SEARCH · PubMed Health

Results for “Drug development”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources

PubMed2003

The potential of the molecular diversity of heparin and heparan sulfate for drug development.

Heparin and heparan sulfate have been shown to interact with a large number of biologically important proteins regulating important physiological processes. Specific oligosaccharide structures within the heterogeneous polysaccharide chains are responsible for the binding to individual proteins. Identification of specific protein-binding oligosaccharides provides lead compounds in pharmaceutical development and in one case has already resulted in an approved drug. The chemical and biosynthetic basis of the molecular diversity of heparin and heparan sulfate, its manifestation in heparin-protein interactions, and recent progress for drug development offered by this diversity are reviewed.

Animals↗

PubMed1999

[Roles of nurses in clinical trials of anticancer drug development].

In Japan nurses were not much involved in clinical trials in connection with new drug development in the field of cancer nursing in the past for the following reasons: 1) systems for cooperations among different services in hospital were not well established. 2) There was a lack of information about the drugs from physicians, 3) It was difficult to obtain informed consent from patients. In the new GCP system of Japan started last April in accordance with ICH-GCP, persons who support patients and assist physician investigators are desperately needed to maintain QA and QC of the clinical trials. Research nurses are the most suitable persons to fulfill such positions. The roles of research nurses in these settings are patient care, coordinator, data collecting and educator in the new system.

Antineoplastic Agents↗

PubMed2004

Quantitative methods for the analysis of protein phosphorylation in drug development.

Most signal transduction and cell signaling pathways are mediated by protein kinases. Protein kinases have emerged as important cellular regulatory proteins in many aspects of neoplasia. Protein kinase inhibitors offer the opportunity to target diseases such as cancer with chemotherapeutic agents specific for the causative molecular defect. In order to identify possible targets and assess kinase inhibitors, quantitative methods for analyzing protein phosphorylation have been developed. This review examines some of the current formats used for quantifying kinase function for drug development.

Animals↗

PubMed2004

Microfilament actin remodeling as a potential target for cancer drug development.

Actin was first identified in non-muscle cells only about three decades ago, and at about the same time, it was found that actin filaments were disrupted in the malignant transformed cells. The actin network is a rather complex, yet important structural and functional system of all eukaryotic cells. Actin filaments provide the basic infrastructure for maintaining cell morphology and functions such as adhesion, motility, exocytosis, endocytosis, and cell division. Growing evidence from this laboratory and others shows that alterations of actin polymerization, or actin remodeling, plays a pivotal role in regulating the morphologic and phenotypic events of a malignant cell. Actin remodeling is the result of activation of oncogenic actin signaling pathways (e.g., Ras and Src), or inactivation of several important actin-binding proteins that have tumor suppressor functions (e.g., gelsolin). Distinctive protein expression patterns of some of these genes in cancer and progressive carcinogenic processes have been observed. It has become evident that actin dynamics are regulated by a complex interplay of the small GTPase proteins of Ras superfamily Rac, Rho, and Cdc42, and efforts to develop specific inhibitors for these small G proteins as anticancer drug are underway. In this review we will discuss how actin remodeling is altered in the malignant transformation process, the functional significance of actin alteration in association with malignant phenotypes, and the approaches of targeting actin remodeling for chemopreventive and chemotherapeutic drug development. Approaches including using nature products directly modulating actin polymerization, using inhibitors of actin pathway small G proteins, and using gene-augmentation for actin binding proteins will be discussed. In addition, the concept of using F/G-actin ratio as a surrogate marker for actin-pathway based therapy will also be introduced.

Actins↗

PubMed2001

The Breast Cancer Continuum: insights from the tamoxifen trials impact future drug development strategies.

