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The aim of this study is to use new drugs capable of crossing the blood-brain barrier (BBB) to develop new radiopharmaceuticals for non-invasive brain imaging. Quetiapine (QTP) and cyclobenzaprine (CBP), as two 5-HT2A receptor antagonists, were successfully labeled with radioactive iodine (125I) using Chloramine-T (CAT) as an oxidizing agent via electrophilic substitution reactions. After studying the parameters affecting the labeling yield (substrate amount, CAT amount, pH of the reaction mix., reaction time and temperature), the highest radiochemical yields of125I-QTP and 125I-CBP were found to be 94.5 % ± 1.0 and 91.7 % ± 0.6, respectively, at pH 2. The biodistribution and the SPECT/CT image showed that the maximum uptake of radioiodinated-QTP by the mouse brain was 10.2% and 10.9% at 120 minutes post-injection, while the radioiodinated-CBP was 7.7% and 12.4% at 240 minutes post-injection. The results have shown that radioiodinated-QTP and radioiodinated-CBP are novel radiopharmaceuticals and may be used for brain imaging.

Aim: The aim of present study was to develop and validate a dissolution test method for Cyclobenzaprine HCL in its formulation using RP-HPLC method. Design: Optimization of chromatographic parameters, development of the dissolution test method using RP-HPLC and to validate the developed methods as per ICH guidelines. Materials and Methods: The optimized dissolution parameters includes USP apparatus II at a paddle rotation rate of 50 rpm and 900 ml of 1.2 pH 0.1N HCL buffer at 37?C0.5?C. Under these conditions, the in vitro release profiles of cyclobenzaprine HCL showed good results. The drug release was estimated by RP-HPLC using column Shodex C18-4E (250×4.6mm×5mm), detection wavelength 289.4 nm having the flow rate 1.0 mL/min using Acetonitrile : phosphate buffer (3.0 pH) in the proportion of 65:35%v/v. Results: The percent drug amount released estimated by proposed method was found to be 99.04%, The method was found to be linear with correlation coefficient was found to be 0.9991 in the concentration range was 2-10 mg/mL. The mean % recovery of Cyclobenzaprine was found to be 100.04.Precision values observed less than 2.All the validation parameters were within the acceptance range. Conclusion: The results obtained by proposed dissolution method for tablet formulation containing Cyclobenzaprine HCL are reliable, precise and accurate. Hence it was routinely adopted for dissolution analysis of the said drugs in the formulation. Keywords: Cyclobenzaprine HCL, Dissolution test, RPHPLC, Validation.

Background EpiFibro (Brazilian Epidemiological Study of Fibromyalgia) was created to study patients with fibromyalgia (FM). Patients were included since 2011 according to the classification criteria for FM of the American College of Rheumatology of 1990 (ACR1990). Objective To analyze the therapeutic measures prescribed by Brazilian physicians. Materials and methods Cross-sectional study of a multicenter cohort. The therapeutic measures were described using descriptive statistics. Results We analyzed 456 patients who had complete data in the registry. The mean age was 54.0 ± 11.9 years; 448 were women (98.2%). Almost all patients (98.4%) used medications, 62.7% received health education, and less than half reported practicing physical exercise; these modalities were often used in combination. Most patients who practiced exercises practiced aerobic exercise only, and a significant portion of patients combined it with flexibility exercises. The most commonly used medication was amitriptyline, followed by cyclobenzaprine, and a minority used medication specifically approved for FM, such as duloxetine and pregabalin, either alone or in combination. Combinations of two or three medications were observed, with the combination of fluoxetine and amitriptyline being the most frequent (18.8%). Conclusion In this evaluation of the care of patients with FM in Brazil, it was found that the majority of patients are treated with a combination of pharmacological measures. Non-pharmacological methods are underused, with aerobic exercise being the most commonly practiced exercise type. The most commonly prescribed single drug was amitriptyline, and the most commonly prescribed combination was fluoxetine and amitriptyline. Drugs specifically approved for FM are seldom prescribed.

Introduction: Nearly 80% of children with epilepsy have one or more chronic comorbidities that require specific drug treatments in several cases. Drug-drug interactions (DDIs) between antiseizure medications (ASMs) and all other drugs (NON-ASMs) used to treat comorbid diseases may have serious consequences. Areas covered: All potential DDIs between 27 ASMs and all NON-ASMs used for oral chronic treatment of those disorders most often comorbid with epilepsy in children were searched for drug compendia. Clinical evidence of the identified DDIs was also searched in the literature. Forty-eight drugs have been identified as potential DDIs with at least one ASM. Most important DDIs are between some ASMs and omeprazole and pantoprazole (drugs for gastrointestinal disorders), ibuprofen and cyclobenzaprine (drugs for musculoskeletal disorders), loratidine, lumacaftor/ivacaftor, montelukast, and theophylline (drugs for respiratory system), levothyroxine, liothyronine and several corticosteroids (systemic hormonal preparations), almotriptan, dihydroergotamine, ergotamine, and several antipsychotics, antidepressants and anxiolytics (drugs for nervous diseases). Clinical evidence of the predicted DDIs was found in a minority of cases. Expert opinion: Treatment of children with epilepsy should be decided considering treatment of both seizures and comorbid diseases and aimed at minimizing the risk of DDIs between ASMs and NON-ASMs.

Almost totality of fibromyalgia patients complain of disturbed sleep, but to date, this topic is at the centre of many controversies. First of all, subjective sleep complaints can be found in all patients, but not all studies observed altered objective parameters when investigating sleep using polysomnography; therefore, currently, no disease-specific sleep alterations have been found. Secondly, sleep disturbances correlate with many fibromyalgia symptoms, and it is now known that the relationship between sleep and pain is bidirectional, but it is still not clear why the sleep of fibromyalgia patients is so disrupted. Putative mechanisms include alterations in the hormonal, neurotransmitter and immune systems, and in the autonomic nervous system. There are also no interventions that are both safe and effective for improving sleep in fibromyalgia patients; hence, treatment must be multidimensional and take into account the multiple causative factors and the frequent fibromyalgia comorbidities. First, it is necessary to adopt behavioural changes, including sleep hygiene practices and regular exercise; secondly, some pharmacological treatments can be tried, such as pregabalin, amitriptyline and very low dose cyclobenzaprine, which are frequently used to treat pain and sleep disturbances in fibromyalgia patients, whilst duloxetine and milnacipran are less effective on sleep. New promising drugs are sodium oxybate, cannabis and cannabinoids. The high frequency of sleep alterations and their complex relationship with other manifestations in fibromyalgia mean that physicians should specifically address them, in order to have a positive effect on patients’ quality of life.

Pyridoxine is an important co-factor for many biochemical reactions in cellular metabolism related to the synthesis and catabolism of amino acids, fatty acids, neurotransmitters. Deficiency of pyridoxine results in impaired transcellular signaling between neurons and presents with muscular convulsions, hyperirritability, and peripheral neuropathy. Deficiency of pyridoxine is usually found in association with other vitamin B deficiencies such as folate (vitamin B9) and cobalamin (vitamin B12). Isolated pyridoxine deficiency is extremely rare. We present the case of a 59-year old female with type 2 diabetes who complained of painful muscle spasms. Her muscle spasms involved in both feet, which have spread proximally to her legs. She also experienced intermittent muscle spasms in her left arm, which is not alleviated by baclofen, cyclobenzaprine. Her plasma pyridoxal 5-phosphate confirmed pyridoxine deficiency. Vitamins B1, B3, B12, and folate were within normal limits. The patient received standard-dose intramuscular pyridoxine injections for three weeks followed by oral supplements for 3 months and her symptoms resolved. This case illustrates the rare instance of isolated pyridoxine deficiency in type 2 diabetes patient manifesting as myoclonic muscle spasms involving the legs and arms in the absence of objective polyneuropathy. Pyridoxine level should, therefore, be assessed in patients with type 2 diabetes, including newly diagnosed patients.

The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications opioids buprenorphine, methadone and oxycodone. The compounds [solubility-limited concentration (μM) studied] were as follows: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes ± pre-incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC50 values determined using either 8-concentration tests for those where the rCYP screen suggested an IC50 was achievable, or a 3-concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable. These results were then extrapolated to determine an inhibitory potential. Six pathway inhibitor combinations were identified with a moderate inhibitory potential (≥2.0 < 5.0): five with chlorzoxazone, R-EDDP, S-EDDP and noroxycodone production by CYP3A4, and R- and S-EDDP production by CYP2B6; and one for the meprobamate effect on noroxycodone production by CYP3A4. An additional eleven combinations were found with a weak inhibitory potential (≥1.25 < 2.0): five with carisoprodol, two each with methocarbamol and meprobamate, and one each with metaxalone and orphenadrine. This represents the first comprehensive study of the inhibitory effect of this class of drugs and suggests that some of them may produce significant drug-drug interactions with opioids that are frequent comedications with skeletal muscle relaxants.

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with β-cyclodextrin (β-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/β-CD and 2/β-CD complexes, with the aromatic ring system entering the cavity from the large rim of the cyclodextrin and the alkylammonium chain protruding out of the cavity and facing the secondary OH rim. These features matched those found in the molecular dynamics (MD) simulations in solution and in the solid state from single-crystal X-ray diffraction of 1/β-CD and 2/β-CD complexes. The latter complex was found in a single conformation in the solid state, whilst the MD simulations in explicit water reproduced the conformational transitions observed experimentally for the free molecule.

This work details the study of the redox behavior of the drugs cyclobenzaprine (CBP), amitriptyline (AMP) and nortriptyline (NOR) through voltammetric methods and computational chemistry. Results obtained in this study show that the amine moiety of each compound is more likely to undergo oxidation at 1a at Ep1a &asymp, 0.69, 0.79, 0.93 V (vs. Ag/AgCl/KClsat) for CBP, AMP and NOR, respectively. Moreover, CBP presented a second peak, 2a at Ep2a &asymp, 0.98 V (vs. Ag/AgCl/KClsat) at pH 7.0. Furthermore, the electronic structure calculation results corroborate the electrochemical assays regarding the HOMO energies of the lowest energy conformers of each molecule. The mechanism for each anodic process is proposed according to electroanalytical and computational chemistry findings, which show evidence that the methods herein employed may be a valuable alternative to study the redox behavior of structurally similar drugs.

Cyclobenzaprine hydrochloride, a skeletal muscle relaxant has been determined using an ecofriendly micellar HPLC method in its pure form and tablets. The chromatographic determination was performed using C8 monolithic column (100mm×4.6mm i.d., 5μm particle size) and micellar eluent which was composed of sodium dodecyl sulfate (0.15M), n-propanol (15%), 0.02M orthophosphoric acid (pH 4.5) and 0.3% triethylamine using UV detection of effluent was set at 225nm. The calibration plot showed good linearity over concentration range from 2-40μg/mL. The assay results were statistically validated for linearity, accuracy, precision and specificity according to ICH guidelines. Additionally, regarding USP guidelines, the uniformity of tablets content and in-vitro dissolution test of the tablets was tested using the proposed method. Simple and rapid applicability of the developed method allowed determination of the drug in its pure and tablet dosage forms. Moreover, the major advantage of micellar HPLC technique is to determine the drug in biological fluids without prior extraction steps. Depending on this, the estimation of cyclobenzaprine in spiked human urine was so simple without traditional tedious procedures. The proposed method offers the advantages of sensitivity and simplicity in addition to short analysis time which didn't exceed 6 minutes.

