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PHARMACOLOGY.

Pharmacology, branch of medicine that deals with the interaction of drugs with the systems and processes of living animals, in particular, the mechanisms of drug action as well as the therapeutic and other uses of the drug.

A truly scientific pharmacology developed only after advances in chemistry and biology in the late 18th century enabled drugs to be standardized and purified. By the early 19th century, French and German chemists had isolated many active substances--morphine, strychnine, atropine, quinine, and many others--from their crude plant sources. Pharmacology was firmly established in the later 19th century by the German Oswald Schmeiderberg (1838-1921). He defined its purpose, wrote a textbook of pharmacology, helped to found the first pharmacological journal, and, most importantly, headed a school at Strasbourg that became the nucleus from which independent departments of pharmacology were established in universities throughout the world. In the 20th century pharmacological research has developed a vast array of new drugs, including antibiotics, such as penicillin, and many hormonal drugs, such as insulin and cortisone. Pharmacology is presently involved in the development of more effective versions of these and a vast array of other drugs through chemical synthesis in the laboratory. Pharmacology also seeks more efficient and effective ways of administering drugs through clinical research on large numbers of patients.

During the early 20th century, pharmacologists became aware that a relation exists between the chemical structure of a compound and the effects it produces in the body. Since that time, increasing emphasis has been placed on this aspect of pharmacology, and studies routinely describe the changes in drug action resulting from small changes in the chemical structure of the drug. Because most medical compounds are organic chemicals, pharmacologists who engage in such studies must necessarily have an understanding of organic chemistry.

The work of pharmacologists in industry deals also with the exhaustive tests that must be made before promising new drugs can be introduced into medical use. Detailed observations of a drug's effects on all systems and organs of laboratory animals are necessary before the physician can accurately predict both the effects of the drug on patients and their potential toxicity to humans in general. The pharmacologist does not himself test the effects of drugs in patients; this is done only after exhaustive tests on animals and is usually conducted by physicians to determine the clinical effectiveness of new drugs. Constant testing is also required for the routine control and standardization of drug products and their potency and purity.

CHRISTIAN FRIEDRICH SAMUEL HAHNEMANN

Hahnemann, Samuel (b. April 10, 1755, Meissen, Saxony [now in Germany]--d. July 2, 1843, Paris, France), German physician, founder of the system of therapeutics known as homeopathy.
Hahnemann studied medicine at Leipzig and Vienna, taking the degree of M.D. at Erlangen in 1779. After practicing in various places, he settled in Dresden in 1784 and then moved to Leipzig in 1789. In the following year, while translating William Cullen's Lectures on the Materia medica into German, he was struck by the fact that the symptoms produced by quinine on the healthy body were similar to those of the disordered states that quinine was used to cure. This observation led him to assert the theory that "likes are cured by likes," similia similibus curantur; i.e., diseases are cured (or should be treated) by those drugs that produce in healthy persons symptoms similar to the diseases. He promulgated his principle in a paper published in 1796; and, four years later, convinced that drugs in small doses effectively exerted their curative powers, he advanced his doctrine.

In 1821 the hostility of apothecaries forced him to leave Leipzig, and at the invitation of the grand duke of Anhalt-Köthen he went to live at Köthen. Fourteen years later he moved to Paris, where he practiced medicine with great popularity until his death.

HOMEOPATHY

Homeopathy, a system of therapeutics, notably popular in the 19th century, which was founded on the stated principle that "like cures like," similia similibus curantur, and which prescribed for patients drugs or other treatments that would produce in healthy persons symptoms of the diseases being treated.

This system of therapeutics based upon the "law of similars" was introduced in 1796 by the German physician Samuel Hahnemann. He claimed that a large dose of quinine, which had been widely used for the successful treatment of malaria, produced in him effects similar to the symptoms of malaria patients. He thus concluded that all diseases were best treated by drugs that produced in healthy persons effects similar to the symptoms of those diseases. He also undertook experiments with a variety of drugs in an effort to prove this. Hahnemann believed that large doses of drugs aggravate illness and that the efficacy of medicines thus increases with dilution. Accordingly, most homeopathists believed in the action of minute doses of medicine.

THE PRACTICE OF PHARMACY

Education.

The course of instruction leading to a bachelor of science in pharmacy extends at least five years. The first and frequently the second year of training, embracing general education subjects, are often provided by a school of arts and sciences. Many institutions also offer graduate courses in pharmacy and cognate sciences leading to the degrees of master of science and doctor of philosophy in pharmacy, pharmacology, or related disciplines. These advanced courses are intended especially for those who are preparing for careers in research, manufacturing, or teaching in the field of pharmacy.
Since the treatment of the sick with drugs encompasses a wide field of knowledge in the biological and physical sciences, an understanding of these sciences is necessary for adequate pharmaceutical training. The basic five-year curriculum in the colleges of pharmacy of the United States, for example, embraces physics, chemistry, biology, bacteriology, physiology, pharmacology, and many other specialized courses. As the pharmacist is engaged in a business as well as a profession, special training is provided in merchandising, accounting, computer techniques, and pharmaceutical jurisprudence.

DRUGS AND DRUG ACTION

Opioid analgesics.

The term opioid has been adopted as a general classification of all of those agents that share chemical structures, sites, and mechanisms of action with the endogenous opioid agonists. Opioid substances encompass all of the natural and synthetic chemical compounds closely related to morphine, whether they act as agonists or antagonists. Although interest in these drugs has always been high because of their value in pain relief and because of problems of abuse and addiction, interest was intensified in the 1970s and 1980s by discoveries about the naturally occurring morphine-like substances, the endogenous opioid neuropeptides.

 Opium is the powder from the dried juice of the poppy Papaver somniferum. When taken orally, opium produces sleep and induces a state of peaceful well-being. Its use dates back at least to Babylonian civilization. In the early 19th century opium extract was found to contain more than 20 distinct complex organic bases, termed alkaloids, of which morphine, codeine, and papaverine are the most important. These pure alkaloids replaced crude opium extracts in therapeutics.
In the 1950s several new morphine-like drugs were suggested. Despite the increase in the number of compounds available for pain relief, however, little was understood of their sites and mechanisms of action. The first real breakthrough came from the discovery, by J.W. Hughes and H.W. Kosterlitz, of two potent naturally occurring analgesic pentapeptides (peptides containing five linked amino acids) in extracts of pig brain. They called these compounds enkephalins, and since then at least six more have been found. Larger peptides, called endorphins, have been isolated; and these contain sequences of amino acids that can be split off as enkephalins. There are at least three types of receptors on brain neurons that are activated by the enkephalins. Morphine and its congeners are thought to exert their effects by activating one or more of these receptors. This is still a rapidly advancing field of research. It is thought that the common final pathway of receptor activation is the movement of calcium ions through the plasma membrane.

Opioid drugs are useful in the treatment of general postoperative pain, severe pain, and other specific conditions. The use of opiates to relieve the pain associated with kidney stones or gallstones presumably depends on their ability to affect opiate receptors in these tissues and to inhibit contractility. By a similar mechanism, opiates are also able to relieve the abdominal distress and fluid loss of diarrhea. Central receptors appear to account for the ability of morphine and analogues to suppress coughing, an effect that requires lower doses than those needed for analgesia. Low doses of opiates given subcutaneously are also specifically advocated for the relief of the respiratory distress that accompanies acute cardiac insufficiency complicated by the buildup of fluid in the lungs, even though the mechanisms of this effect are unknown and despite the fact that opiates are respiratory depressants.

Several commonly used natural or synthetic derivatives of morphine are used in drug therapeutics. Codeine, a naturally occurring opium alkaloid, is also made synthetically and provides a useful adjuvant analgesia as an oral preparation, especially when used in combination with aspirin. Meperidine, also known as Demerol, was one of the earlier synthetic analogues of morphine that was originally thought to be able to provide significant short-lasting analgesia and little or no addiction because of its shortened duration of action. This belief proved false and the drug is widely abused. Methadone, a synthetic opioid analgesic, has long-lasting (six to eight hours) analgesic effects when taken orally and the unique ability to antagonize the euphoria-producing effects of heroin; it is therefore used to moderate the effects of withdrawal from opiate addiction. Among the opioid antagonist drugs, naloxone and its longer lasting orally active version, naltrexone, are used primarily to reverse morphine overdoses and to reverse the chemical stupor of a wider variety of causes, including alcohol intoxication and anesthesia. In opiate overdoses, where the signs of pinpoint pupils, depressed respiration, and unconsciousness help in the diagnosis, these drugs provide an almost miraculous recovery within minutes of injection. They can, however, also precipitate severe withdrawal reactions if the subject had been addicted previously.

The effectiveness of a given dose of an opiate drug declines with its repeated administration in the presence of intense pain. This loss in effectiveness is termed tolerance. Evidence suggests that tolerance is not due to alterations in the brain's responses to drugs. Animals exhibiting tolerance to morphine after repeated injections in a familiar environment show little or no tolerance when given the same doses and tested for pain sensitivity in new environments. Thus, a learned aspect of tolerance seems almost certain. The cellular and molecular mechanisms underlying this loss of responsiveness are not clear, however. Physical dependence and addiction in a person using intravenous administration closely follow the dynamics of drug tolerance; increasing doses are required to produce the psychological effects, while tolerance protects the brain against the respiratory depressant actions of the drug. In the tolerant individual, intense adverse reactions can be precipitated by administration of an opiate antagonist, thus revealing the dynamic internal equilibrium that previously appeared to neutralize the response of the brain to the opiates. The signs of the withdrawal response (yawning, tearing, perspiration, dilation of the pupils, nasal discharge, anxiety, tremors, elevation of blood pressure, abdominal cramps, and hyperthemia) can be viewed as signs of an activated sympathetic nervous system and to some extent an extreme, but nonspecific, arousal response. This may also suggest that tolerance in the face of increasing opiate doses is more properly viewed as a balancing mechanism by this sympathetic activation.

PHARMACEUTICAL

pharmaceutical, substance used in the diagnosis, treatment, or prevention of disease and for restoring, correcting, or modifying organic functions.

A brief treatment of pharmaceuticals follows.

Records of medicinal plants and minerals date to ancient Chinese, Hindu, and Mediterranean civilizations. Ancient Greek physicians such as Galen used a variety of drugs in their profession. During the 16th century AD, after Western medicine began to recover from its long sleep during the Dark and Middle Ages, pharmaceutical practice began to develop rapidly. In 1546 the first pharmacopoeia (list of drugs and their preparation) appeared in Germany, and the profession of pharmacy is considered to have begun in 1617 with the founding of the Society of Apothecaries in London. Among the earliest modern pharmaceuticals were the anesthetics; morphine was first used in 1806, ether in 1842, chloroform in 1847, and cocaine in 1860. Other substances isolated in the 19th century included strychnine (1817), quinine (1820), and nicotine (1828). Joseph Lister first used phenol (carbolic acid) to prevent infection in 1865.

Pharmaceuticals are generally classified by chemical group, by the way they work in the body (pharmacological effect), and by therapeutic use. Alkaloids were the first pure pharmaceuticals derived from natural substances (plants); they include quinine, nicotine, cocaine, atropine, and morphine. Drugs of animal origin include glandular extracts containing hormones, such as insulin for use in treating diabetes.

Antibiotics, vaccines, human blood-plasma fractions, and steroid hormones are other important pharmaceuticals manufactured from natural substances. Vitamins, which were formerly obtained from natural sources, are now often made in the laboratory.

In the preparation of dosages, many pharmaceuticals are ground to varying degrees of fineness. Many medicinal substances are added to water, alcohol, or another solvent so that they can be used in solution form. These may include spirits, elixirs, and tinctures. Ointments are one of many semisolid preparations, which also include creams, pastes, and jellies. Solid pharmaceuticals include pills, tablets, lozenges, and suppositories. In this form the compounds are more stable, with less risk of chemical reaction, and the dosage is easier to determine. Storage and packaging also is made simpler, and solid forms are more efficient to produce.

PHARMACEUTICAL INDUSTRY

Solid dosage forms.

Solid dosages, such as tablets, have many advantages over other types: greater stability, less risk of chemical interreaction between different medicaments, smaller bulk, accurate dosage, and ease of production.

Powders intended for internal use are usually mixtures of two or more ingredients. If two ingredients are present in unequal quantities, then the lesser ingredient (usually the drug) is mixed with an equal weight of the greater ingredient. Next, the resulting mixture is combined with an equal weight of the greater ingredient in steps until the mixture is complete. This process of geometric dilution (or trituration) is essential in order to produce a homogeneous powder. Powders may be sold in a bulk form or in individual packets. Granules, a dosage form related to powders, are particularly suitable for the preparation of solutions or mixtures of drugs, such as antibiotics, that are unstable in the presence of water. Cachets, occasionally used for administration of powdered drugs with an unpleasant taste, consist of shells made of gelatinized starch paste, the powder being placed inside, and the cachet swallowed. More common today is the hard capsule, in which the powder is enclosed in a shell of hard gelatin. Semiliquid and liquid drugs are often enclosed in a soft capsule with a soft gelatin shell.

Pills.

Before the machine-made compressed tablet, pills were a very popular solid dosage form, being prepared at the dispensing bench by the pharmacist. Today pills are rarely prescribed, though some popular types are manufactured by machine. The powdered ingredients are mixed together with a binding agent, such as acacia or tragacanth, and are then made into a plastic mass by incorporation of any liquid drugs and addition of an inert liquid. The resulting mass, known as a pill mass, is then rolled into spheres and coated with talc, gelatin, or sugar.

Tablets.

Tablets, by far the most common method of administration of drugs, are only rarely made by compression of the drug alone (e.g., potassium bromide tablets). Usually, the drug is mixed with suitable diluents, such as dextrin, lactose, salt, starch, or synthetic substances, designed to ensure disintegration of the tablet in the body. To prevent sticking in the machine, a lubricant such as liquid paraffin, stearic acid, talc, or a synthetic substance is usually added. Furthermore, it is essential that the tablet machines are fed with the drug mixture in a free-flowing form to ensure complete filling of the molds. To achieve this, the drug mixture is customarily granulated by mechanically forcing pellets of the mixture through a sheet of perforated metal. The granulated mixture is fed into the tablet machine, which feeds the correct dose into a cavity, the mixture then being compressed by means of a punch that fits into the cavity. To be successful, the tablet maker must choose correct diluents and lubricants, prepare suitable granules, and obtain the right degree of compression in the tablet machine. Excessive compression may mean that the tablet will not disintegrate in the body; insufficient compression results in fragile tablets that may break, causing inaccurate dosage. Coatings of various types may be applied to the tablet--to protect the ingredients from deterioration, to hide the taste of certain drugs, to control the release of the drug from the tablet, or to produce a more attractive tablet. For sugarcoatings, a concentrated sucrose syrup containing suspended starch, calcium or magnesium carbonate, or other suitable substance is applied, each successive layer being dried before the application of the next. After the final layer is dried, it is highly polished to give an elegant finish. Sugarcoatings provide both protection and a sweet taste. The chief drawback to sugarcoating is the long time involved. This led to the development of film coating, in which a very thin transparent film, usually a cellulose derivative, is applied. Enteric coating is designed to resist solution in the stomach and to dissolve in the more alkaline intestinal fluid. Many substances have been used for enteric coatings, one of the more recent being cellulose acetate phthalate (cellacephate). In the manufacture of layered tablets, incorporating two or more drugs, a compressed tablet is fed to a second machine where another layer is compressed around it. In this way, drugs normally incompatible may be formulated in the same tablet.

Other solid dosages.

Troches, also known as lozenges or pastilles, disintegrate or dissolve in the mouth, slowly releasing the active drug. The base usually consists of a mixture of sugar and gum or gelatin. Lozenges are generally manufactured by compression techniques, while pastilles are fabricated by fusion and the use of molds. Dry extracts are prepared by the methods described above for fluid extracts, followed by evaporation, usually under reduced pressure, either to a pilular consistency or to dryness. Dry extracts are usually granulated by being passed through a sieve and may be used for the preparation of tablets. Suppositories are solid, uniformly medicated masses designed for introduction into the rectum. Various bases are used in their preparation, but theobroma oil is the most common. Solid at room temperature, it melts a few degrees below body temperature. Suppositories are manufactured by the use of molds, together with fusion of the suppository mass or cold compression. Pessaries are suppositories intended for introduction into the vagina, while bougies are designed for insertion into the urethra, nostrils, or ears.

THE PHARMACEUTICAL INDUSTRY

The World Health Organization (WHO) defines a drug or pharmaceutical preparation as any substance or mixture of substances manufactured, sold, offered for sale, or represented for use in . . . the diagnosis, treatment, mitigation, or prevention of disease, abnormal physical state or the symptoms thereof in man or animal; [and for use in] . . . restoring, correcting, or modifying organic functions in man or animal. The same organization defines a pharmaceutical specialty as "a simple or compound drug ready for use, and placed on the market under a special name or in a characteristic form." The modern pharmaceutical industry began in the 19th century with the discovery of highly active medicinal compounds that could most efficiently be manufactured on a large scale. As these compounds replaced herbal medicines of earlier times, the occurrence and severity of such diseases as pernicious anemia, rheumatic fever, typhoid fever, lobar pneumonia, poliomyelitis, syphilis, and tuberculosis were greatly reduced. Pharmaceutical industry research has greatly aided medical progress; of the 66 most valuable drugs introduced since aspirin in 1899, 57 were discovered and then produced in industrial laboratories.

PHARMACEUTICAL INDUSTRY

History

The earliest records of medicinal plants and minerals are those of the ancient Chinese, Hindu, and Mediterranean civilizations. In 2735 BC, the Chinese emperor Shen Nung wrote an herbal in which he described the antifever capabilities of a substance known as Ch'ang Shang, since shown to contain antimalarial alkaloids. The school of alchemy that flourished in Alexandria in the 2nd century BC could prepare white lead (lead carbonate) from litharge, arsenic from realgar (arsenic disulfide), and mercury by roasting cinnabar (mercuric sulfide) in a current of air. It is recorded in De materia medica, a book of the 1st century BC, that verdigris (basic cupric acetate) and cupric sulfate were prescribed as medicinal agents. Remarkably, cupric sulfate is still used in medicine today.
Many crude drugs still used now, such as ipecacuanha root (ipecac), were known and employed by the ancients. The Egyptians treated constipation with senna pods and castor oil and employed caraway and peppermint to relieve indigestion. The Greek physician Galen (c. AD 130-c. 200) included hyoscyamus, opium, squill (a plant drug used as an expectorant, cardiac stimulant, and diuretic), and viper toxin among other drugs in his apothecary shop. He also insisted on purity in drugs; i.e., the right variety and age of the botanical specimens.

Pharmaceutical practice improved markedly in the 16th and 17th centuries. In 1546 the first pharmacopoeia, or collected list of drugs and medicinal chemicals with directions for making preparations from them, appeared in Nuremberg (Nürnberg, West Germany). Previous to this time, medical preparations had varied in concentration and even in constituents. Other pharmacopoeias followed, in Basel (1561), Augsburg (1564), and London (1618). Despite its name, the London Pharmacopoeia was mandatory for the whole of England and thus was the first example of a national pharmacopoeia.

In 1617 the Society of Apothecaries, London, was founded, marking the emergence of pharmacy as a distinct profession. The separation of apothecaries from grocers was authorized by King James I; only a member of the society could keep an apothecary's shop and make or sell pharmaceutical preparations. In 1841 the Pharmaceutical Society of Great Britain, London, was founded, placing the education and training of the pharmacist upon a proper scientific basis. Today, pharmaceutical practice and education are carefully supervised throughout the world.

Known as "Hoffman's drops," ether was first employed as an anesthetic in 1842; chloroform followed soon afterward in 1847. Alkaloid compounds were also isolated from plant sources during this period. Narcotine was obtained from opium by a French pharmacist in 1803 and was followed by morphine in 1806, emetine and strychnine (around 1817), brucine and piperine (1819), colchicine and quinine (1820), nicotine (1828), atropine (1833), cocaine (1860), and physostigmine (1867). Isolation of these potent compounds was a milestone in pharmaceutical progress for three reasons. First, accurate doses could now be administered; this had been impossible previously with crude drugs of unknown and variable composition. Second, toxic effects due to impurities in crude drugs could now be eliminated if pure compounds were used; and third, knowledge of the chemical structure of these drugs led to attempts at laboratory synthesis, which led in turn to discovery of valuable related compounds.

Joseph Lister, in England, opened the modern era of antiseptic surgery in 1865 when he used phenol (carbolic acid) to prevent infections. In 1869 the soporific properties of chloral hydrate, the first synthetic hypnotic (sleep-producing drug), were discovered. In 1874 it was found that organic nitrites relax the blood vessels, and, in 1875, salts of salicylic acid were introduced as remedies for fever. The year 1879 witnessed the introduction of saccharin, still in use today as a sweetening agent for diabetic patients. The simple compound acetanilide, introduced in 1886, was one of the first analgesic-antipyretic drugs (i.e., reducing both pain and fever) to be used but was later replaced by the less toxic phenacetin in 1887, by aspirin in 1899, and all of these to some extent by paracetamol in 1956. The hypnotic sulfonal (sulfonmethane) was discovered about 1888, followed a few years later by barbital; this latter led to a whole series of barbiturates, of which phenobarbital is the best known.

Cocaine was the only known potent local anesthetic until about 1900, when the much simpler compound benzocaine was introduced. The closely related local anesthetic procaine followed early in the 20th century.

In 1909 arsphenamine, highly effective against syphilis, was introduced. Since arsphenamine is both insoluble in water and unstable, further work led to neoarsphenamine in 1912, a soluble derivative. Many other synthetic drugs followed, among which was the hormone progesterone, synthesized in 1934. Some thousands of similar compounds have since been prepared, some of which are used as oral contraceptives.

In 1935 it was discovered that sulfanilamide (Prontosil) stopped the growth of bacteria. Over 6,000 derivatives of sulfanilamide--the sulfonamides, or sulfa drugs--were prepared and tested for their antibacterial properties. Today, the sulfonamides have partially been superseded by antibiotics, of which the first was penicillin, first isolated in 1941. In 1959, 6-aminopenicillanic acid was isolated for the first time; this led to production of many semisynthetic penicillins such as ampicillin, carbenicillin, cloxacillin, methicillin, oxacillin, and phenethicillin. Also used as antibiotics are compounds known as cephalosporins, the first of which was isolated in 1961.

ALCHEMY

Alchemy, ancient art practiced especially in the Middle Ages, devoted chiefly to discovering a substance that would transmute the more common metals into gold or silver and to finding a means of indefinitely prolonging human life. Although its purposes and techniques were dubious and often illusory, alchemy was in many ways the predecessor of modern science, especially the science of chemistry.

The birthplace of alchemy was ancient Egypt, where, in Alexandria, it began to flourish in the Hellenistic period; simultaneously, a school of alchemy was developing in China. The writings of some of the early Greek philosophers might be considered to contain the first chemical theories; and the theory advanced in the 5th century BC by Empedocles—that all things are composed of air, earth, fire, and water—was influential in alchemy. The Roman emperor Caligula is said to have instituted experiments for producing gold from orpiment, a sulfide of arsenic, and the emperor Diocletian is said to have ordered all Egyptian works concerning the chemistry of gold and silver to be burned in order to stop such experiments. Zosimus the Theban (about AD 250-300) discovered that sulfuric acid is a solvent of metals, and he liberated oxygen from the red oxide of mercury.
The fundamental concept of alchemy stemmed from the Aristotelian doctrine that all things tend to reach perfection. Because other metals were thought to be less "perfect" than gold, it was reasonable to assume that nature formed gold out of other metals deep within the earth and that with sufficient skill and diligence an artisan could duplicate this process in the workshop. Efforts toward this goal were empirical and practical at first, but by the 4th century AD, astrology, magic, and ritual had begun to gain prominence.

A school of pharmacy flourished in Arabia during the caliphates of the Abbasids from 750 to 1258. The earliest known work of this school is the Summa Perfectionis (Summit of Perfection), attributed to the Arabian scientist and philosopher Geber; the work is consequently the oldest book on chemistry proper in the world and is a collection of all that was then known and believed. The Arabian alchemists worked with gold and mercury, arsenic and sulfur, and salts and acids, and they became familiar with a wide range of what are now called chemical reagents. They believed that metals are compound bodies, made up of mercury and sulfur in different proportions. Their scientific creed was the potentiality of transmutation, and their methods were mostly blind gropings; yet, in this way, they found many new substances and invented many useful processes.

From the Arabs, alchemy generally found its way through Spain into Europe. The earliest authentic works extant on European alchemy are those of the English monk Roger Bacon and the German philosopher Albertus Magnus; both believed in the possibility of transmuting inferior metals into gold. This idea excited the imagination, and later the avarice, of many persons during the Middle Ages. They believed gold to be the perfect metal and that baser metals were more imperfect than gold. Thus, they sought to fabricate or discover a substance, the so-called philosopher's stone, so much more perfect than gold that it could be used to bring the baser metals up to the perfection of gold.
Roger Bacon believed that gold dissolved in aqua regia was the elixir of life. Albertus Magnus had a great mastery of the practical chemistry of his time. The Italian Scholastic philosopher St. Thomas Aquinas, the Catalan churchman Raymond Lully, and the Benedictine monk Basil Valentine (flourished 15th century) also did much to further the progress of chemistry, although along alchemical lines, in discovering the uses of antimony, the manufacture of amalgams, and the isolation of spirits of wine, or ethyl alcohol.

Important compilations of recipes and techniques in this period include The Pirotechnia (1540; trans. 1943), by the Italian metallurgist Vannoccio Biringuccio; Concerning Metals (1556; trans. 1912), by the German mineralogist Georgius Agricola; and Alchemia (1597), by Andreas Libavius, a German naturalist and chemist.

Most famous of all was the 16th-century Swiss alchemist Philippus Paracelsus. Paracelsus held that the elements of compound bodies were salt, sulfur, and mercury, representing, respectively, earth, air, and water; fire he regarded as imponderable, or nonmaterial. He believed, however, in the existence of one undiscovered element common to all, of which the four elements of the ancients were merely derivative forms. This prime element of creation Paracelsus termed alkahest, and he maintained that if it were found, it would prove to be the philosopher's stone, the universal medicine, and the irresistible solvent.

After Paracelsus, the alchemists of Europe became divided into two groups. One group was composed of those who earnestly devoted themselves to the scientific discovery of new compounds and reactions; these scientists were the legitimate ancestors of modern chemistry as ushered in by the work of the French chemist Antoine Lavoisier. The other group took up the visionary, metaphysical side of the older alchemy and developed it into a practice based on imposture, necromancy, and fraud, from which the prevailing notion of alchemy is derived.
After Seymour Z. Lewin

BOTANY

Botany, microbiology, and zoology constitute the science of biology. biologists recognize five kingdoms: monera (bacteria and blue-green algae), protista (one-celled organisms), fungi, plant, and animal. of these, the monerans, the protists that contain chlorophyll, the fungi, and the plants are studied by botanists.

Subdivisions of Botany

The study of plants may be approached from many directions, each of which is a specialization involving an aspect of plant life, for example, classification, form and structure, life processes and functions, diseases, fossils, and heredity and variation.

Plant taxonomy is the study of plant classification, that is, the grouping of plants into species, genera, families, orders, classes, and divisions reflecting evolutionary, or family tree, relationships. Taxonomists provide internationally recognized scientific names for plants. As taxonomy has become more specialized, various branches of the discipline have appeared, including biosystematics, numerical taxonomy, cytotaxonomy, and chemical taxonomy, which reflect different approaches to problems of classification.

Plant morphology is the study of the form and structure of plants. Morphologists may investigate plant life-cycles or internal structure (plant anatomy). Specialized branches of morphology are cytology (study of cell structure and function), palynology (study of pollen and spores), and morphogenesis (study of how plants develop their form).

Plant physiology is the study of life processes of plants, for example, photosynthesis and respiration, and of the functions of different tissues and organs. Many physiologists, working mainly with chemical processes in plants, might well be called biochemists.
Plant ecology is the study of how plants affect, and are affected by, their environment and of the structure and distribution of vegetation, or communities of plants.

Plant pathology is the study of plant diseases. Paleobotany is the study of the fossil record of plants.

A developing science is paleoecology, which considers all fossil life and its environmental relationships. Genetics is the study of heredity and variation. The basic principles and processes of genetics are so similar in plants and animals that little distinction is made between them.

Some additional branches of botany are devoted to particular groups of plants. For example, bacteriology is the study of bacteria; mycology, the study of fungi; and phycology, the study of algae. Workers in these fields may be concerned with any aspect--taxonomy, morphology, physiology, ecology--of the group. Economic botany is concerned with those plants that are of economic importance, because of their usefulness (food, fiber, medicine) or because of the harm they do (weeds, poisonous plants). Ethnobotany is concerned with how primitive societies used plants.

These many facets of botany are not mutually exclusive. Each relies on one or more of the others. Plant pathologists, for example, are interested in taxonomy, morphology, physiology, ecology, and genetics of the disease-causing organisms they study.

History

People have always been interested in plants as sources of useful products or as troublemakers. In prehistoric societies some persons probably were more interested in plants than others, and perhaps it was these "primitive botanists" who discovered that seeds produce plants, that pieces of plants (cuttings) can grow into new plants, and that certain plant parts have healing properties.

The first written records of scientific botany are from the time of the ancient Greeks and Romans. It was among these people that some of the methods of science--observation, description, deduction, and organization of knowledge--first appeared. theophrastus, the "father of botany," wrote extensively about plants--their form, classification, and natural history--but only two of his works, Historia plantarum and De causis plantarum, survive. Pedanius dioscorides wrote De materia medica, a popular herbal that described plants, especially those useful in medicine. It combined fact with superstition. Several Roman authors also contributed to the first literature of botany. In spite of their imperfections, for 1,500 years these early works, especially those by Theophrastus and Dioscorides, were accepted in Europe without serious question.

During the 16th century, after the invention of the printing press, a number of herbals appeared that contained original rather than borrowed observations and that critically evaluated knowledge and authority from earlier times.

Exploration of various parts of the world was making Europeans aware of a great variety of plants, and plants were again studied carefully. Exploration of the invisible world began in the late 16th century when the compound microscope was invented. The pioneer microscopic studies that took place in the 17th century were the start of plant anatomy.

The age of botanical experimentation, a fundamental activity in science, began during the 17th century. Experimental plant physiology had its beginnings when water uptake of a tree was measured by Johannes Baptista van Helmont (1577-1644); the study was published in 1648. The work of Stephen Hales, considered the founder of plant physiology, led to studies of basic processes such as photosynthesis.

Other early physiologists studied the movement of water in plants, and in 1779 the chemist Joseph Priestley showed that plants produce oxygen in sunlight.

In 1753, Carolus Linnaeus published Species plantarum, which described 6,000 species of plants and introduced the consistent use of binomials, two-word names of plants (for example, Quercus alba for white oak), a basis for the classification system in use today. The history of taxonomy since then has involved, primarily, efforts to make plant classification more nearly reflect evolutionary relationships and, secondarily, refining the rules for scientific names of plants.

Vast herbaria (collections of pressed, dried plants) have been built up as research facilities of importance in plant taxonomy. Charles Darwn's exposition of evolution in On the Origin of Species (1859) encouraged taxonomists to build evolutionary classifications, and it profoundly influenced botanical research.

Although plant taxonomy and morphology dominated botany during the 18th century and part of the 19th century, other botanical disciplines eventually matured or developed as the necessary tools and techniques appeared and were improved. Plant diseases have been known since ancient times, but the modern science of plant pathology did not begin to develop until the mid-19th century. The devastating potato blight in Ireland in the 1840s greatly stimulated the study of plant diseases.
Until 1900, plant genetics was concerned largely with practical hybridization and selection in plants, especially crops and ornamentals. Work in genetics had become important in agriculture. The mechanism of heredity and variation, however, was not understood until the late 19th and early 20th centuries. The rediscovery in 1900 of Gregor Johann MENDEL'S then 3-decade-old work on plant breeding completely reoriented research in genetics and led to the remarkable development of modern genetics.

Plant fossils have been known since early times, and some ancient Greek writers recognized that fossils are evidences of past life. This view was replaced in succeeding centuries, however, by fantastic or mystical explanations. Starting in the 15th century, fossils were directly observed and reasonably interpreted, but not until the late 19th century was the debate about the true nature of fossils essentially over. By the early 19th century, as the richness of the fossil record was gradually revealed and the great age of the Earth began to be understood, paleobotany had become well established as a science.

The beginnings of ecology were apparent in Theophrastus's writings on natural history, but ecology did not emerge as a unified science until the late 19th and early 20th centuries. Concern for the environment increased after 1950 and has made ecology one of the most talked-about specialties in biology. Although plant ecology is a logical subdivision of ecology and has its own history, philosophy, and methods, the concept of ecosystem (or total environment) has done much to bring plant and animal ecologies together.

Recent milestones in botany and biology include the following: the development of electron-microscope techniques that allow scientists to observe the three-dimensional structure of living cells; the discovery of fossils of prokaryotes about 3.5 billion years old and the remains of unicellular eukaryotic algae about 1.4 billion years old; the development of radioactive isotopes for dating and tracing materials as they move in biological systems; the rapid expansion of genetic engineering and other areas of biotechnology; the elucidation of the structures of DNA and RNA and their role in protein synthesis; and the appearance of new ideas on the origin of life.
John W. Thieret

DRUG DEPENDENCE

Drug Dependence, psychological and sometimes physical state characterized by a compulsion to take a drug in order to experience its psychological effects. Addiction is a severe form of dependence, usually marked by physical dependence. The latter state exists when the drug has produced physiological changes in the body, as evidenced by the development of tolerance (increasing amounts of the drug are needed to achieve the same effect), and of a withdrawal syndrome after the drug's effects have worn off. The syndrome is marked by such symptoms as nausea, diarrhea, or pain; these vary with the type of drug. Psychological dependence, or habituation, is present when the compulsion to take a drug is strong, even in the absence of physical withdrawal symptoms.

Scientists often measure a drug's potential for abuse by studies with laboratory animals. Drugs that an animal will administer to itself repeatedly are said to have powerful reinforcing properties and a high potential for abuse. Examples include some of the major abused drugs—opium, alcohol, cocaine, and barbiturates. Other drugs, such as marijuana and the hallucinogens, appear to produce habituation in humans even though they are not powerful reinforcers for laboratory animals.
The drugs that are commonly abused, besides substances such as alcohol and tobacco, can be grouped into six classes: the opioids, sedative-hypnotics, stimulants, hallucinogens, cannabis, and inhalants.

Opioids

This class includes drugs derived from opium (such as morphine and heroin) and its synthetic substitutes (such as methadone). Medically, morphine is a potent pain reliever; indeed, it is the standard by which other pain-relieving drugs are measured. It and other opium derivatives also suppress coughing, reduce movements of the intestine (providing relief from diarrhea), and induce a state of psychological indifference. Heroin, a preparation synthesized from morphine, was introduced in 1898 as a cough suppressant and nonaddicting substitute for morphine. The addictive potential of heroin was soon recognized, however, and its use was prohibited in the United States, even in medical practice. Users report that heroin produces a "rush" or a "high" immediately after it is taken. It also produces a state of profound indifference and may increase energy.

Opioids produce different effects under different circumstances. The drug taker's past experience and expectations have some influence, as does the method of administering the drug (by injection, ingestion, or inhalation). Symptoms of withdrawal include kicking movements in the legs, anxiety, insomnia, nausea, sweating, cramps, vomiting, diarrhea, and fever.

In the 1970s, when scientists isolated substances called enkephalins, which are naturally occurring opiates in the brain, they discovered what many believe to be the reason behind physical dependence on opioids—that is, the drugs are thought to mimic the action of enkephalins. If true, this hypothesis suggests that physical dependence on the opioids may develop in persons who have a deficiency in these natural substances.

Sedative-Hypnotics

The principal drugs of abuse in this class are the barbiturates, which have been used since the early 1900s to relieve anxiety and induce sleep. They are also used medically in the treatment of epilepsy. Some abusers of the barbiturates ingest large amounts daily but never appear intoxicated. Others use the drugs for binges of intoxication, and still others use them to boost the effect of heroin. Many abusers, especially those of the first type, obtain their drugs routinely from physicians.

Barbiturates produce severe physical dependence; in this, as in their effects, they closely resemble alcohol. Abrupt withdrawal results in similar symptoms: shaking, insomnia, anxiety, and sometimes, after a day, convulsions and delirium. Death can occur when barbiturates are suddenly discontinued. Toxic doses—often little more than is required to produce intoxication—are often taken accidentally. Barbiturates are particularly lethal when combined with alcohol.

Other sedative-hypnotics include the benzodiazepines, which are marketed under such names as Valium and Librium. These are the so-called minor tranquilizers that are used in the treatment of anxiety, insomnia, and epilepsy. They are generally safer than the barbiturates and are now commonly used instead of the older drugs, but tranquilizer addiction, in turn, has become a problem.

Stimulants

Commonly abused stimulants are cocaine and drugs of the amphetamine family. Cocaine, a white, crystalline powder with a bitter taste, is extracted from the leaves of the South American coca bush. It is used medically to produce anesthesia for surgery of the nose and throat and to constrict blood vessels and reduce bleeding during surgery; but abuse, which increased considerably in the late 1970s, can lead to severe physiological and psychological problems. A highly addictive, smokable form of cocaine, "crack," appeared in the 1980s.

Amphetamines, introduced in the 1930s for the treatment of colds and hay fever, were later found to affect the nervous system. For a while they were commonly used as an appetite suppressant by people trying to lose weight. Today their use is restricted primarily to the treatment of narcolepsy, a sleep disorder characterized by sudden sleep attacks throughout the day; and of hyperactivity in children, in whom amphetamines produce a calming effect. For adults, however, amphetamines rightfully earn their street name, "speed." These drugs heighten alertness, elevate mood, and decrease fatigue and the need for sleep, but they often make users irritable and talkative. Both cocaine and amphetamines, after prolonged daily use, can produce a psychosis similar to acute schizophrenia.
Tolerance to both the euphoric and appetite-suppressing effects of amphetamines and cocaine develops rapidly. Withdrawal from amphetamines, particularly if the drug is injected intravenously, produces depression so unpleasant that the drug user has a powerful incentive to keep taking the drug until he or she collapses.

Hallucinogens

These drugs are not used medically in the U.S. except occasionally in the treatment of dying patients, the mentally ill, drug abusers, and alcoholics. Among the hallucinogens that were widely abused during the 1960s are lysergic acid diethylamide, or LSD, and mescaline, which is derived from the peyote cactus. Although tolerance to these drugs develops rapidly, no withdrawal syndrome is apparent when they are discontinued.

Phencyclidine, or PCP, known popularly by such names as "angel dust" and "rocket fuel," has no current use in humans but is occasionally used by veterinarians as an anesthetic and sedative for animals. It became a common drug of abuse in the late 1970s and is considered a particular menace because it can easily be synthesized. Its effects are quite different from those of other hallucinogens. LSD, for example, produces detachment and euphoria, intensifies vision, and often leads to a crossing of senses (colors are heard, sounds are seen). PCP, by contrast, produces a sense of detachment and a reduction in sensitivity to pain; it may also result in either triggering or producing symptoms so like those of acute schizophrenia that even professionals confuse the two states. The combination of this effect and indifference to pain has sometimes resulted in bizarre thinking, occasionally marked by violently destructive behavior.

Cannabis

The plant Cannabis sativa is the source of both marijuana and hashish. The leaves, flowers, and twigs of the plant are crushed to produce marijuana; its concentrated resin is hashish. Both drugs are usually smoked. Their effects are similar: a state of relaxation, accelerated heart rate, perceived slowing of time, and a sense of heightened hearing, taste, touch, and smell. These effects can be quite different, however, depending on the amount of drug consumed and the circumstances under which it is taken. Marijuana and hashish are not thought to produce psychological dependence except when taken in large daily doses. The drugs can be dangerous, however, especially when smoked before driving. Although the chronic effects are not yet certain, marijuana is probably injurious to the lungs in much the same way that tobacco is. A source of concern is its regular use by children and teenagers, because the intoxication markedly alters thinking and interferes with learning. A consensus exists among physicians and others working with children and adolescents that use is undesirable and may interfere with psychological and possibly physical maturation.

Cannabis has been used as a folk remedy for centuries, but it has no well-established medical use today. Experimental work has been done using its active ingredient, delta-9-tetrahydrocannabinol (THC), for treating alcoholism, seizures, pain, the nausea produced by anticancer medications, and glaucoma. Its usefulness for glaucoma patients seems fairly certain, but its disorienting effects make its possible employment by cancer patients more doubtful.

Inhalants

In this class are substances that usually are not considered drugs, such as glue, gasoline, and aerosols such as nasal sprays. Most such substances sniffed for their psychological effects act to depress the central nervous system. Low doses can produce slight stimulation, but in higher amounts they cause their users to lose control or lapse into unconsciousness. The effects, which are immediate, can last as long as 45 minutes. Headache, nausea, and drowsiness follow. Sniffing inhalants can impair vision, judgment, and muscle and reflex control. Permanent damage can result from prolonged use, and death can result from sniffing highly concentrated aerosol sprays. Although physical dependence does not seem to occur, tolerance to some inhalants does develop. Another source of medical concern is the widespread misuse, for their supposed aphrodisiac effect, of so-called "poppers" — chemicals such as isoamyl nitrite that have legitimate medical functions as blood-vessel dilators. Continued sniffing of these easily obtainable substances can damage the circulatory system and have related harmful effects.

Treatment

With the exception of treatment of opioid dependence, medical attention to the problems of the drug abuser is largely confined to dealing with overdoses, acute reactions to drug ingestion, and the incidental medical consequences of drug use, such as malnutrition and medical problems caused by unsterilized needles. Abusers of barbiturates and amphetamines may require hospitalization for detoxification, as is common among alcoholics. Others, such as those arrested repeatedly for possession of marijuana, may, in lieu of imprisonment, be forced to undergo treatment designed primarily for opioid abusers. Whatever the substance abused, the goal of most treatment programs is abstinence.

Two types of treatment programs are used for most opioid users. Therapeutic communities require the drug abuser to take personal responsibility for his or her problem. Typically, the idea behind this treatment is that the drug abuser is emotionally immature and must be given a second chance to grow up. Harsh encounters with other members of the community are typical; the support of others, together with status and privilege, are used as rewards for good behavior.

The other model for opioid abuse treatment is the use of heroin substitutes. One such substitute is methadone, which acts more slowly than heroin but is still addictive. The idea is to help the user gradually withdraw from heroin use while removing the need for finding the drug on the street. A more recent treatment drug, naltrexone, is nonaddictive but does not provide an equivalent "high"; it also cannot be used by persons with liver problems, which are common among addicts.

Social Issues

Drug use for nonmedical purposes occurs throughout society. For this reason the 1978 President's Commission on Mental Health did not recommend health and mental-health assistance except to persons whose drug use was intense and compulsive. The commission identified heroin as the number one drug problem, because heroin addiction may lead to criminal behavior to pay for the drug. Adding to the problem is the fact that chemically similar drugs can be synthesized and sold on the street because they are not yet classified as controlled substances.

In a 1982 household survey by the National Institute on Drug Abuse, more than two-thirds of young adults (aged 18 to 25) reported experience with an illicit substance. Slightly less than 1 in 3 had used marijuana; about 1 in 5 had used hallucinogens; more than 1 in 4 had used cocaine; and 1.1 percent had used heroin. (Use of heroin tends to be underestimated by household surveys because they miss, for example, the prison population.) Among older adults, more than 1 in 5 reported having used marijuana; more than 1 in 20, hallucinogens; nearly 1 in 10, cocaine; and 1 in 100, heroin. Cocaine use has continued to rise among older adults.
After Robert C. Petersen

DRUG

Drug, chemical used for treatment or prevention of disease. The study of the actions and disposition of drugs in the human body is called pharmacology. The use of drugs dates from prehistoric times; the first list of drugs with instructions for preparation, called a pharmacopeia, appeared in 1546 in Nuremberg, Germany. Drugs can be plant, mineral, animal, or synthetic in origin. Many early folk medicines were derived from plants, including aspirin, digitalis, ergot, opium, quinine, and reserpine. Minerals used as medicines include boric acid, epsom salts, and iodine. Many hormones used to treat disease including ACTH and insulin, are currently obtained from animals. Newer analgesic, sedative, psychoactive, and anesthetic drugs have been developed entirely by chemical synthesis, and many substances formerly obtained from animals are now made synthetically.

ADMINISTRATION OF DRUGS

A drug may be administered by mouth (orally), into a vein (intravenously), into a muscle (intramuscularly), under the skin (subcutaneously), onto the skin (topically), as an enema or suppository (rectally), or by injection into the spinal fluid. Intravenous administration may entail injection by means of a syringe or continuous flow through an indwelling needle. One form of intramuscular injection is the depot preparation, in which the drug is combined with other substances so that it is slowly released into the blood. Insulin, steroids, and some contraceptives are given in this way. Oral drugs can also be compounded to dissolve slowly in the stomach—the so-called "time-release" capsules. Drugs for asthma are often made as aerosols for spraying directly into the respiratory tract. One of the newest developments is the portable insulin pump, a small, battery-driven instrument that continuously delivers a preset amount of insulin into the blood of a diabetic person. This mode of administration approximates the natural release of insulin from the pancreas of a healthy person.

Use of Drugs

An important aid to the effective use of many drugs is the determination of the amount of the drug in the blood; this is called serum monitoring. For some drugs used to treat epilepsy, for example, the difference between a therapeutic and a toxic drug concentration is small, so the exact blood level needs to be known. Use of the anticoagulant heparin also requires precise adjustment of the dose by serum monitoring.

Another important consideration in drug therapy is the risk-to-benefit ratio of the drug. For example, the antibiotic gentamicin, a derivative of streptomycin, can damage the kidneys, so it is used with care when high doses are required. The drug niridazole is useful against schistosomiasis, but it can cause cancer; therefore, it is normally used only for severe infections.

United States Government Regulation

Some drugs, called proprietary drugs, are sold over the counter, whereas the ethical drugs may be obtained legally only with a prescription from an authorized health-care provider. Drugs known to produce addiction are subject to even stricter control by the Harrison Narcotic Act of 1914, supplemented by the Narcotics Control Act of 1957. Jurisdiction over these drugs resides with the Drug Enforcement Administration of the U.S. Department of Justice.

Legal standards for composition and preparation of drugs in the United States are found in the United States Pharmacopeia (USP). Under the 1938 Food, Drug, and Cosmetic Act, as amended in 1962, the Food and Drug Administration has responsibility for determining the safety and efficacy of all new drugs.

When a drug is prescribed, it is important that a doctor have knowledge of other drugs the patient may be taking, including proprietary drugs, because many drugs have adverse side effects through interactions with other drugs or foods as well as in themselves. Such interactions may also simply negate the effectiveness of the drug.

HOMEOPATHY

Homeopathy, system of medical practice based on the principle that diseases can be cured by drugs that produce in a healthy person the same pathological effects that are symptomatic of the disease. This doctrine was first formulated by the German physician Samuel Hahnemann in 1796.
Homeopaths also believe that small doses of a drug are more efficacious than large doses. Homeopathy was introduced into the U.S. in 1825. The American Institute of Homeopathy, the national society of homeopathic physicians, was founded in 1844. Although homeopathy is discounted by most physicians, it is still practiced.

NARCOTICS

Narcotics, term originally applied to all compounds that produce insensibility to external stimuli through depression of the central nervous system, but now applied primarily to the drugs known as opiates—compounds extracted from the opium poppy and their chemical derivatives. Also classed as narcotics are the opioids, chemical compounds that are wholly synthesized, but which resemble the opiates in their actions.

The most important attribute of narcotics is their capacity to decrease pain, not only by decreasing the perception of pain, but also by altering the reaction to it. Although they do have sedative properties when used in large doses, they are not used primarily for sedation.

The major constituent of opium and the prototype of all narcotic analgesics is morphine, which was isolated and chemically analyzed by the German apothecary F. W. A. Setürner between 1805 and 1817. Other narcotics used in the U.S. are meperidine (trade name Demerol), codeine, and propoxyphene (trade name Darvon). Heroin, synthesized from morphine, is a potent analgesic, but its use is forbidden in the U.S. Some of the newer synthetic compounds are 1000 to 10,000 times more potent than morphine.

In addition to their painkilling properties, the narcotic analgesics cause a profound feeling of well-being (euphoria). It is this feeling that is in part responsible for the psychological drive of certain persons to obtain and self-administer these drugs. When taken chronically in large doses, the narcotics have the capacity to induce tolerance (whereby a larger and larger dose is required by the body to achieve the same effect), and ultimately psychological and physical dependence, or addiction. In this respect they are similar to the barbiturates and to alcohol. These properties make the medical use of narcotics extremely difficult and have led to strict regulation of the prescription and dispensing of this class of drugs. Even so, they are widely abused.

The mode of action of the narcotic analgesics is still not fully understood. Recent research has determined that specific regions of the brain and spinal cord have an affinity for binding opiates, and the binding sites in the brain are in the same general areas where pain centers are believed to be. This research has also succeeded in isolating compounds, called enkephalins, that are produced in the body to reduce pain; the compounds consist of five amino acids. Apparently they can depress neurons throughout the central nervous system. They belong to a group of larger compounds called endorphins, consisting of many amino acids, that have also been isolated in the body and that are produced by the pituitary gland. Administration of endorphins, including the enkephalins, results in effects similar to those produced by opiates.

The discovery of a class of compounds that are specific antagonists to the action of the opiates has made it possible to treat opiate overdosage quickly and efficiently. The standard drug for this use is naloxone. Some of the antagonists also have opiatelike properties, and this has led to the introduction of a new class of analgesics, the mixed agonists-antagonists. It is hoped that these drugs will produce analgesia without euphoria, reducing their potential for abuse. The three drugs of this class approved so far in the U.S.—pentazocine, butorphanol, and nalbuphine—are as analgesic as morphine for many uses and induce little or no euphoria. All appear to have a lower abuse potential than morphine or propoxyphene.

After Joseph Cochin

THE OATH

400 BC
by Hippocrates
Translated by Francis Adams

I SWEAR by Apollo the physician, and Aesculapius, and Health, and All-heal, and all the gods and goddesses, that, according to my ability and judgment, I will keep this Oath and this stipulation- to reckon him who taught me this Art equally dear to me as my parents, to share my substance with him, and relieve his necessities if required; to look upon his offspring in the same footing as my own brothers, and to teach them this art, if they shall wish to learn it, without fee or stipulation; and that by precept, lecture, and every other mode of instruction, I will impart a knowledge of the Art to my own sons, and those of my teachers, and to disciples bound by a stipulation and oath according to the law of medicine, but to none others. I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous. I will give no deadly medicine to any one if asked, nor suggest any such counsel; and in like manner I will not give to a woman a pessary to produce abortion. With purity and with holiness I will pass my life and practice my Art. I will not cut persons laboring under the stone, but will leave this to be done by men who are practitioners of this work. Into whatever houses I enter, I will go into them for the benefit of the sick, and will abstain from every voluntary act of mischief and corruption; and, further from the seduction of females or males, of freemen and slaves. Whatever, in connection with my professional practice or not, in connection with it, I see or hear, in the life of men, which ought not to be spoken of abroad, I will not divulge, as reckoning that all such should be kept secret. While I continue to keep this Oath unviolated, may it be granted to me to enjoy life and the practice of the art, respected by all men, in all times! But should I trespass and violate this Oath, may the reverse be my lot!

PHARMACEUTICAL INDUSTRY

The pharmaceutical industry is made up of hundreds of companies that discover, develop, produce, and sell drug products. These products are used by health professionals to prevent and cure some diseases and relieve symptoms of other ailments. Throughout the 20th century and especially from the 1940s on, members of the industry have discovered new drugs that cure previously incurable diseases, prevent diseases that are epidemic in nature, reduce the frequency and length of hospital stays, and increase life expectancy.

Drug Discovery

A large majority of new drugs are discovered and developed by the pharmaceutical industry. Historically, most of these discoveries have been the result of massive chemical syntheses or natural compound extraction programs and subsequent pharmacological screening efforts. This technique is still used today, especially in the search for naturally occurring compounds in previously uncharted locales, such as plants from rain forests. Highly advanced technology, such as recombinant DNA, is being used in order to improve such drugs as insulin, interferon, and certain hormones.

Computer-aided design is also finding growing use in drug discovery. Databases consisting of numerous chemical combinations and their actions are used to design rapidly, by computer, a large number of compounds whose affinity for specific biochemical receptors can be predicted. Following synthesis of the key compounds, these predicted actions can be tested in vivo. Genetic engineering and extraction of drugs from microorganisms have also resulted in the discovery of numerous active compounds.

Research and Development

The research and development (R & D) of a drug and its actual production are heavily regulated by the U. S. FOOD AND DRUG ADMINISTRATION (FDA) and similar agencies throughout the world. The industry spends more than half of its multibillion-dollar profits for R & D activities; safety and efficacy tests account for a majority of these expenditures. Almost all of the money for R & D comes from the pharmaceutical companies themselves. Government funding of research for pharmaceuticals historically has been about 1 percent of the total pharmaceutical industry R & D expenditure, but federal funds have increased for cancer and aids drug research. A federal law passed in 1983 also provides incentives for companies to develop so-called "orphan" drugs--drugs that are otherwise commercially unprofitable to develop because they are used to treat diseases that afflict relatively few people.

Each new product can cost up to $250 to $300 million for R & D; this includes the cost of developing drugs that prove unsuccessful during testing stages. Only one in several thousand compounds tested actually results in a product that is approved for clinical trials. Before a new drug goes on the market, companies must obtain an approved New Drug Application (NDA) from the FDA. This approval follows an average of eight to ten years of chemical, analytical, pharmaceutical, toxicological, pharmacological, and clinical testing. Each of these areas is closely scrutinized by the FDA, especially the clinical trials, where testing is done in three phases, according to specific protocols. (A protocol is the detailed set of instructions used by physicians that define the criteria for patient selection, drug handling and administration, treatment evaluation, and documentation.) Phase I involves demonstration of drug safety with increasing single doses administered to healthy human volunteers or hospitalized patients, depending on the intended therapeutic use. Phase II involves demonstration of efficacy in a limited number of patients. Phase III represents an expansion of Phase II, with both safety and efficacy demonstrated in more patients and at a number of test sites around the country. Each new trial involving new patients, a new test site, change in dose level or administration, or a new protocol, must be approved by the FDA.

Prior to the start of clinical trials, the developer of the drug usually files a patent application. The patent may cover chemical synthesis, pharmaceutical formulation, and medical use. Patents are approved for 17 years, allowing for a certain period of market exclusivity following FDA approval. This exclusivity period provides an opportunity for the firm that developed the drug to use pricing to recover the cost of R & D of this drug as well as the many others that led to this discovery.
Following success in all three phases, all data from clinical trials and from the development effort associated with the manufacture of the drug substance and the drug product are gathered to form the NDA, which is then submitted to the FDA for approval. Only about one in five that are actually tested in humans results in a product that reaches the market. NDAs are very complex, often consisting of enough paperwork to fill a small room. Electronic submission of NDAs is currently being developed by both the pharmaceutical industry and the FDA. About 80 percent of the eight to ten years required for testing and approval of a new drug is taken by preclinical and clinical testing. The remainder is needed for review and negotiations with the FDA for final approval.
Once the patent expires for a particular drug, pharmaceutical companies other than the original patent holder can begin manufacturing similar versions of that drug. These versions, called generic drugs, cost less than the original drug, and are often produced by more than one company. They are known by their pharmaceutical name rather than by a trade or brand name. Generic drug manufacturers must submit abbreviated NDAs to the FDA for approval, with complete chemistry, manufacturing, and control information for their products, but minimal clinical testing reports. The reduced testing requirements are what keep the costs down for generic drug manufacturers. Many states require that prescriptions be filled with less expensive generic drugs when possible.

Manufacture

Both over-the-counter and ethical, or prescription-only, drug products manufactured in the United States and throughout most of the world must be made according to the Good Manufacturing Practices (GMPs), promulgated and enforced by the FDA. Each lot of active and inactive raw material, containers, and closures received in a plant is sampled and tested before it can be used in a pharmaceutical product. The products are made according to strictly written batch records. Qualified pharmacists measure, check, and recheck each step in the manufacturing. The batch is sampled, tested, and approved before it is released for shipment to drug wholesalers, hospitals, and pharmacies. All drug products carry an expiration date on the package label, which informs the user as to the product's duration of potency. Each drug manufacturer must register a list of each product it makes with the FDA. Every two years the FDA inspects the manufacturer for compliance with federal regulations.

Marketing

Over-the-counter pharmaceuticals are sold in retail pharmacies and drug departments in a variety of retail establishments. These products include vitamins, cough and cold remedies, laxatives, analgesics, antiseptics, antacids, and contraceptives. Ethical pharmaceutical products are sold only on a prescription order from a physician or dentist and are dispensed by a pharmacist. The information concerning a product is provided to the physician and the pharmacist by the company's medical-service representative. Some of the prescription-only classes of drugs are antiinfectives, sedatives, ataractics, antispasmodics, cardiovascular drugs and antihypertensives, analgesics, and hormones.

After Rolland I. Poust

PHARMACOLOGY

Pharmacology, science of the interaction between chemical substances and living tissues. If the chemical is primarily beneficial, its study falls under the title therapeutics; if primarily harmful, its study is called toxicology. In either case, pharmacodynamics defines how the material is absorbed by the body, where it acts, what its effect is, and how it is metabolized and excreted.

Pharmacologists determine the therapeutic index of drugs, that is, the relative benefit to toxicity at various doses. This helps define the dosage of a drug that will most benefit a sick person. They also study how various conditions affect the excretion of drugs. For example, many drugs are more slowly metabolized in older persons, so these drugs need to be administered less frequently. Because many chemicals are excreted by the kidney, persons with kidney disease may have impaired drug excretion.

Physicians who specialize in pharmacology are called clinical pharmacologists. Pharmacists who practice in hospitals also specialize in pharmacology, and they can advise physicians on the optimal use of medicinal drugs.

PHARMACY

Pharmacy is a service within the health-care system that is related to drugs, their preparation, and their proper use to treat illness by cure, control, and prevention. Modern pharmacy is so complex and rapidly changing that no one can know or practice all of it. In only one part of the health-care system do pharmacists alone dominate--in the dispensing of drugs prescribed by physicians.
The concerns of pharmacy and pharmacists begin with drug discovery and end with evaluating and improving drug effectiveness in a single patient at a given time. Drugs are created either through synthesis by pharmaceutical chemists or through collection and purification from natural sources by experts in pharmacognosy. The scientific study of drug effects is called pharmacology. Biopharmaceutics and pharmacokinetics study and describe how drugs reach and are removed from their sites of action in the body.

Chemicals that possess desirable drug effects must be put into a finished product, such as a tablet or injection. The drug product must meet many requirements related to stability, safety, and effectiveness. Most drugs that are marketed today are mass-produced by the pharmaceutical industry. In earlier times the apothecary was responsible.

The modern pharmacist is responsible for the quality of the drugs compounded for and dispensed to a patient. The pharmacist is also responsible for helping to ensure that a drug program is appropriate for a patient, based partly on how much detailed and timely knowledge of the patient's condition is at hand. Further, he or she should inform the person administering or taking the drug about its proper use, side effects, and dangers. Federally funded health-care programs require pharmacists to monitor the effectiveness of drug therapy in certain patients and to make recommendations about continuance or change.

 History

Until perhaps only 1,000 years ago practitioners of religion and magic controlled medicine because so many aspects of disease lay outside observation, explanation, and control. Moreover, scientific method and application of scientific principles to pharmacy have taken effect only in the last 50 to 100 years. The oldest accounts relating to pharmacy come from ancient India and China. Healing in these civilizations was based on the belief that disease was caused by the presence of spirits in the body. The concept of purification from sin by a purgative existed in Babylonia, Assyria, Egypt, and parts of Greece. GALEN, in 2d-century Rome, classified drugs in terms of their supposed effects on the four humors--blood, phlegm, yellow bile, and black bile. He thus created a systematic guide for selecting drugs, which, unfortunately, was scientifically incorrect. From the 7th century until the Middle Ages, Arabs contributed a large body of knowledge concerning available drugs.

By 1240, Holy Roman emperor Frederick II issued three regulations that separated the profession of pharmacy from medicine, instituted government supervision of pharmacy, and obliged pharmacists to take an oath to prepare drugs reliably. During the 19th century, pharmacy developed in the United States, including pharmacy organizations, formal education of pharmacists, and official texts, or pharmacopoeias, setting standards of identity and purity of drugs.

Pharmacists and others in the field began to organize to further their professional, economic, and political goals with the formation (1852) of the American Pharmaceutical Association. The U.S. pharmaceutical industry has been represented since 1958 by the Pharmaceutical Manufacturers Association. The Federation Internationale Pharmaceutique, established in 1910, is a worldwide organization of pharmacists based in the Netherlands. Most pharmacists work in retail stores, and the rest work in such areas as hospitals and nursing homes, manufacturing and distribution, government, and teaching.

 Legal Regulation

The U.S. FOOD AND DRUG ADMINISTRATION (FDA) is the strongest force determining directions for U.S. pharmacy because it controls drug manufacturing and distribution. Before FDA release, the distribution and use of an investigational new drug are tightly controlled until the drug has been scientifically proved to be safe and effective. The individual states have the most influence on the practice of pharmacists through their licensing power. States decide who may prescribe and restrict prescribing to physicians as well as osteopaths, dentists, podiatrists, and veterinarians.
Pharmacists can be sued for malpractice if their professional activities cause injury and result from performance below standard. The American Pharmaceutical Association code of ethics requires pharmacists to be ethical in their solicitation of services and to respect the confidentiality of records. Although the FDA closely controls manufactured drugs, it considers the filling of a single compounded prescription as a practice of pharmacy and out of its jurisdiction. Refilling a prescription usually requires authorization of the prescriber.

After Kenneth J. Ballard

PHARMACY

Pharmacy, practice of compounding and dispensing drugs; also the place where such medicinal products are prepared. Pharmacy is an area of materia medica, that branch of medical science concerning the sources, nature, properties, and preparation of drugs. Pharmacists share with the chemical and medical profession responsibility for discovering new drugs and synthesizing organic compounds of therapeutic value. In addition, the community pharmacist, or druggist, is increasingly called upon to give advice in matters of health and hygiene.

Education and Practice

In the U.S. colleges of pharmacy offer 5-year undergraduate programs leading to the degree of bachelor of science in the pharmaceutical sciences. All accept students directly from high school and may grant advanced standing to college students or graduates. Licenses are granted by states after the following requirements have been met: graduation from one of the 72 colleges with programs accredited by the American Council on Pharmaceutical Education; about 1500 hours of internship under a registered pharmacist; satisfactory completion of a state examination. Pharmacists may practice their profession in a pharmacy located in a hospital, nursing home, or special area of a drugstore. They may also be employed by a pharmaceutical company in scientific research or the development and production of new pharmaceutical products.

History

In antiquity, pharmacy and the practice of medicine were often combined, sometimes under the direction of priests, both men and women, who ministered to the sick with religious rites as well. Many peoples of the world continue the close association of drugs, medicine, and religion or faith. Specialization first occurred early in the 9th century in the civilized world around Baghdad. It gradually spread to Europe as alchemy, eventually evolving into chemistry as physicians began to abandon beliefs that were not demonstrable in the physical world. Physicians often both prepared and prescribed medicines; individual pharmacists not only compounded prescriptions but manufactured medicaments in bulk lots for general sale. Not until well into the 19th century was the distinction between the pharmacist as a compounder of medicines and the physician as a therapist generally accepted.

The modern pharmacist deals with complex pharmaceutical remedies far different from the elixirs, spirits, and powders described in the Pharmacopeia of London (1618) and the Pharmacopeia of Paris (1639). In the U.S. today, major medicines, those regarded as having the greatest therapeutic value, are selected for inclusion in the Pharmacopeia of the United States, first published in 1820, by a Committee on Revision on which all colleges of medicine and pharmacy, all state medical and pharmaceutical associations, and the U.S. surgeon general are represented. After the drugs have been chosen, the standards for quality and potency are formulated by pharmacists and pharmaceutical chemists. Similar criteria for drugs regarded by the committee as having less therapeutic value are set forth in the National Formulary, published by the American Pharmaceutical Association (founded 1852) since 1888. Any significant variation from pharmacopeia and formulary standards may be prosecuted by the Food and Drug Administration under the Pure Food and Drug Acts.

PSYCHOACTIVE DRUGS

Psychoactive Drugs, chemical substances that alter mood, behavior, perception, or mental functioning. Throughout history, many cultures have found ways to alter consciousness through the ingestion of substances. In current professional practice, psychoactive substances known as psychotropic drugs have been developed to treat patients with severe mental illness.
Psychoactive substances exert their effects by modifying biochemical or physiological processes in the brain. The message system of nerve cells, or neurons, relies on both electrical and chemical transmission. Neurons rarely touch each other; the microscopic gap between one neuron and the next, called the synapse, is bridged by chemicals called neuroregulators, or neurotransmitters. Psychoactive drugs act by altering neurotransmitter function. The drugs can be divided into six major pharmacological classes based on their desired behavioral or psychological effect: alcohol, sedative-hypnotics, narcotic analgesics, stimulant-euphoriants, hallucinogens, and psychotropic agents.

Alcohol has always been the most widely used psychoactive substance. In most countries it is the only psychoactive drug legally available without prescription. Pleasant relaxation is commonly the desired effect, but intoxication impairs judgment and motor performance. When used chronically, alcohol can be toxic to liver and brain cells and can be physiologically addicting, producing dangerous withdrawal syndromes.

Sedative-hypnotics, such as the barbiturates and diazepam (widely known under the brand name Valium), include brain depressants, which are used medically to help people sleep (sleeping pills), and antianxiety agents, which are used to calm people without inducing sleep. Sedative-hypnotics are used illegally to produce relaxation, tranquillity, and euphoria. Overdoses of sedative-hypnotics can be fatal; all can be physiologically addicting, and some can cause a life-threatening withdrawal syndrome.

Narcotic analgesics—opiates such as morphine and heroin—are prescribed to produce analgesia. Because the relief of pain is one of the primary tasks of medical treatment, opiates have been among the most important and valuable drugs in medicine. Illegal use of narcotic analgesics involves injecting these substances, particularly heroin, into the veins to produce euphoria. Opiates are physiologically addicting and can produce a quite unpleasant withdrawal syndrome.

Stimulant-euphoriants, such as amphetamines, are prescribed by physicians to suppress the appetite and to treat children often diagnosed as hyperactive. Although amphetamines stimulate adults, they have a paradoxically calming effect on certain children who have short attention spans and are hyperactive. Cocaine is used medically as a local anesthetic. Amphetamines and cocaine are used illegally to produce alertness and euphoria, to prevent drowsiness, and to improve performance in physical and mental tasks such as athletic events and college examinations.

Hallucinogens—psychedelic drugs such as LSD, mescaline, and PCP—thus far have little medical use. They are taken illegally to alter perception and thinking patterns. Marijuana is a weak hallucinogen that may be medically useful in suppressing the nausea caused by cancer treatments and possibly in reducing eye pressure in certain severe glaucomas.

Psychotropic drugs have been in use since the early 1950s. Antipsychotic drugs decrease the symptoms of schizophrenia, allowing many schizophrenic patients to leave the hospital and rejoin community life. Antidepressant drugs help the majority of patients with severe depression recover from their disorder. Lithium salts eliminate or diminish the episodes of mania and depression experienced by manic-depressive patients.

After Philip A. Berger

PSYCHOPHARMACOLOGY

Psychopharmacology, study of the relationship between drugs and brain function, including mood, perceptions, and behavior. Psychopharmacology is a branch of pharmacology, the study of the action of drugs on living organisms. Psychopharmacology is employed in psychiatry, psychology, neurology, and in medical specialties concerned with brain function.

Throughout history, almost every culture has sought ways to alter consciousness by experimenting with plant substances that yield many of the psychoactive drugs of today. Important developments in ancient psychopharmacology include the discovery and use of alcohol, cannabis, and opium in Europe and Asia and of caffeine, nicotine, cocaine, and hallucinogenic plants such as peyote and psilocybin in the pre-Columbian Americas. Developments in the 19th century include the isolation of the potent analgesic morphine from opium; the introduction of the anesthetics nitrous oxide, ether, and chloroform; and the early use of cocaine as a stimulant. The first sedative hypnotics, the barbiturates, were introduced in the early 20th century, followed by the discovery and use of amphetamines as psychostimulants in the 1930s; the discovery of the hallucinogenic properties of lysergic acid diethylamide in 1943; the discovery of lithium carbonate as a treatment for manic-depression in 1948; the discovery of the antipsychotic, antischizophrenic activity of chlorpromazine in 1952; and the discovery, in 1957, of two treatments for depression: tricyclic antidepressants and monoamine oxidase (MAO) inhibitors. In the latter 20th century many drugs continue to be found that fall within these major groupings. Also included among the psychoactive agents are the so-called minor tranquilizers, the benzodiazepines.

After Philip A. Berger

PURE FOOD AND DRUG ACTS

Pure Food and Drug Acts, general designation for laws designed to ensure the safety, proper labeling, and purity of foods, drugs, vaccines, devices, and cosmetics. The most important such law in the U.S. is the Food, Drug, and Cosmetic Act of 1938, which is administered by the Food and Drug Administration (FDA) of the Department of Health and Human Services.

Foods, drugs, vaccines, medical devices, veterinary drugs, and cosmetics in interstate commerce must comply with the law, which protects both consumers and manufacturers. Factories where these products are prepared receive inspections covering sanitation, raw materials, adequate processing, and finished product. Penalties for violations include seizure of illegal goods, injunctions to restrain violative shipments, and criminal prosecution of those responsible for the violation, with fines up to $500,000, imprisonment up to 10 years, or both, for repeated offenses.

The first pure food and drug law was enacted in 1906 through the efforts of Harvey Washington Wiley and other crusaders who brought to public attention many abuses in the form of poor health practices and excessive prices. This law, as revised in 1938 and strengthened by subsequent amendments, gives consumers the greatest protection they have ever received from dangerous and impure foods and drugs; it requires labeling that will disclose the nature of the contents of the package when the buyer cannot see the product or judge its composition and value. It also provides safeguards against the introduction of untested new drugs.

A 1951 amendment required that drugs that cannot be used safely without medical supervision must be dispensed only upon prescription. The food additives amendment of 1958 required manufacturers to prove to the FDA the safety of additives before their use in foods. Color additive amendments in 1960 tightened requirements on colors used in foods, drugs, and cosmetics. Both banned the use in foods of substances that cause cancer in animals. Drug amendments passed in 1962 required manufacturers, for the first time, to prove to the FDA the effectiveness, as well as the safety, of drugs before they were marketed. Amendments in 1965 imposed strict controls on abused-drugs—depressants, stimulants, and hallucinogens. The Child Protection Act and the Fair Packaging and Labeling Act of 1966 gave additional protection to the consumer. The Medical Devices Act of 1976 amended the law by providing for controls over medical equipment.
Pure food and drug laws, in the United States, are federal regulations designed to protect the consumer from adulterated or otherwise harmful food, drugs, and cosmetics. Federal efforts to control food and drug adulteration--which had long been considered the domain of the states--began in the second half of the 19th century, and Congress finally passed the Pure Food and Drug Act in 1906. It defined adulteration, outlawed interstate transportation of adulterated foods, and prohibited the misbranding of foods and drugs.

By 1906 relatively little use had been made of advertising, other than the claims made on the label of the product. Hence it was felt that an emphasis on stating the truth on the label would be an adequate protection against misrepresentation and fraudulent terms. Since the act applied only to interstate commerce, however, it was evaded in an unexpected way: Goods were shipped without labels, which were added only after the goods were safely within state jurisdiction. The effectiveness of the law also suffered because it did not anticipate the dramatic changes taking place in consumer marketing and advertising. It did not cover cosmetics, obesity cures, curative devices of a mechanical nature, or the newer habit-forming drugs. The law helped, however, in cutting down on adulterated foods and drugs, contributed somewhat to improved sanitary conditions under which they were made, and discouraged misrepresentation of the labels.

Later, more sharply targeted legislation included the Federal Meat Inspection Act of 1906; the Sherley Amendment of 1912, which tightened the ban on mislabeling; the Net Weight Amendment of 1913; the Gould Amendment of 1913 requiring quantity labels on packaged goods; and the establishment of butter standards in 1923. In 1927 enforcement of the food and drug regulations became the responsibility of the newly created Food, Drug, and Insecticide Administration, renamed in 1931 the FOOD AND DRUG ADMINISTRATION (now part of the Department of Health and Human Services).

In 1938 all these acts and amendments were for the most part superseded by a new comprehensive law, the Pure Food, Drug, and Cosmetic Act. This legislation expanded the affected commodity list, increased penalties, broadened the concepts of adulteration and misbranding, and paid special attention to particularly harmful commodities. Cosmetics and therapeutic devices were brought under the law. Adulteration included the presence of any filthy or decomposed materials or anything that was prepared under unsanitary conditions. False or misleading labeling was banned. Containers that were made, formed, or filled so as to be misleading also were prohibited. Goods were banned from interstate shipment unless they had labels. The law also called for more information on labels--for example, products that contained certain drugs were required to indicate their habit-forming nature. Cosmetics were to be considered adulterated if they contained any poisonous materials that might render them injurious if the products were used in the manner prescribed on the labels.

Provisions were set up to define quality and standards of identity for food items. Tolerances for potentially poisonous or otherwise dangerous ingredients, such as food preservatives, also were regulated strictly. FOOD ADDITIVES could not be used that would make a commodity appear to be bulkier or that would reduce its quality. The use of coal-tar coloring products was regulated. Injunctions could be used to bar questionable practices pending final action. The 1938 Wheeler-Lea Amendment contained specific provisions against false advertising for foods, drugs, cosmetics, and therapeutic devices. Enforcement, however, continued to suffer from inadequate budgets and from judicial interpretations that denied the right of the government to inspect a manufacturer's premises without prior consent. This right was given by Congress to the Food and Drug Administration in 1953.

While it remains the basic federal legislation, since 1938 numerous other amendments have been added to the Pure Food, Drug, and Cosmetic Act. New regulations effective in 1994 finally required that food labels list detailed nutritional information. Unresolved, however, was another long-standing controversy--the issue of pesticide residues on food. The Delaney Clause, a 1958 addition to the Food, Drug, and Cosmetic Act, prohibits even trace amounts of any cancer-causing chemical residue on commodities that are used in processed food. Another rule, however, allows small amounts of carcinogenic pesticide residues on raw foods, if the risk to health they pose is deemed "negligible"--with more than a one-in-a-million chance of causing cancer. In 1993, the Clinton administration proposed replacing the Delaney clause with a single, "negligible risk"standard.
Many other changes and challenges to the Food, Drug, and Cosmetic Act will arise as new technologies and new health concerns create their constituencies. Genetically engineered foods, for example, fall under FDA regulation. In 1993 the agency approved the use of recombinant bovine growth hormone (rBGH) to increase milk production in dairy herds, and in 1994 it approved the distribution of a genetically altered TOMATO. Both were controversial decisions.

After Reuben E. Slesinger

PHARMACOPOEIA

The term pharmacopoeia, derived from the Greek words pharmakon ("medicine") and poiein ("to make"), has been used over the years to refer to a variety of books containing information about the preparation of remedies. Although drug preparations have been acknowledged since Babylonian times, the first official pharmacopoeia was the Dispensatorium of Valerius Cordus, published in 1546 and made legally binding for the practitioners in the imperial city of Nuremberg, Germany. The first pharmacopoeia published in the United States was the Lititz Pharmacopoeia, compiled by Dr. William Brown in 1778 for use in military hospitals during the American Revolution.
In 1820, The Pharmacopoeia of the United States of America was published, a result of the deliberations of the Pharmacopoeial Convention (Washington, D.C.; 1820), which was attended by representatives of U.S. medical societies and colleges. The Pharmacopoeial Convention has reconvened every ten years thereafter, and the Pharmacopoeia itself has been revised every five years since 1940. The decision as to the admission or deletion of a drug in this book is the responsibility of the Committee on Scope, composed largely of physicians. Each drug admitted has an official name assigned to it, and its characterizations are detailed according to a uniform and rigid pattern. The 23d revision of the United States Pharmacopoeia (1995) describes about 3,500 drugs, with many additional monographs on dosage forms.

A supplementary formulary of medicinal preparations, the National Formulary, was published in 1888 by the American Pharmaceutical Association. Since 1906, with the passage of the Pure Food and Drug Act, and continuing with its successor, the Food, Drug and Cosmetic Act of 1938, the United States Pharmacopoeia and the National Formulary have been recognized as legal standards for all drugs therein.

Each country, and often regions within countries, has different standards for drug strength and purity. Efforts to provide an international standard for pharmaceuticals culminated in the Pharmacopoeia Internationalis (1951), revised periodically by the WORLD HEALTH ORGANIZATION(WHO). The need for worldwide standards arose following increased international travel and drug trade.

After Eunice B. Bardell

APOTHECARY

The term apothecary, derived from the Latin apotheca (a storage room for spices and drugs), refers to a person who sells spices and drugs. It is an old-fashioned term for pharmacist that originated in Europe in the late 13th century, when such merchants began to be called apothecaries to distinguish them from the merchants who sold many other kinds of domestic goods as well as drugs. This distinction is preserved in Germany, where a pharmacist is called an Apotheker, whereas a Drogist sells cosmetics, dietetic aids, toiletries, candy, and those drugs and remedies not restricted to pharmacies.

In Britain the term has come to refer to a medical practitioner. As early as the late 16th century, the apothecary became a combination medical and pharmacy practitioner. During the Great Plague in London (1665-66), apothecaries cared for the sick when most of the physicians who survived had fled the city. The apothecaries continued to devote more time to their medical practice than to pharmacy until 1841, when the board of examiners of the Society of Apothecaries noted that the term apothecary did not reflect the duties they performed and suggested instead that apothecaries should be referred to as general practitioners of medicine. In the same year, when the Pharmaceutical Society of Great Britain was founded to elevate the profession of pharmacy, a new class of practitioners of pharmacy was developed: the chemists and druggists, or pharmacists.
In colonial America a pharmacy operated by an apothecary or pharmacist was called an apothecary shop to distinguish it from a doctor's shop, a pharmacy operated by a medical practitioner. The term apothecary was recognized by the Continental Congress in 1775, when it established a medical department headed by a director-general and chief physician with a staff of four surgeons, one apothecary, and others. Two years later the duties of the apothecary were restricted to pharmaceutical tasks for the first time in America.

In the United States today, the term pharmacist denotes one who is licensed to practice pharmacy. Some community pharmacists, however, have adopted the term apothecary to indicate that their pharmacies sell only pharmaceuticals and health service items, unlike other pharmacies that sell a wide variety of merchandise in addition to pharmaceuticals. This meaning dates from 1940, the year that the American College of Apothecaries was organized.


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