Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) is a heritable disorder characterized by symptoms of inattention and/or hyperactivity/impulsivity. Methylphenidate (MPH) has been shown to block the norepinephrine transporter (NET), and genetic investigations have demonstrated that the norepinephrine transporter gene (SLC6A2) is associated with ADHD. The aims of this study were to examine the association of the SLC6A2 -3081(A/T) and G1287A polymorphisms with MPH response in ADHD. Methods This study enrolled 112 children and adolescents with ADHD. A response criterion was defined based on the Clinical Global Impression-Improvement (CGI-I) score, and the ADHD Rating Scale-IV (ARS) score was also assessed at baseline and 8 weeks after MPH treatment. Results We found that the subjects who had the T allele as one of the alleles (A/T or T/T genotypes) at the -3081(A/T) polymorphism showed a better response to MPH treatment than those with the A/A genotype as measured by the CGI-I. We also found a trend towards a difference in the change of the total ARS scores and hyperactivity/impulsivity subscores between subjects with and without the T allele. No significant association was found between the genotypes of the SLC6A2 G1287A polymorphism and response to ADHD treatment. Conclusion Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD

Quantitative prediction of oral bioavailability of a lipophilic antineoplastic drug bexarotene administered in lipidic formulation using a combined in vitro lipolysis/microsomal metabolism approach

For performance assessment of the lipid-based drug delivery systems (LBDDS), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilisation processes. Much of previous research on in vitro lipolysis have mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values (Foral,predicted) of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 1.6% and 36.2 2.6%, respectively, while the in vivo oral bioavailability (Foral) of BEX was tested as 31.5 13.4% and 31.4 5.2%, respectively. The Foral,predicted corresponded well with the Foral for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in [less than] 1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability

Polymyxin-resistant, carbapenem-resistant Acinetobacter baumannii is eradicated by a triple combination of agents that lack individual activity

Objectives: The emergence of polymyxin resistance threatens to leave clinicians with few options for combatting drug-resistant Acinetobacter baumannii . The objectives of the current investigation were to define the in vitro emergence of polymyxin resistance and identify a combination regimen capable of eradicating A. baumannii with no apparent drug susceptibilities. Methods: Two clonally related, paired, A. baumannii isolates collected from a critically ill patient who developed colistin resistance while receiving colistin methanesulfonate in a clinical population pharmacokinetic study were evaluated: an A. baumannii isolate collected before (03-149.1, polymyxin-susceptible, MIC 0.5 mg/L) and an isolate collected after (03-149.2, polymyxin-resistant, MIC 32 mg/L, carbapenem-resistant, ampicillin/sulbactam-resistant). Using the patient's unique pharmacokinetics, the patient's actual regimen received in the clinic was recreated in a hollow-fibre infection model (HFIM) to track the emergence of polymyxin resistance against 03-149.1. A subsequent HFIM challenged the pan-resistant 03-149.2 isolate against polymyxin B, meropenem and ampicillin/sulbactam alone and in two-drug and three-drug combinations. Results: Despite achieving colistin steady-state targets of an AUC 0-24 >60 mg·h/L and C avg of >2.5 mg/L, colistin population analysis profiles confirmed the clinical development of polymyxin resistance. During the simulation of the patient's colistin regimen in the HFIM, no killing was achieved in the HFIM and amplification of polymyxin resistance was observed by 96 h. Against the polymyxin-resistant isolate, the triple combination of polymyxin B, meropenem and ampicillin/sulbactam eradicated the A. baumannii by 96 h in the HFIM, whereas monotherapies and double combinations resulted in regrowth. Conclusions: To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise

Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy

Background Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML). Methods Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity (Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy. Results The 65 patients (median age = 51 years, male:female = 34:31) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1–68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable: liver function abnormality (Grade 2, n = 1; Grade 3, n = 1) and allergic reaction (Grade 2, n = 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety. Conclusions Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML. Trial registration Clinicaltrials.gov NCT02440178, registered May 12th 2015.This study was funded by Astellas Pharma Korea, Inc. Funding source had no role in the study design, data collection, data analysis or data interpretation

Genome-Scale Profiling and High-Throughput Analyses Unravel the Genetic Basis of Arsenic Content Variation in Rice

