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As is. One of the power couple now faces to know exactly how much an individual so often when you're doing a very serious thing if it is critical information and we really didn't have very many techniques to measure blood levels and so we had capital namely snow and sometimes we never. It's affecting those. If we knew more about how much we got was absorbed how much is in the bloodstream. We could learn a great deal more and it would be considerably more effective kinds of research. We can't we really cannot depend upon it and information which is obtained in

animals. This drug which talk about drugs what they are and how they affect modern man. Produced for radio by the American University broadcast center in collaboration with the National Institute of general medical sciences a unit of the National Institutes of Health. In our discussions with authorities on drugs and their use We'll explore where drugs come from how they are discovered. The natural substances provided by nature and the synthetics invented by man. We'll examine why people take drugs of all kinds and the effect of drugs on 20th century society. We'll investigate the latest developments in pharmacological research ways in which the federal government is concerned with drugs and drug use. Drug

laws why we have them and whether they are beneficial. These and other questions facing us all in this drug. The National Institute of general medical sciences is different from the other units of the National Institutes of Health in that it is not concerned with any one category or group of diseases. Its role is to fundamentally improve care of patients in all areas of medicine by helping to expand the breadth and quality of basic biomedical knowledge and to provide the necessary manpower for research and medical education. To this end the institute conducts a series of special multi-disciplinary programs including a national program of research in pharmacology and toxicology to enhance both the safety of drugs and their therapeutic effectiveness. On this the final program in our

series Patricia Wakeling consulting editor of the Optical Society publication applied optics talks with the head of the pharmacology Toxicology Program Byron Clark and two of his consultants John J burns a vice president for research of Hoffman Laroche incorporated and a visiting professor of pharmacology at Cornell Medical College. And Leon Goldberg professor of pharmacology and medicine at Emory University and director of the Center program in clinical pharmacology. The discussion centers on modern pharmacology and the interaction of government and industry and research in relation to the principles of the end I GM s program. Dr. Clark you were the head of the and I JMS pharmacology talks ecology program which is somewhat unique in its aims and achievements. And that program has perhaps revolutionized ology. Indeed perhaps one could say that a new profession has been created to tell us about it.

The pharmacology toxicology program was conceived and formulated 1964 by Dr. James Shannon former director of age. The major objective of this pharmacology Toxicology Program. Was to solve some very important practical problems and pharmacology and toxicology in order to achieve this safer and more effective use of drugs and man. The implementation of this program was assigned to the National Institute general medical sciences since it already had well-established training programs in pharmacology toxicology and related disciplines. These combined research and training elements in the and I GM last pharmacology Toxicology Program have produced during the past two years an explosion

of data having immediate and far reaching clinical significance. For example there has been a gratifying unfolding of useful information about how the human body handles drugs. Providing useful insights and to the great variability of individual responses to the drug. The interactions of two or more drugs in the same individual. The activation and activation of these drugs and most importantly the recognition of new adverse drug reactions. This rapid advancement of knowledge has been made possible largely by the discovery and application of modern technological advances and physical instrumentation. It was hoped that each medical school would have a clinical pharmacology training program by 1978. How does the P.T. education new training program helping you to achieve this a dam or a doctor.

First I might say that the Clinical Pharmacology is a discipline which requires a physician to have extensive training in pharmacology. He must. Prepared myself with many years of training in this discipline it must also be an excellent clinician. This requires a very special training effort and it must be done in a place where there is a condom or search that the that is appropriate to train it. No clinical public colleges. We have at Emory because of the support of the and I jam as a center in clinical pharmacology and toxicology which is concerned with all aspects of human drug study all the way from the synthesis of new drugs to be studied and made and drug interactions and toxicology. Because of the support we are able to accumulate a number of scientists from different backgrounds who can interact to make to find out things about how drugs work and

how we can and how to discover the epic AC of new drugs. And how would you support a National Academy of Sciences Drug Research Board of which Dr Burns who is a member. And it's going to be on drug safety. That committee recently made the point that what is needed is a better understanding of the relative importance of the factors that contribute to biologic video nation and drug metabolism in animals and men. How is that going to be achieved Dr. Burns. The committee that you mentioned spent several years in appraising the present state of our knowledge of drug metabolism especially as it applies to testing new drugs. It came up with a report recently in which it spelled out certain guidelines which would be of help to those of us who are concerned with actual acts of the actual development of new drugs. For instance in the development of a new drug it's very important that we

