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Abstract Objective To evaluate the efficacy of vitamin B-6 in the treatment of premenstrual syndrome. Design Systematic review of published and unpublished randomised placebo controlled trials of the effectiveness of [...]

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mmglucose, 3 % albumin, and 0.4 mmor 0.8 mmpalmitate, 20μmranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mmpalmitate. Dichloroactetate (DCA, 1 mm), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mmbut not 1.2 mmpalmitate. PDHa was significantly increased with 1.2 mmpalmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mmpalmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic non-haemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and ±DCA which itself had little effect. In the absence of fatty acid, ranolazine and /or DCA raised acetyl CoA. In perfusions where octanoate ( ±albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6and C8CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.

It has been proposed that the presence of increasing concentrations of fatty acids may accelerate the development of ischaemic contracture and cardiac damage, and that this may be due to long-chain acyl carnitine accumulation and /or impairment of glucose utilization. In isolated guinea-pig papillary muscles, palmitoyl (DL) carnitine was found to have a positive inotropic effect, with a slow onset of action suggestive of an intracellular site of action, and with a maximal effect of about two-fold at a concentration of 5 –10μm; higher concentrations led to decreased contraction, probably due to increasing detergent-like effects. In isolated fura-2-loaded chick cardiomyocytes, palmitoyl carnitine increased intracellular [Ca2 +]; it is proposed that this is the means by which it increases contraction. The main hypothesis above was studied using isolated guinea-pig hearts perfused with either 11.7 mmor 5 mmglucose, and either albumin alone (3 %) or albumin bound palmitate (1.5 mm) during low-flow ischaemia (92 % reduction in flow) for up to 60 min. With 11.7 mmglucose, the presence of palmitate caused contracture development and increased enzyme release during ischaemia. Contracture also developed when the glucose concentration was reduced to 5 mmin the absence of fatty acid, however, in its presence contracture developed to a greater extent and with increased enzyme release. Long-chain acyl carnitine accumulation was similar in both groups. These studies show that long-chain acyl carnitine accumulation has the potential to induce contracture during ischaemia, although a reduction in glucose availability may also contribute.

BackgroundChildhood overweight and obesity is a major public health priority. Overweight or obese children are likely to become overweight or obese adults, are likely to be at increased risk of a wide range of chronic diseases (eg, type 2 diabetes, cardiovascular disease, and some cancers), and can have broader effects on lifestyle, health, and wellbeing compared with their peers. A clear need exists for cost-effective interventions or programmes that can help with the problems associated with childhood obesity. However, the conduct of cost-effectiveness analyses (and health technology assessment more broadly) in childhood obesity presents challenges. Translation of measures of effectiveness, for example body-mass index, into the potential effects of interventions on future health outcomes, such as prevention of diabetes, is one such challenge. The current methods available to model future outcomes in this way are limited. We aimed to develop a decision-analytic model to estimate the effect of interventions aimed at childhood overweight and obesity, for use in cost-effectiveness analyses in a public health context.