WORLD HEALTH THE W... OF rmE WORLD HEALTH 0114.11.A.10.1 APRIL • UM MA • OSA SOAP Cover design by Peter Davies Contents Man and his medicines by N. Howard-Jones 4 Pressing needs in many lands by T. A. Lambo 12 Are we overconsuming ? by L. Christopher and J. Crooks 16 Monitoring the effects of drugs by B. W. Royal) 22 The future: hopes and fears by F. Gross 28 Give Blood ... Save Life . 33 Catch them young 34 Letters 35 "The Theriac Vendor" by Simon Feilner, Germany, 1752 (see p.4). (Photo WHO) Enormous progress has been made in the field of pharmacology since the Second World War, and the pharmaceu- tical industry has been able, over the last few decades, to develop new products that in many instances have had a positive impact on health and life expectancy. We now have effective weapons against a number of illnesses, particularly the parasitic and infectious diseases, and the advent of modern drugs has undoubtedly brought about a revolution in both public health work and medical practice. Yet side by side with the continuing benefits of this revolution there exist many problems of a complex nature. In the wealthy countries, for example, cases sometimes occur of death due to the misuse of medicines. In the less privileged nations, however, it is only too common for people to die in their thou- sands because vaccines or medicine are simply not available. This contrast be- tween the abundance of pharmaceutical products in certain parts of the world and the dire lack of them in others is highly disturbing, and cries out for urgent action. Drug manufacturers are often criticized for unjustifiably high prices and for failing to direct their research towards actual needs, particularly those of the developing world. Other causes for com- plaint are the duplication of products by different companies, with the wastage this entails, and the constant battery of advertising, seen as a principal cause of the high consumption of medicaments. In addition, the belief is still widespread among all strata of society that there exists a remedy for every ill, and drug advertising does nothing to dispel this illusion. What can be done to fulfil the need for medicines in all countries, and to reduce the wastage that goes on in the richer ones? This issue of World Health does not attempt to propose final solutions to complex questions of this sort, nor can it be exhaustive on such a vast subject. However, following the first article (page 4), which retraces the history of pharmacology and the first successes of modern chemotherapy, the interview on page 12 includes the suggestion that the creation of local pharmaceutical indus- tries in countries seeking to become economically self-sufficient could contrib- ute to both development and health. Increased drug consumption is the subject of the article on page 16, while another (page 22) concerns the safety of pharmaceutical products and the WHO international monitoring system for ad- verse reactions to drugs. So far, nearly 75,000 reports of adverse reactions have been received by WHO; at the request of its Member States, WHO has also under- taken 370 investigations into the safety of certain drugs and the epidemiological aspects of various adverse reactions. The last article (page 28) deals with future prospects in chemotherapy, and includes a warning against over-optimism. A most important point, too often neglected, is that medical students do not receive adequate information during their training about the drugs that they will later be called upon to prescribe. Clinical pharmacology deserves a more prominent place in the medical curriculum, and practising doctors should be able to take refresher courses at regular intervals on the action and use of newly introduced drugs. Lastly, the general public needs to be informed of the dangers of overconsump- tion of drugs, and warned against un- necessary self-medication. ■ medicines past, present and future World Health appears in Arabic, English, French, German, Portuguese, Russian, and Spanish. Articles and photographs not copyrighted may be reproduced provided credit is given to the World Health Organization. Signed articles do not necessarily reflect WHO's views. World Health, WHO, Avenue Appia, 1211 Geneva 27, Switzerland 3 man and his medicines by Dr Norman Howard-Jones Since the dawn of history man has attempted to cure disease or relieve dis- comfort by swallowing foreign substances or applying them externally. Even primi- tive societies, whose only history is tradition handed down by word of mouth, have their own medicines, often admin- istered with magical rites. But modern man has little reason to scorn such practices. In highly-developed countries there are few bathroom cabinets that do not contain a strange assortment of pills, tablets, capsules, powders, ointments and suppositories, which are swallowed, ap- plied, or inserted at the first onset of the most trivial symptoms. It is not without significance that the ordinary name for a bathroom cabinet in French is pharmacie. There is hardly any product of the animal, vegetable, or mineral kingdoms that has not at some time in history or in some place been reputed to have medicinal virtues, from the powdered horn of an animal that never existed—the unicorn— to the dried excrement of dogs. The latter was known by the more respectable name of Album Graecum, and had a special reputation for the treatment of sore throats. For pleurisy, horse-dung was preferred. Throughout man's history there has been, in the words of a famous American physician in 1860, a popular belief that "sick persons should feed on noxious substances". Since these words were written, the fundamental change has been that natural products have been pro- gressively replaced by synthetic chemical substances that never before existed. Nevertheless, modern man still shares with his predecessors the belief that for every disagreeable symptom, however banal, there is an appropriate remedy— usually taken by mouth. The more a minor ailment—such as the common cold —is untreatable by any scientifically valid measures, the greater is the multiplicity of the popular medications employed. While every housewife knows how to treat a cold, this knowledge has not yet pene- trated to the medical profession. There is no correlation between the number of different medicaments em- ployed at a particular period of history and the state of advancement of medical and pharmaceutical science at that time. Over 3,500 years ago the Ebers papyrus listed more than 700 medicinal products. And although very few of the drugs in use only a hundred years ago would today be recognized as effective, Pereira's Elements of the Materia Medica (1854-1857) ran to three volumes comprising a total of 2,577 pages. Pestle and mortar ( 1st century A. D.) now in the Swiss Museum for the History of Pharmacy, Basle. (Photo Hoffmann-La Roche ©) We can only speculate on what first led man to attempt to alleviate his minor or major ills by ingesting or applying various substances. Certainly this was no rational process, for it is only in relatively recent times that man has had any idea of the nature of diseases or the mode of action of drugs. Perhaps a clue may be found in the fact that the first purposeful action of an infant is to feed, and when only a few months old he will instinctively try to put into his mouth any interesting object. Primitive man may have had similar reactions, arriving by a process of trial and error at an idea—almost invariably illusory—of those animal, vegetable, or mineral products that seemed to have some curative properties. Nevertheless, he did manage by purely empirical means to discover not only a variety of products consumed for enjoyment rather than for nutrition or treatment of disease—such as alcohol, tobacco, caffeine-containing bev- erages, opium, coca, and marihuana—but also a number of plants from which highly potent active principles were later to be isolated. The most valuable of the latter in the treatment of disease was the quinine-containing bark of the cinchona tree—popularly known as "Jesuit's bark" —which was effective against malaria. However, because there was no under- standing of the reasons for its effectiveness, the bark was also used indiscriminately for many conditions in which it was useless. The most monstrous medicine Not only were innumerable natural products, almost all of them with no therapeutic action at all, employed as remedies, but they were often combined in formulae of the most incredible com- plexity. The most preposterous—and the most highly prized—example of these polypharmaceutical preparations was known as Theriaca Andromachi, or theriac, which was first concocted almost two thousand years ago and lasted in the official pharmacopoeias of some European countries until the twentieth century. It was based on a slightly less complicated formula, Mithridatium, which legend at- 4 A painting on wood dating from about 1540. The young woman in the centre is fondling an animal that never existed—the unicorn. The powdered horn of the alleged unicorn long enjoyed a reputation as a valuable medicine. (Photo WHO) 40sookV*4.4,4100, • tributes to Mithridates VI (126-64 B.C.), King of Pontus in Asia Minor. In the first century A.D., Nero's physician, Andro- machus, sought to make Mithridatium an even more powerful remedy, especially against venomous bites, by the addition of viper's flesh and a number of other ingredients. The recipe of Galen (130- 200 A.D.) included no less than 63 in- gredients. Theriac was not only the most complex but also the most long-lived of all pharma- ceutical preparations. In cities such as Cairo, Constantinople, Genoa and Venice, which were important for the trade in drugs and spices from the East, it was publicly prepared each year with cere- monies of great pomp attended by civic and religious dignitaries. The preparation made in Venice enjoyed a particularly high reputation, and theriac came to be known in England as "Venice Treacle". This offered an inducement to English pharmacists to include directions printed in Italian with their own concoctions, which an eighteenth-century writer des- cribed as being composed of "the sweep- ings of their shops". By 1837 the theriac of the French pharmacopoeia contained 71 ingredients. It was at about this time that Claude Bernard, later to become one of the greatest of the founders of physiology, was apprenticed to a pharmacist. It is recounted that if his employer noticed that some drug had gone off he would say to Bernard: "Don't throw it away, Monsieur Claude. It will do for the theriac." By 1884 the official French theriac still contained 56 ingredients, and it was directed that the fresh mixture should be put aside for some months before being pounded together. Across the channel, an English physi- cian, William Heberden, had in 1746 published a book called Antitheriaka, which was a forceful plea for the abolition of this irrational "medley of discordant simples", and in which he pointed out that the only active ingredient was opium. Theriac duly disappeared from the next (1788) edition of the London Pharma- copoeia, but it was not until 120 years later that it was dropped from the official Paris equivalent with the following nostal- gic adieu: "After having held so great and so enduring a place in pharmacy and therapeutics, it quits the domain of history to be relegated to that of legend." That theriac and other irrational poly- pharmaceutical preparations should have lasted so long provides eloquent witness to the credulity of man in all that pertains to his health. But in the early years of the nineteenth century there were other trends that were ultimately to point the way to a more rational approach to the problem of man and his medicines. In a revulsion against the universal and indiscriminate administration of pills, potions, plasters and purges, Samuel Hahnemann (1810) proclaimed the doctrine of homoeopathy. No more—but no less—scientific than his contemporaries, he had conceived the idea that infinitesimal doses of a drug that produced symptoms resembling those of a disease would be its cure. "Like is cured by like" was his principle, and in this there was an echo of the earlier "doctrine of signatures", according to which, for example, the cure for jaundice was to be found in a plant with a yellow flower. It was undoubtedly a great merit of homoeopathy that its practitioners did not poison their patients, who probably had a better chance of recovery than those treated by orthodox physicians. A turning-point A great breakthrough—in which para- doxically France, which had for so long cherished theriac, played a major part— was the isolation of the active principles of drugs. It was a German chemist, F. W. A. Sertiirner, who isolated mor- phine from opium in 1805. Some years later, two French chemists, J. B. Caventou and J. Pelletier, isolated strychnine, qui- nine, and several other alkaloids, while P. L. Geiger