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The Antiepileptic Drug Development Program: Orphan Drugs Find a Home
The Antiepileptic Drug Development Program: Orphan Drugs Rnd a Home Not a single new antiepileptic drug has been produced in this country since 1960. Dilantin (phenytoin) was introduced in 1938, the first antiepileptic to result from a deliberate laboratory search. It was a substitute for phenobarbital, in use since 1912. Between 1938 and 1960, an tiepileptics came on the market at the rate of about one per year. But when proof of efficacy became a requirement of drug approval in 1961, antiepileptic drug development was stopped in its tracks-unless one counts diazepam, developed chiefly as a tranquilizer. Not until1974 was Tegretol (carbamazepine) introduced, and it was developed in Europe. Demonstrating efficacy steeply increased the cost of the drug development process. Although two million people in this country experience seizures at some point in their lives-a half-million at least once a month--compared with cancer, hypertension, anxiety, and other chronic diseases, the market for antiepileptic drugs is quite small. Further development thus became uneconomical. There was also a general belief in the 1960s that existing drugs were effective at controlling most kinds of epilepsy. In 1970, however, the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) of NIH determined that available drugs were not adequate. Only 50% of all seizures could be controlled; another 25% were merely improved. Many patients controlled their seizures at the expense of significant chronic toxicity. Unloved, Unborn The well-publicized case of Depakene (valproic acid) helped dramatize what has come to be known as the" orphan drug" problem-potentially valuable compounds that are unloved or unborn as the result of marketplace economics.* Depakene was introduced in France in the late American Pharmacy Vol. NS20, No. B. August 1960/479
sixties and was widely recognized as a superior treatment of absence or petit mal seizures. Abbott Laboratories held the license to produce Depakene in America, but its introduction had to await lengthy trials in this country. Physicians and patients clamored for it. Some blamed FDA for dragging its feet. Others felt that Abbott was going slow because it did not regard Depakene as profitable. Abbott was admittedly reluctant to gamble on a drug it had not developed, especially since the French had not conducted important preclinical studies and much of the clinical work was poor. Depa-
kene was finally released in 1978 with a push from the Epilepsy Branch of NINCDS. Approval is now being sought for its use in the treatment of grand mal as well as petit mal seizures. Well before the Depakene episode, however, NINCDS had begun to confront the orphan drug problem. Any solution would have political overtones: Does the government become a drug company of last resort? Or instead should it simply pay private companies outright to develop otherwise unprofitable drugs? As structured, NINCDS had neither the resources nor the desire to act like a drug company, producing and marketing its wares. Yet large financial subsidies of profit-making companies also were considered in• At the recent APhA Annual Meeting, APhA adopted policy with regard to therapeutic orphans that all applicant drugs should be clinically tested, as part of the drug approval process, in the population groups and for the major indicated uses for which they could reasonably be expected to achieve a substantial degree of use. These tests should be conducted in both the premarketing and postmarketing phase. (See July 1980 Amencan Pharmacy, p. 71.)
appropriate. A middle course was chosen. The chief financial and technical burden of the drug approval process is the clinical efficacy trials. Not only are assembling and maintaining patient populations, finding qualified investigators, and designing proper studies complex and expensive procedures, they are sometimes impossible for private companies. Once completed, clinical trials are often found invalid by the FDA, and the whole process must begin again, all at great cost. The stock in trade of NINCDS, however, is conducting clinical trials. It has access to qualified neurologists, statisticians, programmers, and other necessary staff, and to good medical facilities. NINCDS also maintains or helps maintain a wide variety of patient populations. Were these resources-available nowhere else-to be offered to companies under certain conditions, the cost and uncertainty of drug development could be lowered significantly. Drug Development Incentives In 1968, Dr. J. Kiffin Penry, then chief of the NINCDS Epilepsy Branch, undertook what later became known as the Antiepileptic Drug Development Program. Its strategy: not to subsidize corporate drug development per se, but to provide incentives in the form of NINCDS expertise that would make epileptic drug development more attractive. The branch also sought to demonstrate through epidemiological studies that markets do exist for more specific and less toxic antiepileptic drugs. The initial task of the development program was to hasten the introduction of drugs like (and including) Depakene that were already available in Europe. The Epilepsy Branch, in collaboration with other investigators, conducted trials of six antiepileptic drugs. Support of
55
