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Drug tolerant persister

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https://www.readbyqxmd.com/read/28445002/glucose-metabolism-targeting-therapy-and-withaferin-a-are-effective-for-egfr-tki-induced-drug-tolerant-persisters
#1
Kei Kunimasa, Tatsuya Nagano, Yohei Shimono, Ryota Dokuni, Tatsunori Kiriu, Shuntaro Tokunaga, Daisuke Tamura, Masatsugu Yamamoto, Motoko Tachihara, Kazuyuki Kobayashi, Miyako Satouchi, Yoshihiro Nishimura
In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of EGFR-TKI induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 month...
April 26, 2017: Cancer Science
https://www.readbyqxmd.com/read/28435338/recommendations-for-optimizing-methotrexate-treatment-for-patients-with-rheumatoid-arthritis
#2
REVIEW
Alfonso E Bello, Elizabeth L Perkins, Randy Jay, Petros Efthimiou
Methotrexate (MTX) remains the cornerstone therapy for patients with rheumatoid arthritis (RA), with well-established safety and efficacy profiles and support in international guidelines. Clinical and radiologic results indicate benefits of MTX monotherapy and combination with other agents, yet patients may not receive optimal dosing, duration, or route of administration to maximize their response to this drug. This review highlights best practices for MTX use in RA patients. First, to improve the response to oral MTX, a high initial dose should be administered followed by rapid titration...
2017: Open Access Rheumatology: Research and Reviews
https://www.readbyqxmd.com/read/28431060/catheter-ablation-vs-antiarrhythmic-drug-therapy-in-patients-with-symptomatic-atrioventricular-nodal-re-entrant-tachycardia-a-randomized-controlled-trial
#3
Demosthenes G Katritsis, Theodoros Zografos, George D Katritsis, Eleftherios Giazitzoglou, Vasilios Vachliotis, George Paxinos, A John Camm, Mark E Josephson
Aims: To conduct a randomized trial in order to guide the optimum therapy of symptomatic atrioventricular nodal re-entrant tachycardia (AVNRT). Methods and Results: Patients with at least one symptomatic episode of tachycardia per month and an electrophysiologic diagnosis of AVNRT were randomly assigned to catheter ablation or chronic antiarrhythmic drug (AAD) therapy with bisoprolol (5 mg od) and/or diltiazem (120-300 mg od). All patients were properly educated to treat subsequent tachycardia episodes with autonomic manoeuvres or a 'pill in the pocket' approach...
April 1, 2017: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
https://www.readbyqxmd.com/read/28405132/antianginal-efficacy-and-tolerability-of-ranolazine-as-an-add-on-drug-to-concomitant-medications-primarily-metoprolol-in-chronic-stable-angina-patients-a-prospective-open-label-study
#4
Anant Mahaveer Khot, H V Anuradha, V S Prakash, M C Shivamurathy
OBJECTIVE: To evaluate the efficacy and tolerability of ranolazine as an add-on drug in chronic stable angina patients and the impact of ranolazine on the quality of life in chronic stable angina patients receiving other antianginal medications. MATERIALS AND METHODS: It was a prospective, open-label, hospital-based study involving 144 patients with chronic stable angina. First group received either metoprolol 12.5 or 25 mg/day or other antianginal medications; if the symptoms persist, the dose of metoprolol was increased to 50 mg/day, and to the second group, ranolazine 500 mg BD or 1 g OD was added along with metoprolol or others if the anginal attacks were not subsiding...
January 2017: Journal of Pharmacology & Pharmacotherapeutics
https://www.readbyqxmd.com/read/28396391/enhanced-respiration-prevents-drug-tolerance-and-drug-resistance-in-mycobacterium-tuberculosis
#5
Catherine Vilchèze, Travis Hartman, Brian Weinrick, Paras Jain, Torin R Weisbrod, Lawrence W Leung, Joel S Freundlich, William R Jacobs
Persistence, manifested as drug tolerance, represents a significant obstacle to global tuberculosis control. The bactericidal drugs isoniazid and rifampicin kill greater than 99% of exponentially growing Mycobacterium tuberculosis (Mtb) cells, but the remaining cells are persisters, cells with decreased metabolic rate, refractory to killing by these drugs, and able to generate drug-resistant mutants. We discovered that the combination of cysteine or other small thiols with either isoniazid or rifampicin prevents the formation of drug-tolerant and drug-resistant cells in Mtb cultures...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28363336/active-efflux-in-dormant-bacterial-cells-new-insights-into-antibiotic-persistence
#6
Yingying Pu, Yuehua Ke, Fan Bai
Bacterial persisters are phenotypic variants of an isogenic cell population that can survive antibiotic treatment and resume growth after the antibiotics have been removed. Cell dormancy has long been considered the principle mechanism underlying persister formation. However, dormancy alone is insufficient to explain the full range of bacterial persistence. Our recent work revealed that in addition to 'passive defense' via dormancy, persister cells employ 'active defense' via enhanced efflux activity to expel drugs...
