Drug Induced Mitochondrial Dysfunction

Author: James A. Dykens
Publisher: John Wiley & Sons
ISBN: 0470372524
Format: PDF, Kindle
Download Now
This is the definitive, one-stop resource on preclinical drug evaluation for potential mitochondrial toxicity, addressing the issue upfront in the drug development process. It discusses mitochondrial impairment to organs, skeletal muscle, and nervous systems and details methodologies used to assess mitochondria function. It covers both in vitro and in vivo methods for analysis and includes the latest models. This is the authoritative reference on drug-induced mitochondrial dysfunction for safety assessment professionals in the pharmaceutical industry and for pharmacologists and toxicologists in both drug and environmental health sciences.

Development of Novel Prediction Model for Drug induced Mitochondrial Toxicity by Using Na ve Bayes Classifier Method

Author:
Publisher:
ISBN:
Format: PDF, Mobi
Download Now
Abstract: Mitochondrial dysfunction has been considered as an important contributing factor in the etiology of drug-induced organ toxicity, and even plays an important role in the pathogenesis of some diseases. The objective of this investigation was to develop a novel prediction model of drug-induced mitochondrial toxicity by using a naïve Bayes classifier. For comparison, the recursive partitioning classifier prediction model was also constructed. Among these methods, the prediction performance of naïve Bayes classifier established here showed best, which yielded average overall prediction accuracies for the internal 5-fold cross validation of the training set and external test set were 95±0.6% and 81±1.1%, respectively. In addition, four important molecular descriptors and some representative substructures of toxicants produced by ECFP_6 fingerprints were identified. We hope the established naïve Bayes prediction model can be employed for the mitochondrial toxicity assessment, and these obtained important information of mitochondrial toxicants can provide guidance for medicinal chemists working in drug discovery and lead optimization. Highlights: A novel prediction model of mitochondrial toxicity was developed by using a naïve Bayes classifier. Four molecular descriptors considered as important for mitochondrial toxicity were identified. Substructures of mitochondrial toxicants were obtained.

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

Author: Yvonne Will
Publisher: John Wiley & Sons
ISBN: 1119329744
Format: PDF, Mobi
Download Now
Developed as a one-stop reference source for drug safety and toxicology professionals, this book explains why mitochondrial failure is a crucial step in drug toxicity and how it can be avoided. • Covers both basic science and applied technology / methods • Allows readers to understand the basis of mitochondrial function, the preclinical assessments used, and what they reveal about drug effects • Contains both in vitro and in vivo methods for analysis, including practical screening approaches for drug discovery and development • Adds coverage about mitochondrial toxicity underlying organ injury, clinical reports on drug classes, and discussion of environmental toxicants affecting mitochondria

Mitochondrial Biology and Experimental Therapeutics

Author: Paulo J. Oliveira
Publisher: Springer
ISBN: 3319733443
Format: PDF
Download Now
This book addresses the therapeutic strategies to target mitochondrial metabolism in diseases where the function of that organelle is compromised, and it discusses the effective strategies used to create mitochondrial-targeted agents that can become commercially available drug delivery platforms. The consistent growth of research focused in understanding the multifaceted role of mitochondria in cellular metabolism, controlling pathways related with cell death, and ionic/redox regulation has extended the research of mitochondrial chemical-biological interactions to include various pharmacological and toxicological applications. Not only does the book extensively cover basic mitochondrial physiology, but it also links the molecular interactions within these pathways to a variety of diseases. It is one of the first books to combine state-of-the-art reviews regarding basic mitochondrial biology, the role of mitochondrial alterations in different diseases, and the importance of that organelle as a target for pharmacological and non-pharmacological interventions to improve human health. The different chapters highlight the chemical-biological linkages of the mitochondria in context with drug development and clinical applications.

