Drug Development: Challenges and Hurdles

Drugs are so much part of our lives that we give little thought to the road they have to travel in order to arrive in a bottle in the bathroom cabinet. We read news reports about physicians who cure dangerous diseases with medications, but these stories seldom mention what intellectual effort and technical skill led to the chemicals with which the patient was treated.

Few people understand what medications they use. When asked, they will explain that they take “a prescription,” “green tablets,”and the slightly more knowledgeable take “pills for the heart” or “nerve pills.” Another stratum of patients may know the trade name of a medicament, but almost none knows that the hundreds of drugs on the shelves of drugstores are products of research and development of about 40 or 50 of the great international pharmaceutical firms in the industrialized countries. Their number is shrinking every year because it now costs an average of $ 55 million to place a novel drug on the market. Few companies—only about 22 in the whole world—can finance such ventures and wait out the four to eight years of clinical trials that must satisfy the demands of regulatory government agencies.

Neither do patients understand how drugs act in the body; if they did, they would not abuse them. Many take their physician’s prescription, then consult another doctor who prescribes something similar, and the patient gleefully takes both drugs to be on the safe side. A considerable percentage of hospital beds is occupied by people who have become ill from such duplications and from other drug interactions. These people abuse drugs, although they would not admit that to themselves. Others abuse drugs that alter the mind and thereby have created some of the most far-reaching societal problems of our age. Untold thousands of alcoholics and other drug addicts fill hundreds of expensive and specialized clinical facilities; their productivity and contributions to society are lost during their hospitalization. Then there are those whose religious superstitions will not let them use any medication; they live in therapeutic ignorance, as in the dark ages

Health, our most precious possession, is regarded as a right in all age groups by voters looking to government for the solution of their problems. This is quite a new attitude. Pain and debilitation were once valued as religious attributes and preludes to saintliness. The hemophilia of the male members of Parsifal’s family required the intervention of the Holy Grail, but that was before the K vitamins and other coagulation factors became known as more mundane and more effective remedies. By the end of the 19th century there was foxglove as a source of digitalis, ether for general anesthesia, and liver to contain the manifestations of pernicious anemia. The general practitioner who in 1905 delivered and saw me through the usual diseases of childhood prescribed some medicine each time he visited, although he was aware of the ineffectiveness of many of the medications. He was probably typical of his time, and there was just not much he could prescribe: aspirin for fever from whatever cause, creamed spinach and grape jelly as a diet until appetite returned, and only later those dirty-brown and costly drops of adrenaline solutions to still the bleeding of an eardrum which had been perforated as a sequel to otitis media after a bout of scarlet fever. That was the state of the art, and even professors from the university who were called in as consultants when all other measures had failed did not have anything else to offer.

If you did not want to become pregnant every time you went to bed with your husband or husband-to-be, there was only one thing to do: obey the pope’s admonition to abstain. As Carl Jung wrote to Sigmund Freud on May 18, 1911, “All is well with us, except the worry (another false alarm fortunately) about the blessing of too many children. One tries every conceivable trick to stem the tide of these little blessings, but without much confidence. One scrapes along, one might say, from one menstruation to the next.” But if you wanted two or three children in your family, you’d better have a half dozen because infant mortality was high. And a ruptured appendix spelled certain death, pneumonia was lethal for 75 percent of all patients, and the average life span listed in actuarial tables was 47 years. All this was true as late as 1919, only ten years before the stock market crashed and the talkies hit the screen. Those were the good old days.

The universities and great research institutions have traditionally provided the theoretical approaches to biomedical innovation and have worked out post facto explanations of some of the puzzling mechanisms of action of drugs. The real development of new drugs, their isolation and synthesis, and the pinpointing of which compound deserves the investment in clinical trials is done almost always in the laboratories of pharmaceutical companies. The practical outlook necessary for such studies and the total coordination of chemists and biologists required to attain a common goal is at its best in the industrial environment.

