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1.
McCarthy AD Kennedy JL Middleton LT 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2005,360(1460):1579-1588
Over the last two decades, identification of polymorphisms that influence human diseases has begun to have an impact on the provision of medical care. The promise of genetics lies in its ability to provide insights into an individual's susceptibility to disease, the likely nature of the disease and the most appropriate therapy. For much of its history, pharmacogenetics (PGx-the use of genetic information to impact drug choice) has been limited to comparatively simple phenotypes such as plasma drug levels. Progress in genetics technologies has broadened the scope of PGx efficacy and safety studies that can be implemented, impacting on a broad spectrum of drug discovery and development activities. Recent PGx data show the ability of this approach to generate information that can be applied to dose selection, efficacy determination and safety issues. This in turn will lead to significant opportunities to affect both the approach to clinical development and the probability of success--the latter being an important aspect for pharmaceutical companies and for the patients who will benefit from these new medicines. 相似文献
2.
Mizushima T 《Journal of biochemistry》2011,149(5):499-505
As a new strategy for drug discovery and development, I focus on drug re-profiling as a way to identify new treatments for diseases. In this strategy, the actions of existing medicines, whose safety and pharmacokinetic effects in humans have already been confirmed clinically and approved for use, are examined comprehensively at the molecular level and the results used for the development of new medicines. This strategy is based on the fact that we still do not understand the underlying mechanisms of action of many existing medicines, and as such the cellular responses that give rise to their main effects and side effects are yet to be elucidated. To this extent, identification of the mechanisms underlying the side effects of medicines offers a means for us to develop safer drugs. The results can also be used for developing existing drugs for use as medicines for the treatment of other diseases. Promoting this research strategy could provide breakthroughs in drug discovery and development. 相似文献
3.
Pharmacogenetics place in modern medical science and practice 总被引:2,自引:0,他引:2
Roses AD 《Life sciences》2002,70(13):1471-1480
Pharmacogenetic evidence-based treatment strategies will have major implications for all aspects of the product pipeline, including drug discovery, high throughput target screening protocols, lead optimization, and drug formulation to produce series of medicines for a particular disease which will meet the efficacy needs of the majority of patients. The initial proof of principle experiments involves whole genome screening for DNA variants and determination of specific patterns of variants associated with adverse events of marketed products [SNP Print(sm)]. Pharmacogenetics has the potential of changing the pipeline model of drug discovery, clinical development, and mass customization marketing. 相似文献
4.
Shah RR 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2005,360(1460):1617-1638
Pharmacogenetic factors operate at pharmacokinetic as well as pharmacodynamic levels-the two components of the dose-response curve of a drug. Polymorphisms in drug metabolizing enzymes, transporters and/or pharmacological targets of drugs may profoundly influence the dose-response relationship between individuals. For some drugs, although retrospective data from case studies suggests that these polymorphisms are frequently associated with adverse drug reactions or failure of efficacy, the clinical utility of such data remains unproven. There is, therefore, an urgent need for prospective data to determine whether pre-treatment genotyping can improve therapy. Various regulatory guidelines already recommend exploration of the role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose-response relationship and drug interaction potential. Arising from the global heterogeneity in the frequency of variant alleles, regulatory guidelines also require the sponsors to provide additional information, usually pharmacogenetic bridging data, to determine whether data from one ethnic population can be extrapolated to another. At present, sponsors explore pharmacogenetic influences in early clinical pharmacokinetic studies but rarely do they carry the findings forward when designing dose-response studies or pivotal studies. When appropriate, regulatory authorities include genotype-specific recommendations in the prescribing information. Sometimes, this may include the need to adjust a dose in some genotypes under specific circumstances. Detailed references to pharmacogenetics in prescribing information and pharmacogenetically based prescribing in routine therapeutics will require robust prospective data from well-designed studies. With greater integration of pharmacogenetics in drug development, regulatory authorities expect to receive more detailed genetic data. This is likely to complicate the drug evaluation process as well as result in complex prescribing information. Genotype-specific dosing regimens will have to be more precise and marketing strategies more prudent. However, not all variations in drug responses are related to pharmacogenetic polymorphisms. Drug response can be modulated by a number of non-genetic factors, especially co-medications and presence of concurrent diseases. Inappropriate prescribing frequently compounds the complexity introduced by these two important non-genetic factors. Unless prescribers adhere to the prescribing information, much of the benefits of pharmacogenetics will be squandered. Discovering highly predictive genotype-phenotype associations during drug development and demonstrating their clinical validity and utility in well-designed prospective clinical trials will no doubt better define the role of pharmacogenetics in future clinical practice. In the meantime, prescribing should comply with the information provided while pharmacogenetic research is deservedly supported by all concerned but without unrealistic expectations. 相似文献
5.