understand how a drug is metabolized in an animal species relative to how it's metabolized and then it just tells us an awful lot in terms of the type of clinical studies that we can carry out and in and the degree and sophistication we must apply to these studies. Now this report that you mention of this committee of the National Academy of Science is most helpful to those of us in the pharmaceutical industry in trying to set up guidelines for what we do at each stage in the development of a new drought. One away from the time a drug is shown to have activity an animal. Until a drug is introduced into used by the medical profession. How does that promise your industry related to what is going on in all sponsored by government labs such as energy. Well with the latest research in a way primarily from the standpoint it makes use of the basic knowledge which Council the National Institute of dental medical scientists program.

For instance. Dr Clark has mentioned the question of species differences in drug metabolism. Also the question that different individuals will metabolize a drug differently this information is important to us because it tells us what the proper test that we must carry out with a new drug so it can safely be tested in the animal and man. I'd like to ask Dr. Burns a question one of the things I try to do when I recruit young physicians to become kind of the pharmacologists is to try to give them an idea of what the field offers. And right now as you mentioned we are trying to obtain enough clinical palm ecologists to staff academic centers. And I'd like to ask Dr. Barnes whether he also sees a need in the pharmaceutical industry. You answered a great need for physicians who are trained in Clinical Pharmacology in industry. Because we have to carry out the various studies with a new drug and it's a position in the industry who have to take this prime responsibility and their studies.

And in fact there's a great shortage. Not only in terms of training people in this field of clinical pharmacology but also in the field of pharmacology in general. And I JMS has obviously encouraged development in this area. We would appreciate your comments on how we may do more. I think it's important for that. That the training programs which are so necessary be expanded especially in the new fields such as new application of new physical techniques in the study of drug metabolism. These programs are extremely essential to the proper development of drugs to learning information about the side effects of drugs and to tell a physician and how to use a drug and practice it with respect to research I'd like to add that a very important part of the interaction between academic development and distrait is the ability of industry to supply

materials and the new drug gas backs that aren't being investigated in some 20 of our pharmacology toxicology centers. And I JMS would not have these result is this quote collaboration Mike's work in this area possible. That's perfectly correct Dr. Clark. If we didn't receive the new compounds from ministry we would really have very little to study and I think this is a very important part of our work not only my sweet attempt to discover the mechanism of actions of drugs that are working now and look for interactions among drugs as a physician prescribe today but we must also study new drugs which the industry has developed to see if in fact they're going to be effective and safe and this is a very important part of clinical pharmacology. Wouldn't you also say that the existing drugs that are fairly well established that there is a great need for new information particularly in the area of interactions of one drug with another. We're learning a great deal more about that now. One thing that I was sent a program has been

able to do is to discover things about interactions among drugs and sometimes these are quite accidental. One of our pediatrician investigators was studying a drug called methylphenidate already in children with epilepsy. Just to see if there was an interaction between this drug and others. And he found actually quite by surprise that anti-convulsants that a child would take in the that the blood level was greatly raised and in fact the interaction of these two drugs. Probably led to some toxic symptoms due to the end of convulsing when our best kind of research by having a center there were able to capitalize on this and we now find that this same drug methylphenidate interacts with a great number of other drugs. And there's also a later therapeutic possibility because by the use of this drug we may be able to raise the blood levels of drugs we want to increase their effectiveness. Modern medicine is pretty preoccupied or has been preoccupied with diagnostic problems and therapy up to a point is taking the second place.

Now is that another way of saying that we know a great deal about what is wrong with this but not how to cure it yet. Well I think that we are learning a great deal more about how to cure disease. Unfortunately I don't believe that academic work has yet caught up with the therapeutic revolution. We look back a generation or two ago we see the family physician standing by the bedside of a patient with pneumonia and waiting for the crisis but really having nothing he could do so that medicine really started out with the business of trying to find out what was wrong with the patient and then. Really having very little heat that the doctor could do to help the patient. We do have very potent drugs now and this is part of the problem why we need more teaching of Clinical Pharmacology in medical schools. These drugs are not only effective but they can be dangerous and we've got to teach the students not only which drugs are best to use but the possible dangers of using the wrong drug. Interaction between drugs and this is going to be more and more sophisticated. And I think that we simply going to have to do more teaching of this sort in medical schools and to graduate physicians 90 percent of the

