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Peptides Nov 2023This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles... (Review)
Review
This paper is the forty-fifth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2022 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug abuse and alcohol (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Topics: Animals; Humans; Female; Pregnancy; Opioid Peptides; Analgesics, Opioid; Analgesia; Analgesics, Non-Narcotic; Drug Tolerance
PubMed: 37704079
DOI: 10.1016/j.peptides.2023.171095 -
Journal of Neuroscience Research Sep 2023As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore,... (Review)
Review
As we all know, opioids are the drugs of choice for treating severe pain. However, very often, opioid use leads to tolerance, dependence, and hyperalgesia. Therefore, understanding the mechanisms underlying opioid tolerance and designing strategies for increasing the efficacy of opioids in chronic pain are important areas of research. Microglia are brain macrophages that remove debris and dead cells from the brain and participate in immune defense of the central nervous system during an insult or injury. However, recent studies indicate that microglial activation and generation of proinflammatory molecules (e.g., cytokines, nitric oxide, eicosanoids, etc.) in the brain may contribute to opioid tolerance and other side effects of opioid use. In this review, we will summarize the evidence and possible mechanisms by which proinflammatory molecules produced by activated microglia may antagonize the analgesic effect induced by opioids, and thus, lead to opioid tolerance. We will also delineate specific examples of studies that suggest therapeutic targets to counteract the development of tolerance clinically using suppressors of microglial inflammation.
Topics: Humans; Analgesics, Opioid; Microglia; Morphine; Drug Tolerance; Hyperalgesia; Inflammation
PubMed: 37186407
DOI: 10.1002/jnr.25199 -
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 -
Nature Communications Apr 2022The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we...
The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.
Topics: Animals; Antitubercular Agents; Drug Tolerance; Isoniazid; Mice; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 35459278
DOI: 10.1038/s41467-022-29832-1 -
Nederlands Tijdschrift Voor Geneeskunde Oct 2023Patients with cancer often experience pain that significantly interferes with their daily life. In this review paper the authors discuss the different aspects of cancer... (Review)
Review
Patients with cancer often experience pain that significantly interferes with their daily life. In this review paper the authors discuss the different aspects of cancer pain by answering different questions regarding cancer pain. Items that are discussed include measurement of pain, medical and interventional pain treatment, side effects, opioid tolerance and addiction and barriers that preclude proper treatment of pain. The conclusion of this review paper is that the treatment of cancer pain is complex and warrants a multidisciplinary team effort with a central role for the patient.
Topics: Humans; Cancer Pain; Analgesics, Opioid; Drug Tolerance; Pain; Pain Management; Neoplasms; Chronic Pain
PubMed: 37994720
DOI: No ID Found -
Biological Psychiatry Jan 2020The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a... (Review)
Review
The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.
Topics: Analgesics; Analgesics, Opioid; Chronic Pain; Drug Tolerance; Humans; Opioid-Related Disorders; Pain
PubMed: 31399256
DOI: 10.1016/j.biopsych.2019.06.017 -
Advances in Cancer Research 2023The use of chemotherapeutic agents and the development of new cancer therapies over the past few decades has consequently led to the emergence of myriad therapeutic... (Review)
Review
The use of chemotherapeutic agents and the development of new cancer therapies over the past few decades has consequently led to the emergence of myriad therapeutic resistance mechanisms. Once thought to be explicitly driven by genetics, the coupling of reversible sensitivity and absence of pre-existing mutations in some tumors opened the way for discovery of drug-tolerant persisters (DTPs): slow-cycling subpopulations of tumor cells that exhibit reversible sensitivity to therapy. These cells confer multi-drug tolerance, to targeted and chemotherapies alike, until the residual disease can establish a stable, drug-resistant state. The DTP state can exploit a multitude of distinct, yet interlaced, mechanisms to survive otherwise lethal drug exposures. Here, we categorize these multi-faceted defense mechanisms into unique Hallmarks of Cancer Drug Tolerance. At the highest level, these are comprised of heterogeneity, signaling plasticity, differentiation, proliferation/metabolism, stress management, genomic integrity, crosstalk with the tumor microenvironment, immune escape, and epigenetic regulatory mechanisms. Of these, epigenetics was both one of the first proposed means of non-genetic resistance and one of the first discovered. As we describe in this review, epigenetic regulatory factors are involved in most facets of DTP biology, positioning this hallmark as an overarching mediator of drug tolerance and a potential avenue to novel therapies.