these studies helped lower development costs considerably. It also allowed the branch to develop basic methods and standards for future studies. Three of the six drug studies were found effective: Tegretol (carbamazepine, introduced in 1974), Clonopin (clonazepam, 1975), and Depakene (1978). The three that failed were albutoin, sulthiame, and mexiletine. By 1974 the program had run out of European antiepileptics to test, and U.S. companies still regarded development of new antiepileptics as economically unattractive. Following a recommendation of its advisory committee (a subcommittee of the U.S. Surgeon General's Public Health Service Advisory Committee on the Epilepsies) the Epilepsy Branch began to participate still more deeply in drug development. It decided to screen for completely new entities that had anticonvulsant activity in animals. A contract to develop a screening procedure was awarded to a group at the University of Utah under pharmacologist Ewart Swinyard, PhD, who has worked with animal models since the 1950s. Once a screening procedure was developed, the Epilepsy Branch contracted with a single source for compounds to test. But this yielded a series of compounds that were too similar in structure and activity to be very useful. So the decision was made to solicit compounds from a variety of sources-including drug companies. But no private, profit-making company would supply a government agency with compounds unless its proprietary rights were guaranteed. The National Cancer Institute had already faced this problem, and special legislation had been passed to permit the retention of corporate rights. The Epilepsy Branch extended the same protection to companies under this legislation. Screening Program Initiated In 1975 the call went out to private companies and academic institutions to submit compounds for a
free screening of anticonvulsant activity. The invitation continues today. The only conditions are that the chemical structure must be known and that adequate quantities must be available for testing (approximately 500 mg). Drugs are screened within 90 days of submission. Companies are then given the results and allowed to proceed at their own pace. If a drug looks very promising, however, NIH may find another company willing to pursue its development. (The original company retains a financial interest in proportion to its investment up to that time.) Roger J. Porter, current chief of the Epilepsy Branch, reports that theresponse so far as been favorable. More than 3,000 compounds have been screened, and companies have followed through on most compounds that look promising. New submissions are still vigorously encouraged. This is just the first phase of support for drug development. If a drug does look good in the screening program, the drug company must decide whether to perform further studies. These involve drug administration in two animal species, usually rats and dogs. To encourage companies to move forward, and assuming funds are currently available, the Epilepsy Branch will offer to perform one of the two animal studies. There is one condition, however. The company must formulate the drug in adequate quantities for toxicology tests (approximately 2 kg). This is a significant undertaking. Quantity production of pure, stable and soluble formulations can cost up to $50,000. Until now the development of a drug has cost relatively little and has required no real commitment by corporate management. The decision to move ahead, however, must be carefully considered in the context of long-range marketing strategy and allocation of resources. If a drug does not appear to be toxic in animals, the firm may then seek FDA permission to test the compound in humans. Companies are well equipped to conduct the ini-
humans-~ I
tial toxicology studies in and need little assistance. Most , drugs are eliminated in this phaseonly 10% survive. This is why it is so f important to screen large numbers I of compounds. If there are no significant toxicities I or idosyncratic reactions at therapeutic dose levels, the most expen- ·~ sive and worrisome hurdle looms . ahead: the clinical efficacy trials. But , just as the Epilepsy Branch was able ) to assist in the efficacy trials of De- j pakene and the other European ' drugs, it can help here. If resources ; permit, the Epilepsy Branch may ac- I tually fund one of the studies. If not, [ it may be able to arrange for a study 1 to be conducted in an NINCDS- ~ maintained epilepsy center. In any ~ event, the branch can supply its ex- I[ pertise to help design competent :! studies, to help locate patients, and 1 to enlist investigators. Porter hopes that the first drugs , to emerge from the screening pro- i gram will undergo human efficacy j trials by 1981 or 1982, and that they t might enter the market a year after that. He also foresees a profusion of drug development alternatives, where new antiepileptics may find their way to market through a variety of routes. The branch may participate to different degrees at various points of development-in screening, in toxicology studies, in efficacy trials-or not at all. When fiscal constraints do not permit it to help, it is hoped that companies will proceed , on their own or will negotiate with other companies that may wish to [! do so. If an academic center discov1 ers a prom1smg compound, the branch may be able to find corporate i sponsorship. The Epilepsy Branch is also looking further down the road. Methods used to identify anticonvulsant chemicals have changed little over the last 25 years. New methods based on emerging knowledge about the way antiepileptic drugs work and the chemistry of neurotransmitters may yield drugs far more selective in their action. -Don Stewart American Pharmacy correspondent
1
1
!
