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Journal of Pain and Symptom Management Aug 2004Skeletal muscle relaxants are a heterogeneous group of medications used to treat two different types of underlying conditions: spasticity from upper motor neuron... (Comparative Study)
Comparative Study Meta-Analysis Review
Skeletal muscle relaxants are a heterogeneous group of medications used to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Although widely used for these indications, there appear to be gaps in our understanding of the comparative efficacy and safety of different skeletal muscle relaxants. This systematic review summarizes and assesses the evidence for the comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. Randomized trials (for comparative efficacy and adverse events) and observational studies (for adverse events only) that included oral medications classified as skeletal muscle relaxants by the FDA were sought using electronic databases, reference lists, and pharmaceutical company submissions. Searches were performed through January 2003. The validity of each included study was assessed using a data abstraction form and predefined criteria. An overall grade was allocated for the body of evidence for each key question. A total of 101 randomized trials were included in this review. No randomized trial was rated good quality, and there was little evidence of rigorous adverse event assessment in included trials or observational studies. There is fair evidence that baclofen, tizanidine, and dantrolene are effective compared to placebo in patients with spasticity (primarily multiple sclerosis). There is fair evidence that baclofen and tizanidine are roughly equivalent for efficacy in patients with spasticity, but insufficient evidence to determine the efficacy of dantrolene compared to baclofen or tizanidine. There is fair evidence that although the overall rate of adverse effects between tizanidine and baclofen is similar, tizanidine is associated with more dry mouth and baclofen with more weakness. There is fair evidence that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared to placebo in patients with musculoskeletal conditions (primarily acute back or neck pain). Cyclobenzaprine has been evaluated in the most clinical trials and has consistently been found to be effective. There is very limited or inconsistent data regarding the effectiveness of metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene compared to placebo in patients with musculoskeletal conditions. There is insufficient evidence to determine the relative efficacy or safety of cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone, methocarbamol, and chlorzoxazone. Dantrolene, and to a lesser degree chlorzoxazone, have been associated with rare serious hepatotoxicity.
Topics: Clinical Trials as Topic; Comorbidity; Evidence-Based Medicine; Humans; Motor Neuron Disease; Muscle Spasticity; Musculoskeletal Diseases; Neuromuscular Agents; Peripheral Nervous System Diseases; Treatment Outcome
PubMed: 15276195
DOI: 10.1016/j.jpainsymman.2004.05.002 -
Deutsches Arzteblatt International Jul 2013Recent studies have extended our understanding of the pathophysiology, natural course, and treatment of vestibular vertigo. The relative frequency of the different forms... (Review)
Review
BACKGROUND
Recent studies have extended our understanding of the pathophysiology, natural course, and treatment of vestibular vertigo. The relative frequency of the different forms is as follows: benign paroxysmal positional vertigo (BPPV) 17.1%; phobic vestibular vertigo 15%; central vestibular syndromes 12.3%; vestibular migraine 11.4%; Menière's disease 10.1%; vestibular neuritis 8.3%; bilateral vestibulopathy 7.1%; vestibular paroxysmia 3.7%.
METHODS
Selective literature survey with particular regard to Cochrane reviews and the guidelines of the German Neurological Society.
RESULTS
In more than 95% of cases BPPV can be successfully treated by means of liberatory maneuvers (controlled studies); the long-term recurrence rate is 50%. Corticosteroids improve recovery from acute vestibular neuritis (one controlled, several noncontrolled studies); the risk of recurrence is 2-12%. A newly identified subtype of bilateral vestibulopathy, termed cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), shows no essential improvement in the long term. Long-term high-dose treatment with betahistine is probably effective against Menière's disease (noncontrolled studies); the frequency of episodes decreases spontaneously in the course of time (> 5 years). The treatment of choice for vestibular paroxysmia is carbamazepine (noncontrolled study). Aminopyridine, chlorzoxazone, and acetyl-DL-leucine are new treatment options for various cerebellar diseases.
CONCLUSION
Most vestibular syndromes can be treated successfully. The efficacy of treatments for Menière's disease, vestibular paroxysmia, and vestibular migraine requires further research.