近年来,越来越多药企开始在美国进行植物药的临床试验申请和新药申报,美国 FDA 日益重视植物药的开发,于 2016 年 12 月 发布并实施了修订版的《行业指南:植物药》,为植物药后期开发提供更多专业建议。结合 FDA 已经批准的 2 个植物药案例,详细介绍 植物药 CMC(化学、生产、控制)、临床前研究和过往人用历史方面的基本要求,浅谈 FDA 的申报要求、审评思想和申报策略,以期 为中国中药企业的国际化开发和注册提供参考。 相似文献
6.
Molecular understanding and modern application of traditional medicines: triumphs and trials 总被引:3,自引:0,他引:3
Traditional medicines provide fertile ground for modern drug development, but first they must pass along a pathway of discovery, isolation, and mechanistic studies before eventual deployment in the clinic. Here, we highlight the challenges along this route, focusing on the compounds artemisinin, triptolide, celastrol, capsaicin, and curcumin. 相似文献
7.
Zhijun Wang Chen Xie Ying Huang Christopher Wai Kei Lam Moses S. S. Chow 《Phytochemistry Reviews》2014,13(1):323-337
Drug resistance is a major problem in cancer chemotherapy and such resistance may be responsible for treatment failure in 90 % of patients with metastatic cancer. From the research work in the past 30 years, multi-mechanisms responsible for the development of drug resistance have been identified. However, to date single agents that target specific single mechanisms of resistance have not been proven effective. Theoretically, herbs have the potential to target multi-mechanisms of resistance since they contain multiple components and may provide an exciting potential in overcoming drug resistance. The present paper provides an overview of the known mechanisms of resistance and reviews the existing data on herbal medicines (Chinese medicines) as chemosensitizing agents from both the English and Chinese literature. Our review found that certain herbs are capable of inducing strong chemosensitizing effect with various mechanisms, but relevant information useful for development of herbs as viable products for therapeutic use is generally inadequate. Ideas for improving in vitro screening and animal/clinical studies that could enhance future development of herbal product as chemosensitizing agent for the treatment of resistant cancer are also discussed. 相似文献
8.
V Schulz 《Phytomedicine》2000,7(1):73-81
The therapeutic usefulness of medicines is nowadays usually measured in terms of parameters devised in the artificial surroundings of a double blind clinical trial. The difference between the active drug and the placebo is accepted as being the same as the desired overall effect. Yet, when applied to whole categories of medicines, this yardstick can be misleading, as has become apparent from the discussion which has recently arisen regarding the genuine and the illusory pharmacodynamic effects of synthetic antidepressants. Differentiated analysis of a representative number of placebo-controlled studies has shown that when used for depressive conditions, the psychodynamic components contribute far more to the overall effect than do the pharmacodynamic components. In this respect, modern synthetic antidepressants are no better than Hypericum products of plant origin. Among other things, this means that for depressive states and similar indications, the safety, tolerability and acceptability of a medicine must be given much greater weight than its pharmacodynamic effects as assessed simply by testing against a placebo. The quantification of the two therapeutic components, as can be accomplished by a placebo-controlled drug trial, has revealed that the overall outcome of therapy for various important indications of this kind is attributable predominantly to the psychodynamic component. It may reasonably be assumed that the contribution made by the pharmacodynamic effects to the overall therapeutic response will amount to only about 20-50%. This raises questions regarding the clinical relevance and economic value of placebo-controlled studies. When assessing data on drug efficacy for the purpose of licensing applications, greater attention should be given to this reality. 相似文献
9.
The pharmaceutical industry is facing serious challenges as the drug discovery process is becoming extremely expensive, riskier and critically inefficient. A significant shift from single to multi targeted drugs especially for polygenic syndromes is being witnessed. Strategic options based on natural product drug discovery, ethnopharmacology and traditional medicines are re-emerging to offer good base as an attractive discovery engine. Approaches based on reverse pharmacology may offer efficient development platforms for herbal formulations. Relevant case studies from India and other countries where such approaches have expedited the drug discovery and development process by reducing time and economizing investments with better safety are discussed. 相似文献
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11.