J
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56
American Pharmacy Vol. NS20, No.8, August 1980/480
Childhood Diarrhea Vaccine Possible The Anticonvulsant Screening Project was begun in 1975 to screen large numbers of compounds for anticonvulsant activity. Both academic chemists and pharmaceutical firms are invited to submit compounds free of charge while retaining full proprietary rights. The procedures were developed under contract by a group at the University of Utah headed by Ewart Swinyard. Dr. Harvey Kupferberg acts as proj, ect officer for the NINCDS Epilepsy Branch. To capture a significant portion of the antiepileptic drug market, a new drug must fulfill at least one of the following requirements. It must be more effective or less toxic than ex, isting drugs treating the same seizure type; treat a seizure for which there is currently no treatment; or have superior efficacy in combination with other drugs than existing single-drug treatments. The screening process is designed to highlight such features that are 1 especially relevant to product marketability. For example, the efficacy of the benzodiazepines is limited by the development of tolerance. The screen specifically tests for tolerance. Other steps attempt early , identification of CNS and cardiac depressant effects, diuresis, acidosis, and other toxicities. Currently, the screen consists of seven steps, each representing a decision point. A drug either moves on to the next step, is rejected, or is ~ held back temporarily to permit more promising candidates to advance more quickly. Mice are used in the first five steps, rats in the last two.
Efficacy Evaluates compounds for anticonvulsant activity in two seizure models: the maximal electroshock seizure and the subcutaneous Metrazol (pentylenetetrazol) seizure test. Together these tests can identify all compounds detectable by other tests. Drugs such as phenyAmerican Pharmacy Vol. NS20, No.8, August 1980/481
toin that prevent electroshock seizures are thought to inhibit seizure discharge through the neural tissue, and may potentially treat major motor or grand mal seizures. Compounds such as the benzodiazepines that can inhibit Metrazol seizures are believed to raise the threshold for excitation of neural tissue; they may help treat absence or petit mal seizures.
Quantification Quantifies the level of anticonvulsant activity.
Toxicity Evaluates CNS toxicity in the rotorod ataxia test, which detects neurotoxicity and is used to quantify the therapeutic index. The animal is placed on a knurled plastic rod rotating at 6 rpm. Normal mice can remain on the rotating rod indefinitely; failure to remain for one minute signals neurotoxicity. Additional tests identify other system toxicities.
Absorption Compares oral absorption with parenteral administration.
Drug Differentiation Elaborates on step one to determine which existing drugs it resembles to help elucidate mechanism of action.
Efficacy in Rats The last two steps compare activity in rats to that in mice in preparation for upcoming toxicology studies performed in rats and beagles. Generally, compounds are more active in rats than in mice because of superior absorption in rats.
Toxicity in Rats Compounds usually complete the screen within 90 days of submission. To date, over 3,000 compounds have been screened. Of these, 25% demonstrated efficacy, but most were later eliminated because they were either toxic or poorly absorbed. So far, 21 have passed the screen successfully and warrant two-species toxicology studies.
Scientists from HEW's National Institute of Allergy and Infectious Diseases (NIAID) have succeeded in efficiently growing a virus identified as a major cause of serious diarrhea in infants and young children throughout the world. The virus, known as the rotavirus, was first identified in 1973 by Australian researchers. Since then, extensive epidemiological studies have revealed that rotaviral infection is responsible for approximately 50% of serious diarrheal diseases in hospitalized infants and young children. Diarrheal diseases are a leading cause of death among the very young in many developing countries. The NIAID team, headed by Dr. Richard G. Wyatt, succeeded in growing a type 2 strain of the virus efficiently in monkey kidney cells. This strain, which was preselected from one of 42 stool specimens obtained mostly from young patients with serious diarrhea at Children's Hospital in Washington, DC, is the most prevalent cause of serious diarrheal disease. The accomplishment, reported in the January 11 issue of Science, will enable the investigators to study the connection between the virus's genetic structure and its ability to cause disease. Armed with this information, they may then be able to create a weakened virus that could be used as an effective vaccine.
