Profile of ezogabine (retigabine) and its potential as an adjunctive treatment for patients with partial-onset seizures

Epilepsy is a common disease with significant morbidity and mortality. Approximately one-third of patients with epilepsy are refractory to available seizure medications, emphasizing the need to develop better drugs with novel mechanisms of action. Ezogabine, also known as retigabine, is a new potential adjunctive treatment for adults with intractable partial seizures. Ezogabine has a unique mechanism of action consisting of activating KCNQ2/3 (Kv7) potassium channels. Ezogabine has undergone a number of Phase II and III trials demonstrating efficacy at 600,900 and 1200 mg/day in a dose-dependent fashion. The most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. Urologic symptoms, particularly urinary retention, represent a rare but unique side effect of ezogabine. Ezogabine is predominantly metabolized via glucuronidation. Its half-life is 8 hours, suggesting a need for three-times-a-day administration. Ezogabine exhibits minimal interactions with other seizure medications, except possibly lamotrigine. Ezogabine has potential for clinical applications in other medical conditions beyond epilepsy, such as neuropathic pain, neuromyotonia, and bipolar disease, but these are based primarily on experimental models

N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1.

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA's anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation

Adenosine and oxytocin reverse antagonism of cyclic AMP elevating agents to insulin activation of adipocyte pyruvate dehydrogenase

AbstractACTH, isoprenaline, forskolin, and dibutyryl cyclic AMP prevented insulin from stimulating adipocyte pyruvate dehydrogenase in the presence of adenosine deaminase. Antagonism was reversed by N6-phenyliso-propyladenosine as well as oxytocin. The stimulatory effects of insulin, adenosine and oxytocin on adipocyte pyruvate dehydrogenase appear to be through (a) mechanism(s) which is (are) similar or related

Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy

One-third of patients with epilepsy continue to have seizures despite current treatments, indicating the need for better antiseizure medications with novel mechanisms of action. Ezogabine (retigabine) has recently been approved for adjunctive treatment of partial-onset seizures in adult patients with epilepsy. Ezogabine utilizes a novel mechanism of action, involving activation of specific potassium channels. The most common side effects of ezogabine are shared by most antiseizure medications and primarily consist of central nervous system (CNS) symptoms, such as somnolence, dizziness, confusion, and fatigue. In addition, a small percentage of patients on ezogabine experience a unique adverse effect affecting the bladder, which results in urinary hesitancy; thus, patients on ezogabine should be monitored carefully for potential urological symptoms. Overall, ezogabine appears to be well tolerated and represents a reasonable new option for treating patients with intractable epilepsy

Effect of adenosine on insulin activation of rat adipocyte pyruvate dehydrogenase

AbstractAdenosine and its analogue N6-phenylisopropyladenosine stimulated pyruvate dehydrogenase activity of isolated rat adipocytes. Maximal stimulation was obtained with concentrations between 50 and 100 μM, with the effect decreasing at higher concentrations. The effects of insulin on this enzyme was modified by adenosine. The concentration of insulin (10 μunitsml) that produced almost half-maximal stimulation, had little or no effect, when adenosine deaminase was present. Adenosine also enhanced the effect of suboptimal but not optimal concentrations of insulin. Thus, the mechanism of adenosine action on adipocyte pyruvate dehydrogenase could in some way be similar or related to that of insulin

Silent and suffering : a pilot study exploring gaps between theory and practice in pain management for people with severe dementia in residential aged care facilities

Background: Pain is common in older people, particularly those in residential aged care facilities (RACF) and those with dementia. However, despite 20 years of discourse on pain and dementia, pain is still undetected or misinterpreted in people with dementia in residential aged care facilities, particularly those with communication difficulties. Methods: A topical survey typology with semistructured interviews was used to gather attitudes and experiences of staff from 15 RACF across Northern Sydney Local Health District. Results: While pain is proactively assessed and pain charts are used in RACF, this is more often regulatory-driven than patient-driven (eg, prior to accreditation). Identification of pain and need for pain relief was ill defined and poorly understood. Both pharmacological and non-¬pharmacological regimes were used, but in an ad hoc, variable and unsystematic manner, with patient, staff, and attitudinal obstacles between the experience of pain and its relief. Conclusion: A laborious “pain communication chain” exists between the experience of pain and its relief for people with severe dementia within RACF. Given the salience of pain for older people with dementia, we recommend early, proactive consideration and management of pain in the approach to behaviors of concern. Individualized pain measures for such residents; empowerment of nursing staff as “needs interpreters”; collaborative partnerships with common care goals between patients where possible; RACF staff, doctors, and family carers; and more meaningful use of pain charts to map response to stepped pain protocols may be useful strate¬gies to explore in clinical settings

A cross-sectional study on tobacco use and dependence among women: Does menthol matter?

