Cyclobenzaprine Research Articles

A Novel Method for Determination of Cyclobenzaprine in the Different Matrixes by UHPLC-DAD: Application to Real Human Plasma and Pharmaceutical Formulations.

This study presents a novel and efficient method for determining of cyclobenzaprine (CBP) in human plasma and tablets using simple liquid-liquid microextraction and ultra-high performance liquid chromatography-diode-array detector. The developed method was optimized and validated for selectivity, linearity, precision, accuracy, limit of detection (LOD) and limit of quantification (LOQ). The chromatographic separation was achieved using a C18 column with a mobile phase consisting of a mixture of deionized water containing 0.1% TFA and methanol (30:70, v:v) at a flow rate of 1.0mL/min. The extraction process provided high-efficiency recovery of CBP with a small plasma volume (%94.3). The method showed good linearity within the concentration range of 0.005-10μg/mL, with a correlation coefficient of 0.999. The LOD and LOQ values were found to be 0.0013 and 0.005μg/mL, respectively. The intra- and inter-day %RSD were <8%, and %RE were ranged from -0.50 to 0.01%. The proposed method was successfully applied to the analysis of CBP in real human plasma samples and tablets, indicating its applicability in clinical and pharmaceutical research. In conclusion, the simple, low cost, high sensitivity and rapid nature of this method make it an attractive option for the quantification of CBP in human plasma and pharmaceutical dosage forms.

Energy metabolism as a target for cyclobenzaprine: A drug candidate against Visceral Leishmaniasis

Leishmaniases have a broad spectrum of clinical manifestations, ranging from a cutaneous to a progressive and fatal visceral disease. Chemotherapy is nowadays the almost exclusive way to fight the disease but limited by its scarce therapeutic arsenal, on its own compromised by adverse side effects and clinical resistance. Cyclobenzaprine (CBP), an FDA-approved oral muscle relaxant drug has previously demonstrated in vitro and in vivo activity against Leishmania sp., but its targets were not fully unveiled. This study aimed to define the role of energy metabolism as a target for the leishmanicidal mechanisms of CBP. Methodology to assess CBP leishmanicidal mechanism variation of intracellular ATP levels using living Leishmania transfected with a cytoplasmic luciferase. Induction of plasma membrane permeability by assessing depolarization with DiSBAC(2)3 and entrance of the vital dye SYTOX® Green. Mitochondrial depolarization by rhodamine 123 accumulation. Mapping target site within the respiratory chain by oxygen consumption rate. Reactive oxygen species (ROS) production using MitoSOX. Morphological changes by transmission electron microscopy. CBP caused on L. infantum promastigotes a decrease of intracellular ATP levels, with irreversible depolarization of plasma membrane, the collapse of the mitochondrial electrochemical potential, mild uncoupling of the respiratory chain, and ROS production, with ensuing intracellular Ca2+ imbalance and DNA fragmentation. Electron microscopy supported autophagic features but not a massive plasma membrane disruption. The severe and irreversible mitochondrial damage induced by CBP endorsed the bioenergetics metabolism as a relevant target within the lethal programme induced by CBP in Leishmania. This, together with the mild-side effects of this oral drug, endorses CBP as an appealing novel candidate as a leishmanicidal drug under a drug repurposing strategy.

Radioiodination of Quetiapine and Cyclobenzaprine as Brain Monitoring Agents: Comparative Study on SPECT Imaging

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.