The pharmaceutical industry started hesitatingly around 1870, not because of high purpose and dedication but because otherwise unmarketable chemicals and intermediates in the flourishing manufacture of dyestuffs had to seek other outlets, perhaps as drugs. In other words, the dyestuff industry tried to diversify, just as the pharmaceutical companies today diversify by entering the fields of veterinary medicine, pesticides, surgical and other health care equipment, infant formulas, health foods, reducing diets, etc. Many of the major drug corporations arose from small laboratories in which the founding doctors or pharmacists compounded medicines for their own practice and later for other physicians. Some of these pioneers went a step further and extracted medicinal plants to prepare pure drugs.

All the useful medicines until 1880 were natural products, and synthetics, now in the vast majority, appeared essentially only after 1900. They were found by screening random chemicals in laboratories. For example, the alkaloid cocaine, extracted from the leaves of the South American shrub, Erythroxylon coca, had been used as a local anesthetic for some years, but it also produced many unwanted side effects on the central nervous system including dependence liability. When its chemical structure became known, parts of its molecule were trimmed away, like Victorian curlicues from a functional building, until the remaining molecular skeleton revealed itself as the portion essential for the local anesthetic activity. A few minor changes led to procaine which generations of dentists and surgeons used until longer-lasting and more potent local anesthetics were developed.

Every branch of science remembers a few towering historic figures who transformed its intellectual foundations and foreshadowed the lasting outlines of its potential. In medicinal science, this was Paul Ehrlich (1854—1915) of Frankfurt, Germany. Trained as an immunologist and microbiologist, he studied disease problems important in his day, such as syphilis, sleeping sickness, and some tropical diseases caused by primordial pathogens. He managed to get support from a private health research foundation, surrounded himself with chemists, experimental biologists, and clinicians, and, for the first time, embarked on a systematic search for drugs for those diseases. Each step was built logically on preceding knowledge, even if this turned out to be untenable at a later stage. After 20 years and 605 of such trials, Ehrlich and his group succeeded in synthesizing, testing, and introducing drug No. 606 or arsphenamine for the cure of primary syphilis. Several other drugs followed, some of them improvements over the first in his series. This set a pattern for medicinal drug research and development that has not been changed since 1910 except for incidental details here and there.

II

For all drug design, a toehold is required to start with, a “lead” compound. Many natural products extracted from plants have served for this purpose, and their selection has often been based on folklore going back to tribal medicine men of primitive societies. Such anecdotal therapeutic activities are interesting but on the whole unreliable and inaccurate. If there is no such prototype, one has to screen blindly, one chemical after another, hundreds and often thousands of them, clinging to little favors that reveal themselves as weakly positive test results, until with luck, faith, and persistence a potent test compound turns up as a “lead.” This has been done in crash programs during epidemics or spurred on by national emergencies. More than a quarter of a million compounds have been screened worldwide in animals for activity against cancers, 15,000 for antituberculous effects, about 125,000 as antimalarials, more than 10,000 as variations of the antibacterial sulfanilamides, and another 10,000 as analogs of penicillin. The waste and expense of such adventures is appalling; and after the establishment of the test procedure, the work involved is repetitive and intellectually deadening. Blessedly, this will not have to be done again, unless an infection is imported from outer space without terrestrial parallel.

After a “lead” has been uncovered, the random selection of chemicals can be narrowed down to chemical relatives of the “lead” substance. With unheard-of luck, the next test material may be the answer to one’s hopes, but that has not happened often. An average of 200 to 500 additional compounds may have to be screened before a test drug for in-depth study in animals emerges. Those chemical relatives cannot be pulled out of collections or chemical catalogues. They have to be synthesized by special procedures and according to guidelines of molecular modification. To perform this purposefully, selecting from the infinite number of possible variations and making an optimal choice of the most likely compounds to succeed, is one of the most challenging tasks of medicinal chemistry.

