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CNS Drugs Oct 2019Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with... (Review)
Review
Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.
Topics: Analgesics, Opioid; Chronic Pain; Drug Tolerance; Humans; Hyperalgesia
PubMed: 31578704
DOI: 10.1007/s40263-019-00660-0 -
Nature Reviews. Microbiology Jun 2020Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial... (Review)
Review
Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial proportion of patients do not respond to therapy despite being infected with fungi that are susceptible to the drug. The discordance between overall treatment outcome and low levels of clinical resistance may be attributable to antifungal drug tolerance. In this Review, we define and distinguish resistance and tolerance and discuss the current understanding of the molecular, genetic and physiological mechanisms that contribute to those phenomena. Distinguishing tolerance from resistance might provide important insights into the reasons for treatment failure in some settings.
Topics: Antifungal Agents; Candida; Drug Resistance, Fungal; Drug Tolerance; Humans; Microbial Sensitivity Tests
PubMed: 32047294
DOI: 10.1038/s41579-019-0322-2 -
Cell Host & Microbe Jul 2019Biofilms are surface-associated bacterial communities that play both beneficial and harmful roles in nature, medicine, and industry. Tolerant and persister cells are... (Review)
Review
Biofilms are surface-associated bacterial communities that play both beneficial and harmful roles in nature, medicine, and industry. Tolerant and persister cells are thought to underlie biofilm-related bacterial recurrence in medical and industrial contexts. Here, we review recent progress aimed at understanding the mechanical features that drive biofilm resilience and the biofilm formation process at single-cell resolution. We discuss findings regarding mechanisms underlying bacterial tolerance and persistence in biofilms and how these phenotypes are linked to antibiotic resistance. New strategies for combatting tolerance and persistence in biofilms and possible methods for biofilm eradication are highlighted to inspire future development.
Topics: Anti-Bacterial Agents; Bacteria; Biofilms; Drug Resistance, Bacterial; Drug Tolerance; Microbial Viability
PubMed: 31295420
DOI: 10.1016/j.chom.2019.06.002 -
Nature Reviews. Microbiology Jul 2019Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic... (Review)
Review
Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
Topics: Anti-Bacterial Agents; Bacteria; Biomedical Research; Drug Tolerance; Guidelines as Topic; Terminology as Topic
PubMed: 30980069
DOI: 10.1038/s41579-019-0196-3 -
The Journal of Clinical Investigation Oct 2022Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer...
Although first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is effective for treating EGFR-mutant non-small cell lung cancer (NSCLC), it is now understood that drug-tolerant persister (DTP) cells escaping from initial treatment eventually drives drug resistance. Here, through integration of metabolomics and transcriptomics, we found that the neurotransmitter acetylcholine (ACh) was specifically accumulated in DTP cells, and demonstrated that treatment with EGFR-TKI heightened the expression of the rate-limiting enzyme choline acetyltransferase (ChAT) in ACh biosynthesis via YAP mediation. Genetic and pharmacological manipulation of ACh biosynthesis or ACh signaling could predictably regulate the extent of DTP formation in vitro and in vivo. Strikingly, pharmacologically targeting ACh/M3R signaling with an FDA-approved drug, darifenacin, retarded tumor relapse in vivo. Mechanistically, upregulated ACh metabolism mediated drug tolerance in part through activating WNT signaling via ACh muscarinic receptor 3 (M3R). Importantly, we showed that aberrant ACh metabolism in patients with NSCLC played a potential role in predicting EGFR-TKI response rate and progression-free survival. Our study therefore defines a therapeutic strategy - targeting the ACh/M3R/WNT axis - for manipulating EGFR TKI drug tolerance in the treatment of NSCLC.