January 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/28361736/dna-replication-in-mycobacterium-tuberculosis
#7
Zanele Ditse, Meindert H Lamers, Digby F Warner
Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as Mycobacterium tuberculosis that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable M...
March 2017: Microbiology Spectrum
https://www.readbyqxmd.com/read/28349350/visual-snow-a-potential-cortical-hyperexcitability-syndrome
#8
REVIEW
Alaa Bou Ghannam, Victoria S Pelak
The purpose of this review is to provide an overview of visual snow (VS) and provide information regarding current treatment options for VS. Visual snow (VS) is a rare disorder manifesting with a persistent visual phenomenon of seeing numerous tiny snow-like dots throughout the visual field, and it can cause debilitating visual and psychological consequences. It is emerging as a disorder separate from, but associated with, migraine visual aura, and neuronal cortical hyperexcitability is being considered as a theoretical mechanism for the persistent-positive visual symptoms...
March 2017: Current Treatment Options in Neurology
https://www.readbyqxmd.com/read/28292795/primary-care-management-of-opioid-use-disorders-abstinence-methadone-or-buprenorphine-naloxone
#9
REVIEW
Anita Srivastava, Meldon Kahan, Maya Nader
OBJECTIVE: To advise physicians on which treatment options to recommend for specific patient populations: abstinence-based treatment, buprenorphine-naloxone maintenance, or methadone maintenance. SOURCES OF INFORMATION: PubMed was searched and literature was reviewed on the effectiveness, safety, and side effect profiles of abstinence-based treatment, buprenorphine-naloxone treatment, and methadone treatment. Both observational and interventional studies were included...
March 2017: Canadian Family Physician Médecin de Famille Canadien
https://www.readbyqxmd.com/read/28291085/respiratory-effects-of-the-nociceptin-orphanin-fq-peptide-and-opioid-receptor-agonist-cebranopadol-in-healthy-human-volunteers
#10
Albert Dahan, Merel Boom, Elise Sarton, Justin Hay, Geert Jan Groeneveld, Meike Neukirchen, John Bothmer, Leon Aarts, Erik Olofsen
BACKGROUND: Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify cebranopadol's respiratory effects. METHODS: Twelve healthy male volunteers received 600 μg oral cebranopadol as a single dose...
April 2017: Anesthesiology
https://www.readbyqxmd.com/read/28282553/challenges-in-the-treatment-of-convulsive-status-epilepticus
#11
REVIEW
Gaetano Zaccara, Gianfranco Giannasi, Roberto Oggioni, Eleonora Rosati, Luciana Tramacere, Pasquale Palumbo
Convulsive status epilepticus (CSE) is a medical emergency associated with high mortality and morbidity. The most recent definition of CSE is a convulsive seizure lasting more than 5min or consecutive seizures without recovery of consciousness. In adults, for the treatment of the early stages of CSE, diazepam, lorazepam or midazolam are the most common treatments, although the choice of agent seems less important than rapid treatment. Midazolam, when administered intramuscularly (best evidence), buccally, or nasally, is effective and safe in the pre-hospital setting...
April 2017: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/28280004/connexin-purinergic-signaling-in-enteric-glia-mediates-the-prolonged-effect-of-morphine-on-constipation
#12
Sukhada Bhave, Aravind Gade, Minho Kang, Kurt F Hauser, William L Dewey, Hamid I Akbarali
Morphine is one of the most widely used drugs for the treatment of pain. However, side effects, including persistent constipation and antinociceptive tolerance limit its clinical efficacy. Prolonged morphine treatment results in a "leaky" gut predisposing to colonic inflammation that is facilitated by microbial dysbiosis and associated bacterial translocation. In this study, we examined the role of enteric glia in mediating this secondary inflammatory response to prolonged treatment with morphine. We found that purinergic P2X receptor activity was significantly enhanced in enteric glia that were isolated from mice with long-term morphine treatment (in vivo) but not upon direct exposure of glia to morphine (in vitro)...
March 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28271419/pre-eclampsia-the-potential-of-gsno-reductase-inhibitors
#13
REVIEW
Thomas R Everett, Ian B Wilkinson, Christoph C Lees
PURPOSE OF REVIEW: Pre-eclampsia remains a leading worldwide cause of maternal death and of perinatal morbidity. There remains no definitive treatment except delivery of the fetus. RECENT FINDINGS: Recent insights into the cardiovascular changes that are evident prior to, during, and persist after pre-eclampsia have improved understanding of the underlying pathophysiology-disruption of normal endothelial function and decreased nitric oxide bioavailability. S-nitrosoglutathione (GSNO) is an endogenous S-nitrosothiol that acts as a NO pool and, by replenishing or preventing the breakdown of GSNO, endothelial dysfunction can be ameliorated...
March 2017: Current Hypertension Reports
https://www.readbyqxmd.com/read/28261197/mycobacterial-dormancy-systems-and-host-responses-in-tuberculosis
#14
REVIEW
Vidyullatha Peddireddy, Sankara Narayana Doddam, Niyaz Ahmed
Tuberculosis (TB) caused by the intracellular pathogen, Mycobacterium tuberculosis (Mtb), claims more than 1.5 million lives worldwide annually. Despite promulgation of multipronged strategies to prevent and control TB, there is no significant downfall occurring in the number of new cases, and adding to this is the relapse of the disease due to the emergence of antibiotic resistance and the ability of Mtb to remain dormant after primary infection. The pathology of Mtb is complex and largely attributed to immune-evading strategies that this pathogen adopts to establish primary infection, its persistence in the host, and reactivation of pathogenicity under favorable conditions...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28238966/managing-lafora-body-disease-with-vagal-nerve-stimulation
#15
Mohamad A Mikati, Faysal Tabbara
A 17-year-old female, of consanguineous parents, presented with a history of seizures and cognitive decline since the age of 12 years. She had absence, focal dyscognitive, generalized myoclonic, and generalized tonic-clonic seizures, all of which were drug resistant. The diagnosis of Lafora body disease was made based on a compatible clinical, EEG, seizure semiology picture and a disease-causing homozygous mutation in the EPM2A gene. A vagus nerve stimulator (VNS) was inserted and well tolerated with a steady decrease and then stabilization in seizure frequency during the six months following insertion (months 1-6)...
February 22, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28221264/efficacy-and-safety-of-combined-oral-chelation-with-deferiprone-and-deferasirox-in-children-with-%C3%AE-thalassemia-major-an-experience-from-north-india
#16
Nupur Parakh, Jagdish Chandra, Sunita Sharma, Bhavna Dhingra, Rajesh Jain, DeoNath Mahto
OBJECTIVE: A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with β-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. METHODS: A prospective study was conducted in patients with transfusion-dependent β-thalassemia major in a tertiary care center over 2 years...
April 2017: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/28220940/pharmacologic-conversion-during-dofetilide-treatment-for-persistent-atrial-fibrillation
#17
Jonathan S Steinberg, Yash Shah, Barbara Szepietowska
BACKGROUND: Dofetilide is a pure IKr blocker and is one of the few drugs specifically studied and approved in the United States for the management of persistent AF. Dofetilide has been noted to have a high rate of pharmacologic conversion during initial dosing in prior smaller studies. The intent of the study was to examine the safety of an inpatient loading strategy, and the incidence and patterns of pharmacologic conversion by dofetilide during the treatment of persistent AF in a large consecutive cohort...
February 21, 2017: Pacing and Clinical Electrophysiology: PACE
https://www.readbyqxmd.com/read/28212183/cxcl12-cxcr4-signaling-contributes-to-the-pathogenesis-of-opioid-tolerance-a-translational-study
#18
Chih-Peng Lin, Kai-Hsiang Kang, Huang-Ju Tu, Ming-Yueh Wu, Tzu-Hung Lin, Houng-Chi Liou, Wei-Zen Sun, Wen-Mei Fu
BACKGROUND: Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance. METHODS: The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects...
March 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/28203228/encapsulation-of-antifungals-in-micelles-protects-candida-albicans-during-gall-bladder-infection
#19
Shih-Hung Hsieh, Sascha Brunke, Matthias Brock
Candida albicans is a dimorphic fungus that colonizes human mucosal surfaces with the potential to cause life-threatening invasive candidiasis. Studies on systemic candidiasis in a murine infection model using in vivo real-time bioluminescence imaging revealed persistence of C. albicans in the gall bladder under antifungal therapy. Preliminary analyses showed that bile conferred resistance against a wide variety of antifungals enabling survival in this cryptic host niche. Here, bile and its components were studied for their ability to reduce antifungal efficacy in order to elucidate the underlying mechanism of protection...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28174313/atp-dependent-persister-formation-in-escherichia-coli
#20
Yue Shan, Autumn Brown Gandt, Sarah E Rowe, Julia P Deisinger, Brian P Conlon, Kim Lewis
Persisters are dormant variants that form a subpopulation of cells tolerant to antibiotics. Persisters are largely responsible for the recalcitrance of chronic infections to therapy. In Escherichia coli, one widely accepted model of persister formation holds that stochastic accumulation of ppGpp causes activation of the Lon protease that degrades antitoxins; active toxins then inhibit translation, resulting in dormant, drug-tolerant persisters. We found that various stresses induce toxin-antitoxin (TA) expression but that induction of TAs does not necessarily increase persisters...
February 7, 2017: MBio
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