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Journal of Biomedical Science Oct 2023mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely... (Review)
Review
mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating the immune system. With regard to mRNA vaccines, researchers have modified the mRNA structure to enhance its stability and promote systemic tolerance of antigenic presentation in non-inflammatory contexts. Still, delivery of naked modified mRNAs is inefficient and results in low levels of antigen protein production. As such, lipid nanoparticles have been utilized to improve delivery and protect the mRNA cargo from extracellular degradation. This advance was a major milestone in the development of mRNA vaccines and dispelled skepticism about the potential of this technology to yield clinically approved medicines. Following the resounding success of mRNA vaccines for COVID-19, many other mRNA-based drugs have been proposed for the treatment of a variety of diseases. This review begins with a discussion of mRNA modifications and delivery vehicles, as well as the factors that influence administration routes. Then, we summarize the potential applications of mRNA-based drugs and discuss further key points pertaining to preclinical and clinical development of mRNA drugs targeting a wide range of diseases. Finally, we discuss the latest market trends and future applications of mRNA-based drugs.
Topics: Humans; COVID-19; COVID-19 Vaccines; Drug Tolerance; RNA, Messenger; mRNA Vaccines; Nanoparticles
PubMed: 37805495
DOI: 10.1186/s12929-023-00977-5 -
Cells Jun 2021Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with... (Review)
Review
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with -activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of -mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for -mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.
Topics: Animals; Drug Tolerance; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Signal Transduction
PubMed: 34202566
DOI: 10.3390/cells10071590 -
Experimental and Clinical... Dec 2018Acute tolerance to effects of nicotine plays an important role in nicotine dependence, but the mechanism underlying these effects is unclear. Drug discrimination was...
Acute tolerance to effects of nicotine plays an important role in nicotine dependence, but the mechanism underlying these effects is unclear. Drug discrimination was used in the current study to examine the impact of nicotine pretreatment on sensitivity to the discriminative stimulus effects of nicotine and the FDA-approved smoking cessation pharmacotherapy varenicline. Rhesus monkeys ( = 4) discriminated 0.032 mg/kg nicotine base iv from saline under an FR5 schedule of stimulus-shock termination. Both nicotine and varenicline increased drug-appropriate responding; ED50 values (95% confidence limits) were 0.0087 [0.0025, 0.030] and 0.028 [0.0096, 0.082] mg/kg, respectively. Additional pretreatment injections of the training dose of nicotine (0.032 mg/kg, iv) produced tolerance to its discriminative stimulus effects and the magnitude of this effect was related to the number of pretreatment injections administered. Two pretreatment injections of the training dose of nicotine (0.032 mg/kg, iv) produced a 5.4-fold rightward shift in the nicotine dose-response function and a sevenfold rightward shift in the varenicline dose-response function. The duration of tolerance under these conditions was less than 60 min. These results demonstrate that tolerance to the discriminative stimulus effects of nicotine can be produced by acute nicotine exposure. Acute cross-tolerance from nicotine to varenicline is consistent with similar actions at nAChRs, and suggests that conditions resulting in acute nicotine tolerance could impact sensitivity to other nAChR agonists. (PsycINFO Database Record (c) 2018 APA, all rights reserved).
Topics: Animals; Discrimination Learning; Dose-Response Relationship, Drug; Drug Tolerance; Female; Macaca mulatta; Male; Nicotine; Nicotinic Agonists; Smoking Cessation; Tobacco Use Disorder; Varenicline
PubMed: 30102063
DOI: 10.1037/pha0000226 -
Current Neuropharmacology 2019Despite its various side effects, morphine has been widely used in clinics for decades due to its powerful analgesic effect. Morphine tolerance is one of the major side... (Review)
Review
BACKGROUND
Despite its various side effects, morphine has been widely used in clinics for decades due to its powerful analgesic effect. Morphine tolerance is one of the major side effects, hindering its long-term usage for pain therapy. Currently, the thorough cellular and molecular mechanisms underlying morphine tolerance remain largely uncertain.
METHODS
We searched the PubMed database with Medical subject headings (MeSH) including 'morphine tolerance', 'cytokines', 'interleukin 1', 'interleukin 1 beta', 'interleukin 6', 'tumor necrosis factor alpha', 'interleukin 10', 'chemokines'. Manual searching was carried out by reviewing the reference lists of relevant studies obtained from the primary search. The searches covered the period from inception to November 1, 2017.
RESULTS
The expression levels of certain chemokines and pro-inflammatory cytokines were significantly increased in animal models of morphine tolerance. Cytokines and cytokine receptor antagonist showed potent effect of alleviating the development of morphine tolerance.
CONCLUSION
Cytokines play a fundamental role in the development of morphine tolerance. Therapeutics targeting cytokines may become alternative strategies for the management of morphine tolerance.
