A novel nanozyme doped ZnO/r-GO-based sensor for highly sensitive electrochemical determination of muscle-relaxant drug: cyclobenzaprine HCl.

A nanocomposite of Ce-doped ZnO/r-GO was synthesized using a conventional hydrothermal method. The synthesized nanocomposites were utilized for the purpose of sensitive and selective detection of cyclobenzaprine hydrochloride (CBP). The properties of the composite were extensively analyzed, including its morphology, structure, and electrochemical behavior. This study investigates the application of a modified glassy carbon electrode for the detection of CBP, a muscle relaxant used to treat musculoskeletal diseases that cause muscle spasms. The electrode is modified with Ce-doped ZnO/r-GO. Various detection methods, such as cyclic voltammetric and square wave techniques (SWV), were utilized. The composite material showed high effectiveness as an electron transfer mediator in the oxidation of CBP. The electrode showed a good response for SWV evaluations in CBP identification, with a minimum detection limit of 1.6 × 10-8 M and a wide linear range from 10 × 10-6 M to 0.6 × 10-7 M, under ideal conditions. The rate constant for charge transfer (ks) and the estimation of the electrochemical active surface area were obtained. A developed sensor exhibited desirable selectivity, long-lasting stability, and remarkable reproducibility. A sensor was used to analyze water, human serum, and urine samples, resulting in positive recovery results.

Maternal cyclobenzaprine exposure and risk of birth defects in the National Birth Defects Prevention Study (1997-2011) and Birth Defects Study to Evaluate Pregnancy exposureS (2014-2018).

PURPOSE: Cyclobenzaprine is a muscle relaxant indicated for acute pain. Little is known about cyclobenzaprine's safety during pregnancy. We explored the association between maternal cyclobenzaprine exposure and risk of birth defects among offspring. METHODS: We combined data from two large, multi-site, population-based case-control studies in the United States. Cases were identified from birth defects registries across 10 states; controls were liveborn infants without birth defects randomly selected from the same catchment areas. Participants reported cyclobenzaprine use during the month before conception through the third month of pregnancy ("periconception") via computer-assisted telephone interview. We used logistic regression to assess associations between periconceptional cyclobenzaprine exposure and selected structural birth defects. We calculated crude odds ratios (OR) with corresponding 95% confidence intervals (CI). RESULTS: Our study included 33 615 cases and 13 110 controls. Overall, 51 case (0.15%) and 9 control (0.07%) participants reported periconceptional cyclobenzaprine use. We observed increased risk for all seven defects with ≥3 exposed cases: cleft palate (OR = 4.79, 95% CI 1.71-13.44), cleft lip (OR = 2.50, 95% CI 0.89-7.02), anorectal atresia/stenosis (OR = 6.91, 95% CI 1.67, 28.65), d-transposition of the great arteries (OR = 6.97, 95% CI 2.17-22.36), coarctation of the aorta (OR = 5.58, 95% CI 1.88-16.58), pulmonary valve stenosis (OR = 4.55, 95% CI 1.10-18.87), and secundum atrial septal defect (OR = 3.08, 95% CI 0.83-11.45). CONCLUSIONS: Even in our large sample, cyclobenzaprine use was rare. Our estimates are unadjusted and imprecise so should be interpreted cautiously. These hypothesis-generating results warrant confirmation and further research to explore possible mechanisms.

Cyclobenzaprine utilization for musculoskeletal back pain: Analysis of 2007-2019 National Hospital Ambulatory Medical Care Survey Data.

