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Drug Resistance Updates : Reviews and... Nov 2015A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in... (Review)
Review
A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens based on the distribution of minimal inhibitory concentration (MIC), the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. Tolerance to antifungals has been a much more ignored area. By definition, tolerance operates at antifungal concentrations above individual intrinsic inhibitory values. Important is that tolerance to antifungal agents favours the emergence of persister cells, which are able to survive antifungal therapy and can cause relapses. Here we will review the current knowledge on antifungal tolerance, its potential mechanisms and also evaluate the role of antifungal tolerance in the efficacy of drug treatments.
Topics: Amphotericin B; Antifungal Agents; Dose-Response Relationship, Drug; Drug Resistance, Fungal; Drug Tolerance; Echinocandins; Flucytosine; Fungi; Host-Pathogen Interactions; Humans; Microbial Sensitivity Tests; Mycoses; Triazoles
PubMed: 26690338
DOI: 10.1016/j.drup.2015.10.001 -
Molecular Oncology Apr 2023Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy... (Review)
Review
Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases-first through adaptive development of nongenetic drug tolerance, which is followed by stable resistance through the acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug-tolerant tumors are highly associated with treatment relapse and poor survival. Thereby, novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities but including at least one compound that targets the mitochondria. These mitochondria-targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in the clinical translation of mitochondria-targeting triplet therapies are also discussed.
Topics: Humans; Drug Tolerance; Mitochondria; Neoplasms
PubMed: 36852624
DOI: 10.1002/1878-0261.13406 -
Bioanalysis Nov 2019Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An...
Neutralizing anti-drug antibody (NAb) assays are inherently prone to the interference from drug and its soluble target, potentially resulting in erroneous results. An effective approach to improve drug tolerance of an NAb assay is pretreatment of samples with acid to dissociate immune complexes of NAb and drug, followed by separating NAbs from circulating drug before testing them in the assay. The acid pretreatment conditions were optimized to improve drug tolerance of cell-based and non-cell-based NAb assays. NAbs were further separated from circulating drug either through direct drug removal or purification of NAb from the sample. In addition, an integrated experimental strategy was implemented to simultaneously improve drug and its soluble target tolerance for reliable NAb assessment. The approaches described herein would enable the development of reliable NAb assays that overcome drug and its target interference for more precise and sensitive NAb assessment.
Topics: Acetic Acid; Antibodies, Neutralizing; Drug Tolerance; Hydrogen-Ion Concentration
PubMed: 31829737
DOI: 10.4155/bio-2019-0184 -
Bioresource Technology Jun 2018Using lignocellulosic biomass for the production of renewable biofuel provides a sustainable and promising solution to the crisis of energy and environment. However, the... (Review)
Review
Using lignocellulosic biomass for the production of renewable biofuel provides a sustainable and promising solution to the crisis of energy and environment. However, the processes of biomass pretreatment and biofuel fermentation bring a variety of inhibitors to microbial strains. These inhibitors repress microbial growth, decrease biofuel yields and increase fermentation costs. The production of biofuels from renewable lignocellulosic biomass relies on the development of tolerant and robust microbial strains. In recent years, the advancement of tolerance engineering and evolutionary engineering provides powerful platform for obtaining host strains with desired tolerance for further metabolic engineering of biofuel pathways. In this review, we summarized the inhibitors derived from biomass pretreatment and biofuel fermentation, the mechanisms of inhibitor toxicity, and the strategies for enhancing microbial tolerance.
Topics: Biofuels; Biomass; Drug Tolerance; Fermentation; Metabolic Engineering
PubMed: 29567023
DOI: 10.1016/j.biortech.2018.03.064 -
PLoS Pathogens Nov 2022Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the...
Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the two phenomena is their distinct penetrance within an isogenic population. While with antibiotic persistence, susceptible and persister cells co-exist, antibiotic tolerance affects the entire bacterial population. Here, we show that antibiotic tolerance can be achieved in numerous non-specific ways in vitro and during infection. More importantly, we highlight that, due to their impact on the entire bacterial population, these tolerance-inducing conditions completely mask persistence and the action of its molecular determinants. Finally, we show that even though tolerant populations display a high survival rate under bactericidal drug treatment, this feature comes at the cost of having impaired proliferation during infection. In contrast, persistence is a risk-limiting strategy that allows bacteria to survive antibiotic treatment without reducing the ability of the population to colonize their host. Altogether, our data emphasise that the distinction between these phenomena is of utmost importance to improve the design of more efficient antibiotic therapies.
Topics: Anti-Bacterial Agents; Bacteria; Drug Tolerance
PubMed: 36374854
DOI: 10.1371/journal.ppat.1010963 -
Cardiology Clinics May 2018Statin intolerance is the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk. With the five-step approach, more than 90% of these... (Review)
Review
Statin intolerance is the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk. With the five-step approach, more than 90% of these patients might be treated with statins. The principal approaches are to try not to discontinue statin therapy and to treat these patients as effectively as possible. New therapies with the proprotein convertase subtilisin-kexin type 9 inhibitors and bempedoic acid might be an effective response to these needs. In case of lack of achieved goal of the therapy nutraceuticals with confirmed low-density lipoprotein cholesterol reduction properties may be considered as a part of the lipid-lowering combination therapy.
