共查询到20条相似文献,搜索用时 15 毫秒
1.
Joseph H. Hafkenschiel 《The Western journal of medicine》1967,107(2):159-163
I have tried to trace the new drug development pattern from 1766, when Withering obtained his medical degree, to the present.The role of governmental authority as defined by the 1962 Kefauver-Harris amendments to the 1906 law and the subsequently issued regulations has been summarized. Four phases of testing in man have been detailed.Something of the scientific or research capability of the pharmaceutical industry has been presented.It is concluded that in the period of over two hundred years of medical education in the United States, the university hospital has become more and more the focus of medical research, teaching and practice in the community. The safety and effectiveness in the use of drugs in the future will depend upon the liaison and rapport of the industry physicians, government officials and the university hospital teacher-clinical investigators (phase 1 and 2) in designing the most critical studies of the safety and effectiveness of new drugs.Whether the medical profession as we know it will participate more in the future than has been possible since 1962 in mass clinical trial (phase 3) before new drug approval by governmental authority remains to be seen.The final approbation or disapproval of a drug after NDA approval (phase 4) will continue to be in the hands of the participating physician as long as he can establish scientifically that the drug is the best possible agent for him to use in healing the sick and comforting the dying. 相似文献
2.
Radiation and platinum drug interaction 总被引:1,自引:0,他引:1
A H Nias 《International journal of radiation biology and related studies in physics, chemistry, and medicine》1985,48(3):297-314
Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects. They inhibit recovery from sublethal and potentially lethal radiation damage. They produce a pattern of chromosome aberrations analogous to that from alkylating agents. Cellular sensitivity to platinum is increased when glutathione levels are reduced, just as is radiosensitivity. There is a pattern of drug sensitivity throughout the phases of the cell cycle which is different from that for radiosensitivity. The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. Electron-affinic agents are employed with this aim, but the commoner platinum drugs are only weakly electron-affinic. They do have a quasi-alkylating action however, and this DNA targeting may account for the radiosensitizing effect which occurs with both pre- and post-radiation treatments. Because toxic drug dosage is usually required for this, the evidence of the biological responses to the drug and to the radiation, as well as to the combination, requires critical analysis before any claim of true enhancement, rather than simple additivity, can be accepted. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships. 相似文献
3.
Development of knowledge on lipids has attracted the scientific community for the effective utilization of the natural and synthetic lipids. Bioavailability of poorly water soluble drugs from gastrointestinal tract (GIT) can be enhanced by formulating the drugs in lipid based formulations. This formulation can increase the dissolution of poorly water soluble drugs, and facilitates the formation of solubilized phases from which absorption may occur. The enhanced solubility of lipophilic drugs from lipid-based systems will not necessarily arise directly from the administered lipid, but most likely from the intra luminal processing to which they are subjected prior to absorption. This review will focus on assessment of lipid-based formulations of drugs with a consideration of how gastrointestinal physiology, the choice of lipids and their formulation attribute and the mode of lipid digestion in the GIT influence the bioavailability of lipophilic drugs. 相似文献
4.
B Whiting A W Kelman S M Bryson F H Derkx A H Thomson G H Fotheringham S E Joel 《BMJ (Clinical research ed.)》1984,288(6416):541-545
Clinical pharmacokinetics is an expanding scientific discipline which can make an impact on treatment in coronary care, intensive care, paediatrics, general medicine and surgery, and general practice. The aim of this study was to establish a rapid system of drug assay, to report the result, to assess the influence of pathological and clinical factors on the pharmacokinetics of certain drugs, and to use a computer to determine the optimum dosage of drugs. The clinical pharmacokinetics laboratory in Stobhill is available to all clinical departments and to general practitioners in the area. Digoxin, theophylline, and phenytoin have been assessed. Initial samples of these drugs showed that only about a third were in the therapeutic range; samples obtained after the issue of the laboratory report showed an improvement. The predictive performance of the computer program improved with feedback of one or two drug concentrations. Dosages of drugs chosen on an empirical basis may not lead to optimum treatment, and by testing samples early the dosage of the drug can be adjusted. It is hoped that the results achieved will encourage other clinical, pharmaceutical, and scientific colleagues to develop laboratories along similar lines. 相似文献
5.