BACKGROUND: With musculoskeletal back pain being one of the most common presentations in the emergency department, evidence-based management strategies are needed to address such complaints. Along with other medications, cyclobenzaprine is a muscle relaxant commonly prescribed for patients complaining of musculoskeletal pain, in particular, pain associated with muscle spasms. However, with recent literature questioning its efficacy, the role of cyclobenzaprine use in patients with musculoskeletal back pain remains unclear. OBJECTIVES: The objective of the study is to investigate trends of cyclobenzaprine utilization among patients presenting to the emergency department (ED) in the United States. METHODS: This is a retrospective cohort review of data obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS) between 2007 and 2019. We analyzed ED visits of patients 18 years and older. Visits during which cyclobenzaprine was administered in the ED or prescribed at discharge were identified. Trends were described using a time series analysis of patients' visits who received administration and prescriptions of cyclobenzaprine. RESULTS: Between 2007 and 2019, we identified an estimated 1.35 billion ED visits, 57.2% (772.6 million) were female. From that sample, 2.4% (32.7 million) of all visits received cyclobenzaprine prescription in the ED only, and 0.5% (6.6 million) of total visits were both given the drug in the ED and were prescribed the drug at discharge). Overall trend analysis shows a slight decrease in annual percentages of cyclobenzaprine administration and prescriptions during the study period. Visits of certain subgroups: 26-44 years, white showed relatively higher percentages of administration and prescription of cyclobenzaprine. CONCLUSIONS: Although there was a slight decrease, our study still shows significant cyclobenzaprine utilization in the ED, despite conflicting evidence demonstrating efficacy for patients with musculoskeletal complaints and the concern for adverse effects. Additional studies are needed to examine its overall effectiveness and risk-benefit analysis in treating patients with such conditions.

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.

Treatment of comatose patient from cyclobenzaprine overdose with therapeutic plasma exchange.

We present a case of a 15-year-old female who was admitted in a comatose state with no spontaneous respiratory effort and absence of brainstem reflexes after cyclobenzaprine ingestion. Due to severe presentation and recent ingestion of high plasma protein binding medication with long half-life, therapeutic plasma exchange (TPE) was performed and resulted in full neurological recovery. This case explores the role of TPE as an effective treatment option for life-threatening cyclobenzaprine overdose. TPE is generally beneficial for drugs that have a low volume of distribution and high plasma protein binding. Cyclobenzaprine is known to have a relatively high volume of distribution. However, in the case of drug intoxication with relatively high-volume distribution, high protein binding, and long half-life, TPE could be effective if it is conducted promptly.

The Relative Efficacy of Seven Skeletal Muscle Relaxants. An Analysis of Data From Randomized Studies.

BACKGROUND: Low back pain (LBP) causes 2.6 million visits to U.S. emergency departments (EDs) annually. These patients are often treated with skeletal muscle relaxants (SMRs). OBJECTIVES: The goal of this study was to determine whether efficacy of SMRs is associated with age, sex, or baseline LBP severity. METHODS: This was a planned analysis of data from 4 randomized studies of patients with acute nonradicular LBP. Patients were enrolled during an ED visit and followed-up 1 week later. The primary outcome was improvement in the Roland-Morris Disability Questionnaire (RMDQ) between ED discharge and the 1-week follow-up. We compared the change in RMDQ among 8 groups: placebo, baclofen, metaxalone, tizanidine, diazepam, orphenadrine, methocarbamol, and cyclobenzaprine. All patients also received a nonsteroidal anti-inflammatory drug. We performed analysis of variance to determine statistically significant differences between medications and linear regression to determine the association of age, sex, and baseline severity with the primary outcome. RESULTS: The mean improvement in RMDQ per group was placebo 10.5 (95% confidence interval [CI] 9.5-11.5), baclofen 10.6 (95% CI 8.6-12.7), metaxalone 10.3 (95% CI 8.1-12.4), tizanidine 11.5 (95% CI 9.5-13.4), diazepam 11.1 (95% CI 9-13.2), orphenadrine 9.5 (95% CI 7.4-11.5), methocarbamol 8.1 (95% CI 6.1-10.1), and cyclobenzaprine 10.1 (95% CI 8.3-12). The between-group differences were not statistically significantly different. Results were similar regardless of age, sex, and baseline severity. Higher baseline RMDQ was associated with greater clinical improvement (B coefficient 5.7, p < 0.01). Adverse medication effects were more common with cyclobenzaprine than with placebo (p < 0.01). CONCLUSIONS: Among patients in the ED with acute LBP treated with a nonsteroidal anti-inflammatory drug, SMRs do not improve outcomes more than placebo. Neither age, sex, nor baseline impairment impacts these results.

Utilization Patterns of Skeletal Muscle Relaxants Among Commercially Insured Adults in the United States from 2006 to 2018.

OBJECTIVE: To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States. METHODS: We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥2-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder. RESULTS: 48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1,000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days, respectively. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration. CONCLUSIONS: SMRs are widely used in the United States. Their use slightly increased in recent years, but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use.