drugs prescribed today were not known 25 30 years ago. Instrumentation that's played somewhat of a role in that Dr. Clark. This reminds me of another function of the niceness to General Medical Sciences program is to conduct conferences on drug metabolism drug instrumentation and that cetera specifically. A large impact was made in this area through a symposium held last year at Gaithersburg advances and physical instrumentation. Dr. Burns you were in charge of that meeting would you comment further. There's been a revolution in our study to drug metabolism which have occurred in recent years. By means of highly sophisticated physical chemical techniques mass spectrometry nuclear magnetic resonance and other new developments. We're now able to study the metabolism of a drug by in a way that was not even thought of five or ten years ago. In

fact we can determine metabolites of a drug in a patient receiving a normal clinical dose of the drug and this type of information is very important to answer some of the questions which Dr. Goldberg raised. In fact that the patients are getting many drugs at this time. Many drugs being given together and in some very complicated interactions that do occur but the availability of this new physical chemical methodology will help greatly in understanding some of the interactions which Dr. Goldberg mentioned in a recent interview I was asked to discuss the ways and means by let's this sophisticated information may be brought to the bedside or at least to the average hospital. Dr. Burns. Would you comment on this. But I think it certainly is possible for the future that a doctor in his office may have some techniques by which he will be able to tell by simple

measurements of urine and blood content of drugs and their metabolites in biological material which would be of considerable help in establishing a proper dosage schedule for his patient. This is something I believe for the distant future but I feel in a more immediate future it should be possible for centers to be set up where the doctor can send blood samples from the patient to a center so that analysis can be done and results can be give the doctor a better understanding of the drug the patient has in his body and how the patient handles the drug and possibly give a better clue to the doctor in terms of the treatment of the disease. It's been said that by the use of this sort of instrumentation investigation of very new drugs might be safer. One of the problems that clinical pharmacologist faces is to know exactly how much drought an individual have so I mean when you're doing the very first trial in a human being. This is this is critical information and we really didn't have very many techniques to measure

the blood levels and so we have had to go extremely slowly and sometimes we never reach an effective dose. Now if we knew more about how much the drug was absorbed how much is in the bloodstream we could learn a great deal more and it would be considerably more effective kind of research. We can't we really cannot depend upon the end intimation which is obtained in animals because man may very well be different. I think one can take notice of recent observations have been made. For instance the question came up during a lot of my. There's Aster back only six days. Why wasn't it possible that we could have known about this in animals. Well the trouble there is it was very difficult before knowing that this occurred in the human design the right animal study. But now we know how to do this. And hopefully with the information I have accumulated in a pharmacology toxicology program such as the possibility of such an occurrence in the future it will be minimised even to more

recent. I report a question of interpretation of the findings in rats when cyclamates raises some interesting questions. Nobody knows just because certain things can happen with fact made in rats. Whether or not this had any thing to do with what could happen in a human so we still have a lot of information to learn. And this is very basic and I might say. Essentially an applied problem because it has some enormous ramifications to a public count both an economic and a medical standpoint. Dr Burns as you indicated the testing of drugs in animals and the supposition that they will affect men in the same way has long been a primary tool in drug research along with more of this experimental trial and add up procedures involving patients on the horizon of modern ecology However it seems possible that it is scientific principles might be developed to predict how a particular drug depending upon its chemical structure would act in men.

Doctor these kinds of principles evolving from the Institute's Program and how they are used in modern pharmacology. We believe that we are developing a series of general principles. And the handling of drugs and other aspects of pharmacology and toxicology that can then be applied readily to the large number of drugs and so that especially new drugs which are coming on the market well have had this type of information available on them. It is only compatible to fairly recently I think it's about 1964 that from ecology if I may put it this way should it's not our focuses and great strides have been made in the last five years or so. Maybe I should close this series of programs by asking you to tell us what's going to happen in the next five years the next 10 years in the pharmacology Toxicology Program is began the payoff that is beginning to

