Pharmaceuticals for Developing Countries Conference Proceedings (1979) / Chapter Skim
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THE SCIENTIFIC BASE: OPPORTUNITIES FOR RESEARCH
THE SCIENTIFIC BASE: OPPORTUNITIES FOR RESEARCH
Pages 281-390
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From page 282... ...
Despite the very substantial breakthroughs in basic biological knowledge, which can be labeled as the new molecular biology, relatively little has been exploited to further the understanding of host-parasite interactions. Biological specificity is the basic approach to therapy and prophylaxis.
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From page 283... ...
and host. Thus, Sidney Brenner has pointed out how the water excretion mechanism of trematodes, embodied in a single cell, constitutes a highly specialized physiologic target for specific pharmaceutical development.
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From page 284... ...
This strategy is considered applicable to all infectious disease,^/ and not only for parasitic diseases of major importance in the developing world. The strategy stems in significant measure from our perception of the history of all chemotherapy in the last 70 years and our understanding of the present state of biomedical science and technology.
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From page 285... ...
It is suggested then that specific chemotherapeutic agents can be designed to inactivate proteins essential to multiplication or survival of an infectious agent, whether it be bacterium, virus, protozoan, fungus, or worm. This paper will now elaborate aspects of the history of the development of these facts and indicate some particular applications of the strategy to some of the major parasitic diseases in developing countries.
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From page 286... ...
The development and efficacy of this antibiotic led to further investigations to discover other therapeutic agents produced by organisms. An antibiotic was detected initially by its antibacterial action, and the selectivity of its toxicity was explored relatively late in the sequence of studies seeking therapeutic efficacy.
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From page 288... ...
In fact, with the exception of viroids, all viruses code for specific enzymes and structural proteins essential to virus multiplication, stability, and survival. A large body of information on multiplication of various viruses suggests identity of specific proteins induced by the viral etiological agents of herpes, influenza, foot and mouth disease, and some tumors.
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From page 289... ...
in Infected cells by analogue-substrates of the kinase may lead to resistance to the drugs of Group A in Figure 1.
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From page 290... ...
Although major pharmaceutical companies usually have the multidisciplinary capability to synthesize and screen new agents, and to take important leads through studies of the mode of action, toxicology, clinical pharmacology, and clinical trials, few appear to possess the requisite skills in protein chemistry, or to have incorporated such skills into their programs. On the other hand, although academia is providing most of the basic scientific information, including that on protein structure, academic institutions cannot organize the requisite multidisciplinary approach necessary to exploit the basic science and technology in this field.
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From page 291... ...
Some Protozoan Diseases As noted earlier, the dihydrofolate reductase of malarial parasites, such as Plasmodium berghei, differs from that of mammalian and avian hosts in numerous properties.^/ As presented in Table l, these differences permit a substance such as pyrimethamine to exhibit selective toxicity towards the parasite. It would be of great interest to determine if inhibition of this enzyme leads to thymineless death in the parasite, as appears to be the case in other organisms.17/ If this is so, the apparent deoxycytidine requirement and purine metabolism of Plasmodia 18/ may possibly be manipulated to exacerbate a deficiency for essential thymine.
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From page 292... ...
cruzi is to allopurinol ribonucleotide (HPPR-MP) • This is converted by the adenylosuccinate synthetase to the adenylate analogue, APP ribcnucleotide (APPR-MP)
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CU 4-1 CO 1 1 1 1 1 1 1 1 1 1 4-1 •H CU vO 4J .H cd c/o •H 1 1 1 1 1 1 1 4- + + [T!
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From page 294... ...
Despite some advances in these directions, at present we must consider development of chemotherapeutic agents without much solid information about the specific properties of the organism. In this situation we have assumed that the etiologic agent possesses a relatively specific characteristic of Mycobacteria, which is in fact shared with Corynebacteria and Nocardia, jL.j[.
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From page 295... ...
A concentration on inhibitors specifically reactive on proteins might well avoid problems of mutagenicity and carcinogenicity of compounds designed to affect nucleic acid metabolism. The time required for such an effort should not be greater than the time usually needed for drug development in a pharmaceutical company.
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From page 296... ...
Alving CR, Steck EA, Chapman WL, Waits VB, Hendricks LD, Swartz GM, Hanson WL: Proc Nat Acad Sci USA 75:2959, 1978 16. Gutteridge WE, Coombs GH: Biochemistry of Parasitic Protozoa.