CYCLOBENZAPRINE OVERDOSE PRESENTING WITH RHABDOMYOLYSIS, DISTRIBUTIVE SHOCK, AND MULTIORGAN FAILURE

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Few cases of cyclobenzaprine (CBZ) overdose exist in the literature, and the range of toxicity is not well-defined. We report a case of CBZ overdose with life-threatening shock and multiorgan failure. CASE PRESENTATION: A 51-year-old woman with type 2 diabetes, hypertension, chronic back pain, and depression presented to the emergency department after being found unresponsive near an empty bottle of CBZ. She was hypotensive and mildly tachycardic with a Glasgow coma score of 8. She was intubated and admitted to the intensive care unit. She had multiorgan failure with acute kidney injury (blood urea nitrogen: 57 mg/dL, creatinine: 7.1 mg/dL), elevated liver enzymes, anion gap metabolic acidosis (arterial blood gas pH 7.1, pCO2: 34, pO2: 80, HCO3: 10), creatine kinase level of 39K IU/L, and myoglobin >3000 ng/mL. Her urine drug screen was positive for TCA; her serum qualitative screen was positive for CBZ. Her electrocardiogram (ECG) showed widened QRS with no acute ST changes. Given her hypotension refractory to intravenous (IV) fluid resuscitations, she received 2 inotropic agents for 2 days, maintenance IV fluids, and NaHCO3 infusion. Her QRS interval normalized after 6 hours. She was extubated on day 3 with subsequent normalization of both her kidney and liver functions (Graph 1, 2). Later she reported ingesting the CBZ as a suicide attempt. DISCUSSION: Cyclobenzaprine is a centrally acting muscle relaxant, that is structurally similar to amitriptyline (TCA), differing by only one double bond. CBZ and TCA cause reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation. Toxic effects can be mild (e.g., confusion, visual hallucination, agitation, drowsiness, dry mouth, dizziness) or severe (e.g., cardiac arrhythmias, hypotension, convulsions, stupor, coma). Spiller et al.'s analysis of 402 cases of CBZ toxicity found respiratory failure requiring mechanical ventilation in 12 cases (3%). Only 2 cases had refractory hypotension requiring inotropic support. Rhabdomyolysis is an uncommon complication, reported only in 2 independent case reports. The management of a CBZ overdose is like that of any TCA. Gastrointestinal decontamination by lavage and activated charcoal is time sensitive. QRS widening or intraventricular conduction abnormalities should be treated with NaHCO3. CONCLUSIONS: To our knowledge, this is the first case report of life-threatening shock resulting in concurrent multiorgan failure, including acute renal insufficiency, hepatic injury, rhabdomyolysis, metabolic encephalopathy, and respiratory failure from CBZ overdose. Health care professionals should realize that CBZ overdose can present as a spectrum of toxicities, including life-threatening complications. Early recognition and appropriate intervention can help reverse this otherwise possible fatal condition Reference #1: Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter retrospective review of cyclobenzaprine toxicity. J Emerg Med. 1995;13(6):781–785. doi:10.1016/0736-4679(95)02019-5 Reference #2: Chabria SB. Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity. J Occup Med Toxicol. 2006;1:16. doi:10.1186/1745-6673-1-16 DISCLOSURES: No relevant relationships by Meily Arevalo, source=Web Response No relevant relationships by Mohamed Elmassry, source=Web Response No relevant relationships by John Makram, source=Web Response No relevant relationships by Haneen Mallah, source=Web Response No relevant relationships by Arunee Motes, source=Web Response No relevant relationships by Kenneth Nugent, source=Web Response No relevant relationships by Pablo Paz, source=Web Response

Inclusion complexes of tricyclic drugs and β-cyclodextrin: Inherent chirality and dynamic behaviour.

Amitriptyline (AMT) and cyclobenzaprine (CBZ) are tricyclic drugs used as antidepressant and muscle relaxant, respectively. They show inherently chirality, i.e. they are chiral due to the lack of any symmetry element. As they are used as racemic mixture, diastereomeric inclusion complexes are formed via encapsulation in homochiral βCD. In this work we show that a suitable combination of NMR methods easily provides details on the chiral recognition, geometry of complexation, rotational dynamics and spatial proximity of selected atom pairs. In particular, we show that 13C NMR can be used to unambiguously assess chiral recognition, demonstrating a higher performance over 1H NMR. The mole fraction of the bound drug and the association constant can be worked out through diffusion experiments, whereas the combination of non-selective, selective and bi-selective relaxation spectra gave insights into the rotational motion of the complexed drug and the spatial proximity of selected proton pairs. The toolkit here proposed provides a thorough characterization of CD/drug inclusion complexes from a physicochemical point of view. This can constructively complement the conventional pharmacological and pharmacokinetic experiments, and can shed light on the understanding of CD/drug formulations.