Background: The question of whether mentholation of cigarettes enhances tobacco dependence has generated conflicting findings. Potential mediating factors in a putative relationship between menthol use and tobacco dependence may include race and gender. While an association between menthol use and dependence is mixed, research on the role of race solely among women smokers is scarce. This study examined whether women menthol smokers have higher tobacco use and dependence than non-menthol smokers. Further, the study investigated differences between White and African American smokers. Methods: A cross-sectional study was conducted among 928 women seeking tobacco dependence treatment in Boston, Massachusetts. Measures obtained included preferred brand and menthol content, dependence markers (cigarettes per day (CPD); time to first cigarette in the morning; number of and longest previous quit attempts) and smoking history (age of initiation; years smoking; menthol or non-menthol cigarette preference). Analysis of variance (ANOVA) was used to detect interactions between menthol preference by race for continuous variables, and Pearson’s chi-squared test was used for analyses with dichotomous variables. Results: A greater proportion of menthol smokers smoked their first cigarette within five minutes of waking (p < 0.01) and were less likely to have a previous quit attempt longer than 90 days (p < 0.01). ANOVAs revealed no main effects for menthol preferences. However, African American smokers smoked fewer CPD (p<.001), started smoking later in life (p= .04), and had been smoking the same brand for longer (p= .04). Conclusions: Women menthol smokers showed signs of greater tobacco dependence than non-menthol smokers. African Americans smoked fewer CPD but nevertheless had evidence of greater dependence

The Relationship between Physical Inactivity and Family Life Course Stage

Physical inactivity is a well-documented risk factor for numerous chronic diseases and a major public health problem in Canada. Since social-ecological models suggest that behaviour is influenced by the person as well as the social and physical environment, it is important to be sensitive to other factors when examining physical activity participation. The purpose of this study was to explore the associations between physical inactivity, marital status and family stage for men and women in Canada. The study was based on data from the Canadian Community Health Survey, Cycle 2.1, for adults aged 18-64 living with a spouse or partner (with or without children) or single living with children. Respondents were classified as inactive or active according to self-reported leisure-time physical activity. Logistic regression was used to examine gender differences in the relationship between household composition and physical inactivity. Explanatory variables included parents’ age, sex, age of youngest child, income adequacy and interview mode. Family stage was significantly associated with adult physical inactivity levels. Individuals with very young children (\u3c 6 years old) were more likely to be inactive compared to childless adults or those with older children (\u3e12 years old). Having children between 6-12 years old was related to increased physical activity, possibly due to more family leisure pursuits involving physical activity. Living with a partner was associated with greater physical inactivity, particularly when controlling for income adequacy. Furthermore, those with high income adequacy were less likely to be inactive, and having a very young child increased this difference. In conclusion, family life course stage and income adequacy were most influential in determining levels of physical inactivity. Therefore, physically active leisure programs targeting adults with very young children, particularly those at lower income levels, may be helpful in increasing physical activity and decreasing health risks associated with inactivity. Margo Hilbrecht is a Postdoctoral Fellow at the University of Guelph’s Centre for Families, Work and Well-Being. She recently received her Ph.D. from the University of Waterloo in Recreation and Leisure Studies. Her research focuses on time use and work-life integration as it pertains to non-traditional work arrangements, gender and leisure. These interests extend to perceptions of time pressure and stress associated with the coordination of employment, school, and leisure activities in families with school-age children. Her current research explores the social and health consequences of unpredictable work schedules for parents employed in the retail sector

Homologous recombination repair is essential for repair of vosaroxin-induced DNA double-strand breaks

Vosaroxin (formerly voreloxin) is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, inducing site-selective double-strand breaks (DSB), G2 arrest and apoptosis. Objective responses and complete remissions were observed in phase 2 studies of vosaroxin in patients with solid and hematologic malignancies, and responses were seen in patients whose cancers were resistant to anthracyclines. The quinolone-based scaffold differentiates vosaroxin from the anthracyclines and anthracenediones, broadly used DNA intercalating topoisomerase II poisons. Here we report that vosaroxin induces a cell cycle specific pattern of DNA damage and repair that is distinct from the anthracycline, doxorubicin. Both drugs stall replication and preferentially induce DNA damage in replicating cells, with damage in G2 / M > S >> G1. However, detectable replication fork collapse, as evidenced by DNA fragmentation and long tract recombination during S phase, is induced only by doxorubicin. Furthermore, vosaroxin induces less overall DNA fragmentation. Homologous recombination repair (HRR) is critical for recovery from DNA damage induced by both agents, identifying the potential to clinically exploit synthetic lethality

Sociodemographic Trends in National Ambulatory Care Visits for Hepatitis C Virus Infection

Poor and non-white patients are disproportionately infected with the hepatitis C virus (HCV). The objective of this research is to determine sociodemographic patterns of HCV-related ambulatory care visits over time. Data from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey-Outpatient (NHAMCS-OPD) for the years 1997–2005 were analyzed in 3-year intervals. Demographic and other variables were compared for each period, and multivariable logistic regression was performed to examine whether the likelihood of a visit being HCV-related (versus non-HCV) was independently associated with (1) race and/or (2) Medicaid status over time. The total number of HCV-related ambulatory visits more than doubled from 3,583,585 during the years 1997–1999 to 8,027,166 during 2003–2005. During this time, the proportion of non-whites and Medicaid recipients presenting for HCV-related visits approximately doubled (non-whites: 16% vs. 33%, P = 0.04; Medicaid recipients: 10% vs. 25%, P = 0.07). In 2003–2005, HCV-related visits were more than twice as likely to occur among non-white patients vs. white patients (OR = 2.49; 95% CI: 1.60–3.86) and patients on Medicaid vs. non-Medicaid (3.49; 1.79–6.80). Our results show that HCV-associated ambulatory care visits are increasing, with a greater proportion of visits occurring among non-white patients and Medicaid recipients