Rein Vos

Mapping the dynamics of adverse drug reactions in subsequent time periods using INDSCAL

In this study we have focused on the problem of mapping the dynamics of co-wordmatrices from subsequent time periods. Methods for mapping dynamics are important for following trends in research. We have explored the possibilities of a three way multidimensional scaling method, INDSCAL. We are especially interested to find relations between adverse drug reactions and other words in co-word-matrices from a medical field. Second we want to explore whether the relations between adverse drug reactions and other words have changed in subsequent time periods. The results show that INDSCAL can be a useful tool for mapping dynamics.

HOW ADVERSE DRUG-REACTIONS CAN PLAY A ROLE IN INNOVATIVE DRUG RESEARCH - SIMILARITIES IN ADVERSE DRUG REACTION PROFILES OF CAPTOPRIL AND PENICILLAMINE

We describe how adverse drug reactions (ADRs) can play an important role in pharmaceutical research and drug development. Not only do ADRs represent the risks and drawbacks associated with drugs but they can also be related to other knowledge available in pharmaceutical and medical research. We offer a model that can be used to systematically map the pathways through which ADRs can lead to innovative research. These pathways include chemical, therapeutic or pathophysiological steps that can be taken to arrive at new knowledge based on ADRs. We used the development of angiotensin-converting enzyme inhibitors, especially captopril, as a case study. The similarity between the ADR profiles of captopril and penicillamine was a starting point for further innovation. Historical analysis shows that in several instances research in the field of angiotensin-converting enzyme inhibitors has been triggered by ADRs. The model presented here might be applicable to other areas of innovative drug research.

Design research programs and the logic of their development

Design research programs attempt to bring together the properties of available materials and the demands derived from intended applications. The logic of problem states and state transitions in such programs, including assessment criteria and heuristic principles, is described in settheoretic terms, starting with a naive model comprising an intended profile and the operational profile of a prototype. In a first concretization the useful distinction between structural and functional properties is built into the model. In two further concretizations the inclusion of potential applications is motivated and described for the case of drug research as well as the inclusion of potential realizations for the case of complex products. Next, another line of concretization of the naive model, the incorporation of potentially relevant properties, is sketched. Then the partial analogy between “product-” and “truth-approximation” is indicated. We conclude with some remarks about the usefulness of our models for products reaching the market in comparison to the the so-called social construction of technology approach.

SEARCHING FOR ADVERSE DRUG-REACTIONS AT THE MARGIN OF SCIENTIFIC FIELDS - THE SCIENTOMETRIC DETECTION OF PERIPHERAL BUT POTENTIALLY INNOVATIVE DEVELOPMENTS IN PHARMACEUTICAL RESEARCH

Results are presented of a scientometric analysis focusing on peripheral dynamics in a scientific field. We evaluate different techniques on their appropriateness for detecting relations between aspects that seem to be not of central interest but are important in innovative research. We do so in order to quantify the role that adverse drug reactions can play as trigger points in innovative drug research.

Connecting disconnected structures: The modelling of scientific discovery in medical literature databases

Computer linguistic techniques may be useful as a new, innovative tool in the generation of new conceptual links in biomedical knowledge. We will present results from modelling several cases of discovery in pharmaceutical research. Our approach involves the active reconstruction of disconnected, implicit or hidden logical inference patterns in scientific literature. This approach is attractive, not due to the value of the logical model per se, but because it is or can be linked with specific cultural practices within the scientific community. The following topics related to our modelling of discovery processes in pharmaceutical research will be discussed: 1. The role of social studies of science and technology 2. The computational model used in our research 3. An example study: the development of a new treatment 4. Some results: the ‘intuitive’ search for decision rules 5. Discussion: Integration with the scientific research community.

Verapamil: dying drug or sleeping beauty?

The past decade verapamil (Isoptin) has attracted great interest in the scientific and cardiological community. This interest is due to the fact that the compound represents the prototype of an entirely new class of compounds with a novel therapeutic principle, e.g. the calcium antagonists. Furthermore, verapamil has become a tool in physiological and biochemical research of cardiovascular disease and serves to extend calcium channel research to the molecular level.

Metamorphosis of a disease Profiles of angina pectoris in Anglo-American medicine

This chapter covers the development of views about angina pectoris in Anglo-American medicine. The historical description roughly covers the period 1950–1980 but emphasis is given to shifts in the late 1950s and early 1970s. The aim is to show that changing views on disease can be described adequately in terms of the language of disease profiles.

Industrial research and beta blockade

The previous chapter described how the concept of beta blockade became transformed into a therapeutically meaningful concept. Evidence was provided for the hypothesis that this transformation was not possible without clinical practice that studied cardiac arrhythmias, anginal attacks, exercise tolerance, cardiac failure, bradycardia and bronchial spasm in asthma and bronchitis. The aim of this chapter is to substantiate this hypothesis more firmly by showing that clinical issues have structured industrial research and yielded specific targets for industrial scientists to profile their compounds experimentally.

The controlled clinical trial — A model for the intricate relationships between clinical medicine and drug research

Over the past 30 years the controlled clinical trial has become the norm in clinical medicine and the pharmaceutical sector. Through a comparative analysis of treatment effects in two groups of patients — one group receiving the new remedy, the other group standard therapy or placebo — the effectiveness of the new therapy can be assessed.’ A great deal of the fascination clinicians have in the performance of the controlled clinical trial derives from its rational nature and clearly defined outcome. Moreover, the controlled clinical trial is demanded today by authorities and policy makers in the health field. The regulatory systems that rapidly developed after the thalidomide disaster around 1960, took the controlled clinical trial as the basis for licensing new drugs. It was to form a barrier for the stream of chemical compounds coming out of industrial laboratories, and sift the good from the bad. The controlled trial has structured the way clinical medicine, both in theory and practice, became involved in the drug discovery process.

The enigma of drug discovery

It is generally thought that we are on the eve of a new pharmaceutical revolution, and that the fundamental developments in molecular biology, genetics and biotechnology will soon bear fruit. In this sense it seems as though the “knowledge gap hypothesis” which attributed the decline in drug innovation in the 1960s and 1970s to a lack of fundamental knowledge may prove to be historically correct. The idea that complicated diseases can only be understood and treated at the bio-molecular level is becoming more widely accepted.1 The quest for greater understanding in pathophysiology has led to increased molecular-level experimentation that should allow the drug designer and the biologist to make progress.2 Considering the expansive growth in medical theory, the fundamental role played by medical-pharmaceutical practice in the drug discovery process might be regarded as in danger of becoming an anachronism. This view however is not only incorrect but also dangerous. It contradicts past events and misses the essence of the drug discovery process. It is also a threat to the development of new medical therapies. Because of the strong attractive power of this bio-molecular reductionist thought — in this respect there would seem to be a return of the classic view of drug discovery — it is worthwhile examining and clarifying anew the important role of medical-pharmaceutical practice.