and H. Hesse announced in 1833 the isolation of atropine. Later, many other pure compounds were to be isolated from pharmacologically active plants, in- cluding caffeine, codeine, emetine, nico- tine, and cocaine. These chemical achievements were to presage the scientific approach to drug therapy—the reasoned administration of a single compound with a view to produc- ing a specific effect—but they had very little influence on medical treatment or pharmaceutical practice in their time, although Francois Magendie in France, who may be regarded as the founder of pharmacology, included such active prin- ciples as were then available in his Formulaire of 1822. Towards the middle of the nineteenth century, the French pharmacopoeia still included, in spite of the discovery of morphine almost half a century before, a method for preparing an extract of opium that involved con- tinuous boiling for six months, while replenishing the evaporated water at intervals. In 1913, Sir Thomas Clifford Allbutt, a most distinguished and scholarly physi- cian, recalled with gentle mockery in his 77th year the realities of Victorian drug therapy: "When I began practice it was custom- ary at every consultation to prepare a writing-table, pens, and ink for 'the prescription'. This script . .. was of formidable composition, a drug for every symptom, and a few more for the pool; it was solemnly set forth and signed by two or more physicians; by the patient's friends this was under- stood, if but long enough, to be the organ of his restoration ... If the recipe failed, well the consultant and home doctor together had not hit off the precise formula. If the formula suc- ceeded it was treasured like a bank- note . . ." In 1853 there was another significant development when Alexander Wood of Edinburgh decided to try, not a new drug, but a new method of administration: hypodermic injection. He had erroneously conceived this method as a form of local anaesthesia to deaden the pain of neural- gia by the injection of morphine along the course of nerves at sensitive points, but it was soon realized by others that such in- jections exerted a general effect by rapid absorption into the bloodstream. The first patient to become an unwitting pioneer of this new therapeutic method was an elderly spinster, to whom Wood admin- istered hypodermically at 10 p.m. on 28 November 1853 a large dose of mor- phine. Visiting his patient 13 hours later, Wood was, as he wrote in 1855, "a little annoyed to find that she had never wakened" and that he had to use "some- what energetic stimuli" to arouse her. As a solvent for the morphine, Wood had chosen sherry as being, inter alia, less likely to rust the syringe than water! Many doctors seized upon this new technique to try out the effects of the numerous active principles of drugs that had been discovered, but their efforts were rather directed towards seeing what would happen than based on a reasoned therapeutic approach. Some even claimed remarkable results from the hypodermic injection of water. Today, morphine is still injected to relieve pain, and atropine, in addition to its local use to dilate the pupil of the eye, may be injected as an antispasmodic and inhibitor of bronchial secretions. Other early applications of the technique have faded into history. The German pharmacologist, Carl Binz, wrote of the immense value of morphine injec- tions in relieving the sufferings of the wounded during the Franco-Prussian war of 1870. Unfortunately, neither doctors nor patients realized for many years that such injections produced addiction, and 6 cob jletoz to tic OWL Veragainft Ludgate Church, with- in Block-Fryers Gate-way, at Lii. lies-Read, Liveth your old Friend Dr. Cafe, who faithfully Cures di Grand P—, with all its Symptoms very Cheap, Private, and without the Intl Hin- drance of Buruiefs. Note, He bath been a Phy. titian 33 Years, and gives Advice in any Diftem per gratis: All ye that are of Yenta Ram Apply your fel res to Dr. Cafe; Who, with s Box or two of F ILLS, Will Loon remove your painful' ILLS. man and his medicines The author of this advertisement (right), "Dr Case", undertakes to cure the Grand Pox—the popular name for syphilis—by "a box or two" of his pills. He claims that his treatment is not only cheap and private, but "without the least hindrance to business". Moreover, he points out that he gives free advice for any disease—if only you will buy his pills! His advertisement shows the inevitable pestle and mortar. Until well into the 19th century, the ministrations of licensed physicians had no demonstrable advantages over the attentions of those whom the Faculty called quacks. There were, in fact, licensed and unlicensed quacks. This beautiful 18th-century French jar (below) was a fitting receptacle for theriac, a medicine that for nearly two thousand years was regarded as a sovereign remedy for almost all the ills to which human flesh is heir. Recipes for theriac sometimes contained more than 70 ingredients, and the preparation did not disappear from some European pharmacopoeias until the beginning of the 20th century. The jar is in the Swiss Museum for the History of Pharmacy in Basle. (Photo Hoffmann-La Roche ©) . • • „ I 1, • Ao r )14‘ • • A 1 a 14e" • • = many patients became morphinomaniacs. Here, at last, was something that really worked—but at a very heavy price. New age of synthetic drugs In 1867, Lauder Brunton, an English physician-pharmacologist, first described the use of a synthetic compound—amyl nitrite—in the treatment of angina pectoris, an acutely painful spasm of the arteries of the heart. Brunton based this treatment, which was purely symptomatic, on the knowledge that amyl nitrite caused dila- tation of the coronary arteries in animals. As he was to write 40 years later, this was "the first complete example of rational therapeutics based on experimental patho- logical and pharmacological data". In the succeeding years there was to be an explosive development of the use of synthetic chemicals in medicine. Chloral hydrate had first been produced by the eminent German chemist, J. von Liebig, in 1832, but it was not until 37 years later that his compatriot, 0. Liebreich, intro- duced it into medicine as a hypnotic in the mistaken belief that it would be broken down into chloroform in the body. In spite of this theoretical error, chloral hydrate proved to be for many years a useful hypnotic and sedative. Among the many other synthetic prod- ucts introduced into medical practice were antipyrine (1884), phenacetin (1887), and aspirin (1893). The last-named of these products might almost be said to have inherited the mantle of theriac by the multiplicity of the uses to which it is put —from the young wife who has caught her husband kissing her best friend, to the Minister of State who retires to bed with two aspirins, a hot whisky-and-lemon, and many blankets, determined to cure his cold by "sweating it out". In 1903 the discovery of the first of the ever-expanding family of barbiturates—barbitone—was announc- ed by E. Fischer and J. von Mering in a publication entitled (in German) "On a new class of hypnotics". The medical uses of synthetic chemicals were not limited to drugs in the strict sense of the term, for in the middle of the nineteenth century they were to revolution- ize surgery by making possible anaesthesia and antisepsis. It was an American dentist, W.T.G. Morton, who effectively introduc- ed ether as an anaesthetic agent, and a Scottish obstetrician, J.Y. Simpson, who did the same with chloroform, respectively in 1846 and 1847. Henceforth, surgery ceased to be a form of benevolent torture. There remained, however, the terrible problem of infections following surgery —then often called "hospital gangrene"— and it was an English surgeon, Joseph Lister, who showed in 1867 how such infections could be prevented by another chemical product—carbolic acid—which had been isolated from coal-tar by F.F. Runge of Germany in 1834. Crude as was Lister's method, it was the first giant step towards modern aseptic surgical tech- niques. Lister had been inspired by the work on fermentation and putrefaction of Louis Pasteur of France, a chemist who had not at that time directly applied his genius to medical problems. These two great men were later to conceive a mutual admiration for each other that was not marred by the slightest trace of rivalry. Birth of chemotherapy The father of chemotherapy was Paul Ehrlich, a German physician of outstand- ing creative ability, who not only coined the term but originated the concept that it represented. In an address to the Berlin Medical Society on 13 February 1907 he proclaimed: "What we want is a Chemo- therapia specifica, that is, we are looking for chemical agents which, on the one hand, are taken up by certain parasites and are able to kill them and, on the other hand, in the quantities necessary for this lethal action, are tolerated by the organism without too great damage." In the same address Ehrlich broadly distinguished between drugs that were organotropic, with a direct action on some organ of the body, and those that were etiotropic, and aimed at an invading cause of disease rather than at the body itself. Ehrlich's great concept of chemotherapy had been fired by his observation of the affinity of a dye, methylene blue, for nervous tissue, and in 1890 he had written that "only those substances can really influence the cell that are, if the expression may be permitted, eaten by it". Later he enunciated the aphorism corpora non agunt nisi fixata, which may be loosely rendered as "sub- 8 man and his medicines Left, a painting from a 13th-century Arabic manuscript in the National Library of Austria. It shows the laborious preparation of theriac. The time, effort and misplaced ingenuity that went into "improving" recipes for theriac resulted only in a saleable commodity that had none of the effects claimed for it. (Photo Hoffmann-La Roche t',) Right, towards mechanization: the downward thrust of the pestle is achieved by a combination of its weight and the effort of the operator; the pestle is raised by the recoil of the how- shaped spring. The lady is judiciously sprink- ling a powder into the mixture in order to hit off the right formula. (Photo Hoffmann-La Roche ((''.)) stances (i.e. drugs) are not active unless they are fixed". While Ehrlich's contributions to medical science were numerous, he is chiefly remembered for his introduction in 1910, with the Japanese scientist Sahachiro Hata, of the organic arsenical drug Salvarsan (arsphenamine) for the treatment of syph- ilis. Two years later—and only three years before his death—he introduced an im- proved version of this drug in the form of Neosalvarsan (neoarsphenamine). These were, to employ Ehrlich's terminology, "etiotropic" drugs, in that they were aimed at the microbe responsible for syphilis and not at its unwilling human host. They were far from meeting Ehrlich's ideal requirements, in that they had poisonous effects on the human body. Moreover, the treatment was intensely disagreeable, since it required intramuscu- lar injections over a period of many months. Nevertheless, neoarsphenamine remained for over thirty years the mainstay of the treatment of a disease that, if left to run its natural course, produced the most devastating results. Ehrlich had shown the way, and in the first decades of the twentieth century much progress was made in the development of synthetic chemotherapeutic drugs in the treatment of tropical diseases, notably malaria and sleeping sickness. But all attempts to combat the more universal bacterial diseases—such as scarlet fever, pneumonia, and septic infections—re- mained fruitless. Treatment of these was mainly "supportive" or "expectant", con- sisting of alleviating symptoms while hoping for the best. The patient either died or recovered, and in the absence of specific weapons both doctors and nurses had to endure the cruel recognition that there was little or nothing that they could do. Chemotherapy comes of age The tide started to turn some 40 years ago when a German physician reported at a meeting in Diisseldorf on 17 May 1933 that a new drug, then called Streptozon (later Prontosil), had caused a dramatic recovery in a 10-month-old boy who had been at death's door from a bacterial infec- tion. During the next two years there were a few isolated reports to the same effect, but they did not arouse the interest that might have been expected. On 15 February 1935, another German physician, Gerhard Domagk, published what has been describ- ed as an "epoch-making communication" entitled (in German) "A Contribution to the Chemotherapy of Bacterial Infections". This described the remarkable results obtained by the treatment with Prontosil of experimental infections in mice. Although Domagk's work was to be recognized by the award in 1939 of the Nobel Prize for Physiology and Medicine (which his government did not allow him to accept), its importance