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Clinical Pharmacologists in Ophthalmology
AMERICAN JOURNAL OF OPHTHALMOLOGY FRANK
W.
NEWELL,
Editor-in-Chief
160 East Grand Ave., Chicago, Illinois 60611
Editor-in-Chief Emeritus 2450 Lakeview Avenue, Chicago, Illinois 60614
DERRICK VAIL,
E D I T O R I A L BOARD Bernard Becker, St. Louis Frederick C. Blodi, Iowa City Benjamin F. Boyd, Panama Thomas Chalkley, Chicago Sir Stewart Duke-Elder, London DuPont Guerry III, Richmond Michael J. Hogan, San Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman, Gainesville Arthur H. Keeney, Philadelphia Bertha A. Klien, Chicago Alex E. Krill, Chicago
Carl Kupfer, Bethesda, Maryland James E. Lebensohn, Chicago Irving H. Leopold, New York A. Edward Maumenee, Baltimore Edward \V. D. Norton, Miami Albert M. Potts, Chicago Algernon B. Reese, New York Marvin L. Sears, New Haven David Shoch, Chicago George K. Smelser, New York Phillips Thygeson, San Francisco Gunter K. von Noorden, Baltimore
Published monthly by the Ophthalmic Publishing Company Directors:
DERRICK VAIL, President; ALGERNON B. REESE, Vice-President; FRANK W. NEWELL, Secretary and Treasurer; A. EDWARD MAUMENEE, MICHAEL J. HOGAN, EDWARD W. D. NORTON
CLINICAL PHARMACOLOGISTS IN OPHTHALMOLOGY The field of drug development is charac terized generally by highly productive work. Most of this productivity has been the result of highly ingenious organic chemists. They have developed a variety of chemicals with unusual biological activities. In order for those to be of practical importance in medi cine, they have to be evaluated for their effect on the biological systems. The past 50 years have been a favorable time for research in all fields of medicine. This has been particularly striking in phar
macology. Von Euler pointed out that the fast growth of the bioscientific achievements follows an exponential function, doubling every 10 to 15 years. The rapid growth of pharmacology, like other sciences, has inter esting corollaries. This implies that accumu lated total knowledge—the amount of data that we see—is probably the result of re search work done in the last decade. It is dif ficult to keep track of all this information. One can look on this as a menacing ava lanche of data. It is essential that this be pre sented to the busy ophthalmologist, as well as all physicians, free from all unnecessary ap pendages. 137
138
AMERICAN JOURNAL OF OPHTHALMOLOGY
The trends of pharmacologie research may be fascinating. Very often, an idea is fash ionable and rapidly insures the interest of a large group of investigators. Sometimes it is the correct one, but not always. It is often difficult and slow, tiresome, to try to change the trend. Periodicals devoted to pharmacol ogy continue to proliferate. Yet they cannot keep pace with the flood of pieces of phar macologie information that cross our desks. Critical reviews of pharmacology are desper ately needed in ophthalmology if scientists and, particularly, ophthalmologists are to succeed in understanding what current ocu lar pharmacology presents. Fortunately, there are many fine investi gators in ocular pharmacology. More are needed. Competent reviewers are necessary to bring the many separate items of pharma cologie knowledge together to reveal in suc cinct and clear fashion the total picture. Two decades ago, great interest was expressed in antibiotics. This still continues but there is much more work now going on in enzyme interaction, drug interactions, and the neces sity of understanding enzymatic actions. Pharmacology is a vast expanding discipline. There are many textbooks but they tend to become stereotyped. There are difficulties encountered by mem bers of the ophthalmic profession in obtain ing drug information they want and must have. There is so much information that it may be comparable to an overdose of a drug which produces toxic levels. In this case, the toxicity expresses itself in defeatism. The enormity of the problem discourages the busy practitioner from seeking out the infor mation he needs unless he can find it clearly expressed in new textbooks or current jour nals. It is essential that we have pharmacolo gists working in ophthalmology who are clinically oriented and can interpret the vast amount of scientific information rapidly ac cumulating in the research institutions throughout the world. Clinical pharmacolo gists should be able to participate in discus sions at the clinical level as well as in the ba
JANUARY, 1972
