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At least 343 records · Page 19Linked to original sources
PubMed2005

Targeting HER2 as a therapeutic strategy for breast cancer: a paradigmatic shift of drug development in oncology.

Targeted therapies are causing a dramatic change in cancer drug development. Trastuzumab, a humanized recombinant monoclonal antibody that recognizes the extracellular domain of HER2 trans-membrane protein, is among the first target-specific drugs that have been licensed for clinical use and its development represents a model of integration of new agents with classical treatment strategies. In preclinical models, trastuzumab has demonstrated a marked antiproliferative effect and a synergistic action with several chemotherapeutic agents. Monotherapy trials indicate that trastuzumab is active as a single agent in HER2 positive patients, is well tolerated, and is associated with preservation of quality of life (QoL). Furthermore, as first line therapy for metastatic breast cancer overexpressing HER2 receptor, the addition of trastuzumab to taxane-based chemotherapy significantly increased rate of objective response, time to disease progression and survival when compared with chemotherapy alone. Trastuzumab has shown important activity when used with many chemotherapeutic agents such as platinum salts, gemcitabine, vinorelbine and capecitabine and liposomal anthracyclines. Various trials are now ongoing to optimize the use of trastuzumab and to investigate its role in the adjuvant and in the neo-adjuvant setting.

Animals↗
PubMed2003

Anticancer drug development at the US National Cancer Institute.

Anticancer drug discovery and development is a rapidly evolving field. Recent advances in molecular oncology and the effort to completely sequence the human genome has led to an explosion in our understanding of the mechanisms involved in the transformation and growth of malignant cells. This in turn has led to major changes in our approach to traditional drug discovery and development. A dynamic example of how genomics is affecting cancer developmental therapeutics is provided by the ongoing changes being implemented in the anticancer drug development program run by the US National Cancer Institute (NCI). This review summarizes the history of drug screening and development efforts at the NCI over the past five decades from its inception up to its current state emphasizing molecularly targeted therapies. These changes have not only had an impact on drug discovery, but they are also providing new paradigms for the design and conduct of preclinical and early clinical trials.

Animals↗
PubMed2005

Keynote review: in vitro safety pharmacology profiling: an essential tool for successful drug development.

Broad-scale in vitro pharmacology profiling of new chemical entities during early phases of drug discovery has recently become an essential tool to predict clinical adverse effects. Modern, relatively inexpensive assay technologies and rapidly expanding knowledge about G-protein coupled receptors, nuclear receptors, ion channels and enzymes have made it possible to implement a large number of assays addressing possible clinical liabilities. Together with other in vitro assays focusing on toxicology and bioavailability, they provide a powerful tool to aid drug development. In this article, we review the development of this tool for drug discovery, its appropriate use and predictive value.

Animals↗
PubMed2005

In vitro screening of drug metabolism during drug development: can we trust the predictions?

Due to the importance of drug metabolism for drug action, side effects, interactions and interindividual differences, in vitro assays of drug metabolism are widely employed during drug development. Validation of the in vitro systems is still in a rather elementary stage, but some tentative conclusions about their performance for predicting various important in vivo characteristics of drugs can be attempted. So far, prediction of drug-drug interactions on the basis of in vitro screens has been advanced to a relatively reliable level. Prediction of other important characteristics, such as metabolic stability and consequent half-life and dosage schedule, or induction potential, is less reliable. Although metabolite profiles and participating enzymes are predicted quite accurately with advanced analytical techniques, an important problem here is the lack of reliable methods to detect reactive metabolites or products, which may be of significance regarding toxicity.

Animals↗
PubMed2003

The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development.

The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.

Acetylcholine↗
PubMed1999

Is it possible to develop drugs that act more selectively on large arteries?