Drug encapsulation and chiral recognition in deep eutectic solvents/β-cyclodextrin mixtures

Hybrid materials resulting from the combination of Deep Eutectic Systems (DES) with well-known encapsulating agents like β-cyclodextrin (βCD) can open up new possibilities in the design of novel drug delivery systems or chiral-recognizing platforms. Here, 1:1 inclusion complexes of βCD and the tricyclic drugs amitriptyline (AMT) and cyclobenzaprine (CBZ) are studied in DES choline chloride:urea (reline) using a combination of NMR experiments. 1H complexation-induced chemical shift and intermolecular host-guest NOEs in the rotating frame (ROESY) confirm genuine drug encapsulation, and diffusion and relaxation measurements are used to study the dynamics of the guest-host inclusion complexes at the molecular level. Given the inherent chirality of AMT and CBZ, 13C NMR spectra unambiguously indicate the formation of diastereomeric inclusion complexes, demonstrating for the first time the retained enantiorecognition ability of βCD in DES. The proposed supramolecular systems combine then effectively the properties of DES and CDs.

Electrochemical Characterization of Central Action Tricyclic Drugs by Voltammetric Techniques and Density Functional Theory Calculations.

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 ≈ 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 ≈ 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.

Investigation of Cyclobenzaprine Interactions with P450 Cytochromes CYP1A2 and CYP3A4 through Molecular Docking Tools

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.

Raman Spectroscopy vs Voltammetry: A Voltammetric Approach to Elucidate Different Chemicals in a Range of Pharmaceutical Tablets

Over the years, Electroanalysis has been widely applied to elucidate redox behavior of novel molecules. The selectivity and low cost are spotlight features in pharmacopeial methods of identification, that can be reached by voltammetric approaches. In this work, differential pulse voltammetric (DPV) profile and the slope of the linear regression obtained from calibration graphs along with the scan study are proposed as new perspective of identification assays. With the proposed methodology we were able to identify the similarities among DPV profile and the slopes obtained for each tablet. In addition, this new technology was successfully employed to identify the following chemicals: Paracetamol (PAR), Promethazine (PMZ), Diclofenac (DIC), Piroxicam (PRX), Indomethacin (IND) and Cyclobenzaprine (CBP) in pharmaceutical assays using Pencil Graphite Electrodes. Furthermore, our new methodology was effectively compared to Raman Spectroscopy for the analysis of the range of chemicals in the pharmaceutical assays.

276 No Evidence of Sedation of Tolperisone Compared to Cyclobenzaprine in a Crossover Driving Simulation Study

Tolperisone is a centrally acting muscle relaxant being developed in the US as a treatment for acute and painful symptoms of neck and low back muscle spasms. This study explores the impact of tolperisone on driving simulation endpoints, sedation, and cognition compared to placebo (PBO) and cyclobenzaprine (CYC). The CYC half-life is long (>19 hours) and accumulated over the 3 days of the trial. Tolperisone has a Tmax of 1 hour, and a 2- to 3-hour half-life. This was a 3-way, randomized, blinded, crossover study of tolperisone in 31 healthy volunteers. Treatment groups were 450 mg tolperisone administered 3-times a day (150 mg TID), 30 mg CYC (10 mg TID), and PBO (TID). Participants spent 3 days of 3 consecutive weeks in the research unit. Dosing occurred in the morning (AM) and at midday (PM) on Days 1-3 and at bedtime on Days 1 and 2. Subjects were administered a DSST followed by 100 km (60 minute) of simulated driving on Day 1 one hour after their midday dose (at drug Tmax), and the morning of Day 2 (pre-dosing) to assess next day residual effects. Tests were the morning of Day 3 (post-dose) to assess the drug at steady-state. Subjects returned to the clinic on Days 7 and 14 to repeat these procedures. For the primary endpoint of Standard Deviation of Lateral Position (SDLP) over 100-km of driving, tolperisone was no different than PBO, whereas CYC showed significant impairment (p=<0.001). The distribution of SDLP for PBO and tolperisone showed symmetry around zero, while CYC was markedly different; a subset of subjects had a level of impairment associated with increased crash risk, demonstrated by SDLP values above 4.4 cm (consistent with normative Blood Alcohol Concentration (BAC) levels of above 0.05%). Secondary measures confirmed a lack of sedation for tolperisone relative to PBO: Digit Symbol Coding Day 1 p= 0.84, Day 2 p= 0.21, Day 3 p= 0.12; and Karolinska Sleepiness Scale: Day 1 p= 0.47, Day 2 p= 0.47, and Day 3 p= 0.49. Additional measures of driving indicated no impairment for tolperisone versus PBO. Tolperisone 150 mg TID had no impact on various measures of driving, self-reported sleepiness, and cognition, in contrast to CYC 10 mg TID. Data confirms impairment in cognition and driving for healthy subjects taking CYC.Table 1Secondary Driving Endpoints: p values for Treatment ComparisonsTOL vs PBOTOL vs CYCCYC vs PBOMaintenance of Lane PositionLane exceedance number0.8181<0.001<0.001Lane exceedance Maximum0.41270.00090.019Lane Exceedance Duration0.8064<0.001<0.001Speed ControlAverage Speed0.67510.67160.3871Speed Deviation0.1533<0.0010.0009Speedings Count0.65870.06680.0207Speedings Ratio0.84780.05000.0272Divided AttentionCorrect Response0.21350.87400.1537Omission Errors0.27190.65510.1196Commission Errors0.92970.16590.1903Reaction Time (RT)0.01550.00010.1130Std Deviation of RT0.03420.06930.7215Other SafetyTotal Crashes0.50000.06250.0938Excessive Cornering0.76830.03090.0148Patients taking CYC perceived a lack of effect discrimination and reported feeling safe to drive on Days 2 and 3. Open table in a new tab

