Vernakalant for Rapid Cardioversion of Recent-Onset Atrial Fibrillation: Results from the SPECTRUM Study.

AIMS: Rapid restoration of sinus rhythm using pharmacological cardioversion is commonly indicated in patients with symptomatic recent-onset atrial fibrillation (AF). The objectives of this large, international, multicenter observational study were to determine the safety and effectiveness of intravenous (IV) vernakalant for conversion of AF to sinus rhythm in daily practice. METHODS AND RESULTS: Consenting patients with symptomatic recent-onset AF (< 7 days) treated with IV vernakalant were enrolled and followed up to 24 h after the last infusion or until discharge, in order to determine the incidence of predefined serious adverse events (SAEs) and other observed SAEs and evaluate the conversion rate within the first 90 min. Overall, 2009 treatment episodes in 1778 patients were analyzed. The age of patients was 62.3 ± 13.0 years (mean ± standard deviation). Median AF duration before treatment was 11.1 h (IQR 5.4-27.0 h). A total of 28 SAEs occurred in 26 patients including 19 predefined SAEs, i.e., sinus arrest (n = 4, 0.2%), significant bradycardia (n = 11, 0.5%), significant hypotension (n = 2, 0.1%), and atrial flutter with 1:1 conduction (n = 2, 0.1%). There were no cases of sustained ventricular arrhythmias or deaths. All patients who experienced SAEs recovered fully (n = 25) or with sequelae (n = 1). Conversion rate to sinus rhythm was 70.2%, within a median of 12 min (IQR 8.0-28.0 min). CONCLUSIONS: This large multicenter, international observational study confirms the good safety profile and the high effectiveness of vernakalant for the rapid cardioversion of recent-onset AF in daily hospital practice.

Systematic Review and Meta-analysis Appraising Efficacy and Safety of Vernakalant for Cardioversion of Recent-Onset Atrial Fibrillation.

Vernakalant is a novel, relatively atrial-selective antiarrhythmic agent. Despite its good efficacy profile and rapid onset of action, there was still controversial evidence regarding vernakalant-related adverse events. We searched PubMed and Embase for studies that compared intravenous vernakalant with placebo or antiarrhythmic agents in patients with recent-onset atrial fibrillation (AF) lasting no more than 7 days. Efficacy and safety outcomes were the treatment-induced cardioversion rate within 90 minutes and adverse events after first exposure to study drug respectively. Nine randomized controlled trials enrolling 1296 patients were analyzed. Quantitative synthesis showed that vernakalant was superior to placebo for cardioversion of recent-onset AF within 90 minutes [49.7% vs. 6.2%, risk ratio (RR) 8.13, 95% confidence interval (CI) 5.35-12.36, P < 0.00001], and it did not achieve statistical significance in cardioversion when vernakalant was compared with ibutilide (62.4% vs. 47.3%, RR 1.32, 95% CI 1.00-1.73, P = 0.05). As for safety assessment, no significant differences were found in occurring serious adverse events (9.9% vs. 10.4%, RR 0.91, 95% CI 0.67-1.25, P = 0.57) and hypotension (5.3% vs. 3.3%, RR 1.53, 95% CI 0.86-2.73, P = 0.15) between vernakalant and comparator (either placebo, ibutilide, or amiodarone). There were trends that patients receiving vernakalant experienced more drug discontinuation (2.5% vs. 1.0%, RR 2.21, 95% CI 0.96-5.11, P = 0.06) and less any ventricular tachycardia (6.1% vs. 8.1%, RR 0.70, 95% CI 0.49-1.00, P = 0.05) than those receiving comparator, but the differences were not statistically significant. Furthermore, vernakalant was associated with a higher risk of bradycardia in comparison with comparator (6.3% vs. 1.1%, RR 4.04, 95% CI 1.67-9.75, P = 0.002). Vernakalant is effective in converting recent-onset AF to sinus rhythm rapidly, while significantly more bradycardia events are related to vernakalant in our meta-analysis.

25B-NBOMe, a novel N-2-methoxybenzyl-phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential.

An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1 ), dopamine D2 (DRD2 ), and serotonin 2A (5-HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD1 , DRD2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.

Developing Medical Surveillance Examination Guidance for New Occupational Hazards: The IMX-101 Experience.