Cyclobenzaprine (CBP) is a centrally acting muscle relaxant whose myriad of therapeutic applications imply the need of better understanding its pharmacokinetics and thermodynamics. Henceforth, this work was concerned with an in silico investigation of CBP main metabolizers in the human organism, namely CYP1A2 and CYP3A4. For this purpose, computational methods were employed, such as molecular docking and other semi-empirical approaches. Results evidenced that the model herein depicted for CBP-CYP1A2 may not reproducibly represent the physiological interaction between CBP and this enzyme. Moreover, CBP-CYP3A4 docking results evidence thermodynamic feasibility of the molecular docking model and were further corroborated by literature, what may reproducibly represent a possible interaction between CBP and this macromolecule.

As part of early drug development, preformulation studies are used to comprehensively explore the properties of new drugs. In particular, this includes the biopharmaceutical characterization and evaluation of impacting factors (e.g. excipients, microenvironmental conditions etc.) by permeation studies. To overcome the limitations of current studies, a novel standardized ex vivo procedure using esophageal mucosa as surrogate has been established successfully and applied to preformulation studies for oromucosal delivery of cyclobenzaprine hydrochloride, a tricyclic muscle relaxant with potential for psychopharmacotherapeutic use. By using the standardized ex vivo permeation process, a twofold enhancement of permeability (0.98 ± 0.16 to 1.96 ± 0.10 * 10-5 cm/s) was observed by adjustment and controlling of microenvironmental pH, empowering a targeted and effective development of sublingual formulations. Predictivity and suitability were superior compared to in vitro experiments using artificial biomimetic membranes, revealing a determination coefficient (R2) of 0.995 vs. 0.322 concerning pH-dependent permeability of cyclobenzaprine. In addition, diffusion properties were extensively examined (e.g. influence of mucosal thicknesses, tissue freezing etc.). The alignment of the study design regarding physiologically/clinically relevant conditions resulted in ex vivo data that allowed for the estimation of plasma AUC levels in the extend of reported in vivo ranges.

The aim of this study was to improve the transdermal delivery of cyclobenzaprine (CBZ) from drug-in-adhesive patch which showed less side effects and better compliance. CBZ base was prepared and then characterized using differential scanning calorimetry (DSC). The interaction between CBZ and pressure-sensitive adhesive (PSA) was determined by Fourier Transform Infrared Spectroscopy (FT-IR). The influences of PSAs, penetration enhancers, patch thickness and drug content on the transdermal delivery of CBZ were studied thoroughly in vitro. Both CBZ releasing from patch and penetrating through the skin showed very great effect on the transdermal delivery of CBZ. The percentage of drug released from patch was increased with the decreasing of patch thickness, and so did the permeation percentage. The stratum corneum (SC) contributed approximately 57% resistance of total skin permeation resistance, and Span 20 increased the transdermal permeation by approximately 1.59-fold. The pharmacokinetic parameters were obtained through in vivo experiments of the optimized formulation using rabbit. Furthermore, the in vitro skin permeation results of CBZ patch correlated well with the in vivo absorption results in rabbit.

Tissue-based ex-vivo studies on the oromucosal permeability of drugs are often insufficiently adapted to physiological and clinical conditions, which limits their predictivity. Moreover, the scientific community demands for the standardization of ex-vivo studies, since conceptual limitations (e.g. low sensitivity of analytical methods, insufficient monitoring, different designs) restrict the wide implementation in preclinical drug development. Therefore, an innovative ex-vivo permeation process consisting of novel Kerski diffusion cell coupled to fully automated sampling and sample preparation with LC-MS/MS quantification was developed and standardized. Novel assays for routine examination of tissue integrity and viability were developed and embedded in a comprehensive analytical control system. The high level of standardization and automation reduced the differences of between-run to within-run precision to ≤ 0.27 % CV. Successful validation proved a broad calibration range of 0.93-952.38 ng/mL of the model drug cyclobenzaprine with guideline-compliant relative errors from -7.9-12.6 % (between-run accuracy). Consequently, the method allowed the physiological-clinical alignment of the study conditions to therapeutic doses and the short residence time of intraoral drugs (sampling times 1-60 min). Applicability was demonstrated by assessing the oromucosal permeability for different sublingual cyclobenzaprine hydrochloride formulations representing the excipient selection as a common aspect during galenic development. Thereby, expressive evaluation of the dosage forms was achieved resulting in an improved permeation by replacing croscarmellose into polyvinylpyrrolidone (cumulative amount of 42.6 vs. 112.6 μg/cm²). Thus, the automated permeation process ensured lean, standardized and reproducible assessment of oromucosal permeability within quality-controlled academic and regulatory environments. Simultaneously, the improved ex-vivo predictivity through physiological-clinical adjustments facilitates the reduction of costly in-vivo studies.

Objetivo: Revisar a literatura acerca da eficácia de fármacos antidepressivos no tratamento de pacientes com disfunções musculares faciais crônicas em termos de redução da dor e efeitos adversos. Métodos: Pesquisaram-se os descritores “Antidepressive Agents”, “Facial Pain”, “Drug Therapy,”, conectados pelo operador booleano “AND”, na base de dados Pubmed dos últimos 10 anos. Obtiveram-se 40 artigos, dos quais foram selecionados 10 com base na leitura de títulos e resumos. Foram incluídos estudos e ensaios clínicos que relataram tratamentos de disfunções musculares faciais crônicas com fármacos antidepressivos. Resultados: 3 estudos concluíram que houve redução da dor em pacientes tratados com Amitriptilina e naqueles que receberam Amitriptilina com Pindolol. 2 estudos perceberam efeitos positivos nos pacientes tratados com Milnacipran. 2 estudos inferiram que, após o início da administração de Duloxetina, houve redução significativa da dor. 2 estudos sugeriram eficácia em pacientes com disfunções musculares faciais crônicas e que utilizaram Amitriptilina e Nortriptilina. 1 estudo observou o uso de Tizanidina ou Ciclobenzaprina, e concluiu sua ineficácia comparado ao placebo. Considerações finais: Os fármacos antidepressivos possuem a capacidade de tratar com eficácia as dores miofasciais, principalmente dores crônicas, devido a capacidade de possuir efeitos analgésicos, sendo a Amitriptilina considerada padrão-ouro para esses tratamentos.