was not generally recognized at the time. There were, however, two leading medical scientists who at once saw its significance : Sir Henry Hallet Dale of the National Institute for Medical Research, London, and Professor Constantin Levaditi of the Institut Pasteur, Paris. The former wrote in March 1935 and the latter in the following April to the manufacturers of Prontosil requesting samples for experimental purposes. In London, carefully-controlled trials showed that the drug was highly effective against puerperal streptococcal infections (child- bed fever), and it was the publication of these results that aroused the interest of the English-speaking world. A remarkable feature of the new drug, which was of very complex chemical structure, was that while it was of un- doubted efficacy against both experimental and natural infections it did not kill or inhibit the growth of germs cultured outside the animal or human body. This obser- vation led to the idea that Prontosil did not exert a direct effect upon the invading microbes but in some way reinforced the resistance of the host. But this idea was soon to be demolished by workers at the Institut Pasteur, who made the astonishing discovery that Prontosil owed its action to its breakdown in the body to a much simpler substance, now known as sulfa- nilamide, which was active both against infections and bacterial cultures. Since then, many allied substances —collectively known as sulfonamides— active against a wide range of bacteria have been synthesized. One of the most extraordinary features of this whole story is that sulfanilamide had been synthesized in 9 Germany as long ago as 1908 by P. Gelmo. For almost three decades this synthetic compound—which could have saved countless lives—had been available but had not been used medically. In some minds arose the unworthy suspicion that the formula of Prontosil might have been made deliberately complex in order to make it patentable. The discovery of the antibacterial action of the sulfonamides was the most impor- tant single event in the history of drug treatment. It was to be followed only a few years later by another historic event that heralded the new age of antibiotics. In 1928, Alexander Fleming, in London, had observed that a mould called Penicillium notatum produced a substance that in- hibited the growth of cultures of harmful bacteria. Fleming never succeeded in isolating the substance, but named it "penicillin" and predicted that it might prove to be of value in the treatment of bacterial infections. Some ten years later Professor (later Lord) Howard Florey assembled a team of physicians and chemists in Oxford to make a systematic study of naturally occurring substances with an antibacterial action. It soon became evident that Fleming's mould offered the most promis- ing approach, and after laborious efforts Florey's team managed to isolate a small quantity of a crude preparation of penicil- lin and to demonstrate its effectiveness against experimental infections of mice. On 12 October 1940 a policeman was admitted to hospital in Oxford with a serious staphylococcal infection compli- cated by a secondary streptococcal in- vasion. Florey and his wife—also a physician—decided to use their precious stock of penicillin for a trial in this case— the first patient in history ever to be treated with an antibiotic. Penicillin is partially excreted by the kidneys, and so infinitesimal was Florey's supply of the drug that the patient's urine was harvested in order to extract from it the penicillin that it contained and re-inject it. There was a striking improvement in the patient's condition, but before this could be main- tained the supply of penicillin ran out and the patient died. Later trials, when more supplies of the antibiotic became available, showed it to be a life-saving drug such as had never been known before. But Britain's economy was by then on a war footing, and there were other priorities that prevented the development of penicillin on an industrial scale. Florey therefore visited the United States and soon persuaded American industry to engage in large-scale production of the antibiotic. It was the Desert War in North Africa that provided the scene for the first mass clinical trials of penicillin. Today there are numerous other antibiotics that have special advantages in certain infec- tions. Nevertheless, penicillin has not been superseded, and is probably still the most extensively used antibiotic today. Penicillin was never patented, and neither Fleming nor Florey and his collaborators derived any financial benefit from it. Had they done so, they would have been multi-millionaires. However, they received a reward greater than money could buy, for in 1945 Fleming, Florey and the chief chemist of the Oxford team, Boris Chain, were jointly awarded the Nobel Prize for Physiology and Medi- cine. It has not been possible within the scope of this article, which has no claim to be other than an impressionistic sketch of major trends, to list the vast number of useful synthetic drugs that are now em- ployed in medicine, nor even to mention some of the older natural remedies, such as digitalis, that are still of value. The trail that has led from theriac to today's drugs has been a long one, but now more progress is made in two years than was previously made in two thousand. In the old days, the physician's prescrip- tions had no demonstrable advantage over the domestic medicines of the patient. Today the physician has at his disposal a wealth of drugs of controlled potency and purity, produced under conditions that only the vast resources of the chemical industry can provide, and the individual pharmacist no longer has any legitimate role in the compounding of medicines. Nevertheless, domestic medicine still lin- gers on, as witnessed by the innumerable non-prescription drugs that are available and to be found side-by-side with prescrip- tion drugs in millions of bathroom cabinets. The lesson of the whole history of drugs is that man has always found it difficult to believe that he should not be a sort of ambulant pharmacy. ■ 1 0 • man and his medicines Opposite page, woodcut of men: from the Faroe Islands hacking up a whale, doubtless to be used to provide meat for the table and oil jrO lamps. An unofficial pharmacopoeia published in London in 1707 credited the fat of the whale with curing scabies, while adding that its liver smelt of violets. Above, woodcut published in Venice in 1554. The man portrayed is not an animal-lover who likes to keep vipers as pets; he is collecting them to sell them to pharmacists. For many centuries the dried flesh of vipers was held in an esteem as great as it was unmerited as an antidote against all kinds of poisons. Here was the first glimmering of the concept of immunology. Right, a picture dating from the 17th century and showing a female viper giving birth. She encircles a drawing of the heart and liver of a viper. Below her are lozenges of dried viper flesh, which were used in the preparation of theriac and other remedies. (Photos WHO) pressing needs in many lands An interview with Dr T. Adeoye Lambo Deputy Director-General, WHO World Health: Dr Lambo, what is the extent of the need for drugs in the devel- oping countries? Dr Lambo: There is no doubt that the developing countries need drugs badly, and the root of the problem is that while the old diseases—the infective processes, the communicable diseases—are still ram- pant in those countries, most of the pharmaceutical producers are located in developed countries where such diseases are no longer their main preoccupation and therefore their investments in terms of money and research are minimal. So there is a huge need to produce appropriate and effective therapeutic agents to treat the diseases peculiar to the developing countries, and to produce them in quantity, but this is not being done. In fact, most of the developing countries do spend a high proportion of their budgets on drugs imported from overseas. At the last WHO Executive Board, for instance, it was pointed out that in one country, although only a quarter of the government's health budget was allocated to drugs, four times the amount of that total health budget was actually spent on drug imports. So we see that in the developing countries not only are the needs great but also the drugs they buy may not be the appropriate ones, may not be effective against the diseases they have to deal with, and if they are, they may be too costly. In some cases their quality is in doubt. World Health: Do you think anything can be done to remedy the situation, and how can wHo help? Dr Lambo: WHO has a prime role to play in this respect. A number of resolu- tions have of course been passed on the subject at various World Health Assem- blies, aimed at stimulating research into the developing countries' needs and encouraging them to meet these needs. Where WHO can take the lead, and has begun to do so, is in helping countries to build up their own local and national pharmaceutical industries, and this is something I myself try to promote, particularly in the developing countries of Latin America, Asia and Africa. The need for these nations to have machineries for the control of the quality of these drugs and for monitoring their adverse effects is great. The developing countries should do their utmost to organize national or regional pharmaceutical industries that will be under their own control, so that they can both cope with their needs and direct research towards an all-out attack on their most prevalent diseases, which still hinder their broad socio-economic development. This may also improve the cost-benefit ratio of their drug expenditure. In certain instances, not only are there several drugs on the market for the same disease or syndrome, but some of them are new and in some cases have not been adequately tested under local conditions and among the local populations. They may be effective in a temperate climate but lose their potency in the tropics, for example. In addition, there are many biological and social variables which have to be taken into consideration. So, if the developing nations could muster the re- sources to set up their own pharmaceutical industries, they should be able both to in- crease the efficacy of the drugs they use and bring the tremendous costs which, at the moment, are crippling them. At the same time these countries could develop new drugs which would be directed towards specific tropical conditions. World Health: Many countries today are making special efforts to plan for health service expenditure within the framework of their overall economy. But isn't it extremely difficult to separate the cost of drugs from the cost of other medical services and to decide how much to allocate to a drug budget? Dr Lambo: Yes, it can be very difficult to define the exact cost of drugs in relation to the other elements of treatment. There is a certain amount of overlapping, and the longer and more complicated the treatment, with hospitalization, X-ray fees, laboratory tests, etc., the more difficult it is to separate out the costs. On the other hand, in those countries still afflic- ted with the communicable diseases the priorities are relatively easy to establish— it is in everyone's interest to deal first with the obvious diseases, e.g., schistoso- miasis, filariasis, malaria, tuberculosis, malnutrition, or whichever diseases are the main problems in the area. In such cases, the priority spending has to be on preventive and curative chemotherapy, including vaccines, to protect the popula- tion against the main scourges. And of course, provided a mass campaign against a communicable disease is successful, then this type of expenditure has to continue only as long as the campaign itself. World Health: Isn't tuberculosis a good example of a disease for which drugs are available but may be too costly for many countries? Dr Lambo: Yes, between 15 and 20 mil- lion people have TB and three-quarters of them live in the developing world. Drugs are now available to treat them, and there is no doubt that this has had a tremendous success and pharmaceutical research in this connection has saved many lives. 