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Nutrition, Metabolism, and... Oct 2014Many patients treated with statins are considered statin-resistant because they fail to achieve adequate reduction of low density lipoprotein cholesterol (LDL-C) levels.... (Review)
Review
BACKGROUND AND AIMS
Many patients treated with statins are considered statin-resistant because they fail to achieve adequate reduction of low density lipoprotein cholesterol (LDL-C) levels. Some patients are statin-intolerant because they are unable to tolerate statin therapy at all or to tolerate a full therapeutic statin dose because of adverse effects, particularly myopathy and increased activity of liver enzymes.
RESULTS
The resistance to statins has been associated with polymorphisms in the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-R), P-glycoprotein (Pg-P/ABCB1), breast cancer resistance protein (BCRP/ABCG2), multidrug resistance-associated proteins (MRP1/ABCC1 and MRP2/ABCC2), organic anion transporting polypeptides (OATP), RHOA, Nieman-Pick C1-like1 protein (NPC1L1), farnesoid X receptor (FXR), cholesterol 7alpha-hydroxylase (CYP7A1), Apolipoprotein E (ApoE), proprotein convertase subtilisin/kexin type 9 (PCSK9), low density lipoprotein receptor (LDLR), lipoprotein (a) (LPA), cholesteryl ester transfer protein (CETP), and tumor necrosis factor α (TNF-α) genes. However, currently, there is still not enough evidence to advocate pharmacogenetic testing before initiating statin therapy. Patients with inflammatory states and HIV infection also have diminished LDL-C lowering as a response to statin treatment. Pseudo-resistance due to nonadherence or non-persistence in real-life circumstances is probably the main cause of insufficient LDL-C response to statin treatment.
CONCLUSIONS
If a patient is really statin-resistant or statin-intolerant, several other treatment possibilities are nowadays available: ezetimibe alone or in combination with bile acid sequestrants, and possibly in the near future mipomersen, lomitapide, or monoclonal antibodies against PCSK9.
Topics: Anticholesteremic Agents; Azetidines; Benzimidazoles; Bile Acids and Salts; Cholesterol, LDL; Drug Resistance; Drug Therapy, Combination; Drug Tolerance; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Multidrug Resistance-Associated Protein 2; Pharmacogenetics; Polymorphism, Genetic
PubMed: 24996502
DOI: 10.1016/j.numecd.2014.05.009 -
The Annals of Pharmacotherapy Apr 2023To assess mavacamten's role in hypertrophic cardiomyopathy treatment. (Review)
Review
OBJECTIVE
To assess mavacamten's role in hypertrophic cardiomyopathy treatment.
DATA SOURCES
In addition to clinical guidelines, package inserts, and general reviews, we searched PubMed using the term mavacamten from inception to June 11, 2022.
STUDY SELECTION AND DATA EXTRACTION
English language studies describing mavacamten's mechanism of action, pharmacokinetics, drug interactions, clinical and economic outcomes, and adverse events.
DATA SYNTHESIS
Mavacamten reduces left ventricular outflow obstruction and New York Heart Association functional class while improving Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores in patients with obstructive hypertrophic cardiomyopathy. With an acquisition cost of $245.20 per capsule, it would cost $1.2 million for every additional quality-adjusted life year. In those with unobstructive hypertrophic cardiomyopathy, there were improvements in -terminal probrain natriuretic peptide and high-sensitivity cardiac troponin biochemical markers. Mavacamten is a substrate for CYP2C19 and CYP3A4, and a CYP enzyme inducer.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
Patients with obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% have a new option if they remain symptomatic despite maximally tolerated β-blocker or non-dihydropyridine calcium channel blocker therapy. It is an alternative to disopyramide therapy, which has poor patient tolerance, or septal reduction therapies, which are invasive. However, mavacamten is not cost-effective and its role in nonobstructive hypertrophic cardiomyopathy is not well established.
CONCLUSIONS
Mavacamten is a new option for patients with refractory obstructive hypertrophic cardiomyopathy and an ejection fraction ≥55% but its pricing makes therapy not cost-effective. Final health outcomes are not fully elucidated and additional studies are needed to determine long-term effects.
Topics: Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Cytochrome P-450 CYP3A; Drug Tolerance
PubMed: 35950315
DOI: 10.1177/10600280221117812 -
Neuropharmacology Feb 2023Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here,...
Morphine tolerance (MT) caused by long-term use of morphine is a major medical problem. The underlying molecular mechanisms of morphine tolerance remain unclear. Here, we establish the morphine tolerance model in mice and verify whether a novel circRNA, circRalgapa1 is involved in morphine tolerance and its specific molecular mechanism. We show that the expression of circRalgapa1 in the spinal cord is significantly down-expressed in the spinal cord of morphine-tolerant mice. CircRalgapa1 is mainly located in the neuronal cytoplasm and co-localizes with miR-873a-5p. Mechanically, circRalgapa1 acts as competing endogenous RNAs (ceRNAs) to regulate the inhibitory of miR-873a-5p on A20 (also known as tumor necrosis factor α-induced protein 3, TNFAIP3). Functionally, overexpression of circRalgapa1 by intrathecal injection of adeno-associated virus (AAV- circRalgapa1) attenuated the formation of morphine tolerance and partially reversed the development of morphine tolerance. Moreover, overexpression of miR-873a-5p blocked the effect of AAV-circRalgapa1 on alleviating morphine tolerance in mice. In conclusion, chronic morphine administration-mediated down-regulation of circRalgapa1 in the spinal cord contributes to morphine tolerance via miR-873a-5p/A20 axis in mice. Overexpression of circRalgapa1 may be a promising RNA-based therapy for morphine tolerance.
