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Pharmacotherapy.

Pharmacotherapy Publications,

0277-0008

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    3页
      原文链接:
    • NSTL

    Analysis of the frequency distribution of five single‐nucleotide polymorphisms of the MTRRgene in a Chinese pediatric population with acute lymphoblastic leukemia

    Miao LiXiao‐Yan KongShu‐Mei Wang
    11页
    查看更多>>摘要：Abstract Study Objective The objective of the present study was to examine the frequency distribution of five single‐nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL). Design This was a retrospective single‐center study, and all analyses were exploratory. Setting Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China. Patients One hundred and forty pediatric patients with ALL. Intervention All patients were treated according to the Chinese Children's Leukemia Group (CCLG)‐ALL 2008 protocol. Measurements and Main Results Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p?<?0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose‐normalized concentrations of MTX in serum at 24?h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p?=?0.04). Compared with children with AA‐CC‐AA‐CC‐CC diplotype, a significantly higher risk of relapse was observed in children with AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes (p?=?0.03 and 0.003, respectively). Conclusions The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes were significantly associated with higher risk of relapse of ALL.
      原文链接:
    • NSTL
    • Wiley

    A pilot study of ADRA2A genotype association with doses of dexmedetomidine for sedation in pediatric patients

    Todd C. SkaarAshwin BijuJames SlavenEmma M. Tillman...
    7页
    查看更多>>摘要：Abstract Study Objective Dexmedetomidine is titrated to achieve sedation in the pediatric and cardiovascular intensive care units (PICU and CVICU). In adults, dexmedetomidine response has been associated with an ADRA2A polymorphism (rs1800544); CC genotype is associated with an increased sedative response compared with GC and GG. To date, this has not been studied in children. Design We conducted a pilot study to determine whether ADRA2A genotype is associated with dexmedetomidine dose in children. Measurements and Main Results Forty intubated PICU or CVICU patients who received dexmedetomidine as a continuous infusion for at least 2?days were genotyped for ADRA2A with a custom‐designed TaqMan? Assay. Ten (25%) subjects were wildtype (GG), 15 (37.5%) were heterozygous (GC), and 15 (37.5%) were homozygous (CC) variant. The maximum dexmedetomidine doses (mCg/kg/h) were not different between genotype groups CC (1, 0.3–1.2), GC (1, 0.3–1.3), and GG (0.8, 0.3–1.2), (p?=?0.37); neither were mean dexmedetomidine doses for these respective genotype groups 0.68 (0.24–1.07), 0.72 (0.22–0.98), 0.58 (0.3–0.94), (p?=?0.67). Conclusions These findings did not confirm the results from adult studies where ADRA2A polymorphisms correlate with dexmedetomidine response, therefore highlighting the need for pediatric studies to validate PGx findings in adults prior to implementation in pediatrics.
      原文链接:
    • NSTL
    • Wiley

    Machine learning to predict vasopressin responsiveness in patients with septic shock

    Aileen ScheibnerKevin D. BetthauserAlice F. BewleyPaul Juang...
    12页
    查看更多>>摘要：Abstract Study Objectives The objective of this study was to develop and externally validate a model to predict adjunctive vasopressin response in patients with septic shock being treated with norepinephrine for bedside use in the intensive care unit. Design This was a retrospective analysis of two adult tertiary intensive care unit septic shock populations. Setting Barnes‐Jewish Hospital (BJH) from 2010 to 2017 and Beth Israel Deaconess Medical Center (BIDMC) from 2001 to 2012. Patients Two septic shock populations (548 BJH patients and 464 BIDMC patients) that received vasopressin as second‐line vasopressor. Intervention Patients who were vasopressin responsive were compared with those who were nonresponsive. Vasopressin response was defined as survival with at least a 20% decrease in maximum daily norepinephrine requirements by one calendar day after vasopressin initiation, without a third‐line vasopressor. Measurements Two supervised machine learning models (gradient‐boosting machine [XGBoost] and elastic net penalized logistic regression [EN]) were trained in 1000 bootstrap replications of the BJH data and externally validated in the BIDMC data to predict vasopressin responsiveness. Main Results Vasopressin responsiveness was similar among each cohort (BJH 45% and BIDMC 39%). Mortality was lower for vasopressin responders compared with nonresponders in the BJH (51% vs. 73%) and BIDMC (45% vs. 83%) cohorts, respectively. Both models demonstrated modest discrimination in the training (XGBoost area under receiver operator curve [AUROC] 0.61 [95% confidence interval (CI) 0.61–0.61], EN 0.59 [95% CI 0.58–0.59]) and external validation (XGBoost 0.68 [95% CI 0.63–0.73], EN 0.64 [95% CI 0.59–0.69]) datasets. Conclusion Vasopressin nonresponsiveness is common and associated with increased mortality. The models' modest performances highlight the complexity of septic shock and indicate that more research will be required before clinical decision support tools can aid in anticipating patient‐specific responsiveness to vasopressin.
      原文链接:
    • NSTL
    • Wiley