The reactivity of Cyproheptadine and Cyclobenzaprine in Pd-catalyzed arylation via C-H bond functionalizations was investigated. From Cyproheptadine using aryl bromides as aryl sources and 5 mol% of a palladium catalyst, the C10-arylated Cyproheptadine derivatives were regioselectively obtained. The highest yields were obtained with electron-rich aryl bromides, but the reaction tolerated useful functional groups on the aryl bromide such as dimethylamino, methoxy, hydroxyl, alkyl, aryl, fluoro, chloro and trifluoromethyl. Cyclobenzaprine was also reactive under the same reaction conditions. © 2019 Elsevier Science. All rights reserved.

Skeletal muscle relaxants are frequently prescribed for low back pain and other musculoskeletal pain with or after failure of first-line treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs). While there can be benefits of using skeletal muscle relaxants in the short term, the long-term effects are unclear. These medications are heterogeneous and not chemically related and have several important adverse effects that should be considered given their widespread utilization. In the United States, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine are FDA approved for acute musculoskeletal conditions. Baclofen, tizanidine, and dantrolene are approved for spasticity. There is no clear evidence to show superiority of one muscle relaxant over another in managing acute low back pain, and most studies only evaluate results at 12 weeks or less. Most guidelines and current evidence support short-term use for all medications discussed in this chapter.

Fibromyalgia is a syndrome characterized by chronic generalized pain in addition to different symptoms such as fatigue, sleep disturbances, stiffness, cognitive impairment, and psychological distress. Multidisciplinary treatment combining pharmacological and nonpharmacological therapies is advised.Publications describing randomized controlled trials and long-term extension studies evaluating drug treatment for fibromyalgia were searched in PubMed and Scopus and included in this review.Different drugs are recommended for the treatment of fibromyalgia by different published guidelines, although only three of them have been approved for this indication by the US FDA, and none have been approved by the European Medicines Agency. According to the available evidence, pregabalin, duloxetine and milnacipran should be the drugs of choice for the treatment of this disease, followed by amitriptyline and cyclobenzaprine. Other drugs with at least one positive clinical trial include some selective serotonin reuptake inhibitors, moclobemide, pirlindole, gabapentin, tramadol, tropisetron, sodium oxybate and nabilone. None of the currently available drugs are fully effective against the whole spectrum of fibromyalgia symptoms, namely pain, fatigue, sleep disturbances and depression, among the most relevant symptoms. Combination therapy is an option that needs to be more thoroughly investigated in clinical trials.

A rapid and sensitive liquid chromatography–tandem mass spectrometry method was developed and validated for the quantification of cyclobenzaprine in dog plasma. After extracted with organic solvent, post-treatment samples were separated on an Agela C18 column interfaced with a triple quadrupole tandem mass spectrometer in positive electrospray ionization mode. Multiple reaction monitoring was performed using the transitions of m / z 276.2 → 216.1 and m / z 325.1 → 109.0 to quantify cyclobenzaprine and escitalopram (internal standard), respectively. The mobile phase consisted of acetonitrile: 5 mM ammonium acetate: formic acid (90:10:0.01, v/v/v) at a flow rate of 0.3 ml/min. The total analysis time was 2.4 min. The method was linear over the concentration range of 0.0200–10.0 ng/ml. The intra- and inter-day precision was within 12.8% in terms of relative standard deviation (RSD%) and the accuracy within 5.6% in terms of relative error. This method was successfully applied in a pharmacokinetic study of extended-release cyclobenzaprine in dogs.

Introduction Sexual dysfunction is a well-known side effect of antidepressants. Painful ejaculation is a rare side effect that has been reported with the use of some psychiatric drugs such as triclyclic antidepressants. Cyclobenzaprine is a muscle relaxant that is structurally similar to tricyclic antidepressants. It is the most commonly prescribed muscle relaxant in the United States and accounts for 18% of all prescriptions written for chronic back pain. Methods A 55-year-old man was referred to our pain medicine clinic for evaluation and treatment of pain with ejaculation. Main outcome Measure The main outcome measure was to review the current published literature and case reports on painful ejaculation from medication use, in particular tricyclic antidepressants. Results After discontinuation of cyclobenzaprine, our patient's sexual dysfunction resolved. This result was consistent with the literature reviewed on the topic. Conclusion Painful ejaculation is likely an underreported side effect of tricyclic antidepressants and cyclobenzaprine use. Fortunately, these symptoms are reversible and discontinuation of these medications is typically an effective cure.

Fibromyalgia is a chronic disorder characterized by widespread pain and tenderness, often accompanied by fatigue, memory problems, and sleep disturbances. Therapy includes both nonpharmacological (education, cognitive behavioral therapy, and exercise) and pharmacological treatment (including medicines as pregabalin, duloxetine, milnacipran, amitriptyline, serotonin selective reuptake inhibitors, and cyclobenzaprine). A number of surveys have reported that cannabis products are frequently used in patients with fibromyalgia. Results showed that most of the patients who tried medical marijuana found it to be effective or very effective for the therapy of some symptoms of this condition. Significant relief of pain and stiffness has been reported after cannabis self-administration. The efficacy and tolerability of oral nabilone for the treatment of pain and sleep difficulty have been established in some noncontrolled studies and two randomized-controlled clinical trials. Nabilone significantly reduced pain and improved quality of life in comparison to placebo. Nabilone was more effective than amitriptyline in improving sleep in fibromyalgia. More studies are needed to evaluate the efficacy and safety of cannabinoids in fibromyalgia.