Muscle Relaxant Use Among Hemodialysis Patients: Prevalence, Clinical Indications, and Adverse Outcomes.

RATIONALE & OBJECTIVE: Muscle relaxants are often used to treat musculoskeletal pain or cramping, which are commonly experienced by hemodialysis patients. However, the extent to which muscle relaxants are prescribed in this population and the risks associated with their use have not been characterized. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 140,899 Medicare-covered adults receiving hemodialysis in 2011, identified in the US Renal Data System. EXPOSURE: Time-varying muscle relaxant exposure. OUTCOMES: Primary outcomes were time to first emergency department visit or hospitalization for altered mental status, fall, or fracture. Secondary outcomes were death and composites of death with each of the primary outcomes. ANALYTICAL APPROACH: Multivariable Cox regression analysis. RESULTS: 10% of patients received muscle relaxants in 2011. 11%, 6%, 3%, and 13% had an episode of altered mental status, fall, fracture, and death, respectively. Muscle relaxant use was associated with higher risk for altered mental status (HR, 1.39; 95% CI, 1.29-1.51) and fall (HR, 1.18; 95% CI, 1.05-1.33) compared to no use. Muscle relaxant use was not statistically significantly associated with higher risk for fracture (HR, 1.17; 95% CI, 0.98-1.39). Muscle relaxant use was associated with lower hazard of death (HR, 0.85; 95% CI, 0.76-0.94). However, hazards were higher for altered mental status or death (HR, 1.17; 95% CI, 1.10-1.25), fall or death (HR, 1.14; 95% CI, 1.06-1.22), and fracture or death (HR, 1.10; 95% CI, 1.01-1.20). LIMITATIONS: A causal association between muscle relaxant use and outcomes cannot be inferred, and residual confounding cannot be excluded. Exposure and outcomes were ascertained using administrative claims. CONCLUSIONS: Muscle relaxant use was common in hemodialysis patients and associated with altered mental status and falls. We could not rule out a clinically meaningful association between muscle relaxant use and fracture. The lower risk for death with muscle relaxants may have been the result of residual confounding. Future research to define the appropriate use of muscle relaxants in this population is warranted.

The diversion of nonscheduled psychoactive prescription medications in the United States, 2002 to 2017.

PURPOSE: Systematic studies of the diversion of nonscheduled drugs, except for gabapentin, are not apparent. We searched diversion case reports of all other nonscheduled psychoactive prescription drugs in the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System. METHODS: Case report data are drawn from a quarterly survey of prescription drug diversion completed by a national sample of law enforcement and regulatory agencies. Rates of diversion per 100 000 population were calculated for each year from 2002 to 2017 for prescription medications with greater than 400 reported cases during the period. RESULTS: Cyclobenzaprine, quetiapine, and trazodone met criteria for analysis. We found a significant and steady increase in the diversion of each drug over the period. The 2017 annual rates of diversion per 100 000 population for the three medications range from 0.0428 to 0.0726. Although these rates of diversion are much lower than the rate for total opioid analgesics, they are all more than five times higher in 2017 compared with 2002. While diversion rates for opioids have decreased in recent years, rates for cyclobenzaprine, quetiapine, and trazodone have continued to increase. CONCLUSIONS: A common attribute of the three nonscheduled drugs studied here is that all are used for the treatment and/or self-treatment of opioid withdrawal symptoms, and the increasing diversion of these drugs may be related to the ongoing opioid epidemic and to increasing levels of control over pharmaceutical opioid availability in the United States. Prescribers need to be aware of illicit markets for these medications and prescribe to their patients with appropriate caution.

Multi-Spectroscopic Characterization of Human Serum Albumin Binding with Cyclobenzaprine Hydrochloride: Insights from Biophysical and In Silico Approaches.

