- Email: [email protected]
Quest for New Drugs
to meet needs of modern medicine. •
•
for new drugs by Bruce W. Halstead, MD
T
he demands for new biologicallyactive chemical substances have increased greatly during the last decade of the cold war age. The international race in the development of new chemical agents to meet the needs of modern medical and military activity and the impetus given by the requirements of space biology and medicine present a formidable challenge to the drug and organic chemical industries. The need for drugs is further augmented by the demands of a rapidly expanding world population for a greater abundance of low-priced nutrients. Natural products have much to offer the drug and chemical industries in their quest for new compounds. In recent years emphasis in new drug development has been placed on synthetic chemistry. Although synthetic chemistry has certain obvious economic and technical advantages, the synthetic chemist finds it difficult to compete with nature in developing new compounds with a vast array of intricate molecular structures and striking biological activity. The commercial successes of such drugs as digitalis, curare, ephedrine, morphine, qumme, antibiotics, reserpine and a number of others testify to the rich potential of natural products. Investigations in natural products chemistry frequently open to the synthetic chemist entirely new vistas of chemical activity which have direct application to valuable pharmaceutical agents. Consistent research efforts through the years by European and Asiatic pharmaceutical manufacturers have contributed heavily to the advancement of natural products chemistry. It is encouraging to observe the recent trends among American companies in this direction . Some pharmaceutical companies purposely have avoided natural products as a source of new drugs because of problems in procuring raw materials, extracting and isolating active principles. Screening crude extracts for biological activity is laborious and expensive. Difficulties are sometimes encountered in obtaining adequate patent protection. Another hampering aspect of natural products research which affects many pharmaceutical companies is the lack of an adequate multidisciplinary research team.
Areas of research sometimes overlooked by the pharmaceutical manufacturer are ecology, marine biology, epidemiology, ethnobotany, venomology, systematics and other related fields. The need for trained personnel in pharmacognosy, pharmacology, biochemistry and organic chemistry is obvious and there is little difficulty in selling a board of directors on the need for financial support in these sciences. However, when properly oriented, valuable leads may be obtained from less obviously pertinent disciplines. Failure to explore these ancillary sciences has resulted in valuable pharmaceutical agents lying dormant for many decades. The problem of obtaining new drug leads is a complex one and many approaches have been used-literature surveys, botanical, chemical, pharmacological and anthropological studies, screening of crude materials, etc. However, the medical missionary is one of the most valuable and least used sources of new drug leads. He has the advantage of having crossed the language barrier, being acquainted with the customs of the people and having the opportunity of making first hand observations on the use of crude medicinal agents in humans. When properly organized, this avenue can be extremely productive and offers the distinct advantage of serving as a preliminary clinical screen. Generally drug responses are known only as a result of animal studies which all too frequently do not agree with those produced in man. Leads from medical missionaries are of particular value in that they are based on first hand clinical observations made by trained medical personnel. However, this approach is beset by certain complications. The average medical missionary has little time available for the commercial development of drugs since his mission in life is providing medical service to underprivileged peoples on a charitable basis. Understaffing, excessive work loads and an appalling number of patients are not conducive to following the type of an investigative program a sponsoring drug company might desire . Experience has shown that financial support of a more general type than is
usually given and utilization of an intermediary agency oftentimes enhances the productivity of the program. Despite the problems encountered in working with missionaries, the rich potential in new drug development is worth the time and effort expended. The World Life Research Institute was incorporated in January 1959 as a scientific nonprofit organization for conducting research in the broad field of natural products chemistry. The staff has conducted extensive field studies in crude drug procurement and development in Africa, Asia, Europe, Mexico, Central and South America and the tropical Pacific Islands. Moreover, a network of world-wide crude drug procurement contacts has been established involving more than 200 medical mission groups. Estimates presently indicate these channels have more than 500 crude drugs available for investigation.
.. . . . .. . . . . . . . . . .
Bruce W. Halstead, MD, director of the World Life Research Institute in California, has traveled the world and plunged to ocean depths in search of new drugs. As a University of California student, he served as assistant in ichthyology at the California Academy of Sciences. Following his graduation from what is now Loma Linda University, he was on the faculties of several colleges including his alma mater. In 1959 he took over his present post. His membership in scientific organizations extends from AAAS through 18 international, national and local groups.
Vol. NS3, No .3,
March
1963
129
Diving for poisonous fishes in the Marshall Islands is Author Bruce Halstead . Much of his work is concerned with marine biotoxins and he calls the ocean his underwater laboratory.
Research emphasis within the In stitute is placed on compounds derived from two sources, phytochemicals and marine biotoxins. Medicinal plant leads are obtained either through missionaries who have observed the drug being used by native peoples or directly through our staff working in the field. Technical identification of all plant materials is secured by the Institute's work in conjunction with various plant systematists. Plants for herbarium and pharmacological purposes are collected and information is obtained on the native name, locality, ecology, native medicinal l1se and method of preparation of each plant. These data are valuable and useful for subsequent pharmacological and clinical investigations. Initial pharmacological studies are guided somewhat by the ethnobotanical and field clinical data that are provided. These studies are generally continued to a point where the biological activity present has been at least grossly evaluated. The amount of subsequent research conducted upon the drug depends entirely upon the nature of its chemical and pharmacological properties and the interests of the research staff. The field of marine pharmaceutical chemistry offers a vast untapped wealth of powerful biologically-active substances, many of which will someday find their way into the armamentarium of the practicing physician. Seaweeds have been fo und to be good sources of t hiamine, niacin, riboflavin, folic acid, alpha-tocopherol, vitamin A, ascorbic acid and ergosterol. T he mineral ash content of some seaweed may be as 130
high as 38.9 percent. The predominating minerals are the halides, sulfates, phosphates and oxides of calcium, magnesium, potassium and sodium, but in addition there are present numerous trace elements of nutritional value. Phycocolloids are used extensively in the drug, food and cosmetic industries because of their properties as gelling, emulsifying, thickening and suspending agents. Alginates have been found to be useful as absorbable agents in surgery.
Extracts from some of the sea weeds have been known to have definite antibiotic properties and anticoagulants have been obtained from red algae. Several of the poisons obtained from fishes and other marine animals have been used commercially in Asia in an attenuated form as therapeutic agents. Toxic pharmacological agents are widely distributed throughout the marine inhabitants of the animal kingdom- in protozoans, sponges, coelenterates, mollusks, annelids, arthropods, echinoderms, fishes , sea snakes, turtles and certain marine mammals. Marine biotoxins are becoming of increased medical and economic significance as potential pharmaceutical agents. Expeditions have been sent to many ocean areas of the world in search of new drugs and collecting technics have been developed which offer considerable promise in the quest for new drugs from the sea. Undoubtedly, man in the future will continue to direct his attention to the sea for lifegiving substances. There is need today in industry for a serious re-evaluation of what natural products research has to offer in the search for new products. More productive exploitation of this field is dependent upon improved procurement methods, more effective means of preserving crude botanicals and their phytochemical constituents in the field and more thorough pharmacological screening technics than now exist. Most disappointments in natural products research stem largely from our own technological failures to meet the challenge of the fie ld. •
scheduled for 'May release; •••
pharmacy manpower study
N
ow nearing completion, the pharmacy manpower study prepared by the Public Health Service division of public health methods is slated for press in May 1963. The nlanuscript on the study was reviewed prior to publication at a meeting on January 21. Technical advisers were William S. Apple, George F. Archambault, Charles W. Bliven, Howard L . Binkley, W. Paul Briggs, Joseph Cohen, Charles B. Dunnington and Fred T . Mahaffey. These members of the pharmacy profession had been recommended at an ~dvisory group meeting on October 26, 1961 to which 16 organizations were invited. Information on the numbers, lbcation and characteristics of pharmacists in the United States has been compiled from four sources for presentation in the pUblication.
Jo urn a l of the AMERICAN PHARMACEUT ICAL ASSOCIATION
The sources 'are the 1962 national inventory of licensed pharmacists, the 1962 sample survey of pharmacists, pharmacists reported in the 1960 census of popUlation and the 1961 state registrations of pharmacists reported by the National Association of Boards of Pharmacy. Also included are statistics on undergraduate student enrollments and graduates of U.S. schools of pharmacy prepared by the American Association of Colleges of Pharmacy. Auth()red by D.r. Paul Q. Peterson and Mrs. Maryland Y . Pennell, the publication will be the 15th in a series on health manpower issued by the .P ublicHealth Service to provide · information to persons and organizations concerned with the provision of health services. I t will be designatedPHSPublication Number 263, section 15. •
•
for new drugs by Bruce W. Halstead, MD
T
he demands for new biologicallyactive chemical substances have increased greatly during the last decade of the cold war age. The international race in the development of new chemical agents to meet the needs of modern medical and military activity and the impetus given by the requirements of space biology and medicine present a formidable challenge to the drug and organic chemical industries. The need for drugs is further augmented by the demands of a rapidly expanding world population for a greater abundance of low-priced nutrients. Natural products have much to offer the drug and chemical industries in their quest for new compounds. In recent years emphasis in new drug development has been placed on synthetic chemistry. Although synthetic chemistry has certain obvious economic and technical advantages, the synthetic chemist finds it difficult to compete with nature in developing new compounds with a vast array of intricate molecular structures and striking biological activity. The commercial successes of such drugs as digitalis, curare, ephedrine, morphine, qumme, antibiotics, reserpine and a number of others testify to the rich potential of natural products. Investigations in natural products chemistry frequently open to the synthetic chemist entirely new vistas of chemical activity which have direct application to valuable pharmaceutical agents. Consistent research efforts through the years by European and Asiatic pharmaceutical manufacturers have contributed heavily to the advancement of natural products chemistry. It is encouraging to observe the recent trends among American companies in this direction . Some pharmaceutical companies purposely have avoided natural products as a source of new drugs because of problems in procuring raw materials, extracting and isolating active principles. Screening crude extracts for biological activity is laborious and expensive. Difficulties are sometimes encountered in obtaining adequate patent protection. Another hampering aspect of natural products research which affects many pharmaceutical companies is the lack of an adequate multidisciplinary research team.
Areas of research sometimes overlooked by the pharmaceutical manufacturer are ecology, marine biology, epidemiology, ethnobotany, venomology, systematics and other related fields. The need for trained personnel in pharmacognosy, pharmacology, biochemistry and organic chemistry is obvious and there is little difficulty in selling a board of directors on the need for financial support in these sciences. However, when properly oriented, valuable leads may be obtained from less obviously pertinent disciplines. Failure to explore these ancillary sciences has resulted in valuable pharmaceutical agents lying dormant for many decades. The problem of obtaining new drug leads is a complex one and many approaches have been used-literature surveys, botanical, chemical, pharmacological and anthropological studies, screening of crude materials, etc. However, the medical missionary is one of the most valuable and least used sources of new drug leads. He has the advantage of having crossed the language barrier, being acquainted with the customs of the people and having the opportunity of making first hand observations on the use of crude medicinal agents in humans. When properly organized, this avenue can be extremely productive and offers the distinct advantage of serving as a preliminary clinical screen. Generally drug responses are known only as a result of animal studies which all too frequently do not agree with those produced in man. Leads from medical missionaries are of particular value in that they are based on first hand clinical observations made by trained medical personnel. However, this approach is beset by certain complications. The average medical missionary has little time available for the commercial development of drugs since his mission in life is providing medical service to underprivileged peoples on a charitable basis. Understaffing, excessive work loads and an appalling number of patients are not conducive to following the type of an investigative program a sponsoring drug company might desire . Experience has shown that financial support of a more general type than is
usually given and utilization of an intermediary agency oftentimes enhances the productivity of the program. Despite the problems encountered in working with missionaries, the rich potential in new drug development is worth the time and effort expended. The World Life Research Institute was incorporated in January 1959 as a scientific nonprofit organization for conducting research in the broad field of natural products chemistry. The staff has conducted extensive field studies in crude drug procurement and development in Africa, Asia, Europe, Mexico, Central and South America and the tropical Pacific Islands. Moreover, a network of world-wide crude drug procurement contacts has been established involving more than 200 medical mission groups. Estimates presently indicate these channels have more than 500 crude drugs available for investigation.
.. . . . .. . . . . . . . . . .
Bruce W. Halstead, MD, director of the World Life Research Institute in California, has traveled the world and plunged to ocean depths in search of new drugs. As a University of California student, he served as assistant in ichthyology at the California Academy of Sciences. Following his graduation from what is now Loma Linda University, he was on the faculties of several colleges including his alma mater. In 1959 he took over his present post. His membership in scientific organizations extends from AAAS through 18 international, national and local groups.