6.
Jong Pil Park Jin Hee Kim Moon Ki Park Jong Won Yun 《Biotechnology and Bioprocess Engineering》2011,16(6):1065-1076
Many classes of bioactive drug-like molecules derived from traditional herbal plants are becoming attractive as alternative
medicines for the treatment of severe chronic diseases such as cancer and obesity. A set of chemically synthesized drugs that
is capable of both inhibiting cancer growth and reducing body weight for treatment of obesity have severe side effects including
nausea, vomiting, diarrhea as well as producing increased blood pressure and headache, respectively. For decades, drug candidates
from herbal plants have been considered as potential therapeutic agents because they are generally safer, less toxic, and
have fewer lethal side effects than chemically synthesized or semi-synthetic drugs. Understanding the key factors affecting
pharmacological effects and clinical outcomes has been a critical theme of natural product research. However, standardized
sample preparation methods, well-controlled scientific studies, and validation studies are needed before herbal therapeutics
can be introduced into the global market. This review will address the current advances in using traditional herbal plants,
including the pharmacological effects and the challenges faced during the development of new drugs. The safety issues associated
with toxicity and the effectiveness of the herbs in specific diseases such as cancer and obesity are also discussed. 相似文献
7.
Gerlai R 《Genes, Brain & Behavior》2003,2(4):187-190
In a recent article Rose (2002) raises numerous crucial issues with regard to the research into and the use of cognition or memory enhancing agents. Although development of 'smart' drugs is in its infancy, his paper delineates some issues society may have to face when these drugs arrive. Questions about the development of such drugs may be interesting to several readers of Genes Brain and Behavior given the wealth of information expected to be gained on brain function from studies using genetic approaches including mutagenesis, transgenic techniques and genomics in general. Besides the scientific questions, several ethical issues may need to be addressed that are of interest to us all. Rose (2002 ) discusses some of these questions, but perhaps presents a too negative view on the problems, especially with regard to the present and future of memory research. This paper is intended to focus mainly on the scientific questions and argues that our fear of complex ethical problems should not make us throw the baby (i.e., our research and discoveries) out with the bath water. 相似文献
8.
Christa E. Müller 《化学与生物多样性》2009,6(11):2071-2083
Low water solubility and low bioavailability are frequent problems in drug development, particularly in the area of central nervous system (CNS) drugs. This short review describes selected prodrug approaches which have been developed to enhance the bioavailability of drugs, especially that of poorly soluble drugs. Some of the most successful drugs on the market are prodrugs. With a better understanding of active‐transport processes at cell membranes in the gut as well as at the blood–brain barrier, the importance of prodrug approaches will further increase in the future. Prodrug approaches will already be considered in the early phase of drug discovery. 相似文献
9.
10.
Current efforts to control human soil-transmitted helminth (STH) infections involve the periodic mass treatment of people, particularly children, in all endemic areas, using benzimidazole and imidothiazole drugs. Given the fact that high levels of resistance have developed to these same drugs in roundworms of livestock, there is a need to monitor drug efficacy in human STHs. The faecal egg count reduction test (FECRT), in which faecal egg output is measured pre- and post-drug treatment, is presently under examination by WHO as a means of detecting the emergence of resistance. We have examined the potential impact of density dependent fecundity on FECRT data. Recent evidence with the canine hookworm indicates that the density dependent egg production phenomenon shows dynamic properties in response to drug treatment. This will impact on measurements of drug efficacy, and hence drug resistance. It is likely that the female worms that survive a FECRT drug treatment in some human cases will respond to the relaxation of density dependent constraints on egg production by increasing their egg output significantly compared to their pre-treatment levels. These cases will therefore underestimate drug efficacy in the FECRT. The degree of underestimation will depend on the ability of the worms within particular hosts to increase their egg output, which will in turn depend on the extent to which their egg output is constrained prior to the drug treatment. As worms within different human cases will likely be present at quite different densities prior to a proposed FECRT, there is potential for the effects of this phenomenon on drug efficacy measurements to vary considerably within any group of potential FECRT candidates. Measurement of relative drug efficacy may be improved by attempting to ensure a consistent degree of underestimation in groups of people involved in separate FECRTs. This may be partly achieved by omission of cases with the heaviest infections from a FECRT, as these cases may have the greatest potential to increase their egg output upon removal of density dependent constraints. The potential impact of worm reproductive biology on the utility of the FECRT as a resistance detection tool highlights the need to develop new drug resistance monitoring methods which examine either direct drug effects on isolated worms with in vitro phenotypic assays, or changes in worm genotypes. 相似文献
11.