    Norepinephrine reuptake inhibitors and risk of antihypertensive treatment intensification and major adverse cardiovascular events in patients with stable hypertension and depression

    Raj DesaiHaesuk ParkJoshua D. BrownRajesh Mohandas...
    11页
    查看更多>>摘要：Abstract Study Objective To compare the risk of antihypertensive treatment intensification (TI) and major adverse cardiovascular events (MACE) with the initiation of serotonin norepinephrine reuptake inhibitors compared to selective serotonin reuptake inhibitors (SSRIs) in patients with stable hypertension and depression. Design Retrospective cohort study. Data Source IBM MarketScan? commercial claims database and Medicare Supplemental claims database from 2007 to 2019. Patients Patients aged 18?years or older with stable treated hypertension and depression who newly initiate either serotonin norepinephrine reuptake inhibitors or SSRIs. Intervention Serotonin norepinephrine reuptake inhibitors versus SSRIs. Measurements and Main Results The primary outcomes were: (1) TI (first occurrence of antihypertensive regimen augmentation or dose escalation); (2) MACE (first occurrence of stroke or acute myocardial infarction). Baseline risk between the two groups was balanced via 1:1 propensity score (PS) matching. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio (aHR) and 95% confidence intervals (95% CI). After 1:1 PS matching, we included 19,160 patients in the study cohort (mean age: 52?years, 62% females) of which 9580 initiated serotonin norepinephrine reuptake inhibitors and 9580 initiated SSRIs. Patients who initiated serotonin norepinephrine reuptake inhibitors had 15 MACE events (incidence rate per 1000 person‐years [IR], 3.9) and 1675 TI events (IR, 540.2), compared with 17 MACE events (IR, 4.0) and 1774 TI events (IR, 518.5) in the SSRI group. The risk of TI (aHR: 1.01, [95% CI: 0.94, 1.08]) and MACE (aHR: 0.98, [95% CI: 0.49, 1.96]) did not differ among patients initiated serotonin norepinephrine reuptake inhibitors versus SSRIs. Conclusions Among patients with stable hypertension and depression, initiation of serotonin norepinephrine reuptake inhibitors had a similar risk of antihypertensive TI and MACE compared to initiation of SSRIs. Future study with a larger sample size is needed to confirm our findings.
      原文链接:
    • NSTL
    • Wiley

    Association between glucagon‐like peptide‐1 receptor agonists and biliary‐related diseases in patients with type 2 diabetes: A?nationwide cohort study

    Sengwee TohYaa‐Hui DongJo‐Hsuan WuChia‐Hsuin Chang...
    12页
    查看更多>>摘要：Abstract Study Objective Clinical trials have suggested that glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) may be associated with a higher risk of biliary‐related diseases in patients with type 2 diabetes. Limited real‐world studies have examined the comparative biliary safety of GLP‐1RAs versus other antihyperglycemic drugs. We aimed to estimate the comparative risk of biliary‐related diseases between GLP‐1RAs and sodium glucose cotransporter 2 inhibitors (SGLT2is), which are indicated for patients with similar diabetes severity in Taiwan. Design Retrospective cohort study. Data Source Taiwan National Health Insurance Database during 2011 to 2018. Patients Patients with type 2 diabetes who initiated GLP‐1RAs or SGLT2is. Intervention GLP‐1RAs versus SGLT2is. Measurements and Main Results We used an on‐treatment approach to examine the effect of continuous use and an intention‐to‐treat approach to assess the effect of initiation of GLP‐1RAs versus SGLT2is. We used Coxregression models to estimate the hazard ratios (HRs) and 95% confidenceintervals (CIs) for the composite hospitalized biliary‐related diseases, including acute cholecystitis or cholecystectomy, choledocholithiasis, and acute cholangitis, after matching each GLP‐1RA initiator to up to 10 SGLT2iinitiators using propensity scores (PSs). Among 78,253 PS‐matched patients, GLP‐1RA use was associated with a numerically higher risk of biliary‐related diseases versus SGLT2i use in the on‐treatment analysis, with an HR of 1.20 (95% CI, 0.93–1.56) for the composite outcome, an HR of 1.22 (95% CI, 0.92–1.62) for acute cholecystitis or cholecystectomy, an HR of 1.20 (95% CI, 0.69–2.07) for choledocholithiasis, and an HR of 1.14 (95% CI,0.82–2.42) for acute cholangitis. The HRs were more pronounced in theintention‐to‐treat analysis (1.27 [95% CI, 1.05–1.53] for the composite outcome, 1.29 [95% CI, 1.04–1.58] foracute cholecystitis or cholecystectomy, 1.74 [95% CI, 1.23–2.46] for choledocholithiasis, and 1.31 [95% CI, 0.89–1.94] for acute cholangitis). The increased risk of the composite outcome associated with GLP‐1RAs was more evident in patients aged ?60 years, women, and 120 days after treatment initiation. Liraglutide, but not dulaglutide, was associated with an elevated risk. Conclusions GLP‐1RAs might be associated with an elevated risk of biliary‐related diseases compared to SGLT2is in Asian patients with type 2 diabetes.
      原文链接:
    • NSTL
    • Wiley

