Metoprolol blunts the time-dependent progression of infarct size.

Early metoprolol administration protects against myocardial ischemia-reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

Myotonic dystrophy type 1 and high ventricular vulnerability at the electrophysiological evaluation: ICD yes or not?

A significant number of sudden death (SD) is observed in myotonic dystrophy (DM1) despite pacemaker implantation and some consider the ICD to be the preferential device in patients with conduction disease. According to the latest guidelines, prophylactic ICD implantation in patients with neuromuscular disorder should follow the same recommendations of non-ischemic dilated cardiomyopathy, being reasonable when pacing is needed. We here report a case of DM1 patient who underwent ICD implantation even in the absence of conduction disturbances on ECG and ventricular dysfunction/fibrosis at cardiac magnetic resonance. The occurrence of syncope, non-sustained ventricular tachycardias at 24-Holter ECG monitoring and a family history of SD resulted associated with ventricular fibrillation inducibility at electrophysiological study, favouring ICD implantation. On our advice, DM1 patient with this association of SD risk factors should be targeted for ICD implantation.

X indening oral liquid improves cardiac function of rats with chronic cardiac failure via TGF-ß1/Smad3 and p38 MAPK pathway.

OBJECTIVE: Xindening oral liquid (Xin) is a widely used traditional Chinese medicine for the treatment of chronic heart failure (CHF). However, the exact mechanisms related to its therapeutic effects against CHF remain unclear. In the present study, we investigate the effects of Xin on cardiac function in CHF rats and the possible mechanisms involved. METHODS: Transverse aortic constriction (TAC) was conducted to induce a CHF rat model in this study. Sixty male Wistar rats were randomly assigned to six groups 28 days after TAC: sham; CHF model; Xin at concentrations of 5 ml/kg, 10 mL/kg, and 20 mL/kg; and QiLi 0.6 g/kg. After four weeks, the rats were treated with Xin (5, 10, or 20 mL/kg/d) for six weeks consecutively. At the end of the study, the cardiac function, heart weight index (HWI) and left ventricular mass index (LVMI), serum level of LDH, B-type natriuretic peptide (BNP), cTnI and CK-MB, and collagen volume fraction were studied. The expression of transforming growth factor-ß1 (TGF-ß1), drosophila mothers against decapentaplegic protein 3 (Smad3), and p38 mitogen activated protein kinase (p38 MAPK) were detected. RESULTS: The results showed that Xin treatment significantly improved cardiac function but decreased the serum level of LDH, BNP, cTnI, and CKMB of CHF rats. In addition, it reduced the HWI, LVMI, and collagen volume fraction compared with the model group. Xin treatment significantly improved cardiac function and attenuated cardiac fibrosis by suppressing the p38 MAPK and TGF-ß1/Smad3 signaling pathway in CHF rats. CONCLUSION: These results suggested that Xin might be a promising complementary treatment for CHF. More detailed experimental studies will be carried out in our subsequent research.

Piecewise function parameters as responses of the design of experiment in the development of a pulsatile release chronopharmaceutical system.

The aim of this work was to develop a pulsatile release system with metoprolol for chronotherapeutical use by coating swellable mini-tablets with Eudragit RS. To study the influence of the formulation factors (amount of coating polymer, plasticizer percentage in film coating and swelling agent percentage in mini-tablets), a Box-Behnken design of experiment (DoE) was used. To evaluate the influence of the studied factors on the sigmoid shape of the dissolution profile, piecewise function parameters were used as the responses of DoE. The results show that higher concentrations of coating polymer and higher concentrations of plasticizer polymer led to a thicker and more elastic polymeric film, which led to a delay in drug release. Using the parameters of the piecewise function as DoE responses, an optimum formulation with a sigmoid shape dissolution profile and a 2.5-h lag time followed by rapid drug release were obtained.

Randomized controlled trial of relaxation music to reduce heart rate in patients undergoing cardiac CT.

