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Trends in Pharmacological Sciences May 2016In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss... (Review)
Review
In neuropsychiatric drug development, the rate of successful translation of preclinical to clinical efficacy has been disappointingly low. Tolerance, defined as a loss of efficacy with repeated drug exposure, is rarely addressed as a potential source of clinical failures. In this review, we argue that preclinical methods of tolerance development may have predictive validity and, therefore, inclusion of studies using repeated drug exposure early during the drug discovery and development process should serve to mitigate a proportion of clinical failures. Our analysis indicates that many published preclinical efficacy studies in the neuropsychiatry arena are conducted with acute drug administration only. Furthermore, specifically in the field of schizophrenia, there are several examples where tolerance development may be suspected as a factor contributing to translational failures. These and other examples highlight the need for built-for-purpose tolerance studies to be conducted, regardless of the target interaction mode of the drugs (i.e., agonist or antagonist, allosteric or orthosteric). We suggest that, for compounds that have failed in clinical studies, preclinical efficacy data sets need to be revisited to estimate the potential impact of tolerance development, one of the most significant known unknowns in the preclinical-to-clinical translation.
Topics: Animals; Drug Discovery; Drug Evaluation, Preclinical; Drug Tolerance; Humans; Neurosciences; Psychotropic Drugs; Translational Research, Biomedical
PubMed: 26935643
DOI: 10.1016/j.tips.2016.01.008 -
American Journal of Cardiovascular... Aug 2014Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually... (Review)
Review
Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually administered nitrates are well established. Nitroglycerin is indicated for the relief of an established attack of angina and for prophylactic use, but its effects are short lived. In an effort to increase the duration of beneficial effects, long-acting orally administered and topical applications of nitrates have been developed; however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy. By providing a nitrate-free interval, or declining nitrate levels at night, one can overcome or reduce the development of tolerance, but cannot provide 24-h anti-anginal and anti-ischemic protection. In addition, patients may be vulnerable to occurrence of rebound angina and myocardial ischemia during periods of absent nitrate levels at night and early hours of the morning, and worsening of exercise capacity prior to the morning dose of the medication. This has been a concern with nitroglycerin patches but not with oral formulations of isosorbide-5 mononitrates, and has not been adequately studied with isosorbide dinitrate. This paper describes problems associated with nitrate tolerance, reviews mechanisms by which nitrate tolerance and loss of efficacy develop, and presents strategies to avoid nitrate tolerance and maintain efficacy when using long-acting nitrate formulations.
Topics: Angina Pectoris; Delayed-Action Preparations; Drug Interactions; Drug Tolerance; Heart Failure; Humans; Myocardial Ischemia; Nitrates; Prevalence; Vasodilator Agents
PubMed: 24664980
DOI: 10.1007/s40256-014-0072-5 -
Microbiology Spectrum Oct 2014A major factor complicating efforts to control the tuberculosis epidemic is the long duration of treatment required to successfully clear the infection. One reason that... (Review)
Review
A major factor complicating efforts to control the tuberculosis epidemic is the long duration of treatment required to successfully clear the infection. One reason that long courses of treatment are required may be the fact that mycobacterial cells arise during the course of infection that are less susceptible to antibiotics. Here we describe the paradigms of phenotypic drug tolerance and resistance as they apply to mycobacteria. We then discuss the mechanisms by which phenotypically drug-tolerant and -resistant cells arise both at a population level and in specialized subpopulations of cells that may be especially important in allowing the bacterium to survive in the face of treatment. These include general mechanisms that have been shown to alter the susceptibility of mycobacteria to antibiotics including growth arrest, efflux pump induction, and biofilm formation. In addition, we discuss emerging data from single-cell studies of mycobacteria that have identified unique ways in which specialized subpopulations of cells arise that vary in their frequency, in their susceptibility to drug, and in their stability over time.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Drug Tolerance; Mycobacterium
PubMed: 26104360
DOI: 10.1128/microbiolspec.MGM2-0031-2013 -
Proteomics Apr 2022Antibiotic resistance, the ability of a microbial pathogen to evade the effects of antibiotics thereby allowing them to grow under elevated drug concentrations, is an... (Review)
