Chemicals and Drugs Commons^™

Structural And Thermodynamic Basis Of Amprenavir/Darunavir And Atazanavir Resistance In Hiv-1 Protease With Mutations At Residue 50, Seema Mittal, Rajintha Bandaranayake, Nancy King, Moses Prabu-Jeyabalan, Madhavi Nalam, Ellen Nalivaika, Nese Yilmaz, Celia Schiffer

Celia A. Schiffer

Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I50V/L substitutions emerge in patients, compromising drug susceptibility and leading to treatment failure. The I50V substitution is often associated with amprenavir (APV) and darunavir (DRV) resistance, while the I50L substitution is observed in patients failing atazanavir (ATV) therapy. To explain how APV, …

Potentially Inappropriate Use Of Antipsychotics In Community-Dwelling Adults With Dementia More Common In Those With Low Income, Jennifer Tjia

Jennifer Tjia

Comment on: The essential and potentially inappropriate use of antipsychotics across income groups: an analysis of linked administrative data. [Can J Psychiatry. 2012]

Compliance With The Centers For Disease Control And Prevention Recommendations For The Diagnosis And Treatment Of Sexually Transmitted Diseases, Bryan Kane, Linda Degutis, Helen Sayward, Gail D'Onofrio

Bryan G Kane MD

No abstract provided.

Structure And Dynamics Of A Primordial Catalytic Fold Generated By In Vitro Evolution, Fa-An Chao, Aleardo Morelli, John C. Haugner Iii, Lewis Churchfield, Lei Shi, Larry R. Masterson, Ritimukta Sarangi, Gianluigi Veglia, Burckhard Seelig

Larry Masterson

Pharmacological Modulation Of Cgmp Levels By Phosphodiesterase 5 Inhibitors As A Therapeutic Strategy For Treatment Of Respiratory Pathology In Cystic Fibrosis., Hongwei Yu, Jens Poschet, Graham Timmons, Jennifer Taylor-Cousar, Wojciech Ornatowski, Joseph Fazio, Elizabeth Perkett, Kari Wilson, Hugo De Jonge, Vojo Deretic

Hongwei Yu

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na(+) channel in cystic fibrosis (CF) respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though reduced nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5 corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial …

Effects Of A Selective Cannabinoid Cb2 Agonist And Antagonist On Intravenous Nicotine Self Administration And Reinstatement Of Nicotine Seeking, Islam Gamaleddin, Alexander Zvonok, Alexandros Makriyannis, Steven Goldberg, Bernard Le Foll

Alexander Zvonok

Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to …

Conformational Equilibrium Of N-Myristoylated Camp-Dependent Protein Kinase A By Molecular Dynamics Simulations, Alessandro Cembran, Larry R. Masterson, Christopher L. Mcclendon, Susan S. Taylor, Jiali Gao, Gianluigi Veglia

Larry Masterson

Does Inorganic Mercury Play A Role In Alzheimer's Disease? A Systematic Review And An Integrated Molecular Mechanism, Joachim Mutter, Annika Curth, Johannes Naumann, Richard Deth, Harald Walach

Richard Deth

Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer’s disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a predefined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two …

Cost-Effectiveness Of Lowering Blood Pressure With A Fixed Combination Of Perindopril And Indapamide In Type 2 Diabetes Mellitus: An Advance Trial-Based Analysis, Paul Glasziou, Philip Clarke, Jan Alexander, Mohana Rajmokan, Elaine Beller, Mark Woodward, John Chalmers, Neil Poulter, Anushka Patel

Elaine Beller

Objective: To determine the cost-effectiveness of routine administration, irrespective of blood pressure (BP), of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus.

Design, setting and participants: Prospective cost-effectiveness analysis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, an international, multicentre, randomised controlled trial of 11 140 participants with type 2 diabetes randomly allocated to receive perindopril plus indapamide (4mg-1.25mg/day) or placebo.

