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Drug tolerant persister

William James Deardorff, George T Grossberg
Currently available therapies for the treatment of Alzheimer's disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce...
2016: Drug Design, Development and Therapy
Nazanin Ebrahimiadib, Bobeck S Modjtahedi, Samaneh Davoudi, C Stephen Foster
PURPOSE: To evaluate the efficacy of chlorambucil in the treatment of serpiginous choroiditis. METHODS: Patient records from the Massachusetts Eye Research and Surgery Institution (MERSI) were reviewed from over the past 10 years. In total, 17 patients with the diagnosis of serpiginous choroiditis treated with chlorambucil were identified. QuantiFERON gold was negative in all of them. Chlorambucil was started at 0.15 mg/kg and dosage was titrated up using weekly white blood cell (WBC) count to achieve a target cell number of 3...
October 18, 2016: Ocular Immunology and Inflammation
Cristina Velázquez-Marrero, Alexandra Burgos, José O García, Stephanie Palacio, Héctor G Marrero, Alexandra Bernardo, Juliana Pérez-Laspiur, Marla Rivera-Oliver, Garrett Seale, Steven N Treistman
: It has been suggested that drug tolerance represents a form of learning and memory, but this has not been experimentally established at the molecular level. We show that a component of alcohol molecular tolerance (channel internalization) from rat hippocampal neurons requires protein synthesis, in common with other forms of learning and memory. We identify β-catenin as a primary necessary protein. Alcohol increases β-catenin, and blocking accumulation of β-catenin blocks alcohol-induced internalization in these neurons...
October 12, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Daniele Muser, Pasquale Santangeli, Simon A Castro, Rajeev K Pathak, Jackson J Liang, Tatsuya Hayashi, Silvia Magnani, Fermin C Garcia, Mathew D Hutchinson, Gregory G Supple, David S Frankel, Michael P Riley, David Lin, Robert D Schaller, Sanjay Dixit, Erica S Zado, David J Callans, Francis E Marchlinski
BACKGROUND: Catheter ablation (CA) of ventricular tachycardia (VT) in patients with nonischemic dilated cardiomyopathy can be challenging because of the complexity of underlying substrates. We sought to determine the long-term outcomes of endocardial and adjuvant epicardial CA in nonischemic dilated cardiomyopathy. METHODS AND RESULTS: We examined 282 consecutive patients (aged 59±15 years, 80% males) with nonischemic dilated cardiomyopathy who underwent CA. Ablation was guided by activation/entrainment mapping for tolerated VT and pacemapping/targeting of abnormal electrograms for unmappable VT...
October 2016: Circulation. Arrhythmia and Electrophysiology
Pietro Enea Lazzerini, Pier Leopoldo Capecchi, Giacomo Maria Guidelli, Enrico Selvi, Maurizio Acampa, Franco Laghi-Pasini
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease primarily affecting synovial joints and is characterized by persistent high-grade systemic inflammation. Proinflammatory cytokines, particularly interleukin-6 (IL-6), are of crucial importance in the pathogenesis of the disease, driving both joint inflammation and extra-articular comorbidities. Tocilizumab, a humanized IL-6 receptor-inhibiting monoclonal antibody, has been the first, and, to date, the only, IL-6 inhibitor approved for the treatment of RA...
2016: Drug Design, Development and Therapy
Theresa Mallick-Searle, Brett Snodgrass, Jeannine M Brant
Herpes zoster, also known as shingles, is a distinctive clinical condition caused by the reactivation of latent varicella zoster (chickenpox) virus following an initial infection. Approximately 1 million cases of herpes zoster occur annually in the US, and one in every three people develops herpes zoster during their lifetime. Postherpetic neuralgia is a neuropathic pain syndrome characterized by pain that persists for months to years after resolution of the herpes zoster rash. It stems from damage to peripheral and central neurons that may be a byproduct of the immune/inflammatory response accompanying varicella zoster virus reactivation...