Vol. NS3, No .3,
March
1963
129
Diving for poisonous fishes in the Marshall Islands is Author Bruce Halstead . Much of his work is concerned with marine biotoxins and he calls the ocean his underwater laboratory.
Research emphasis within the In stitute is placed on compounds derived from two sources, phytochemicals and marine biotoxins. Medicinal plant leads are obtained either through missionaries who have observed the drug being used by native peoples or directly through our staff working in the field. Technical identification of all plant materials is secured by the Institute's work in conjunction with various plant systematists. Plants for herbarium and pharmacological purposes are collected and information is obtained on the native name, locality, ecology, native medicinal l1se and method of preparation of each plant. These data are valuable and useful for subsequent pharmacological and clinical investigations. Initial pharmacological studies are guided somewhat by the ethnobotanical and field clinical data that are provided. These studies are generally continued to a point where the biological activity present has been at least grossly evaluated. The amount of subsequent research conducted upon the drug depends entirely upon the nature of its chemical and pharmacological properties and the interests of the research staff. The field of marine pharmaceutical chemistry offers a vast untapped wealth of powerful biologically-active substances, many of which will someday find their way into the armamentarium of the practicing physician. Seaweeds have been fo und to be good sources of t hiamine, niacin, riboflavin, folic acid, alpha-tocopherol, vitamin A, ascorbic acid and ergosterol. T he mineral ash content of some seaweed may be as 130
high as 38.9 percent. The predominating minerals are the halides, sulfates, phosphates and oxides of calcium, magnesium, potassium and sodium, but in addition there are present numerous trace elements of nutritional value. Phycocolloids are used extensively in the drug, food and cosmetic industries because of their properties as gelling, emulsifying, thickening and suspending agents. Alginates have been found to be useful as absorbable agents in surgery.
Extracts from some of the sea weeds have been known to have definite antibiotic properties and anticoagulants have been obtained from red algae. Several of the poisons obtained from fishes and other marine animals have been used commercially in Asia in an attenuated form as therapeutic agents. Toxic pharmacological agents are widely distributed throughout the marine inhabitants of the animal kingdom- in protozoans, sponges, coelenterates, mollusks, annelids, arthropods, echinoderms, fishes , sea snakes, turtles and certain marine mammals. Marine biotoxins are becoming of increased medical and economic significance as potential pharmaceutical agents. Expeditions have been sent to many ocean areas of the world in search of new drugs and collecting technics have been developed which offer considerable promise in the quest for new drugs from the sea. Undoubtedly, man in the future will continue to direct his attention to the sea for lifegiving substances. There is need today in industry for a serious re-evaluation of what natural products research has to offer in the search for new products. More productive exploitation of this field is dependent upon improved procurement methods, more effective means of preserving crude botanicals and their phytochemical constituents in the field and more thorough pharmacological screening technics than now exist. Most disappointments in natural products research stem largely from our own technological failures to meet the challenge of the fie ld. •
scheduled for 'May release; •••
pharmacy manpower study
N
ow nearing completion, the pharmacy manpower study prepared by the Public Health Service division of public health methods is slated for press in May 1963. The nlanuscript on the study was reviewed prior to publication at a meeting on January 21. Technical advisers were William S. Apple, George F. Archambault, Charles W. Bliven, Howard L . Binkley, W. Paul Briggs, Joseph Cohen, Charles B. Dunnington and Fred T . Mahaffey. These members of the pharmacy profession had been recommended at an ~dvisory group meeting on October 26, 1961 to which 16 organizations were invited. Information on the numbers, lbcation and characteristics of pharmacists in the United States has been compiled from four sources for presentation in the pUblication.
Jo urn a l of the AMERICAN PHARMACEUT ICAL ASSOCIATION
The sources 'are the 1962 national inventory of licensed pharmacists, the 1962 sample survey of pharmacists, pharmacists reported in the 1960 census of popUlation and the 1961 state registrations of pharmacists reported by the National Association of Boards of Pharmacy. Also included are statistics on undergraduate student enrollments and graduates of U.S. schools of pharmacy prepared by the American Association of Colleges of Pharmacy. Auth()red by D.r. Paul Q. Peterson and Mrs. Maryland Y . Pennell, the publication will be the 15th in a series on health manpower issued by the .P ublicHealth Service to provide · information to persons and organizations concerned with the provision of health services. I t will be designatedPHSPublication Number 263, section 15. •