Hepatitis New Insights for the Healthcare Professional 2011 Edition

Author:
Publisher: ScholarlyEditions
ISBN: 1464900930
Format: PDF, Kindle
Download Now
Hepatitis: New Insights for the Healthcare Professional: 2011 Edition is a ScholarlyEditions™ eBook that delivers timely, authoritative, and comprehensive information about Hepatitis. The editors have built Hepatitis: New Insights for the Healthcare Professional: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Hepatitis in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Hepatitis: New Insights for the Healthcare Professional: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.

A Combined in Vitro Approach to Improve the Prediction of Mitochondrial Toxicants

Author:
Publisher:
ISBN:
Format: PDF
Download Now
Abstract: Drug induced mitochondrial dysfunction has been implicated in organ toxicity and the withdrawal of drugs or black box warnings limiting their use. The development of highly specific and sensitive in vitro assays in early drug development would assist in detecting compounds which affect mitochondrial function. Here we report the combination of two in vitro assays for the detection of drug induced mitochondrial toxicity. The first assay measures cytotoxicity after 24 h incubation of test compound in either glucose or galactose conditioned media (Glu/Gal assay). Compounds with a greater than 3-fold toxicity in galactose media compared to glucose media imply mitochondrial toxicity. The second assay measures mitochondrial respiration, glycolysis and a reserve capacity with mechanistic responses observed within one hour following exposure to test compound. In order to assess these assays a total of 72 known drugs and chemicals were used. Dose–response data was normalised to 100 × Cmax giving a specificity, sensitivity and accuracy of 100%, 81% and 92% respectively for this combined approach. Highlights: Assessment of two in vitro assays to detect mitochondrial toxicity in HepG2 cells. Measurement of mitochondrial respiration, glycolysis and reserve capacity by XF e 96. Potential mechanism of mitochondrial toxicity can be predicted using the extracellular flux assay. Combining Glu/Gal and extracellular flux assays improves predictivity of mitochondrial toxicants.

Adverse Drug Reactions

Author: Jack Uetrecht
Publisher: Springer Science & Business Media
ISBN: 9783642006630
Format: PDF
Download Now
This book provides the current state of knowledge of basic mechanisms of adverse drug reactions (ADRs). The main focus is on idiosyncratic drug reactions because they are the most difficult to deal with. It starts with a general description of the major targets for ADRs followed by a description of what are presently believed to be mediators and biochemical pathways involved in idiosyncratic drug reactions. There is also a description of several examples of ADRs that serve to illustrate specific aspects of ADR mechanisms. Eventually the book shows that ultimately better methods are needed to predict which drug candidates are likely to cause ADRs and which patients are at increased risk. But at present research seems to be far from this goal.

HAART Drugs Induce Oxidative Stress and Mitochondrial Dysfunction in Blood brain Barrier

Author: Kalyan Chakravarthy Reddy Manda
Publisher:
ISBN:
Format: PDF, Mobi
Download Now
"The era of highly active antiretroviral therapy (HAART) has controlled AIDS and its related disorders considerably; however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) has been on the rise in the post-HAART era. In view of these developments, we investigated whether a HAART drug combination of 3'-Azido-2', 3'-deoxythymidine (AZT) and Indinavir (IDV) can alter the functionality of the blood-brain barrier (BBB) endothelial cells, thereby exacerbating the condition. Viability of hCMEC/D3 cells (in vitro model of BBB) that were exposed to the drugs was significantly reduced after a 72 hr treatment, in a dose-dependent manner. Reactive oxygen species (ROS) were highly elevated after the exposure, indicating that mechanisms that induce oxidative stress were involved. Measures of oxidative stress such as glutathione (GSH) and malondialdehyde (MDA) were found to be altered in the treated groups. Loss of mitochondrial membrane potential ([delta][psi][subscript m]) assessed with fluorescent microscopy and decreased levels of ATP indicated that cytoxicity was mediated through mitochondrial dysfunction. Furthermore, AZT + IDV treatment caused apoptosis in endothelial cells as assessed by the expression of cytochrome c and procaspase-3 proteins. In vivo experiments with HIV-1 transgenic animal treated with AZT+ IDV showed decrease in GSH in the BBB and brain and increase in MDA levels in the BBB. Thiol antioxidant N-acetylcysteine amide (NACA) reversed some of the pro-oxidant effects of AZT+IDV in both invitro and invivo studies. Results from our studies indicate that the AZT + IDV combination can affect the BBB and may play a role in contributing to neurocognitive disorders in HIV-1 infected individuals treated with HAART drugs"--Abstract, leaf iii.

