The influence of CYP3A,PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients

Purpose

Tacrolimus (Tac) and cyclosporine (CsA) are mainly metabolized by CYP3A4 and CYP3A5. Several studies have demonstrated an association between the CYP3A5 genotype and Tac dose requirements. Recently, CYP3A4, PPARA, and POR gene variants have been shown to influence CYP3A metabolism. The present study investigated potential associations between CYP3A5*3, CYP3A4*22, PPARA c.209-1003G>A and c.208?+?3819A>G, and POR*28 alleles and dose-adjusted concentrations (C/D) of Tac and CsA in 177 renal transplant patients early post-transplant.

Methods

All patients (n?=?177) were genotyped for CYP3A4*22, CYP3A5*3, POR*28, PPARA c.209-1003G>A, and PPARA c.208?+?3819A>G using real-time polymerase chain reaction (PCR) and melting curve analysis with allele-specific hybridization probes or PCR restriction fragment length polymorphisms (RFLP) methods. Drug concentrations and administered doses were retrospectively collected from patient charts at Oslo University Hospital, Rikshospitalet, Norway. One steady-state concentration was collected for each patient.

Results

We confirmed a significant impact of the CYP3A5*3 allele on Tac exposure. Patients with POR*28 and PPARA variant alleles demonstrated 15 % lower (P?=?0.04) and 19 % higher (P?=?0.01) Tac C₀/D respectively. CsA C₂/D was 53 % higher among CYP3A4*22 carriers (P?=?0.03).

Conclusion

The results support the use of pre-transplant CYP3A5 genotyping to improve initial dosing of Tac, and suggest that Tac dosing may be further individualized by additional POR and PPARA genotyping. Furthermore, initial CsA dosing may be improved by pre-transplant CYP3A4*22 determination.     

The IST registry

Intracoronary brachytherapy has been established in Europe and the US as an evidence-based treatment of in-stent restenoses. The objective of the IST Registry is to register all patients treated in Germany with intracoronary radiation and to observe the clinical outcome for a duration of 5 years. The required set of data for each patient is kept to a minimum to encourage participation. All data are entered online. In the internet, each participating site can, at any time, check their most important parameters and compare them with those of other sites. Presently, the Novoste System is used in 58 catheter labs and the Guidant System in 16, while several sites use both. The requirements regarding radiation safety in intracoronary application of gamma radiation are very strict in Germany, so the Cordis-Gamma System is used in only one German lab. In a first analysis of 332 radiated stenoses, it was observed that late vessel occlusion could occur even after 6-month administration of clopidogrel (in addition to ASA)--without new stents being implanted within the brachytherapy session. Clopidogrel should thus be administered in addition to aspirin for at least a year. Ca. 270 patients per month receive intracoronary radiation in Germany, so the IST Registry will provide important data regarding long-term observation and a foundation for future negotiations with insurance companies potentially bearing the costs. At present, neither the physician's service nor the material costs are reimbursed. The IST Registry can furthermore be used as a comparative database regarding long-term outcome following implantation of antiproliferative-coated stents.     

Synthesis and thermal stability of ZrO2@SiO2 core–shell submicron particles

ZrO₂@SiO₂ core–shell submicron particles are promising candidates for the development of advanced optical materials. Here, submicron zirconia particles were synthesized using a modified sol–gel method and pre-calcined at 400 °C. Silica shells were grown on these particles (average size: ∼270 nm) with well-defined thicknesses (26 to 61 nm) using a seeded-growth Stöber approach. To study the thermal stability of bare ZrO₂ cores and ZrO₂@SiO₂ core–shell particles they were calcined at 450 to 1200 °C. After heat treatments, the particles were characterized by SEM, TEM, STEM, cross-sectional EDX mapping, and XRD. The non-encapsulated, bare ZrO₂ particles predominantly transitioned to the tetragonal phase after pre-calcination at 400 °C. Increasing the temperature to 600 °C transformed them to monoclinic. Finally, grain coarsening destroyed the spheroidal particle shape after heating to 800 °C. In striking contrast, SiO₂-encapsulation significantly inhibited grain growth and the t → m transition progressed considerably only after heating to 1000 °C, whereupon the particle shape, with a smooth silica shell, remained stable. Particle disintegration was observed after heating to 1200 °C. Thus, ZrO₂@SiO₂ core–shell particles are suited for high-temperature applications up to ∼1000 °C. Different mechanisms are considered to explain the markedly enhanced stability of ZrO₂@SiO₂ core–shell particles.

Silica encapsulation dramatically enhances the thermal stability of zirconia submicron particles by grain growth inhibition and tetragonal phase stabilization.     

Ventricular structure,function, and focal fibrosis in anabolic steroid users: a CMR study

Purpose

Anabolic steroid (AS) misuse is widespread amongst recreational bodybuilders; however, their effects on the cardiovascular system are uncertain. Our aim was to document the impact of AS use on cardiac structure, function and the presence of focal fibrosis using the gold standard cardiovascular magnetic resonance imaging (CMR).

Methods

A cross-sectional cohort design was utilised with 21 strength-trained participants who underwent CMR imaging of the heart and speckle-tracking echocardiography. Thirteen participants (30 ± 5 years) taking AS for at least 2 years and currently on a “using”-cycle were compared with age and training-matched controls (n = 8; 29 ± 6 years) who self-reported never having taken AS (NAS).

Results

AS users had higher absolute left ventricular (LV) mass (220 ± 45 g) compared to NAS (163 ± 27 g; p < 0.05) but this difference was removed when indexed to fat-free mass. AS had a reduced right ventricular (RV) ejection fraction (AS 51 ± 4 % vs. NAS 59 ± 5 %; p < 0.05) and a significantly lower left ventricular E’:A’ myocardial tissue velocity ratio [AS 0.99(0.54) vs. NAS 1.78(0.46) p < 0.05] predominantly due to greater tissue velocities with atrial contraction. Peak LV longitudinal strain was lower in AS users (AS ?14.2 ± 2.7 % vs. NAS ?16.6 ± 1.9 %; p < 0.05). There was no evidence of focal fibrosis in any participant.

Conclusions

AS use was associated with significant LV hypertrophy, albeit in-line with greater fat-free mass, reduced LV strain, diastolic function, and reduced RV ejection fraction in male bodybuilders. There was, however, no evidence of focal fibrosis in any AS user.     

The effects of smoking deprivation on caloric intake in women with bulimia nervosa

Smoking is known to affect appetite and weight in both animals and humans. We examined the relation between smoking deprivation and caloric intake in five women with bulimia nervosa in whom the weight regulation aspects of smoking may be particularly salient. Subjects participated in a within-subjects study designed to examine the effects of smoking regular nicotine cigarettes, smoking lownicotine cigarettes, and smoking deprivation on caloric intake and mood. Total caloric intake, grams of fat consumed, and cigarette cravings were significantly greater under smoke-deprived than smoking conditions.