Review
Antibiotic resistance, the ability of a microbial pathogen to evade the effects of antibiotics thereby allowing them to grow under elevated drug concentrations, is an alarming health problem worldwide and has attracted the attention of scientists for decades. On the other hand, the clinical importance of persistence and tolerance as alternative mechanisms for pathogens to survive prolonged lethal antibiotic doses has recently become increasingly appreciated. Persisters and high-tolerance populations are thought to cause the relapse of infectious diseases, and provide opportunities for the pathogens to evolve resistance during the course of antibiotic therapy. Although proteomics and other omics methodology have long been employed to study resistance, its applications in studying persistence and tolerance are still limited. However, due to the growing interest in the topic and recent progress in method developments to study them, there have been some proteomic studies that yield fresh insights into the phenomenon of persistence and tolerance. Combined with the studies on resistance, these collectively guide us to novel molecular targets for the potential drugs for the control of these dangerous pathogens. In this review, we surveyed previous proteomic studies to investigate resistance, persistence, and tolerance mechanisms, and discussed emerging experimental strategies for studying these phenotypes with a combination of adaptive laboratory evolution and high-throughput proteomics.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Drug Resistance, Microbial; Drug Tolerance; Proteomics
PubMed: 35143120
DOI: 10.1002/pmic.202100409 -
Molecular Cancer Research : MCR Jan 2022In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of... (Review)
Review
In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of patients due to early molecular adaptation in cancer cells. A growing body of evidence suggests that a subpopulation of drug-tolerant persister cells-a reversible phenotype characterized by reduced drug sensitivity and decreased cell proliferation-maintains residual disease and may serve as a reservoir for resistant phenotypes. The survival of these residual tumor cells can be caused by reactivation of specific signaling pathways, phenotypic plasticity (i.e., transdifferentiation), epigenetic or metabolic reprogramming, downregulation of apoptosis as well as transcriptional remodeling. In this review, we discuss the molecular mechanisms that enable adaptive survival in drug-tolerant cells. We describe the main characteristics and dynamic nature of this persistent state, and highlight the current therapeutic strategies that may be used to interfere with the establishment of drug-tolerant cells, as an alternative to improve objective response to systemic therapies and delay the emergence of resistance to improve long-term survival.
Topics: Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Tolerance; Humans; Neoplasms
PubMed: 34389691
DOI: 10.1158/1541-7786.MCR-21-0038 -
MBio Jun 2023Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological...
Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological nutrient concentrations, pathogens encounter a relatively restrictive environment . We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically relevant mild nutrient stress (or "metabolic priming") triggers increased tolerance of a potent antimalarial drug. We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in metabolism or using a media formulation that simulates the human plasma environment. We determined that priming-induced tolerance was restricted to parasites that had newly invaded the host red blood cell, but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic tolerance, including translational repression and protein export. This finding suggests that regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently compared to the stable environment, priming-induced drug tolerance has ramifications for how results translate to studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to slow the evolution of resistance. There is a dire need for effective treatments against microbial pathogens. Yet, the continuing emergence of drug resistance necessitates a deeper knowledge of how pathogens respond to treatments. We have long appreciated the contribution of genetic evolution to drug resistance, but transient metabolic changes that arise in response to environmental factors are less recognized. Here, we demonstrate that short-term growth of malaria parasites in a nutrient-limiting environment triggers cellular changes that lead to better survival of drug treatment. We found that these strategies are similar to those employed by drug-tolerant parasites, which suggests that starvation "primes" parasites to survive and potentially evolve resistance. Since the environment of the human host is relatively nutrient restrictive compared to growth conditions in standard laboratory culture, this discovery highlights the important connections among nutrient levels, protective cellular pathways, and resistance evolution.