Drug development for paediatric applications entails a number of challenges, such as the wide age spectrum covered - from birth to adolescence - and developmental changes in physiology during biological maturation that influence the efficacy and toxicity of drugs. Safe and efficacious antiparasitic drugs for children are of pivotal importance given the large proportion of burden attributable to parasitic diseases in this age group, and growing efforts to administer, as widely as possible, antiparasitic drugs to at-risk populations, such as infants and school-aged children, often without prior diagnosis. The purpose of this review is to investigate whether antiparasitic drugs have been adequately studied for use in paediatrics. We approached this issue through a systematic review using PubMed and the Cochrane Central Register of Trials covering a period of 10 years and 8 months until the end of August 2010 to identify trials that investigated efficacy, safety and pharmacokinetic (PK) parameters of antiparasitic drugs for paediatrics. Overall, 269 clinical drug trials and 17 PK studies met our inclusion criteria. Antimalarial drugs were the most commonly studied medicines (82·6%). Most trials were carried out in Africa and children aged 2-11 years were the age group most often investigated. Additionally, we critically examined available drug formulations for anthelminthics and identified a number of shortcomings that are discussed. Finally, we shed new light on current proposals to expand 'preventive chemotherapy' to preschool-aged children and emphasise that new research, including risk-benefit analyses, are needed before such a strategy can be adopted more widely. 相似文献
12.
Cong Y Pawlisz E Bryant P Balan S Laurine E Tommasi R Singh R Dubey S Peciak K Bird M Sivasankar A Swierkosz J Muroni M Heidelberger S Farys M Khayrzad F Edwards J Badescu G Hodgson I Heise C Somavarapu S Liddell J Powell K Zloh M Choi JW Godwin A Brocchini S 《Bioconjugate chemistry》2012,23(2):248-263
The efficacy of protein-based medicines can be compromised by their rapid clearance from the blood circulatory system. Achieving optimal pharmacokinetics is a key requirement for the successful development of safe protein-based medicines. Protein PEGylation is a clinically proven strategy to increase the circulation half-life of protein-based medicines. One limitation of PEGylation is that there are few strategies that achieve site-specific conjugation of PEG to the protein. Here, we describe the covalent conjugation of PEG site-specifically to a polyhistidine tag (His-tag) on a protein. His-tag site-specific PEGylation was achieved with a domain antibody (dAb) that had a 6-histidine His-tag on the C-terminus (dAb-His(6)) and interferon α-2a (IFN) that had an 8-histidine His-tag on the N-terminus (His(8)-IFN). The site of PEGylation at the His-tag for both dAb-His(6)-PEG and PEG-His(8)-IFN was confirmed by digestion, chromatographic, and mass-spectral studies. A methionine was also inserted directly after the N-terminal His-tag in IFN to give His(8)Met-IFN. Cyanogen bromide digestion studies of PEG-His(8)Met-IFN were also consistent with PEGylation at the His-tag. By using increased stoichiometries of the PEGylation reagent, it was possible to conjugate two separate PEG molecules to the His-tag of both the dAb and IFN proteins. Stability studies followed by in vitro evaluation confirmed that these PEGylated proteins retained their biological activity. In vivo PK studies showed that all of the His-tag PEGylated samples displayed extended circulation half-lives. Together, our results indicate that site-specific, covalent PEG conjugation at a His-tag can be achieved and biological activity maintained with therapeutically relevant proteins. 相似文献
13.
Thamil Vaani Komarasamy Nur Amelia Azreen Adnan William James Vinod RMT Balasubramaniam 《PLoS neglected tropical diseases》2022,16(4)
Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials. 相似文献
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15.
In order to ensure most Chinese patients, particularly in the population with relatively low incomes, have access to safe, low cost, effective and quality-assured medicines, a number of "stand-alone" biological products, which have good quality, safety and efficacy have been marketed in China. Many countries and regions' regulatory agencies are actively engaging in the development of bio-similar guidance and documents, which is being coordinated by WHO. As a major developing country of new drug development, China is now working hard to promote the process of new similar biotherapeutic products (SBPs) approval and also actively involved in developing and updating technical documents. 相似文献
16.
N. Gericke 《South African Journal of Botany》2011,77(4):850-856
The limited commercial opportunity for bioprospecting for isolated pure natural compounds or their derivatives from plants for novel pharmaceuticals is discussed. A broad overview of the key research inputs involved in the commercialisation of indigenous medicinal plants as botanical medicines is given to assist young researchers in contextualising research from an industry perspective, and to encourage university-industry collaboration. Compliance with the Biodiversity Act of 2004, and the regulations under this Act is stressed. The chain of research and development (R&D) activities is briefly described including ethnobotanical research, raw material supply, identification of active compounds, extract development, absorption studies, formulation development, in vitro, in vivo, and clinical safety and efficacy studies, and protection of intellectual property. Ultimately obtaining international marketing authorization for a novel botanical medicine is a lengthy and costly undertaking, with high risk of failure. Elements of botanical medicine R&D can be applied to functional foods, novel foods and personal care products, which can reach the market faster and with less risk than botanical medicines. 相似文献
17.
