Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.     

RF ablation of longstanding persistent atrial fibrillation in patient with familial dilated cardiomyopathy

A vicious circle of interactions between dilated cardiomyopathy and longstanding persistent AF/AFL may cause symptoms of advanced congestive heart failure. In a 31-year-old patient with diagnosis of familial dilated cardiomyopathy and permanent AF lasting for five years, gradually decreased left ventricular ejection fraction (LVEF) and increased diameter of heart chambers - left ventricular diastolic dimension (LVdD) 7.7 cm, left atrium (LA) 5.4 cm, and LVEF 15% were noted. Pharmacological treatment was ineffective Successful RF ablation of AF/AFL substrate (CTI block, PVs isolation, CFAE ablation, roof and MIG line, CS applications) reversed symptoms of significant heart remodeling (LVdD 5.9 cm, LA 4.3 cm, LVEF 50%).     

Successful RF ablation of permanent VT in a patient with acute coronary syndrome treated by complex angioplasty and stent implantation

We describe a case of a 59-year-old male with permanent VT in the course of an acute coronary syndrome. Coronary angiography revealed acute occlusion of the right coronary artery. Although the underlying condition was treated by implantation of 4 stents with excellent haemodynamic effect (TIMI 3), the tachycardia continued, being refractory to drugs (amiodarone). The attempts to restore sinus rhythm by DC electrical cardioversion or transvenous pacing were unsuccessful. The patient was referred to the EP lab. A critical isthmus localised at the paraseptal region of the LV and parallel to the mitral annulus was identified. The isthmus was closed by linear RF application, resulting in VT termination. Due to impaired LV ejection fraction (<30%) the patient was scheduled for ICD implantation. During 6-week follow-up the patient remained free of arrhythmia.     

The Accelerated Aging Impact on Mechanical and Thermal Properties of Polypropylene Composites with Sedimentary Rock Opoka-Hybrid Natural Filler

This paper presents the impact of accelerated aging on selected mechanical and thermal properties of isotactic polypropylene (iPP) composites filled with sedimentary hybrid natural filler-Opoka rock. The filler was used in two forms: an industrial raw material originating as a subsieve fraction natural material, and a rock calcinated at 1000 °C for production of phosphorous sorbents. Fillers were incorporated with constant amount of 5 wt % of the resulting composite, and the material was subjected to accelerated weathering tests with different exposition times. The neat polypropylene and composites with calcium carbonate as a reference filler material were used for comparison. The aim of the research was to determine the possibility of using the Opoka rock as a new hybrid filler for polypropylene, which could be an alternative to the widely used calcium carbonate and silica. The thermal, mechanical, and structural properties were evaluated by means of differential scanning calorimetry (DSC), tensile tests, scanning electron microscopy (SEM), and Fourier-transform infrared spectroscopy with attenuated total reflectance (FTIR/ATR) prior to and after accelerated aging. As a result, it was found that the composites of polypropylene with Opoka were characterized by similar or higher functional properties and higher resistance to photodegradation compared to composites with conventional calcium carbonate. The results of measurements of mechanical properties, structural and surface changes, and the carbonyl index as a function of accelerated aging proved that Opoka was an effective ultraviolet (UV) stabilizer, significantly exceeding the reference calcium carbonate in this respect. The new hybrid filler of natural origin in the form of Opoka can therefore be used not only as a typical powder filler, but above all as a UV blocker/stabilizer, thus extending the life of polypropylene composites, especially for outdoor applications.     

Prognostic value of exercise tests performed 3 months after coronary artery grafting in evaluation cardiac events. 6 years follow-up

Prognostic value of exercise test in evaluation of cardiac events were examined in 326 pts after coronary artery bypass grafting (CABG). During 6 years follow up 18 (5.5%) cardiac deaths and 23 (7.1%) myocardial infarctions were observed. Chest pains persisted in 116 pts (35.6%) and 37 (11.3%) pts needed hospital treatment. Coronary and bypass angiography were performed in 25 pts (7.7%) followed by PTCA in 8 pts (2.5%) and CABG in 5 (1.5%) pts. Exercise duration and maximal work capacity in exercise tests were significantly lower in pts with cardiac events. Reasons of exercise termination: ST segment depression, heart rate and blood pressure values were not different in pts with and without cardiac events and didn't have prognostic value. Patients with cardiac events had significantly reduced left ventricle function. The value of ejection fraction influenced significantly relative risk of cardiac death (p < 0.05).     

Interleaved asymmetric echo-planar imaging

A version of interleaved echo-planar imaging (EPI) is presented in which only one polarity of the readout gradient is used for signal acquisition to avoid ghosting artifacts. Two possible forms of the phase encoding gradient, blipped and constant, are discussed. With the constant phase encoding, interleaving of partial trajectories in the Fourier domain (k-space) is controlled automatically by the echo train delay. The constant phase encoding gradient introduces a shear distortion of the k-space grid. A modification of the reconstruction procedure is given which corrects for this effect. The method provides a 128 × 128 image in 1 s on a clinical system with standard gradients.     

Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study

BACKGROUND: The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. METHODS: This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). RESULTS: The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. CONCLUSION: Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.     

Effect of orlistat therapy on carbohydrate, lipid, vitamin and hormone plasma levels in obese subjects

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY. CONCLUSIONS: (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.