Modulation of ionotropic GABA receptors by 6-methoxyflavanone and 6-methoxyflavone.

We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type α1/α2ß2γ2L GABAA and ρ1 GABAC receptors and on mutant ρ1I307S, ρ1W328 M, ρ1I307S/W328 M GABAC receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant α1ß2γ2L and α2ß2γ2L GABAA receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at α1ß2 GABAA receptors. 6-Methoxyflavanone inhibited [(3)H]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at ρ1, ρ1I307S and ρ1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive ρ1I307S/W328 M GABA receptors. This double mutant retains ρ1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at ρ1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at α1ß2 GABAA receptors and it's partial agonist action at ρ1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.

Interventions for preventing obesity in children.

BACKGROUND: Prevention of childhood obesity is an international public health priority given the significant impact of obesity on acute and chronic diseases, general health, development and well-being. The international evidence base for strategies that governments, communities and families can implement to prevent obesity, and promote health, has been accumulating but remains unclear. OBJECTIVES: This review primarily aims to update the previous Cochrane review of childhood obesity prevention research and determine the effectiveness of evaluated interventions intended to prevent obesity in children, assessed by change in Body Mass Index (BMI). Secondary aims were to examine the characteristics of the programs and strategies to answer the questions "What works for whom, why and for what cost?" SEARCH METHODS: The searches were re-run in CENTRAL, MEDLINE, EMBASE, PsychINFO and CINAHL in March 2010 and searched relevant websites. Non-English language papers were included and experts were contacted. SELECTION CRITERIA: The review includes data from childhood obesity prevention studies that used a controlled study design (with or without randomisation). Studies were included if they evaluated interventions, policies or programs in place for twelve weeks or more. If studies were randomised at a cluster level, 6 clusters were required. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of included studies.  Data was extracted on intervention implementation, cost, equity and outcomes. Outcome measures were grouped according to whether they measured adiposity, physical activity (PA)-related behaviours or diet-related behaviours.  Adverse outcomes were recorded. A meta-analysis was conducted using available BMI or standardised BMI (zBMI) score data with subgroup analysis by age group (0-5, 6-12, 13-18 years, corresponding to stages of developmental and childhood settings). MAIN RESULTS: This review includes 55 studies (an additional 36 studies found for this update). The majority of studies targeted children aged 6-12 years.  The meta-analysis included 37 studies of 27,946 children and demonstrated that programmes were effective at reducing adiposity, although not all individual interventions were effective, and there was a high level of observed heterogeneity (I(2)=82%).  Overall, children in the intervention group had a standardised mean difference in adiposity (measured as BMI or zBMI) of -0.15kg/m(2) (95% confidence interval (CI): -0.21 to -0.09).  Intervention effects by age subgroups were -0.26kg/m(2) (95% CI:-0.53 to 0.00) (0-5 years), -0.15kg/m(2) (95% CI -0.23 to -0.08) (6-12 years), and -0.09kg/m(2) (95% CI -0.20 to 0.03) (13-18 years). Heterogeneity was apparent in all three age groups and could not explained by randomisation status or the type, duration or setting of the intervention.  Only eight studies reported on adverse effects and no evidence of adverse outcomes such as unhealthy dieting practices, increased prevalence of underweight or body image sensitivities was found.  Interventions did not appear to increase health inequalities although this was examined in fewer studies. AUTHORS' CONCLUSIONS: We found strong evidence to support beneficial effects of child obesity prevention programmes on BMI, particularly for programmes targeted to children aged six to 12 years. However, given the unexplained heterogeneity and the likelihood of small study bias, these findings must be interpreted cautiously. A broad range of programme components were used in these studies and whilst it is not possible to distinguish which of these components contributed most to the beneficial effects observed, our synthesis indicates the following to be promising policies and strategies:·         school curriculum that includes healthy eating, physical activity and body image·         increased sessions for physical activity and the development of fundamental movement skills throughout the school week·         improvements in nutritional quality of the food supply in schools·         environments and cultural practices that support children eating healthier foods and being active throughout each day·         support for teachers and other staff to implement health promotion strategies and activities (e.g. professional development, capacity building activities)·         parent support and home activities that encourage children to be more active, eat more nutritious foods and spend less time in screen based activitiesHowever, study and evaluation designs need to be strengthened, and reporting extended to capture process and implementation factors, outcomes in relation to measures of equity, longer term outcomes, potential harms and costs.Childhood obesity prevention research must now move towards identifying how effective intervention components can be embedded within health, education and care systems and achieve long term sustainable impacts.  

Gemcitabine administered as a short infusion versus a fixed dose rate in combination with cisplatin for the treatment of patients with advanced non-small cell lung cancer.

Previous studies have indicated that, in combination with cisplatin, fixed dose rate gemcitabine may be more efficacious than standard infusion gemcitabine. This open-label, randomised phase II study was aimed to compare the efficacy and safety of these regimens as treatment for advanced non-small cell lung cancer (NSCLC) in Latin American patients. Sixty-four patients were randomised to receive up to six cycles of treatment with cisplatin 75 mg/m(2) on Day 1 plus either gemcitabine 1000 mg/m(2) over 30 min on Days 1 and 8 of a 21-day cycle (standard arm, N=33) or gemcitabine 1000 mg/m(2) at a fixed dose rate of 10 mg/m(2)/min on Days 1 and 8 of a 21-day cycle (FDR arm, N=31). In the standard arm, 9 of 33 (27%) patients responded compared with 6 of 30 (20%) patients in the FDR arm (odds ratio: 0.67, 95% CI, 0.21-2.2; p=0.56). Median overall survival was 7.5 months in the standard arm and 9.9 months in the FDR arm. One-year survival rates were 35% and 37% in the standard arm and the FDR arm, respectively. Patients in the FDR arm experienced more grade 3/4 haematological toxicity than those in the standard arm (48% versus 21%). The results of this trial do not support FDR administration of gemcitabine in preference to the standard administration in Latin American patients with NSCLC.