BACKGROUND: Patients with high pulse pressures have an increased risk for cardiovascular events. Drugs that selectively decrease high pulse pressure may be of interest for these patients. Such drugs have a more pronounced effect on large arteries than on resistance vessels. OBJECTIVE: To compare the selectivity to large arteries of the new nitric oxide donor sinitrodil with the classic nitrate isosorbide dinitrate in healthy young men in order to investigate whether it is possible to develop drugs that act more selectively on large arteries. DESIGN: The study had a double-blind, 5-way cross-over design. In randomized order, subjects received a single oral dose of 10 mg sinitrodil, 20 mg sinitrodil, 40 mg sinitrodil, isosorbide dinitrate and placebo. Measurements were performed before and 45 min after administration of the drugs. Between each drug administration, at least 3 days of wash-out was allowed. METHODS: The effects of the drugs on large arteries and resistance vessels were assessed by their effects on brachial artery compliance and total peripheral resistance, respectively. RESULTS: Brachial artery compliance increased gradually with increasing doses of sinitrodil (by 10, 20 and 27% with 10, 20 and 40 mg sinitrodil, respectively). Total peripheral resistance index decreased with isosorbide dinitrate (by 11%) and 40 mg sinitrodil (by 7%), while it remained unchanged with 10 mg and 20 mg sinitrodil. CONCLUSIONS: The results of this study show that it may be possible to develop drugs with a higher selectivity for large arteries. Such drugs may be good candidates to decrease high pulse pressure without substantially decreasing mean and diastolic blood pressures.

Adult↗
PubMedDate not supplied

[New strategies for drug development].

The strategy how new drugs are being developed has dramatically changed during the last decade. Until then a rational, target-aimed design of drugs was not possible, because the molecular basis of disease was largely unexplored. The progress in basic science has revealed that many diseases are caused by the malfunction of proteins. These proteins are targets for drugs, which should bind to the protein and inhibit its function. Knowledge of the three dimensional structure of the target protein is helpful to find binding pockets for the drug on the molecular surface. The strategy of this knowledge-based or structure-based drug-design is explained with the help of several examples for recently approved drugs, antivirals against influenza and AIDS, and a drug against a rare cancer, chronic myeloic leukemia.

Animals↗
PubMed1993

Frontiers in biological psychiatry: new drug development.

This past decade has been a fertile time for new drug developments for the central nervous system. This article discusses cutting edge treatments for depression, anxiety, and psychosis. Some of these medications now are approved; many still are being researched.

Anxiety Disorders↗
PubMed2006

Targeting opioid receptor heterodimers: strategies for screening and drug development.

G-protein-coupled receptors are a major target for the development of new marketable drugs. A growing number of studies have shown that these receptors could bind to their ligands, signal, and be internalized as dimers. Most of the evidence comes from in vitro studies, but recent studies using animal models support an important role for dimerization in vivo and in human pathologies. It is therefore becoming highly relevant to include dimerization in screening campaigns: the increased complexity reached by the ability to target 2 receptors should lead to the identification of more specific hits that could be developed into drugs with fewer side effects. In this review, we have summarized results from a series of studies characterizing the properties of G-protein-coupled receptor dimers using both in vitro and in vivo systems. Since opioid receptors exist as dimers and heterodimerization modulates their pharmacology, we have used them as a model system to develop strategies for the identification of compounds that will specifically bind and activate opioid receptor heterodimers: such compounds could represent the next generation of pain relievers with decreased side effects, including reduced drug abuse liability.

Animals↗
PubMedDate not supplied

Statistical concepts in the planning and evaluation of drug safety from clinical trials in drug development: issues of international harmonization.

The assessment of the safety of new drugs during pre-marketing clinical studies is an important and integral part of the drug development and regulatory evaluation process. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory decision-makers of Europe, Japan and the United States of America and the experts from the pharmaceutical industry in the three regions to seek ways to eliminate redundant and duplicative technical requirements among the developed countries for registering new medicinal substances and products. The ICH is developing guidelines or position papers to achieve the goal of harmonizing technical standards in three broad areas, namely, drug efficacy, safety and quality. Within the area of drug safety, this paper will discuss three of the safety topics because of their relevant statistical framework, and because these topics have not, to date, received any attention by the statistical community. The three issues under consideration by the International Conference on Harmonization (ICH), are: 1. Dose-response information to support drug registration (especially dose/toxicity relationships). 2. Studies in support of special populations; Geriatrics, A Draft Guideline. 3. ICH Draft Guideline 3 on 'The extent of population exposure required to assess clinical safety for drugs intended for long-term-treatment of non-life-threatening conditions'. The ICH special population guideline concerning studies in geriatric patients is closely related to a recent Food and Drug Administration 'Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs', which is another example of a 'subgroup' for whom specific interest exists to evaluate drug safety and efficacy.