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From page 297... ...
Rick PD, Osborn MJ: J Biol Chem 252:4895, 1977 297
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From page 298... ...
I shall focus this discussion on three main regulatory mechanisms: parasite motility, control of metabolism, and chemotaxis. An important purpose of this article is to draw the attention of persons interested in chemotherapy of parasitic diseases to the action of diverse drugs at various regulatory sites, and possible utilization of these sites for selection of new antiparasitic agents.
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From page 299... ...
While studying the effects of drugs on the liver fluke Fasciola hepatica 3/ by means of bioassays, we demonstrated the presence of acetylcholine concentrations in extracts of the worms _5/ which were almost as high as those found in mammalian brains. The presence of both the synthesizing enzyme, acetycholine synthetase, and the hydrolyzing enzyme, true cholinesterase, was also reported in Fasciola,5/ and in a related trematode parasite, Schistosoma mansoni.6/ Subsequently, several workers demonstrated the presence of acetylcholine and its two allied enzymes in other trematodes, and in nematodes and cestodes._7/ This evidence, when added to pharmacological data on diverse neuromuscular preparations from these parasites, strongly indicates that acetylcholine or a related compound functions in the neuromuscular activity of these helminths.
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From page 300... ...
Cheniotherapeutic Agents that Affect Parasite Motility Several studies indicate that particular chemotherapeutic agents are effective because they modify one or another regulatory mechanism involved in motility. Santonin, an obsolete anthelmintic once used exclusively against nematodes, was found by Baldwin 2_/ to paralyze only the anterior neuromuscular preparations in Ascaris at low concentrations, and to stimulate intermediate preparations.
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From page 301... ...
A similar effect was demonstrated in mammalian tissues, but only at very high drug concentrations. The selective effect of this drug as a chemotherapeutic agent seems to depend on a differential sensitivity of nematode neuromuscular receptors to its action.
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From page 302... ...
Nippostrongylus muris to leave the mucus of the rat's intestinal wall, after which they were expelled while still alive by movement of gut contents. A closely related phenomenon was observed by Standen 28/ in his early studies on antischistosomal agents.
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From page 303... ...
enzyme with multiple components for its control. While basal activity (without activators)
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From page 304... ...
These kinetics were considered in terms of the Monod-Changeux-Wyman model for allosteric proteins .^4. Thus, the parasite enzyme is well endowed with all the control mechanisms necessary for reversible conversion from active to inactive form through changes in the tertiary and in the quaternary structure of the enzyme, a classic example of a regulatory enzyme.
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From page 305... ...
antimonials against parasitic helminth phosphofructokinases. This enzyme model is amenable to selective inhibition by chemotherapeutic agents.
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From page 306... ...
Recently, Maclnnis' group has investigated chemicals emanating from food sources which can attract or trap the snail._7_2/ Fractionation of lettuce by these workers revealed that the portion containing free amino acids was the primary attractant for Biomphalaria glabrata, the snail host for Schistosoma mansoni. These amino acids have been identified as glutamate and proline.
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From page 307... ...
The available information concerning cellular regulatory processes in parasitic helminths is scanty, and much research is needed in this important area. Workers in this field may benefit significantly from the recent explosion of knowledge of cellular regulation in bacterial and mammalian cells.
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From page 308... ...
Hillman GR, Senft AW: J Pharmacol Exp Ther 185:177-184, 1973 5. Chance MRA, Mansour TE: Br J Pharmacol 8:134-138, 1953 6.
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Boston, Massachusetts, Little, Brown, 1962, p 43 25. Chou T-CT, Bennett JL, Pert C, Bueding EJ: Pharmacol Exp Ther 186:408-415, 1973 26.
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Mansour TE, Mansour JM: J Biol Chem 237:629-634, 1962 42. Stone DB, Mansour TE: Mol Pharmacol 3:16l-176, 1967 43.
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Gerisch G, Wick U: Biochem Biophys Res Communi 65:364-370, 1975 68. Kincaid RL, Mansour TE: Exp Cell Res 116:365-375, 1978 69.
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From page 312... ...
In fact, as is evident from the classical studies of Ehrlich on malaria and trypanosomes, these organisms served as the model for development of chemotherapeutic agents in general.jY In recent years, however, the pharmaceutical industry lacked incentive to find new drugs for diseases of the developing world. This has been brought about by two factors: the substantial amount of capital necessary to evaluate safety and efficacy of possible new agents; and the limited resources of the developing world.
