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Preclinical Development (preclinical + development)
Selected AbstractsKP1019, A New Redox-Active Anticancer Agent , Preclinical Development and Results of a Clinical Phase I Study in Tumor PatientsCHEMISTRY & BIODIVERSITY, Issue 10 2008Christian Abstract The promising drug candidate indazolium trans -[tetrachlorobis(1H -indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et,al., J. Inorg. Biochem.2006, 100, 891,904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects. [source] Preclinical development of hybrid cell vaccines for multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2007Renata Walewska Abstract Immunotherapy may provide alternative or supplementary treatment of multiple myeloma (MM). We propose that hybrid cells, formed by fusing professional antigen-presenting cells with malignant plasma cells, would induce immune responses capable of mediating tumour regression. The human B-lymphoblastoid cell line, HMy2, was fused in vitro with CD138+ bead-separated myeloma plasma cells from five patients with MM. The hybrid cell lines generated in these studies grew stably in tissue culture, and maintained their phenotypic and functional characteristics, providing self-renewing cell lines with potential for therapeutic vaccination. The hybrid cells stimulated allogeneic and autologous T-cell proliferative responses in vitro to a considerably greater degree than their respective parent myeloma plasma cells, and directly activated both CD4+ and CD8+ T-cell responses. The enhanced T-cell stimulation correlated with expression of CD80 on the hybrid cells, and was inhibited by CTLA4-Ig fusion protein. The hybrid cell lines expressed several tumour-associated antigens known to be expressed in myeloma. These data show that self-replicating cell lines with enhanced immunostimulatory properties and potential for therapeutic vaccination can be generated by in vitro fusion of ex vivo myeloma cells and B-lymphoblastoid cell lines. [source] Preclinical development of velcade (bortezomib; formerly PS-341) for multiple myelomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2003J. Adams First page of article [source] Polymeric Materials for Gene Delivery and DNA VaccinationADVANCED MATERIALS, Issue 8 2009David N. Nguyen Abstract Gene delivery holds great potential for the treatment of many different diseases. Vaccination with DNA holds particular promise, and may provide a solution to many technical challenges that hinder traditional vaccine systems including rapid development and production and induction of robust cell-mediated immune responses. However, few candidate DNA vaccines have progressed past preclinical development and none have been approved for human use. This Review focuses on the recent progress and challenges facing materials design for nonviral DNA vaccine drug delivery systems. In particular, we highlight work on new polymeric materials and their effects on protective immune activation, gene delivery, and current efforts to optimize polymeric delivery systems for DNA vaccination. [source] A solid-state approach to enable early development compounds: Selection and animal bioavailability studies of an itraconazole amorphous solid dispersionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2010David Engers Abstract A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3901,3922, 2010 [source] Compartmental transport model of microbicide delivery by an intravaginal ringJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 8 2010Anthony R. Geonnotti Abstract Topical antimicrobials, or microbicides, are being developed to prevent HIV transmission through local, mucosal delivery of antiviral compounds. While hydrogel vehicles deliver the majority of current microbicide products, intravaginal rings (IVRs) are an alternative microbicide modality in preclinical development. IVRs provide a long-term dosing alternative to hydrogel use, and might provide improved user adherence. IVR efficacy requires sustained delivery of antiviral compounds to the entire vaginal compartment. A two-dimensional, compartmental vaginal drug transport model was created to evaluate the delivery of drugs from an intravaginal ring. The model utilized MRI-derived ring geometry and location, experimentally defined ring fluxes and vaginal fluid velocities, and biophysically relevant transport theory. Model outputs indicated the presence of potentially inhibitory concentrations of antiviral compounds along the entire vaginal canal within 24,h following IVR insertion. Distributions of inhibitory concentrations of antiviral compounds were substantially influenced by vaginal fluid flow and production, while showing little change due to changes in diffusion coefficients or ring fluxes. Additionally, model results were predictive of in vivo concentrations obtained in clinical trials. Overall, this analysis initiates a mechanistic computational framework, heretofore missing, to understand and evaluate the potential of IVRs for effective delivery of antiviral compounds. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3514,3521, 2010 [source] New strategies for polymer development in pharmaceutical science , a short reviewJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2001A. Godwin We are developing synthetic polymers for pharmaceutical and medical applications. These applications can be broadly grouped on how the polymer will be utilized e.g. material, excipient or molecule. Our focus is to develop polymers with more defined structures that are based on biological, physicochemical and/or materials criteria. Strategies are being developed to more efficiently optimize structure,property correlations during preclinical development. We describe two examples of our research on pharmaceutical polymer development: narrow molecular weight distribution (MWD) homopolymeric precursors which can be functionalized to give families of narrow MWD homo- and co-polymers, and hydrolytically degradable polymers. [source] Density functional study on the structural conformations and intramolecular charge transfer from the vibrational spectra of the anticancer drug combretastatin-A2JOURNAL OF RAMAN SPECTROSCOPY, Issue 4 2009L. Padmaja Abstract Combretastatin-A2 (CA2), a potential anticancer drug in advanced preclinical development, is extracted from the medicinal plant Combretum caffrum. The NIR-FT Raman and FT-IR spectral studies of the molecule were carried out and ab initio calculations performed at the B3LYP/6-31G(d) level to derive the equilibrium geometry as well as the vibrational wavenumbers and intensities of the spectral bands. The vibrational analysis showed that the molecule has a similar geometry as that of cis-stilbene, and has undergone steric repulsion resulting in twisting of the phenyl ring with respect to the ethylenic plane. Vibrational analysis was used to investigate the lowering of the stretching modes, and enhancement of infrared band intensities of the C,H stretching modes of Me2 may be attributed to the electronic effects caused by back-donation and induction from the oxygen atom. Analysis of phenyl ring modes shows that the CA2 stretching mode 8 and the aromatic C,H in-plane bending mode are equally active as strong bands in both IR and Raman spectra, which can be interpreted as the evidence of intramolecular charge transfer (ICT) between the OH and OCH3groups via conjugated ring path and is responsible for bioactivity of the molecule. Copyright © 2008 John Wiley & Sons, Ltd. [source] Review article: investigational agents for chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2009A. J. V. THOMPSON Summary Background, The need for effective treatment for chronic hepatitis C infection has driven the development of novel antiviral agents that target specific steps in the viral replication cycle. Aim, To evaluate the current literature concerning investigational agents for chronic hepatitis C virus infection. Methods, Resources used included PubMed, conference proceedings from the American and European Liver Associations' meetings 2005,2008 and the National Institute of Health's clinical trials website (http://www.clinicaltrials.gov). The focus was restricted to investigational agents that have progressed beyond preclinical development. Results, Over 50 investigational agents for chronic hepatitis C infection are currently in clinical development. Specifically targeted anti-viral therapy for HCV (STAT-C) shows great promise with NS3/4a protease inhibitors now entering phase 3 programmes. New interferon-, and ribavirin formulations aim to optimize anti-viral efficacy yet limit toxicity. Other candidates include novel immunomodulators and therapeutic vaccines. Conclusions, A new era of therapy for chronic hepatitis C beckons, promising increased cure rates with shortened duration of therapy. However, the era will not be without challenges including viral resistance, drug toxicity and the need to optimize combination therapy in the face of a rapidly evolving therapeutic arsenal. [source] Gene expression profiling in autoantibody-positive patients with arthralgia predicts development of arthritis,ARTHRITIS & RHEUMATISM, Issue 3 2010Lisa G. M. van Baarsen Objective To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers. Methods The study group comprised 109 anti,citrullinated protein antibody (ACPA), and/or rheumatoid factor,positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction. Results In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at-risk patients, based on differential expression of immune-related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN),mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8,156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN-mediated immunity and/or cytokine/chemokine-activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21,0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease. Conclusion The results of this study indicate that IFN-mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine. [source] | |||||||||||||