Die Bulletproof Di t

Author: Dave Asprey
Publisher: Riva Verlag
ISBN: 3864139694
Format: PDF, Kindle
Download Now
Mit Mitte 20 war Dave Asprey ein erfolgreicher Unternehmer im Silicon Valley und Multimillionär. Doch er wog auch 140 Kilo, und das obwohl er der Empfehlung seiner Ärzte folgte, an sechs Tagen pro Woche nur 1800 Kalorien zu essen und 90 Minuten zu trainieren. Als sein Übergewicht ihm zunehmend die Sinne zu vernebeln begann und Heißhungerattacken ihm Energie und Willenskraft raubten, fing Asprey an, die Technologien, mit denen er reich geworden war, selbst zu nutzen, um seine eigene Biologie zu »hacken«. Er investierte 15 Jahre und 300?000 Dollar in alle erdenklichen Testverfahren und Selbstversuche, vom EEG bis zu einem Aufenthalt in einem tibetischen Kloster, um herauszufinden, wie er seinem Körper und Geist ein maximales Upgrade verschaffen konnte. Bulletproof – auf Deutsch »kugelsicher« oder »unverwundbar« – nennt er den Status, in dem man konstante Höchstleistung bringen kann, ohne auszubrennen oder krank zu werden. Asprey gelang es, seinen IQ um mehr als 20 Punkte zu erhöhen, sein biologisches Alter zu senken und ohne Kalorienzählen oder Sport 50 Kilo abzunehmen. Seine vielfältigen Erkenntnisse versammelt er in diesem Buch. Die Bulletproof-Diät hemmt entzündliche Prozesse im Körper, sorgt für schnellen, hungerfreien Gewichtsverlust und höchste Leistungsfähigkeit. Anstelle eines Frühstücks gibt es den berühmten Bulletproof-Kaffee mit Kokosöl und Butter, der lange sättigt und einen dauerhaften Energieschub verschafft. Kalorienzählen ist nicht nötig und auch bei weniger Schlaf und weniger Sport wird das überschüssige Fett nur so dahinschmelzen.

Mitochondrial Disorders

Author: Claude Desnuelle
Publisher: Springer Science & Business Media
ISBN: 2817809297
Format: PDF, ePub
Download Now
The concept of mitochondrial diseases originated in 1962 with the description by Luft and coworkers of a patient with nonthyroidal hypermetabolism due to loose coupling of oxidation and phosphorylation in muscle mitochondria. Over the following quarter of a century, thanks to W. King Engel's "ragged-red fibres" as convenient markers for mitochondrial pathology, numerous papers described clinical, morphological, and biochemical features of "mitochondrial myopathies." In 1988 the discovery of mutations in mitochondrial DNA led to an explosive expansion of research into mitochondrial disorders. Throughout the 1990s the rapid identification of multiple mitochondrial gene defects associated with clinically diverse disorders has left practitioners puzzled about diagnosing such heterogeneous and complex syndromes. Through updated data, this book discusses now what Luft aptly called "mitochondrial medicine." In so doing, it considers the pivotal role of mitochondria in drug sensitivity, their key roles in ageing, apoptosis, and neurodegeneration along with primary mitochondrial diseases due to mutations in the nuclear genome, in the mitochondrial genome, or in the cross-talk between the two genomes.