Cyclobenzaprine hydrochloride (CBH) is a well-known muscle relaxant that is widely used to relieve muscle spasms and other pain associated with acute musculoskeletal conditions. In this study, we elucidated the binding characteristics of this muscle relaxant to human serum albumin (HSA). From a pharmaceutical and biochemical viewpoint, insight into the structure, functions, dynamics, and features of HSA-CBH complex holds great importance. The binding of CBH with this major circulatory transport protein was studied using a combination of biophysical approaches such as UV-VIS absorption, fluorescence quenching, and circular dichroism (CD) spectroscopy. Various in silico techniques, molecular docking and molecular dynamics, were also used to gain deeper insight into the binding. A reduction in the fluorescence intensities of HSA-CBH complex with a constant increase in temperature, revealed the static mode of protein fluorescence quenching upon CBH addition, which confirmed the formation of the HSA-CBH ground state complex. The alteration in the UV-VIS and far-UV CD spectrum indicated changes in both secondary and tertiary structures of HSA upon binding of CBH, further proving CBH binding to HSA. The analysis of thermodynamic parameters ∆H° and ∆S° showed that binding of CBH to HSA was dominated by intermolecular hydrophobic forces. The results of the molecular docking and molecular dynamics simulation studies also confirmed the stability of the complex and supported the experimental results.

Inclusion complexes of ß-cyclodextrin with tricyclic drugs: an X-ray diffraction, NMR and molecular dynamics study.

Tricyclic fused-ring cyclobenzaprine (1) and amitriptyline (2) form 1:1 inclusion complexes with ß-cyclodextrin (ß-CD) in the solid state and in water solution. Rotating frame NOE experiments (ROESY) showed the same geometry of inclusion for both 1/ß-CD and 2/ß-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/ß-CD and 2/ß-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.

The rapid recovery study: Cyclobenzaprine's effect on recovery following joint arthroplasty.

Introduction: Skeletal muscle relaxants have previously not been examined in multimodal anesthesia regimens following joint arthroplasty. We sought to evaluate cyclobenzaprine's effect on postoperative opioid consumption as well as surgical recovery following joint arthroplasty. Materials and methods: In this retrospective cohort study, 471 patients undergoing 554 joint arthroplasty procedures were evaluated. Patients were divided into cohorts who did and did not receive cyclobenzaprine postoperatively, and postoperative opioid consumption and functional recovery measures were recorded in each cohort. Results: In the unadjusted model, the cyclobenzaprine cohort experienced a 1.11 increase in pain scores on postoperative day zero (95% CI (0.60, 1.62), p < 0.0001). After adjusting for age, sex, BMI, CCI, perioperative MME, laterality, procedure, anesthesia, pre-op opioid use, pre-operative other controlled substance uses and pre-op benzodiazepine use, the cyclobenzaprine cohort's pain scores were 1.08 units higher at rest (95% CI (0.59, 1.56), p < 0.0001) and 1.25 units higher with activity on postoperative-day-zero (95% CI (0.78, 1.72), p < 0.0001). Both cohorts experienced statistically insignificantly different changes in mobility scores between postoperative day zero and postoperative day one, range of motion at 6 and 12 weeks, and readmission in <90 days. Postoperative morphine milliequivalents were insignificantly different between cohorts after controlling for pain in all models (base model mean ratio: 1.06, 95% CI (0.87,1.29), p = 0.5599) (Full model mean ratio: 1.09, 95% CI (0.91,1.30), p = 0.3608). Conclusions: Cyclobenzaprine shows utility in a multimodal anesthetic approach after joint arthroplasty in patients with higher baseline pain.

TLR4 inhibitors through inhibiting (MYD88-TRIF) pathway, protect against experimentally-induced intestinal (I/R) injury.