sic areas of pharmacology. Some institutions in the country already have a few pharma cologists in departments of opthalmology who are acquiring clinical information. We have well-trained ophthalmologists who are obtaining special training over several years in pharmacology departments without losing their contact with ophthalmology. These are the ones who are going to keep us informed of the latest changes in pharmacogenetic as pects of drug metabolisms and how they are important in ophthalmology and the various factors affecting drug metabolism, the clini cal implications of enzyme induction and pharmacokinetics. It is most essential that pharmacologists realize that they are part of medicine and that clinicians realize that fundamental work with drugs has applicability in practical ther apeutics. Within the past few years, an awareness has developed that therapeutic agents may exert an effect directly upon the patient, but two or more drugs may react within the patient to produce various unex pected results. Such reactions may reduce or even cancel out the beneficial properties of one or more drugs. They may result in a dis proportionate potentiation of one or both drugs or an undesirable side effect with toxic manifestation not associated with the respec tive drugs individually, and then may result, as well, in a planned beneficial effect for the patient. A great deal has been written about the re lationship between molecular structure and biological activity. This has led to a better understanding of receptors and this is bear ing fruit in practical therapy. This type of research has led to a knowledge of the exis tence of two kinds of adrenergic receptors, for example, alpha and beta, which was first suggested in 1948 by Ahlquist. These recep tors are now being explored with stimulators as well as blocking agents, for their effect on intraocular pressure and other phases of ocular function. The question has been raised whether bio logical responses to \'arious drugs may not
VOL. 73, NO. 1
EDITORIAL
be constant but are subject to random varia tions which appear to be related to circadian (about 24 hours) or circannual (about one year) rhythms. 1 Advances in chronopharmacology demand standardized studies on large groups of hu man subjects for long spans of time with eventual collection of data. Methods are be ing developed to evaluate the traditional pa rameters of rhythms in different geographi cal locations. For years, ophthalmologists have been aware of the diurnal curves of intraocular pressure and have often pre scribed medication for control of elevated intraocular pressure by applying the drugs through knowledge of the variations each day to prevent the peaks from occurring. This therapy might be useful in other as pects of ocular disorders. The ophthalmologist needs more informa tion concerning the studies of embryology and pathology which deal with abnormal de velopment and congenital malformations. It is not sufficient to refrain from advising the use of drugs in individuals during pregnancy for fear of the ocular malformations which might occur. More information is needed as to which drugs can be harmful, which ones can be used with safety, also mechanisms for determining whether or not they are safe. Antiparasite chemotherapy, cancer che motherapy, drug absorption and transfer need ophthalmic investigation. Chemother apy is fast becoming a clinical rule in the management of malignancy rather than the exception. Opthalmologists have usually proceeded from foundations established by other investigators. Stimulating results seemed to have been achieved in premalignant kératoses, superficial basal cell carcino mas, and epidermoid carcinomas in situ, ei ther by inducing a localized hypersensitivity reaction with dinitrochlorobenzene or by cytotoxic effect of fluorouracil. In some se ries, results were 95% in appropriately se lected patients. Although there were some local undesirable side effects, the systemic toxicity was minimal. The reasons for these
139
beneficial effects were not clear. Most clinical ophthalmologists are inter ested primarily in the effect of drugs on man, and particularly his eyes. This empha sis on human pharmacology is understand able, for the overall purpose of our study is to improve man's condition. It is also evident that each of us is an individual and not all of us will react the same way to a drug. This can only be found out by testing in humans. However, we are limited sometimes in our study of drug effect in man for technical or ethical reasons and our selection of drugs must be based, in part, on prior pharmaco logie evaluation in animals. The clinical pharmacologist who is to guide us must therefore have knowledge of animal pharma cology, must know what species to use, and how to interpret the data which he obtains in animals for trial in man. After we have learned about the action of drugs at the cellular level as influenced by microsomes, DNA, RNA, their distribution, metabolism, excretion and interaction, we finally come to the main purpose of drugs, the prevention or treatment of disease. To prop erly evaluate these, careful studies must be done. An understanding of the mechanisms of clinical evaluations can be much more dif ficult than similar studies performed in ex perimental animals. Drug therapy must be based upon correlation of effects of drugs with physiologic and biochemical and microbiologic kinetic aspects of disease. Only through basic knowledge can we understand toxicology and limitations of drugs and how limitations can be overcome. There is no question but that we must train more indi viduals in ocular pharmacology so that they can provide us with a fair knowledge of oph thalmology, pharmacology, and the clinical applications of the basic science in this fasci nating specialty. Irving H. Leopold REFERENCE
1. Reinberg, A., and Holberg, F.: Circadian rhythm. Ann. Rev. Pharm. 2:455, 1971.
W.
NEWELL,
Editor-in-Chief
160 East Grand Ave., Chicago, Illinois 60611
Editor-in-Chief Emeritus 2450 Lakeview Avenue, Chicago, Illinois 60614
DERRICK VAIL,
E D I T O R I A L BOARD Bernard Becker, St. Louis Frederick C. Blodi, Iowa City Benjamin F. Boyd, Panama Thomas Chalkley, Chicago Sir Stewart Duke-Elder, London DuPont Guerry III, Richmond Michael J. Hogan, San Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman, Gainesville Arthur H. Keeney, Philadelphia Bertha A. Klien, Chicago Alex E. Krill, Chicago
Carl Kupfer, Bethesda, Maryland James E. Lebensohn, Chicago Irving H. Leopold, New York A. Edward Maumenee, Baltimore Edward \V. D. Norton, Miami Albert M. Potts, Chicago Algernon B. Reese, New York Marvin L. Sears, New Haven David Shoch, Chicago George K. Smelser, New York Phillips Thygeson, San Francisco Gunter K. von Noorden, Baltimore
Published monthly by the Ophthalmic Publishing Company Directors:
DERRICK VAIL, President; ALGERNON B. REESE, Vice-President; FRANK W. NEWELL, Secretary and Treasurer; A. EDWARD MAUMENEE, MICHAEL J. HOGAN, EDWARD W. D. NORTON
CLINICAL PHARMACOLOGISTS IN OPHTHALMOLOGY The field of drug development is charac terized generally by highly productive work. Most of this productivity has been the result of highly ingenious organic chemists. They have developed a variety of chemicals with unusual biological activities. In order for those to be of practical importance in medi cine, they have to be evaluated for their effect on the biological systems. The past 50 years have been a favorable time for research in all fields of medicine. This has been particularly striking in phar
macology. Von Euler pointed out that the fast growth of the bioscientific achievements follows an exponential function, doubling every 10 to 15 years. The rapid growth of pharmacology, like other sciences, has inter esting corollaries. This implies that accumu lated total knowledge—the amount of data that we see—is probably the result of re search work done in the last decade. It is dif ficult to keep track of all this information. One can look on this as a menacing ava lanche of data. It is essential that this be pre sented to the busy ophthalmologist, as well as all physicians, free from all unnecessary ap pendages. 137
138
AMERICAN JOURNAL OF OPHTHALMOLOGY
The trends of pharmacologie research may be fascinating. Very often, an idea is fash ionable and rapidly insures the interest of a large group of investigators. Sometimes it is the correct one, but not always. It is often difficult and slow, tiresome, to try to change the trend. Periodicals devoted to pharmacol ogy continue to proliferate. Yet they cannot keep pace with the flood of pieces of phar macologie information that cross our desks. Critical reviews of pharmacology are desper ately needed in ophthalmology if scientists and, particularly, ophthalmologists are to succeed in understanding what current ocu lar pharmacology presents. Fortunately, there are many fine investi gators in ocular pharmacology. More are needed. Competent reviewers are necessary to bring the many separate items of pharma cologie knowledge together to reveal in suc cinct and clear fashion the total picture. Two decades ago, great interest was expressed in antibiotics. This still continues but there is much more work now going on in enzyme interaction, drug interactions, and the neces sity of understanding enzymatic actions. Pharmacology is a vast expanding discipline. There are many textbooks but they tend to become stereotyped. There are difficulties encountered by mem bers of the ophthalmic profession in obtain ing drug information they want and must have. There is so much information that it may be comparable to an overdose of a drug which produces toxic levels. In this case, the toxicity expresses itself in defeatism. The enormity of the problem discourages the busy practitioner from seeking out the infor mation he needs unless he can find it clearly expressed in new textbooks or current jour nals. It is essential that we have pharmacolo gists working in ophthalmology who are clinically oriented and can interpret the vast amount of scientific information rapidly ac cumulating in the research institutions throughout the world. Clinical pharmacolo gists should be able to participate in discus sions at the clinical level as well as in the ba
JANUARY, 1972
sic areas of pharmacology. Some institutions in the country already have a few pharma cologists in departments of opthalmology who are acquiring clinical information. We have well-trained ophthalmologists who are obtaining special training over several years in pharmacology departments without losing their contact with ophthalmology. These are the ones who are going to keep us informed of the latest changes in pharmacogenetic as pects of drug metabolisms and how they are important in ophthalmology and the various factors affecting drug metabolism, the clini cal implications of enzyme induction and pharmacokinetics. It is most essential that pharmacologists realize that they are part of medicine and that clinicians realize that fundamental work with drugs has applicability in practical