Neurokinin-1 receptor antagonists for postoperative nausea and vomiting: a systematic review and meta-analysis / Antagonistas do receptor da neurocinina-1 no tratamento de náusea e vômito no pós-operatório: Revisão sistemática e meta-análise

Abstract Background: Postoperative Nausea and Vomiting (PONV) is a common complication of general anesthesia. Several kinds of antiemetics, including 5-Hydroxytryptamine3 (5-HT3) receptor antagonists, and Neurokinin-1 (NK-1) receptor antagonists have been used to treat PONV. Objectives: To compare the antiemetic effect of NK-1 receptor antagonists, including fosaprepitant. Data sources: Online databases (PubMed, MEDLINE, Scopus, The Cochrane Library databases) were used. Study eligibility criteria, participants, and interventions: Randomized Controlled Trials (RCTs) performed in patients over 18 years with ASA-PS of I‒III, aimed to assess the efficacy of antiemetics including NK-1 receptor antagonists and 5-HT3 receptor antagonists, and compared the incidence of PONV were included. Study appraisal and synthesis methods: All statistical assessments were conducted by a random effect approach, and odds ratios and 95% Confidence Intervals were calculated. Results: Aprepitant 40 mg and 80 mg significantly reduced the incidence of vomiting 0‒24 hours postoperatively (Odds Ratio [OR = 0.40]; 95% Confidence Interval [95% CI 0.30‒0.54]; p < 0.001, and OR = 0.32; 95% CI 0.19‒0.56; p < 0.001). Fosaprepitant could also reduce the incidence of vomiting significantly both 0‒24 and 0‒48 hours postoperatively (OR = 0.07; 95% CI 0.02‒0.24; p < 0.001 and OR = 0.07; 95% CI 0.02‒0.23; p < 0.001). Limitations: Risk factors for PONV are not considered, RCTs using multiple antiemetics are included, RCTs for fosaprepitant is small, and some bias may be present. Conclusions and implications of key findings: Aprepitant and fosaprepitant can be effective prophylactic antiemetics for postoperative vomiting. However, more studies are required for higher-quality meta-analyses. Systematic review registration number: CRD42019120188.

Resumo Histórico: Náusea e Vômito no Pós-Operatório (NVPO) é um evento adverso frequente da anestesia geral. Várias classes de antieméticos, incluindo antagonistas do receptor 5-Hidroxitriptamina3 (5-HT3) e antagonistas do receptor da Neurocinina-1 (NK-1), têm sido utilizados para tratar a NVPO. Objetivo: Comparar o efeito antiemético dos antagonistas do receptor NK-1, incluindo o fosaprepitanto. Fontes de dados: Foram utilizadas bases de dados on-line (PubMed, MEDLINE, Scopus, The Cochrane Library). Critérios de elegibilidade do estudo, participantes e intervenções: Foram incluídos Estudos Clínicos Randomizados (ECR) realizados em pacientes acima de 18 anos classificação ASA I a III, com o objetivo de avaliar a eficácia de antieméticos que incluíssem antagonistas do receptor NK-1 e antagonistas do receptor 5-HT3, e que comparassem a incidência de NVPO. Métodos de avaliação e síntese do estudo: Todas as avaliações estatísticas foram realizadas por abordagem de efeito aleatório e foram calculadas razões de chances e Intervalos de Confiança de 95%. Resultados: As doses de 40 mg e 80 mg de aprepitanto reduziram significantemente a incidência de vômito no período de 0 a 24 horas pós-operatórias (razão de chances [OR = 0,40]; Intervalo de Confiança de 95% [95% IC] 0,30-0,54; p < 0,001 e OR = 0,32; 95% IC 0,19-0,56; p < 0,001). O fosaprepitanto pode também reduzir significantemente a incidência de vômito tanto de 0-24 horas como no período de 0-48 horas pós-operatórias (OR = 0,07; 95% IC 0,02-0,24; p < 0,001 e OR = 0,07; 95% IC 0,02-0,23; p < 0,001). Limitações: Os fatores de risco para NVPO não foram analisados, ECRs usando múltiplos antieméticos foram incluídos, ECRs para fosaprepitanto tinham amostras pequenas, podendo haver algum viés. Conclusões e implicações dos principais achados: Aprepitanto e fosaprepitanto podem ser drogas antieméticas profiláticas efetivas para vômito no pós-operatório. No entanto, são necessários mais estudos para elaboração de meta-análises de melhor qualidade. Número de registro da revisão sistemática: CRD42019120188.