New materials are constantly being created to address the operational needs of the US Army. These materials provide challenges to occupational health practitioners by presenting unknown health risks and possible effects to workers they evaluate. The responsibility for developing a medical surveillance exam, as part of a comprehensive workplace surveillance program, may become the responsibility of the provider working in a clinic on a military installation where manufacturing, testing, and/or use of the material is being conducted. Insensitive munitions explosive (IMX) has presented such an opportunity for Army occupational medicine providers within the last few years. This article describes the course of action taken by the occupational health clinics, personnel of Army ammunition plants producing IMX-101, and the US Army Public Health Center-Army Institute of Public Health to address the situation of developing a medical surveillance examination during a time when little to no information existed about the components of this new explosive compound.

Efficacy of tenuigenin and ß-asarone as augmentations for memantine in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that has no cure at present. This study was carried out to evaluate whether the combination of ß-asarone and tenuigenin could improve the efficacy of memantine as a monotherapy in the treatment of AD. Patients with AD were recruited and assigned to two groups. Patients in the control group received memantine (5-20 mg/day) and those in the experimental group received memantine (5-20 mg/day), ß-asarone (20 mg/day), and tenuigenin (20 mg/day). The Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), Clinical Dementia Rating Scale (CDR) scores and drug-related side-effects were assessed. Treatment was continued for 12 weeks. In total, 93 AD patients (45 in the control group and 48 in the experimental group) were recruited. Before treatment, both the groups had similar average MMSE scores, ADL scores, and CDR scores, whereas all the average scores improved significantly after treatment. However, compared with the control group, the experimental group had a significantly higher average MMSE score (P=0.00001) and lower average ADL (P=0.00604) and CDR (P=0.00776) scores after treatment. Moreover, the two groups had similar rates of drug-related side-effects. These results indicated that the combination of ß-asarone and tenuigenin was an effective augmentation for memantine in the treatment of AD and did not cause more drug-related side-effects. This novel method is worthy of further investigation.

Efficacy and safety of intravenous vernakalant for the rapid conversion of recent-onset atrial fibrillation: A meta-analysis.

BACKGROUND: Atrial fibrillation is a common cardiac arrhythmia with increasing prevalence in the aging population. It is a major cause of emergency department visits worldwide. Vernakalant, a relatively new antiarrhythmic drug with selectively preferential effects on the atrial tissue is currently used in many European countries for the termination of recent-onset atrial fibrillation. Presently, the drug is still not approved by the United States Food and Drug Administration due to safety concerns. We evaluate the efficacy and safety of vernakalant for the conversion of recent-onset atrial fibrillation or atrial flutter into normal sinus rhythm (NSR). METHODS: PubMed/MEDLINE (1993-2017), the Cochrane Central Register of Controlled Trials (2000-2017), and reference lists of relevant articles were searched for randomized controlled trials (RCTs) comparing vernakalant to a control drug and extracted subsequently. RESULTS: Nine RCTs were identified and included in the meta-analysis. Pooled analysis of events extracted for a total of 1421 patients with recent-onset atrial fibrillation showed a statistically significant increase in cardioversion within 90 minutes from drug infusion (Relative Risk [RR], 6.61; 95% Confidence Interval [CI], 2.78 - 15.71; p < .00001). In terms of adverse events, vernakalant was considered safe in comparison to control drugs (RR, 0.80; 95% CI, 0.61-1.05; p = .11). CONCLUSION: Vernakalant is effective for rapid conversion of recent-onset atrial fibrillation into NSR. However, although it showed a safe profile in terms of side effects in this analysis, we are still hesitant about this conclusion and few safety issues should be addressed within specific patients' subgroups.

Pharmacology and toxicology of α- and ß-Asarone: A review of preclinical evidence.