Age Factors↗
PubMed1996

Strategy and planning for chemopreventive drug development: clinical development plans II.

This is the second publication of Clinical Development Plans from the National Cancer Institute, Division of Cancer Prevention and Control, Chemoprevention Branch and Agent Development Committee. The Clinical Development Plans summarize the status of promising chemopreventive agents regarding evidence for safety and chemopreventive efficacy in preclinical and clinical studies. They also contain the strategy for further development of these drugs, addressing pharmacodynamics, drug effect measurements, intermediate biomarkers for monitoring efficacy, toxicity, supply and formulation, regulatory approval, and proposed clinical trials. Sixteen new Clinical Development Plans are presented here: curcumin, dehydroepiandrosterone, folic acid, genistein, indole-3-carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, 13-cis-retinoic acid, l-selenomethionine and 1, 4-phenylenebis(methylene)selenocyanate, sulindac sulfone, tea, ursodiol, vitamin A, and (+)-vorozole. The objective of publishing these plans is to stimulate interest and thinking among the scientific community on the prospects for developing these and future generations of chemopreventive drugs.

Animals↗
PubMedDate not supplied

Clinical trial simulation in drug development.

The simulation of therapeutic models and clinical trial simulation have recently attracted attention as emerging techniques for developing new active molecules and the exploration of possible clinical trial results. Such approaches have benefited from fundamental progress in the development of 'in silico' models, as well as progress in nonlinear mixed-effect pharmacokinetic-pharmacodynamic models. Mixing the two approaches allows simulation of 'virtual' patients, who receive virtual treatments or placebo. These have various uses, such as proof of concept, decision analysis or experimental design optimisation. Also, the effect of departures from protocol on clinical trial results can easily be evaluated by the use of simulation. This technique is now implemented by the pharmaceutical industry for optimising phase II and III experimental designs when a good biomarker or a clinical outcome model is available, but the use of an in silico therapeutic model as a proof of concept is only just beginning. In order to see such methodologies used more widely in drug development, multidisciplinary efforts need to be initiated, new modelling and simulation tools developed, and sound modelling and simulation practice documents need to be adopted. A reduction in the number of failed clinical development projects, the number of negative phase II and III clinical trials, or in just their cost and duration, are among the expected benefits of modelling and simulation in clinical drug development.

Clinical Trials as Topic↗
PubMed2001

Translating the basic and clinical cognitive neuroscience of schizophrenia to drug development and clinical trials of antipsychotic medications.

Neurocognitive deficits have become increasingly important defining features of schizophrenia and its treatment. Multiple domains of neurocognitive functions are impaired in schizophrenia patients, and these impairments are considered to be core features of the disorder. Many recent reports support the importance of the relationship of these neurocognitive deficits to measures of "functional outcome" such as social skills acquisition, social problem solving, and community outcome. Neurocognitive deficits appear to be improved with newer (atypical) antipsychotic medications across a broad range of domains in schizophrenia patients. Together with clinical neuroscience advances, basic research in cognitive neuroscience ranging from animal models of gating functions to early gene expression induced by antipsychotic medications has illuminated the specific neural basis of neurocognitive deficits in schizophrenia and the neurobiology of antipsychotic actions. These translational basic and clinical studies provide powerful screening tools and strategies for drug development and the subsequent assessment of the clinical efficacy of new antipsychotic medications. These interlocking clinical and basic research findings have substantial implications for improving both drug development and improving clinical trials methodology for antipsychotic medications. Thus, there is an informed translation and cross-fertilization between basic and clinical research focused on the development and assessment of putative new antipsychotic compounds.

Antipsychotic Agents↗
PubMed2005

Positron Emission Tomography: applications in drug discovery and drug development.