[Neurokinin-1 receptor antagonists for postoperative nausea and vomiting: a systematic review and meta-analysis]. / Antagonistas do receptor da neurocinina­1 no tratamento de náusea e vômito no pós­operatório: Revisão sistemática e meta­análise.

BACKGROUND: Postoperative Nausea and Vomiting (PONV) is a common complication of general anesthesia. Several kinds of antiemetics, including 5-Hydroxytryptamine3 (5-HT3) receptor antagonists and Neurokinin-1 (NK-1) receptor antagonists, have been used to treat PONV. OBJECTIVES: To compare the antiemetic effect of NK-1 receptor antagonists, including fosaprepitant. DATA SOURCES: Online databases (PubMed, MEDLINE, Scopus, The Cochrane Library databases) were used. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Randomized Controlled Trials (RCTs) performed in patients over 18 years with ASA-PS of I-III, aimed to assess the efficacy of antiemetics including NK-1 receptor antagonists and 5-HT3 receptor antagonists, and compared the incidence of PONV were included. STUDY APPRAISAL AND SYNTHESIS METHODS: All statistical assessments were conducted by a random effect approach and odds ratios and 95% Confidence Intervals were calculated. RESULTS: Aprepitant 40mg and 80mg significantly reduced the incidence of vomiting 0-24hours postoperatively (Odds Ratio [OR = 0.40]; 95% Confidence Interval [95% CI 0.30-0.54]; p < 0.001, and OR = 0.32; 95% CI 0.19-0.56; p < 0.001). Fosaprepitant could also reduce the incidence of vomiting significantly both 0-24h and 0-48hours postoperatively (OR = 0.07; 95% CI 0.02-0.24; p < 0.001 and OR = 0.07; 95% CI 0.02-0.23; p < 0.001). LIMITATIONS: Risk factors for PONV are not considered, RCTs using multiple antiemetics are included, RCTs for fosaprepitant is small, and some bias may be present. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Aprepitant and fosaprepitant can be effective prophylactic antiemetics for postoperative vomiting. However, more studies are required for higher-quality meta-analyses. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42019120188.

Adolescent Exposure to WIN 55212-2 Render the Nigrostriatal Dopaminergic Pathway Activated During Adulthood.

BACKGROUND: During adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood. METHODS: Male Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72-78). RESULTS: Repeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure. CONCLUSIONS: These results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum.

Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.

RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.

Combinatorial Use of Chitosan Nanoparticles, Reversine, and Ionising Radiation on Breast Cancer Cells Associated with Mitosis Deregulation.

Breast cancer is the most commonly occurring cancer in women worldwide and the second most common cancer overall. The development of new therapies to treat this devastating malignancy is needed urgently. Nanoparticles are one class of nanomaterial with multiple applications in medicine, ranging from their use as drug delivery systems and the promotion of changes in cell morphology to the control of gene transcription. Nanoparticles made of the natural polymer chitosan are easy to produce, have a very low immunogenic profile, and diffuse easily into cells. One hallmark feature of cancer, including breast tumours, is the genome instability caused by defects in the spindle-assembly checkpoint (SAC), the molecular signalling mechanism that ensures the timely and high-fidelity transmission of the genetic material to an offspring. In recent years, the use of nanoparticles to treat cancer cells has gained momentum. This is in part because nanoparticles made of different materials can sensitise cancer cells to chemotherapy and radiotherapy. These advances prompted us to study the potential sensitising effect of chitosan-based nanoparticles on breast cancer cells treated with reversine, which is a small molecule inhibitor of Mps1 and Aurora B that induces premature exit from mitosis, aneuploidy, and cell death, before and after exposure of the cancer cells to X-ray irradiation. Our measurements of metabolic activity as an indicator of cell viability, DNA damage by alkaline comet assay, and immunofluorescence using anti-P-H3 as a mitotic biomarker indicate that chitosan nanoparticles elicit cellular responses that affect mitosis and cell viability and can sensitise breast cancer cells to X-ray radiation (2Gy). We also show that such a sensitisation effect is not caused by direct damage to the DNA by the nanoparticles. Taken together, our data indicates that chitosan nanoparticles have potential application for the treatment of breast cancer as adjunct to radiotherapy.

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway.

This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 µM), or norbinaltorphimine (norBIN, 1 µM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.

Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway.

Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA.

Aprepitant in pediatric patients using moderate and highly emetogenic protocols: a systematic review and meta-analyses of randomized controlled trials.

AIMS: To review the efficacy and safety of aprepitant in combination with ondansetron and dexamethasone (triple therapy) in children and adolescents on moderate to highly emetogenic chemotherapy. METHODS: Medline, Embase, Scielo, Lilacs, Cochrane and congress abstracts published until September 2016 were used as data sources. Two reviewers independently selected manuscripts and extracted data. A third reviewer solved discrepancies in study selection and data extraction. The primary outcome was overall complete response (no vomiting from 0 to 120 h). Secondary outcomes were: response in acute phase, delayed phase and reported toxicities. Each study was considered a unit of analysis. Summarized relative risks were recalculated based on reported data. All meta-analyses used a random-effects model and heterogeneity was reported using the I2 method. RESULTS: From 1004 studies, we screened 288 titles and abstracts and included three trials for data extraction. The population comprised 451 patients. Most patients were males, ranging from 6 months to 19 years of age, and weighing from 6 to 134 kg. Bone cancer was the most incident (≥50%) neoplasm, followed by rhabdomyosarcoma and Hodgkin's lymphoma. Triple therapy was associated with a reduced risk of developing chemotherapy-induced vomiting (CIV) (RR = 0.48; 95% CI 0.34-0.67). There were no differences in incidence of febrile neutropenia between groups (RR = 1.02; 95% CI 0.66-1.58). CONCLUSIONS: Triple therapy decreased CIV risk, without increasing the occurrence of febrile neutropenia. However, this review could not address which subpopulations would most benefit from using this strategy. Future studies should focus on assessing risk factors for nausea and vomiting, as many patients did not achieve a complete antiemetic response.

Reboxetine Improves Auditory Attention and Increases Norepinephrine Levels in the Auditory Cortex of Chronically Stressed Rats.

Chronic stress impairs auditory attention in rats and monoamines regulate neurotransmission in the primary auditory cortex (A1), a brain area that modulates auditory attention. In this context, we hypothesized that norepinephrine (NE) levels in A1 correlate with the auditory attention performance of chronically stressed rats. The first objective of this research was to evaluate whether chronic stress affects monoamines levels in A1. Male Sprague-Dawley rats were subjected to chronic stress (restraint stress) and monoamines levels were measured by high performance liquid chromatographer (HPLC)-electrochemical detection. Chronically stressed rats had lower levels of NE in A1 than did controls, while chronic stress did not affect serotonin (5-HT) and dopamine (DA) levels. The second aim was to determine the effects of reboxetine (a selective inhibitor of NE reuptake) on auditory attention and NE levels in A1. Rats were trained to discriminate between two tones of different frequencies in a two-alternative choice task (2-ACT), a behavioral paradigm to study auditory attention in rats. Trained animals that reached a performance of ≥80% correct trials in the 2-ACT were randomly assigned to control and stress experimental groups. To analyze the effects of chronic stress on the auditory task, trained rats of both groups were subjected to 50 2-ACT trials 1 day before and 1 day after of the chronic stress period. A difference score (DS) was determined by subtracting the number of correct trials after the chronic stress protocol from those before. An unexpected result was that vehicle-treated control rats and vehicle-treated chronically stressed rats had similar performances in the attentional task, suggesting that repeated injections with vehicle were stressful for control animals and deteriorated their auditory attention. In this regard, both auditory attention and NE levels in A1 were higher in chronically stressed rats treated with reboxetine than in vehicle-treated animals. These results indicate that NE has a key role in A1 and attention of stressed rats during tone discrimination.

Determination of Pinaverium Bromide in Human Plasma by a Sensitive and Robust UPLC-MS-MS Method and Application to a Pharmacokinetic Study in Mexican Subjects.