Medication Found Effective in Traveler's Diarrhea Another medication to control traveler's diarrhea has proven effective for many individuals. The product is subsalicylate bismuth, found effective by Dr. Herbert L. Dupont of the University of Texas Medical School, Houston, in trials of the drug among 150 American students attending summer classes in Guadalajara, Mexico. 57
Oral Gold Developed for Arthritis A new way of giving gold to patients with rheumatoid arthritis is in the offing. An oral form of the agent is currently undergoing extensive clinical trials . The new agent, not yet given a trade name but known as auranofin, has been developed by SmithKline Corporation of Philadelphia. The company has kept pretty closemouthed about the new drug. But at the annual meeting of the American Rheumatism Association in Atlanta in May, several clinical reports were presented that indicated that the drug was safe and effective, although the optimum dosage schedule has not yet been worked out. Gold has been used for more than 50 years in the management of rheumatoid arthritis, a condition estimated to affect 2-3% of the U.S. population. Only about 70% of patients with rheumatoid arthritis are candidates for gold therapy. No Gold Build-Up Until now the agent has been available only in an injectable form. Apart from the inconvenience and expense to patients who must visit a physician for the injections, the treatment ultimately leads to a build-up of gold in the tissues. The oral form seems to avoid this problem, according to Dr. Norman L. Gottlieb, professor of medicine at the University of Miami School of Medicine and author of one of the Atlanta reports. Gottlieb reviewed data on 18 patients, seven of whom had been treated with the new agent for more than two years. The other study, presented by Dr. Andrew Baldassare, assistant clinical professor of internal medicine at St. Louis University School of Medicine, was on 25 patients treated for up to 18 months. Both studies used two dosage schedules: 2 mg and 6 mg daily. Efficacy was evaluated in terms of relieving painful and swollen joints, improving grip strength, and reducing morning stiffness. 58
Both studies found that the higher dose was necessary to produce a statistically significant benefit. Gottlieb felt, in fact, that even the 6 mg daily dose was inadequate to achieve maximum improvement. He indicated that broader trials at various doses with larger numbers of patients are still needed to determine the optimum dosage. Although no one knows how gold works to relieve arthritis, laboratory studies done by Baldassare's group in the patients receiving oral gold showed decreases in various biochemical factors that are abnormally high in rheumatoid arthritis. These include red cell sedimentation rate, immunoglobulins of various types, immune complexes, and the presence of rheumatoid factor. No Severe Toxicity Toxicities cited by Baldassare in his patients include six cases of maculopapular rash, three instances of inflammation of the oral tissues, and two patients with diarrhea and abdominal pain. Gottlieb reported cases of dermatitis, oral tissue inflammation and proteinuria-and indication of possible kidney damage-but he noted that they occurred in the oral gold treated patients less often than they do in patients treated with the injectable form. No patient was dropped from the study because of gold toxicity, he added. Auranofin is still in its investigational stages. However, the studies necessary to provide the data for Food and Drug Administration approval now involve 50 centers and over 750 patients. The company had no word on precisely when it would apply to FDA for approval of the drug, but one source at the company estimated that it would be in about 18 months. Not the least interesting aspect of the advent of auranofin is that it is an American drug development. Unlike many new drugs, which recently have become widely used abroad before reaching the Ameri-
Study Results Outline Treatment for Crohn' s Disease Results of a five-year study show ·:: that two drugs have proven useful I in treating Crohn's disease, a severe i chronic digestive disorder of the · small and large intestine . The disease affects more than 10,000 Americans, and its cause is unknown . 1 The study, funded by the National ~? Institutes of Health, involved 14 t< university centers and more than 700 patients. Three drugs were tested: sulfasaIazine, prednisone, and azathio- \ prine . The study demonstrated that I&' sulfasalazine is a useful and relative- 1 Iy less toxic drug for initial treat- I ment of Crohn's disease. Pred- ,. nisone was found the most effective 1 treatment for disease of moderate ) and greater severity. Both pred- I nisone and sulfasalazine were " found to be significantly better than f. a placebo in causing a remission of l active Crohn's disease. Azathio- ·lprine was somewhat better than a placebo, but not enough to be statistically significant. None of the ( three drugs was better than a placebo in preventing flare-ups or recurrence of the disease for more ~ than a period of one or two years. A second phase studied prednisone and sulfasalazine in combi- I nation and showed that if anything, \ the combination was less effective ~ than prednisone alone for inducing remission. l The complete results of the ' NIAMDD cooperative study were r reported in the journal Gastroenterology, Vol. 77, No. 4, Part 2. o r-----------------------------~· can market, auranofin stands a good chance of reaching the American patient first. Although studies with auranofin are being conducted in Europe, the American studies lead the field in · terms of numbers and duration. This last factor is important for any drug likely to be recommended for rheumatoid arthritis, since the disease is a chronic disorder, and most treatment is of necessity prolonged.