The Breast Cancer Continuum includes women at high risk, as in the Breast Cancer Prevention Trial; those with a history of atypical ductal hyperplasia (ADH) or lobular carcinoma in situ (LCIS); women with ductal carcinoma in situ (DCIS); those with <1 cm invasive disease or node-negative or node-positive disease; and those at risk of developing contralateral breast cancer. Women in all these categories benefit from therapeutic intervention with tamoxifen because each clinical state is associated with a certain probability of having early undiagnosed invasive breast cancer responsive to tamoxifen. This framework, relating these disorders to each other through their 5-year incidence of developing invasive breast cancer, leads to important conclusions relative to pharmaceutical drug development strategies, including chemoprevention investigations.

Antineoplastic Agents, Hormonal↗

PubMed1989

Antiepileptic drug development program: a cooperative effort of government and industry.

The most important step in antiepileptic drug discovery is the choice of an appropriate animal model for the initial screening as well as for the more complex procedures that elucidate mechanisms of action. The currently available models fall short in their inability to identify all drugs for all types of seizures in a mechanism-independent manner. Nevertheless, spontaneous models of epilepsy are the most commonly used, and chemically or electrically induced seizures in rodents can also identify potential anticonvulsants. In the latter models, the intensity of the seizure stimulus is of paramount importance. The Antiepileptic Drug Development Program evaluates approximately 800 compounds each year, using two models for preliminary screening. One model assesses the ability of a compound to prevent seizure spread; the other weighs the ability to raise seizure threshold. In vivo tests, featuring amygdala- and corneal-kindled seizures, and in vitro assays, employing gamma-aminobutyric acid (GABA) receptors and synaptosomal uptake of adenosine, define drug-drug interactions and elucidate the pharmacological profiles of potential anticonvulsants.

Animals↗

PubMed2001

[Modern drug development by molecular- and cell-biological methods].

V79 cells have been genetically modified for metabolism functions of humans in drug metabolism and metabolic activation of chemicals. All V79 constructs together form the V79 Cell Battery by which GenPharmTox BioTech AG, Tutzing, Germany, is capable of checking drug metabolism early on during preclinical drug development with immediate relevance for the clinical testing of drugs. It is impossible to obtain those data from animal testing. Therefore, the intrinsic problems in extrapolating data generated from animal testing to humans has been circumvented.

Animal Testing Alternatives↗

PubMed2005

Bioinformatics in drug development and assessment.

Bioinformatics is playing an increasingly important role in nearly all aspects of drug discovery, drug assessment, and drug development. This growing importance lies not only in the role that bioinformatics plays in handling large volumes of data, but also in the utility of bioinformatics tools to predict, analyze, or help interpret clinical and preclinical findings. This review focuses on describing and evaluating some of the newer or more important bioinformatics resources (i.e., databases and software) that are of growing importance to understanding or predicting drug metabolism, especially with respect to the absorption, distribution, metabolism, excretion, (ADME), and toxicity (T) of both existing drugs and potential drug leads. Detailed descriptions and critical assessments of a number of potentially useful bioinformatics/cheminformatics databases and predictive ADMET software tools are provided. Additionally, several pharmaceutically important applications of both the databases and software are highlighted. Given the rapid growth in this area and the rapid changes that are taking place, a special emphasis is placed on freely available or Web-accessible resources.

Animals↗

PubMed2007

Experiences with dose finding in patients in early drug development: the use of biomarkers in early decision making.

With the increasing cost and complexity of drug development, biomarkers will play an increasing role in the early phases. Biomarkers can be classified into target, mechanistic, or outcome with varying degrees of linkage to disease or treatment effect. They can be used to determine proof of concept by characterising the efficacy or safety profiles, or determining differentiation from any competitor drugs. PK/PD modelling of biomarker data for novel and marketed compounds can be used to predict outpatient dose response. Subsequent simulations may replace or reduce the size and cost of larger phase 2b outpatient studies. Two examples of biomarkers and PK/PD modelling used to characterise dose response are presented. Penile plethysmography (RigiScan Plus) in male erectile dysfunction and phenylephrine challenge urethral pressure in benign prostatic hyperplasia are used to reduce time and cost to reach major exploratory development decision points in these indications.

Biomarkers↗

PubMed2004

Drug-induced torsades de pointes and implications for drug development.

Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarization changes, their preclinical and clinical evaluation, and the risk-to-benefit interpretation of drug-induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug-induced torsades within the larger evaluation of drug-related risks and benefits.

Anti-Arrhythmia Agents↗

PubMed2004

Drug development in patients with advanced non-small cell lung cancer and poor performance status.

Drug development represents a significant challenge in patients with advanced non-small cell lung cancer and poor performance status (PS) because of the short survival time of these patients and heterogeneity in the cause of poor PS. Historically, these patients have been excluded from clinical trials. However, there is now evidence that certain treatments can produce responses and increase survival in patients with poor PS. Several clinical trials have been conducted recently to investigate treatment options in these patients. This article reviews the need for such trials, the potentially greater risks with evaluating new drugs in such patients, recommendations for designing trials in the population, and the results in recently completed and ongoing clinical trials designed specifically for the PS2 population.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Pharmacokinetic/pharmacodynamic modelling in oncological drug development.

For many oncological agents, myelosuppression is the dose-limiting toxicity and the quantitative characterisation of the relationship between drug dose, plasma concentration and haematological toxicity is of importance in the drug development. Mechanism-based population pharmacokinetic-pharmacodynamic models have been developed for this purpose and the applications of these in candidate selection, first-in-man studies, prodrug and formulation development, dose finding, schedule optimisation, assessing influence of modifying agents, drug combination studies, subgroup identification and feedback individualisation are reviewed.

Animals↗

PubMed2006

MR in oncology drug development.

This article reviews the use of MR in preclinical and clinical experiments to aid drug development. In particular it concentrates on the use of MR to study tumor microvasculature following treatment with anti-vascular agents and the use of MRS to study tumor metabolism following treatment with a variety of anti-cancer agents. The advantages and disadvantages of a variety of techniques including contrast- and noncontrast-enhanced methods are discussed and the data from clinical trials using these techniques are reviewed. Despite the consensus documents produced to date for both dynamic contrast-enhanced MRI and MRS, most of the trials reported used alternative methods, and different nomenclature for the MR parameters used. This continues to inhibit the comparison between novel therapeutics and between different trials with the same compound. Comprehensive data from multicenter trials on the reproducibility of techniques is still lacking in the literature and the implications of the available data on clinical trial design is also discussed.

Clinical Trials as Topic↗

PubMed2004

Correcting the QT interval for changes in HR in pre-clinical drug development.

OBJECTIVES: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. Drug-induced prolongation of the QT interval can result in life-threatening ventricular arrhythmia. In pre-clinical drug development, animal experiments are used to study this possible effect. Researchers have become aware that correction formulae derived for human beings are not applicable to animal experiments. METHODS: We investigated some of the proposed models by comparing the outcomes of the analyses on the same data. The data was derived from telemetry measurements on Labrador dogs. We propose the use of both the correlation with heart rate (or RR interval) and a measure of predictive performance. As a sufficiently large number of observations were available, the data was subdivided into a training and a test set. The training set serves to estimate the respective parameters while the test set is used to determine the performance of the model. Here, a kind of PRESS statistic was used. Next, the models were considered for treated animals, using the estimated parameters. Both positive and negative controls were used. CONCLUSIONS: Most models under consideration performed quite well. These models eliminated the correlation for the most part and were reasonably predictive. Furthermore, they reliably differentiate between positive and negative controls. The next steps in identifying the best correction will be to consider additional compounds as well as other species to validate our current results.

Animals↗

PubMed2003

Application of toxicogenomics in drug development.

The recognition of toxicological potential in new chemical entities early on in development would be highly desirable in streamlining and reducing the cost of drug development. Analysis of gene expression profiles using microarrays is one of the most fashionable methods for achieving this objective. The procedure relies on developing a gene expression profile related to compound exposure and then matching this against a database of profiles associated with known mechanisms of toxicity. Studies profiling tumors and associating these with pathology and phenotype have shown the potential of the technique. However, application of the technique in toxicology is only at the preliminary stage. This article examines current state of development in toxicology and its future potential.