854. Phase 2 Multisite Double-Blind Placebo-Controlled Trial of TNX-102 Sl in Military-Related Posttraumatic Stress Disorder (PTSD): Mediators and Moderators of Treatment Response

Evidence-based pharmacotherapies are lacking for military-related PTSD. TNX-102 SL* is a proprietary formulation of cyclobenzaprine (CBP) for bedtime sublingual administration that bypasses first pass metabolism and antagonizes 5-HT2A, 1-adrenergic and histaminergic-1 receptors. It is hypothesized to improve PTSD via effects on core symptoms of sleep disturbance and hyperarousal.

Cyclobenzaprine Raises ROS Levels in Leishmania infantum and Reduces Parasite Burden in Infected Mice.

BackgroundThe leishmanicidal action of tricyclic antidepressants has been studied and evidences have pointed that their action is linked to inhibition of trypanothione reductase, a key enzyme in the redox metabolism of pathogenic trypanosomes. Cyclobenzaprine (CBP) is a tricyclic structurally related to the antidepressant amitriptyline, differing only by the presence of a double bond in the central ring. This paper describes the effect of CBP in experimental visceral leishmaniasis, its inhibitory effect in trypanothione reductase and the potential immunomodulatory activity.Methodology/Principal FindingsIn vitro antileishmanial activity was determined in promastigotes and in L. infantum-infected macrophages. For in vivo studies, L. infantum-infected BALB/c mice were treated with CBP by oral gavage for five days and the parasite load was estimated. Trypanothione reductase activity was assessed in the soluble fraction of promastigotes of L. infantum. For evaluation of cytokines, L. infantum-infected macrophages were co-cultured with BALB/c splenocytes and treated with CBP for 48 h. The supernatant was analyzed for IL-6, IL-10, MCP-1, IFN-γ and TNF-α. CBP demonstrated an IC50 of 14.5±1.1μM and an IC90 of 74.5±1.2 μM in promastigotes and an IC50 of 12.6±1.05 μM and an IC90 of 28.7±1.3 μM in intracellular amastigotes. CBP also reduced the parasite load in L. infantum-infected mice by 40.4±10.3% and 66.7±10.5% in spleen at 24.64 and 49.28 mg/kg, respectively and by 85.6±5.0 and 89.3±4.8% in liver at 24.64 and 49.28mg/kg, after a short-term treatment. CBP inhibited the trypanothione reductase activity with a Ki of 86 ± 7.7 μM and increased the ROS production in promastigotes. CBP inhibited in 53% the production of IL-6 in infected macrophages co-culture.Conclusion/SignificanceTo the best of our knowledge, this study is the first report of the in vivo antileishmanial activity of the FDA-approved drug CBP. Modulation of immune response and induction of oxidative stress in parasite seem to contribute to this efficacy.