A high-throughput ultra-performance liquid chromatography coupled to tandem mass spectrometry (LC-ESI-MS-MS) method was developed for the determination of pinaverium bromide in human plasma. Protein precipitation with acetonitrile was used to extract pinaverium and itraconazole (as internal standard) from 500 µL plasma samples. The chromatographic separation was achieved with an Acquity UPLC BEH C18 column (1.7 µm, 2.1 × 100 mm) using a mixture of acetonitrile-5 mM ammonium formate (80:20, v/v) as mobile phase. Isocratic elution at 0.3 mL/min was used. Detection was performed by positive ion electrospray tandem mass spectrometry on a XEVO TQ-S by multiple reaction monitoring mode. The mass transitions monitorized were as follows: m/z 511.2 → 230 for pinaverium bromide, and m/z 705.29 → 392.18 for the itraconazole. The method was validated over a concentration range of 12-12,000 pg/mL. The chromatographic method runtime is 2.5 min and was applied to characterize the pharmacokinetics of pinaverium bromide after the oral administration of 100 mg to healthy Mexican subjects.

Quality of life in patients with Irritable Bowel Syndrome (IBS), assessed using the IBS-Quality of Life (IBS-QOL) measure after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide: results of an international prospective observational cohort study in Poland, Egypt, Mexico and China.

BACKGROUND AND OBJECTIVE: Irritable Bowel Syndrome (IBS) has a substantial impact on health-related quality of life (HR-QoL) but high-quality data pre- and post-treatment using the IBS-Quality of Life (IBS-QOL) measure are limited. The objective of this study was to evaluate the changes from baseline of the IBS-QOL scores, symptom scores and health economic data in IBS patients, after 4 and 8 weeks of treatment with mebeverine hydrochloride or pinaverium bromide. METHODS: This was a prospective observational cohort study in patients with IBS, diagnosed using the Rome III criteria in four countries (Poland, Egypt, Mexico and China). RESULTS: A total of 607 patients were enrolled. At baseline, the IBS-QOL total scores were 52.0 in Poland, 48.9 in Egypt, 51.9 in Mexico, 76.4 in China and 56.4 overall. Increases in IBS-QOL total score were statistically significant at Weeks 4 and 8 overall and in each country (overall: 11.8 at Week 4, 24.3 at Week 8; p < 0.001). Improvements were shown in all IBS-QOL subscales and scores. Symptoms and health economic outcomes were improved. Furthermore, the favourable safety profile of these treatments was confirmed in this study. CONCLUSIONS: This study demonstrated that IBS patients have a substantially reduced HR-QoL and that treatment with mebeverine hydrochloride or pinaverium bromide improved HR-QoL.

Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion.

BACKGROUND: Anticoagulation before, during, and after cardioversion is effective in reducing stroke risk in patients with atrial fibrillation. OBJECTIVE: The objective of this study is to explore the efficacy and safety of rivaroxaban 20 mg once daily (15 mg if creatinine clearance is 30-49 mL/min) compared with dose-adjusted vitamin K antagonists (VKAs; international normalized ratio 2.0-3.0) in patients scheduled for elective cardioversion. METHODS: This is a prospective, randomized, open-label, parallel group comparison of approximately 1,500 patients from 17 countries with hemodynamically stable nonvalvular atrial fibrillation of >48 hours or unknown duration. Patients will be randomized 2:1 (rivaroxaban:VKA) using 2 cardioversion strategies: the first approach is early cardioversion with the precardioversion anticoagulation goal of 1 to 5 days using rivaroxaban or usual therapy (heparin + VKA). In these patients, transesophageal echocardiography will be encouraged to exclude atrial thrombi. The alternative approach is delayed cardioversion. Rivaroxaban or VKA will be administered for 21 to 56 days before cardioversion. All patients will receive study treatment for 6 weeks postcardioversion. The primary efficacy end point is a composite of all strokes, transient ischemic attacks, noncentral nervous system systemic emboli, myocardial infarctions, and cardiovascular deaths. Each primary end point component will be evaluated separately, and additional composites will be investigated. The principal safety end point is major bleeding. CLINICAL CONTEXT: This will be the first prospective study of a novel oral anticoagulant in the setting of cardioversion. It will provide important information regarding the use of rivaroxaban in the periods preceding and after cardioversion in a broad patient population.

Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain.

Studies have suggested that the endocannabinoid system is implicated in the pathophysiology of schizophrenia. We have recently reported that Spontaneously Hypertensive Rats (SHRs) present a deficit in social interaction that is ameliorated by atypical antipsychotics. In addition, SHRs display hyperlocomotion - reverted by atypical and typical antipsychotics. These results suggest that this strain could be useful to study negative symptoms (modeled by a decrease in social interaction) and positive symptoms (modeled by hyperlocomotion) of schizophrenia and the effects of potential drugs with an antipsychotic profile. The aim of this study was to investigate the effects of WIN55-212,2 (CB1/CB2 agonist), ACEA (CB1 agonist), rimonabant (CB1 inverse agonist), AM404 (anandamide uptake/metabolism inhibitor), capsaicin (agonist TRPV1) and capsazepine (antagonist TRPV1) on the social interaction and locomotion of control animals (Wistar rats) and SHRs. The treatment with rimonabant was not able to alter either the social interaction or the locomotion presented by Wistar rats (WR) and SHR at any dose tested. The treatment with WIN55-212,2 decreased locomotion (1mg/kg) and social interaction (0.1 and 0.3mg/kg) of WR, while the dose of 1mg/kg increased social interaction of SHR. The treatment with ACEA increased (0.3mg/kg) and decreased (1mg/kg) locomotion of both strain. The administration of AM404 increased social interaction and decreased locomotion of SHR (5mg/kg), and decreased social interaction and increased locomotion in WR (1mg/kg). The treatment with capsaicin (2.5mg/kg) increased social interaction of both strain and decreased locomotion of SHR (2.5mg/kg) and WR (0.5mg/kg and 2.5mg/kg). In addition, capsazepine (5mg/kg) decreased locomotion of both strains and increased (5mg/kg) and decreased (10mg/kg) social interaction of WR. Our results indicate that the schizophrenia-like behaviors displayed by SHR are differently altered by cannabinoid and vanilloid drugs when compared to control animals and suggest the endocannabinoid and the vanilloid systems as a potential target for the treatment of schizophrenia.

Cannabinoid type-1 receptor ligands, alone or in combination with cocaine, affect vigilance-related behaviors of marmoset monkeys.

Endocannabinoids (eCB) have been functionally linked to cocaine׳s rewarding effects. However, results differ at the behavioral level, with few reports in nonhuman primates (NHPs). Here we analyzed whether repeatedly administered cannabinoid type-1 receptor (CB1r) agonist WIN 55-212,2 (WIN) or antagonist AM 251 (AM) induce effects per se and if concurrent pre-treatments affect cocaine-induced changes in marmoset behavior. Six groups were tested: WIN-saline; WIN-cocaine; AM-saline; AM-cocaine; vehicle-cocaine; and vehicle-saline. Subjects were pre-treated with either WIN (1mg/kg), AM (2mg/kg) or vehicle and then injected with cocaine (5mg/kg) or saline. Six exposures were held at 48 h intervals. Behaviors were scored during 15-min in an open-field on days 1 and 6, as well as a withdrawal (WD) trial. Marmosets became hypervigilant during cocaine exposures, which did not condition to the injection context. CB1r activation induced an equivalent response, whereas AM had no effect on its own. However, when given as a pre-treatment to cocaine, CB1r blockade enhanced the former׳s hypervigilance effect and potentially conditioned this response to the exposure context. Enhancement may have resulted from AM׳s inhibition of eCB-potentiated cocaine-induced anxiogenesis and/or its action independent of the eCB system, or even CB1r-mediated changes in synaptic plasticity involved in cocaine reward-learning. All effects were independent of motor function. Thus, changes in CB1r function - alone and in combination with cocaine - affected stereotyped vigilance-related behaviors in this NHP, further implicating the eCB system in the neurobiological mechanisms of cocaine addiction.