Topics: Humans; Plasmodium falciparum; Artemisinins; Malaria; Antimalarials; Drug Tolerance; Drug Resistance; Nutrients
PubMed: 37097173
DOI: 10.1128/mbio.00705-23 -
Physiology (Bethesda, Md.) Sep 2021Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut...
Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects.
Topics: Analgesics, Opioid; Drug Tolerance; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Opioid Epidemic
PubMed: 34431418
DOI: 10.1152/physiol.00014.2021 -
Best Practice & Research. Clinical... Dec 2017Opioids are the most potent drugs used to control severe pain. However, neuroadaptation prevents opioids' ability to provide long-term analgesia and produces opposite... (Review)
Review
Opioids are the most potent drugs used to control severe pain. However, neuroadaptation prevents opioids' ability to provide long-term analgesia and produces opposite effects, i.e., enhancement of existent pain and facilitation of chronic pain development. Neuroadaptation to opioids use results in the development of two interrelated phenomena: tolerance and "opioid-induced hyperalgesia" (OIH). Tolerance, a pharmacologic concept, and OIH, a clinical syndrome, have been mostly observed under experimental conditions in animals and in human volunteers. In contrast, their occurrence and relevance in clinical practice remain debated. In perioperative setting, intraoperative administration of high doses of opioids increases postoperative opioid requirements and worsens pain scores (acute tolerance or perioperative OIH). Further, preoperative chronic opioid intake and postoperative long-term use of opioid analgesics beyond the normal healing period have a negative effect on surgical outcome. Conversely, observations of improved patient's recovery after opioid-sparing anesthesia techniques stand as an indirect evidence that perioperative opioid administration deserves caution. To date, perioperative OIH has rarely been objectively assessed by psychophysics tests in patients. A direct relationship between the presence of perioperative OIH and patient outcome is missing and certainly deserves further studies.
Topics: Analgesics, Opioid; Anesthesia; Animals; Drug Tolerance; Humans; Hyperalgesia; Intraoperative Care; Pain Management
PubMed: 29739537
DOI: 10.1016/j.bpa.2017.05.003 -
Bioanalysis Jul 2023The presence of di-/multi-meric forms of soluble target in biological samples can interfere in anti-drug antibody (ADA) assays, leading to increased background values...
The presence of di-/multi-meric forms of soluble target in biological samples can interfere in anti-drug antibody (ADA) assays, leading to increased background values and potentially false positivity. The authors investigated the use of the high ionic strength dissociation assay (HISDA) to reduce target interference in two different ADA assays. Interference caused by homodimeric FAP was successfully eliminated to enable cut point determination after applying HISDA. Biochemical experiments confirmed the dissociation of homodimeric FAP after treatment with high ionic strength conditions. HISDA is a promising approach to simultaneously achieve high drug tolerance and reduced interference by noncovalently bound dimeric target molecules in ADA assays without extensive optimization, which is particularly advantageous in routine use.
Topics: Antibodies; Drug Tolerance
PubMed: 37326333
DOI: 10.4155/bio-2023-0082 -
Frontiers in Cellular and Infection... 2022Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is... (Review)
Review
Treatment of ( infections is particularly arduous. One challenge to effectively treating tuberculosis is that drug efficacy often fails to match drug efficacy This is due to multiple reasons, including inadequate drug concentrations reaching at the site of infection and physiological changes of in response to host derived stresses that render the bacteria more tolerant to antibiotics. To more effectively and efficiently treat tuberculosis, it is necessary to better understand the physiologic state of that promotes drug tolerance in the host. Towards this end, multiple studies have converged on bacterial central carbon metabolism as a critical contributor to drug tolerance. In this review, we present the evidence that changes in central carbon metabolism can promote drug tolerance, depending on the environment surrounding . We posit that these metabolic pathways could be potential drug targets to stymie the development of drug tolerance and enhance the efficacy of current antimicrobial therapy.
Topics: Carbon; Drug Tolerance; Humans; Metabolic Networks and Pathways; Mycobacterium tuberculosis; Tuberculosis, Lymph Node
PubMed: 36072222
DOI: 10.3389/fcimb.2022.958555