MPFF 1000 mg chewable once daily vs. MPFF 500 mg twice daily in chronic venous disease: the double-blind, randomized, non-inferiority CHEWY trial.

BACKGROUND: The efficacy and tolerability of the new micronized purified flavonoid fraction (MPFF) 1000 mg once-daily chewable formulation in comparison with the established MPFF 500 mg conventional tablet at the same daily dose are unknown. METHODS: CHEWY was an international, multicenter, double-blind, double-dummy, randomized, parallel group, non-inferiority phase III study conducted in adult patients with symptomatic chronic venous disease (CVD). Patients were randomly allocated to MPFF 1000 mg chewable or MPFF 2x500 mg daily treatment. The primary efficacy endpoint for clinical non-inferiority (non-inferiority margin predefined at 1 cm) was lower limb discomfort (LLD) assessed by a 10 cm electronic visual analog scale (eVAS) at 8 weeks. Secondary endpoints included leg pain (LP), leg heaviness (LH), and quality of life (QoL) measured by the eCIVIQ-14 questionnaire. Overall acceptability was assessed at each visit by patient and investigator. RESULTS: Three hundred and nine patients were randomized to MPFF 1000 mg chewable and 302 to MPFF 2x500 mg. After 8 weeks, LLD decreased from baseline by -3.6±2.4 cm and -3.6±2.5 cm in the MPFF chewable and 2x500 mg groups, respectively. Non-inferiority of the once-daily chewable formulation compared with twice daily tablets on improving LLD was demonstrated (adjusted between-group difference [Standard Error]) (E [SE]) = 0.00 (0.18) cm, 95%CI -0.35; 0.35, non-inferiority P value <0.0001. Decreases of similar magnitude were observed at 8 weeks for LP and LH in both treatment arms: -3.4±2.3 cm and -3.5±2.5 cm, respectively for LP, and -3.5±2.5 cm and -3.5±2.6 cm, respectively for LH. QoL (global score) improved by -21.0±17.2 and -22.5±20.1 in the MPFF 1000 mg chewable group and 2x500 mg groups, respectively (E [SE]=1.03 [1.20], 95%CI [-1.32; 3.38]), with similar improvements in the QoL subscore components in both groups. Treatment acceptability was high for both patients and physicians and tolerability similar to the tablet formulation. CONCLUSIONS: MPFF 1000 mg chewable was non-inferior to MPFF 2x500 mg tablets with respect to its effect on LLD. Both formulations were associated with improvements of similar magnitude in lower limb symptoms and QoL. The chewable formulation was observed to be well tolerated and well accepted. Once-daily MPFF chewable tablet offers patients with CVD a good alternative treatment regimen.

Three-dimensional digital imaging is as accurate and reliable to measure leg ulcer area as transparent tracing with digital planimetry.

OBJECTIVE: An accurate and reliable method for measuring venous leg ulcer (VLU) area is important in assessing treatment effects. The new three-dimensional (3D) LifeViz digital imaging system (QuantifiCare S.A., Valbonne, France) combines a compact, easy to use stereovision camera and image management software to provide 3D medical images. The aim of this prospective study was to investigate whether the 3D LifeViz digital imaging system could be considered a suitable alternative to manual transparent wound tracing for the measurement of VLU area and 4-week healing rates. METHODS: A prospective cohort study was conducted in two tertiary centers between November 2013 and January 2014. The intrarater variability of the digital imaging system was assessed by comparison of the target wound (TW) areas obtained at the inclusion visit (W0) and 2 days after W0 for each local rater. The inter-rater variability of the two methods at W0 and the study end visit was assessed using the TW area measurements obtained by local and central raters. RESULTS: A total of 36 consecutive outpatients, each presenting with at least one VLU and representing a total of 44 TWs, were recruited. At inclusion, comparable results were observed with both methods in terms of mean VLU area, showing a good correlation of the digital imaging method with the transparent tracing method (concordance correlation coefficient [CCC], 0.989; 95% confidence interval [C], 0.983-0.992). Furthermore, this system detected the same changes in the 4-week healing rate as the transparent tracing method, showing that both methods were equivalent in measuring changes in VLU areas over time (CCC, 0.996; 95% CI, 0.994-0.997). Strong intrarater and inter-rater concordances demonstrated good reproducibility of the digital imaging system for VLU area measurements (CCC, 0.994 [95% CI, 0.992-0.995] for intrarater variability; and CCC ≥0.99 for each center for inter-rater variability). Moreover, regardless of the operator measuring the VLUs, the reliability of image capture and image quality remained excellent. CONCLUSIONS: The 3D LifeViz digital imaging system is a noncontact stereophotographic method that provides measurements of VLU area or changes in VLU areas that are as accurate and reliable as those obtained using the planimetry method and in conditions as close as possible to those of a clinical trial.