l
I
-CSM
American Pharmacy Vol. NS20, No. 8, August 1980/482
sixties and was widely recognized as a superior treatment of absence or petit mal seizures. Abbott Laboratories held the license to produce Depakene in America, but its introduction had to await lengthy trials in this country. Physicians and patients clamored for it. Some blamed FDA for dragging its feet. Others felt that Abbott was going slow because it did not regard Depakene as profitable. Abbott was admittedly reluctant to gamble on a drug it had not developed, especially since the French had not conducted important preclinical studies and much of the clinical work was poor. Depa-
kene was finally released in 1978 with a push from the Epilepsy Branch of NINCDS. Approval is now being sought for its use in the treatment of grand mal as well as petit mal seizures. Well before the Depakene episode, however, NINCDS had begun to confront the orphan drug problem. Any solution would have political overtones: Does the government become a drug company of last resort? Or instead should it simply pay private companies outright to develop otherwise unprofitable drugs? As structured, NINCDS had neither the resources nor the desire to act like a drug company, producing and marketing its wares. Yet large financial subsidies of profit-making companies also were considered in• At the recent APhA Annual Meeting, APhA adopted policy with regard to therapeutic orphans that all applicant drugs should be clinically tested, as part of the drug approval process, in the population groups and for the major indicated uses for which they could reasonably be expected to achieve a substantial degree of use. These tests should be conducted in both the premarketing and postmarketing phase. (See July 1980 Amencan Pharmacy, p. 71.)
appropriate. A middle course was chosen. The chief financial and technical burden of the drug approval process is the clinical efficacy trials. Not only are assembling and maintaining patient populations, finding qualified investigators, and designing proper studies complex and expensive procedures, they are sometimes impossible for private companies. Once completed, clinical trials are often found invalid by the FDA, and the whole process must begin again, all at great cost. The stock in trade of NINCDS, however, is conducting clinical trials. It has access to qualified neurologists, statisticians, programmers, and other necessary staff, and to good medical facilities. NINCDS also maintains or helps maintain a wide variety of patient populations. Were these resources-available nowhere else-to be offered to companies under certain conditions, the cost and uncertainty of drug development could be lowered significantly. Drug Development Incentives In 1968, Dr. J. Kiffin Penry, then chief of the NINCDS Epilepsy Branch, undertook what later became known as the Antiepileptic Drug Development Program. Its strategy: not to subsidize corporate drug development per se, but to provide incentives in the form of NINCDS expertise that would make epileptic drug development more attractive. The branch also sought to demonstrate through epidemiological studies that markets do exist for more specific and less toxic antiepileptic drugs. The initial task of the development program was to hasten the introduction of drugs like (and including) Depakene that were already available in Europe. The Epilepsy Branch, in collaboration with other investigators, conducted trials of six antiepileptic drugs. Support of
55
these studies helped lower development costs considerably. It also allowed the branch to develop basic methods and standards for future studies. Three of the six drug studies were found effective: Tegretol (carbamazepine, introduced in 1974), Clonopin (clonazepam, 1975), and Depakene (1978). The three that failed were albutoin, sulthiame, and mexiletine. By 1974 the program had run out of European antiepileptics to test, and U.S. companies still regarded development of new antiepileptics as economically unattractive. Following a recommendation of its advisory committee (a subcommittee of the U.S. Surgeon General's Public Health Service Advisory Committee on the Epilepsies) the Epilepsy Branch began to participate still more deeply in drug development. It decided to screen for completely new entities that had anticonvulsant activity in animals. A contract to develop a screening procedure was awarded to a group at the University of Utah under pharmacologist Ewart Swinyard, PhD, who has worked with animal models since the 1950s. Once a screening procedure was developed, the Epilepsy Branch contracted with a single source for compounds