BACKGROUND: Asarone is one of the most researched phytochemicals and is mainly present in the Acorus species and Guatteria gaumeri Greenman. In preclinical studies, both α- and ß-asarone have been reported to have numerous pharmacological activities and at the same time, many studies have also revealed the toxicity of α- and ß-asarone. PURPOSE: The purpose of this comprehensive review is to compile and analyze the information related to the pharmacokinetic, pharmacological, and toxicological studies reported on α- and ß-asarone using preclinical in vitro and in vivo models. Besides, the molecular targets and mechanism(s) involved in the biological activities of α- and ß-asarone were discussed. METHODS: Databases including PubMed, ScienceDirect and Google scholar were searched and the literature from the year 1960 to January 2017 was retrieved using keywords such as α-asarone, ß-asarone, pharmacokinetics, toxicology, pharmacological activities (e.g. depression, anxiety). RESULTS: Based on the data obtained from the literature search, the pharmacokinetic studies of α- and ß-asarone revealed that their oral bioavailability in rodents is poor with a short plasma half-life. Moreover, the metabolism of α- and ß-asarone occurs mainly through cytochrome-P450 pathways. Besides, both α- and/or ß-asarone possess a wide range of pharmacological activities such as antidepressant, antianxiety, anti-Alzheimer's, anti-Parkinson's, antiepileptic, anticancer, antihyperlipidemic, antithrombotic, anticholestatic and radioprotective activities through its interaction with multiple molecular targets. Importantly, the toxicological studies revealed that both α- and ß-asarone can cause hepatomas and might possess mutagenicity, genotoxicity, and teratogenicity. CONCLUSIONS: Taken together, further preclinical studies are required to confirm the pharmacological properties of α-asarone against depression, anxiety, Parkinson's disease, psychosis, drug dependence, pain, inflammation, cholestasis and thrombosis. Besides, the anticancer effect of ß-asarone should be further studied in different types of cancers using in vivo models. Moreover, further dose-dependent in vivo studies are required to confirm the toxicity of α- and ß-asarone. Overall, this extensive review provides a detailed information on the preclinical pharmacological and toxicological activities of α-and ß-asarone and this could be very useful for researchers who wish to conduct further preclinical studies using α- and ß-asarone.

Sleep promoting potential of low dose α-Asarone in rat model.

Commonly used hypnotics have undesirable side-effects, especially during continuous usage. On the other hand, some herbal products, which are used for prolonged periods, are suggested to have a sleep inducing property, though the claims have not been validated scientifically. The hypnotic potential of α-Asarone, an active principle of Acorus species, was tested in the present study by first identifying the optimal dose of α-Asarone for improving sleep, followed by studies that evaluated the effect of repeated administration of this optimal dose for five days on sleep deprived rats. Of all the doses tested (2, 10, 40, 80 and 120 mg/kg), 10 mg/kg α-Asarone improved the quality of sleep, as indicated by an increased NREM bout duration, reduced arousal index, and decreased bout frequencies of NREM sleep and wakefulness. A marginal decrease in the hypothalamic and body temperatures was also observed. Higher doses, on the other hand, not only reduced the quantity and quality of sleep, but also produced hypothermia. In sleep deprived rats, administration of 10 mg/kg α-Asarone for five consecutive days improved the quality of sleep in contrast to the vehicle and a known hypnotic midazolam. Improvement in NREM sleep quality was observed when the difference between the hypothalamic and the body temperature was minimum. An enhanced association between NREM sleep bout duration and hypothalamic temperature was also observed after administration of 10 mg/kg α-Asarone. This comprehensive study is the first report on the hypnotic property of α-Asarone, which validates its potential to be considered for treatment of insomnia.

Blunt Craniofacial Trauma as a Manifestation of Excited Delirium Caused by New Psychoactive Substances.

The body of a 19-year-old male was found apparently concealed underneath bushes with recent head and facial trauma, and multiple superficial abrasions. Subsequently, it was discovered that the decedent had been running into objects and buildings following the ingestion the evening before of what was thought to be lysergic acid diethylamide (LSD). Blood staining of a nearby wall close to where the body was lying was in keeping with the described behavior. Toxicology revealed 3,4-methylenedioxymethamphetamine (Ecstasy), in addition to two only recently available drugs 2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine, (25B-NBOMe), and 1-(3,4-methylenedioxyphenyl)-2-(1-pyrrolidinyl)-1-butanone, (MDPBP). At autopsy, the skull was fractured with cerebral swelling, contusions, and subarachnoid hemorrhage. Death was due to blunt cranial trauma against a background of mixed drug toxicity. The case demonstrates a rare cause of death in a drug-induced acute delirium, as well as highlighting two new designer street drugs that may result in significant aberrant behavior.

OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): A phase-II randomized, double-blind, placebo-controlled study.