Mohan Yellishetty P. G. Ranjith A. Tharumarajah Sheshanath Bhosale 《The International Journal of Life Cycle Assessment》2009,14(3):257-267
Background, aim and scope
The mining sector provides materials that are essential elements in a wide range of goods and services, which create value by meeting human needs. Mining and processing activities are an integral part of most complex material cycles so that the application of life cycle assessment (LCA) to minerals and metals has therefore gained prominence. In the past decade, increased use of LCA in the mineral and metal sector has advanced the scientific knowledge through the development of scientifically valid life cycle inventory databases. Though scientifically valid, LCA still needs to depend on several technical assumptions. In particular, measuring the environmental burden issues related to abiotic resource depletion, land use impacts and open-loop recycling within the LCA are widely debated issues. Also, incorporating spatial and temporal sensitivities in LCA, to make it a consistent scientific tool, is yet to be resolved. This article discusses existing LCA methods and proposed models on different issues in relation to minerals and metals sector.Main features
A critical review was conducted of existing LCA methods in the minerals and metals sector in relation to allocation issues related to indicators of land use impacts, abiotic resource depletion, allocation in open-loop recycling and the system expansions and accounting of spatial and temporal dimension in LCA practice.Results
Evolving a holistic view about these contentious issues will be presented with view for future LCA research in the minerals and metals industry. This extensive literature search uncovers many of the issues that require immediate attention from the LCA scientific community.Discussion
The methodological drawbacks, mainly problems with inconsistencies in LCA results for the same situation under different assumptions and issues related to data quality, are considered to be the shortcomings of current LCA. In the minerals and metals sector, it is important to increase the objectivity of LCA by way of fixing those uncertainties, for example, in the LCA of the minerals and metals sector, whether the land use has to be considered in detail or at a coarse level. In regard to abiotic resource characterisation, the weighting and time scales to be considered become a very critical issue of judgement. And, in the case of open-loop recycling, which model will best satisfy all the stake holders? How the temporal and spatial dimensions should be incorporated into LCA is one of the biggest challenges ahead of all those who are concerned. Addressing these issues shall enable LCA to be used as a policy tool in environmental decision-making. There has been enormous debate with respect to on land use impacts, abiotic resource depletion, open-loop recycling and spatial and temporal dimensions, and these debates remain unresolved. Discussions aimed at bringing consensus amongst all the stake holders involved in LCA (i.e. industry, academia, consulting organisations and government) will be presented and discussed. In addition, a commentary of different points of view on these issues will be presented.Conclusions
This review shall bring into perspective some of those contentious issues that are widely debated by many researchers. The possible future directions proposed by researchers across the globe shall be presented. Finally, authors conclude with their views on the prospects of LCA for future research endeavours.Recommendations and outlook
Specific LCA issues of minerals and metals need to be investigated further to gain more understanding. To facilitate the future use of LCA as a policy tool in the minerals and metals sector, it is important to increase the objectivity with more scientific validity. Therefore, it is essential that the issues discussed in this paper are addressed to a great detail. 相似文献12.