Trimetazidine normalizes postischemic function of hypertrophied rat hearts.

The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 microM trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by approximately 30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.

Prevention of heart failure in rats by trimetazidine treatment: a consequence of accelerated phospholipid turnover?

Heart failure is known for alteration of cardiac catecholamine responsiveness involving adrenergic receptor (AR) down-regulation. Trimetazidine, a metabolically active anti-ischemic drug, accelerates the turnover of phospholipids. The present study evaluated the consequences of trimetazidine treatment (supposed to increase phospholipid synthesis) on AR in heart failure in rats. In control rats, trimetazidine (7.5 mg/day supplied in the diet) induced after 8 weeks a significant increase in both beta- (+54%) and alpha-AR (+30%) density, although after 12 weeks, the receptor density was normalized. Heart failure was obtained by ascending aortic banding. These heart failure rats developed a severe cardiac hypertrophy, mainly affecting the left ventricle, which was significantly reduced in the trimetazidine-treated group. The plasma level of brain natriuretic peptide (BNP), a marker of heart failure severity, was significantly increased in the heart failure group as compared with the sham group (900 and 1200% after 8 and 12 weeks, respectively). In the trimetazidine-treated group, the plasma BNP increase was significantly lower. The development of heart failure was associated with a decrease in beta- and alpha-AR sites (-23 and -36% versus sham, respectively) after 8 weeks and continued to decrease after 12 weeks (-37 and -48% versus sham, respectively). This down-regulation was prevented by trimetazidine without alteration in affinity. These results suggest that trimetazidine prevents AR desensitization and cardiac hypertrophy, in a pressure-overload model of heart failure. This cytoprotection suggests that membrane homeostasis preservation may be considered as a therapeutic target in the treatment of heart failure.

Trimetazidine effect on phospholipid synthesis in ventricular myocytes: consequences in alpha-adrenergic signaling.

The anti-anginal drug trimetazidine (TMZ) has been shown to increase the synthesis of phospholipids in ventricular myocytes, including phosphatidyl-inositol (PI). This study focused on the consequences of increasing PI metabolism on alpha-adrenergic signaling pathway in cultured rat cardiomyocytes. In the cells treated with TMZ, the synthesis of PI from inositol was largely increased as compared with the control (+55% in 60 min). The stimulation of alpha-adrenergic receptors by phenylephrine (PE) induced a dose-dependent production of inositide phosphates (IPs) by phospholipase C (PLC) activation. However, the amount of available IPs was significantly lower in TMZ-treated cells, in a dose-dependent manner. This effect was observed in the presence and absence of the IP1-phosphatase inhibitor LiCl. The in vitro determination of PLC activity revealed that this effect could not be attributed to the direct inhibition of the enzyme by TMZ. The TMZ-induced reduction of IPs in the PE-stimulated cardiomyocytes should be attributed to the increase of inositol recycling and incorporation in membrane structures, elicited by increased phospholipid synthesis. The consequences of this reduction in IPs availability were investigated on the cardiomyocyte hypertrophy induced by alpha-adrenergic chronic stimulation. Acute stimulation with PE increased protein synthesis (+50%), but this increase was largely prevented by TMZ. In conclusion, TMZ reduces cell available IPs, by accelerating their recycling in membranes as PI. This effect results in a cytoprotection in the pathological process of hypertrophy elicited by chronic alpha-adrenergic stimulation.