BACKGROUND: Peripheral leukocytes in patients with atopic dermatitis (AD) have elevated phosphodiesterase-4 activity, which is associated with production of proinflammatory mediators. OPA-15406 is a phosphodiesterase-4 inhibitor with high selectivity for phosphodiesterase-4-B. OBJECTIVES: We sought to assess effectiveness and tolerability of topical OPA-15406 in patients with AD. METHODS: This was a randomized, double-blind, vehicle-controlled, phase-II study. Patients 10 to 70 years of age with mild or moderate AD received topical OPA-15406 0.3% (n = 41), OPA-15406 1% (n = 43), or vehicle (n = 37) twice daily for 8 weeks. RESULTS: The primary end point, Investigator Global Assessment of Disease Severity score of 0 or 1 with greater than or equal to 2-grade reduction, was met at week 4 in the OPA-15406 1% group (P = .0165 vs vehicle). Mean percentage improvement from baseline Eczema Area and Severity Index score for OPA-15406 1% was notable in week 1 (31.4% vs 6.0% for vehicle; P = .0005), even larger in week 2 (39.0% vs 3.0%; P = .0001), and persisted for 8 weeks. Visual analog scale pruritus scores improved from moderate to mild within the first week in the OPA-15406 1% group (36.4% mean change; P = .0011). OPA-15406 levels in blood were negligible. Incidence of adverse events was low, with most events mild in intensity. LIMITATIONS: Further confirmatory phase-III studies are required. CONCLUSION: OPA-15406 ointment may provide an effective therapeutic modality for patients with mild to moderate AD.

Safety and efficacy of vernakalant for the conversion of atrial fibrillation to sinus rhythm; a phase 3b randomized controlled trial.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with significant health risks. One strategy to mitigate the risks associated with long-term AF is to convert AF to sinus rhythm (SR). This study assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to SR. METHODS: Patients with recent-onset (duration >3 h- ≤ 7 days) symptomatic AF and no evidence or history of congestive heart failure were randomized in a 2:1 ratio to receive vernakalant or placebo. Patients received an infusion of vernakalant (3 mg/kg) or placebo over 10 min, followed by a second infusion of vernakalant (2 mg/kg) or placebo 15 min later if AF had not been terminated. The primary efficacy endpoint was conversion of AF to SR for at least 1 min within 90 min of the start of drug infusion. The primary safety endpoint was a composite of: occurrence of clinically significant hypotension, clinically significant ventricular arrhythmia (including torsades de pointes, ventricular tachycardia or ventricular fibrillation) or death within 2 h of starting the drug infusion. RESULTS: A total of 217 patients were randomized to receive vernakalant (n = 145) or placebo (n = 72). Of the 129 individuals who received vernakalant, 59 (45.7 %) converted to SR compared with one of the 68 patients (1.5 %) who received placebo (p < 0.0001). Conversion to SR was significantly faster with vernakalant than with placebo (p < 0.0001), and a greater proportion of patients who received vernakalant than those who received placebo reported no AF-related symptoms at 90 min (p = 0.0264). The primary composite safety endpoint was observed in one patient receiving vernakalant and in no patients receiving placebo. In the vernakalant arm, dysgeusia, paraesthesia and sneezing were the most common treatment-emergent adverse events, and three serious adverse events occurred that were considered to be related to study drug. CONCLUSIONS: Vernakalant resulted in rapid cardioversion of recent-onset AF in almost half of the study population and was generally well tolerated. The safety outcomes affirmed the need for careful selection and management of haemodynamically stable candidates for cardioversion. TRIAL REGISTRATION: NCT00989001 .

Immunohistochemical Expression of Cyclin D1, Cytokeratin 20, and Uroplakin III in Proliferative Urinary Bladder Lesions Induced by o-Nitroanisole in Fischer 344/N Rats.