Orive G Hernández RM Rodríguez Gascón A Domínguez-Gil A Pedraz JL 《Current opinion in biotechnology》2003,14(6):659-664
Drug delivery is becoming a whole interdisciplinary and independent field of research and is gaining the attention of pharmaceutical makers, medical doctors and industry. A targeted and safe drug delivery could improve the performance of some classical medicines already on the market and, moreover, will have implications for the development and success of new therapeutic strategies, such as peptide and protein delivery, glycoprotein administration, gene therapy and RNA interference. Many innovative technologies for effective drug delivery have been developed, including implants, nanotechnology, cell and peptide encapsulation, microfabrication, chemical modification and others. On the long way from the clinic to market, however, several issues will have to be addressed, including suitable scientific development, specific financial support as a result of altered scientific policy, government regulations and market forces. 相似文献
13.
Milo Gibaldi 《Chirality》1993,5(6):407-413
A surprisingly large number of marketed drugs are racemic mixtures. The pharmacokinetic literature on racemic drugs contains a vast amount of information on drug–drug interactions derived from the measurement of total drug concentrations in plasma and urine. The appreciation of the role of stereochemistry in drug interactions with racemic warfarin resulted in a long-overdue scientific rigor being applied to the study of drug interactions. It also compelled us to recognize that much of the literature was uninterpretable. A better understanding of oxidative metabolism, particularly the complexity of the cytochrome P-450 family of enzymes, has also strengthened the scientific basis of drug interactions. We now recognize that investigators and clinicians must consider both stereoselectivity and isozyme selectivity in the study of drug interactions to understand the nature of the interaction so as to more effectively use new and potent drugs. © 1993 Wiley-Liss, Inc. 相似文献
14.
Polypharmacology, the ability of drugs to interact with multiple targets, is a fundamental concept of interest to the pharmaceutical industry in its efforts to solve the current issues of the rise in the cost of drug development and decline in productivity. Polypharmacology has the potential to greatly benefit drug repurposing, bringing existing pharmaceuticals on the market to treat different ailments quicker and more affordably than developing new drugs, and may also facilitate the development of new, potent pharmaceuticals with reduced negative off-target effects and adverse side effects. Present day computational power, when combined with applications such as supercomputer-based virtual high-throughput screening (docking) will enable these advances on a massive chemogenomic level, potentially transforming the pharmaceutical industry. However, while the potential of supercomputing-based drug discovery is unequivocal, the technical and fundamental challenges are considerable. 相似文献
15.
Although a very useful guideline for orally bioavailable small-molecule drug design, the 'rule-of-five' (also known as 'Lipinski's rule of drug-likeness') has to some extent been overemphasized. Firstly, only 51% of all FDA-approved small-molecule drugs are both used orally and comply with the 'rule-of-five'. This does not even include the increasing number of biologicals of which several have reached 'blockbuster' status. Secondly, it does not cover natural product and semisynthetic natural product drugs, which constitute over one-third of all marketed small-molecule drugs. A more balanced and programmatic approach to drug discovery should be more productive than to rely on an overemphasis of 'rule-of-five' compliance. Rather it should consider proactively the development of parenteral drugs in parallel to oral drugs and to consider the development of therapeutic antibodies in parallel to small-molecule drugs. These are particularly relevant for efforts against 'first-in-class' and/or particularly challenging targets such as proteases and those involving protein-protein interactions. In addition, more effort should be invested in natural product research. Emerging novel technologies such as synthetic biology (genetic engineering of living organisms to produce small-molecule therapeutics) may address several challenging issues of natural product-based drug discovery including synthetic feasibility and ligand efficiency. 相似文献
16.
Human genome project: pharmacogenomics and drug development 总被引:2,自引:0,他引:2
Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great impact on our ability to uncover the cause of individual variation in response to therapeutics. The study of association between genetics and drug response is called pharmacogenomics. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual differences in drug disposition and effects, thereby enhancing the drug discovery and providing a stronger scientific basis of each patient's genetic constitution. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics by developing more personalized drug therapies. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs. 相似文献
17.
