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Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy…

admin — Tue, 17 Aug 2010 10:24:12 +0000

Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy Design Principles. PLoS Comput Biol. 2010;6(8): Authors: Aviran S, Shah PS, Schaffer DV, Arkin AP Gene therapy is an emerging alternative to conventional anti-HIV-1 drugs, and can potentially control the virus while alleviating major limitations of current approaches. Yet, HIV-1’s ability to rapidly acquire mutations and escape therapy presents a critical challenge to any novel treatment paradigm. Viral escape is thus a key consideration in the design of any gene-based technique. We develop a computational model of HIV’s evolutionary dynamics in vivo in the presence of a genetic therapy to explore the impact of therapy parameters and strategies on the development of resistance. Our model is generic and captures the properties of a broad class of gene-based agents that inhibit early stages of the viral life cycle. We highlight the differences in viral resistance dynamics between gene and standard antiretroviral therapies, and identify key factors that impact long-term viral suppression. In particular, we underscore the importance of mutationally-induced viral fitness losses in cells that are not genetically modified, as these can severely constrain the replication of resistant virus. We also propose and investigate a novel treatment strategy that leverages upon gene therapy’s unique capacity to deliver different genes to distinct cell populations, and we find that such a strategy can dramatically improve efficacy when used judiciously within a certain parametric regime. Finally, we revisit a previously-suggested idea of improving clinical outcomes by boosting the proliferation of the genetically-modified cells, but we find that such an approach has mixed effects on resistance dynamics. Our results provide insights into the short- and long-term effects of gene therapy and the role of its key properties in the evolution of resistance, which can serve as guidelines for the choice and optimization of effective therapeutic agents. PMID: 20711350 [PubMed - in process]

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Computational Models of HIV-1 Resistance to Gene Therapy Elucidate Therapy…

N-alkylated oligoamide alpha-helical proteomimetics.

jos — Sat, 14 Aug 2010 03:15:45 +0000

Related Articles N-alkylated oligoamide alpha-helical proteomimetics. Org Biomol Chem. 2010 May 21;8(10):2344-51 Authors: Campbell F, Plante JP, Edwards TA, Warriner SL, Wilson AJ Generic approaches for the design and synthesis of small molecule inhibitors of protein-protein interactions (PPIs) represent a key objective in modern chemical biology. Within this context, the alpha-helix mediated PPIs have received considerable attention as targets for inhibition using small molecules, foldamers and proteomimetics. This manuscript describes a novel N-alkylated aromatic oligoamide proteomimetic scaffold and its solid-phase synthesis–the first time such an approach has been used for proteomimetics. The utility of these scaffolds as proteomimetics is exemplified through the identification of potent microM inhibitors of the p53-hDM2 helix mediated PPI–a key oncogenic target. PMID: 20448891 [PubMed - indexed for MEDLINE]

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N-alkylated oligoamide alpha-helical proteomimetics.

Modelling time to growth of Escherichia coli as a function of water…

admin — Thu, 05 Aug 2010 15:08:28 +0000

Related Articles Modelling time to growth of Escherichia coli as a function of water activity and undissociated lactic acid. Lett Appl Microbiol. 2010 Mar;50(3):308-13 Authors: Lindblad M, Lindqvist R AIMS: To model the effect of water activity (a(w)) and concentration of undissociated lactic acid (HLac) on the time to growth (TTG) and the growth/no growth boundary of acid-adapted generic Escherichia coli, used as model organisms for Shiga toxin-producing E. coli (STEC). METHODS AND RESULTS: For each of two E. coli strains, the TTG in brain heart infusion broth at 27 degrees C was estimated at 30 combinations of a(w) (range 0.945-0.995) and concentration of HLac (range 0-6.9 mol m(-3)) by using an automated turbidity reader. Survival analysis was used to develop a model predicting the TTG and the growth/no growth boundary. CONCLUSIONS: The present model can be used to predict the TTG and to indicate the growth/no growth boundary of acid-adapted E. coli strains as a function of a(w) and concentration of HLac. SIGNIFICANCE AND IMPACT OF THE STUDY: Fermented food products have been implicated as sources of STEC in several outbreaks. The study results are relevant for modelling of growth of STEC in fermented food and can be used in microbiological risk assessments or in the design and validation of food-production processes. PMID: 20102508 [PubMed - indexed for MEDLINE]

Assessing the bioequivalence of analogues of endogenous substances…

admin — Thu, 18 Mar 2010 18:58:10 +0000

Related Articles Assessing the bioequivalence of analogues of endogenous substances (’endogenous drugs’): considerations to optimize study design. Br J Clin Pharmacol. 2010 Mar;69(3):238-44 Authors: Dissanayake S WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * The complexities of assessing the bioequivalence of endogenous drugs are recognised. * The FDA have published guidelines regarding the evaluation of levothyroxine and potassium chloride bioequivalence, whilst other authors have documented specific strategies to counter biases inherent in biostudies of endogenous drugs. * A consolidated consideration of valid methods to optimise the design of such studies is however lacking. WHAT THIS STUDY ADDS * This paper is to the author’s knowledge the first summarising various key approaches used to assess the bioequivalence of endogenous drugs, and to propose a series of recommendations for studies in this field. BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs. METHODS A literature search of the EMBASE and PubMed databases was performed. RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ’substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses. CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed. PMID: 20233194 [PubMed - in process]

Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products…

admin — Sat, 06 Feb 2010 14:56:28 +0000

Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products (OIPs): Workshop Summary Report. J Aerosol Med Pulm Drug Deliv. 2010 Feb;23(1):1-29 Authors: Adams WP, Ahrens RC, Chen ML, Christopher D, Chowdhury BA, Conner DP, Dalby R, Fitzgerald K, Hendeles L, Hickey AJ, Hochhaus G, Laube BL, Lucas P, Lee SL, Lyapustina S, Li B, O’Connor D, Parikh N, Parkins DA, Peri P, Pitcairn GR, Riebe M, Roy P, Shah T, Singh GJ, Sharp SS, Suman JD, Weda M, Woodcock J, Yu L Abstract This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating “local pulmonary delivery” equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented. PMID: 20131983 [PubMed - in process]

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