o-Nitroanisole is an intermediate in the manufacture of azo dyes. In a National Toxicology Program stop-exposure study,o-nitroanisole induced hyperplasia, papillomas, and papillary carcinomas in the urinary bladder of Fischer 344/N rats.o-Nitroanisole was investigated since occupational or environmental exposure to aniline and azo dyes is a risk factor for urinary bladder cancer in humans. The current study describes the morphology of urinary bladder neoplasms seen in rats with respect to those observed in humans. This study also evaluated immunohistochemical expression of the cell cycle-related proteins cyclin D1 and p53 and the differentiation markers cytokeratin 20 and uroplakin III in hyperplastic (n= 11) and neoplastic (n= 6 papillomas,n= 11 carcinomas) lesions of the urinary bladder epithelium from rats treated with o-nitroanisole and in normal (n= 6) urinary bladders from untreated rats. The tumors observed were more similar to the papillary type rather than the muscle-invasive type of urinary bladder cancer in humans. The preneoplastic and neoplastic lesions observed suggest progression from hyperplasia to papilloma to papillary carcinoma. With neoplastic progression (hyperplasia to papilloma to carcinoma), cyclin D1 immunoreactivity progressively increased in intensity, percentage of cells staining, and distribution. Overexpression of p53 was not found. Cytokeratin 20 staining decreased in superficial cells, while uroplakin III staining increased in intermediate and basal cells with progression from hyperplasia to carcinoma. The results are consistent with increased cell cycle dysregulation or proliferation (cyclin D1), decreased differentiation (cytokeratin 20), and abnormal differentiation (uroplakin III) as lesions progress toward malignancy.

Metabolite profiling of tissues of Acorus calamus and Acorus tatarinowii rhizomes by using LMD, UHPLC-QTOF MS, and GC-MS.

Acorus calamus and its related species are of significant importance to the food and fragrance industries due to their varied applications. They are also a cause of critical concern due to their toxic ß-asarone content. Several toxicity cases have occurred due to high ß-asarone compositions in food products. Hence, limits for their use are strictly regulated by the Food and Drug Administration, the European Union, and legislations of different countries. The identification of species with a lower ß-asarone content is of great significance. In this report, the metabolite profiles and essential oil content of A. calamus and Acorus tatarinowii rhizomes were analysed and compared using UHPLC-QTOF-MS and GC-MS techniques. The metabolite profiles were similar; however, ß-asarone content was higher in A. calamus rhizomes. The developed methods can be applied for microscopic and macroscopic identification, and quality control of food products containing ß-asarone.

Systemic delivery of alpha-asarone with Kolliphor HS 15 improves its safety and therapeutic effect on asthma.

The commercially available alpha-asarone injections (CA-ARE) were frequently found to cause severe anaphylactic reactions by the solubilizer contained in the formulation such as polysorbate 80 and propylene glycol. This study aimed to develop a new ARE injection using Kolliphor HS 15 as solubilizing agent (HS 15-ARE) by the dissolution method to resolve its poor solubility problem and reduce the anaphylaxis of CA-AREs caused by Polysorbate 80. The HS 15-ARE micelle showed a homogeneous round shape with the mean particle size of around 13.73 ± 0.02 nm, polydisperse index (PDI) of 0.19 ± 0.01 and solubilizing efficiency of 95.7% ± 2.4%. In vitro and in vivo studies showed that HS 15-ARE is a stable injection presenting the same pharmacokinetic profile with CA-ARE. Moreover, improved therapeutic effect was observed for HS 15-ARE in treating asthma compared to CA-ARE (p < 0.05) with no anaphylactic reactions observed. These results demonstrate that the new formulation of ARE (HS 15-ARE) has a great potential for replacing CA-AREs injections.

Analysis of the volatile organic compounds from leaves, flower spikes, and nectar of Australian grown Agastache rugosa.

BACKGROUND: The foraging choices of honey bees are influenced by many factors, such as floral aroma. The composition of volatile compounds influences the bioactivity of the aromatic plants and honey produced from them. In this study, Agastache rugosa was evaluated as part of a project to select the most promising medicinal plant species for production of bioactive honey. METHODS: Headspace solid-phase microextraction HS-SPME /GC-MS was optimized to identify the volatile bioactive compounds in the leaves, flower spikes, and for the first time, the flower nectar of Australian grown A. rugosa. RESULTS: Methyl chavicol (= estragole) was the predominant headspace volatile compound in the flowers with nectar, flower spikes, and leaves, with a total of 97.16%, 96.74% and 94.35%, respectively. Current results indicate that HS-SPME/GC-MS could be a useful tool for screening estragole concentration in herbal products. CONCLUSION: Recently, estragole was suspected to be carcinogenic and genotoxic, according to the European Union Committee on Herbal Medicinal Products. Further studies are needed on safe daily intake of Agastache as herbal tea or honey, as well as for topical uses.