to test. But this yielded a series of compounds that were too similar in structure and activity to be very useful. So the decision was made to solicit compounds from a variety of sources-including drug companies. But no private, profit-making company would supply a government agency with compounds unless its proprietary rights were guaranteed. The National Cancer Institute had already faced this problem, and special legislation had been passed to permit the retention of corporate rights. The Epilepsy Branch extended the same protection to companies under this legislation. Screening Program Initiated In 1975 the call went out to private companies and academic institutions to submit compounds for a
free screening of anticonvulsant activity. The invitation continues today. The only conditions are that the chemical structure must be known and that adequate quantities must be available for testing (approximately 500 mg). Drugs are screened within 90 days of submission. Companies are then given the results and allowed to proceed at their own pace. If a drug looks very promising, however, NIH may find another company willing to pursue its development. (The original company retains a financial interest in proportion to its investment up to that time.) Roger J. Porter, current chief of the Epilepsy Branch, reports that theresponse so far as been favorable. More than 3,000 compounds have been screened, and companies have followed through on most compounds that look promising. New submissions are still vigorously encouraged. This is just the first phase of support for drug development. If a drug does look good in the screening program, the drug company must decide whether to perform further studies. These involve drug administration in two animal species, usually rats and dogs. To encourage companies to move forward, and assuming funds are currently available, the Epilepsy Branch will offer to perform one of the two animal studies. There is one condition, however. The company must formulate the drug in adequate quantities for toxicology tests (approximately 2 kg). This is a significant undertaking. Quantity production of pure, stable and soluble formulations can cost up to $50,000. Until now the development of a drug has cost relatively little and has required no real commitment by corporate management. The decision to move ahead, however, must be carefully considered in the context of long-range marketing strategy and allocation of resources. If a drug does not appear to be toxic in animals, the firm may then seek FDA permission to test the compound in humans. Companies are well equipped to conduct the ini-
humans-~ I
tial toxicology studies in and need little assistance. Most , drugs are eliminated in this phaseonly 10% survive. This is why it is so f important to screen large numbers I of compounds. If there are no significant toxicities I or idosyncratic reactions at therapeutic dose levels, the most expen- ·~ sive and worrisome hurdle looms . ahead: the clinical efficacy trials. But , just as the Epilepsy Branch was able ) to assist in the efficacy trials of De- j pakene and the other European ' drugs, it can help here. If resources ; permit, the Epilepsy Branch may ac- I tually fund one of the studies. If not, [ it may be able to arrange for a study 1 to be conducted in an NINCDS- ~ maintained epilepsy center. In any ~ event, the branch can supply its ex- I[ pertise to help design competent :! studies, to help locate patients, and 1 to enlist investigators. Porter hopes that the first drugs , to emerge from the screening pro- i gram will undergo human efficacy j trials by 1981 or 1982, and that they t might enter the market a year after that. He also foresees a profusion of drug development alternatives, where new antiepileptics may find their way to market through a variety of routes. The branch may participate to different degrees at various points of development-in screening, in toxicology studies, in efficacy trials-or not at all. When fiscal constraints do not permit it to help, it is hoped that companies will proceed , on their own or will negotiate with other companies that may wish to [! do so. If an academic center discov1 ers a prom1smg compound, the branch may be able to find corporate i sponsorship. The Epilepsy Branch is also looking further down the road. Methods used to identify anticonvulsant chemicals have changed little over the last 25 years. New methods based on emerging knowledge about the way antiepileptic drugs work and the chemistry of neurotransmitters may yield drugs far more selective in their action. -Don Stewart American Pharmacy correspondent
1
1
!