Rapid validated liquid chromatographic method coupled with Tandem mass spectrometry for quantification of nintedanib in human plasma

Purpose: To develop and validate a fast, sensitive, and simple liquid chromatographic method coupled with tandem mass spectrometry for the determination of the potent tyrosine kinase inhibitor, ninetedanib (NTB) in plasma, utilizing cyclobenzaprine (CBP) as internal standard (IS). Methods: Separation of the two components (NTB and CBP) was performed on a pentafluorophenyl (PFP) reversed phase column (50 × 2 mm, 3μm) at ambient temperature using isocratic elution with acetonitrile-water (60:40, v/v) containing 0.01 M ammonium formate buffer (pH 4.2) at a flow rate of 0.4 mL/min. NTB and CBP were monitored by a triple quadrupole tandem mass spectrometer with electrospray ionization source in the positive ion mode. The current method was validated following the European Medicines Agency (EMA) guidelines Results: The proposed method allowed rapid and specific quantification of NTB in the calibration range of 2 - 150 ng/mL and determination coefficient of ≥ 0.999. Intra- and inter-day accuracy and precision were < 4 % in all cases. Conclusion: The developed procedure is rapid, specific, reliable, and validated for quantification of NTB in human plasma, and thus can be applied efficiently for the analysis of clinical samples containing NTB. Keywords: Nintedanib assay, Cyclobenzaprine, LC-MS/MS, Validation

Two steps modification for improvement of cyclobenzaprine transdermal delivery: releasing from patch and penetrating through skin

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.

Avoid Sedatives and Opioids for Treating Low Back Pain

Cyclobenzaprine (Flexeril) is a tricyclic antidepressant that is viewed as having “muscle relaxant” properties, even though it has no effect on motor

Effects of Bedtime Very Low Dose Cyclobenzaprine on Symptoms and Sleep Physiology in Patients with Fibromyalgia Syndrome: A Double-blind Randomized Placebo-controlled Study

To determine the effects of bedtime very low dose (VLD) cyclobenzaprine (CBP) on symptoms and sleep physiology of patients with fibromyalgia (FM), unrefreshing sleep, and the α-nonREM sleep electroencephalographic (EEG) anomaly at screening. Of 37 patients with FM in the screened population, 36 were randomized and treated in this 8-week, double-blind, placebo-controlled, dose-escalating study of VLD CBP 1-4 mg at bedtime. We evaluated changes in subjective symptoms including pain, tenderness, fatigue, mood [Hospital Anxiety and Depression Scale (HAD)], and objective EEG sleep physiology (at screening, baseline, and Weeks 2, 4, and 8). In the VLD CBP-treated group (n = 18) over 8 weeks, musculoskeletal pain and fatigue decreased, tenderness improved; total HAD score and the HAD depression subscore decreased; patient-rated and clinician-rated fatigue improved. In the placebo-treated group (n = 18), none of these outcome measures changed significantly. Compared to placebo at 8 weeks, VLD CBP significantly improved pain, tenderness, and the HAD Depression subscore. Analysis of cyclic alternating pattern (CAP) sleep EEG revealed that significantly more subjects in the VLD CBP group than the placebo group had increased nights of restorative sleep in which CAP(A2+A3)/CAP(A1+A2+A3) = CAP(A2+A3(Norm)) ≤ 33%. For VLD CBP-treated subjects, the increase in nights with CAP(A2+A3(Norm)) ≤ 33% was correlated to improvements in fatigue, total HAD score, and HAD depression score. Bedtime VLD CBP treatment improved core FM symptoms. Nights with CAP(A2+A3(Norm)) ≤ 33% may provide a biomarker for assessing treatment effects on nonrestorative sleep and associated fatigue and mood symptoms in persons with FM.