Fibromyalgia is a chronic disorder with a broad spectrum of clinical manifestations such as muscular weakness and pain, fatigue and sleep disturbances. In this case we describe a female patient, frequent tea consumer with a classic presentation of fibromyalgia, initially treated with paracetamol+caffeine, due to poor control of symptoms cyclobenzaprine was prescribed, after a few months the symptoms got worse and duloxetine was added to the pharmacotherapy, few days later her muscle pain and weakness worsened, this could be explained by either the acrylamide from tea that mimics the fibromyalgia symptoms or food-drug interactions. Palpitations, insomnia, restless legs syndrome and anxiety associated to a mild serotoninergic syndrome could be due to drug-drug interactions. The novelty of this article is the presence of neurotoxic acrylamide in tea and the interactions it may have, not only with disease but with conventional pharmacotherapy also. It is of relevance to raise awareness about the possible toxic compounds found in food.

A collaborative study was conducted to investigate discrepancies in recoveries of two commonly prescribed compounds, amitriptyline and cyclobenzaprine, in patient urine samples when hydrolyzed with different enzymes from different sources. A 2- to 10-fold increase in analyte recoveries was seen for patient samples hydrolyzed using a recombinant β-glucuronidase (IMCSzyme™) over samples hydrolyzed with β-glucuronidase from Haliotis rufescens We report outcomes from four commercially available β-glucuronidase enzymes (IMCSzyme™, Patella vulgata, Helix pomatia and H. rufescens) on patient samples that tested positive for amitriptyline and cyclobenzaprine. Our results confirm reduced hydrolysis of glucuronides by β-glucuronidases isolated from mollusks, but near complete conversion when using the recombinant enzyme. Our premise is that systematic differences in hydrolysis efficiencies due to varying substrate affinity among enzyme subtypes potentially impacts accuracy and reliability of measurements.

Fibromyalgia (FM) affects up to 6% of U.S. adults, resulting in a significant burden on the health care system and poor quality of life for patients. Duloxetine, pregabalin, and milnacipran are approved for management of FM; however, consensus is lacking regarding optimal therapy. Patients with FM taking approved medications often do not experience meaningful symptom relief, and many experience intolerable adverse events.To assess treatment patterns associated with available and commonly used medications for the management of FM using U.S. health insurance claims.This retrospective analysis used the MarketScan claims database to identify adults with a first diagnosis of FM (ICD-9-CM code 729.1) between 2009 and 2011 with continuous health plan enrollment for 12 months pre- and post-index. Medications of interest were pregabalin, gabapentin, duloxetine, milnacipran, cyclobenzaprine, and tramadol. These are 6 of the 8 medications recommended by the American College of Rheumatology (ACR) for treating FM; the other 2 (amitriptyline and venlafaxine) were only included in some initial assessments. The Charlson Comorbidity Index (CCI) was used to assess overall comorbidity burden. Endpoints included proportion of patients treated within 1 year after first diagnosis; initial treatment pattern; adherence over the first-year follow-up period for the medications of interest; and discontinuation, switching, and combination therapy patterns among pain medications of interest at different time points. Proportion of days covered (PDC; defined as number of days in the period when the patient had drug supply divided by the number of days in the period) was used to define adherence, which was categorized as low (PDC50%), medium (PDC 50% to80%), or high (PDC ≥ 80%). The time to discontinuation (defined as the first drug supply gap ≥ 90 days) was estimated using Kaplan-Meier analysis.Overall, 240,144 patients met the inclusion criteria. Patients were predominantly women (68%), had preferred provider organization insurance coverage (68%), and had a CCI score1 at baseline (69%). Only 31% (n = 74,738) initiated a treatment with a prescription medication listed in the ACR guidelines, and many patients received less than the recommended dose. Most (n = 70,919) patients initially received monotherapy with one of the 8 prescription medications. Of those who started with ≥ 2 medications (n = 3,819), cyclobenzaprine plus tramadol was the most frequent combination. Adherence was suboptimal for all 6 medications of interest. Duloxetine had the highest mean PDC (59%); for all other agents, mean PDC was50%. With the exception of duloxetine, discontinuation rates at 6 months were50% for all agents. Alterations in therapy were common. Among patients who discontinued their initial treatment of duloxetine, pregabalin, or milnacipran, approximately one-third had switched treatments within 90 days after their first prescription. For those who maintained their initial treatment agent, approximately 50% of patients added a second pain medication within 1 year of treatment initiation.The evidence suggests that patients with FM often do not receive 1 of the prescription medications recommended by ACR guidelines, and those who do are commonly prescribed lower-than-recommended doses, potentially resulting in poor effectiveness and tolerability. Discontinuation, switching, and addition of new pain medications are common, which may indicate low levels of satisfaction with initial treatment. New therapies with improved effectiveness and better tolerability are urgently needed for patients with FM.