A logical approach to bringing order into blind screening for a “lead” compound appears in the biochemical study of a disease. A drug, after all, is just a chemical, and all it can do is to react with other chemicals or, if it is similar enough, take their place in some reaction. It has been known for 50 years that most if not all drugs affect the reactions of enzymes, the catalysts of all life processes. Some drugs take the place of natural substrates of enzymic reactions, or they slow down such reactions by altering the shape of enzyme molecules. If we can connect some enzyme with a cause or symptom of a disease, a hint about drugs to interfere with the reactions of that enzyme might be elaborated.

That is easier said than done, but in recent years the biochemistry of normal and some abnormal conditions has unfolded because fantastically sensitive instruments have been devised for such studies. These instruments originated in optics, electronics, spectroscopy, space programs, and other sources not directly relevant to medicine. Enzymes do not occur in large amounts in blood and tissues, but some of these sensitive apparatus can register minute changes in enzyme substrates and the rates at which these small quantities are synthesized and transformed in the organism. Qualitative and quantitative changes of bioreactions during diseases have been divulged in this way. The normal chemicals in the animal body are partially lost or become more abundant in disease; some are changed to abnormal metabolic products. Their chemistry has been studied in some cases, and they can be imitated as analogs in the laboratory. Normal and pathological metabolites can thus serve as prototypes for molecular modification until a potent and not-too-toxic drug for the disease can be developed.

Some medicinal chemists with a leaning toward physics have proposed that chemical similarity to a compound with known biological activity is less important than analogy of physical properties. Indeed, as a drug travels through the body before reaching its place of action, it traverses many membranes, gets side-tracked by attacking chemicals that destroy it, and is excreted by the kidney, the bile, and the skin. All these processes require that the drug dissolve in body water and body lipids, i. e. fats and fat-like materials. The rate at which this happens is related in many although not in all cases to the observed activity of the drug in a disease.

As long as chemists deal with the theory of drug design and put it to work in the laboratory, they can do almost anything their ingenuity and acumen devise and their budget permits. To be sure, the Environmental Protection Agency will not let them dump toxic chemicals in nearby waterways and will admonish them not to kill themselves in their experiments, but otherwise they are on their own. As soon as laboratory animals come into the picture, the pharmacologists who use them in experiments become subject to strict public supervision. Mice and rats do some $3 billion damage to grain crops every year and are exterminated energetically and not always pleasantly by pesticide poisons, mousetraps, and other devices. But in the pharmacological laboratory, that is another side of the coin. Local chapters of the SPCA and antivivisection organizations have joined federal agencies in applying legal strictures for the care and maintenance and treatment of laboratory animals. Of course it is impossible to avoid experimental pain. If an anticonvulsant drug is to be tested, some of the animals will have to be convulsed, and analgetic drugs cannot be evaluated without producing measurable pain in the test subjects. In all cases suffering is held to a minimum. Nevertheless, recently a bill was introduced in Congress asking that test-tube (in vitro) experiments controlled by computers be substituted for experiments on laboratory animals. The computer is to simulate the transport of drugs and their action in the animal body so that animals need no longer be used in the pharmacological evaluation of medicinal agents. It is utterly improbable that a computer can be programmed for all the interwoven events in the animal body—many of which are not understood—and that such programs would predict the behavior of a drug in the much more complex human organism.

All drugs have to be tested for acute and chronic toxicity. To measure acute toxicity, increasing doses are administered until some toxic reaction and ultimately death occur in 50 percent of the animals. Chronic toxicity is studied by giving the drug to at least two different species of animals; within each species they are matched for strain, sex, weight, and age. Treatment is continued for several months or even years. Then the surviving animals are “sacrificed”, i.e. put to sleep gently, and necropsied. Pathological study of their organs reveals any tissue damage including tumors induced by the drug. After these trials, and tests for the effect of the drug on the fetuses of pregnant females, a decision will be made whether the drug should be tried in humans. If any teratogenic (fetus-damaging), mutagenic effect, or tumor formation has been observed, clinical trials are excluded by law. Likewise, severe chronic toxicity will preclude the PDA from issuing an IND, that is a permit to investigate the new drug in the clinic.

The clinical trials of a new drug are carried out by clinical pharmacologists, usually specialists in internal medicine with research training in human reactions to medicinal agents. The patients are healthy paid volunteers, and later patients with pertinent diseases; their consent must be secured, and their treatment and hospital expenses are paid by the sponsoring pharmaceutical company. The PDA is kept informed of all protocols during the trials, of any positive activity, of any untoward or toxic reaction to the drug, and of any lack of drug activity observed. Mountains of paper work with multiple copies accumulate during the months and years of the trials, slowing down and hampering progress. For this reason, hundreds of clinical pharmacologists have withdrawn from such experiments; many have gone into other branches of medicine and the number of active clinical pharmacologists in the U.S.A. has shrunk. This has forced pharmaceutical companies to conduct clinical studies abroad in many cases/After years of distrust of foreign clinical evaluations, the PDA has only recently accepted some data from such trials, although especially British, German, and Scandinavian test procedures are beyond reproach. The reason for this distrust of foreign data may be the question of access to raw data before they are summarized and presented. It is difficult if not impossible to sequester laboratory notebooks from foreign investigators.

All domestic trials may be terminated at any time if the agency sees so fit on the basis of the protocols submitted by the physicians. That means that for every hard-won candidate drug, one or usually two backup compounds will have to be readied in chemical and animal studies to take the place of the first drug, should this one fail. Add up all this plus the cost of physicians, nurses, hospitalization, wear and tear on diagnostic and therapeutic equipment, and your figures will approach the $55 million per new drug before the FDA approves an NDA, a new drug application for marketing.

Ill

Competition in the pharmaceutical industry is fierce, and patent protection is inadequate. Several years elapse from the date of application for a patent to the date of issue. In the U.S.A., patents provide monopolistic protection for 17 years, but patents for medicinal agents usually reach issue dates while the drug is still in the stage of laboratory development. Then come the years of clinical study, and if, when, and as permission to market the drug is granted—after exasperating waiting and negotiation—an average of six to eight years of the patent’s life span has been used up without a single penny’s sale. To recoup the giant investment, the price of the drug must be set high enough so that the remaining years of the proprietary period will furnish the profits needed to repay the accumulated debt and leave a basis for the next venture into the therapeutic unknown.

In any event, someone has to defray the costs of creating and developing a new drug, and the sales department of a pharmaceutical firm is always consulted before an R & D project is undertaken. If the drug therapy of a disease, regardless of how interesting and approachable it may be scientifically, will not benefit at least several hundred thousand patients, it will be doomed to economic failure before it is even started. In the case of tropical diseases the vast majority of patients are so disadvantaged financially that they could not think of purchasing medications. Even though there are hundreds of millions of cases—a huge potential market—of bacterial and protozoal infections, worm infestations, and other diseases prevalent in hot, humid climates, drugs for these conditions are not widely studied because they cannot be sold. In some cases the regional governments pay for the drugs and distribute them almost free, but most of those countries cannot afford that luxury.

After a drug patent has expired, anyone can market the drug under its generic name. The proprietary trade name remains the property of the company to which it was awarded, that is, usually the company which developed the agent. Competing companies frequently begin manufacturing profitable drugs as soon as the patent expires. They are supposed to prove that their product is identical to that originally marketed under a proprietary label. The purity and chemical identity of generic drugs are seldom in question, but their bioavailability is, that is, whether the drug will reach the organs where it is supposed to act. Therefore the generic drug firms are under close scrutiny concerning the compression and grain sizes of their tablets and the coating of their capsules.