Comparison of raloxifene and bisphosphonates based on adherence and treatment satisfaction in postmenopausal Asian women.

We evaluated adherence with raloxifene therapy compared with daily bisphosphonate in Asian postmenopausal women at increased risk of osteoporotic fractures. In this 12-month observational study conducted in Asia (Hong Kong, Malaysia, Pakistan, Philippines, Singapore, Taiwan), 984 postmenopausal women (aged 55 years or older) were treated with raloxifene 60 mg/day (n = 707; 72%) or daily bisphosphonate (alendronate 10 mg/day; n = 206; 21%, or risedronate 5 mg/day; n = 71; 7%) during their normal course of care. Patients were assessed at baseline, 6, and 12 months. Baseline characteristics (including age, race, education, menopausal status, and baseline fractures) were comparable between the raloxifene and bisphosphonate groups. More women on raloxifene completed the study compared with those on bisphosphonate (50.2% versus 37.5%; P < 0.001). Patients also took raloxifene for a longer period than bisphosphonate (median, 356 versus 348 days; P = 0.011). Compared with those taking bisphosphonate, significantly fewer patients taking raloxifene discontinued the study because of stopping treatment (5.7% versus 10.1%, P = 0.017) or changing treatment (2.8% versus 9.7%, P < 0.001). Inconvenient dosing was reported as a primary reason for discontinuation due to stopping or changing treatment in 19 (6.9%) bisphosphonate patients compared with 0 raloxifene patients. The percentage of patients who had consumed 80% or more of their study medication was similar for raloxifene patients (48-56 weeks; 95.2%) and bisphosphonate patients (48-56 weeks; 93.3%). More raloxifene patients responded that they were satisfied with their medication than bisphosphonate patients at 48-56 weeks (P = 0.002). We concluded that Asian postmenopausal women at increased risk of osteoporotic fractures showed a greater propensity to remain on raloxifene compared with bisphosphonate. The women on raloxifene exhibited lower discontinuation rates and higher treatment satisfaction.

6-Methylflavanone, a more efficacious positive allosteric modulator of gamma-aminobutyric acid (GABA) action at human recombinant alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus oocytes.

6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho1 GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC(10-20) GABA responses were 22 microM, 10 microM and 6 microM and the maximum potentiations were 120%, 417% and 130% at alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha2-containing GABA(A) receptors, while sedation is thought to be mediated via alpha1-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 microM) produced positive allosteric modulation at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha2beta2gamma2L GABA(A) receptors and found to maximally potentiate the EC(10-20) GABA response by 183+/-39% which is similar to that previously observed for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha2beta2gamma2L over alpha1beta2gamma2L GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha2beta2gamma2L GABA(A) receptors, and less efficacious at alpha1beta2gamma2L GABA(A) receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors, the positive modulation of GABA responses at alpha1beta2gamma2L and alpha2beta2gamma2L GABA(A) receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via "high-affinity" benzodiazepine sites.

Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.

In view of the ability of flavones to displace radiolabelled benzodiazepines from brain tissue and the interesting behavioural profile of these compounds, the present study investigated the activity of 6-methylflavone at ionotropic gamma-aminobutyric acid (GABA) receptors expressed in Xenopus laevis oocytes. 6-Methylflavone (1-100 microM) was found to be a positive allosteric modulator at alpha1beta2gamma2L and alpha1beta2 GABAA receptors with no significant difference between the enhancement seen at either receptor subtype. At 100 microM, 6-methylflavone enhanced the response to 5 microM GABA by 183+/-20% at alpha1beta2gamma2L GABAA receptors. The methyl substituent was important since the parent flavone was significantly weaker as a positive modulator (103+/-24% enhancement of 5 microM GABA by 100 microM flavone). This enhancement is not mediated via high-affinity benzodiazepine sites as it was not inhibited by the classical benzodiazepine antagonist flumazenil under conditions where flumazenil inhibits the potentiation of the GABA response to diazepam. 6-Methylflavone (60 microM) did not significantly affect the GABA dose-response curve at rho1 GABAC receptors. 6-Methylflavone acts as a positive modulator of recombinant GABAA receptors at sites independent of flumazenil-sensitive benzodiazepine sites.

Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors.

Amentoflavone is found in a number of plants with medicinal properties, including Ginkgo biloba and Hypericum perforatum (St. John's Wort). We have developed a rapid and economic semi-synthetic preparation of amentoflavone from biflavones isolated from autumnal Ginkgo biloba leaves. Several studies have shown that amentoflavone binds to benzodiazepine receptors. Using two electrode voltage-clamp methodology, amentoflavone has been shown to be a negative modulator of GABA at GABA(A) alpha(1)beta(2)gamma(2L) receptors expressed in Xenopus laevis oocytes This action appears to be independent of the flumazenil-sensitive benzodiazepine modulatory sites on the GABA(A) receptor.