Objective. This study was designed to describe burden of illness and treatment patterns, and to examine the patient, physician, and care factors associated with the treatment choices of individuals receiving new prescriptions for fibromyalgia (FM). Design. This is a baseline assessment of the Real-World Examination of Fibromyalgia: Longitudinal Evaluation of Costs and Treatments (REFLECTIONS), a prospective observational study. Baseline data (including a physician survey, a patient visit form, and computer-assisted telephone interviews) were collected from July 2008 through May 2010 in 58 care settings in the United States, including Puerto Rico. Results. Patients (N = 1,700) were mostly female (94.6%) and white (82.9%). Mean age was 50.4 years and mean duration of illness was 5.6 years. Mean Fibromyalgia Impact Questionnaire total score was 54.4 (range 0–80), and Brief Pain Inventory average pain severity level was 5.5 (range 0–10). Patients reported high annual health care use and numerous work limitations related to FM. Patients were taking 182 unique types of medications prescribed for FM, including duloxetine (26.8%), nonsteroidal anti-inflammatory drugs (26.6%), pregabalin (24.5%), opioids (24.2%), tramadol (15.3%), benzodiazepines (15.2%), cyclobenzaprine (12.9%), milnacipran (8.9%), and others. Most patients took more than one medication concurrently (77.8%). Type of current medications used was most strongly associated with medication history and physician specialty. Conclusions. Burden of illness was high for patients with FM, and treatment patterns were highly variable. Importantly, the treatments with the most evidence to support their use were not always the most frequently chosen.

A sensitive, specific, and rapid high-pressure liquid chromatography/mass spectrometry/mass spectrometry method was developed for the quantitation of 11 tricyclic antidepressants and/or their metabolites; fluoxetine and norfluoxetine; cyclobenzaprine; and trazodone in urine. Samples were alkalinized with 0.2 N NaOH and extracted into 2 ml of hexane: ethyl acetate (1:1), evaporated to dryness, and reconstituted with 100 μl of 20 mM ammonium formate: methanol (20:80). The chromatographic separation was performed using an Allure Biphenyl 100 × 3.2 mm, 5-μ column with a mobile phase consisting of 20 mM ammonium formate: methanol (20:80 v/v) at a flow rate of 0.5 ml/min. The detection was accomplished by multiple-reaction monitoring via electrospray ionization source operating in the positive ionization mode. The calibration curve was linear over the investigated concentration range, 25-2,000 ng/ml, for each analyte using 1.0 ml of urine. The lower limit of quantitation for each analyte was 25 ng/ml. The intra- and inter-day precisions had coefficient of variation less than 15% and the accuracy was within the range from 88% to 109%. The method proved adequate for the tricyclic antidepressants analysis of urine for emergency clinical toxicology and pain management compliance testing.

Objective: Tinnitus is defined as an intrinsic sound sensation that cannot be attributed to an external sound source. Currently there are no standardized drug therapies for the treatment of tinnitus. Based on the analogy between pain and tinnitus it is suggested that among all antidepressant families that have been used for tinnitus, particular interest should be paid to the tricyclic group of drugs as they have an analgesic effect. The aim of the present study was to investigate the effect of a tricyclic pharmacological agent, namely cyclobenzaprine for the relief of tinnitus complaints. Subjects and methods: 65 patients, who received the drug treatment, were compared to 30 patients on a waiting list, who received no treatment. Results: Analysis shows that cyclobenzaprine offers some benefit to patients with tinnitus on both tinnitus intensity and tinnitus distress, while a waiting list control group does not demonstrate any improvement: 24% of the tinnitus patients showed a clear response to cyclobenzaprine with a reduction of 53% on tinnitus intensity and 25% had a clear response to cyclobenzaprine with a reduction of 55% on tinnitus distress. It was further demonstrated that particular subgroups, namely pure tone tinnitus patients and unilateral tinnitus patients, respond better to cyclobenzaprine. Conclusion: Our results indicate that cyclobenzaprine is a promising drug to treat tinnitus particularly in certain subgroups. As there is a good risk-benefit ratio and there are currently no well-established, specific treatments for tinnitus, cyclobenzaprine might be worthwhile to further investigate.

A sensitive, rapid and simple liquid chromatography–electrospray ionization mass spectrometry (LC-ESI-MS/MS) method was developed for the quantitative determination of cyclobenzaprine in human plasma, to study the pharmacokinetic behavior of cyclobenzaprine capsule in healthy Chinese volunteers. With escitalopram as the internal standard (IS), sample pretreatment involved a one-step liquid–liquid extraction using saturated sodium carbonate solution and hexane–diethyl ether (3:1, v/v). The separation was performed on an Ultimate XB-CN column (150 × 2.1 mm, 5 µm). Isocratic elution was applied using acetonitrile–water (40:60, v/v) containing 10 m M ammonium acetate and 0.1% formic acid. The detection was carried out on a triple-quadrupole tandem mass spectrometer in multiple reaction monitoring mode via electrospray ionization. The ion-pairs including m/z 276.2–216.2 for cyclobenzaprine and m/z 325.2–109.1 for IS were used for monitoring. Linear calibration curves were obtained over the range of 0.049–29.81 ng/mL with the lower limit of quantification at 0.049 ng/mL. The intra- and inter-day precision showed ≤6.5% relative standard deviation. The established method laid the groundwork for follow-up studies and provided basis for the clinical administration of cyclobenzaprine. Copyright © 2011 John Wiley & Sons, Ltd.

Dear Editor: We report a case of serotonin syndrome in a patient taking five agents that have known or reported serotonergic association. Symptoms began a year prior and were missed by multiple clinicians despite the addition of more serotonergic agents. We would like to discuss the importance of medication review, physical examination, and awareness of serotonin syndrome. A 41-year-old 84-kg woman presented to our chronic pain management clinic for removal of a lumbar spinal stimulator. Her past medical history included lumbar spondylosis with radiculopathy, cervical spondylosis with radiculopathy, anxiety, depression, osteoarthritis of the shoulders, and seasonal allergic rhinitis. Her surgical history included the placement of a spinal cord stimulator 3 years prior, multiple lumbar facet joint injections, a lumbar nerve radiofrequency ablation, a cervical epidural steroid injection, and two cesarean sections. Her medication list at the time of presentation was amitriptyline 50 mg daily, carisoprodol 350 mg three times daily, cetirizine 10 mg daily, cyclobenzaprine 5–10 mg at bedtime, duloxetine 120 mg at bedtime, gabapentin 800 mg three times daily, and tramadol 50 mg four times daily. She had been treated by a chronic pain specialist up to 3 years prior to her presentation with us. She received multiple injections and eventually a spinal cord stimulator for her lumbar back pain. She reported taking duloxetine for several years at 60 mg daily. She also reported taking a combination of duloxetine, celecoxib, pregabalin, and over-the-counter analgesics during that time …