Topics: Analgesics, Opioid; Animals; Cytokines; Drug Tolerance; Humans; Models, Animal; Morphine
PubMed: 29189168
DOI: 10.2174/1570159X15666171128144441 -
Frontiers in Cellular and Infection... 2022Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are... (Review)
Review
Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Drug Therapy, Combination; Leprostatic Agents; Tuberculosis; Drug Tolerance
PubMed: 36733851
DOI: 10.3389/fcimb.2022.1085946 -
Experimental and Clinical... Aug 2020Increasing sensitivity due to alcohol intake has been explored using molecular and cellular mechanisms of sensitization and adaptive biobehavioral changes as well as... (Review)
Review
Increasing sensitivity due to alcohol intake has been explored using molecular and cellular mechanisms of sensitization and adaptive biobehavioral changes as well as through negative experiences of altered function during withdrawal. However, within both a preclinical and human laboratory setting, little has been elucidated toward understanding the neural substrates of decreased sensitivity to alcohol effects, that is, alcohol tolerance. More paradigms assessing alcohol tolerance are needed. Tolerance can be assessed through both self-reported response (subjective) and observed (objective) measurements. Therefore, sensitivity to alcohol is an exploitable variable that can be utilized to disentangle the diverse alcohol use disorder (AUD) phenotypical profile. This literature review focuses on preclinical models and human laboratory studies to evaluate alcohol tolerance and its modulating factors. Increased understanding of alcohol tolerance has the potential to reduce gaps between preclinical models and human laboratory studies to better evaluate the development of alcohol-related biobehavioral responses. Furthermore, alcohol tolerance can be used as an AUD phenotypic variable in randomized clinical trials designed for developing AUD therapies. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Topics: Alcohol Drinking; Alcoholism; Drug Tolerance; Ethanol; Humans; Research Design
PubMed: 32212746
DOI: 10.1037/pha0000366 -
Behavioural Pharmacology Apr 2020Although the gut and brain are separate organs, they communicate with each other via trillions of intestinal bacteria that collectively make up one's gut microbiome.... (Review)
Review
Although the gut and brain are separate organs, they communicate with each other via trillions of intestinal bacteria that collectively make up one's gut microbiome. Findings from both humans and animals support a critical role of gut microbes in regulating brain function, mood, and behavior. Gut bacteria influence neural circuits that are notably affected in addiction-related behaviors. These include circuits involved in stress, reward, and motivation, with substance use influencing gut microbial abnormalities, suggesting significant gut-brain interactions in drug addiction. Given the overwhelming rates of opioid overdose deaths driven by abuse and addiction, it is essential to characterize mechanisms mediating the abuse potential of opioids. We discuss in this review the role of gut microbiota in factors that influence opioid addiction, including incentive salience, reward, tolerance, withdrawal, stress, and compromised executive function. We present clinical and preclinical evidence supporting a bidirectional relationship between gut microbiota and opioid-related behaviors by highlighting the effects of opioid use on gut bacteria, and the effects of gut bacteria on behavioral responses to opioids. Further, we discuss possible mechanisms of this gut-brain communication influencing opioid use. By clarifying the relationship between the gut microbiome and opioid-related behaviors, we improve understanding on mechanisms mediating reward-, motivation-, and stress-related behaviors and disorders, which may contribute to the development of effective, targeted therapeutic interventions in opioid dependence and addiction.
Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Brain; Drug Tolerance; Gastrointestinal Microbiome; Humans; Motivation; Opioid-Related Disorders; Reward
PubMed: 31895059
DOI: 10.1097/FBP.0000000000000538 -
The Journal of Biological Chemistry Jun 2016Microbial biofilms demonstrate a decreased susceptibility to antimicrobial agents. Various mechanisms have been proposed to be involved in this recalcitrance. We focus... (Review)
Review
Microbial biofilms demonstrate a decreased susceptibility to antimicrobial agents. Various mechanisms have been proposed to be involved in this recalcitrance. We focus on two of these factors. Firstly, the ability of sessile cells to actively mediate efflux of antimicrobial compounds has a profound impact on resistance and tolerance, and several studies point to the existence of biofilm-specific efflux systems. Secondly, biofilm-specific stress responses have a marked influence on cellular physiology, and contribute to the occurrence of persister cells. We provide an overview of the data that demonstrate that both processes are important for survival following exposure to antimicrobial agents.
Topics: Adaptation, Physiological; Anti-Infective Agents; Biofilms; Biological Transport; Drug Resistance, Bacterial; Drug Tolerance; Humans; Microbial Sensitivity Tests; Microbial Viability; Models, Biological
PubMed: 27129224
DOI: 10.1074/jbc.R115.707257 -
Journal of Zhejiang University....Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been... (Review)
Review
Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Topics: Humans; Calcitonin Gene-Related Peptide; Drug Tolerance; Hypoglycemic Agents; Microglia; MicroRNAs; Minocycline; Morphine; Neuralgia; Plant Extracts; Signal Transduction
PubMed: 32133798
DOI: 10.1631/jzus.B1900425 -
Anesthesiology Feb 2016
Review
Topics: Analgesics, Opioid; Drug Tolerance; Humans; Hyperalgesia
PubMed: 26594912
DOI: 10.1097/ALN.0000000000000963