Pharmacokinetic and pharmacodynamic profiles of a novel phospholipid-aspirin complex liquid formulation and low dose enteric-coated aspirin: results from a prospective,randomized, crossover study

Journal of Thrombosis and Thrombolysis - Low dose enteric-coated aspirin (EC-ASA) is routinely used for secondary cardiovascular event prevention. However, absorption of EC tablets is poor, which...     

Glucagon induces the plasma membrane insertion of functional aquaporin-8 water channels in isolated rat hepatocytes

Although glucagon is known to stimulate the cyclic adenosine monophosphate (cAMP)-mediated hepatocyte bile secretion, the precise mechanisms accounting for this choleretic effect are unknown. We recently reported that hepatocytes express the water channel aquaporin-8 (AQP8), which is located primarily in intracellular vesicles, and its relocalization to plasma membranes can be induced with dibutyryl cAMP. In this study, we tested the hypothesis that glucagon induces the trafficking of AQP8 to the hepatocyte plasma membrane and thus increases membrane water permeability. Immunoblotting analysis in subcellular fractions from isolated rat hepatocytes indicated that glucagon caused a significant, dose-dependent increase in the amount of AQP8 in plasma membranes (e.g., 102% with 1 micromol/L glucagon) and a simultaneous decrease in intracellular membranes (e.g., 38% with 1 micromol/L glucagon). Confocal immunofluorescence microscopy in cultured hepatocytes confirmed the glucagon-induced redistribution of AQP8 from intracellular vesicles to plasma membrane. Polarized hepatocyte couplets showed that this redistribution was specifically to the canalicular domain. Glucagon also significantly increased hepatocyte membrane water permeability by about 70%, which was inhibited by the water channel blocker dimethyl sulfoxide (DMSO). The inhibitors of protein kinase A, H-89, and PKI, as well as the microtubule blocker colchicine, prevented the glucagon effect on both AQP8 redistribution to hepatocyte surface and cell membrane water permeability. In conclusion, our data suggest that glucagon induces the protein kinase A and microtubule-dependent translocation of AQP8 water channels to the hepatocyte canalicular plasma membrane, which in turn leads to an increase in membrane water permeability. These findings provide evidence supporting the molecular mechanisms of glucagon-induced hepatocyte bile secretion.     

Interventricular mechanical dyssynchrony: a novel marker of cardiac events in Brugada syndrome.

BACKGROUND: Risk stratification in Brugada syndrome is controversial, especially in asymptomatic individuals. OBJECTIVE: The purpose of this study was to evaluate tissue Doppler echocardiography in risk stratification of Brugada syndrome. METHODS: Patients with Brugada ECG pattern were enrolled in the study. Left ventricular (LV) preejection period was defined as the time interval between onset of the QRS complex and onset of LV lateral wall systolic wave. Right ventricular (RV) preejection period was defined as the time interval between onset of the QRS complex and onset of RV lateral wall systolic wave. Delay in onset of contraction between RV and LV was defined as RV preejection time - LV preejection time [PET((RV-LV))]. RESULTS: Type 1, 2, and 3 Brugada ECG pattern was found in 30, 56, and 31 patients, respectively. PET((RV-LV)) was significantly greater in type 1 Brugada patients (39.2 +/- 3.2 ms) compared with type 2 (5 +/- 0.3 ms) and 3 (5 +/- 0.4 ms) Brugada patients as well as controls (4.6 +/- 0.3 ms, P <.01 for all comparisons). Among type 1 Brugada patients, PET((RV-LV)) was significantly greater in patients who had previous cardiac events compared with asymptomatic subjects (48.2 +/- 4.3 ms vs 29.5 +/- 3.6 ms, P <.05). In the presence of type 1 Brugada ECG pattern, PET((RV-LV)) > or =40 ms identifies patients likely to have cardiac events, with 85.7% sensitivity and 93.7% specificity. CONCLUSION: PET((RV-LV)) is an important risk indicator for Brugada syndrome.     

Truncal fat determined by dual-energy X-ray absorptiometry is an independent predictor of coronary artery disease extension

BACKGROUND: Controversy prevails regarding the existence of a correlation between the severity of coronary artery disease (CAD) and the extent and distribution of obesity. PURPOSE: To assess the correlation between total fat, truncal fat (TF), and lean mass, obtained with dual-energy X-ray absorptiometry (DEXA) and standard anthropomorphic indices (body mass index, waist circumference, waist-to-hip ratio) and to verify whether DEXA indices can predict the extent and severity of CAD. MATERIALS AND METHODS: Fifty-eight patients (19 females) consecutively referred for coronary angiography underwent physical examination and DEXA assessment of body composition. RESULTS: Of the 58 patients enrolled, 22 were overweight and 13 were obese. Significant CAD was found in 39 (67%) patients. DEXA-derived total mass and fat mass enabled us to distinguish overweight from obese patients (P<0.005), whereas just TF mass correlated with the number of diseased vessels after adjusting for body mass index, sex, age, and smoking habit (odds ratio, 8.68; 95% confidence interval: 1.02-74.10). CONCLUSION: TF determined by DEXA is independently related with CAD extension.     