Nuevos anticoagulantes orales en la prevención del ataque cerebrovascular / New oral anticoagulants in stroke prevention

Introduction: Atrial fibrillation (AF) is the most common arrhythmia. AF increases stroke risk by 5-fold and accounts for 15 percent of stroke. For more than 50 years, vitamin K antagonists were the only available oral anticoagulation. The two major classes of novel oral agents are direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban or rivaroxaban). These new agents require no routine laboratory monitoring and they are administered in a fixed dose. Method: A non systematic literature review was performed. Results: We performed a critical review of articles about new oral anticoagulants in stroke prevention. We evaluated properties of these agents and we compare efficacy and safety outcomes shown in clinical trials about new oral anticoagulants in AF. Discussion: New oral anticoagulants are at least as good as warfarin at preventing stroke in patients with AF. They seem to be safer than warfarin with significantly less intracranial bleeding. Trials demonstrate dabigatran to be the most effective in decreasing ischemic strokes, apixaban superior to warfarin with statistically lower mortality, and rivaroxaban no worse than warfarin for those with higher stroke risk. Conclussion: New oral anticoagulants have several advantages in comparison with warfarin, but we need further trials to know better the efficacy and safety of these new agents.

Introducción: La fibrilación auricular (FA) es la arritmia más frecuente, se asocia a un riesgo 5 veces mayor de ataque cerebrovascular (ACV), y da cuenta del 15 por ciento de los ACV isquémicos. Por más de medio siglo el tratamiento anticoagulante oral en FA ha estado limitado al uso de antagonistas de la vitamina K. Los nuevos anticoagulantes orales, se clasifican en dos categorías principales: inhibidores de la trombina como el dabigatrán y los inhibidores del factor Xa, como el apixabán y el rivaroxabán. Estos fármacos no requieren monitorización de los niveles de anticoagulación y se administran en dosis fija. Método: Revisión no sistemática de la literatura. Resultados: Se analizan de manera crítica los artículos sobre nuevos anticoagulantes orales en la prevención de ACV. Se evalúan las propiedades de estos nuevos agentes y se comparan los desenlaces de eficacia y de seguridad de los ensayos clínicos de los estos fármacos. Discusión: Los nuevos anticoagulantes orales son al menos tan efectivos que la warfarina en la prevención de ACV cardioembólico en pacientes con FA. Parecen ser más seguros con menor frecuencia de hemorragia intracranial. El dabigatrán es el más efectivo en disminuir el ACV isquémico, el apixabán es superior a la warfarina con una mortalidad significativamente inferior, y el rivaroxabán es no inferior a warfarina para pacientes con alto riesgo de ACV. Conclusión: Los nuevos anticoagulantes orales ofrecen varias ventajas en comparación a warfarina, sin embargo, se requiere se estudios adicionales para conocer más detalladamente su efectividad y perfil de seguridad.

The new oral anticoagulants: a challenge for hospital formularies.

Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated.

Oral thromboprophylaxis in pelvic trauma: a standardized protocol.

BACKGROUND: Thromboprophylaxis for deep vein thrombosis (DVT) after lower-extremity trauma could include rivaroxaban, an oral medication that does not need laboratory monitoring. OBJECTIVE: To assess rivaroxaban's efficacy in preventing DVTs after pelvic trauma compared to its historical incidence. MATERIALS AND METHODS: All patients admitted with pelvic fractures in a 12-month period followed a standardized thromboprophylaxis protocol: 1) rivaroxaban 10 mg/day within 24 h of injury or upon hemodynamic stability; 2) pre-operative, post-operative, and 30-day extremity ultrasound; 3) ventilation-perfusion scintigraphy for clinical signs of pulmonary embolus; and 4) a 45-, 90-, and 120-day re-evaluation. Rivaroxaban administration ceased the day of surgery and restarted 12 h post-operatively or upon hemodynamic stability, continuing for 30 days. Excluded patients had severe neurological or hepatosplenic injuries, heparin hypersensitivity, or hemodynamic instability. RESULTS: Of 113 patients assessed, 84 patients (66 males), average age 46.6 years (range 19-69 years), were included. They had isolated pelvic trauma (n = 37), associated lower limb injuries (n = 47), average Injury Severity Score 21.4 (range 16-50), and average Glasgow Coma Scale score 13.6 (range 9-15). Patients receiving thromboprophylaxis soon after their fracture (n = 64) had a lower incidence of DVT than those receiving delayed thromboprophylaxis (n = 20) (p = 0.02). One patient (1.2%) died from a pulmonary embolus; 13 had asymptomatic below-the-knee DVTs. Rivaroxaban did not increase intra- or post-operative bleeding in surgical wounds. CONCLUSIONS: DVT incidence after pelvic fractures is reduced by administering antithrombotics within 24 h of injury or, if the patient is hemodynamically unstable, 24 h after stabilization. Rivaroxaban is a safe and effective method of providing this thromboprophylaxis.