Goal: To review and systematize the recently published data about the therapeutic management of the fibromyalgic patient. Data sources: National Guideline Clearinghouse, Cochrane, Dare, Bandolier e Medline. Review methods: Search of guidelines, meta-analysis, systematic reviews and original studies written in english and portuguese, published between 1998 and September 2008, using the keywords: “Fibromyalgia” and “Therapeutics”. Recommendations of scientific societies were also searched and those in which the level of evidence was analyzed were selected. 2 guidelines, 3 meta-analysis, 11 systematic reviews and 4 original studies were included. SORT taxonomy was used to attribute the level of evidence and strength of recommendation. Results: The management of Fibromyalgia requires an assessment of pain severity, function, psychosocial context and associated morbidities. Regarding pharmacological therapy, there is strong evidence supporting the use of duloxetine, pregabalin and gabapentin for pain management. Moderate evidence supports the use of amitriptyline and cyclobenzaprine (specially if associated sleep disorders) and fluoxetine. Milnacipran and pirlindole showed promising results but further studies and needed. The positive effects reported with fluoxetine, duloxetine and milnacipran were independent of the presence of mood disorders and the dosages used were similar or higher than those recommended for antidepressive treatment, allowing the management of associated depression. As for non-pharmacological therapy, there is moderate evidence supporting aerobic exercise and heated pool treatment. Conclusions:Multiple pharmacological and non-pharmacological treatments showed positive effects in the control of pain and related symptoms. In the absence of a treatment that targets all the symptoms of fibromyalgia, an optimized management will require an individualized multidisciplinary approach.

Cyclobenzaprine is a tricyclic pharmacologic agent that has enjoyed considerable use since its availability. Most clinical usages have focused on the muscle relaxant properties, the mechanism of action being more recently redefined. Higher orders of the CNS are, nevertheless, affected, and the latter contributes to the spectrum of proclaimed side effects that are otherwise largely anticholinergic in nature. Cyclobenzaprine has a reasonable safety profile and overdoses are not as problematic as those for accepted tricyclic psychotherapeutic agents. Clinical studies have given supportive, albeit not conclusive, evidence for treatment roles in the short-term management of acute neck and back pain, and fibromyalgia. Further and more exacting science is warranted to explore the value of this drug in other neurological and psychiatric contexts.

OBJECTIVE To evaluate cyclobenzaprine interference on tricyclic antidepressant assays. DATA SOURCES Literature was identified through a MEDLINE search (1966–August 2004) using the search terms cyclobenzaprine, tricyclic antidepressant, toxicology, and assay. DATA SYNTHESIS Cyclobenzaprine is structurally similar to tricyclic antidepressants and is often identified as a tricyclic antidepressant on toxicology assays. Older chromatographic assays demonstrate retention time differences of only seconds and nearly identical color stains between cyclobenzaprine and individual tricyclic antidepressants. In comparison, ultraviolet absorption ratios of 4.18 for amitriptyline and 1.85 for cyclobenzaprine are easily distinguished. Spectroscopy also consistently identifies cyclobenzaprine's unique mass-to-charge ratio peaks of 275 and 215 compared with those of amitriptyline. Available bioanalytic techniques are reviewed for their ability to correctly identify cyclobenzaprine and differentiate the drug from tricyclic antidepressants. CONCLUSIONS When assays are positive for tricyclic antidepressants without a history of their use, an attempt should be made to identify confounders, such as cyclobenzaprine. Newer bioanalytic techniques, such as ultraviolet absorption and mass spectroscopy, accurately identify cyclobenzaprine in such instances.

This case discusses the pharmacokinetic interaction between cyclobenzaprine and smoked tobacco resulting in cyclobenzaprine toxicity due to reversal of enzyme induction. Cyclobenzaprine is a cytochrome P450 1A2 substrate. Smoked tobacco is a 1A2 inducer.

Muscle relaxant medications are chosen based upon their symptomatic need, side effect profile, and tolerability. Often patients with a primary pain issue may experience secondary muscle spasm; therefore, practitioners sometimes use muscle relaxants concurrently with other medications to adequately treat their patient’s pain.

The deceased was a 35 year old female who was found by her husband in the bathtub with her head and face submerged in the water. Autopsy findings were unremarkable. Toxicological analysis revealed the presence of ethanol (215 mg/dL) and cyclobenzaprine (1.786 mg/l) in the blood. This high concentration of cyclobenzaprine (Flexeril®) in combination with alcohol proved to be fatal.

Serotonin syndrome is a potentially lethal adverse drug reaction that may occur in patients taking proserotoninergic medications. Drug interactions are often responsible for the causation of this syndrome. We report two cases of severe serotonin syndrome induced by the administration of cyclobenzaprine in postoperative patients already receiving another proserotoninergic drug (phenelzine in one case and duloxetine in the other). In both cases, symptoms of autonomic instability and severe agitation started within hours of initiation of cyclobenzaprine and fully resolved within 3 days after discontinuing the proserotoninergic drugs. We conclude that cyclobenzaprine should be used with extreme caution in patients receiving other serotonin-enhancing drugs; these patients should be closely monitored for manifestations of serotonin syndrome.

A full-term male infant presented shortly after birth with respiratory distress. An echocardiogram done within the first hour of life showed an elevated pulmonary artery pressure, an associated right ventricular hypertrophy without a patent ductus arteriosus. The patient was treated for persistent pulmonary hypertension with favorable response. Maternal history was unremarkable except for chronic low back pain treated with cyclobenzaprine (Flexeril®). A proposed mechanism for cyclobenzaprine includes inhibition of norepinephrine and serotonin reuptake, factors known to inhibit prostaglandin and nitric oxide. These two factors are the leading causes of in-utero ductal closure. This report is the first to indicate that cyclobenzaprine use during late pregnancy should be considered a potential cause of early ductal closure.

The fungus, Cunninghamella elegans, was used as a microbial model of mammalian drug metabolism to biotransform a tricyclic antidepressant, cyclobenzaprine. Seventy-five percent of this drug at a concentration of 1 mM was metabolized within 72 h by C. elegans grown on Sabouraud dextrose broth. Milligram amounts of fungal metabolites were isolated by reversed-phase high performance liquid chromatography (HPLC) and their structures were characterized by 1H NMR spectroscopy, mass spectrometry, and UV spectroscopy analyses. The major fungal metabolites of cyclobenzaprine were 2-hydroxycyclobenzaprine (59%), N-desmethylcyclobenzaprine (21%), cyclobenzaprine trans-10,11-dihydrodiol (5%), N-desmethyl-2-hydroxy-cyclobenzaprine (3%), 3-hydroxycyclobenzaprine (3%), and cyclobenzaprine N-oxide (1%). These fungal metabolites were used as standards to investigate the metabolism of cyclobenzaprine by rat liver microsomes. Rat liver microsomes also biotransformed cyclobenzaprine to produce similar metabolites as the fungus. The isotope labeling of 2-hydroxycyclobenzaprine by 18O2 and the trans-configuration of the dihydrodiol suggested that these reactions were catalyzed by cytochrome P-450 monooxygenases in C. elegans. These results also demonstrated that the fungal biotransformation system could be used to predict and synthesize the mammalian drug metabolites.

The centrally acting muscle relaxant cyclobenzaprine was thought to be an alpha 2-adrenoceptor agonist that reduced muscle tone by decreasing the activity of descending noradrenergic neurons. In the present study, we examined the effects of cyclobenzaprine on descending neurons by measuring the monosynaptic reflex in rats. Cyclobenzaprine reduced the monosynaptic reflex amplitude dose dependently and this effect was not inhibited by the alpha 2-adrenoceptor antagonists idazoxan and yohimbine. Cyclobenzaprine-induced monosynaptic reflex depression was not attenuated by noradrenergic neuronal lesions produced by 6-hydroxydopamine. However, cyclobenzaprine inhibited monosynaptic reflex facilitation induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, a 5-HT2 receptor agonist, in spinalized rats markedly, and 5-HT depletion by DL-p-chlorophenylalanine inhibited the depressive effect of cyclobenzaprine on the monosynaptic reflex. These results suggest that cyclobenzaprine is a 5-HT2 receptor antagonist and that its muscle relaxant effect is due to inhibition of serotonergic, not noradrenergic, descending systems in the spinal cord.

Cyclobenzaprine and its major metabolite, norcyclobenzaprine, differ from amitriptyline and nortriptyline only by the presence of a double bond in the cycloheptane ring. Three patients developed sufficient levels of cyclobenzaprine and norcyclobenzaprine because of either rapid or long-term ingestion of cyclobenzaprine to cause positive interferences in both a Syva EMIT assay and a high-performance liquid chromatographic (HPLC) assay for identification and quantitation of tricyclic antidepressants in serum. Cyclobenzaprine coeluted with amitriptyline, and norcyclobenzaprine eluted slightly earlier than, but was poorly resolved from, nortriptyline in this HPLC assay. We found that cyclobenzaprine could be distinguished from amitriptyline and that norcyclobenzaprine could be distinguished from nortriptyline on the basis of gas chromatographic retention times upon gas chromatographic-mass spectrometric analyses after derivatization with trifluoroacetic anhydride. The compounds were also distinguishable by mass spectrometric criteria.

This chapter is about drugs approved to treat both spastic upper motor neuron conditions like cerebral palsy or multiple sclerosis and drugs that are used to relieve muscle spasm associated with musculoskeletal conditions such as acute non-radicular cervical or low back pain. Unlike other analgesic classes such as opioids and NSAIDS, the muscle relaxant drugs as a group share neither chemical structure nor mechanism of action. For example, two drugs approved to treat spasm, baclofen, and tizanidine work by different mechanisms. The former blocks GABA-B receptors and the latter is an alpha-2 agonist. Cyclobenzaprine, a drug approved for treating spasm-type pain in the low back, except for one double bond, is chemically identical to the tricyclic antidepressant amitriptyline.

A simple, fast and accurate liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for the quantification of cyclobenzaprine in human plasma. After a simple single-step liquid–liquid extraction with ethyl acetate, the analyte was separated in an Intersil ODS-3 column through isocratic elution with methanol–water containing 0.1% formic acid (80:20, v/v) at a flow rate of 0.2 ml/min and analyzed by mass spectrometry in the positive ion MRM mode. Good linearity was achieved from 0.04 to 50 ng/ml. The intra- and interday precisions were less than 12.1%, and accuracy ranged from 99.6 to 106.2%. The elimination half-lives (t1/2 Z) after a single oral administration of 5, 10, and 15 mg cyclobenzaprine tablets were 25.5, 26.2, and 26.4 h, respectively. The means ofCmax and AUC increased proportionally to the cyclobenzaprine doses. The pharmacokinetics of cyclobenzaprine fit the linear dynamics of the cyclobenzaprine dose range in healthy Chinese volunteers. Key words: Cyclobenzaprine, liquid chromatography, electrospray ionization, tandem mass spectrometry.