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From page 313... ...
The biochemical difference we have exploited is inability of trypanosomes to synthesize heme._/y As a result of this deficiency, and the avid binding of heme to serum proteins in mammalian hosts, the bloodstream form of African trypanosomes has no detectable heme or hemoproteins such as cytochrome or catalase. This in turn leads to an accumulation of intracellular hydrogen peroxide in these organisms which renders them susceptible to killing by agents that promote homolytic cleavage of hydrogen peroxide to yield hydroxy (OH.)
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From page 314... ...
Another method of rendering trypanosomes more susceptible to radicals generated by porphyrin-induced decomposition of hydrogen peroxide would be to decrease the level of intracellular radical scavengers 314
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From our in vitro studies to date, it is apparent that the combination of a series of drugs which can increase hydrogen peroxide 315
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From page 316... ...
Once a biochemical difference is identified, it could perhaps be handed over to organic chemists in the pharmaceutical industry who could best synthesize and identify more efficacious anlogues. Because much of the cost of drug development today is consumed in safety evaluation of the new compound, sharing of these costs between the pharmaceutical industry and public health organizations might achieve this last and important objective.
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From page 317... ...
Meshnick SR, Grady RW, Blobstein SH, Cerami A: J Pharmacol Exp Therap 207:104l-1050, 1978 7. Chang KP, Chang CS, Sassa S: Proc Natl Acad Sci USA 72:2979-2985, 1975 8.
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From page 318... ...
John R David In considering some infectious diseases in the developing world that are the subject of this meeting, it became clear that, as in the course of political events, one must know the past to understand the future.
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From page 319... ...
We must obtain more information on the role and mechanism of immunity in specific parasite diseases, develop better serodiagnostic tools, and obtain more basic information on regulation of the immune response in general. The latter goal I will return to at the end of this presentation.
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From page 320... ...
This development, a method of producing monoclonal antibodies using lymphocyte hybridomas, is revolutionizing the field and already is spreading to other disciplines.^/ The technology has so many applications to development of serodiagnostic tools and vaccines for parasitic diseases that I will take a few minutes to explain it and its potential. It is based on the fact that each antibody-producing cell in the body makes only one kind of antibody, directed at a single antigenic determinant.
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From page 321... ...
For example, the schistosomula, the stage of the parasite which makes its odyssey through man, does not divide. We are currently attacking this problem by attempting to define antigen or antigens that elicit an effective immune response by generating monoclonal antibodies.
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From page 322... ...
In recent studies with Butterworth, and in collaboration with Gerald Gleich, we have shown that damage to larvae is mediated by major basic protein, the main protein found in eosinophilic granules.14/ Until this time, there was no known function for this protein. Probably the most important and exciting area of investigation in immunology today is on the basic control of the immune response.
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From page 323... ...
What is more, parasites appear to be ideal organisms for study and analysis of control mechanisms of the immune response. There is no doubt that much of the information we gain from intensive study of parasite immunology will spin off to directly affect conditions in the industrialized world and in the developing world.
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From page 324... ...
Nature 265:539-54l, 1977 7. Dean DA: Decreased binding of cytotoxic antibody by developing Schistosoma mansoni.
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J Exp Med 145:136-150, 1977 14. Butterworth AE, Wassom DL, Gleich GJ, Loegering DA, David JR: Damage to schistosomula of Schistosoma mansoni induced directly by eosinophil major basic protein.
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From page 326... ...
Turning now to practical applications, long established methods in microbial breeding should certainly be exploited for production of attenuated live vaccines. Surely, Mycobacterium leprae, though still eluding cultivation in artificial media, can be made to exchange 326
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From page 327... ...
On such a map, it will be easy to locate polymorphisms for genetic susceptibility/resistance to parasitic and infectious diseases, and in turn to the physiological controls that can be exploited for hygienic ends. The most exciting opportunities stem from new technologies of DNAsplicing or genetic engineerig.
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From page 328... ...
The insights of molecular biology -- having already generated such powerful and valuable tools as the AMES test -- may very well also give us more effective policy criteria for predicting effects in human application of suspect agents having irreplaceable therapeutic value. This remark is essentially a call foi establishment of a sorely needed new discipline, a comparative toxicology that can call in all of the tools and wisdom of traditional fields of comparative biology, genetics, and evolution.