Since the distributors of generic drugs have had no R & D expenses, they can price their products more reasonably than the originator of the drug. Health plan insurance agencies may reimburse the patient only for the lowest-priced medicines, and in many states the pharmacists are entitled, or even required, to substitute generic drugs for more highly priced proprietary prescription agents. Public acceptance of generic drugs has been divided. Most patients taking such things as “heart pills” do not want to know more about such a disagreeable subject. The generic drug firm may not be permitted to shape and color its product in the same way as the original trade-marked material, and your aunt may be upset about a “change” in a trusted medication.

After solving the technical manufacturing problems, the coating of tablets and capsules, the packaging and distribution to hundreds of thousands of pharmacists and physicians, the company starts to promote the drug. Quite commonly the president of the company calls a press conference and announces the contribution of his staff to the health of the nation. The stock of the company usually rises several points, and the reporters write glowingly about the new miracle drug. Physicians traditionally are wary of new drugs, but they succumb to the blandishments and promotional skills of the company’s detail men—and lately women. The curve of enthusiasm for the drug occasionally keeps on climbing if the drug represents a real medical breakthrough. Hoffmann-La Roche’s diazepam (Valium) and Smith Kline’s cimetidine (Tagamet) are examples of such prescription successes in recent years. But even if the drug had been tested in thousands of statistically valid patients before it was marketed, its ultimate utility and drawbacks reveal themselves only when hundreds of thousands or millions of prescriptions have been filled.

Let a famous violinist play one sour note in a concert performance, and his reputation with the critics will never be the same. Likewise with a new drug: a few cases of a serious or near-serious side effect reported in a reputable medical journal will make the drug suspect. It takes years to balance out benefits and risks after such a condemnation. There are still those who look for drugs without any risk; that is impossible. We are not all created equal physiologically and genetically. A drug given to middle-class merchants in Boston or Liverpool could be metabolized differently in Japanese individuals of similar life style. Most of us can tolerate huge doses of penicillin, but 10 to 20 percent of the population reacts violently to this antibiotic and not so few people have been killed by it. Diphenhydramine (Benadryl) is an excellent antiallergic medicine, but almost half of those who have taken it get so drowsy, sleepy, and cross that they cannot use the drug in the daytime. Methamphetamine is a stimulant that keeps one awake at night if needed for the performance of tasks demanding attention such as driving or piloting, but repeated or larger doses can cause psychoses virtually indistinguishable from paranoid psychotic episodes in schizophrenic patients. In fact, as a drug alters a biological process and if it is specific, it must be defined as selectively toxic to that process. Ehrlich called hoped-for non-toxic drugs magic bullets, but they have never been seen.

In the long run, most drugs settle down to “fill a niche in therapy.” A few will remain standards in performance and may furnish generations of patients relief from some disease condition. Many other drugs will survive in an uneasy fashion, used and tolerated by some physicians for lack of anything better and denounced by others as probably useless. Particularly drugs for vascular problems and minor emotional disorders carry a tag of uncertainty through the years, and many physicians think of them as placebos but keep on prescribing them because giving the patient a prescription is part of establishing confidence in the doctor-patient relationship.

Those medications with unreliable effectiveness are the prime and justified targets of scrutiny by the PDA. The Food, Drug, and Cosmetics Act, as amended in 1938 and 1962, decrees that a drug must be effective and safe. As to total safety, in the words of Chief Justice Warren Burger, “perfect safety is a chimera; regulations must not strangle human activity in a search for the impossible.” On the other hand, the requirement for effectiveness seems justified beyond doubt. Effectiveness in some pharmacological areas is not easy to establish, but some of these questionable agents have become highly profitable to the industry, so much that smaller firms scramble into the same therapeutic area for a share of the market. When competitive drugs are promoted by different companies, the best sales force will come out on top. It should not be forgotten, however, that the genetically predetermined different reaction to a drug by patients of different origin, age, and sex justifies the development of virtually equal but just a bit different drugs for use in the overall patient population.