Topics: Acetylcholine; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Choline O-Acetyltransferase; Drug Resistance, Neoplasm; Drug Tolerance; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors
PubMed: 36048538
DOI: 10.1172/JCI160152 -
The Journal of Clinical Psychiatry Sep 2021reatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic... (Review)
Review
reatment-resistant schizophrenia (TRS) represents a major clinical challenge. The broad definition of TRS requires nonresponse to at least 2 sequential antipsychotic trials of sufficient dose, duration, and adherence. Several demographic, clinical, and neurologic predictors are associated with TRS. Primary (or early) TRS is present from the beginning of therapy, while patients with secondary (or later-onset) TRS initially respond to antipsychotics but become resistant over time, often after relapses. Guidelines worldwide recognize clozapine as the most effective treatment option for TRS, but clozapine is underused due to various barriers. Importantly, studies indicate that response rates are higher when clozapine is initiated earlier in the treatment course. Side effects are common with clozapine, particularly in the first few weeks, but can mostly be managed without discontinuation; they do require proactive assessment, intervention, and reassurance for patients. Furthermore, plasma leucocyte and granulocyte levels must be monitored weekly during the first 18-26 weeks of treatment, and regularly thereafter, according to country regulations. Therapeutic drug monitoring of clozapine trough plasma levels is helpful to guide dosing, with greatest efficacy at plasma clozapine levels ≥350 µg/L, although this level is not universal. Notably, plasma clozapine levels are generally greater at lower doses in nonsmokers, patients with heavy caffeine consumption, in women, in obese people, in those with inflammation (including COVID-19 infection), and in older individuals. Earlier and broader use of clozapine in patients with TRS is an important measure to improve outcomes of patients with this most severe form of the illness.
Topics: Antipsychotic Agents; Clozapine; Drug Resistance; Drug Tolerance; Female; Humans; Male; Schizophrenia
PubMed: 34496461
DOI: 10.4088/JCP.MY20096AH1C -
Nature Communications Mar 2021Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor...
Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cholesterol; Drug Combinations; Drug Discovery; Drug Resistance, Neoplasm; Drug Tolerance; Epithelial-Mesenchymal Transition; ErbB Receptors; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mutation; Neoplasms; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; U937 Cells
PubMed: 33712615
DOI: 10.1038/s41467-021-21884-z -
Journal of Palliative Medicine May 2023The objective of this systematic review is to consolidate the existing evidence on opioid use, including administration, dosing, and efficacy, for the relief of dyspnea... (Review)
Review
The objective of this systematic review is to consolidate the existing evidence on opioid use, including administration, dosing, and efficacy, for the relief of dyspnea at end of life. The overarching goal is to optimize clinical management of dyspnea by identifying patterns in opioid use, improving opioid management of dyspnea, and to prioritize future research. Opioids are commonly used in the management of dyspnea at end of life, yet specific administration guidelines are limited. A greater understanding of the effectiveness of opioids in relieving end-of-life dyspnea with consideration of study design, patients, and opioids, including dyspnea evaluation tools and outcomes, will leverage development of standardized administration and dosing. A PRISMA-guided systematic review using six databases identified quality studies of opioid management for patients with dyspnea at end of life. Twenty-three references met review inclusion criteria, which included terminally ill cancer and noncancer patients with various diagnoses. Studies included two randomized controlled trials, and three nonrandomized experimental, three prospective observational, one cross-sectional, and one case series. Thirteen retrospective chart reviews were also included due to the limited rigorous studies rendered by the search. Thirteen studies evaluated morphine, followed by fentanyl (6), oxycodone (5), general opioid use (4), and hydromorphone (2). Routes of administration were parenteral, oral, combination, and nebulization. Dyspnea was evaluated using self-reporting and non-self-reporting evaluation tools. Sedation was the most reported opioid-related adverse effect. Challenges persist in conducting end-of-life research, preventing consensus on standardization of opioid treatment for dyspnea within this specific palliative time frame. Future robust prospective trials using specific, accurate assessment with reassessment of dyspnea/respiratory distress, and consideration of opioid tolerance, polypharmacy, and comorbidities are required.
Topics: Humans; Analgesics, Opioid; Prospective Studies; Retrospective Studies; Cross-Sectional Studies; Drug Tolerance; Morphine; Dyspnea; Death; Observational Studies as Topic
PubMed: 36453988
DOI: 10.1089/jpm.2022.0311 -
Science Advances Feb 2023Opioid tolerance develops as a learned response to drug-associated cues and is thus a dynamic effect modulated by the interaction between drug and environment. (Review)
Review
Opioid tolerance develops as a learned response to drug-associated cues and is thus a dynamic effect modulated by the interaction between drug and environment.
Topics: Analgesics, Opioid; Conditioning, Classical; Drug Tolerance; Learning; Cues
PubMed: 36753539
DOI: 10.1126/sciadv.adg6086 -
Neuron Nov 2023Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility...
Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.
Topics: Rats; Animals; Humans; Analgesics, Opioid; Chronic Pain; Acetylcholine; Rats, Sprague-Dawley; Pain Measurement; Drug Tolerance; Periaqueductal Gray; Cholinergic Agents; Receptors, Nicotinic
PubMed: 37734381
DOI: 10.1016/j.neuron.2023.08.017