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From page 329... ...
to be administered to a patient. Thus, a single active substance may be prepared in various dosage forms: tablets, 329
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From page 330... ...
The life-saving hormone, insulin, illustrates the practical value of dosage forms. Everyone recognizes what a problem it is that the only effective dosage form of insulin is the injectable, and how much we could improve both therapy and the quality of life for diabetics if a better dosage form existed for the active substance, insulin.
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From page 331... ...
Unfortunately, one-time administration of a pharmaceutical rarely suffices, because most active substances are metabolically inactivated and/or excreted within a few hours to a day or two. Thus, the key step of dosage form administration has to be repeated.
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From page 332... ...
Moreover, it is apparent that timing of self-medication is often erratic, as Kass has shown with his recent work using an ingeniously microcomputerized dispensing monitor for eyedrops in treatment of glaucoma.8/ The conclusion is inescapable that noncompliance is a major worldwide problem with today's pharmaceuticals. It logically follows that improving methods of administering active substances -- old or new -- to make them far simpler to use could improve therapeutic outcome.
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From page 333... ...
Conventional dosage forms -- including sustained-release tablets and capsules -- deliver their active substance(s) in what Is called first-order fashion: delivery occurs at rates that are highest initially, and then decline steadily thereafter.
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From page 334... ...
The elapsed time from dosing until loss of effect can be prolonged by putting more active substance into the dosage form: the initial rate of release will then be higher, and drug concentration at the critical site will take longer to fall below its minimum effective level; however, the penalty of such prolongation is a more widely fluctuating concentration of drug in blood and tissues, and thus more widely fluctuating effects and side effects. Using firstorder dosage forms, one sees the first-order pharmacology of drugs: a time-dependent mixture of side effects and desired effects, with side effects tending to predominate early in the interval following the dose.
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From page 335... ...
TABLE 1. THREE EXAMPLES OF ZERO-ORDER PHARMACOLOGY Drug Delivery Rate Pilocarpine a/ Theophylline Scopolamine lowest ocular hypotension bronchodilation miosis myopia ciliary spasm, browache nausea & vomiting tachycardia slight insomnia highest systemic effects, e^jj.
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From page 336... ...
, tolerance to narcotic analgesics, adrenergically induced "down" regulation of adrenergic receptors, and others. The zero-order rubric cannot accommodate nonstationary actions, but neither can one claim that conventional first-order dosage forms optimally deliver agents with such properties.
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From page 337... ...
New Path for Pharmacology The demonstration of multiday, continuous, controlled drug delivery has thus opened up a new path for pharmacology, which is illustrated by another example from ocular pharmacology in treatment of a parasitic disease. Instead of regarding the eye as the subject of a somewhat arcane specialty, let us regard it as a tissue model for the whole body, having the useful property of allowing direct visual observation.
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From page 338... ...
In addition, recent developments, in membrane, polymer, and elastomer technology applied to continuous controlled drug delivery give promise of broadening the scope of practical dosage schedules beyond those that have been possible with traditional formulations." Developmental Status of Rate-Specified Dosage Forms Many advances in therapeutic systems technology are still in the developmental phase, but some noteworthy achievements or work in progress include: • One-week-duration ocular therapeutic systems in the form of a thin elliptical film, worn beneath the eyelid for delivery of an antiglaucoma drug;2l-23/ • One- and three-year-duration therapeutic systems, in the form of a T, providing intrauterine delivery of progesterone for contraception with concomitant reduction of 338
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From page 339... ...
Their potential value in therapeutic problems of developing countries is discussed in references 26, 28, 37, and 49.
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COMPARATIVE COSTS OF POCKET CALCULATORS (197l-1978) General Purpose a/ Scientific _b/ 1971 $150 $395 1978 $ 10 S 50 a/Datamath, Texas Instruments.
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From page 341... ...
Technical developments in controlling administration of active substances have fundamental significance for the science of pharmacology, both animal and clinical. The prospect of having controlled delivery dosage forms for a wide variety of active substances should increase the priority of research on zero-order pharmacology of many older, basic agents.
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From page 342... ...
Yet now we see that the therapeutic systems class of dosage forms has made obsolete that restrictive thinking; the practical ability to conceptualize drug action in terms of zero-order pharmacology provides a new basis for seeking and finding specificity of drug action. The new therapeutic systems class of dosage forms allows unprecedented latitude in tailoring therapeutic regimens to human needs.