recognize this nationally becoming highly visible and especially the cooperation which is developing as Ben and extremely worthwhile venture. We predict. Confidently that this program will continue to grow at a moderate more moderate right but that the quality and application from this program will progressively increase. We really need to continue our development all areas of pharmacology and basic science. I certainly want to try to have more clinical pharmacologist but I think the development of new drugs is a multidisciplinary effort and we've got a concerted all the way from the chemist who said the size of new drugs to the pharmacologists who studies them to the toxicologist to help avoid adverse reactions to the clinical pharmacologist who first administer the drugs to man. So I think we really should keep our effort up in the direction that I JMS has been going to your broad support all these areas

now with respect to what's going to happen because no one can really tell us. We can almost be certain that what that advances that already been made and the basic understanding of the way drugs act. That we're going to develop some more specific and more rational drugs in the past most about new drugs have been developed sort of by chance. A physician observed an unusual action of a drug. This action was then utilized later. But there are people example when the sulfa drugs were being used to treat infections. Very clever physician observed his patient was excluding more urine than usual this eventually led to new direction this kind of thing should continue the training of physicians to be observant about drug reactions will continue but I think the great advances will take place without a basic understanding of how drugs work and we know a lot about it but we need to learn a great deal more. One example of how basic science has resulted in the discovery of a new therapy is the use of

L-dopa for the treatment of Parkinson's disease others L-dopa. I don't as an amino acid present in the body naturally and is converted in the body to another substance called open meaning. Now I like develop this a little bit more rather than tell you more about the chemical structure of L-dopa and to give you an idea of how basic science eventually led to the discovery of a new drug. It had been known for many years that this substance Dopa Mean was present in the brain and this was the first discovery was made in a basic science laboratory. Then the scientists were studying the brains of patients who had Parkinson's disease and they found interesting Lee that there was very little Dopa Mean in that part of the brain which was affected by the disease. Other scientists their doctor thought well why not try to put more dopamine back into the brain and one way to do this is by giving this amino acid L-dopa. You cannot you have dopamine because it will

not cross the blood blood brain barrier so you have to give the amino acid L-dopa which is then converted by a chemical reaction called take a box Aleisha into dopamine in the brain. This was actually discovered about 961 in a few early clinical trials with intravenous L-dopa. But the therapy really didn't get going until very recently when Dr. George concious found that he could give oral L-dopa to patients in parts Izzy's by a very slow build up of the drug and found that patients with pocket disease were very very greatly improved. Now this I think leads us to another important area that is how. Do we bring this discovery to the practicing physician. This is an area that they and IDM asked at the National Institute of help have helped coordinate this early research but then it's up to the end astray to make the drug available to the bats in possession. Dr. Goldberg said it was most pertinent especially when one

considers the cooperation that can exist between the pharmaceutical industry and National Institutes of Health and the academic community. As Dr. Goldberg pointed out a very effective agent. For the treatment of this rather discouraging disease at least is discouraging from the standpoint of a physician and a patient because we never had adequate therapy for this particular disease. When L-dopa was shown to be effective. The question came up well how can we. Answer certain questions the first question with one answer. How effective is it and how safe is it when it's when it's to be administered. The second question is how can we get enough dopa so that it can be given to the large number of patients in this country who may need it but treatment of this disease. In fact it's been estimated anywhere from a half and million to over a million patients and this country have this disabling disease now L-dopa. As Dr. Goldberg pointed

out it's a naturally occurring substance. Up until very recently it was only available in very limited amounts and very expensive. So it just wasn't available for treatment of the patient. Major stimulant drugs. Yes I think I'd only want to stimulate a whole new class of drugs but I think what we have to do before we think about the new drugs is that we know that it works and because of fact L-dopa works. It's extremely important that we start to make available to the position and to give to his patients sufficient help. Back in the early part of this year. The company which I'm associated with along with the National Institutes of Health and twenty seven major medical centers undertook a collab program to make this drug available for treatment a POC and Sony and patient. This required a mammoth technical effort in order to make sufficient amount of this drug available or to carry out the necessary clinical studies

animal studies etc. in order to show the safety and effectiveness of the drug and its disease. Hopefully this drug will be made available sometime next year. The patients who need this drug. And I think that this demonstrates the need for good clout cooperation between government industry and the academic community because each of these segments of the medical community can contribute certain things to a to a program such as that. But you really need a combined effort of all three to gain final success. With. Patricia Wakeling has discussed modern pharmacology and be an eye GMF pharmacology Toxicology Program with the program director Byron Clarke and consultant John Jaber. Rings and Leon Goldberg on this final program in the series. This