12 Distribution of badly-needed medicine in an African country. (Photo WHO/D. Henrioud) ' •k, Even so, the cheapest way of dealing with TB—mass preventive vaccination with BCG—although it costs less than 10 US cents per head, is still expensive for some countries where the budget for their entire health programme may not amount to a dollar per head. Tuberculosis is a disease whose prevalence could be dramatically reduced if developing coun- tries could only afford the cost of the systematic effort required; we should invest more in preventive measures, with special emphasis on environmental health. World Health: Since treatment for TB is such a long process it must be important to make sure that the patients are actually taking their drugs, to prevent wastage? Dr Lambo: It is essential to see that they do, not only to prevent wastage but for the success of the treatment. But of course this is a problem everywhere, regardless of a country's state of develop- ment. There are always some patients who are self-disciplined and others who, for various reasons, don't follow the doctor's prescription and advice. This is more so in communities that are not terribly enlightened. World Health: Do you think that placebos, inactive preparations, have a useful place in medicine? Dr Lambo: Undoubtedly, placebos can have a psychological value. Our present world is a turbulent one—people are restless, disturbed, their livelihood or their future tends to be uncertain and, as a consequence, they ask for drugs to help them live through their frustrations. Even if they are given something inactive, it can have a psychotherapeutic effect— they "take it" and they "feel better". Generally speaking, placebos are more successful in the developing countries, because to take a "drug" is part and parcel of the culture, of the mythology and of giving yourself some form of divine energy. By taking something by mouth you incorporate it into yourself and revitalize yourself. World Health: It has something of a magical effect, therefore? Dr Lambo: Yes, it has a magical effect, that is the word. World Health: Do you consider that in the developing countries the witch-doctors still have a role to play? Dr Lambo: There is no doubt that in our world today we are becoming more and more aware of the need to look at the totality of man—matter and mind, the body and the mind Biological medicine, or medicine as practised today, cannot cater sufficiently for what I call the wholeness of man, and therefore there is no doubt that some of these so-called witch-doctors, whom I would prefer to call traditional 14 pressing needs in many lands WHO's main aid to countries is of a technical and advisory nature, but in an emergency the Organization can rush medical supplies to areas stricken by disasters or epidemics. Left, cholera vaccine and rehydration fluid destined for Calcutta are loaded in Geneva on , to a plane provided by the British Government. (Photo WHO'D. Henrioud) Right, a traditional healer performs a ritual ceremony with drum accompaniment Jver a sick man in Sri Lanka. (Photo L. Irmes (0) healers, are just as valuable as psychothe- rapists or psychiatrists in the western world. People are becoming more and more isolated and they are absolutely yearning to talk to someone and be given some opportunity to ventilate their emo- tions. Human beings in all cultures still need rituals in spite of our technological civilization. World Health: And the traditional healer, of course, listens and has a helpful word to say. Dr Lambo: Yes, they listen, but they also perform a ritual, and man, whether he is sophisticated or unsophisticated, needs a certain amount of ritual and his basic metaphysical yearnings have to be met. For example, people who belong to churches or religious sects may have fewer conflicts in their lives—they are often able to resolve their conflicts much more readily. World Health: It might be a good idea, therefore, for the public health services to try to co-operate with traditional healers in some of these cultures? Dr Lambo: I would be inclined to think so. I think their methods could be refined and they could be given an acceptable place in their society. The People's Republic of China is an example, and a commendable one, of the capacity of a country to mobilize and utilize all its resources, and simply refuse to imitate the developed countries. I think the people in the developing countries are ready, in fact, to mobilize and utilize their resources in this way. In many cases they attend their hospitals but they still attend the traditional healers too. It would certainly be a good thing for the traditional healers to be given an official position within the community and to be recognized by the health authorities and the political leaders, so that their services too could be incorporated into the overall health services of their nation. There is no such thing as one medicine. Ackerknecht, the great medical historian, has warned us that "our medicine is not the medicine nor our religion the religion, and there is not one medicine but numerous and quite different medicines in different parts of the world and in the past, present and future. Measuring everything by our everyday standards, we will never understand either the past or the future." He further stated that traditional medicine, of which psycho- therapy is the cardinal and most powerful weapon, "is not a queer collection of errors and superstitions, but a number of living unities in living cultural patterns, quite able to function through the centuries in spite of their fundamental differences from the western pattern...". ■ 15 are we overconsuming? by Dr Lloyd Christopher Drug Evaluation and Monitoring Unit, WHO and Professor James Crooks Department of Pharmacology and Therapeutics, University of Dundee, UK Some idea of the extent of the medical use of drugs in countries where data are available can be obtained from drug manufacturers' sales figures, government purchases, the number of prescriptions dispensed and field surveys on drug use in the population. Estimates made on these bases reveal a vast increase in drug use and, though the evidence is wholly cir- cumstantial, there are signs that there may be a growing problem of drug over-use. For example, the'increase in the use of psycho-active drugs is so striking in the highly industrialized countries that it might well contain a component of over-use; the too liberal prescription of antibiotics, including unnecessary prophylactic treat- ment, could account for the resistant strains of bacteria increasingly reported; and the widespread belief among the general public that medical science has produced a pill to alleviate every illness or discomfort may be influencing the prescribing habits of doctors. Although these observations are not proof of drug over-use, it is important to give them prompt and careful attention before too much ground is lost. Direct evidence of the overconsumption of drugs is difficult to obtain because in most countries data are not available on the relation between drug consumption and illness. Only a few countries with well developed national health systems or drug control legislation can provide even esti- mates of consumption, while accurate and up-to-date country-wide illness statistics are not available anywhere. Drug use estimates in England and Wales, Sweden and the United States are strikingly high. In England and Wales the number of prescriptions dispensed by chemists between 1949 and 1964 fluctuated between 188 and 212 million per year, followed by a rapid rise between 1964 and 1967, and a levelling-off between 1968 and 1971, the 1970 figure being 247 million. The table below shows the number of prescriptions dispensed for selected groups of drugs in the years 1967 and 1971. Figures for Sweden collected by the National Board of Health show a steady increase between 1954 and 1966 of from 20.9 to 33.8 million prescriptions dis- pensed, a more rapid rise during 1966 to 1968 from 33.8 to 38.1 million and, as in the UK, a levelling-off in 1969 and 1970. Number of prescriptions dispensed by chemists in England and Wales Drug Group Millions of Prescriptions 1967 1971 Laxatives and purgatives 6.1 7.3 Diuretics 5.3 8.0 Anti-hypertensives 3.9 5.2 Psycho-active drugs 37.7 41 .7 Hypnotic non-barbiturates • 4.5 7.1 Hypnotic barbiturates * 15.0 1 0.9 Tranquillizers * 13.6 1 7.1 Antidepressants* 4.6 6.6 Preparations used in rheumatic diseases 5.9 7.7 Antipyretic analgesics 18.9 15.6 Expectorants and cough suppressants 19.2 15.5 * Sub-groups of psycho-active drugs. Sources: Annual Reports of the Department of Health and Social Security for England and Wales. In the United States, approximately two thousand million prescriptions were dis- pensed in 1970, a 50 per cent increase over the previous decade, and this figure is expected to rise. Total consumer expendi- ture for prescription and non-prescription drugs and other health aids were estimated at $19 thousand million. In France, allowing for the rise in prices, total national expenditure on pharma- ceuticals increased by 170 per cent between 1959 and 1972. In 1970 the increase on the previous year was 14.4 per cent, and in 1971 and 1972 it was 10.8 and 11 per cent respectively, despite the fact that new regulations made only 70 per cent of the cost of drugs reimbursable under the social security system, as opposed to 100 per cent previously. It is undoubtedly true that the large number of therapeutically useful drugs made available by pharmacological and pharmaceutical research has contributed to the increased use of drugs. Another important contributory factor is the in- creased life expectancy of most popula- tions, which has brought about a change in disease patterns and a rising incidence of chronic and degenerative diseases. Greater numbers of the elderly now seek and receive medical treatment, which accounts to some extent for the increasing use of diuretics and preparations that act on the heart. In the UK between 1970 and 1971, there was an increase of more than 15 per cent and 20 per cent respectively in the number of prescriptions for these drugs, or over a million prescriptions more for each group. It is likely, however, that a number of other factors are contributing to the in- creased use of drugs. Information about these factors is beginning to accumulate, albeit slowly, as a consequence of studies of drug usage both in the community and hospital practice. In a study of 1,400 households in the UK in 1969 it was found that four-fifths 16 Self-medication is dangerous. Drugs hoarded for months or years are likely not to have the same effects as when they were fresh and may also cause adverse reactions. (Photo WHO/ D. Henrioud)
of the adults and more than half the children had used some kind of medication in the preceding two weeks; in over 50 per cent of cases it had been prescribed more than a year previously, and 75 per cent of the drugs had been obtained on repeat prescriptions. From this study it was calculated that more than half the adult population and almost one-third of all children take some kind of medication every day. All such studies indicate that women take more medicines than men and that the consumption of medicines increases with age; women over 65 take more drugs than any other group by age or sex. In France, children under two years of age are high consumers. In Sweden, married persons of either sex are significantly more frequent drug con- sumers than the unmarried when similar age-groups are compared. Balint and his co-workers, in their study of general practice patients receiving long- term repeat prescriptions, found two com- mon characteristics : (a) the need to main- tain some connexion with the doctor, even via a third party (the pharmacist), and (b) the reluctance to have a deeper relationship of frank communication with the doctor about personal problems and predicaments which might remain below the surface for years. The total psycho- social relationship between doctor and patient, and its connexion, if any, with drug over-use, needs further investigation. Socio-economic factors such as level of education, occupation, income, conditions of work and social status may also be significant, but apart from a few isolated studies little has been done in this area. Hospital studies, though by necessity restricted, have yielded firm evidence of drug over-use. For example, a study in the United States showed that of 1,035 hospital patients receiving anti-microbial drugs, 36.2 per cent actually had infections and 54.1 per cent were given them prophy- lactically. A large number of the latter group had undergone surgical procedures considered "clean", i.e. with minimal risk of infection, while over 20 per cent of the total study cases were judged to have had "irrational" treatment, i.e. combination therapy when only one drug would have sufficed, an inappropriate drug, or treat- ment not considered necessary. In 1966, in Canada, 4,894 patient charts were examined to determine patterns of use of anti-microbial drugs. In 48.5 per cent of cases an infection was present, in 10.5 per cent the treatment was sympto- matic, in 37.1 per cent it was prophylactic and in 3.5 per cent no indication for use could be found. According to the test results, a "wrong" drug was chosen in 62.5 per cent of cases and corrected later in 46.9 per cent, but was allowed to continue in the remaining 15.6 per cent. The increasing use of psycho-pharmaceu- ticals has been the cause of much concern and a great deal of research is required to identify all the reasons for this increase and whether over-use exists. In 1970, as many as 214 million prescrip- tions for psycho-therapeutic