Intestinal ischemia/reperfusion (I/R) injury is a serious condition that causes intestinal dysfunction and can be fatal. Previous research has shown that toll-like receptor 4 (TLR4) inhibitors have a protective effect against this injury. This study aimed to investigate the protective effects of TLR4 inhibitors, specifically cyclobenzaprine, ketotifen, amitriptyline, and naltrexone, in rats with intestinal (I/R) injury. Albino rats were divided into seven groups: vehicle control, sham-operated, I/R injury, I/R-cyclobenzaprine (10 mg/kg body weight), I/R-ketotifen (1 mg/kg body weight), I/R-amitriptyline (10 mg/kg body weight), and I/R-naltrexone (4 mg/kg body weight) groups. Anesthetized rats (urethane 1.8 g/kg) underwent 30 min of intestinal ischemia by occluding the superior mesenteric artery (SMA), followed by 2 h of reperfusion. Intestinal tissue samples were collected to measure various parameters, including malondialdehyde (MDA), nitric oxide synthase (NO), myeloperoxidase (MPO), superoxide dismutase (SOD), TLR4, intercellular adhesion molecule-1 (ICAM-1), nuclear factor kappa bp65 (NF-ĸBP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), macrophages CD68, myeloid differentiation factor 88 (MYD88), and toll interleukin receptor-domain-containing adaptor-inducing interferon ß (TRIF). The use of TLR4 inhibitors significantly reduced MDA, MPO, and NO levels, while increasing SOD activity. Furthermore, it significantly decreased TLR4, ICAM-1, TNF-α, MCP-1, MYD88, and TRIF levels. These drugs also showed partial restoration of normal cellular structure with reduced inflammation. Additionally, there was a decrease in NF-ĸBP65 and macrophages CD68 staining compared to rats in the I/R groups. This study focuses on how TLR4 inhibitors enhance intestinal function and protect against intestinal (I/R) injury by influencing macrophages CD86 through (MYD88-TRIF) pathway, as well as their effects on oxidation and inflammation.

Case report: Treatment of cyclobenzaprine ingestion in two dogs with intravenous intralipid therapy.

Introduction: The objective of this case series is to describe the clinical signs and outcome of cyclobenzaprine ingestion in two dogs treated with intralipid emulsion (ILE) and supportive care. Case or series summary: Two dogs presented for evaluation of cyclobenzaprine ingestion. A 4-year-old female spayed Rat Terrier (dog 1) presented within 4 h of ingestion of cyclobenzaprine (between 9.7 and 25.9 mg/kg). The dog experienced abnormal behavior, agitation, tremors, tachycardia, and hypertension. There were no significant clinicopathological abnormalities. The dog was treated with ILE, cyproheptadine, and activated charcoal. All clinical signs resolved after treatment. A 5-month-old female intact mixed-breed dog (dog 2) presented after ingestion of an unknown amount of cyclobenzaprine 2-3 h prior to presentation. The dog experienced dull mentation, tremors, loss of gag reflex, tachycardia, and hypertension. There were no significant clinicopathological abnormalities. Orogastric decontamination was performed via gastric lavage, and activated charcoal was given via orogastric tube, followed by ILE. All clinical signs resolved after therapeutic intervention. Discussion: This is the first report documenting clinical signs of cyclobenzaprine toxicity in two dogs followed by successful treatment with gastric emptying, ILE, and supportive care.

Development of Extended-Release Formulations Containing Cyclobenzaprine Based on Physiologically Based Biopharmaceutics Modeling and Bioequivalence Safe Space.

The use of physiologically based biopharmaceutics modeling (PBBM) and bioequivalence safe space is increasingly common for immediate-release drug products. However, for extended-release (ER) formulations there are only a few examples of this application. In this study, we developed ER formulations containing cyclobenzaprine 15 mg, supported by PBBM and bioequivalence safe space. Four formulations were prepared, F1, F2, F3 (ER mini-tablet formulations) and F4 (ER tablet formulation), and the dissolution profiles were evaluated. The dissolution profile of the reference drug product was also evaluated and used to set a bioequivalence safe space. A PBBM was set up, evaluated, and used to predict the in vivo behavior of the formulations. The bioequivalence safe space was calculated to be between - 25% and + 75% of the k1 and Tlag values of the dissolution profile of the reference drug product when applying the first-order dissolution kinetic model. All time points of the dissolution profile of the ER mini-tablet formulation F2, were within the safe space, and was approved in 10 of 10 trials of crossover virtual bioequivalence studies. Based on the PBBM strategy and bioequivalence safe space, it was possible to develop an ER mini-tablet formulation virtually bioequivalent to the reference drug product, even though this formulation failed the f2 test.

Serotonin syndrome from combination hydrocodone and cyclobenzaprine in a patient with cerebral palsy.