Topics: Brain Diseases; Causality; Comorbidity; Disease Progression; Disease-Free Survival; Evidence-Based Medicine; Humans; Prevalence; Risk Factors; Treatment Outcome; Vertigo; Vestibular Diseases
PubMed: 24000301
DOI: 10.3238/arztebl.2013.0505 -
Frontiers in Immunology 2022Cuproptosis is a recently discovered form of programmed cell death; however, its role in ulcerative colitis (UC) remains a void.
OBJECTIVES
Cuproptosis is a recently discovered form of programmed cell death; however, its role in ulcerative colitis (UC) remains a void.
METHODS
Three gene expression profiles were acquired from the GEO database. Subsequently, the single sample gene set enrichment analysis (ssGSEA) was performed to identify the immune infiltration characteristics of UC. Correlation analysis between cuproptosis and immune infiltration was further conducted, and the cuproptosis-related genes were applied to construct a UC diagnostic model. Subsequently, analysis results of microarray data were experimentally validated by DSS-induced colitis in mice. Finally, therapeutic agents for the cuproptosis-related genes were screened owing to the gaping field of therapeutic agents on cuproptosis.
RESULTS
Three gene expression profiles with 343 samples (290 UC and 53 healthy samples) were included. Immune infiltration revealed that UC patients had a higher level of DCs, B cells, CD8 T cells, iDCs, Macrophages, neutrophils, pDCs, T helper cells, Tfh, Th1 cells, Th2 cells, TIL and Treg than normal subjects. Moreover, almost all cuproptosis-related genes were significantly negatively associated with immune infiltration in UC patients. The risk prediction model based on cuproptosis-related genes showed an excellent discrimination for UC. Animal experiments revealed significant alterations in genes essential for cuproptosis between DSS-induced colitis mice and healthy controls, providing experimental validation for the analysis results of microarray data. Further analysis revealed that latamoxef, vitinoin, clomipramine, chlorzoxazone, glibenclamide, pyruvic acid, clindamycin, medrysone, caspan, and flavin adenine dinucleotide might be the target agents for cuproptosis-related genes.
CONCLUSIONS
In conclusion, cuproptosis was significantly associated with immune infiltration in UC, and the cuproptosis-related genes showed an excellent discrimination for UC.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Colitis; Colitis, Ulcerative; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory; Copper; Apoptosis
PubMed: 36389705
DOI: 10.3389/fimmu.2022.1008146 -
Danish Medical Journal May 2016In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the... (Clinical Trial)
Clinical Trial
INTRODUCTION
In Denmark, it is estimated that 3-5% of children are obese. Obesity is associated with pathophysiological alterations that may lead to alterations in the pharmacokinetics of drugs. In adults, obesity was found to influence important drug-metabolising enzyme pathways. The impact of obesity-related alterations on drug metabolism and its consequences for drug dosing remains largely unknown in both children and adults. An altered drug metabolism may contribute significantly to therapeutic failure or toxicity. The aim of this trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 substrates in obese versus non-obese children.
METHODS
The CYTONOX trial is an open-label explorative pharmacokinetic trial. We intend to include 50 obese and 50 non-obese children. The primary end points are: in vivo clearance of CYP3A4, CYP2E1 and CYP1A2 substrates, which will be defined by using well-tested probes; midazolam, chlorzoxazone and caffeine. Each of the probes will be administered as a single dose. Subsequently, blood and urine samples will be collected at pre-specified times.
CONCLUSION
The aim of the CYTONOX trial is to investigate the in vivo activity of CYP3A4, CYP2E1 and CYP1A2 in obese and non-obese children. The results are expected to be used in the future as a basis for drug dosing recommendations in obese children.
FUNDING
The study was funded by the Danish Regions' "Medicinpuljen". The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
TRIAL REGISTRATION
EudraCT: 2014-004554-34.