Positron Emission Tomography (PET) is a sophisticated nuclear imaging modality that affords researchers the ability to conduct both functional and molecular imaging on biological and biochemical processes in vivo. In functional imaging, biological parameters such as metabolic rate and perfusion that can be altered by disease or treatment are monitored. In molecular imaging, PET can be used to examine and quantify cellular events such as cell trafficking, receptor binding and gene expression. Therefore, PET is an important tool to elucidate mechanisms associated with diseases and drug actions. In addition to PET, microPET is designed to image small animals. A great tool to facilitate preclinical studies and basic research, it can eliminate the need of sacrificing the animal by enabling noninvasive, longitudinal, and serial studies. The results from preclinical studies using microPET can be directly correlated with clinical studies using PET, thus bridging the chasm that used to separate the 2 pivotal phases in drug development. This review first describes the basic principles of PET and compares it to other imaging modalities. Then, PET procedures and PET isotopes and tracers synthesis are outlined. Next, functional and molecular PET imaging applications in the fields of oncology, neurology, and cardiology in both humans and animals are presented. Spanning a wide range, these applications demonstrate the versatility of PET and how it can be used to accelerate drug discovery and development. Finally, the advantages and limitations of PET and how it can be used in the future to minimize risks of drug development are discussed.

Animals↗
PubMed1990

Research challenges, new drug development, preclinical and clinical trials in the ageing population.

The aged are now viewed as a special population for the purposes of drug development. This has produced challenges for the investigator, in that separation of age- and disease-related changes in drug effect is only beginning to be defined. In addition, development of measurement tools for use in the elderly, particularly for central nervous system-active drugs, is an important ongoing process. As investigations proceed, we can look forward to an improved understanding of the physiology of normal ageing and the impact of disease processes and drugs on this physiological functioning. For the regulatory agency, evaluation of both efficacy and toxicity data in elderly patients for a drug-in-development is required; however, at present these data will be obtained in a 'young' elderly group, whereas much of the clinical use of the drug will be in the 'old' elderly. Extrapolation from one group to the other is required, although the relevance of this extrapolation is unknown. It is reassuring that, so far, few if any drug effects or toxicities have been identified which are truly unique to the elderly, though the magnitude of pharmacological or toxicological effects may differ.

Aged↗
PubMed2005

Studies on the crystallinity of a pharmaceutical development drug substance.

The crystallinity and amorphous content of a micronized pharmaceutical development drug substance have been independently determined. An evaluation of different techniques for this purpose has been carried out, and it was found that solid-state nuclear magnetic resonance (ss NMR) and X-ray powder diffraction (XRPD) were suitable for the former and latter, respectively. The baseline intensities of X-ray powder diffractograms, associated with the amorphous component of the sample, have been used to detect levels of non-crystalline material greater than 5%w/w with an absolute accuracy of +/-3%. ss NMR has been employed to quantify crystalline defects at levels of greater than 3%w/w with an estimated uncertainty of +/-2%. It is proposed that such crystalline defects arise from molecular conformational differences that only have a small effect on crystal lattice parameters and, by implication, only have small effects on X-ray powder diffractograms. In both cases the techniques are shown to be highly reproducible and require minimal sample preparation. Excellent linearity is demonstrated for the determination of amorphous material using prepared standards. The present account describes the choice of analytical method, method validation and the results obtained for typical samples of drug substance. It is demonstrated that solid-state NMR should be used as a complementary technique with respect to XRPD for studying crystallinity.

Calorimetry, Differential Scanning↗
PubMed1998

Relevance of pheno- and genotyping in clinical drug development.

Individual variability in the plasma concentration of a xenobiotic is a considerable problem in the clinical use as well as in the clinical development of a new drug. In clinics altered drug response and drug toxicity are predominant findings. In clinical development (especially in the early phases) problems with the interpretation of individual pharmacokinetics and appearance of unexpected drug reactions may occur. One major reason for the inter-and intraindividual variability is based on variations in the metabolism of the drug that are dependent on the genetic variations of the metabolising enzymes. However, while the first of these so-called polymorphisms has already been described in 1979 (for a review see [Daly 1995]) and knowledge of these polymorphisms are still growing, the impact on clinical practice as well on the selection and development of drug candidates in the pharmaceutical industry at present is still limited. This may change in the near future as recent advances in molecular biology and especially in the diagnosis of individual genomic characteristics will result in a better understanding of the basic principles of the polymorphisms. High throughput screening methods will reveal information on the distribution of these polymorphic alleles in the target population and enable the broad characterization of the drug candidate in in vitro systems. The early knowledge as to whether a polymorphic pathway is involved in drug metabolism/action and of its clinical relevance will lead to a reduction of time and costs in the development of a new drug.

Decision Trees↗