The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC , C and t of aripiprazole were higher and clearance of aripiprazole, AUC of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC (p = 0.039) and C of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.
Background: Prepectoral breast reconstruction following mastectomy has become a more widely performed technique in recent years because of its numerous benefits for women. These include full pectoralis muscle preservation, reduced loss of strength, reduced pain, and elimination of animation deformity. As with any breast reconstruction technique, widespread adoption is dependent on a low morbidity profile in the setting of postmastectomy radiation therapy, as this adjuvant therapy is routine in breast cancer treatment. The authors assess the clinical outcomes of patients undergoing postmastectomy radiation therapy following prepectoral breast reconstruction, and compare these to outcomes of patients undergoing postmastectomy radiation therapy with submuscular reconstruction. Methods: A single surgeon’s experience with immediate prepectoral breast reconstruction, followed by postmastectomy radiation therapy, from 2015 to 2017 was reviewed. Patient demographics and incidence of complications during the tissue expander stage were assessed. In addition, the morbidity profile of these patients was compared to that of patients undergoing submuscular/dual-plane reconstruction and postmastectomy radiation therapy over the same period. Results: Over 3 years, 175 breasts underwent immediate prepectoral reconstruction, and 236 breasts underwent immediate submuscular/dual-plane reconstruction. Overall rates of adjuvant radiation therapy (postmastectomy radiation therapy) were similar between prepectoral [26 breasts (14.9 percent)] and submuscular [31 breasts (13.1 percent)] (p = 0.6180) reconstruction. There were no significant differences in complication rates between the two reconstructive cohorts, in the setting of postmastectomy radiation therapy, including rates of explantation (15.4 percent versus 19.3 percent; p = 0.695). Conclusions: Prepectoral breast reconstruction is a safe and effective option in the setting of postmastectomy radiation therapy. The morbidity profile is similar to that encountered with submuscular reconstruction in this setting. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
BackgroundAttention deficit hyperactivity disorder (ADHD) has a strong genetic component. The study is aimed to test the association of 34 polymorphisms with ADHD symptomatology considering the role of clinical subtypes and sex in a Spanish population.MethodsA cohort of ADHD 290 patients and 340 controls aged 6–18 years were included in a case–control study, stratified by sex and ADHD subtype. Multivariate logistic regression was used to detect the combined effects of multiple variants.ResultsAfter correcting for multiple testing, we found several significant associations between the polymorphisms and ADHD (p value corrected ≤0.05): (1) SLC6A4 and LPHN3 were associated in the total population; (2) SLC6A2, SLC6A3, SLC6A4 and LPHN3 were associated in the combined subtype; and (3) LPHN3 was associated in the male sample. Multivariable logistic regression was used to estimate the influence of these variables for the total sample, combined and inattentive subtype, female and male sample, revealing that these factors contributed to 8.5, 14.6, 2.6, 16.5 and 8.5 % of the variance respectively.ConclusionsWe report evidence of the genetic contribution of common variants to the ADHD phenotype in four genes, with the LPHN3 gene playing a particularly important role. Future studies should investigate the contribution of genetic variants to the risk of ADHD considering their role in specific sex or subtype, as doing so may produce more predictable and robust models.Electronic supplementary materialThe online version of this article (doi:10.1186/s12993-015-0084-6) contains supplementary material, which is available to authorized users.
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