Efficiency of antisense oligonucleotide drug discovery 总被引:1,自引:0,他引:1
Bennett CF 《Antisense & nucleic acid drug development》2002,12(3):215-224
The costs for discovering and developing new drugs continue to escalate, with current estimates that the average cost is more than $800 million for each new drug brought to the market. Pharmaceutical companies are under enormous pressure to increase their efficiency for bringing new drugs to the market by third-party payers, shareholders, and their patients, and at the same time regulators are placing increased demands on the industry. To be successful in the future, pharmaceutical companies must change how they discover and develop new drugs. So far, new technologies have done little to increase overall efficiency of the industry and have added additional costs. Platform technologies such as monoclonal antibodies and antisense oligonucleotides have the potential of reducing costs for discovery of new drugs, in that many of the steps required for traditional small molecules can be skipped or streamlined. Additionally the success of identifying a drug candidate is much higher with platform technologies compared to small molecule drugs. This review will highlight some of the efficiencies of antisense oligonucleotide drug discovery compared to traditional drugs and will point out some of the current limitations of the technology. 相似文献
18.
Zhao L Nicholson JK Lu A Wang Z Tang H Holmes E Shen J Zhang X Li JV Lindon JC 《Journal of proteome research》2012,11(7):3509-3519
Most chronic diseases impairing current human public health involve not only the human genome but also gene-environment interactions, and in the latter case the gut microbiome is an important factor. This makes the classical single drug-receptor target drug discovery paradigm much less applicable. There is widespread and increasing international interest in understanding the properties of traditional Chinese medicines (TCMs) for their potential utilization as a source of new drugs for Western markets as emerging evidence indicates that most TCM drugs are actually targeting both the host and its symbiotic microbes. In this review, we explore the challenges of and opportunities for harmonizing Eastern-Western drug discovery paradigms by focusing on emergent functions at the whole body level of humans as superorganisms. This could lead to new drug candidate compounds for chronic diseases targeting receptors outside the currently accepted "druggable genome" and shed light on current high interest issues in Western medicine such as drug-drug and drug-diet-gut microbial interactions that will be crucial in the development and delivery of future therapeutic regimes optimized for the individual patient. 相似文献
19.
Binetti P 《Journal of biological regulators and homeostatic agents》2004,18(3-4):255-260
Biotechnology represents such an important challenge for present day culture that one can speak of a biotechnological revolution in many other scientific fields as well, such as biology, clinical medicine, pharmacology, and genetic engineering. It also significantly affects political and economic choices to such a degree that they call for a new kind of attention from jurisprudence which has to regulate an ever changing world. Many important queries arise particularly at a bioethical level, issues that will also affect future generations. Scientific progress has unexpectedly widened the biological knowledge of human kind. Thanks to the contribution of continuously more refined and advanced technology, it has nurtured the hope of solving all problems and of overcoming all limits. The scientist's intellectual curiosity, encompassing these new resources, is spurred on by the desire for knowledge and understanding. However sometimes he loses sight of the repercussions and of the possible uses his achievements may have. Only a profound personal education, integrated with the scientist's technical and scientific expertise, will allow science to knock down some barriers, advancing constantly but without losing respect for man's dignity. However the separation between scientific and ethical expertise can only raise new barriers and create limits to the freedom of science which will appear just restrictive, while a kind of medieval obscurantism will be opposed to ethical rigour. 相似文献
20.
Progress has been made recently in developing antibody-drug conjugates (ADCs) that can selectively deliver cancer drugs to tumor cells. In principle, the idea is simple: by attaching drugs to tumor-seeking antibodies, target cells will be killed and nontarget cells will be spared. In practice, many parameters needed to be addressed to develop safe and effective ADCs, including the expression profiles of tumor versus normal tissues, the potency of the drug, the linker attaching the drug and placement of the drug on the antibody, and the pharmacokinetic and stability profiles of the resulting ADC. All these issues had been taken into account in developing brentuximab vedotin (Adcetris), an ADC that recently received accelerated approval by the US Food and Drug Administration for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Research is under way to extend the applications of brentuximab vedotin and to advance the field by developing other ADCs with new linker and conjugation strategies. 相似文献