J
~----------~----------~------------
56
American Pharmacy Vol. NS20, No.8, August 1980/480
Childhood Diarrhea Vaccine Possible The Anticonvulsant Screening Project was begun in 1975 to screen large numbers of compounds for anticonvulsant activity. Both academic chemists and pharmaceutical firms are invited to submit compounds free of charge while retaining full proprietary rights. The procedures were developed under contract by a group at the University of Utah headed by Ewart Swinyard. Dr. Harvey Kupferberg acts as proj, ect officer for the NINCDS Epilepsy Branch. To capture a significant portion of the antiepileptic drug market, a new drug must fulfill at least one of the following requirements. It must be more effective or less toxic than ex, isting drugs treating the same seizure type; treat a seizure for which there is currently no treatment; or have superior efficacy in combination with other drugs than existing single-drug treatments. The screening process is designed to highlight such features that are 1 especially relevant to product marketability. For example, the efficacy of the benzodiazepines is limited by the development of tolerance. The screen specifically tests for tolerance. Other steps attempt early , identification of CNS and cardiac depressant effects, diuresis, acidosis, and other toxicities. Currently, the screen consists of seven steps, each representing a decision point. A drug either moves on to the next step, is rejected, or is ~ held back temporarily to permit more promising candidates to advance more quickly. Mice are used in the first five steps, rats in the last two.
Efficacy Evaluates compounds for anticonvulsant activity in two seizure models: the maximal electroshock seizure and the subcutaneous Metrazol (pentylenetetrazol) seizure test. Together these tests can identify all compounds detectable by other tests. Drugs such as phenyAmerican Pharmacy Vol. NS20, No.8, August 1980/481
toin that prevent electroshock seizures are thought to inhibit seizure discharge through the neural tissue, and may potentially treat major motor or grand mal seizures. Compounds such as the benzodiazepines that can inhibit Metrazol seizures are believed to raise the threshold for excitation of neural tissue; they may help treat absence or petit mal seizures.
Quantification Quantifies the level of anticonvulsant activity.
Toxicity Evaluates CNS toxicity in the rotorod ataxia test, which detects neurotoxicity and is used to quantify the therapeutic index. The animal is placed on a knurled plastic rod rotating at 6 rpm. Normal mice can remain on the rotating rod indefinitely; failure to remain for one minute signals neurotoxicity. Additional tests identify other system toxicities.
Absorption Compares oral absorption with parenteral administration.
Drug Differentiation Elaborates on step one to determine which existing drugs it resembles to help elucidate mechanism of action.
Efficacy in Rats The last two steps compare activity in rats to that in mice in preparation for upcoming toxicology studies performed in rats and beagles. Generally, compounds are more active in rats than in mice because of superior absorption in rats.
Toxicity in Rats Compounds usually complete the screen within 90 days of submission. To date, over 3,000 compounds have been screened. Of these, 25% demonstrated efficacy, but most were later eliminated because they were either toxic or poorly absorbed. So far, 21 have passed the screen successfully and warrant two-species toxicology studies.
Scientists from HEW's National Institute of Allergy and Infectious Diseases (NIAID) have succeeded in efficiently growing a virus identified as a major cause of serious diarrhea in infants and young children throughout the world. The virus, known as the rotavirus, was first identified in 1973 by Australian researchers. Since then, extensive epidemiological studies have revealed that rotaviral infection is responsible for approximately 50% of serious diarrheal diseases in hospitalized infants and young children. Diarrheal diseases are a leading cause of death among the very young in many developing countries. The NIAID team, headed by Dr. Richard G. Wyatt, succeeded in growing a type 2 strain of the virus efficiently in monkey kidney cells. This strain, which was preselected from one of 42 stool specimens obtained mostly from young patients with serious diarrhea at Children's Hospital in Washington, DC, is the most prevalent cause of serious diarrheal disease. The accomplishment, reported in the January 11 issue of Science, will enable the investigators to study the connection between the virus's genetic structure and its ability to cause disease. Armed with this information, they may then be able to create a weakened virus that could be used as an effective vaccine.