Aim: Serotonin syndrome (SS) is a life-threatening syndrome that occurs with the use of serotonergic drugs, most commonly due to two or more agents. Cerebral palsy is associated with mood disorders, and more commonly pain, with a prevalence of up to 50-80%. Case presentation: A 58-year-old female with cerebral palsy, metastatic malignancy and mood disorder who presented to the emergency department with acute-on-chronic pain, and signs of SS. She was initiated on iv. dilaudid, titrated off oral medications and scheduled for a left-sided sacroiliac joint injection. Results: It was suspected that due to additional doses of hydrocodone and cyclobenzaprine, she developed moderate-SS. Conclusion: Physicians need to be cognizant of comorbidities and uncommon pain medications that can predispose patients to SS.

Randomized clinical trial of bedtime sublingual cyclobenzaprine (TNX-102 SL) in military-related PTSD and the role of sleep quality in treatment response.

Effective posttraumatic stress disorder (PTSD) pharmacotherapy is needed. This 12-week randomized multicenter trial evaluated efficacy and safety of TNX-102 SL, a bedtime sublingual formulation of cyclobenzaprine, in patients with military-related PTSD randomized to TNX-102 SL 2.8 mg or 5.6 mg, or placebo. Primary analysis comparing change from baseline in Clinician-Administered PTSD Scale-5 score between 2.8 mg (n=90) and placebo (n=92) was not significant. Secondary analysis of 5.6 mg (n=49) vs placebo demonstrated a mean difference of -4.5 units, p=.05, or, accounting for missing data by multiple imputation, -5.0 units, p=.03. Clinician Global Impression - Improvement responder rate was greater in 5.6 mg than placebo (p=0.04), as was mean functional improvement in Sheehan Disability Scale social domain (p=.03) and trended in work domain (p=.05). Post-hoc analyses showed early sleep improvement predicted improvement in PTSD after 12 weeks for TNX-102 SL (p<.01), not for placebo. Most common administration site reaction in TNX-102 SL groups was oral hypoaesthesia (5.6 mg, 36%; 2.8 mg, 39%; placebo, 2%), while most common systemic adverse event was somnolence (5.6 mg, 16%; 2.8 mg, 12%; placebo, 6%). This provides preliminary evidence that TNX-102 SL 5.6 mg reduces PTSD symptoms, improves sleep and psychosocial function, and is well tolerated. Clinicaltrials.gov Identifier: NCT02277704.

6-Nitrodopamine is an endogenous mediator of rat isolated epididymal vas deferens contractions induced by electric-field stimulation.

6-nitrodopamine (6-ND) is released from human umbilical cord vessels and modulates vascular reactivity by acting as a dopamine antagonist. Here we investigate whether 6-ND is released by the rat isolated vas deferens and its effect on this tissue. Dopamine, noradrenaline, adrenaline and 6-ND levels were quantified in rat isolated vas deferens by LC-MS-MS. Electric-field stimulation (EFS) and concentration-response curves to 6-ND, noradrenaline, dopamine and adrenaline were performed in the absence and in the presence (30 min) of L-NAME, SCH-23390, haloperidol, PG-01037, sonepiprazole, desipramine, clomipramine, amitriptyline, cyclobenzaprine, carbamazepine, maprotiline, paroxetine, oxcarbazepine and ketanserin in the rat isolated epididymal vas deferens (RIEVD). Basal releases of 6-ND and noradrenaline were detected from the rat isolated vas deferens. 6-ND release was reduced by tissue incubation with L-NAME and from the vas deferens obtained from L-NAME-treated rats. SCH-23390 caused leftward shifts on concentration-response curves to 6-ND without affecting dopamine- or EFS-induced RIEVD contractions. Haloperidol, PG-01037 and sonepiprazole caused significant rightward shifts on concentration-response curves to dopamine but had no effect on either the 6-ND or EFS-induced RIEVD contractions. The tricyclic compounds desipramine, clomipramine, amitriptyline, cyclobenzaprine and carbamazepine induced rightward shifts on 6-ND concentration-response curve but did not reduce the noradrenaline, dopamine and adrenaline contractile responses. They also reduced the EFS-induced RIEVD contractions in control but not in tissues obtained from L-NAME-treated animals. Maprotiline, oxcarbazepine, paroxetine and ketanserin had no effect in either 6-ND or EFS-induced RIEVD contractions. Thus, 6-ND modulates RIEVD contractility, and desipramine, clomipramine, amitriptyline, cyclobenzaprine and carbamazepine act as selective 6-ND receptor antagonists.