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From page 343... ...
ACKNOWLEDGEMENTS The author is indebted to many colleagues who have made major contributions, by thought, word, or deed, to the concepts and developments described here: Max Anliker, Ernst Barany, William F Bayne, Harriet Benson, Pieter Bonsen, Richard G
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From page 344... ...
Yates FE, Benson H, Buckles R, Urquhart J, Zaffaroni A: Engineering development of therapeutic systems: A new class of dosage forms for the controlled delivery of drugs, Advances in Biomedical Engineering. Edited by JHU Brown, JF Dickson.
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From page 345... ...
:48-56, 1974 15. Corrigan 0I, Timoney RF: Some aspects of the influence of formulation on the bioavailability of drugs from solid dosage forms.
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From page 346... ...
Amsterdam, Excerpta Medica, 1978 25. Pharriss BB: Clinical experience with the intrauterine progesterone contraceptive system.
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Clin Pharmacol Ther 21(l)
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Clin Pharmacol Ther 22:37l-374, 1977 48. Chandrasekaran SK, Benson H, Urquhart J: Methods to achieve controlled drug delivery: The biomedical engineering approach, Sustained and Controlled Release Drug Delivery Systems.
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From page 349... ...
Like all other types of modern technology, controlled clinical trials require such a careful evaluation. During the past 30 years, controlled clinical trials have been developed as a powerful method for evaluating agents used therapeutically either to prevent or to remedy disease.
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From page 350... ...
These two problems can be removed in the modern design of controlled clinical trials, because treatments are compared concurrently with presumably similar diagnostic standards and with similar kinds of ancillary therapy. Even with concurrent comparison, however, an important scientific hazard can be produced by the way in which the treatments 350
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From page 351... ...
Outcome The reduction or elimination of this problem is a second major advantage of modern clinical trials. They are designed as a planned experiment, as shown in Figure 4, using randomization as a mechanism for allocating treatment in an unbiased way that allows good risks and poor risks to be equally distributed within the limitations of the chance introduced by randomization.
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From page 352... ...
Figure 6, which shows how this problem is avoided -- by use of "double blind" observers and/or a "hard endpoint," such as death -- is the third major scientific advantage of modern clinical trials, in addition to concurrent comparisons and randomized allocation of treatment.
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From page 353... ...
These exclusions may eliminate people who have particularly high or low degrees of clinical severity, or who have the co-morbidity of additional diseases beyond the one under study, or who are receiving other medication that may affect the action of the treatments under study, or who give the impression that they may be non-cooperative in complying with instructions for maintaining either the prescribed treatment or the schedule of follow-up visits. The eligible people who are not excluded for any of these reasons then form the group who are admitted to the trial and randomized for therapeutic comparison.
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From page 354... ...
Furthermore, the idea that randomization has equalized distribution of good risks and poor risks may make investigators fail to identify and analyze results separately for good risks and for poor risks. Consequently, we are left in a position analogous to that of having performed clinical trials in groups of mice, dogs, and elephants who are not otherwise identified and who are simply lumped together and called "animals." The person who reads the results might like to know what happened separately in mice, dogs, and elephants -- but the investigator reports only what happened in the randomized "animals." The third issue -- objectivity in observation -- creates several problems.
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From page 355... ...
As the fifth main feature of design, statistically significant numbers may be mathematically convincing, but may sometimes lead to an excessive focus on statistical rather than clinical issues in design of the research; and need for large numbers often creates major logistic complexity in acquiring, standardizing, and maintaining the data when multiple institutions must collaborate. Beyond these difficulties, certain additional problems have arisen in the way that controlled clinical trials have been designed and supported by Federal agencies in English-speaking countries in the past two decades.
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From page 356... ...
For example, in the celebrated controversy over the UGDP study of diabetes mellitus, one of the points at issue is that treatments were analyzed exclusively according to the therapeutic regimen, but not according to the good, fair, or poor degree with which blood sugar was regulated. Another difficulty has been an inadequate assessment of compliance with oral medication.
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From page 357... ...
The question of effectiveness can seldom be answered with controlled clinical trials, because the trials are usually not large enough or long enough to cover the huge spectrum of people who must be evaluated and followed for protracted periods of time. Consequently, answers to the question of effectiveness will often require not controlled trials, but observational surveys, such as the type of Phase-4 surveillance studies now being developed for new pharmaceutical agents.