ther apeutics. Within the past few years, an awareness has developed that therapeutic agents may exert an effect directly upon the patient, but two or more drugs may react within the patient to produce various unex pected results. Such reactions may reduce or even cancel out the beneficial properties of one or more drugs. They may result in a dis proportionate potentiation of one or both drugs or an undesirable side effect with toxic manifestation not associated with the respec tive drugs individually, and then may result, as well, in a planned beneficial effect for the patient. A great deal has been written about the re lationship between molecular structure and biological activity. This has led to a better understanding of receptors and this is bear ing fruit in practical therapy. This type of research has led to a knowledge of the exis tence of two kinds of adrenergic receptors, for example, alpha and beta, which was first suggested in 1948 by Ahlquist. These recep tors are now being explored with stimulators as well as blocking agents, for their effect on intraocular pressure and other phases of ocular function. The question has been raised whether bio logical responses to \'arious drugs may not
VOL. 73, NO. 1
EDITORIAL
be constant but are subject to random varia tions which appear to be related to circadian (about 24 hours) or circannual (about one year) rhythms. 1 Advances in chronopharmacology demand standardized studies on large groups of hu man subjects for long spans of time with eventual collection of data. Methods are be ing developed to evaluate the traditional pa rameters of rhythms in different geographi cal locations. For years, ophthalmologists have been aware of the diurnal curves of intraocular pressure and have often pre scribed medication for control of elevated intraocular pressure by applying the drugs through knowledge of the variations each day to prevent the peaks from occurring. This therapy might be useful in other as pects of ocular disorders. The ophthalmologist needs more informa tion concerning the studies of embryology and pathology which deal with abnormal de velopment and congenital malformations. It is not sufficient to refrain from advising the use of drugs in individuals during pregnancy for fear of the ocular malformations which might occur. More information is needed as to which drugs can be harmful, which ones can be used with safety, also mechanisms for determining whether or not they are safe. Antiparasite chemotherapy, cancer che motherapy, drug absorption and transfer need ophthalmic investigation. Chemother apy is fast becoming a clinical rule in the management of malignancy rather than the exception. Opthalmologists have usually proceeded from foundations established by other investigators. Stimulating results seemed to have been achieved in premalignant kératoses, superficial basal cell carcino mas, and epidermoid carcinomas in situ, ei ther by inducing a localized hypersensitivity reaction with dinitrochlorobenzene or by cytotoxic effect of fluorouracil. In some se ries, results were 95% in appropriately se lected patients. Although there were some local undesirable side effects, the systemic toxicity was minimal. The reasons for these
139
beneficial effects were not clear. Most clinical ophthalmologists are inter ested primarily in the effect of drugs on man, and particularly his eyes. This empha sis on human pharmacology is understand able, for the overall purpose of our study is to improve man's condition. It is also evident that each of us is an individual and not all of us will react the same way to a drug. This can only be found out by testing in humans. However, we are limited sometimes in our study of drug effect in man for technical or ethical reasons and our selection of drugs must be based, in part, on prior pharmaco logie evaluation in animals. The clinical pharmacologist who is to guide us must therefore have knowledge of animal pharma cology, must know what species to use, and how to interpret the data which he obtains in animals for trial in man. After we have learned about the action of drugs at the cellular level as influenced by microsomes, DNA, RNA, their distribution, metabolism, excretion and interaction, we finally come to the main purpose of drugs, the prevention or treatment of disease. To prop erly evaluate these, careful studies must be done. An understanding of the mechanisms of clinical evaluations can be much more dif ficult than similar studies performed in ex perimental animals. Drug therapy must be based upon correlation of effects of drugs with physiologic and biochemical and microbiologic kinetic aspects of disease. Only through basic knowledge can we understand toxicology and limitations of drugs and how limitations can be overcome. There is no question but that we must train more indi viduals in ocular pharmacology so that they can provide us with a fair knowledge of oph thalmology, pharmacology, and the clinical applications of the basic science in this fasci nating specialty. Irving H. Leopold REFERENCE
1. Reinberg, A., and Holberg, F.: Circadian rhythm. Ann. Rev. Pharm. 2:455, 1971.