Topics: Animals; Mice; Cytoplasm; Down-Regulation; MicroRNAs; Morphine; Spinal Cord; RNA, Circular; Drug Tolerance
PubMed: 36455645
DOI: 10.1016/j.neuropharm.2022.109353 -
Biochemical Pharmacology Apr 2019Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance... (Review)
Review
Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations. Recently, it has been suggested that a subpopulation of drug tolerant cells present in cancer populations and called "persisters" play a major role in this resistance. Recent studies have shown that microorganisms share similar properties. Still, how persister/tolerant cells intervene in the development of resistance is not completely elucidated but seems to be related to epigenetic changes in treated cells and the capacity of persisters to modulate and/or highjack their microenvironment. Due to the complexity of this process, the input from mathematicians, as well as new methods of bioinformatics and statistics, is necessary to fully comprehend the acquisition of resistance/tolerance deriving from and leading to the heterogeneous cell populations. The present review will give a brief overview of the most recent data available on drug tolerant cells in cancers and their similarities with microorganisms.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Drug Resistance, Neoplasm; Drug Tolerance; Humans; Neoplasms; Tumor Microenvironment
PubMed: 30414937
DOI: 10.1016/j.bcp.2018.11.004 -
Microbial Pathogenesis Mar 2022The increase in antibiotic non-responsive bacteria is the leading concern in current research oriented to eliminate pathogens. Nowadays, the excess use of antibiotics...
The increase in antibiotic non-responsive bacteria is the leading concern in current research oriented to eliminate pathogens. Nowadays, the excess use of antibiotics without specifically understanding the potentiality of killing pathogens and bacterial survival patterns has helped bacteria emerge indefatigably. Bacteria use various mechanisms such as resistance, persistence, and tolerance to ensure survival. Among these, persistence is a mechanism by which bacteria reside in their dormant state, bypassing the effects of treatments, making it crucial for bacterial survival. Persistent bacterial cells arise from the normal bacterial population as a slow-growing subset of bacteria with no metabolic flux. This behavior renders it to survive for a longer duration and at higher concentrations of antibiotics. They are one of the underlying causes of recurrence of bacterial infections. The present article explains the detailed molecular mechanisms and strategies of bacterial persistence, including the toxin-antitoxin modules, DNA damage, the formation of inactive ribosomal complexes, (p)ppGpp network, antibiotic-induced persistence, which are triggered by drug-induced stress. The article also comprehensively covers the epigenetic memory of persistence in bacteria, and anti-persistent therapeutics like antimicrobial molecules, synthetic peptides, acyldepsipeptide antibiotics, and endolysin therapy to reduce persister cell formation and control their frequency. These strategies could be utilized in combating the pathogenic bacteria undergoing persistence.
Topics: Anti-Bacterial Agents; Antitoxins; Bacteria; Bacterial Infections; Drug Tolerance; Humans
PubMed: 35092834
DOI: 10.1016/j.micpath.2022.105423 -
International Review of Neurobiology 2016The etiology of diabetic peripheral neuropathy (DPN) involves an interrelated series of metabolic and vascular insults that ultimately contribute to sensory neuron... (Review)
Review
The etiology of diabetic peripheral neuropathy (DPN) involves an interrelated series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small-molecule inhibitors have targeted proteins and pathways regarded as "diabetes specific" as well as others whose activity are altered in numerous disease states. These efforts have not yielded any significant therapies, due in part to the complicating issue that the biochemical contribution of these targets/pathways to the progression of DPN does not occur with temporal and/or biochemical uniformity between individuals. In a complex, chronic neurodegenerative disease such as DPN, it is increasingly appreciated that effective disease management may not necessarily require targeting a pathway or protein considered to contribute to disease progression. Alternatively, it may prove sufficiently beneficial to pharmacologically enhance the activity of endogenous cytoprotective pathways to aid neuronal tolerance to and recovery from glucotoxic stress. In pursuing this paradigm shift, we have shown that modulating the activity and expression of molecular chaperones such as heat shock protein 70 (Hsp70) may provide translational potential for the effective medical management of insensate DPN. Considerable evidence supports that modulating Hsp70 has beneficial effects in improving inflammation, oxidative stress, and glucose sensitivity. Given the emerging potential of modulating Hsp70 to manage DPN, the current review discusses efforts to characterize the cytoprotective effects of this protein and the benefits and limitations that may arise in drug development efforts that exploit its cytoprotective activity.