Main outcome measures: Health-related quality-of-life measured by the EuroQol-5D, resource utilisation, and cost-effectiveness (cost per death averted at 4.3 years' average follow-up, and …

A Survey Of Drug-Dose Calculation Skills Of Australian Tertiary Hospital Doctors, Chanelle Simpson, Gerben Keijzers, James Lind

Gerben Keijzers

Objective: To assess the ability of doctors to calculate drug doses and their workplace prescribing and calculation habits. Design and setting: Prospective, questionnaire-based observational study conducted at a 570-bed teaching hospital in February 2007. Participants: Convenience sample of 190 doctors, representing all acute medical and surgical disciplines and diverse levels of experience. Main outcome measures: Demographic data, self-reported prescribing habits, predicted score on a 12-item test of ability to calculate drug doses, score considered adequate for peers, and actual score. Results: 141 doctors (74%) completed the questionnaire. The mean actual score on the test was 72.5% (95% CI, 67.8%–77.3%), which …

Structural And Dynamic Basis Of Phospholamban And Sarcolipin Inhibition Of Ca2+-Atpase, Nathaniel J. Traaseth, Kim N. Ha, Raffaello Verardi, Lei Shi, Jarrod J. Buffy, Larry R. Masterson, Gianluigi Veglia

Larry Masterson

Transition-State Variation In Human, Bovine, And Plasmodium Falciparum Adenosine Deaminases, Minkui Lou, Vipender Singh, Erika Taylor, Vern Schramm

Erika A. Taylor, Ph.D.

Adenosine deaminases (ADAs) from human, bovine, and Plasmodium falciparum sources were analyzed by kinetic isotope effects (KIEs) and shown to have distinct but related transition states. Human adenosine deaminase (HsADA) is present in most mammalian cells and is involved in B- and T-cell development. The ADA from Plasmodium falciparum (PfADA) is essential in this purine auxotroph, and its inhibition is expected to have therapeutic effects for malaria. Therefore, ADA is of continuing interest for inhibitor design. Stable structural mimics of ADA transition states are powerful inhibitors. Here we report the transition-state structures of PfADA, HsADA, and bovine ADA (BtADA) solved …

Acyclic Ribooxacarbenium Ion Mimics As Transition State Analogues Of Human And Malarial Purine Nucleoside Phosphorylases, Erika Taylor, Keith Clinch, Peter Kelly, Lei Li, Gary Evans, Peter Tyler, Vern Schramm

Erika A. Taylor, Ph.D.

Transition state analogues of PNP, the Immucillins and DADMe-Immucillins, were designed to match transition state features of bovine and human PNPs, respectively. A third generation of inhibitors has been designed that contain an acyclic iminoalcohol to replace the cyclic mimic of the ribooxacarbenium ion at the transition states of PNPs. The best third generation inhibitor is equivalent to the best inhibitors found in the previous transition state analogues.

Synthesis Of 5‘-Methylthio Coformycins:  Specific Inhibitors For Malarial Adenosine Deaminase, Peter Tyler, Erika Taylor, Richard Froehlich, Vern Schramm

Erika A. Taylor, Ph.D.

Transition state theory suggests that enzymatic rate acceleration (kcat/knon) is related to the stabilization of the transition state for a given reaction. Chemically stable analogues of a transition state complex are predicted to convert catalytic energy into binding energy. Because transition state stabilization is a function of catalytic efficiency, differences in substrate specificity can be exploited in the design of tight-binding transition state analogue inhibitors. Coformycin and 2‘-deoxycoformycin are natural product transition state analogue inhibitors of adenosine deaminases (ADAs). These compounds mimic the tetrahedral geometry of the ADA transition state and bind with picomolar dissociation constants to enzymes from bovine, …

Neighboring Group Participation In The Transition State Of Human Purine Nucleoside Phosphorylase, Andrew Murkin, Matthew Birck, Agnes Rinaldo-Matthis, Wuxian Shi, Erika Taylor, Steven Almo, Vern Schramm

Erika A. Taylor, Ph.D.

No abstract provided.