drugs were dispensed in the USA, 17 per cent of the total number of prescriptions (including repeats) for that year. The UK figure was 47.2 million prescriptions, 19 per cent of the total. Tranquillizers and sedatives, together with hypnotics, account for over 50 per cent of all psycho-therapeutic drugs prescribed in the USA and the UK, and current evidence shows that they are the fastest growing sub-groups among the psycho-pharmaceuticals in both countries. Although similarity-in-use estimates may at first sight lead one to accept the increased consumption of this group of drugs as a "normal" trend, they may in fact reflect a universal pattern of excessive and inappropriate use. The potential problem of over-use of this group of drugs is related not to the "well-defined" mental illnesses—psychoses and neuroses—but to a large number of symptom complexes that come mainly under the care of the general practitioner; some of them may be classed as neuroses, 18 are we overconsuming? In Czechoslovakia, doctors in four of Prague's ten districts now write their prescriptions on punched cards (left and right). The patient takes the card to the chemist, who dispenses the medicine and sends the card on to a central computer unit. Information from the cards can later be used for surveys, comparing con- sumption in different districts, for example. About 1,000 different drugs are marketed in Czechoslovakia, most of them manufactured within the country and all distributed by one' national supplier. Only about 180 items can be obtained without a prescription. A Board for Appropriate Pharmacotherapy regularly evalu- ates data on drug consumption, sending rec- ommendations based on its findings to all the country's doctors. (Photos WHO/E. Schwab) but many remain vague and indeterminate. It is often difficult to distinguish those patients whose tensions and worries are acceptable or bearable from those whose normal life is so seriously affected as to require treatment. Many questions remain unanswered : Is the accepted "norm" of well-being increasingly difficult to attain without the use of psycho-active drugs? Is a higher standard of well-being now sought by more people? How is this related to specific factors operating in the society? Are individuals becoming more intolerant of the everyday stresses that affect them physically or mentally? Are these stresses more prevalent in today's world and, if so, why? How is this related to alcohol consumption, tobacco-smoking, drug dependence? Even with the limited information available on psycho-active drug consumption, the extent of the increase is sufficiently marked to warrant intensive investigation by experts in socio- logy, psychology, epidemiology, psychiatry and general medical practice. If the suspicion is confirmed that drugs are used inappropriately in medical prac- tice to an extent that would merit the description of overconsumption, three factors that may influence doctors' pres- cribing habits should be considered: the undergraduate and postgraduate educa- tion of doctors, the marketing practices of the pharmaceutical industry, and the type of medical care system in various countries. It is generally accepted that undergradu- ate training in clinical pharmacology and therapeutics is inadequate, and much remains to be done in the preparation of the doctor to meet the complex problems of drug therapy. Lack of knowledge of this discipline increases the frequency of irrational drug therapy and can in turn result in an over-use of drugs. Some common instances are : the use of combi- nation drugs when a single component would suffice; the use of a higher dose regimen than necessary; the use of drugs when other regimens could equally well be tried; the unnecessary use of prophylactic antibiotics in "clean" surgical procedures; and the mere alleviation of symptoms rather than treatment of their underlying cause. The reason for the neglect of drug therapy in medical curricula is the emphasis on diagnostic medicine, inherited from the time when few effective drug treatments were available, as well as the fact that clinical pharmacology is only now begin- ning to be recognized as an acceptable medical speciality. Postgraduate education in the rational use of drugs is no less important than undergraduate training. In the UK, for example, about 70 per cent of all currently marketed drugs were unknown or unavail- able 15 years ago, when more than half of the doctors practising today were receiving or had already completed their training. Furthermore, specialists, includ- ing clinical pharmacologists, are faced with the problem of keeping abreast with a rapidly evolving knowledge of drug therapy; the difficulty must be multiplied many times for the non- specialist who is responsible for the bulk of medical care in most communities. A recent US study of prescribing habits showed that the better prescribers— judged on a close concordance of opinion with a selected expert panel of pharma- cologists—had certain characteristics in common, some of which were : they were more recently qualified; they had more postgraduate training; they tended to be in group practice with more ancillary personnel; they saw more patients but wrote fewer prescriptions per patient; they more often consulted and were consulted by their colleagues on matters of therapeutics; they relied mainly on journal articles and drug compendia for pre- scribing information; and they disclosed more about therapeutic regimens to their patients. Much evidence was also obtained to support the concept that prescribing 19 s patterns are determined largely by educa- tional experiences. All these considerations lead to the conclusion that undergraduate teaching should have as one of its objec- tives the provision of a firm foundation of basic pharmacological principles, supple- mented by courses on applied clinical pharmacology and therapeutics. Regular postgraduate refresher courses should be planned and designed specially to meet the needs of the general practitioner, who could then approach the management of his patient in a more informed and critical way. It is estimated that pharmaceutical firms operating in the UK and the USA spend about 14 and 20 per cent respect- ively of their gross income on sales promotion. A considerable sum must also be spent on related market research activities. Since the average general practitioner cannot find time either to attend the limited number of postgraduate seminars on therapeutics, or to keep abreast of medical literature and refer to pharmaco- logy text books or drug compendia, he becomes more and more dependent on promotional literature and the pharma- ceutical representative. The industry there- fore remains the most important source of drug information for the general practi- tioner. While the liaison between the pharmaceutical representative and the doctor often provides the latter with a useful and convenient means of learning about important innovations in drug therapy, and an opportunity for the former to collect evidence of the perfor- mance of his drugs in the field, it must be conceded that the information the doctor receives is orientated to selling the product. Contra-indications, types of patients who may develop side-effects, interaction potential, and uncommon side-effects may not be adequately discussed. Furthermore, drug advertisements frequently lay stress on symptomatology rather than on the identification of the underlying disease. When a disease entity is difficult to define, this fact may be exploited by the advertiser to broaden the indications for use of his product. In the USA, drug regulatory authorities now demand that false or misleading claims for drugs be deleted from promotional material; this is helpful but emphasizes the defects in medical education discussed above, which if corrected would prevent the doctor from being misled. Another trend to be deprecated is the use of the mass media of press and television to promote unjustifiable claims for over- the-counter products.Sales pressure of this type militates against the public using such drugs sensibly to reduce the pressure on medical care systems for the treatment of minor ailments. It is unfortunate that methods of liaison have not as yet been satisfactorily devised which would more closely link the vast economic and expertise resources of the drug industry with the needs of the practising physician. Instead, a state of mutual mistrust is common. As Lasagna has remarked, "... there is a certain conflict between the goals of advertising and the goals of the physician and the patient, and no amount of wishful think- ing can alter this fact". However, the continued support of research and inves- tigation for better methods of safe and effective therapy should be regarded by the pharmaceutical industry as the ideal way to build and maintain a sound public image and there are indications that this policy is being followed more frequently. The general practitioner is still hard- pressed to find adequate time for the proper management of individual patients. A survey by the American Medical Association in 1971 showed that the average doctor in office-based practice saw 91.6 patients per week during a 51.3 hour week for 47.9 weeks per year. The number of patients seen was highest for general practitioners (129) and pedia- tricians (125). This time schedule yielded an estimated 17 minutes' direct care per patient and reveals a fairly rigid frame- work within which it is likely many doctors operate. There is thus considerable pressure on the doctor to terminate a consultation after a certain time, and this is conven- iently signalled by writing a prescription. This satisfies the patient that something needing treatment has been discovered and action has been taken to deal with it, and a line of mutual communication has been opened. A prescription is often given even when nothing definite has in fact been found, or nothing serious enough to warrant treatment, since to reassure a patient that there is nothing wrong is time-consuming and from the doctor's viewpoint limits further his time for seeing cases of more serious or more clearly identifiable illness. It is a reason- able prediction that in any system which allowed the doctor to give more time to his patients, fewer prescriptions would be issued. Research into the interaction between available medical resources and patient attitudes to and expectations from medical care might point the way to the reduction of overprescribing of drugs from this cause. In the National Health Service of England and Wales, the direct cost of drugs obtained by prescription has varied from no charge at all to 12.5 pence per item. To some extent this is reflected in the yearly totals of prescriptions dispensed. As would be expected, increase in the prescription charge is associated with some reduction in the yearly total, and conversely a reduction in the charge is associated with an increase in the total for the next one or two years. A closer exami- nation of the UK figures shows that these fluctuations are temporary and do not appear to change the overall trend signifi- cantly. As mentioned above, the recent reduction in reimbursement to the patient of the cost of drugs in France did little to reduce the annual incremental rise in expenditure. It is widely believed that in a highly socialized system, where drugs are avail- able at nominal cost, there will be a strong tendency towards overconsump- tion. So far, inter-country comparison does not support this view. For example, the ratios between estimated psycho- active drug use in the US and UK and the total population of these countries are similar, indicating a similar rate of use. A small field study carried out in a number of western European countries also shows close conformity between countries despite differences in the types of health services. However, in countries with state-suppor- ted medical care systems the degree to which increase in prescription cost de- prives those in need of drug treatment from receiving it, or reduction in cost leads to overprescribing, are subjects which merit considerably more investigation. Certain priorities stand out in this picture of increasing drug use. Problem areas should be looked for and more clearly defined, and examined to determine whether the increase represents a legitimate response to therapeutic needs. If not, the underlying reasons should be sought and corrected. The co-operation of government agencies, drug manufacturers, clinical teachers, general practitioners and socio- economic experts is vital. Since, as mentioned above, drugs may be taken by as many as 50 per cent of all adults every day, and since many of them exert powerful effects, the extent. and gravity of the potential problems cannot easily be disregarded. These conclusions are based on what is known about trends in drug consumption in the industrialized countries, but could be taken into account