There has been much complaining about the fact that more new drugs have been introduced more promptly in Europe and Japan than in the U.S. since the Kefauver Amendments in 1962. These claims have been aired in the medical literature and in congressional committee hearings both by representatives of the medical profession and by the pharmaceutical industry. They have accused the FDA with overregulation and even total inertia in some cases. As is so often true in such disputes, there is fire where there is smoke, but both sides are to blame. Analysis of the figures quoted reveals that overall generalizations are useless and more careful classification is necessary to lead to valid conclusions. Really novel drugs, those that constitute needed therapeutic innovation, do lag behind in the U.S. as a rule but not more than a few months or a year. There have been unfortunate exceptions to this rather insignificant time lapse, as in the case of propranolol, which the FDA did not admit for several years, and then the agency repeated this delay for each new use of the drug as it was discovered. But most of the agents which were slow in reaching American medicine are me-too drugs, those analogs synthesized or compounded largely for competitive commercial reasons. Since effective prototype drugs of these analogs were to be had in every pharmacy, such delays were only part of the justifiable hurdles which a not very impressive therapeutic imitation has to face. Then there are also the dozens of “drugs” advertised on TV and in the tabloid papers. They are mixtures of this and that, sometimes with a weakly active ingredient, sometimes without one. They are sold to the gullible and those who do not want to face the expense of a visit to a doctor’s office to obtain a prescription for a manageable discomfort. The preparations that do not contain any active ingredient are, of course, outright frauds. One widely advertised material for the relief from hemorrhoidal symptoms contains nothing related to those bothersome conditions. For the relief from overall pain, aspirin and acetaminophen are sold over the counter without a prescription and are mixed in various proportions and then advertised for backache, headache, arthritis pain, etc. These are the “drugs” the PDA should interdict.

On the other hand, it would be shocking to relax the regulations that have advanced therapeutic health care from the medicine cart with its snake bite aids to the aseptic and painless age of modern medicine. I am not talking about what the research-based pharmaceutical houses would do if they were suddenly deregulated. They have too many scientists on their staffs, men and women of the highest ethical caliber and professional qualifications to let some unscrupulous person in sales or promotion run away with the company’s hard-earned reputation. It has happened, but it has never gone unpunished. The trouble lies with the approximately 180 regional and local small firms which sell patent medicines. As long as their advertisements appeared in obscure magazines sold at the checkout counter in supermarkets, the harm they did could be localized and isolated. But the more daring of these firms have handed over their sales promotion to Madison Avenue and have invaded TV commercials vacated by the ban on cigarette ads. Have you seen the one in which a woman is asked to choose between three preparations, two of which contain the same amount of “pain killer,” while the third one contains 40 or 50 percent more of it? She tries the third one and, of course, gets more relief. Had she taken a double dose of the lower-potency mixtures she would have gotten even more relief.

The public’s attitude toward medicinal agents has fluctuated from one extreme to another. There has always been the childish faith in the healing power of medicines but also the fear of their poisonous potential. Perhaps there is an intuitive understanding that all chemicals are toxic depending on their dose. Intertwined with these feelings is our hope to be protected from mishaps, accidents, and our own follies. As a consequence, unscrewing a medicine bottle has become an exercise in frustration. It should save the lives of children whose explorations take them up to the bathroom cabinet and to those chocolate-flavored pills, but why should a bachelor have to struggle with child-proof bottle caps? As far as that goes, why should males of all ages be deprived of effective medicines which cannot gain PDA approval because they lead to limbless mouse pups when given to pregnant mother mice? Is the intelligence of women really so low that they cannot read and will not follow warnings on the label that such medicines should not be taken during pregnancy? Of course, a girl cannot always predict whether she will become pregnant the night after taking a medication or even after drinking three cups of coffee during her breaks at the office, and therein lies the danger. If she should be on contraceptives, she could dismiss the thought of pregnancy, but too many women aged 15 to 48 have been turned away from steroids because of the acknowledged low risk of circulatory disorders. In native women in Africa and India such risks should not even be considered because the danger of increased numbers of children that cannot be fed healthily is much, much greater than the small incidence of side actions following estrogen therapy. However, even the effects of widely used over-the-counter medicines on the growing fetus are not fully understood. There is little disagreement about the effects of the most commonly used drugs on the fetus, ethyl alcohol and nicotine. Both interfere with cellular life, and, in the case of children of heavy smokers, retardation of the learning ability has been documented in scholarship statistics.

IV

The real concern of the public, the law-enforcing agencies, and the psychiatric profession is not about drugs for functional or infectious diseases that have survived the weeding-out process of drug development and control. Even drugs for psychoses, endogenous depressions, and other severe mental disorders are seldom abused. But drug abuse has spread far beyond the confines of medical art and science. It has always existed, but in the last 50 years such abuse has contaminated people of all ages and every station, particularly the young, at an unprecedented rate. For many people the term “drug” has come to mean psychotropie, mind-altering agents and beyond that, their unnecessary and unchecked, desperately damaging abuse.

Three million years ago cave dwellers, most likely the cave women who did the cooking, brewed soporific beers for themselves and their families to make them forget the dreariness of their short lives, the hazards of childbirth, and the dangers lurking in their prehistoric environment. In more recent times, the ancient Greeks and Romans smiled at their god of wine and revelry, Bacchus, and their nymphs frolicked with fauns in drunken orgies. The Chinese poet Li-Tai-Po (702—763 AD) recited the “Drunkard in the Spring,” set to music later by Gustav Mahler in his Lied von der Erde, The Crusaders brought home tales of a Mid-Eastern assassin society whose members prepared themselves for their murderous tasks by smoking hashish, the potent condensate of Cannabis. Powhatan was seldom seen without a tobacco pipe to put him in a mellow humor, and the stinking dens of India and China resounded from the stuporous snores of opium smokers. De Quincey’s book, Confessions of an English Opium Eater, recounted the joys of the smokers’ dreams and caused sophisticated European salons of the 19th century to experiment with opium and later with cocaine. All these abusers wanted to escape reality and imagine they had entered a more perfect or depraved, sensuous, or carefree world. The “bad trips” were played down, and the exorbitant cost of the snuffs and tarry concoctions which led to violent crimes was not mentioned.

At the turn of the century, a German pharmacologist heated salicylic acid with acetic anhydride and got acetylsalicylic acid which he called aspirin. So great was the success of this molecular modification, that he applied the same process to the acetylation of other substances with known biological activity. Among them was morphine, the principal active alkaloid of opium which had been isolated and purified 65 years earlier from that sticky condensate of the juice of Oriental poppy seeds. The diacetylmorphine of Dreser’s was about 50 percent more potent than morphine in relieving severe pain and was adopted promptly by many of the world’s pharmacopoieas, the reference volumes of drug standards, under the name of heroin. The secret of this drug came to light soon: it causes an unmatched euphoria, and after a few episodes the body becomes dependent on it and withdrawal is a painful, violent, and desperate ordeal. The addicts usually cannot face this horror without medical help and must acquire a new supply of the drug to satisfy their dependence liability. Since heroin was outlawed quickly in most countries, the black market became the only source of the drug, and the distributors soon raised its price to unrealistic figures. But addicts have to acquire it, they have no other choice, and will rob and kill to get the funds that stand between them and the withdrawal symptoms.

Many other euphoriants and hallucinogens have made their appearance. Several synthetics first used medically as anesthetics have become notorious as street drugs after whole communities of youngsters practicing drug cults experimented with them and landed in pitiful condition in mental hospitals. Compared with these “hard” drugs, the grassy plant, Cannabis sativa, which grows almost everywhere and has furnished hemp for ropes for centuries, is a less dangerous material but certainly still dangerous. It is smoked as marijuana or in more concentrated form as hashish, and it leads to a dreamy, sedated state that leaves users listless, void of drive and ambition, and in the long run without much use in intellectually demanding occupations. The active ingredient, tetrahydrocannabinol (THC), produces these effects in minute doses. Because of the relationship between marijuana and “hard drugs,” rather harsh laws have been passed prohibiting the possession, use, and above all the sale of the material.