Time to response in patients treated with immediate- and extended-release cyclobenzaprine

Time to response is a clinically-meaningful assessment in the treatment of acute, painful musculoskeletal conditions. Prompt interruption of the spasmpain-spasm cycle can ease discomfort and enable a more rapid return to function. This analysis examined data from patients with muscle spasm of cervical/lumbar origin, randomly assigned to 1 of 4 groups: cyclobenzaprine extendedrelease (CER) 15mg QD (n=117), CER 30mg QD (n=121), cyclobenzaprine immediate-release (CIR) 10mg TID (n=118), and placebo (n=117). Three variables were analyzed: patient's rating of medication helpfulness, relief from local pain, and restriction of movement. The Kaplan-Meier method was used to estimate time to response distributions; differences between treatment groups and placebo were tested using the log-rank test. Results showed time to response was accelerated with CER and CIR. For medication helpfulness, time to achieve a very good/excellent rating was a median 10 days with CER 15mg (95% CI: 7,11; p=0.0199), 8 with CER 30mg (7,10; p=0.0038), 7 with CIR 10mg (6,8; p<0.001), and >14 (9,.) with placebo. For relief from local pain, time to achieve a lot/complete relief was 6 days with CER 15mg (5,7; p=0.0157), 5 with CER 30mg (4,7; p=0.0022), 5 with CIR 10mg (4,6; p=0.002), and 8 (6,11) with placebo. For restriction of movement, time to achieve a lot/complete relief was 6 days with CER 15mg (5,7; p=0.0643), 5 with CER 30mg (4,6; p=0.0041), 5 with CIR 10mg (4,6; p=0.009), and 7 (6,9) with placebo. Adverse events were generally mild. Somnolence rates were lower with CER 15mg (0.8%) and 30mg (1.6%) than with CIR 10mg (7.3%). Overall, patients taking cyclobenzaprine responded more rapidly than those taking placebo, CER being associated with less somnolence than CIR. Given muscle spasm may affect the ability to work, these findings may have economic consequences, with accelerated response allowing patients to resume normal activities sooner. (Sponsored by Cephalon, Inc.) Time to response is a clinically-meaningful assessment in the treatment of acute, painful musculoskeletal conditions. Prompt interruption of the spasmpain-spasm cycle can ease discomfort and enable a more rapid return to function. This analysis examined data from patients with muscle spasm of cervical/lumbar origin, randomly assigned to 1 of 4 groups: cyclobenzaprine extendedrelease (CER) 15mg QD (n=117), CER 30mg QD (n=121), cyclobenzaprine immediate-release (CIR) 10mg TID (n=118), and placebo (n=117). Three variables were analyzed: patient's rating of medication helpfulness, relief from local pain, and restriction of movement. The Kaplan-Meier method was used to estimate time to response distributions; differences between treatment groups and placebo were tested using the log-rank test. Results showed time to response was accelerated with CER and CIR. For medication helpfulness, time to achieve a very good/excellent rating was a median 10 days with CER 15mg (95% CI: 7,11; p=0.0199), 8 with CER 30mg (7,10; p=0.0038), 7 with CIR 10mg (6,8; p<0.001), and >14 (9,.) with placebo. For relief from local pain, time to achieve a lot/complete relief was 6 days with CER 15mg (5,7; p=0.0157), 5 with CER 30mg (4,7; p=0.0022), 5 with CIR 10mg (4,6; p=0.002), and 8 (6,11) with placebo. For restriction of movement, time to achieve a lot/complete relief was 6 days with CER 15mg (5,7; p=0.0643), 5 with CER 30mg (4,6; p=0.0041), 5 with CIR 10mg (4,6; p=0.009), and 7 (6,9) with placebo. Adverse events were generally mild. Somnolence rates were lower with CER 15mg (0.8%) and 30mg (1.6%) than with CIR 10mg (7.3%). Overall, patients taking cyclobenzaprine responded more rapidly than those taking placebo, CER being associated with less somnolence than CIR. Given muscle spasm may affect the ability to work, these findings may have economic consequences, with accelerated response allowing patients to resume normal activities sooner. (Sponsored by Cephalon, Inc.)