Topics: Adolescent; Caffeine; Child; Chlorzoxazone; Clinical Protocols; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Denmark; Female; Humans; Male; Midazolam; Pediatric Obesity
PubMed: 27127017
DOI: No ID Found -
Danish Medical Journal Mar 2018Increasing evidence indicate that pain is insufficiently treated following surgical procedures. It is essential that pain treatment is effective with a minimum of side... (Review)
Review
Increasing evidence indicate that pain is insufficiently treated following surgical procedures. It is essential that pain treatment is effective with a minimum of side effects in order to promote postoperative rehabilitation. Multimodal analgesia is most likely an important strategy in reducing postoperative pain. Combinations of different analgesics with different mechanisms of action may have an additive analgesic effect with fewer side effects compared to using a single drug. However, there is still a pronounced lack of documentation for the effect and side effects of these multimodal analgesic regimes. More than 6,000 spine surgeries are performed annually in Denmark and spine surgery has been associated with high levels of pain compared to other surgical procedures. Therefore, we considered spine surgery to pose a group of well-defined surgical procedures and we used this model to investigate the efficacy of 3 adjuvant analgesics aiming to improve the multimodal approach in pain management. In study I and II we hypothesized that preoperative IV dexamethasone 16 mg would reduce acute postoperative pain, opioid consumption and persistent pain after lumbar disk surgery. We found that dexamethasone significantly reduced acute pain during mobilization. The clinical relevance is however debatable and we could not demonstrate an opioid sparing effect. Further, we discovered significantly higher pain levels in the dexamethasone group compared to placebo 1 year postoperatively. In study III we explored the effect of 500 mg of oral chlorzoxazone on acute postoperative pain and opioid consumption in patients with moderate to severe pain after spine surgery and found no effect of chlorzoxazone compared to placebo. In study IV we hypothesized that intraoperative ketamine would reduce postoperative opioid consumption and persistent pain after spinal fusion surgery in chronic pain patients with opioid dependency. We found a significantly reduced opioid consumption in the ketamine group and a reduced level of persistent pain 6 months postoperatively. In conclusion, dexamethasone and ketamine are potential adjuvant analgesics for postoperative pain. Possibly ketamine also inhibits the development of persistent pain. Chlorzoxazone has no immediate effect as an adjuvant in acute pain management.
Topics: Analgesia; Analgesics, Opioid; Chlorzoxazone; Chronic Pain; Dexamethasone; Humans; Intraoperative Period; Ketamine; Pain Measurement; Pain, Postoperative; Randomized Controlled Trials as Topic; Spine
PubMed: 29510816
DOI: No ID Found -
British Journal of Clinical Pharmacology Oct 2019Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Chlorzoxazone is the paradigm marker substrate for CYP2E1 phenotyping in vivo. Because at the commonly used milligram doses (250-750 mg) chlorzoxazone acts as an inhibitor of the CYP3A4/5 marker substrate midazolam, previous attempts failed to combine both drugs in a common phenotyping cocktail. Microdosing chlorzoxazone could circumvent this problem.
METHOD
We enrolled 12 healthy volunteers in a trial investigating the dose-exposure relationship of single ascending chlorzoxazone oral doses over a 10,000-fold range (0.05-500 mg) and assessed the effect of 0.1 and 500 mg of chlorzoxazone on oral midazolam pharmacokinetics (0.003 mg).
RESULTS
Chlorzoxazone area under the concentration-time curve was dose-linear in the dose range between 0.05 and 5 mg. A nonlinear increase occurred with doses ≥50 mg, probably due to saturated presystemic metabolic elimination. While midazolam area under the concentration-time curve increased 2-fold when coadministered with 500 mg of chlorzoxazone, there was no pharmacokinetic interaction between chlorzoxazone and midazolam microdoses.
CONCLUSION
The chlorzoxazone microdose did not interact with the CYP3A marker substrate midazolam, enabling the simultaneous administration in a phenotyping cocktail. This microdose assay is now ready to be further validated and tested as a phenotyping procedure assessing the impact of induction and inhibition of CYP2E1 on chlorzoxazone microdose pharmacokinetics.
Topics: Administration, Oral; Adult; Area Under Curve; Chlorzoxazone; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Midazolam; Middle Aged; Phenotype; Young Adult
PubMed: 31222796
DOI: 10.1111/bcp.14040 -
Journal of Fluorescence Jul 2023Lower back pain is a universal dilemma leaving a negative effect on both health and life quality. It was found that a fixed dose combination of chlorzoxazone and...