Topics: Animals; Diabetic Neuropathies; Drug Tolerance; Glucose; Humans; Molecular Chaperones; Neurodegenerative Diseases; Oxidative Stress; Sensory Receptor Cells
PubMed: 27133150
DOI: 10.1016/bs.irn.2016.03.001 -
Molecular Pain May 2015Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid... (Review)
Review
Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. Although the mechanisms underlying chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia remain to be uncovered, mammalian target of rapamycin (mTOR) is involved in these disorders. The mTOR complex 1 and its triggered protein translation are required for the initiation and maintenance of chronic pain (including cancer pain) and opioid-induced tolerance/hyperalgesia. Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia.
Topics: Analgesics, Opioid; Animals; Chronic Pain; Drug Tolerance; Humans; Hyperalgesia; Pain Threshold; TOR Serine-Threonine Kinases
PubMed: 26024835
DOI: 10.1186/s12990-015-0030-5 -
Antimicrobial Agents and Chemotherapy Feb 2018Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug...
Tuberculosis (TB) recently became the leading infectious cause of death in adults, while attempts to shorten therapy have largely failed. Dormancy, persistence, and drug tolerance are among the factors driving the long therapy duration. Assays to measure drug susceptibility of bacteria in pulmonary lesions are needed if we are to discover new fast-acting regimens and address the global TB threat. Here we take a first step toward this goal and describe an assay developed to measure the cidal activity of anti-TB drugs against bacilli present in cavity caseum obtained from rabbits with active TB. We show that caseum bacilli are largely nonreplicating, maintain viability over the course of the assay, and exhibit extreme tolerance to many first- and second-line TB drugs. Among the drugs tested, only the rifamycins fully sterilized caseum. A similar trend of phenotypic drug resistance was observed in the hypoxia- and starvation-induced nonreplicating models, but with notable qualitative and quantitative differences: (i) caseum exhibits higher drug tolerance than nonreplicating in the Wayne and Loebel models, and (ii) pyrazinamide is cidal in caseum but has no detectable activity in these classic nonreplicating assays. Thus, caseum constitutes a unique tool to evaluate drug potency against slowly replicating or nonreplicating bacilli in their native caseous environment. Intracaseum cidal concentrations can now be related to the concentrations achieved in the necrotic foci of granulomas and cavities to establish correlations between clinical outcome and lesion-centered pharmacokinetics-pharmacodynamics (PK-PD) parameters.
Topics: Animals; Antitubercular Agents; Drug Tolerance; Mycobacterium tuberculosis; Pyrazinamide; Rabbits; Rifamycins; Tuberculosis
PubMed: 29203492
DOI: 10.1128/AAC.02266-17 -
World Neurosurgery Mar 2023The purpose of this study is to determine if increased postoperative prescription opioid dosing is an isolated predictor of chronic opioid use after anterior cervical...
OBJECTIVE
The purpose of this study is to determine if increased postoperative prescription opioid dosing is an isolated predictor of chronic opioid use after anterior cervical diskectomy and fusion (ACDF).
METHODS
A retrospective cohort analysis of patients undergoing ACDF for degenerative diseases from 2016-2019 at a single institution was performed. Preoperative and postoperative opioid and benzodiazepine prescriptions, including morphine milligram equivalents (MMEs) and duration of use, were obtained from the Pennsylvania Prescription Drug Monitoring Program. Univariate analysis compared patient demographics and surgical factors across groups on the basis of postoperative opioid dose (high: MME ≥90, low: MME <90) and chronicity of use (chronic: ≥120 days or >10 prescriptions). Logistic regressions identified predictors of high opioid dose and chronic use.
RESULTS
A total of 385 patients were included. Preoperative opioid tolerance and tobacco use were associated with high postoperative opioid dose and chronic usage. Younger age correlated with high-dose prescriptions. Increased body mass index and preoperative benzodiazepine use were associated with chronic opioid use. Chronic postoperative opioid use correlated with high-dose prescriptions, change in opioid prescribed, private pay scripts, and more than 1 prescriber and pharmacy. Logistic regression identified high postoperative opioid dose, opioid tolerance, increased body mass index, and no prior cervical surgery as predictors of chronic opioid use. Regression analysis determined younger age, increased medical comorbidities, and opioid tolerance to be predictors for high MME prescriptions.
CONCLUSIONS
High postoperative opioid dose independently predicted chronic opioid use after ACDF regardless of preoperative opioid tolerance.
Topics: Humans; Analgesics, Opioid; Retrospective Studies; Pain, Postoperative; Drug Tolerance; Opioid-Related Disorders; Practice Patterns, Physicians'
PubMed: 36566977
DOI: 10.1016/j.wneu.2022.12.083 -
Headache Apr 2015Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research... (Review)
Review
Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by Toll-like receptor 4, purinergic, ceramide, and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted.
Topics: Analgesia; Analgesics, Opioid; Animals; Central Nervous System; Drug Tolerance; Humans; Hyperalgesia; Signal Transduction; Toll-Like Receptor 4
PubMed: 25833219
DOI: 10.1111/head.12552