    The safety of rapid infusion levetiracetam: A systematic review

    Alexa JenseAlyssa DouvilleAshley Weiss
    9页
    查看更多>>摘要：Abstract Epilepsy is a common diagnosis and can quickly progress to status epilepticus which requires rapid treatment. Levetiracetam is a frequent treatment choice in these situations. The approved administration of intravenous levetiracetam is an infusion over 15?min. In recent years, studies have been published on faster infusion rates of levetiracetam. The objective of this review is to discuss the safety of levetiracetam as an intravenous push at a rate quicker than recommended. A literature search using PubMed, Cochrane Library, ClinicalTrials.gov, and Google Scholar resulted in 192 articles. Inclusion criteria consisted of English language, human studies, use of levetiracetam administered intravenously at a rate faster than 15?min, discussion of safety, and full‐text availability. After screening, nine articles remained for inclusion. Of the nine articles, one was a prospective, open‐label study, six were retrospective studies, and two were open‐label, randomized controlled trials. The most common rapid infusion speed was 5 min and doses ranged from 280 to 4500?mg. Some of these trials used undiluted levetiracetam and many reported that peripheral access was used for a portion or all of the administrations. There were few adverse effects, including specific adverse effects relating to medication concentration and speed of infusion, in all the studies. Administration of intravenous levetiracetam at a rate faster than recommended in the labeling information appears to be safe and tolerable and can be given via a peripheral line. Rapid infusion of levetiracetam is a beneficial method of administration in an acute care setting where patients need rapid attainment of therapeutic levels of antiepileptic medications. Additional research is needed to ensure that rapid administration of intravenous levetiracetam is as efficacious as the traditional dosing method.
      原文链接:
    • NSTL
    • Wiley

    The effect of antipsychotic treatment on hormonal, inflammatory, and metabolic biomarkers in healthy volunteers: A systematic review and meta‐analysis

    Kyle Jon BurghardtWasym MandoBerhane SeyoumZhengping Yi...
    10页
    查看更多>>摘要：Abstract Antipsychotic medications demonstrate a variable range of efficacy and side effects in patients with mental illness. Research has attempted to identify biomarkers associated with antipsychotic effects in various populations. Research designs utilizing healthy volunteers may have the added benefit of measuring the effect of antipsychotics on a given biomarker (s) independent of the varied environmental and clinical factors that often accompany patient populations. The aim of this systematic review and meta‐analysis was to synthesize the current evidence of hormonal, inflammatory, and metabolic biomarker studies of antipsychotic treatment in study designs using healthy volunteers. The systematic review was performed according to established guidelines and a random effects meta‐analysis of biomarkers appearing in at least three studies was performed while biomarkers in two or less studies were qualitatively summarized. A total of 28 studies including 28 biomarkers were identified. Meta‐analyses were carried out for 14 biomarkers, showing significant effects within six biomarkers (cortisol, C‐peptide, free fatty acids, leptin, thyroid‐stimulating hormone, and prolactin). Many of these effects were associated with olanzapine, the most used antipsychotic amongst the trials, observed on sub‐analyses. When combining biomarkers into categories, some additional effects were observed, for example, when grouping inflammatory biomarkers. These findings suggest that antipsychotics exert potentially strong effects on several biomarkers of interest independent of psychiatric disease which could be used to spur future investigations, however, replication work is needed for many biomarkers included in this review.
      原文链接:
    • NSTL
    • Wiley

    Corrigendum

    1页
      原文链接:
    • NSTL
    • Wiley