2016: Journal of Multidisciplinary Healthcare
Vittorio Magri, Emanuele Montanari, Emanuela Marras, Gianpaolo Perletti
Although fluoroquinolones are first-line agents for the treatment of National Institutes of Health (NIH) category II chronic bacterial prostatitis (CBP), therapy with these agents is not always feasible due to the increasing worldwide resistance of causative uropathogens. New therapeutic options are urgently required, as drugs such as β-lactam antibiotics distribute poorly to prostatic sites of infection and trimethoprim therapy is often unfeasible due to high resistance rates. The present study aimed to analyze the efficacy of aminoglycosides, administered to a cohort of 78 patients affected by fluoroquinolone-resistant CBP, or excluded from fluoroquinolone therapy due to various contraindications...
October 2016: Experimental and Therapeutic Medicine
Stefania Castello, Genesis D'Aloisio, Carlos Arias, Juan Carlos Molina
Drugs of abuse, as cocaine or amphetamine, induce locomotor sensitization during infancy and adulthood of the rat. This effect during the preweanling period is observed only after a short interval of time between training and testing. We recently reported short-term locomotor sensitization induced by ethanol in pups chronically exposed to the drug during the second postnatal week of life. The present series of experiments was designed to explore the persistence of the sensitization effect across the preweanling period...
September 30, 2016: Pharmacology, Biochemistry, and Behavior
Valerie W C Soo, Brian W Kwan, Héctor Quezada, Israel Castillo-Juárez, Berenice Pérez-Eretza, Silvia Julieta García-Contreras, Mariano Martínez-Vázquez, Thomas K Wood, Rodolfo García-Contreras
Despite the fact that bacterial infections are one of the leading causes of death worldwide and that mortality rates are increasing at alarming rates, no new antibiotics have been produced by the pharmaceutical industry in more than a decade. The situation is so dire that the World Health Organization warned that we may enter a "post-antibiotic era" within this century; accordingly, bacteria resistant against all known antibiotics are becoming common and already producing untreatable infections. Although several novel approaches to combat bacterial infections have been proposed, they have yet to be implemented in clinical practice...
September 30, 2016: Current Topics in Medicinal Chemistry
Guangming Ren, Min Zhou, Ning Ding, Ning Zhou, Qingling Li
The aim of the present study was to examine the clinical distribution and drug resistance of Acinetobacter baumannii infection, and provide evidence of clinical medication as well as the prophylaxis for the treatment of drug resistance bacteria. In total, 306 Acinetobacter baumanniis selected from routine culture were collected between January 2012 and December 2013, to analyze the distributions among clinical specimens and wards and their drug resistance state. Of the 306 Acinetobacter baumanniis, the main distribution of specimens was sputum, accounting for 77...
September 2016: Experimental and Therapeutic Medicine
Kum Ja Lee, Vivian Chow, Ashley Weissman, Sunil Tulpule, Ibrahim Aldoss, Mojtaba Akhtari
Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated...
2016: Therapeutics and Clinical Risk Management
J Vockley, J Charrow, J Ganesh, M Eswara, G A Diaz, E McCracken, R Conway, G M Enns, J Starr, R Wang, J E Abdenur, J Sanchez-de-Toledo, D L Marsden
Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols...
August 27, 2016: Molecular Genetics and Metabolism
Paulo Jardim, Isadora Cristina da Silva Santos, João Alexandre Ribeiro Gonçalves Barbosa, Sônia Maria de Freitas, Napoleão Fonseca Valadares
Persisters are individual bacterial cells that exhibit a phenotype characterized by slow growth, low metabolic rate and multidrug tolerance. The processes that drive cells into a persistence state constitute an active but incipient research field, and structural data regarding its components are scarce. The molecular targets of many therapeutic drugs are involved in cell wall synthesis and cell division, and these cellular processes are down-regulated in persister cells, consequently these cells are more likely to survive antibiotic treatment...
September 23, 2016: Biochemical and Biophysical Research Communications
Jeroen de Keijzer, Arnout Mulder, Arnoud H de Ru, Dick van Soolingen, Peter A van Veelen
: The spread of multidrug resistant Mycobacterium tuberculosis is one of the major challenges in tuberculosis control. In Eurasia, the spread of multidrug resistant tuberculosis is driven by the M. tuberculosis Beijing genotype. In this study, we examined whether selective advantages are present in the proteome of Beijing isolates that contribute to the emergence of this genotype. To this end, we compared the proteome of M. tuberculosis Beijing to that of M. tuberculosis H37Rv, both in the presence and absence of the first-line antibiotic rifampicin...
August 26, 2016: Journal of Proteomics
Bram Van den Bergh, Joran E Michiels, Tom Wenseleers, Etthel M Windels, Pieterjan Vanden Boer, Donaat Kestemont, Luc De Meester, Kevin J Verstrepen, Natalie Verstraeten, Maarten Fauvart, Jan Michiels
The evolution of antibiotic resistance is a major threat to society and has been predicted to lead to 10 million casualties annually by 2050(1). Further aggravating the problem, multidrug tolerance in bacteria not only relies on the build-up of resistance mutations, but also on some cells epigenetically switching to a non-growing antibiotic-tolerant 'persister' state(2-6). Yet, despite its importance, we know little of how persistence evolves in the face of antibiotic treatment(7). Our evolution experiments in Escherichia coli demonstrate that extremely high levels of multidrug tolerance (20-100%) are achieved by single point mutations in one of several genes and readily emerge under conditions approximating clinical, once-daily dosing schemes...
2016: Nature Microbiology
Kamran Hosseini, Richard L Lindstrom, Gary Foulks, Kelly K Nichols
PURPOSE: To evaluate the clinical efficacy and safety of a 1% azithromycin-0.1% dexamethasone combination in DuraSite ("combination") compared to 0.1% dexamethasone in DuraSite, 1% azithromycin in DuraSite, and vehicle in the treatment of subjects with blepharitis. MATERIALS AND METHODS: This was a Phase III, double-masked, vehicle-controlled, four-arm study in which 907 subjects with blepharitis were randomized to combination (n=305), 0.1% dexamethasone (n=298), 1% azithromycin (n=155), or vehicle (n=149)...
2016: Clinical Ophthalmology
M Moreno Gonzales, L Myhre, T Taner
BACKGROUND: Oral tacrolimus (Tac) is currently the pillar of maintenance immunosuppression after solid organ transplantation. Recent studies proposed sublingual (SL) administration as an alternative; however, data regarding its use in adult liver transplant (LT) recipients are limited. METHODS: Three LT recipients were included. Two (patients 1 and 2) were transitioned from oral to SL Tac owing to persistently erratic serum concentrations and 1 (patient 3) because of severe oral intolerance...
July 2016: Transplantation Proceedings
Caroline K Kramer, Bernard Zinman, Haysook Choi, Ravi Retnakaran
OBJECTIVE: In early type 2 diabetes (T2DM), short-term intensive insulin therapy (IIT) for 2-4 weeks can decrease insulin resistance, reduce glucagonemia, improve β-cell function, and even induce a remission of diabetes that can last up to 1 year in some patients. However, little is known about the predictors of such a sustained remission. METHODS: We evaluated data from the placebo arm of a double-blind randomized controlled trial in which patients with early T2DM (≤7 years duration) underwent 4 weeks of IIT (basal detemir, bolus aspart), followed by placebo therapy for 48 weeks (n=25)...
2016: BMJ Open Diabetes Research & Care
Yu-Min Chuang, Noton K Dutta, Chien-Fu Hung, T-C Wu, Harvey Rubin, Petros C Karakousis
Mycobacterium tuberculosis (Mtb) remains a global health threat largely due to the lengthy duration of curative antibiotic treatment, contributing to medical nonadherence and the emergence of drug resistance. This prolonged therapy is likely due to the presence of Mtb persisters, which exhibit antibiotic tolerance. Inorganic polyphosphate (poly(P)) is a key regulatory molecule in the Mtb stringent response mediating antibiotic tolerance. The polyphosphate kinase PPK1 is responsible for poly(P) synthesis in Mtb, while the exopolyphosphatases PPX1 and PPX2, and the GTP synthase PPK2 are responsible for poly(P) hydrolysis...
August 15, 2016: Antimicrobial Agents and Chemotherapy
Dawn Shao Ting Lim, Maria Fleseriu
PURPOSE: Uncontrolled acromegaly results in approximately 2-fold excess mortality. Pituitary surgery is first-line therapy, and medical treatment is indicated for persistent disease. While cabergoline and pegvisomant are used in select patients, somatostatin receptor ligands (SRLs) remain the cornerstone of medical treatment. Management of patients poorly responsive to SRLs is therefore, challenging. The purpose of this review is to highlight the options for combination medical therapy in the treatment of acromegaly, with an emphasis on efficacy and safety...
August 13, 2016: Pituitary
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