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From page 358... ...
As developing countries grasp the opportunity to use the technology of controlled clinical trials, the primary considerations -- as in all other modern uses of technology -- are to concentrate on choosing worthwhile questions and arranging to get worthwhile answers. Technology is an important but a secondary contributor to those primary goals.
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From page 359... ...
Problems may exist only in certain neglected areas of clinical research. Reorientation of existing activities towards tropical diseases may be possible.
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From page 360... ...
This will avoid branding as ineffectual a compound that the patients have not actually taken, or having the design of the study blamed for results that are difficult to explain. Separate guidelines may be provided for management of adverse reactions, and work manuals for the pharmacist or drug supervisor have proven useful.
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From page 361... ...
When an appropriate site has been identified, it is appropriate to: - Explore the will to investigate a disease problem of local importance and global consequences. - Make a contract with national and local authorities, including national research councils, so that any agreement will extend throughout the administration from the Ministry of Health to the local authorities, and designate the project as national or local with no emphasis on internationality.
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From page 362... ...
Clinical trials offer to young physicians training in planning and executing a time-1imited project, and the opportunity to collaborate with senior scientists. Such an experience may well be the first step on the ladder to a research career.
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From page 363... ...
In selection of school children for a clinical trial of a schistosomicide, for example, urban schools or rural schools located near a clinic are to be avoided, if possible. The drop-out rate is usually minimal from a study which is well conceived, planned, and explained to the subject population.
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From page 364... ...
individual. Such a body should be created if it does not exist.
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From page 365... ...
country, leaving no further trace of that export except a publication many years later from a laboratory in another part of the world.
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From page 366... ...
Conclusion If these specific guidelines are observed, clinical studies carried out in tropical countries on the diseases endemic in those countries can proceed as smoothly as trials carried out in more developed, temperate countries; the results obtained will be just as reliable. Acknowledgements The authors wish to acknowledge the review of the text and other valuable contributions to this presentation by Dr.
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From page 367... ...
As this essay will try to demonstrate, applications to specialized diseases must be an integral part of the discovery process in general if we are in fact to use industry's existing and proved assets and capabilities rather than to artificially create well-meaning programs that may turn out to be wasteful and unrewarding. Insofar as opportunities for research in American pharmaceutical laboratories cannot easily be segregated along therapeutic lines or disease states, opportunities and problems related to diseases of developing nations must be viewed and examined in the context of the entire research base and structure of this industry.jY This essay will therefore address primarily the general features of research and development (R&D)
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From page 368... ...
Because of the overwhelming significance of constraints that handicap all drug R&D, and because of my belief that much of this constraint results from a lack of understanding of the factors involved in drug research, I will address here some of these general principles rather than directing my comments to specific programs where there is research opportunity in a defined, limited class of disease states. I will try to develop the theme that novel drug therapies will almost certainly arise primarily out of basic R&D programs of the pharmaceutical industry.
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From page 369... ...
, were discovered and introduced by the pharmaceutical industry. For example, Schwartzman kj estimates that industry accounted for 91 percent of all such discoveries and introductions in the United States in the period 1960-1969 (Table l)
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From page 370... ...
In addition, non-industrial research is not equipped to deal with the complex regulatory processes which are in today's world intrinsic to and inseparable from the process of drug discovery itself. However, as will be described later, these institutions can contribute along with industry in important ways to specific programs of drug development.
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From page 371... ...
This is one of the reasons why many laboratories have curtailed research in tropical diseases. It is notable that despite this, several research-based pharmaceutical companies have maintained large programs directed to diseases of the Third World, a situation that may be judged by some dispassionate observers as being economically foolhardy.
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From page 372... ...
It must thus be recognized that it is not just tropical diseases or rare disorders that have apparently been "neglected" in terms of the supply of new, improved drugs. The reduced productivity is, instead, a reflection of an affliction which has affected drug discovery in general.
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From page 373... ...
Drug development should proceed in a regulatory environment dominated by encouragement and optimism, not suspicion, adversarial postures or hostility. The fundamental role of the pharmaceutical industry in drug discovery needs to be recognized.
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From page 374... ...
Characteristics of Industrial Drug R&D In an era of enormous potential and great need for discovery, but also of abundant disincentives, it is particularly important that academia, government, and even industry be well-informed about the special skills and technical resources required for successful, innovative drug development. It is sometimes said that basic research and discoveries should be left to academic and government research institutions, and that industry should concentrate on "applying" or "developing" those "discoveries" in the form of new drugs.