Relative bioavailability of a 5 mg mosapride/10 mg rabeprazole fixed dose combination tablet versus separate single tablets in healthy volunteers: a single-dose randomized open-label crossover study.

OBJECTIVE: To evaluate the relative bioavailability of a new formulation containing 5 mg mosapride and 10 mg rabeprazole (T) and compare it with the branded formulations of both drugs co-administered in separate tablets (R) to meet the regulatory requirements of bioequivalence in Argentina. METHODS: A randomized-sequence, open-label, two-period crossover study was conducted on 24 healthy Caucasian volunteers in a fasting state. A single oral dose of either T or R formulations was followed by a 7-day washout period. Blood samples for mosapride were collected before administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 24 h after administration. Samples for rabeprazole were taken baseline and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8 and 10 h after dosing. Mosapride and rabeprazole concentrations were determined using a validated LC-MS/MS method. Adverse events were monitored based on clinical parameters and volunteer reports. RESULTS: The geometric means (90% CI) C(max) for mosapride in T and R were 23.13 (20.05-39.45) and 23.09 (21.69-32.37) ng/mL, the AUC(0-)(t) were 70.80 (66.23-102.37) and 70.81 (66.35-93.26) ng h/mL and the AUC(0-∞) were 74.05 (69.29-106.11) and 74.98 (70.43-97.77) ng h/mL. For rabeprazole T and R the C(max) were 197.42 (186.12-239.91) and 195.50 (186.08-250.07) ng/mL, the AUC(0-)(t) were 294.90 (275.13-374.15) and 296.96 (280.11-387.89) ng h/mL and the AUC(0-∞) were 301.12 (280.78-380.82) and 304.07 (286.60-394.21), respectively. No differences were detected between the formulations. The T/R ratios (90% CI) for C(max), AUC(0-)(t) and AUC(0-∞) were 100.17% (82.35-121.84), 99.99% (87.58-114.16) and 98.77% (87.02-112.11) for mosapride, and 100.99% (85.14-119.77), 99.31% (84.74-116.38) and 99.03% (85.07-115.28) for rabeprazole. No subject complained of adverse events. CONCLUSIONS: In this single-dose study, the mosapride/rabeprazole tablets (test formulation) met the criterion for bioequivalence with the reference formulations. Study limitations include single-dose, open-label design, and a small sample of healthy volunteers.

Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists.

Δ9-THC is a component of Cannabis sativa that increases food intake in animals and humans, an effect prevented by selective CB1 receptor antagonists. Cannabidiol (CBD) is another constituent of this plant that promotes several opposite neuropharmacological effects compared to Δ9-THC. CBD mechanisms of action are still not clear, but under specific experimental conditions it can antagonize the effects of cannabinoid agonists, block the reuptake of anandamide and act as an agonist of 5-HT1A receptors. Since both the cannabinoid and serotoninergic systems have been implicated in food intake control, the aim of the present work was to investigate the effects caused by CBD on hyperphagia induced by agonists of CB1 or 5-HT1A receptors. Fed or fasted Wistar rats received intraperitoneal (i.p.) injections of CBD (1, 10 and 20 mg/kg) and food intake was measured 30 min later for 1 h. Moreover, additional fed or fasted groups received, after pretreatment with CBD (20 mg/kg) or vehicle, i.p. administration of vehicle, a CB1 receptor agonist WIN55,212-2 (2 mg/kg) or a 5-HT1A receptor agonist 8-OH-DPAT (1 mg/kg) and were submitted to the food intake test for 1 h. CBD by itself did not change food intake in fed or fasted rats. However, it prevented the hyperphagic effects induced by WIN55,212-2 or 8-OH-DPAT. These results show that CBD can interfere with food intake changes induced by a CB1 or 5-HT1A receptor agonist, suggesting that its role as a possible food intake regulator should be further investigate.