Integrating research and development: the emergence of rational drug design in the pharmaceutical industry

Rational drug design is a method for developing new pharmaceuticals that typically involves the elucidation of fundamental physiological mechanisms. It thus combines the quest for a scientific understanding of natural phenomena with the design of useful technology and hence integrates epistemic and practical aims of research and development. Case studies of the rational design of the cardiovascular drugs propranolol, captopril and losartan provide insights into characteristics and conditions of this integration. Rational drug design became possible in the 1950s when theoretical knowledge of drug-target interaction and experimental drug testing could interlock in cycles of mutual advancement. The integration does not, however, diminish the importance of basic research for pharmaceutical development. Rather, it can be shown that still in the 1990s, linear processes of innovation and the close combination of practical and epistemic work were interdependent.     

Role of neurologists in the pharmaceutical industry.

Important advances in the field of clinical neuropharmacology have created an increasing demand by the pharmaceutical industry for neurologists. As recently as a decade ago, neurologists were relatively rare in the pharmaceutical industry. I describe the roles played by industrial neurologists and review both the opportunities and risks in this career path.     

甾体微生物转化在制药工业中的应用

对几种重要的甾体微生物转化反应如甾体边链降解、甾体羟基化反应的机理及其发展与应用作了概述;同时也介绍了固定化微生物细胞、非水溶液中酶催化反应及混合发酵等微生物转化技术在制药工业中的应用。     

The return of the pharmaceutical industry to the market of contraception

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.     

原位干细胞研究给教学的启示思考

就生命前沿的湿性医疗技术机理－原位干细胞研究突破揭示了;对干细胞的重新认识,概念的界定,在MEBO药物重塑生理环境的作用下,锁定了人类角蛋白19型胚胎干细胞探索思路,指出国外体外培养干细胞组织工作的局限,原位干细胞的研究及进展是生命科学最终的汇集点,将是一场核裂变,将波及医学和未来的生命科学,从而给生物教学观念带来新的思考。     

Microscale chiral HPLC in support of pharmaceutical process research

Some recent developments in the use of microscale chiral HPLC for supporting pharmaceutical process research are reviewed, including multiparallel high throughput analysis to support high throughput experimentation studies, rapid multiparallel chromatographic method development, and on-line reaction monitoring. Green chemistry advantages of the approach include greatly reduced solvent consumption, waste generation, and stationary phase requirement relative to conventional chiral HPLC.     

The use of transgenic systems in pharmaceutical research.

Those pharmaceutical companies whose goal is to generate novel innovative drugs are faced with the challenge that only a fraction of the compounds tested in clinical trials eventually become a registered drug. This problem of attrition is compounded by the fact that the clinical trial or development stage is by far the most costly phase of bringing a new drug to market, consuming around 80 per cent of the total spend. Transgenic technology represents an attractive approach to reducing the attrition rate of compounds entering clinical trials by increasing the quality of the target and compound combinations making the transition from discovery into development. Transgenic technology can impact at many points in the discovery process, including target identification and target validation, and provides models designed to alert researchers early to potential problems with drug metabolism and toxicity, as well as providing better models for human diseases. In target identification, transgenic animals harbouring large DNA fragments can be used to narrow down genetic regions. Genetic studies often result in the identification of large genomic regions and one way to decrease the region size is to do complementation studies in transgenic animals using, for example, inserts from bacterial artificial chromosome (BAC) clones. In target validation, transgenic animals can be used for in vivo validation of a specific target. Considerable efforts are being made to establish new, rapid and robust tools with general utility for in vivo validation, but, so far, only transgenic animals work reliably on a wide range of targets. Transgenic animals can also be used to generate better disease models. Predictive animal models to test new compounds and targets will significantly speed up the drug discovery process and, more importantly, increase the quality of the compounds taken further in the research and development process. Humanised transgenic animals harbouring the human target molecule can be used to understand the effect of a compound acting on the human target in vivo. Also, models mimicking human drug metabolism will provide a means of assessing the effect of human-specific metabolites and of understanding the pharmacokinetic properties of potential drugs. In toxicology studies, transgenic animals are providing more predictive models. A good example of this are those models routinely used to look for carcinogenicity associated with new compounds.     

Functional assessment of cryopreserved human aortas for pharmaceutical research

We evaluated the impact of standard cryopreservation on functional properties of human aortic homografts. From seven human donors, the thoracic descending aorta was obtained. Effects of cryopreservation on contractibility and endothelium function were tested. After cryopreservation no endothelium-dependent or endothelium-independent relaxation was found and the contractibility was strongly affected. Arteries showed no function and loss of endothelial integrity after cryopreservation and thawing.