Ionomics, the study of the composition of mineral nutrients and trace elements in organisms that represent the inorganic component of cells and tissues, has been widely studied to explore to unravel the molecular mechanism regulating the elemental composition of plants. However, the genetic factors of rice subspecies in the interaction between arsenic and functional ions have not yet been explained. Here, the correlation between As and eight essential ions in a rice core collection was analyzed, taking into account growing condition and genetic factors. The results demonstrated that the correlation between As and essential ions was affected by genetic factors and growing condition, but it was confirmed that the genetic factor was slightly larger with the heritability for arsenic content at 53%. In particular, the cluster coefficient of japonica (0.428) was larger than that of indica (0.414) in the co-expression network analysis for 23 arsenic genes, and it was confirmed that the distance between genes involved in As induction and detoxification of japonica was far than that of indica. These findings provide evidence that japonica populations could accumulate more As than indica populations. In addition, the cis-eQTLs of AIR2 (arsenic-induced RING finger protein) were isolated through transcriptome-wide association studies, and it was confirmed that AIR2 expression levels of indica were lower than those of japonica. This was consistent with the functional haplotype results for the genome sequence of AIR2, and finally, eight rice varieties with low AIR2 expression and arsenic content were selected. In addition, As-related QTLs were identified on chromosomes 5 and 6 under flooded and intermittently flooded conditions through genome-scale profiling. Taken together, these results might assist in developing markers and breeding plans to reduce toxic element content and breeding high-quality rice varieties in future

Risk factors for and clinical outcomes of carbapenem non-susceptible gram negative bacilli bacteremia in patients with acute myelogenous leukemia

Background Carbapenem is frequently used when gram negative bacilli (GNB) bacteremia is detected especially in neutropenic patients. Consequently, appropriate treatment could be delayed in GNB bacteremia cases involving organisms which are not susceptible to carbapenem (carba-NS), resulting in a poor clinical outcomes. Here, we explored risk factors for carba-NS GNB bacteremia and its clinical outcomes in patients with acute myelogenous leukemia (AML) that underwent chemotherapy. Methods We reviewed all GNB bacteremia cases that occurred during induction or consolidation chemotherapy, over a 15-year period, in a tertiary-care hospital. Results Among 489 GNB bacteremia cases from 324 patients, 45 (9.2%) were carba-NS and 444 (90.8%) were carbapenem susceptible GNB. Independent risk factors for carba-NS GNB bacteremia were: carbapenem use at bacteremia onset (adjusted odds ratio [aOR]: 91.2; 95% confidence interval [95%CI]: 29.3–284.1; P < 0.001); isolation of carbapenem-resistant Acinetobacter baumannii (aOR: 19.4, 95%CI: 3.4–112.5; P = 0.001) in the prior year; and days from chemotherapy to GNB bacteremia (aOR: 1.1 per day, 95%CI: 1.1–1.2; P < 0.001). Carba-NS bacteremia was independently associated with in-hospital mortality (aOR: 6.6, 95%CI: 3.0–14.8; P < 0.001). Conslusion Carba-NS organisms should be considered for antibiotic selection in AML patients having these risk factors

Randomized Comparison of Four-Times-Daily versus Once-Daily Intravenous Busulfan in Conditioning Therapy for Hematopoietic Cell Transplantation

AbstractSixty patients were randomized to receive intravenous busulfan (iBU) either as 0.8 mg/kg, over 2 hours 4 times a day (BU4 arm) or 3.2 mg/kg, over 3 hours once a day (BU1 arm) in conditioning therapy for hematopoietic cell transplantation. The complete pharmacokinetic parameters for the first busulfan dose were obtained from all patients and were comparable between the 2 arms: for the BU4 and BU1 groups, elimination half-life (mean ± SD) was 2.75 ± 0.22 versus 2.83 ± 0.21 hours, estimated daily AUC was 6058.0 ± 1091.9 versus 6475.5 ± 1099.4 μM·min per day, and clearance was 2.05 ± 0.36 versus 1.91 ± 0.31 mL/min/kg, respectively. Times to engraftment after transplantation were similar between the 2 arms. No significant differences were evident in the occurrence of acute graft-versus-host disease (aGVHD) and hepatic veno-occlusion disease (VOD). Moreover, other toxicities observed within 100 days after transplantation were not significantly different between the 2 arms. The cumulative incidence of nonrelapse mortality was 20.8% in BU4 arm and 13.3% in BU1 arm. In conclusion, our randomized study demonstrates that the pharmacokinetic profiles and posttransplant complications are similar for once-daily iBU and traditional 4-times-daily iBU

High-intensity meropenem combinations with polymyxin B: new strategies to overcome carbapenem resistance in Acinetobacter baumannii

The pharmacodynamics of polymyxin/carbapenem combinations against carbapenem-resistant Acinetobacter baumannii (CRAB) are largely unknown. Our objective was to determine whether intensified meropenem regimens in combination with polymyxin B enhance killing and resistance suppression of CRAB