Lower back pain is a universal dilemma leaving a negative effect on both health and life quality. It was found that a fixed dose combination of chlorzoxazone and ibuprofen gave a higher efficiency than analgesic alone in treatment of acute lower back pain. Based on the significant benefit of that combination, a green, sensitive, rapid, direct, and cost-effective method is created for concurrent determination of ibuprofen and chlorzoxazone in presence of 2-amino para chlorophenol (a synthetic precursor and potential impurity of chlorzoxazone) adopting the synchronous spectrofluorimetric technique. Synchronous spectrofluorimetric technique is adopted to avoid the highly overlapped native spectra of both drugs. The synchronous spectrofluorometric method was applied at Δλ = 50 nm, ibuprofen was measured at 227 nm while chlorzoxazone was measured at 282 nm with no hindering from one to another. The various experimental variables affecting the performance of the suggested technique were explored and adjusted. The suggested technique showed good linearity from 0.02 to 0.6 and 0.1 to 5.0 µg/mL for ibuprofen and chlorzoxazone, respectively. The produced detection limits were 0.27 × 10 and 0.03, while the quantitation limits were 0.82 × 10 and 0.09 µg/mL for ibuprofen and chlorzoxazone, respectively. The suggested approach was successfully applied for the analysis of the studied drugs in the synthetic mixture, different pharmaceutical preparations, and spiked human plasma. The suggested technique was validated with respect to the International Council of Harmonization (ICH) recommendations. The suggested technique was found to be simpler and greener with lower cost compared to the earlier reported methods which required complicated techniques, longer time of analysis, and less safe solvents and reagents. Green profile assessment for the developed method compared with the reported spectrofluorometric method was performed using four assessment tools. These tools confirmed that the recommended technique attained the most possible green parameters, so it could be used as a greener option in routine quality control for analyzing the two drugs in genuine form and pharmaceutical preparations.
Topics: Humans; Ibuprofen; Chlorzoxazone; Fluorescence; Low Back Pain; Pharmaceutical Preparations; Spectrometry, Fluorescence
PubMed: 36809413
DOI: 10.1007/s10895-023-03175-6 -
Frontiers in Chemistry 2022This study synthesized a LaO@snowflake-like CuS composite to fabricate an electrochemical sensor for sensitively simultaneous detection of diclofenac and chlorzoxazone...
Simultaneous Electrochemical Determination of Chlorzoxazone and Diclofenac on an Efficient Modified Glassy Carbon Electrode by Lanthanum Oxide@ Copper(I) Sulfide Composite.
This study synthesized a LaO@snowflake-like CuS composite to fabricate an electrochemical sensor for sensitively simultaneous detection of diclofenac and chlorzoxazone exploiting an easy hydrothermal approach, followed by analysis with XRD, FE-SEM, and EDX methods. According to voltammetric studies, the electrocatalytic diclofenac and chlorzoxazone oxidations on the electrode modified with LaO@SF-L CuS composites were increased, with greater oxidation currents, as well as the oxidation potential was significantly decreased due to synergetic impact of LaO@SF-L CuS composites when compared with the pure SF-L CuS NS-modified electrode. The differential pulse voltammetry findings showed wide straight lines (0.01-900.0 μM) for LaO NP@SF-L CuS NS-modified electrode with a limit of detection (LOD) of 1.7 and 2.3 nM for the detection of diclofenac and chlorzoxazone, respectively. In addition, the limit of quantification was calculated to be 5.7 and 7.6 nM for diclofenac and chlorzoxazone, respectively. The diffusion coefficient was calculated to be 1.16 × 10and 8.4 × 10 cm/s for diclofenac and chlorzoxazone oxidation on the modified electrode, respectively. Our proposed electrode was examined for applicability by detecting diclofenac and chlorzoxazone in real specimens.
PubMed: 35783211
DOI: 10.3389/fchem.2022.889590 -
Journal of Advanced Research Jul 2022Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered...
INTRODUCTION
Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.
OBJECTIVES
In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.
METHODS
The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.
RESULTS
The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.
CONCLUSION
Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.
Topics: Animals; Chlorzoxazone; Gastrointestinal Microbiome; Metoprolol; Mice; Midazolam; Non-alcoholic Fatty Liver Disease; Omeprazole; Pharmaceutical Preparations; Phenacetin; Tolbutamide
PubMed: 35777915
DOI: 10.1016/j.jare.2021.10.004