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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 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 -
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 -
Current Opinion in Microbiology Aug 2023Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials... (Review)
Review
Antimicrobial susceptibility testing is the cornerstone of antibiotic treatments. Yet, active drugs are frequently unsuccessful in vivo and most clinical trials investigating antibiotics fail. So far, bacterial survival strategies, other than drug resistance, have been largely ignored. As such, drug tolerance and persisters, allowing bacterial populations to survive during antibiotic treatments, could fill a gap in antibiotic susceptibility testing. Therefore, it remains critical to establish robust and scalable bacterial viability measures and to define the clinical relevance of bacterial survivors across various bacterial infections. If successful, these tools could improve drug design and development to prevent tolerance formation or target bacterial survivors, to ultimately reduce treatment failures and curb resistance evolution.
Topics: Humans; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Drug Resistance, Bacterial; Drug Tolerance
PubMed: 37245488
DOI: 10.1016/j.mib.2023.102328 -
Current Topics in Behavioral... 2018Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of... (Review)
Review
Discriminative stimulus and other drug effects are determined by the concentration of drug at its target receptor and by the pharmacodynamic consequences of drug-receptor interaction. For in vivo procedures such as drug discrimination, drug concentration at receptors in a given anatomical location (e.g., the brain) is determined both by the dose of drug administered and by pharmacokinetic processes of absorption, distribution, metabolism, and excretion that deliver drug to and from that anatomical location. Drug discrimination data are often analyzed by strategies of dose-effect analysis to determine parameters such as potency and efficacy. Pharmacokinetic-Pharmacodynamic (PKPD) analysis is an alternative to conventional dose-effect analysis, and it relates drug effects to a measure of drug concentration in a body compartment (e.g., venous blood) rather than to drug dose. PKPD analysis can yield insights on pharmacokinetic and pharmacodynamic determinants of drug action. PKPD analysis can also facilitate translational research by identifying species differences in pharmacokinetics and providing a basis for integrating these differences into interpretation of drug effects. Examples are discussed here to illustrate the application of PKPD analysis to the evaluation of drug effects in rhesus monkeys trained to discriminate cocaine from saline.
Topics: Animals; Discrimination, Psychological; Drug Tolerance; Humans; Prodrugs; Psychotropic Drugs
PubMed: 27571746
DOI: 10.1007/7854_2016_36 -
Brain Research Jun 2020The neuropeptide oxytocin (OXT) plays a key role in adaptive processes associated with reward, tolerance, memory and stress responses. Through interactions with brain... (Review)
Review
The neuropeptide oxytocin (OXT) plays a key role in adaptive processes associated with reward, tolerance, memory and stress responses. Through interactions with brain reward and stress systems, OXT is known to play a role in several neuropsychiatric disorders, particularly those that involve altered social integration, such as alcohol and drug addiction (Heilig et al., 2016). As such, there is growing interest in the oxytocin system as a potential therapeutic target for the treatment of alcohol and substance use disorders. Accumulating preclinical evidence suggests that administration of OXT influences the development of tolerance, sensitization and withdrawal symptoms, and modulates numerous alcohol/drug-seeking and alcohol/drug-taking behaviors. Further, there is some evidence to suggest that OXT may help to reverse neuroadaptations that occur as a result of chronic alcohol or drug exposure. To date, there have been only a handful of clinical studies conducted in alcohol and drug dependent populations. This review summarizes the preclinical and clinical literature on the effects of OXT administration on alcohol- and drug-related behaviors. In addition, we discuss OXT interactions with the hypothalamic-pituitaryadrenal axis and multiple neurotransmitter systems within addiction circuitry.
Topics: Alcoholism; Animals; Behavior, Addictive; Drug Tolerance; Drug-Seeking Behavior; Humans; Oxytocin; Recurrence; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 32142721
DOI: 10.1016/j.brainres.2020.146761 -
PLoS Pathogens Oct 2020
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Tolerance; Evolution, Molecular; Humans
PubMed: 33057409
DOI: 10.1371/journal.ppat.1008892 -
Journal of Psychopharmacology (Oxford,... Aug 2016Antipsychotic sensitization and tolerance refer to the increased and decreased drug effects due to past drug use, respectively. Both effects reflect the long-term... (Review)
Review
Antipsychotic sensitization and tolerance refer to the increased and decreased drug effects due to past drug use, respectively. Both effects reflect the long-term impacts of antipsychotic treatment on the brain and result from the brain's adaptive response to the foreign property of the drug. In this review, clinical evidence of the behavioral aspect of antipsychotic sensitization and tolerance is selectively reviewed, followed by an overview of preclinical literature that examines these behavioral characteristics and the related pharmacological and nonpharmacological factors. Next, recent work on the developmental impacts of adolescent antipsychotic sensitization and tolerance is presented and recent research that delineates the neurobiological mechanisms of antipsychotic sensitization and tolerance is summarized. A theoretical framework based on "drug learning and memory" principles is proposed to account for the phenomena of antipsychotic sensitization and tolerance. It is maintained that antipsychotic sensitization and tolerance follow basic principles of learning or acquisition ("induction") and memory ("expression"). The induction and expression of both effects reflect the consequences of associative and nonassociative processing and are strongly influenced by various pharmacological, environmental, and behavioral factors. Drug-induced neuroplasticity, such as functional changes of striatal dopamine D2 and prefrontal serotonin (5-HT)2A receptors and their mediated signaling pathways, in principle, is responsible for antipsychotic sensitization and tolerance. Understanding the behavioral characteristics and neurobiological underpinnings of antipsychotic sensitization and tolerance has greatly enhanced our understanding of mechanisms of antipsychotic action, and may have important implications for future drug discovery and clinical practice.
Topics: Adolescent; Animals; Antipsychotic Agents; Brain; Drug Tolerance; Humans; Neuronal Plasticity; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D2; Signal Transduction
PubMed: 27371498
DOI: 10.1177/0269881116654697