The present situation with illicit drugs is very similar to that of bootlegged alcohol during the days of Prohibition in the 1920’s. Cannabis is smuggled by the thousands of tons into Florida from Central and South America, heroin in kilogram quantities from Turkey, Pakistan, and other Mideastern states. All attempts to stem this traffic have been to little avail. There is no question that the “hard drugs” must be stopped; the marijuana laws are under constant discussion because they obviously do not achieve what they are designed to do.

The effect of drug abuse on drug development has been dramatic. Manufacturing schedules have been changed to divorce pharmaceutical companies from drugs declared illegal. Some research lines have been revised. THC and some of its analogs have shown promise in reducing intraocular pressure and are therefore of potential value in the treatment of glaucoma, but which company would want to be associated with materials found in Cannabis? Similar situations have arisen in researches on amphetamines.

So much is unknown about drug abuse that the problem cannot yet be approached by standard scientific measures. In the case of agents used for the relief from pain, and abused for their euphoric effects, our thinking was directed into new channels five years ago, when small protein-like compounds were discovered in the brain and in other tissues which exert brief but powerful analgetic effects similar to those produced by opiates and their analogs (“endogenous morphines = endorphin”). Will they be an answer to the search for potent analgesics without dependence liability?

Even more interesting may be the role of endorphins in explaining how many drugs act. It has always been a puzzle how the biological action of a chemical found by chance might be interpreted. Nature or evolution cannot possibly foresee what unexpected biologically active substance a chemist might stumble upon tomorrow and thus cannot have planned reagents in the cells of animals to interact with the new drug once it is discovered. The molecules of proteins and nucleic acids which act as drug receptors appear to be folded in just the right manner so that many kinds of chemicals fit snugly into their folds. The purpose of the endorphins in the animal body is not known but seems to be a hormone-like activation in case of need. If a painful event occurs such as childbirth or trauma, the endorphins are biosynthesized from other inert proteins to counteract the devastating stimuli at nerve junctions. Acupuncture may activate this biosynthesis and thereby provide endorphins for pain relief; the opiates appear to cause a similar bioactivation, although the details of these events are not yet understood.

The three decades from 1935 to 1965 have been proclaimed as the golden age of medicinal discovery and the introduction of miracle drugs. The 1962 amendments to the Food, Drug, and Cosmetics Act curbed this steady growth, and soothsayers, pharmacologists, and network commentators have tried to analyze the causes of the slump. Aside from complaining about the FDA, the most common explanation has been that all the “easy” discoveries had been made and the exciting period of scientific breakthroughs run its course. The proponents of this hypothesis forget that fundamental advances occur erratically and infrequently; a period of intense forward thrust in any human activity is followed inevitably by stock taking, retrenchment, and rest. The quiet period of the last 16 years has now come to an end. As one reads the primary journals, the effect of new instrumental refinements on medicinal science and drug discovery is apparent. Insight into physiological processes at subcellular and molecular levels through the use of the electron microscope and spectrometers has sharpened our understanding of many diseases that had remained intractable a paltry few years ago. At the same time, immunology and molecular biology—sciences barely 30 years old—have opened a plethora of fundamental biochemical discoveries that have been seized upon as new “leads” in drug design. By altering the genes of a few bacteria which can be cultured easily, these organisms have been transformed into biochemical factories which can already synthesize insulin and other complex proteins of therapeutic importance.

The public has not yet waked up to this upward trend, but investment bankers, with an eye to the future, have. For the next 20 years, the therapeutic future looks bright indeed, and all of us will be winners in longer, healthier, and happier living.