Topics: Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Tolerance; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk Factors
PubMed: 29609752
DOI: 10.1016/j.ccl.2017.12.004 -
Nature Communications Mar 2023Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and...
Candida glabrata is a major fungal pathogen notable for causing recalcitrant infections, rapid emergence of drug-resistant strains, and its ability to survive and proliferate within macrophages. Resembling bacterial persisters, a subset of genetically drug-susceptible C. glabrata cells can survive lethal exposure to the fungicidal echinocandin drugs. Herein, we show that macrophage internalization induces cidal drug tolerance in C. glabrata, expanding the persister reservoir from which echinocandin-resistant mutants emerge. We show that this drug tolerance is associated with non-proliferation and is triggered by macrophage-induced oxidative stress, and that deletion of genes involved in reactive oxygen species detoxification significantly increases the emergence of echinocandin-resistant mutants. Finally, we show that the fungicidal drug amphotericin B can kill intracellular C. glabrata echinocandin persisters, reducing emergence of resistance. Our study supports the hypothesis that intra-macrophage C. glabrata is a reservoir of recalcitrant/drug-resistant infections, and that drug alternating strategies can be developed to eliminate this reservoir.
Topics: Drug Tolerance; Antifungal Agents; Echinocandins; Candida glabrata; Macrophages; Drug Resistance
PubMed: 36864040
DOI: 10.1038/s41467-023-36882-6 -
Bulletin of Experimental Biology and... Sep 2021The development of morphine tolerance in C57BL/6j mice was estimated by the analgesic effect in tail-flick and hot plate tests. Morphine hydrochloride (10 mg/kg body...
The development of morphine tolerance in C57BL/6j mice was estimated by the analgesic effect in tail-flick and hot plate tests. Morphine hydrochloride (10 mg/kg body weight) was administered to animals twice for 5 days and once on the sixth day, saline or myelopeptides were injected 15 min before morphine administration (2 μg/kg body weight). In the tail-flick test, all studied myelopeptides suppressed the development of tolerance to morphine and did not show their own analgesic activity. In the hot plate test, only three myelopeptides (MP2, MP5, and MP6) were found to reduce the formation of morphine tolerance. MP1 significantly reduced the analgesic effect of morphine on days 1-3 of administration, but contributed to the preservation of the analgesic effect during the period of tolerance development.
Topics: Analgesics, Opioid; Animals; Drug Tolerance; Male; Mice; Mice, Inbred C57BL; Morphine; Nociception; Oligopeptides; Pain; Pain Measurement
PubMed: 34617173
DOI: 10.1007/s10517-021-05282-5 -
Zhonghua Yi Xue Za Zhi Sep 2021Benzodiazepines have been on the market for more than half a century and are widely used in clinical practice. Their use in many countries has been limited in recent...
Benzodiazepines have been on the market for more than half a century and are widely used in clinical practice. Their use in many countries has been limited in recent decades due to drug dependence and dose tolerance in some patients. Currently, benzodiazepines are still effective in treating many mental disorders, but some patients and doctors refuse to use them for fear of drug dependence and dementia caused by long-term use. The author suggests that benzodiazepines should be objectively evaluatedand rationally used.
Topics: Anti-Anxiety Agents; Benzodiazepines; Drug Tolerance; Fear; Humans; Substance-Related Disorders
PubMed: 34551489
DOI: 10.3760/cma.j.cn112137-20201218-03388 -
Mini Reviews in Medicinal Chemistry 2020Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there... (Review)
Review
Opioid receptor agonist drugs, such as morphine, are very effective for treating chronic and severe pain; but, tolerance can develop with long-term use. Although there is a lot of information about the pathophysiological mechanisms of opioid tolerance, it is still not fully clarified. Suggested mechanisms for opioid tolerance include opioid receptor desensitisation, reduction of sensitivity G-proteins, activation of Mitogen-Activated Protein Kinase (MAPK), altered intracellular signaling pathway including nitric oxide, and activation of mammalian Target of Rapamycin (mTOR). One way to reduce opioid tolerance and increase the analgesic potential is to use low doses. Combination of cannabinoids with opioids has been shown to manifest the reduction of the opioid dose. Experimental studies revealed an interaction of the endocannabinoid system and opioid antinociception. Cannabinoid and opioid receptor systems use common pathways in the formation of analgesic effect and demonstrate their activity via G Protein Coupled Receptors (GPCR). Cannabinoid drugs modulate opioid analgesic activity at a number of distinct levels within the cell, ranging from direct receptor associations to post-receptor interactions through shared signal transduction pathways. This review summarizes the data indicating that with combining cannabinoids and opioids drugs may be able to produce long-term analgesic effects, while preventing the opioid analgesic tolerance.
Topics: Analgesics, Opioid; Animals; Cannabinoids; Drug Tolerance; Humans
PubMed: 32167427
DOI: 10.2174/1389557520666200313120835