Jong Hyun Kim Min Wang Jaehun Lee Han-Jin Park Chungseong Han Hee Su Hong Jeong Seong Kim Geun Ho An Kijung Park Hee-Kyung Park Shi Feng Zhu Xiao-Bo Sun Jong-Hoon Kim Dong-Hun Woo 《Cell biology and toxicology》2018,34(1):51-64
Drug-induced liver toxicity is a main reason for withdrawals of new drugs in late clinical phases and post-launch of the drugs. Thus, hepatotoxicity screening of drug candidates in pre-clinical stage is important for reducing drug attrition rates during the clinical development process. Here, we show commercially available hepatocytes that could be used for early toxicity evaluation of drug candidates. From our hepatic differentiation technology, we obtained highly pure (≥98%) hepatocytes from human embryonic stem cells (hESCs) having mature phenotypes and similar gene expression profiles with those of primary human tissues. Furthermore, we optimized 96-well culture condition of hESC-derived hepatocytes suitable for toxicity tests in vitro. To this end, we demonstrated the efficacy of our optimized hepatocyte model for predicting hepatotoxicity against the Chinese herbal medicines and showed that toxicity patterns from our hepatocyte model was similar to those of human primary cultured hepatocytes. We conclude that toxicity test using our hepatocyte model could be a good alternative cell source for pre-clinical study to predict potential hepatotoxicity in drug discovery industries. 相似文献
18.
Sileshi Belew Mestawet Getachew Sultan Suleman Tesfaye Mohammed Habetewold Deti Matthias D'Hondt Evelien Wynendaele Zeleke Mekonnen Jozef Vercruysse Luc Duchateau Bart De Spiegeleer Bruno Levecke 《PLoS neglected tropical diseases》2015,9(9)
BackgroundThere is a worldwide upscale in mass drug administration (MDA) programs to control the morbidity caused by soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura and hookworm. Although anthelminthic drugs which are used for MDA are supplied by two pharmaceutical companies through donation, there is a wide range of brands available on local markets for which the efficacy against STHs and quality remain poorly explored. In the present study, we evaluated the drug efficacy and quality of two albendazole brands (Bendex and Ovis) available on the local market in Ethiopia.Conclusion/SignificanceThe study revealed that differences in efficacy between the two brands of albendazole (ABZ) tablets against hookworm are linked to the differences in the in-vitro drug release profile. Differences in uptake and metabolism of this benzimidazole drug among different helminth species may explain that this efficacy difference was only observed in hookworms and not in the two other species. The results of the present study underscore the importance of assessing the chemical and physicochemical quality of drugs before conducting efficacy assessment in any clinical trials to ensure appropriate therapeutic efficacy and to exclude poor drug quality as a factor of reduced drug efficacy other than anthelminthic resistance. Overall, this paper demonstrates that “all medicines are not created equal”. 相似文献
19.
鸦片用于镇痛治疗有千余年历史, 其滥用导致药物成瘾, 带来严重的社会和医学问题。关于鸦片等精神活性物质的研究主要围绕
神经元,当前的戒毒药物作用于神经元的阿片受体或离子通道受体,然而其戒毒效果非常有限。神经元不是中枢神经系统中调节神经信号
转导的唯一组分,神经小胶质细胞占中枢神经系统的 10%~15%,然而其作用和功能在很长一段时间被忽视。鸦片、可卡因、冰毒及其他
精神活性物质激活 Toll 样受体 4 (TLR4),活化小胶质细胞,产生大量炎症因子,从而调节奖赏信号通路,增加神经元的兴奋性,导致药物
依赖和成瘾,因而 TLR4 是开发新型戒毒药物的靶点。综述药物成瘾的小胶质细胞分子机制以及靶向小胶质细胞的治疗药物成瘾的药物发现。 相似文献
20.
Nathan Geffen 《Developing world bioethics》2016,16(1):45-54
Drug‐resistant tuberculosis (TB) has a high mortality rate. Most medicines used to treat it are poorly tested and have terrible side effects. Activists have campaigned for patients with drug‐resistant TB to have access to experimental drugs, particularly one called bedaquiline, before these have been approved by regulatory authorities such as the Food and Drug Administration (FDA) in the United States (US) and the Medicines Control Council (MCC) in South Africa. Some activists have also campaigned for bedaquiline to be approved by regulatory authorities before testing of the drug is completed. These campaigns raise ethical concerns about whether patients should be offered experimental, unapproved, medicines for the treatment of life‐threatening illnesses, and if authorities should approve drugs for life‐threatening illnesses when vital questions about safety and efficacy remain outstanding. 相似文献