobacter pylori, caused 80% of stomach ulcers and over 90% of duodenal ulcers.

Cancer treatments

Important new chemotherapeutic agents for cancer were discovered in plant material. The Madagascar periwinkle (Vinca rosea, renamed Catharanthus roseus), first grown in the Chelsea Physic Garden in the 18th century, produced the vinca alkaloids, vincristine, vinblastine, and vindesin. These were used to treat leukaemia, lymphoma, and other cancers such as breast and lung. The bark of the slow-growing Pacific yew tree, a native of the forests of the Northwest Pacific, yielded an anti-cancer drug called Taxol (paclitaxel) which was first used in 1984 to treat women with advanced ovarian cancer. It was later approved for use in breast cancer, and in 1997, for Kaposi's sarcoma, an AIDS-related skin cancer. By 2000, the search for methods of synthesising Taxol became imperative because of its low yield in nature. Treatment for one patient required 60 pounds of bark, or 3, 100-year-old trees.

Tamoxifen, a drug used to treat breast cancer, was developed in Britain during the 1960s, and the first clinical trial was carried out at the Christie Hospital, Manchester, in 1970. In 1998, tamoxifen was also approved in the United States for women at high risk of developing breast cancer although it was also found to increase the risk of these women developing cancer of the womb lining (endometrium). By 2000, scientists in Nottingham were investigating a breast cancer treatment which combined tamoxifen and the plant, borage (Borago officinalis), also called the starflower because of its star-shaped blue flowers. The concentrated amounts of gamma linolenic acid (GLA) in borage were believed to inhibit the spread of tumours by restricting growth of blood vessels.

Medicines to change the mind - lithium

The 1950s brought a range of mind-altering (psychotropic) medicines onto the market. The first was lithium carbonate, first used in 1949 by Australian psychiatrist, John Cade, to treat patients with manic-depressive illness. An alkaline metal, lithium was discovered in 1817 by a student of the Swedish chemist, Johan Jakob Berzelius (1779-1848). It is present in nearly all mineral water. Early 20th century textbooks of psychiatry suggested that the mineral springs of Cornwall, Scotland, and Wales, helped to cure mania. Lithium salts were used in the 19th century to dissolve bladder stones formed by uric acid, and also to treat gout and rheumatism. In 1927, lithium bromide began to replace potassium bromide as a treatment for epilepsy because it had a greater sedative action, but was found to cause heart and kidney damage.

In 1951, French psychiatrists reported some success with lithium in the treatment of manic-depressive (bipolar) illness. However, it was a Danish psychiatrist, Mogens Schou, who persistently used lithium carbonate throughout the 1950s although he could persuade few colleagues to do so. From 1959-1963, there were only 15 publications citing lithium in the treatment of manic-depressive illness. Pharmaceutical companies were reluctant to commit to large-scale production of lithium for clinical use because the salts were readily available (`Dr Gustin's lithium salts' was a popular fizzy drink in France) and could not be patented. Eventually, by 1970, lithium was marketed for both the prevention and treatment of mood swings in manic-depressive illness, and by 1975, there were more than 3000 reports of its efficacy in the medical literature.

Medicines to change the mind - chlorpromazine

Chlorpromazine (Largactil) was synthesised in 1950 by the chemist, Paul Charpentier, working at the French pharmaceutical company, Rhône-Poulenc. It had powerful anti-histamine properties but its potential was not immediately appreciated so it was kept on a reserve shelf. Histamine, a chemical produced naturally in the body (discovered by English physiologist, Sir Henry Dale, 185-1968), had been implicated in a number of conditions such as asthma and allergy. The Swiss physiologist, Daniel Bovet (1907-1992), experimented with anti-histamine compounds to counteract the pathological effects of histamine. Anti-histamines were also shown to have a sedative effect. It was this property which interested the French neurosurgeon, Henri Laborit, who used antihistamine drugs to calm his patients before surgery. He had experienced some success with the antihistamine, promethiazine, but decided to try a more powerful version.

Rhône-Poulenc gave him a sample of chlorpromazine. He found that it induced a sense of `detachment' in his patients, and his colleagues considered its use in psychiatry. The first clinical trials on patients with schizophrenia were performed, in 1953, at the Val-de-Grâce Hospital, Paris. Within a decade, it was claimed that patients who had been confined to mental hospitals were able to leave, the padded cells were shut, and the strait waistcoats confined to cupboards. In reality, high doses of chlorpromazine caused symptoms similar to Parkinson's disease because it blocked production of the neurotransmitter, dopamine (patients with Parkinson's disease have reduced dopamine levels). It also caused other symptoms such as weight gain, hypersensitivity to sunlight, and tardive dyskinesia (TD), characterised by facial grimaces and other head movements.

Medicines to change the mind - benzodiazepines

During the 1960s, the tranquiliser, Librium (chlordiazepoxide), was the most prescribed drug in the world until overtaken in the 1970s by the chemically related Valium (diazepam). Both were discovered in 1958 by Hungarian-born chemist, Leo Sternbach, working at the American laboratory of Swiss pharmaceutical company, Hoffman-La Roche. Librium was an accidental discovery in that Sternbach synthesised 41 compounds during 1955, 40 of which were found to have no tranquilising properties. Sternbach and his team then went on to other work and the 41st compound lay on the laboratory shelf for two years. In 1957, it was `re-discovered' and found to possess quite different molecular properties than the 40 useless compounds.

The director of biological research at Hoffman-La Roche demonstrated its extraordinary tranquilising effect by commissioning a film which showed how wild animals including tigers, panthers, and pumas, could be approached and trained on `Librium'. For humans, the benzodiazepines were an important group of medicines because they had both a tranquilising and an anxiolytic effect. They helped people overcome excessive anxiety, fear, or worry. Nevertheless, by the 1980s, there were concerns that benzodiazepines were being over-prescribed, and were causing problems of dependence in some people. A study in Oxford revealed that, in 1978, benzodiazepines were used in 41% of drug overdose cases. By 1989, this had reduced to 17.2% in line with a reduction in prescribing. The benzodiazepines were, nevertheless, extremely valuable sedatives during minor medical and surgical procedures such as endoscopy and biopsies.

Medicines to change the mind - antidepressants

The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.

Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.

Medicines to change the mind - antidepressants

The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.

Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.