Medication Found Effective in Traveler's Diarrhea Another medication to control traveler's diarrhea has proven effective for many individuals. The product is subsalicylate bismuth, found effective by Dr. Herbert L. Dupont of the University of Texas Medical School, Houston, in trials of the drug among 150 American students attending summer classes in Guadalajara, Mexico. 57
Oral Gold Developed for Arthritis A new way of giving gold to patients with rheumatoid arthritis is in the offing. An oral form of the agent is currently undergoing extensive clinical trials . The new agent, not yet given a trade name but known as auranofin, has been developed by SmithKline Corporation of Philadelphia. The company has kept pretty closemouthed about the new drug. But at the annual meeting of the American Rheumatism Association in Atlanta in May, several clinical reports were presented that indicated that the drug was safe and effective, although the optimum dosage schedule has not yet been worked out. Gold has been used for more than 50 years in the management of rheumatoid arthritis, a condition estimated to affect 2-3% of the U.S. population. Only about 70% of patients with rheumatoid arthritis are candidates for gold therapy. No Gold Build-Up Until now the agent has been available only in an injectable form. Apart from the inconvenience and expense to patients who must visit a physician for the injections, the treatment ultimately leads to a build-up of gold in the tissues. The oral form seems to avoid this problem, according to Dr. Norman L. Gottlieb, professor of medicine at the University of Miami School of Medicine and author of one of the Atlanta reports. Gottlieb reviewed data on 18 patients, seven of whom had been treated with the new agent for more than two years. The other study, presented by Dr. Andrew Baldassare, assistant clinical professor of internal medicine at St. Louis University School of Medicine, was on 25 patients treated for up to 18 months. Both studies used two dosage schedules: 2 mg and 6 mg daily. Efficacy was evaluated in terms of relieving painful and swollen joints, improving grip strength, and reducing morning stiffness. 58
Both studies found that the higher dose was necessary to produce a statistically significant benefit. Gottlieb felt, in fact, that even the 6 mg daily dose was inadequate to achieve maximum improvement. He indicated that broader trials at various doses with larger numbers of patients are still needed to determine the optimum dosage. Although no one knows how gold works to relieve arthritis, laboratory studies done by Baldassare's group in the patients receiving oral gold showed decreases in various biochemical factors that are abnormally high in rheumatoid arthritis. These include red cell sedimentation rate, immunoglobulins of various types, immune complexes, and the presence of rheumatoid factor. No Severe Toxicity Toxicities cited by Baldassare in his patients include six cases of maculopapular rash, three instances of inflammation of the oral tissues, and two patients with diarrhea and abdominal pain. Gottlieb reported cases of dermatitis, oral tissue inflammation and proteinuria-and indication of possible kidney damage-but he noted that they occurred in the oral gold treated patients less often than they do in patients treated with the injectable form. No patient was dropped from the study because of gold toxicity, he added. Auranofin is still in its investigational stages. However, the studies necessary to provide the data for Food and Drug Administration approval now involve 50 centers and over 750 patients. The company had no word on precisely when it would apply to FDA for approval of the drug, but one source at the company estimated that it would be in about 18 months. Not the least interesting aspect of the advent of auranofin is that it is an American drug development. Unlike many new drugs, which recently have become widely used abroad before reaching the Ameri-
Study Results Outline Treatment for Crohn' s Disease Results of a five-year study show ·:: that two drugs have proven useful I in treating Crohn's disease, a severe i chronic digestive disorder of the · small and large intestine . The disease affects more than 10,000 Americans, and its cause is unknown . 1 The study, funded by the National ~? Institutes of Health, involved 14 t< university centers and more than 700 patients. Three drugs were tested: sulfasaIazine, prednisone, and azathio- \ prine . The study demonstrated that I&' sulfasalazine is a useful and relative- 1 Iy less toxic drug for initial treat- I ment of Crohn's disease. Pred- ,. nisone was found the most effective 1 treatment for disease of moderate ) and greater severity. Both pred- I nisone and sulfasalazine were " found to be significantly better than f. a placebo in causing a remission of l active Crohn's disease. Azathio- ·lprine was somewhat better than a placebo, but not enough to be statistically significant. None of the ( three drugs was better than a placebo in preventing flare-ups or recurrence of the disease for more ~ than a period of one or two years. A second phase studied prednisone and sulfasalazine in combi- I nation and showed that if anything, \ the combination was less effective ~ than prednisone alone for inducing remission. l The complete results of the ' NIAMDD cooperative study were r reported in the journal Gastroenterology, Vol. 77, No. 4, Part 2. o r-----------------------------~· can market, auranofin stands a good chance of reaching the American patient first. Although studies with auranofin are being conducted in Europe, the American studies lead the field in · terms of numbers and duration. This last factor is important for any drug likely to be recommended for rheumatoid arthritis, since the disease is a chronic disorder, and most treatment is of necessity prolonged.
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American Pharmacy Vol. NS20, No. 8, August 1980/482