in other countries where the provision of a rational system of drug therapy within their own evolving systems of medical care is a matter of concern. ■ <—An Indian housewife receiving drug treatment for tuberculosis. Medicines are sorely needed 21 throughout the developing world. (Photo WHO/P. A. Pittet) monitor* the effects of drugs by Dr B. W. Royall Chief, Drug Evaluation and Monitoring Unit, WHO Advances in the pharmaceutical sci- ences over the past 40 years have changed the face of medicine by making a wide range of effective drugs available. Their contribution to preventive and curative . treatment in almost all categories of disease has been outstanding. However, modern drug treatment can in some re- spects be likened to the car or the aeroplane — both are generally accepted as essential to progress, but may produce unwanted effects of an unpredictable and sometimes serious nature. The idea of conducting controlled clinical trials to compare the effects of different forms of treatment is fairly new, and indeed, until relatively recently, all treatment for illness was mainly empir- ical. To do nothing that might harm the patient has always been one of the basic axioms of the medical profession, but in former centuries the outcome of the physician's prescription was often largely a matter of chance. In 1799, for example, George Washing- ton, first President of the United States of America, developed a sore throat and temperature after going out riding on his estate and being drenched by a sudden rainstorm. Gargles of vinegar and molass- es and sage tea were prescribed for him and his throat was blistered with can- tharides, or "Spanish fly", but his strength ebbed rapidly and he died. Blistering, like blood-letting and purging, was an accepted treatment at the time, but it now seems likely that Washington was suffering from a streptococcal sore throat, or possibly a diphtheric infection, and that the treat- ment served only to hasten his untimely death. One of the first scientific attempts to evaluate medical treatment was made at the Charite hospital in Paris in 1828 by Pierre Louis—a study of the effects of blood-letting on patients with pneumonia. At that time the practice was so firmly established that failure to bleed seriously ill patients amounted almost to profes- sional negligence. However, Louis con- cluded that the longer the blood-letting was delayed, the better the chances of recovery for the patient, and even went so far as to suggest that it might be still better not to bleed at all. In 1877, one of the earliest collaborative studies on suspected adverse reactions took place when a small committee of the British Medical Association met in Man- chester to investigate sudden deaths asso- ciated with the administration of the anaesthetic chloroform, which had first been used in the 1840s. In the days of open anaesthesia, when the anaesthetic was dropped on a gauze held over the patient's face, chloroform had several advantages over ether, and was easier to administer. But, as its use in surgery increased, it was found that patients occasionally died suddenly during the induction of anaesthesia. These deaths were especially tragic when the operation was for some minor malady in young and healthy patients. After a three-year inves- tigation, including studies in animals, the committee concluded that the use of chlo- roform was hazardous, not only because it depressed respiration but also because it had deleterious effects on the heart and might cause sudden cardiac arrest. These findings were challenged by many experi- enced physicians and anaesthetists, and authoritative clinical confirmation was not forthcoming until 1890. Today, it is well established that chloroform does indeed affect the heart, and can be fatal. The so-called pharmaceutical revolution is mainly due to advances in three sci- entific and technological areas: firstly, our expanding knowledge of disease processes and their causes; secondly, new informa- tion about the mechanisms of drug action and its effects on specific organs; and thirdly, the greater facilities and resources for drug screening, production, distribu- tion and promotion. Increased activity in this last-named area has been evident predominantly in the industrial sector, but government-sponsored research and academic institutions have also contrib- uted. These advances should produce better health, a longer life span, better medical care and a gain to the economy through decreases in the time lost by the national work force. Such benefits have certainly accrued in considerable measure even if they have not so far been enjoyed to the fullest extent by all populations. What is less widely realized is the extent to which the development of drugs has been accompanied by an increase in adverse effects, many being trivial but an appreci- able proportion being sufficiently serious to offset a substantial part of the benefits. The systematic study of these effects has been rather slow to develop. A therapeutic drug begins as a chemical compound of unknown biological activity. It may have been synthesized because of prior indications of its value or it may be merely one of a large number of compounds thought worth investigation. (One recently introduced drug began life as a rocket fuel, another as a paint solvent which was a by-product of the manu- facture of paper.) The vast majority of new compounds examined will never be useful drugs, and those without value need 22 Testing the action of a drug on animal tissue, a preliminary stage in the develop- ment of a new pharmaceutical product. (Photo Wellcome Foundation)
to be identified and eliminated quickly. This requires comparative tests, usually in an animal species, in which effectiveness can be fairly rapidly measured. Com- pounds thought to be of possible value then need more rigorous comparison in well-designed experiments. The very few compounds that reach this point will certainly not have been administered to enough animals to ensure the detection of uncommon toxic effects. Since the thalidomide episode, the opinion has grown that an intensive search for toxicity, or for any precursor of toxic symptoms, should be made in at least two distinct animal species. The chief elements of the investigation are a careful search in live and dead animals for any sign of acute or chronic toxicity, and full recording of information for future refer- ence, with attention concentrated on any part of the biological system known to be adversely affected by similar compounds. Except for substances that produce a severe toxic effect by a direct and obvious mechanism, remarkably little is known about why toxic reactions to the same drug vary in different animal species. Of course, even a compound that has shown encouraging signs of therapeutic value in animals and a high therapeutic ratio in two or more species may later be found to have a human toxicity that makes it unsafe. Whether the first human recipients of a drug are to be research workers or healthy or sick volunteers will depend upon the nature of the drug. Inevitably, trials must be made with inadequate know- ledge, particularly with regard to the magnitude of the dose given. It must be relatively small, but there are no rules to say how small. For example, a dose one- tenth of that found therapeutically effec- tive in mice might be dangerous in man. monitoring the effects of drugs Right, part of the aseptic area in a labora- tory. Some pharmaceutical products require sterile conditions and must be protected from contamination during manufacturing and testing. (Photo CIBA-Geigy) Below, inspection of ampoules in a factory, prior to quality testing for the purity, potency and sterility of their contents. (Photo Welcome Foundation) ISI Since every human use of a new drug is experimental, medical ethics require that the question "is this drug superior to existing treatments for this disease in a certain class of patients?" be answered quickly and reliably by a well planned clinical trial. The past 20 years have produced extensive literature on this sub- ject, but careful examination of moral issues and scientific logic has shown the legitimacy and practicability of soundly based clinical trials, though many prob- lems still remain to be solved. After so much careful testing, why should any risk remain that a drug is dangerous as well as beneficial? Firstly, as was stated earlier, research on animals is an incomplete guide to human reac- tions: apart from physiological differ- ences, the complexity of the biological and social environment may produce effects in man, such as sensory disturb- ances, that do not occur or that are not easily detected in animals. Secondly, planned human testing for toxicity is rarely practicable. If a drug produces adverse effects in 10 per cent of patients, this should be observable in a clinical trial. However, these trials are generally carried out on only 50 to 300 cases, enough to demonstrate therapeutic benefit but far too few to identify an infrequent danger. A blood abnormality or disturb- ance of vision that could affect between 0.1 and 3 per cent of patients might not appear in a trial made on only 150. A drug that could cause adverse effects more frequently but in a particular segment of the population—say children under 10, or workers in oil refineries—might appear safe because the susceptible sub-popula- tion was not represented in a clinical trial. There are thousands of drugs on the market, and the number of different adverse reactions—ranging from nausea, insomnia, severe jaundice or blood ab- normalities to sudden death and foetal malformation—is also very large. Al- though certain associations of drug and reaction may seem more likely on general <–Tablets fresh from the machine. They will be sampled and tested before being packaged and distributed. (Photo Wellcome Foundation) biological grounds, each one is a possi- bility and the greater danger may lie with those that are least expected. Stand- ard statistical procedures such as spe- cifically designed experiments and sample surveys seem inadequate and are virtually impossible to apply. Awareness that more systematic ap- proaches were needed to provide informa- tion on the nature of serious adverse effects grew only slowly. Certain drugs still in use have been associated with ad- verse effects since as long ago as the thirties and forties, and the argument as to whether or not they should be used continues. The first systematic recording of adverse reactions began in the 1950s, and a registry of blood abnormalities caused by certain drugs was established under the auspices of the American Medi- cal Association. More stringent require- ments for the testing of safety of drugs, including the demand for information on adverse effects experienced by patients during clinical trials, were also introduced by the Food and Drug Administration in the USA during this period. It was, however, not until the thalido- mide experience that public health author- ities became fully aware that the safety of marketed drugs could not be relied upon with the existing systems of chemi- cal and biological quality control, and with responsibility for the safety and efficacy of drugs left almost entirely in the hands of the drug manufacturers, research scientists, and the medical pro- fession. Legislation and new requirements for testing and evaluating the safety of drugs have now been introduced in many countries. Several have established sys- tems for monitoring adverse reactions to marketed drugs and are collaborating with wHo in developing an international ex- change of information on serious adverse reactions to drugs. wHo's action in drug monitoring began in May 1962, a few months after the dangers of thalidomide were first recognized; previously, there had been no systematic provision for the international exchange of information on drug hazards. Member countries adopted a resolution requesting the Organization to set up a programme to promote drug safety and efficacy and explore ways of developing the systematic collection of information on adverse effects. It was considered that the programme could usefully be developed in three directions : Member States should be encouraged to establish systematic drug monitoring programmes, recording the occurrence of suspected adverse effects in such a way that the data can be studied by expert groups and, when necessary, be the subject of validation or follow-up programmes. Groups of experts on drug monitoring should be convened to exchange ideas and advise on ways of promoting a more scientific approach to this complex prob- lem at both the national and the inter- national levels. A test to verify chemical content. (Photo Wellcome Foundation) Ways should be found for evaluating information coming from different coun- tries on suspected cases of adverse reac- tions to drugs. As a result of this programme, the WHO Research Centre for Monitoring Adverse Reactions to Drugs began operations in Geneva in 1971. Its primary objective is to identify as early as possible the liability of a drug to produce undesirable effects not detected or established during clinical trials. Monitoring centres in 18 Member nations collaborate, supplying the WHO Centre with information which is recorded and transmitted to the other Members. Once a suspected adverse reaction has been identified, additional factors—epi- demiological, clinical and pharmacological —must be studied to determine whether there is evidence of any cause-and-effect relationship and to obtain more exact information that will enable practising physicians to assess the risks inherent in prescribing the drug, taking into account such factors as the patient's age, sex, heredity, current state of health and pre- vious medical history, and whether or not the drug will be used in combination with other drugs. So far, WHO has been mainly concerned here with promoting the development of national systems for identifying patients exposed to the risk of suspected drug reactions and studying them retrospectively or prospectively. Summarized compilations of data are forwarded to national centres every three months, on: all suspected reactions re- ported, listed by drug name; all drugs reported, listed by suspected adverse reactions; all drugs and suspected reac- tions reported, listed by reporting coun- try; drugs newly reported in connexion with adverse reactions; and those drugs most frequently reported, with particular reference to those associated with fatal reactions or with foetal disorders or malformations. With the aid of the computer, a series of signalling programmes is being devel- oped to increase the effectiveness of the early warning system. Two such program- mes are now in operation: the "new to the system" programme, indicating drugs, adverse reactions, and drug-adverse-reac- tion associations reported for the first time; and the "increased rate of report- ing" programme, signalling increases in the number of reports concerning a specific drug, adverse reaction, or drug- adverse-reaction combination. By the end of 1973, the WHO Centre had received nearly 75,000 reports on over 6,000 different drugs. In addition, the Organization has carried out some 370 surveys on the safety of certain drugs and continues to disseminate to all its Mem- bers decisions taken on the prohibition or limitation of various compounds in individual countries. By reducing the time taken to detect and notify adverse reactions and, therefore, the number of potential victims, the WHO drug monitor- ing programme is confirming once again the value of international collaboration and co-operation in the health field. ■ 27 Are these the pills you've been taking? the future: hopes and fears by Dr Franz Gross Department of Pharmacology University of Heidelberg, Federal Republic of Germany The dramatic progress made in drug research during the past three decades has had its influence on nearly all man- kind and remarkable advances have been made in many forms of therapy. Hundreds of millions of people have come into contact with modern drugs, and the general public is aware of the possibilities of treating infectious diseases by antibio- tics, or of preventing epidemics by vacci- nation. It knows of drugs affecting mood and mind, of hormones, of vitamins, and of many others. It has, however, also wit- nessed the deplorable consequences of severe adverse reactions, of drug abuse and addiction, and is scared of potent poisons and their abominable misuse in warfare. Clearly such a situation, which is aggravated by the wide publicity that drugs and drug-related problems receive in the press and other media, stimulates reflexion and speculation on those sub- stances still to be discovered. Although, in general, drugs are considered to be of benefit to mankind and of social utility, suspicion and apprehension of the magic power ascribed to them are also felt as an inherent threat. Drug research and the development of new drugs have gone and will go along with advances in biomedical sciences and will be affected by the living conditions that man has to face in the future or, more correctly, prepares for himself. Man is continuously challenged by his creations, and drugs are no exception to this rule; besides all the benefits they have brought, they have also produced hitherto unknown hazards that have pointed up the need for more extensive regulations to assess drug safety. Moreover, despite the long-term studies for possible toxic effects that any new drug has to undergo before it can be given to man, it is beyond any doubt that forthcoming drugs will not only be beneficial but also carry new risks. It is, however, not only the inherent risk factor in drugs that may cause unwanted or dangerous effects, but more their inappro- priate or inexperienced use--a hazard not limited to drugs but associated with all powerful tools, instruments, devices, or chemicals that man has created. Anti-viral drugs The most spectacular advances so far have been made in the treatment of the infectious and some parasitic diseases. Pneumonia, septicaemia, typhoid fever, venereal diseases, tuberculosis, and leprosy can now be treated effectively, as can malaria, amoebiasis and schistosomiasis. On the other hand, little progress has been made in anti-viral chemotherapy. Vaccination against certain severe virus infections, such as poliomyelitis and yellow fever, has been successful; encouraging progress has been made in controlling rubella (German measles); but little has been achieved in protection against the in- fluenza, Coxsackie and many other viruses. Research on the interaction between virus and host cells is going on in numer- ous laboratories, and practical conse- quences may be expected for both the prevention and treatment of virus infec- tions. Humoral factors, such as the inter- ferons, which are responsible for cellular resistance, have been studied intensively, and some have already been chemically identified as glycoproteins, but is it as yet uncertain whether such compounds will ever be useful for the treatment of virus infections in man. Despite all these difficulties, however, it may be expected that anti-viral chemotherapy will advance. Cancer Anti-viral chemotherapy is to a certain extent connected with the treatment of malignant tumours, since the knowledge of mechanisms responsible for cellular resi- stance gained in studies on virus-host interactions will also be useful for under- standing the uninhibited growth charac- teristic of malignancies. Since 1950, nu- merous drugs have been introduced for the treatment of cancer and related diseases, and some cancers can now be controlled by chemotherapy. Progress may, however, be slow and a "cure for cancer" cannot necessarily be expected 28 A large-scale distillation plant in a pharma- ceutical factory—some idea of its size is given by the man standing on the platform, right. The modern drug industry has at its command a wealth of highly sophisticated equipment for both research and production. (Photo CIBA- Geigy) in the near future. Because of the various mechanisms that control the growth of specific cells or tissues in a complex organ- ism, and as a consequence of the immu- nological barriers preventing unlimited expansion of undifferentiated cells and tissues, it is hard to predict whether the approach to the treatment of cancer will be indirect, by influencing cellular resist- ance, or direct, by action on the malignant cells. All currently available cytostatic drugs affect not only malignant but also normal cells, and it is improbable that, by means of the methods now used for screening and investigating drugs for cytostatic activities, compounds will be found that act more specifically or even exclusively on cancer cells. It is likewise questionable whether such a specific action may exist at all. Much more extensive knowledge is needed of the pathogenesis of cancer, of the differences in cell metabolism between various types of normal and malignant cells, of interactions of cells in various organs and tissues, and of the way carcinogens affect cellular resistance and interfere with genetic material. Although it can be predicted that, within the next 25 years, a more profound insight into the underlying biochemical processes will be obtained, it is very doubt- ful that the progress to be expected in molecular biology will have immediate consequences for therapy. Fear of cancer has produced financial contributions to research far exceeding those received in other fields of biomedical science, but even further increases in expenditure cannot achieve a more rapid solution to the crucial problem. We have to live with the fact that progress in the treatment or prevention of cancer will not be specta- cular, but at best will bring temporary suppression of malignant growth or im- proved prospects of keeping certain types of tumours under reasonable therapeutic control. Cardiovascular diseases Quantitatively, the most important dis- eases are those affecting the cardiovascular system. Cardiac failure, hypertension, and 29 arteriosclerosis and its consequences, such as myocardial infarct and stroke, are the most frequent causes of sudden death and reduction of life-span. Remarkable thera- peutic progress has been made in some areas, especially in hypertension, and the drugs available today that effectively lower blood pressure make successful anti-hypertensive therapy possible. However, none of the compounds are free from unpleasant side effects and adverse reactions; furthermore, epide- miological studies undertaken in some countries have revealed that no more than 10 to 15 per cent of all patients suffering from hypertension are adequately treated. This demonstrates that the avail- ability of effective drugs need not imply their appropriate application, and that additional efforts are needed to achieve their proper use. New anti-hypertensives will be developed and marketed, but it is doubtful that they will have decisive advantages over those now at hand. It is more probable that in the field of anti- hypertensives we shall witness over the next 25 years a situation of slow progress by marginal advantages or an "asymp- totic" development (that is, a continuous improvement never quite reaching the ideal), which often occurs after an initial breakthrough. Arteriosclerosis still awaits a successful treatment comparable with that achieved for hypertension, and it is not yet clear whether the pharmacologically induced lowering of blood cholesterol or tri- glycerides is of real benefit to patients suffering from this condition. Whereas it is relatively easy to detect substances that lower plasma lipids, such as do- fibrate, it is by no means established how such an effect is related to the process responsible for the arterial disease. Hence, further drugs which lower blood lipids may be discovered, but that they will represent a more effective treatment may hardly be expected. Since high blood pressure is one of the causes of arterios- clerosis, its adequate control may be a more suitable means of preventing the development or progression of arterios- clerosis than the lowering of plasma lipids. In addition, we have to realize that a tissue or organ that has undergone severe degenerative alterations cannot be restored to normal by pharmacological interven- tion. The ability of drugs to repair is very limited and will remain so in the future. Psychiatric disorders An area on which much interest is concentrated today is the treatment of psychiatric disorders and the possibilities of influencing mind and mood by drugs. Remarkable progress has been made in the treatment of patients suffering from psychoses, such as schizophrenia, severe 30 the future: hopes and fears Left, tablets requiring an added coating are processed in these machines. (Photo CIBA- Geigy) Right, the snail that acts as host to the vector of schistosomiasis being studied in the labora- tory. This research is aimed at finding more effective and less expensive drugs against the disease. (Photo Wellcome Foundation) depression and manic episodes. As in other fields that have been successfully opened up to drug therapy during the past 20 years, it may be expected that advances will be less significant in the near future. An additional difficulty in finding drugs that will be effective in treating certain types of human disorders is the lack of suitable animal models for testing the drugs. On the other hand, insight into the biochemistry of the central nervous system could reveal a possible relationship between some mental disturbances and changes in fundamental biochemical processes. However, it is not only the treatment of patients with psychiatric disorders that is of interest today, but also the relief of discomfort not necessarily associated with mental disturbance, such as feelings of stress, anxiety and difficulty in coping with