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From page 375... ...
Industrial laboratories involved seriously in drug discovery must have large groups of specialists in many different disciplines, and they must work together collectively and efficiently over protracted time periods. Even within disciplines a broad spectrum of specialists must be present to obtain optimal scientific cross-fertilization and to exploit various leads and ideas simultaneously in many systems.
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From page 376... ...
Regulatory factors have become dominant in drug research, and industrial research laboratories have emerged as new and powerful technological centers. Importantly, the nature of academic research has also undergone significant evolution in form and objectives.
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From page 377... ...
Yet, scientists of earlier eras are today exalted without explicit appreciation of the fact that many of these were in fact involved in "applied" research in that they continuously sought therapeutically useful goals. Many "academic" drug discoveries of earlier eras would for many reasons today be virtually impossible to reproduce in our academic centers.
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From page 378... ...
Investigators are being literally scared away by, or are finding it professionally repugnant to deal with, the regulatory framework of clinical drug research. The increasing administrative red-tape, continuous monitoring (by drug firms and regulatory bodies)
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From page 379... ...
Given the difficulties and expenditures that we are encountering in clinical studies of new drugs intended for important diseases of the United States, we are frankly very discouraged with the potential problems that we would face should these other drugs for tropical diseases merit study in man. For diseases of developing countries a very serious problem is that present law prohibits exporting a drug even for investigational purposes until an IND has been approved in this country.
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From page 380... ...
Basic research grants in tropical diseases to academic institutions, administered through NIH or other governmental agencies through established competitive channels, would certainly be of value. The principal impact would be to focus general attention and interest on these diseases by the American scientific community.
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From page 381... ...
Workers in other fields, for example, would begin to think about the problems, and discoveries in apparently unrelated fields could eventually be most decisive for the long-term goals of discovering new therapies. An effect of this type of improvement of general awareness and credibility of this field of study would be to encourage industrial laboratories to initiate programs in tropical diseases, which would be integrated with their other research activities.
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From page 382... ...
Greater visibility and recognition of the scientific accomplishments by industrial scientists can be of help. If consideration is to be given to funding and establishing special research centers here or abroad which are to be directed to the conduct of studies in tropical diseases, attention should be given to some of the concepts described in this essay that relate to drug research.
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From page 383... ...
In addition to difficulties related to availability of proper patient populations for study, especially for diseases of developing nations, many other general problems exist in this area which industry R&D is not as well equipped to handle as are academic and government institutions. Clinical research is becoming increasingly difficult because of FDA, HEW, regulatory and ethical considerations and constraints, and the increasing sophistication of properly controlled clinical trials.
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From page 384... ...
The veterinary research programs of major American pharmaceutical companies recognize the close interplay between drug development for both medical and veterinary indications. At this time, industrial research is providing one of the few effective bases for coordinated efforts to develop veterinary medicinals and insecticides.
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From page 385... ...
If trends which now discourage or prevent drug discovery in general can be reversed, I am confident that today's advanced state of science and technology will in the future provide society with new, innovative therapies for many diseases, including those occurring in developing nations. In order to begin to reverse the currently reduced degree of commitment to drug discovery, and the prospect of an ever dwindling rate of new drug introductions, it is essential to understand the complex forces, mechanisms, and sources involved in drug innovation and discovery.
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From page 386... ...
Participation of industry in development of drugs for tropical diseases is not a new or recent commitment. It is of historical interest that establishment in 1901 of the Wellcome Tropical Research Laboratories at the Medical College of Khartoum in the Egyptian-Sudan actually preceded that of the research center in London which was later named the Wellcome Laboratories of Tropical Medicine.
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From page 387... ...
13. It is generally recognized that many developing nations cannot "afford" available drugs, and the solution to this problem has often been directed to the pharmaceutical industry.
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From page 388... ...
14. De Haen P: New Product Survey and Nonproprietary Name Index; and U.S.
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From page 389... ...
Lucas to comment on Dr. Cuatrecasas• advocacy of centering basic drug development research in places where the requisite expertise exists, instead of centering it in countries where the diseases occur.
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From page 390... ...
One cannot consider tropical disease research separately from infectious diseases generally, since the scientific aspects of these two fields are intrinsically linked.
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