Comparison of the Single-Dose Pharmacokinetics of Once-Daily Cyclobenzaprine Extended-Release 30 mg and Cyclobenzaprine Immediate-Release 10 mg Three Times Daily in the Elderly

The clinical utility of cyclobenzaprine for the treatment of muscle spasm associated with acute, painful musculoskeletal conditions is limited by cholinergic adverse effects associated with its use. As expected, these effects may be pronounced in the elderly in whom altered renal and hepatic function may change drug pharmacokinetics. The goal of this study was to characterize the pharmacokinetics of the extended-release formulation of cyclobenzaprine (CER) in elderly volunteers. This randomized, open-label, two-period crossover study compared the pharmacokinetics, safety and tolerability of a single oral 30-mg dose of CER with those of 10 mg of cyclobenzaprine immediate-release (CIR) administered every 8 hours for a total of three doses in 18 healthy volunteers aged 65-75 years. Volunteers were assigned to either CER or CIR on days 1 and 15 (separated by a 14-day washout). Outcome measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours (AUC168) and infinity (AUC infinity), peak plasma cyclobenzaprine concentration (Cmax), time to observed Cmax (tmax) and terminal elimination half-life of cyclobenzaprine. Adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Eighteen subjects were randomized and completed the first treatment period; 17 completed both periods of the study. The pharmacokinetics of CER 30 mg were characterized by an absorption phase with a median t(max) of 8 hours compared with an initial peak for CIR (following the first dose) at about 5 hours. Plasma cyclobenzaprine concentrations at 5 hours were 13.6 ng/mL for CER and 11.0 ng/mL for CIR. Systemic cyclobenzaprine exposure (AUC168, AUC infinity and Cmax) was similar for a single dose of CER and three doses of CIR and met bioequivalence criteria. Most AEs were mild in intensity; the most common AE was somnolence. No serious AEs or discontinuations as a result of AEs were reported during the study. Once-daily CER 30 mg exhibited controlled release of cyclobenzaprine and resulted in systemic exposure similar to that of CIR in subjects aged 65-75 years.

Single-Dose Pharmacokinetics of Once-Daily Cyclobenzaprine Extended Release 30 mg versus Cyclobenzaprine Immediate Release 10 mg Three Times Daily in Healthy Young Adults

Cyclobenzaprine immediate release (CIR) has shown efficacy in the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. An extended-release formulation of cyclobenzaprine (CER) has been developed to provide effective muscle spasm relief with once-daily dosing. The objective of this study was to compare the pharmacokinetics of CER and CIR. This was a single-centre study of 18 healthy young adults (aged 18-45 years). Healthy volunteers were assigned to receive either a single dose of CER 30 mg or three doses of CIR 10 mg on days 1 and 15 (separated by a 14-day washout) in an open-label, two-period crossover study. Pharmacokinetic parameters were monitored through 168 hours after the last dose in each dose period; adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Cyclobenzaprine was administered as a single oral 30 mg dose of CER or three 10 mg oral doses of CIR given every 8 hours over 24 hours. Statistical tests were conducted against a two-sided alternative hypothesis at a 0.05 level of significance with equivalence limits of 80% and 125%. Measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours and infinity, maximum plasma cyclobenzaprine concentration (C(max)), and time to observed C(max) (t(max)). Eighteen subjects were randomized and 17 completed both periods of the study. CER exhibited a consistent concentration-time profile with a single peak, in contrast to the pharmacokinetic profile for CIR, which displayed multiple peaks and troughs over the 24-hour period. The pharmacokinetic profile of CER 30 mg was characterized by an absorption phase with a median t(max) of approximately 6 hours, compared with the initial peak of CIR (following the first dose) of about 4 hours. Mean plasma concentrations at 4 hours were comparable (12.1 ng/mL for CER; 12.4 ng/mL for CIR). Systemic cyclobenzaprine exposure (AUC and C(max)) was similar across both formulations. The C(max) for CER 30 mg was 19.2 ng/mL (median t(max) = 6 hours) and for CIR (following the third dose) was 18.1 ng/mL (median t(max) = 12 hours). All AEs were mild in intensity; the most common AE was somnolence. The pharmacokinetic profile of once-daily CER reflected the mode of administration, providing a controlled release of cyclobenzaprine with sustained plasma concentrations, in contrast to the fluctuating profile of CIR. CER 30 mg once daily and CIR 10 mg three times daily resulted in comparable systemic exposures.

Cyclobenzaprine Improves Pain and Stiffness in Fibrositis

Cyclobenzaprine Improves Pain and Stiffness in Fibrositis