Topics: Humans; Epigenome; Drug Resistance, Neoplasm; Neoplasms; Antineoplastic Agents; Drug Tolerance; Tumor Microenvironment
PubMed: 36990531
DOI: 10.1016/bs.acr.2022.12.002 -
PLoS Pathogens Oct 2020
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Tolerance; Evolution, Molecular; Humans
PubMed: 33057409
DOI: 10.1371/journal.ppat.1008892 -
The AAPS Journal Jul 2023Evolving immunogenicity assay performance expectations and a lack of harmonized neutralizing antibody validation testing and reporting tools have resulted in significant...
Evolving immunogenicity assay performance expectations and a lack of harmonized neutralizing antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. A team of experts within the American Association of Pharmaceutical Scientists' Therapeutic Product Immunogenicity Community across industry and the Food and Drug Administration addressed challenges unique to cell-based and non-cell-based neutralizing antibody assays. Harmonization of validation expectations and data reporting will facilitate filings to health authorities and are described in this manuscript. This team provides validation testing and reporting strategies and tools for the following assessments: (1) format selection; (2) cut point; (3) assay acceptance criteria; (4) control precision; (5) sensitivity including positive control selection and performance tracking; (6) negative control selection; (7) selectivity/specificity including matrix interference, hemolysis, lipemia, bilirubin, concomitant medications, and structurally similar analytes; (8) drug tolerance; (9) target tolerance; (10) sample stability; and (11) assay robustness.
Topics: Antibodies, Neutralizing; Pharmaceutical Preparations; Drug Tolerance
PubMed: 37421491
DOI: 10.1208/s12248-023-00830-5 -
Drug Metabolism Reviews Aug 2022Uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) are an enzyme superfamily that catalyzes glycosyl residues transfer from activated nucleotide sugars to... (Review)
Review
Uridine diphosphate sugar-utilizing glycosyltransferases (UGTs) are an enzyme superfamily that catalyzes glycosyl residues transfer from activated nucleotide sugars to acceptor molecules. In addition to various endogenous compounds, numerous xenobiotics are substrates of UGTs. As the glycosides formed are generally less active/toxic and more hydrophilic than aglycones, UGTs effectively protect organisms from potentially harmful xenobiotics. Therefore, increased UGT expression and/or activity improve the protection of the organism and may contribute to the development of individuals that become more resistant to certain xenobiotics. While the function of UGTs in the resistance of human cancer cells to chemotherapy is now well known, other organisms and other xenobiotics have attracted much less attention. This review was designed to fill this knowledge gap by presenting complex information about the role of UGTs in xenobiotic-resistance in various organisms. This summarization and evaluation of the available information reveals that UGTs play an important role in defense against xenobiotics not only in humans, but in countless other organisms such as parasites, insects, and plants. Moreover, many recent studies clearly show the participation of UGTs in the resistance of nematodes to anthelmintics, insects to insecticides, weeds to herbicides as well as humans to various drugs (not only those used in cancer therapy but also in the treatment of epilepsy, psychiatric disorders, hypertension, hypercholesterolemia, and HIV infection). Nevertheless, although the contribution of UGTs to xenobiotic resistance in diverse organisms has become obvious, many pieces of information remain missing, for example with regard to the mechanisms of UGT regulation.
Topics: Animals; Drug Resistance; Drug Tolerance; Glycosyltransferases; Humans; Phylogeny; Uridine Diphosphate; Xenobiotics
PubMed: 35635097
DOI: 10.1080/03602532.2022.2083632