Antineoplastic Agents↗

PubMed1982

Meeting requirements for primate animals in drug development.

An overview on the numbers and species of monkeys used in the area of drug development in the USA and Europe during the years 1975 to 1981 is presented. A marked decline of 25% to 40% in the numbers used is due to a more critical use of the various species, besides a shortage of available animals. However, because for certain experiments some primate species are the animals of choice, there is a limit to further reductions. For future supplies, intensive breeding units, semifree-range colonies, and game farming may be considered. Using the revenue of exported animals, a financial contribution to the conservation of feral animals in the countries of origin could be made.

Animal Husbandry↗

PubMed1994

Mechanistic considerations in chemopreventive drug development.

This overview of the potential mechanisms of chemopreventive activity will provide the conceptual groundwork for chemopreventive drug discovery, leading to structure-activity and mechanistic studies that identify and evaluate new agents. Possible mechanisms of chemopreventive activity with examples of promising agents include carcinogen blocking activities such as inhibition of carcinogen uptake (calcium), inhibition of formation or activation of carcinogen (arylalkyl isothiocyanates, DHEA, NSAIDs, polyphenols), deactivation or detoxification of carcinogen (oltipraz, other GSH-enhancing agents), preventing carcinogen binding to DNA (oltipraz, polyphenols), and enhancing the level or fidelity of DNA repair (NAC, protease inhibitors). Chemopreventive antioxidant activities include scavenging reactive electrophiles (GSH-enhancing agents), scavenging oxygen radicals (polyphenols, vitamin E), and inhibiting arachidonic acid metabolism (glycyrrhetinic acid, NAC, NSAIDs, polyphenols, tamoxifen). Antiproliferation/antiprogression activities include modulation of signal transduction (glycyrrhetinic acid, NSAIDs, polyphenols, retinoids, tamoxifen), modulation of hormonal and growth factor activity (NSAIDs, retinoids, tamoxifen), inhibition of aberrant oncogene activity (genistein, NSAIDs, monoterpenes), inhibition of polyamine metabolism (DFMO, retinoids, tamoxifen), induction of terminal differentiation (calcium, retinoids, vitamin D3), restoration of immune response (NSAIDs, selenium, vitamin E), enhancing intercellular communication (carotenoids, retinoids), restoration of tumor suppressor function, induction of programmed cell death (apoptosis) (butyric acid, genistein, retinoids, tamoxifen), correction of DNA methylation imbalances (folic acid), inhibition of angiogenesis (genistein, retinoids, tamoxifen), inhibition of basement membrane degradation (protease inhibitors), and activation of antimetastasis genes. A systematic drug development program for chemopreventive agents is only possible with continuing research into mechanisms of action and thoughtful application of the mechanisms to new drug design and discovery. One approach is to construct pharmacological activity profiles for promising agents. These profiles are compared among the promising agents and with untested compounds to identify similarities. Classical structure-activity studies are used to find optimal agents (high efficacy with low toxicity) based on good lead agents. Studies evaluating tissue-specific and pharmacokinetic parameters are very important. A final approach is design of mechanism-based assays and identification of mechanism-based intermediate biomarkers for evaluation of chemopreventive efficacy.

Animals↗

PubMed2005

Focused metabolomic profiling in the drug development process: advances from lipid profiling.

The highly parallel analytical technologies comprising 'omics promised to dramatically improve drug development efficiency by increasing knowledge and improving decision-making capabilities. On this point, the 'omics have largely been a disappointment. The major reason genomics, transcriptomics and proteomics fail to improve decision making capabilities is that they produce so many false positive results that it is difficult to be sure that findings are valid. Metabolomics is not immune to this problem but, when practiced effectively, the technology can reliably produce knowledge to aid in decision making. In particular, focused metabolomics platforms - those that restrict their target analytes to those measured well by the technology - can produce data with properties that maximize sensitivity and minimize the false discovery problem. The most developed focused metabolomics area is lipid profiling.

Animals↗