The CB1 cannabinoid receptor mediates glucocorticoid-induced effects on behavioural and neuronal responses during lactation

It has been shown that glucocorticoids can modulate oxytocin (OT) secretion and disrupt maternal behaviour. Because the CB1 receptor (CB1R) has been implicated in some rapid glucocorticoid-induced actions, the present study aimed to evaluate the possible involvement of CB1Rs in maternal behaviour and neuronal activation during lactation. For this purpose, lactating female rats were pre-treated with dexamethasone (DEX) or saline, followed by treatment with AM251, a CB1R antagonist, or vehicle 90 min later. All of the experiments were performed 30 min after the administration of AM251 or vehicle. To evaluate maternal behaviour, the pups were returned to their home cages to the side of the cage opposite the previous nest after 12 h of separation and were filmed for the next 30 min. Aggressive behaviour was evaluated for 10 min following the placement of a male rat in the home cage. For the evaluation of behavioural performance, lactating rats were subjected to a T-maze and open-field tests. The amount of weight gained by the pups was evaluated 15 min after the onset of suckling to determine the amount of milk that they had obtained from the dam. In the central nervous system of lactating rats, c-Fos-positive nuclei were counted in the medial preoptic area, in both the ventral (v) and dorsal (d) parts of the median preoptic nucleus and in the bed nucleus of the stria terminalis (BNST). The number of neurons that were double-labelled for c-Fos/OT was counted in the medial magnocellular subdivision of the paraventricular nucleus, in the periventricular hypothalamic nucleus and in the supraoptic nucleus of the lactating rats. The results show that DEX had the following effects: (1) decreased the amount time the dam spent licking the pups, the amount of time the dam spent in an arched-nursing position and full maternal behaviour; (2) increased the latency to the first attack and decreased front attacks; (3) increased anxiety-like behaviour; and (4) decreased weight gain in the pups. In addition, DEX decreased neuronal activation in all of the investigated hypothalamic and forebrain areas. AM251 administration reversed these parameters, indicating that the behavioural effects and neuronal responses produced by DEX in lactating rats are likely to be mediated by CB1Rs.     

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ? h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.     

Effect of green tea-loaded chitosan nanoparticles on leathery dentin microhardness

The purpose of this study was to assess the effect of a chitosan-based nanoformulation containing green tea on leathery (remaining) dentin subsurface microhardness. Size distribution, polydispersity index (PDI) and zeta potential (mV) of nanoformulations were previously determined by dynamic light scattering (DLS). Human dentin specimens were exposed to Streptococcus mutans for 14 d. Soft dentin were selectively removed by Er:YAG laser (n?=?30) or bur (n?=?30). Remaining dentin was biomodified with chitosan nanoparticles (Nchi, n?=?10) or green tea-loaded chitosan nanoparticles (Gt?+?Nchi, n?=?10) for 1 min. Control group (n?=?10) did not receive any treatment. Subsurface microhardness (Knoop) was evaluated in hard (sound) and soft dentin, and then, in leathery dentin and after its biomodification, at depths of 30, 60 and 90 μm from the surface. Nchi reached an average size of?≤?300 nm, PDI varied between 0.311 and 0.422, and zeta potential around?+?30 mV. Gt?+?Nchi reached an average size of?≤?350 nm, PDI?<?0.45, and zeta potential around?+?40 mV. Soft dentin showed significantly reduced microhardness at all depths (p?>?0.05). The subsurface microhardness was independent of choice of excavation method (p?>?0.05). At 30 µm from the surface, Gt?+?Nchi increased the leathery dentin microhardness compared to untreated group (p?<?0.05). Nchi promoted intermediate values (p?>?0.05). Both nanoformulations showed an average size less than 350 nm with nanoparticles of different sizes and stability along the 90-day period evaluated. Subsurface microhardness of bur-treated and laser-irradiated dentin was similar. At 30 µm, the biomodification with Gt?+?Nchi improved the microhardness of leathery dentin, independently of caries excavation method used.

     

Improving bonding to eroded dentin by using collagen cross-linking agents: 2 years of water storage

Clinical Oral Investigations - The aim of this study was to investigate the effects of collagen cross-linking agents on nanomechanical and bonding properties of eroded dentin (ED), 24&nbsp;h...     

Usefulness of chronotropic incompetence to dipyridamole in predicting myocardial perfusion defects in heart transplant recipients

The aim of this report was to assess the relation between heart rate response to dipyridamole infusion and perfusion defects at quantitative sestamibi single-photon emission computed tomographic imaging. We demonstrated in 166 heart transplant recipients that chronotropic incompetence to dipyridamole is the only significant and independent predictor of perfusion defects.     

Systemic venous atrium stimulation in transvenous pacing after mustard procedure

We present the case of a young woman corrected with a Mustard procedure undergoing successful transvenous double chamber pacemaker implantation with the atrial lead placed in the systemic venous channel. The case presented demonstrates that, when the systemic venous atrium is separate from the left atrial appendage, the lead can be easily and safely placed in the systemic venous left atrium gaining satisfactory sensing and pacing thresholds despite consisting partially of pericardial tissue.