life's requirements. The extensive use of certain tranquillizers in many countries clearly indicates a widespread desire for relief from anxiety and tension. Alcohol, the most widely known and accepted mood modifier, is used more than ever before; an increasing number of people try to find relaxation or escape from discomfort by means of this and other drugs. It would be easy to say that the extensive use of alcohol and tranquilli- zers is not justified, but it would be more useful to search for the reasons behind the demand for, and acceptance of, such drugs, and for means of dealing with tensions other than through the use of mood modifiers. Drug dangers It is not surprising that chemicals that are so effective in small amounts and affect vital functions have created appre- hension about their improper use as therapeutics and their possible adverse reactions. Demonstration of efficacy and safety is today required for each new drug in most countries, and the ratio of benefit to risk is carefully evaluated. However, it has to be recognized that each effective drug has inherent risk .factors and may produce side effects and adverse reactions, and that the term "safety" can be used only in a relative sense. Safety of a drug is established today on the basis of extensive experi- mental studies (to determine whether it is poisonous, or likely to cause deformities or cancer) and by clinical investigation, but none of these procedures can exclude a risk. The question of how safe a drug is can be answered only after its release for general use, and even then it may still be several years before possible adverse reactions can be connected with it. Knowledge of the relationship between benefical and toxic effects of a drug in animals and in man is much better than it was 20 years ago, and it will increase further, but we cannot expect that drugs will become safer in the future. More elaborate toxicity studies—longer-lasting or tried out on more species—or other tests will not improve the benefit-to-risk ratio. On the contrary, some with potential therapeutic value might never be given to man because of suspicions raised on the basis of experimental data. The best guarantee for the safety of a drug will result from its appropriate use under careful medical supervision. The more widely and indiscriminately drugs are prescribed or taken, the greater will be the risk of adverse reactions. The public is also concerned about the possibility that, by means of drugs, indi- viduals or large groups of people might be manipulated, lose their will-power and do things they would not otherwise do. It cannot be denied that the minds of individuals may be affected by drugs avail- able today, mainly in the sense that they can reduce activity, or create indifference, depressive mood, and carelessness, but it is evident that such effects are easily detected. The fear that drugs may be developed that could be applied to large groups with the aim of influencing them in a certain direction and the misuse of drugs as a political instrument can be excluded. Even if one assumed that such drugs, which would have to be applied as a spray or through the water supply, existed, their effects would be most uncer- tain because of the different individual responses to drugs that affect mood or mind. Depending on the dose and on the individual's state, the resulting effects could differ both quantitatively and qua- Harvesting virus to make rubella (German measles) vaccine. The rubella virus was isolated in 1962, and several countries now have large- scale vaccination programmes. (Photo Well- come Foundation) litatively and might not come up at all to what had been wished or expected. Such speculations serve only to demon- strate that an uncomfortable feeling does exist among the public about powerful chemicals, which for some people still contain an element of magic. Although the idea of drugs encourages such fan- tasies and fiction, the reality is more sober, and the slow progress that will be made in the direction of more effective medical care will not be outweighed by an increas- ing danger or threat of drugs that may be applied to affect the behaviour of mankind in an undesirable way. What we have to face today is the abuse of drugs that are habit-forming or addictive, or help to flee from reality. Other psy- chotropic agents may be found and abused, but the danger of becoming addicted to drugs depends on factors other than drug development. The outlook With respect to the development of new drugs, the forthcoming years or even decades will be meagre as compared with the past. To a certain degree, this trend is the consequence of increasing restraints that national health authorities impose on the marketing of new drugs, but it is hoped that a more flexible interpretation of regulations and the international accept- ance of clinical research data will at least in part compensate for the unavoidable delay inherent in the careful establishment of efficacy and safety before a new drug can be approved for marketing. Various efforts are being made towards a better harmonization of drug assessment and national drug regulations, and WHO should continue to advise national drug control authorities on how to avoid unnecessary duplication. New drugs will appear continuously, but in most areas progress will be slow. I assume that the future will not be fundamentally different from the present, and that predictions should be made on the assumption that the diseases to be treated will be the same as those from which mankind suffers today. Prevention of certain disorders, either by drugs or by other means, may become of increasing importance, although, in practice, pro- phylactic measures are always difficult to apply over prolonged periods. The increasing number of aged people will make it necessary to look for better and more efficient care and assistance for them. However, it is an illusion to think that drugs may appear that will effectively preclude the decline of physical and mental capacities in the aging organ- ism. We should also not expect drugs that will really prolong human life, and the fact that the chances of living longer than fifty years ago have been improved by drugs and better health care delivery does not mean that drugs may be expected to provide longevity. With respect to the average life-span in the most favoured countries, man will be lucky to maintain his present position, which is threatened by himself, by technical developments, and by the exhaustion of resources. One prediction can be made with certainty: no drugs will ever be discovered that would permit man to put himself beyond the laws of nature. ■ 32 GIVE BLOOD ...SAVE LIFE "Give Blood . . . Save Life" is the slogan of World Red Cross Day, 8 May 1974. The aim of this World Day will be to emphasize the vital need for the voluntary donation of blood, as well as the humanitarian value of such a gift. For the 121 national Red Cross, Red Crescent, and Red Lion and Sun Societies throughout the world, Wednesday 8 May will be an occasion for redoubled efforts to increase the numbers of voluntary blood donors. The need for blood is growing all the time. Requirements rise annually by about 10 per cent, but the number of donors increases each year by only about 6 to 7 per cent. This shortfall is serious. For over 40 years the Red Cross has played a leading role in blood donor recruitment and blood transfusion services. In 13 countries, at government request, the Red Cross assumes entire responsibility for the national blood programme, while in 46 others it operates transfusion centres and mobile collection units. All the national societies give top priority to blood donor recruitment. "Blood Is Red All Over The World" is the title of a new 13-minute colour film produced by the Red Cross to promote blood donation. Further details of the film are obtainable direct from the League of Red Cross Societies, Case Postale 276, 1211 Geneva 19, Switzerland. WORLD RED CROSS DAY, 8 MAY 1974 catch them young ! Few children are immune to the attraction of the comic-strip, perhaps the liveliest art-form of our time. Thought by some to have its origins in the cave-drawings of prehistory, the modern comic-strip is a vivid reflection of man and his behaviour. Comic-strip creators from many countries met recently at an international congress. Cartoonist and film-maker Ion Popescu- Gopo took advantage of the occasion to ask each of them to produce a drawing illustrating a health topic. Pens and brushes were soon in action. The resulting cartoons were presented to WHO by the artists and, together with a series of children's drawings on the environment, put on exhibition at WHO Headquarters. Visiting schoolchildren from Geneva and nearby France were delighted to find their favourite comic-strip characters — Tintin, Asterix, Tarzan and many others — well represented. A good way of getting the health message across to the younger members of the community ! ■ 34 Don't be your own doctor! WORLD HEALTH for readers everywhere ORDER FORM Please enter my subscription to World Health as follows: US $ * £* Sw.fr. * One Year 5.60 2.40 16.— Two Years 9.80 4.20 28.— Three Years 14.— 6.— 40.— One year: I Two years: I Three years: I enclose cheque/postal order in the amount of Name: Street: City: Country: • or equivalent in local currency. World Health, WHO, Avenue Appia, 1211 Geneva 27, Switzerland letters to the editor Dear Sir, Allow me to comment on the article "Malta Fever in Peru" (World Health, September 1973), to which my attention has just been drawn. The term "Malta fever" recurs repeatedly in this article where the names "undulant fever" or "brucellosis" would have been more appropriately used. In the history of medical progress the Island of Malta holds an honoured place in the elucidation of the causation of undulant fever, for it was in Malta that Sir David Bruce discovered the germ of the disease in the human spleen (1886) and that Sir Themistocles Zammit recovered the microbe from goat's milk ( 1905); but the label "Malta fever" has tended to saddle the island with the responsibility of a disease by no means peculiar to it. For this reason various attempts have been made by the Maltese medical profession and by the Government of Malta to induce health authorities abroad to abandon the name "Malta fever", which is unscientific and prejudicial to the fair name of Malta, and to replace it by a more suitable one. It is relevant to point out that since the enforce- ment of pasteurization of goat's milk on a national scale in 1938 and the banning of the sale of raw milk, the disease has practically disappeared from the Maltese Islands, incidence having fallen from 2,410 cases in 1946 to 51 in 1970. Paul Cassar, M.D. Royal University of Malta Dear Sir, I cannot help but comment on the juxtaposition of two photographs in your excellent magazine (September 1973). Thus, on page 29 you show a photograph of a man smoking a "factory mass-produced cigarette, the most lethal instrument man has invented for peaceful use". While not disagreeing in any way with the message conveyed, one cannot help wonder whether the photograph on the opposite page (p. 28) showing a "community health nurse giving a baby its bottle" in West Africa may not represent a still greater and more lethal mass- produced health hazard. While cancer of the lung is an increasing problem in adults in cigarette smoking communities, there is no doubt whatsoever that a vastly higher number of deaths is occurring and increasingly so in poorly sanitated developing countries mostly in the tropics as a result of diarrheal disease and marasmus following the disastrous spread of bottle feeding in communities where this custom cannot be followed in any way adequately because of inadequate environmental hygiene and quite inadequate incomes to purchase more than token quantities. I would have preferred both photographs to have been on one page with the joint title "Occi- dentogenic health hazards"— that is health hazards derived from harmful practices and customs from the so-called Western world currently being imported into developing countries to their detriment. Derrick B. Jelliffe, M.D. Head, Division of Population, Family and International Health University of California, Los Angeles, USA fa, or. arpli■ •••••••• •••■ Am, Pr in te d in S w itt ed an d I m e rim er ie s Rd un ie s S. A. L a PHARMACY IN VENICE The woodcut shows the preparation of theriac almost 500 years ago. This was the most elaborate, the most long-lived, and among the most useless medicines of all time. It lasted from the =irst century A.D. until well into the twentieth, and some recipes for it contained more than 70 ingredients and required that the mixture be kept fcr six months before use. The theriac made in Venice enjoyed an espe- cially high reputation, and in this picture the banner of the Repub'ic of Venice with the lion of St. Mark is seen on each side of the table. (Photc WHO)