OBJECTIVES: To evaluate the heart rate lowering effect of relaxation music in patients undergoing coronary CT angiography (CCTA), pulmonary vein CT (PVCT) and coronary calcium score CT (CCS). METHODS: Patients were randomised to a control group (i.e. standard of care protocol) or to a relaxation music group (ie. standard of care protocol with music). The groups were compared for heart rate, radiation dose, image quality and dose of IV metoprolol. Both groups completed State-Trait Anxiety Inventory anxiety questionnaires to assess patient experience. RESULTS: One hundred and ninety-seven patients were recruited (61.9 % males); mean age 56y (19-86 y); 127 CCTA, 17 PVCT, 53 CCS. No significant difference in heart rate, radiation dose, image quality, metoprolol dose and anxiety scores. 86 % of patients enjoyed the music. 90 % of patients in the music group expressed a strong preference to have music for future examinations. The patient cohort demonstrated low anxiety levels prior to CT. CONCLUSION: Relaxation music in CCTA, PVCT and CCS does not reduce heart rate or IV metoprolol use. Patients showed low levels of anxiety indicating that anxiolytics may not have a significant role in lowering heart rate. Music can be used in cardiac CT to improve patient experience. KEY POINTS: • Relaxation music does not reduce heart rate in cardiac CT • Relaxation music does not reduce beta-blocker use in cardiac CT • Relaxation music has no effect on cardiac CT image quality • Low levels of anxiety are present in patients prior to cardiac CT • Patients enjoyed the relaxation music and this results in improved patient experience.

Modification of pharmacological activity of nebivolol due to Maillard reaction.

Lactose is used as an excipient in solid dosage forms of nebivolol. Ultraviolet spectroscopy, Fourier-transform infrared spectroscopy and differential scanning calorimetry were used to study the interaction between nebivolol and lactose. The formation of a Maillard product was noted in aqueous mixtures of nebivolol and lactose heated at 60°C at unbuffered and buffered alkaline pH. A similar Maillard adduct formation was evident within 15 days in a dry physical mixture of nebivolol and lactose maintained at 40°C and 75% relative humidity in the dark. High-performance liquid chromatography and liquid chromatography-mass spectrometry analyses of the reaction mixtures confirmed the formation of a nebivolol-lactose adduct. The effects of intravenously administered nebivolol and the nebivolol-lactose adduct on the blood pressure and heart rate of anesthetized normotensive rats were investigated. The bradycardic effect of the adduct was significantly less than that of nebivolol. The present investigation reveals an incompatibility between nebivolol and lactose, leading to the loss of the pharmacological activity of nebivolol. Hence, the use of lactose as an excipient in dosage forms of nebivolol, a secondary amine, needs reconsideration.

Early regression of left ventricular hypertrophy after treatment with esmolol in an experimental rat model of primary hypertension.

Certain ß-adrenergic blockers have proven useful in the regression of ventricular remodeling when administered as long-term treatment. However, early regression of left ventricular hypertrophy (LVH) has not been reported, following short-term administration of these drugs. We tested the hypothesis that short-term administration of the cardioselective ß-blocker esmolol induces early regression of LVH in spontaneously hypertensive rats (SHR). Fourteen-month-old male SHRs were treated i.v. with vehicle (SHR) or esmolol (SHR-E) (300 µg kg(-1) min(-1)). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 h, left ventricular morphology and function were assessed using M-mode echocardiograms (left ventricular mass index (LVMI), ejection fraction and transmitral Doppler (early-to-atrial filling velocity ratio (E/A), E-wave deceleration time (Edec time)). The standardized uptake value (SUV) was applied to evaluate FDG (2-deoxy-2[18F]fluoro-D-glucose) uptake by the heart using PET/CT. Left ventricular subendocardial and subepicardial biopsies were taken to analyze changes in cross-sectional area (CSA) of left ventricular cardiomyocytes and the fibrosis was expressed as collagen volume fraction (CVF). LVMI was lower in SHR-E with respect to SHR (P=0.009). There were no significant differences in EF, E/A ratio or Edec time in SHR-E compared with SHR (P=0.17, 0.55 and P=0.80, respectively). PET acquisitions in SHR-E showed lower (18)F-FDG uptake than SHR (P=0.003). Interestingly, there were no significant differences in SUV in either SHR-E or WKY (P=0.63). CSA in subendocardial and subepicardial regions was minor in SHR-E with respect to SHR (P<0.001), and there were no significant differences in CVF between both groups. Esmolol reverses early LVH in the SHR model of stable compensated ventricular hypertrophy. This is the first study to associate early regression of LVH with administration of a short-term ß-blocker.

Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose.

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems.