Publications by authors named "Ya-Hui Hu"

61 Publications

Therapeutic drug monitoring of caffeine and its primary metabolites in plasma using LC-ESI-MS/MS for apnea of prematurity treatment: Evaluation of ultrapure water as a surrogate matrix.

Biomed Chromatogr 2022 Jul 26:e5462. Epub 2022 Jul 26.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

The growing evidence has endorsed the view that therapeutic drug monitoring of caffeine for apnea of prematurity is helpful for dose tailoring when the therapeutic response is lacking or toxicity is suspected. However, plasma without caffeine is difficult to obtain. Therefore, a method was developed and validated to measure caffeine and its three primary metabolites (paraxanthine, theobromine and theophylline) using LC-ESI-MS/MS in human plasma and several surrogate matrices. The chromatographic separation of analytes was finally achieved on a Waters Symmetry C (4.6 × 75 mm, 3.5 μm) column. Several strategies were successfully applied to overcome the matrix effects: (a) appropriate dilution for sample cleanup; (b) a starting lower proportion of organic phase; and (c) multiple individual stable-labeled isotopic internal standards. The parallelism between the authentic matrix and surrogate matrices was convincing. The recovery of the analytes in both human plasma and rat plasma was acceptable over the linear range (0.500-50.0 μg/ml for caffeine and 0.0100-1.00 μg/ml for three metabolites). The method was successfully applied in 118 samples from 74 preterm infants with apnea of prematurity. The rat plasma or ultrapure water as a surrogate matrix is worthy of recommendation for routine therapeutic drug monitoring of caffeine.
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http://dx.doi.org/10.1002/bmc.5462DOI Listing
July 2022

Effect of long-term valproic acid therapy on lipid profiles in paediatric patients with epilepsy: a meta-analysis

Epileptic Disord 2022 10;24(5):1-9

Objective: Despite the potential role of valproic acid (VPA) in weight gain, the effects of VPA therapy on lipid profiles remain unclear. This study aimed to review the influence of VPA therapy on serum lipid profiles in children with epilepsy.

Methods: This meta-analysis was conducted on data from PubMed, Web of Science, Cochrane Library, and Embase databases. Case-controlled studies, which assessed the effects of VPA therapy on lipid profiles, were included. All outcomes were recorded as continuous variables, and the effect size was measured.

Results: VPA therapy was associated with a significant reduction in total cholesterol (mean difference [MD]=-6.34, 95% confidence interval [CI]: -12.30, -0.37, p=0.04) and low-density lipoprotein cholesterol levels (MD = -7.75, 95% CI: -13.48, -2.0, p=0.008). No significant effects were observed regarding the levels of high-density lipoprotein cholesterol and triglycerides.

Significance: In conclusion, this meta-analysis indicates that VPA therapy causes a decrease in the levels of total cholesterol and low-density lipoprotein cholesterol.
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http://dx.doi.org/10.1684/epd.2022.1460DOI Listing
October 2022

A Novel Somatic Mutation of p.V1937M in Unilateral Primary Hyperaldosteronism.

Front Endocrinol (Lausanne) 2022 9;13:816476. Epub 2022 Jun 9.

Department of Urology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.

Background: Somatic mutations for excess aldosterone production have been frequently identified as important roles in the pathogenesis of unilateral primary hyperaldosteronism (uPA). Although mutation represents a minor etiology in primary aldosteronism, it plays a significant role in causing uPAs in sporadic cases.

Objective: To identify novel somatic mutation in patients with uPA and investigate the pathophysiological, immunohistological, and clinical characteristics of the variant.

Methods: We applied a customized and targeted gene panel next-generation sequencing approach to detect mutations from the uPA cohort in Taiwan Primary Aldosteronism Investigation study group. Information from pre-diagnostic to postoperative data was collected, including past history, medications, blood pressure readings, biochemical data, and image studies. The functional role of the variant was confirmed by studies, demonstrating aldosterone production in variant-transfected human adrenal cell lines.

Results: We identified a novel somatic mutation c.5809G>A (p.Val1937Met) in a uPA case. The gene encodes the pore-forming alpha-1H subunit of the voltage-dependent T-type calcium channel Cav3.2. This somatic p.V1937M variant showed excellent clinical and biochemical outcomes after ipsilateral adrenalectomy. The functional effect of somatic p.V1937M variant results in increased CYP11B2 expression and aldosterone biosynthesis in HAC15 cells. A distinct heterogeneous foamy pattern of CYP11B2 and CYP17A1 expression was identified in immunohistological staining, supporting the pathological evidence of aldosterone synthesis.

Conclusions: The somatic mutation of p.V1937M might be a pathogenic driver in aldosterone overproduction. This study provides new insight into the molecular mechanism and disease outcomes of uPA.
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http://dx.doi.org/10.3389/fendo.2022.816476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218183PMC
June 2022

Oxidative Stress and Antioxidative Therapy in Pulmonary Arterial Hypertension.

Molecules 2022 Jun 9;27(12). Epub 2022 Jun 9.

Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.

Pulmonary arterial hypertension (PAH) is clinically characterized by a progressive increase in pulmonary artery pressure, followed by right ventricular hypertrophy and subsequently right heart failure. The underlying mechanism of PAH includes endothelial dysfunction and intimal smooth muscle proliferation. Numerous studies have shown that oxidative stress is critical in the pathophysiology of PAH and involves changes in reactive oxygen species (ROS), reactive nitrogen (RNS), and nitric oxide (NO) signaling pathways. Disrupted ROS and NO signaling pathways cause the proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary vascular smooth muscle cells (PASMCs), resulting in DNA damage, metabolic abnormalities, and vascular remodeling. Antioxidant treatment has become a main area of research for the treatment of PAH. This review mainly introduces oxidative stress in the pathogenesis of PAH and antioxidative therapies and explains why targeting oxidative stress is a valid strategy for PAH treatment.
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http://dx.doi.org/10.3390/molecules27123724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9229274PMC
June 2022

The Mechanism, Clinical Efficacy, Safety, and Dosage Regimen of Atomoxetine for ADHD Therapy in Children: A Narrative Review.

Front Psychiatry 2021 9;12:780921. Epub 2022 Feb 9.

Department of Children Health Care, Children's Hospital of Nanjing Medical University, Nanjing, China.

Atomoxetine, a selective norepinephrine (NE) reuptake inhibitor, was approved for attention deficit/hyperactivity disorder (ADHD) treatment in children, adolescents and adults. We searched the database PubMed/MEDLINE (2000 to October 1, 2021). Only publications in English were considered. Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of NE throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex (PFC). The novel mechanism of atomoxetine also includes several new brain imaging studies and animal model studies. It is mainly metabolized by the highly polymorphic drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Atomoxetine is effective and generally well tolerated. ADHD is often accompanied by multiple comorbidities. A series of studies have been published suggesting that atomoxetine is effective in the treatment of ADHD symptoms for children with various types of comorbidity. In some cases, it is possible that atomoxetine may have a positive influence on the symptoms of comorbidities. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, and has a negligible risk of abuse or misuse. The latest guideline updated that clinical dose selection of atomoxetine was recommended based on both genotype and the peak concentration. To have a more comprehensive understanding of atomoxetine, this review sets the focus on the mechanism, clinical efficacy and dosage regimen in detail, and also touches on those studies regarding adverse reactions of atomoxetine.
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http://dx.doi.org/10.3389/fpsyt.2021.780921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8863678PMC
February 2022

Caffeine Therapy for Apnea of Prematurity: Role of the Circadian Gene Polymorphism.

Front Pharmacol 2021 25;12:724145. Epub 2022 Jan 25.

Neonatal Intensive Care Unit, Children's Hospital of Nanjing Medical University, Nanjing, China.

Standard-dose caffeine citrate has been routinely prescribed for apnea of prematurity (AOP) management; however, some preterm infants respond well to the therapy while others do not. The AOP phenotype has been attributed solely to the immature control of the respiratory system consequent to preterm birth, but there are also important genetic influences. Based on our previous report, we tested the hypothesis that the human circadian locomotor output cycles kaput () gene polymorphisms play a role in the response to caffeine citrate therapy in preterm infants. We also studied the interactions of the circadian clock with aryl hydrocarbon receptor (AHR) signaling pathways in preterm babies who received caffeine citrate. This single-center study collected data from 112 preterm infants (<35 weeks gestational age) between July 2017 and July 2018, including apnea-free ( = 48) and apneic ( = 64) groups. Eighty-eight candidate single nucleotide polymorphisms (SNPs) were tested using the MassARRAY system. Association analysis was performed using the PLINK Whole Genome Data Analysis Toolset and SNPStats software. Linkage disequilibrium (LD) and haplotype analyses were performed using Hapview software. No significant intergroup differences in allele distributions or genotype frequencies of , , , and were detected in our study on preterm babies. Two more SNPs in were found to be associated with determining the response to caffeine citrate therapy in our pediatric patients. Of the 46 candidate SNPs in gene, 26 were found to be associated with determining the response to caffeine treatment in these babies. Interestingly, a significant association was retained for 18 SNPs in the gene after false discovery rate correction. Moreover, strong LD formed in those variants in , , and genes was confirmed to be significantly associated with a better response to standard-dose caffeine therapy. In summary, gene polymorphisms play a role in determining the response to caffeine therapy in premature neonates with AOP. However, whether the AHR and CLOCK signaling pathways crosstalk with each other during caffeine treatment remains largely unclear. Future clinical studies including more immature babies and basic research are needed to explore the mechanism by which circadian rhythms affect the response to caffeine therapy.
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http://dx.doi.org/10.3389/fphar.2021.724145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8822171PMC
January 2022

Vincristine-Induced Peripheral Neuropathy in Childhood Acute Lymphoblastic Leukemia: Genetic Variation as a Potential Risk Factor.

Front Pharmacol 2021 9;12:771487. Epub 2021 Dec 9.

Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, TN, United States.

Vincristine (VCR) is the first-line chemotherapeutic medication often co-administered with other drugs to treat childhood acute lymphoblastic leukemia. Dose-dependent neurotoxicity is the main factor restricting VCR's clinical application. VCR-induced peripheral neuropathy (VIPN) sometimes results in dose reduction or omission, leading to clinical complications or affecting the patient's quality of life. With regard to the genetic basis of drug responses, preemptive pharmacogenomic testing and simultaneous blood level monitoring could be helpful for the transformation of various findings into individualized therapies. In this review, we discussed the potential associations between genetic variants in genes contributing to the pharmacokinetics/pharmacodynamics of VCR and VIPN incidence and severity in patients with acute lymphoblastic leukemia. Of note, genetic variants in the gene have great potential to be translated into clinical practice. Such a genetic biomarker may help clinicians diagnose VIPN earlier. Besides, genetic variants in other genes, such as and have been reported to be associated with the VIPN, but more evidence is needed to validate the findings in the future. In fact, a variety of complex factors jointly determine the VIPN. In implementing precision medicine, the combination of genetic, environmental, and personal variables, along with therapeutic drug monitoring, will allow for a better understanding of the mechanisms of VIPN, improving the effectiveness of VCR treatment, reducing adverse reactions, and improving patients' quality of life.
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http://dx.doi.org/10.3389/fphar.2021.771487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8696478PMC
December 2021

Switching Between LC-ESI-MS/MS and EMIT Methods for Routine TDM of Valproic Acid in Pediatric Patients With Epilepsy: What Clinicians and Researchers Need to Know.

Front Pharmacol 2021 23;12:750744. Epub 2021 Nov 23.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Currently, immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS), resulting a potential lack of concordance between laboratories. In this study, plasma VPA concentrations were determined for 711 pediatric patients with epilepsy by a routine EMIT assay and by a validated in-house LC-ESI-MS/MS method on the same group of samples, aimed to address the aforementioned concern. Consistency between two assays was evaluated using linear regression and Bland-Altman analysis. The calibration curve was linear in the range of 5.00-300 μg/ml for LC-ESI-MS/MS method and 1.00-150 μg/ml for EMIT assay, respectively. The two methods were proven to be accurate with quality control samples. As a result, a significant correlation between two methods was obtained with a regression equation described as ( = 0.9281). Bland-Altman plot showed a mean bias of 14.5 μg/ml (95% confidence interval (CI) (-0.2, 29.2) and a mean increase of 27.8% (95% CI (3.3, 52.4) measured by EMIT assay more than that measured by LC-ESI-MS/MS method. In conclusion, two methods were closely correlated, but EMIT assay overestimate VPA levels in human plasma compared with LC-ESI-MS/MS method. Due to the observed significant discordance between the tested methods, switching from immunoassays to LC-based techniques for TDM of VPA deserves close attention and therapeutic range of 35.0-75.0 μg/ml may be feasible. However, further studies are needed to evaluate the eligibility of this alternative range in the clinical practice. Clinicians should be informed when switching the VPA quantitation methods during the clinical practice.
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http://dx.doi.org/10.3389/fphar.2021.750744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650496PMC
November 2021

Population Pharmacokinetics Modeling of Vancomycin Among Chinese Infants With Normal and Augmented Renal Function.

Front Pediatr 2021 20;9:713588. Epub 2021 Sep 20.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

There have been good amounts of population pharmacokinetics (PPK) models of vancomycin for Chinese pediatric patients, but none of them had a special focus on modeling infant population with different levels of renal function. Since renal function variability is prominent among infant population and the clearance (CL) of vancomycin is heavily related to renal excretion, it is important to establish precise PPK models based on individual renal function levels. We employed a PPK approach to develop three models of vancomycin in parallel for Chinese pediatric patients with normal renal function [estimated glomerular filtration rate (eGFR) between 30 and 86 ml/min/1.73 m, Model 1], with augmented renal function (eGFR ≥ 86 ml/min/1.73 m, Model 2), or with all levels of renal function (Model 3). Three one-compartment models with first-order elimination kinetics were established. The predictive ability of Model 1 and Model 2 among each certain population is comparable with that of Model 3 with no statistical difference. Our study revealed that among the infant population with augmented renal function, only body weight was included as a covariate, which indicated that for an infant whose eGFR ≥ 86 ml/min/1.73 m, taking blood sample is not compulsory for predicting vancomycin blood concentration, which avoids unnecessary injury to vulnerable infants.
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http://dx.doi.org/10.3389/fped.2021.713588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489377PMC
September 2021

Caffeine for the Pharmacological Treatment of Apnea of Prematurity in the NICU: Dose Selection Conundrum, Therapeutic Drug Monitoring and Genetic Factors.

Front Pharmacol 2021 26;12:681842. Epub 2021 Jul 26.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

Caffeine citrate is the drug of choice for the pharmacological treatment of apnea of prematurity. Factors such as maturity and genetic variation contribute to the interindividual variability in the clinical response to caffeine therapy in preterm infants, making the optimal dose administered controversial. Moreover, the necessity for therapeutic drug monitoring (TDM) of caffeine is still worth discussing due to the need to achieve the desired target concentrations as well as concerns about the safety of higher doses. Therefore, we reviewed the pharmacokinetic profile of caffeine in preterm infants, evidence of the safety and efficacy of different doses of caffeine, therapeutic concentration ranges of caffeine and impact of genetic variability on caffeine therapy. Whereas the safety and efficacy of standard-dose caffeine have been demonstrated, evidence for the safety of higher administered doses is insufficient. Thus, preterm infants who lack clinical response to standard-dose caffeine therapy are of interest for TDM when dose optimization is performed. Polymorphisms in pharmacodynamics-related genes, but not in pharmacokinetics-related genes, have a significant impact on the interindividual variability in clinical response to caffeine therapy. For preterm infants lacking clinical response, how to develop individualized medication regimens for caffeine remains to be explored.
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http://dx.doi.org/10.3389/fphar.2021.681842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350115PMC
July 2021

CaMKII and Ca3.2 T-type calcium channel mediate Connexin-43-dependent inflammation by activating astrocytes in vincristine-induced neuropathic pain.

Cell Biol Toxicol 2021 Jul 20. Epub 2021 Jul 20.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.

Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, VCR therapy can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain (VINP) was accompanied by astrocyte activation; the upregulation of phospho-CaMKII (p-CaMKII), Ca3.2, and Connexin-43 (Cx43) expression; and the production and release of inflammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures. Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L-Ascorbic acid (a Ca3.2 inhibitor). In addition, KN-93 and L-Ascorbic acid inhibited the increase in [Ca] associated with astrocyte activation. We also verified that knocking down or inhibiting Cx43 level via intrathecal injection of Cx43 siRNA or Gap27 (a Cx43 mimetic peptide) relieved pain hypersensitivity and reduced the release of inflammatory factors; however, they did not affect astrocyte activation or p-CaMKII and Ca3.2 expression. Besides, the overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII and Ca3.2 expressions in vitro. Therefore, CaMKII and Ca3.2 may activate astrocytes by increasing [Ca], thereby mediating Cx43-dependent inflammation in VINP. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced inflammation, apoptosis, and mitochondrial damage. Collectively, our findings show a novel mechanism by which CaMKII and Ca3.2 mediate Cx43-dependent inflammation by activating astrocytes in neuropathic pain induced by VCR.
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http://dx.doi.org/10.1007/s10565-021-09631-yDOI Listing
July 2021

Dose tailoring of tacrolimus based on a non-linear pharmacokinetic model in children with refractory nephrotic syndrome.

Int Immunopharmacol 2021 Sep 17;98:107827. Epub 2021 Jul 17.

Department of Pharmacy, Shanghai Chest Hospital, Shanghai, China. Electronic address:

The population pharmacokinetics (PPK) of tacrolimus (TAC) in children with refractory nephrotic syndrome (RNS) have not been well-characterized. This study aimed to investigate the significant factors affecting the TAC PPK characteristics of children with RNS and to optimize the dosing regimen. A total of 494 concentrations from 108 children were obtained from routine therapeutic drug monitoring between 2016 and 2018. Information regarding the demographic features, laboratory test results, genetic polymorphisms of CYP3A5 (rs776746) and co-therapy medications were collected. PPK analysis was performed using the nonlinear mixed-effects modelling (NONMEM) software and two modelling strategies (the linear one-compartment model and nonlinear Michaelis-Menten model) were evaluated and compared. CYP3A5 genotype, weight, daily dose of TAC and daily dose of diltiazem were retained in the final linear model. The absorption rate constant (Ka) was set at 4.48 h in the linear model, and the apparent clearance (CL/F) and volume of distribution (V/F) in the final linear model were 14.2 L/h and 172 L, respectively. CYP3A5 genotype, weight and daily dose of diltiazem were the significant factors retained in the final nonlinear model. The maximal dose rate (V) and the average steady-state concentration at half-Vmax (K) in the final nonlinear model were 2.15 mg/day and 0.845 ng/ml, respectively. The nonlinear model described the pharmacokinetic data of TAC better than the linear model in children with RNS. A dosing regimen was proposed based on weight, CYP3A5 genotype and daily dose of diltiazem according to the final nonlinear PK model, which may facilitate individualized drug therapy with TAC.
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http://dx.doi.org/10.1016/j.intimp.2021.107827DOI Listing
September 2021

Determination of atomoxetine levels in human plasma using LC-MS/MS and clinical application to Chinese children with ADHD based on CPIC guidelines.

Anal Methods 2021 06 17;13(21):2434-2441. Epub 2021 May 17.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.

The Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines for personalized atomoxetine therapy are based on the CYP2D6 genotype information and the peak plasma concentrations of atomoxetine. Therefore, a highly rapid, sensitive, and reproducible method is critical for the clinical implementation of the guidelines. In this study, an LC-MS/MS approach was developed and validated for the determination of atomoxetine levels in human plasma using atomoxetine-d3 as the internal standard. Samples were prepared by simple protein precipitation method with MeOH. The analyte was separated using a Kinetex C18 column (2.1 mm × 50 mm, 2.6 μm, Phenomenex) with a flow rate of 0.25 mL min, using a gradient elution. A MeOH and water solution containing 5 mM ammonium acetate and 0.1 mM formic acid (pH 6.26) was used as the mobile phase and successfully solved the problem of inconsistent retention time between the plasma samples and the solution samples of atomoxetine. Detection was performed under positive-electrospray-ion multiple reaction-monitoring mode using the 256.4 → 43.8 and 259.3 → 47.0 transitions for atomoxetine and atomoxetine-d3, respectively. Linearity was achieved using an extremely wide range, from 0.500 to 2000 ng mL in plasma. The intra- and inter-batch precision and accuracy, dilution accuracy, recovery, and stability of the method were all within the acceptable limits and no matrix effect was observed. With a complex needle wash solution containing ACN : MeOH : isopropanol : HO (4 : 4:1 : 1, v/v/v/v), carryover contamination was eliminated successfully. This method was successfully implemented on pediatric patients with attention-deficit/hyperactivity disorder and provided valuable information to enable clinicians to do dose selection and titration.
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http://dx.doi.org/10.1039/d1ay00521aDOI Listing
June 2021

Determination of atomoxetine levels in human plasma using LC-MS/MS and clinical application to Chinese children with ADHD based on CPIC guidelines.

Anal Methods 2021 06 17;13(21):2434-2441. Epub 2021 May 17.

Pharmaceutical Sciences Research Center, Department of Pharmacy, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.

The Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines for personalized atomoxetine therapy are based on the CYP2D6 genotype information and the peak plasma concentrations of atomoxetine. Therefore, a highly rapid, sensitive, and reproducible method is critical for the clinical implementation of the guidelines. In this study, an LC-MS/MS approach was developed and validated for the determination of atomoxetine levels in human plasma using atomoxetine-d3 as the internal standard. Samples were prepared by simple protein precipitation method with MeOH. The analyte was separated using a Kinetex C18 column (2.1 mm × 50 mm, 2.6 μm, Phenomenex) with a flow rate of 0.25 mL min, using a gradient elution. A MeOH and water solution containing 5 mM ammonium acetate and 0.1 mM formic acid (pH 6.26) was used as the mobile phase and successfully solved the problem of inconsistent retention time between the plasma samples and the solution samples of atomoxetine. Detection was performed under positive-electrospray-ion multiple reaction-monitoring mode using the 256.4 → 43.8 and 259.3 → 47.0 transitions for atomoxetine and atomoxetine-d3, respectively. Linearity was achieved using an extremely wide range, from 0.500 to 2000 ng mL in plasma. The intra- and inter-batch precision and accuracy, dilution accuracy, recovery, and stability of the method were all within the acceptable limits and no matrix effect was observed. With a complex needle wash solution containing ACN : MeOH : isopropanol : HO (4 : 4:1 : 1, v/v/v/v), carryover contamination was eliminated successfully. This method was successfully implemented on pediatric patients with attention-deficit/hyperactivity disorder and provided valuable information to enable clinicians to do dose selection and titration.
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http://dx.doi.org/10.1039/d1ay00521aDOI Listing
June 2021

Changes in Glucose Metabolism after Adrenalectomy or Treatment with a Mineralocorticoid Receptor Antagonist for Primary Aldosteronism.

Endocrinol Metab (Seoul) 2020 12 2;35(4):838-846. Epub 2020 Dec 2.

Division of Urology, Department of Surgery, Far-Eastern Memorial Hospital, New Taipei, Taiwan.

Background: Data on the effects of excess aldosterone on glucose metabolism are inconsistent. This study compared the changes in glucose metabolism in patients with primary aldosteronism (PA) after adrenalectomy or treatment with a mineralocorticoid receptor antagonist (MRA).

Methods: Overall, 241 patients were enrolled; 153 underwent adrenalectomy and 88 received an MRA. Fasting glucose, homeostatic model assessment of insulin resistance (HOMA-IR), and homeostatic model assessment of β-cell function (HOMA-β) were compared between the treatment groups after 1 year. Plasma aldosterone concentration (PAC) and factors determining HOMA-IR and PAC were evaluated.

Results: No baseline differences were observed between the groups. Fasting insulin, HOMA-IR, and HOMA-β increased in both groups and there were no significant differences in fasting glucose following treatment. Multiple regression analysis showed associations between PAC and HOMA-IR (β=0.172, P=0.017) after treatment. Treatment with spironolactone was the only risk factor associated with PAC >30 ng/dL (odds ratio, 5.2; 95% confidence interval [CI], 2.7 to 10; P<0.001) and conferred a 2.48-fold risk of insulin resistance after 1 year compared with surgery (95% CI, 1.3 to 4.8; P=0.007).

Conclusion: Spironolactone treatment might increase insulin resistance in patients with PA. This strengthened the current recommendation that adrenalectomy is the preferred strategy for patient with positive lateralization test. Achieving a post-treatment PAC of <30 ng/dL for improved insulin sensitivity may be appropriate.
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http://dx.doi.org/10.3803/EnM.2020.797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803597PMC
December 2020

Vincristine-induced peripheral neuropathy: A mini-review.

Neurotoxicology 2020 12 11;81:161-171. Epub 2020 Oct 11.

Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Vincristine (VCR), an alkaloid extracted from vinca, is often used in combination with other chemotherapeutic drugs to treat a variety of cancers, such as acute lymphoblastic leukaemia (ALL), malignant lymphoma, and neuroblastoma. However, VCR possesses dose-dependent neurotoxicity, which is the main factor restricting its application. Vincristine-induced peripheral neuropathy (VIPN) not only limits the dose of VCR and leads to the discontinuation of treatment but also triggers serious damage to the physical and mental health of patients. In addition, VIPN brings huge healthcare costs to patients and society. Individuals with VIPN often exhibit mechanical allodynia, sensory/tactile disorders, and numbness in the hands and feet. Unfortunately, VIPN is easily ignored due to its variable symptoms, which gives rise to insufficient research on the aetiology and pathogenesis of this disease, thereby resulting in a lack of appropriate preventive and therapeutic management. We performed a comprehensive review of the latest findings on VIPN in terms of symptoms, risk factors, potential mechanisms, and prevention and treatment measures. The purpose was to help clinicians better understand and accurately diagnose VIPN, select appropriate intervention measures and reduce the damage to cancer patients.
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http://dx.doi.org/10.1016/j.neuro.2020.10.004DOI Listing
December 2020

Arterial Stiffness Is Associated with Clinical Outcome and Cardiorenal Injury in Lateralized Primary Aldosteronism.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Context: The association between arterial stiffness and clinical outcome in lateralized primary aldosteronism (PA) patients after adrenalectomy has not been clearly identified.

Objective: We hypothesized that arterial stiffness estimated by brachial-ankle pulse wave velocity (baPWV) before adrenalectomy was associated with the clinical outcomes and cardiorenal injury in lateralized PA patients after adrenalectomy.

Design And Patients: We designed a retrospective observational cohort study. We collected lateralized PA patients who had undergone adrenalectomy between 2013 and 2016 from the Taiwan Primary Aldosteronism Investigation database. The primary outcome was achieving complete clinical success at 1 year after adrenalectomy. The secondary outcome was estimated glomerular filtration rate declining over 20% and improved left ventricular mass index.

Results: We enrolled 221 patients with lateralized PA (50.7% men; mean age, 51.9 years), of whom 101 patients (45.7%) achieved complete clinical success at the 1-year follow-up assessment after adrenalectomy. Lower baPWV before adrenalectomy (odds ratio = 0.998; 95% confidence interval, 0.996-0.999; P = 0.003) correlated with higher likelihood of complete clinical success by multivariate logistic regression analysis. Multifactorial adjusted generalized additive model demonstrated that preoperative baPWV<1600 cm/sec was significantly associated with complete cure of hypertension. In addition, higher preoperative baPWV was associated with renal function decline and less left ventricular mass regression after adrenalectomy in lateralized PA patients during the follow-up period.

Conclusions: Our study demonstrated that the preoperative severe arterial stiffness was associated with absent complete clinical success in lateralized PA patients after adrenalectomy, and this effect may contribute to cardiorenal injury, which at least partially explains kidney function deterioration and lessened regression of heart mass.
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http://dx.doi.org/10.1210/clinem/dgaa566DOI Listing
November 2020

Two new species of Lobellini from Central-South China (Collembola: Neanuridae).

Zootaxa 2019 Dec 18;4712(1):zootaxa.4712.1.5. Epub 2019 Dec 18.

Department of Life and Environmental Science, Hunan University of Arts and Science. Changde 415000, Hunan, China..

Four species of the tribe Lobellini (Collembola: Neanuridae: Neanurinae) are recorded from Langshan National Geopark, Hunan Province, Central-South China. Two of them, Crossodonthina langshanensis sp. nov. and Lobellina gladius sp. nov., are new to science and described in this paper. Crossodonthina langshanensis sp. nov. is characterized by 2+2 black eyes on head; labral chaetotaxy as 2/4, 2; cephalic chaeta O present; mandible with 2 teeth and 2 fringed rami; maxilla outer lamella with filaments on inner edge. Lobellina gladius sp. nov. can be recognized by mandible with six teeth, cephalic chaeta O present and included in tubercle Fr, non-cross type chaetotaxy on cephalic posterior area, cephalic lateral tubercle Dl, L and So independent, Ant. I with 9 chaetae, Th. I with 4+4 tubercles, VT with 6-8 (usually 7) chaetae. New localities of Crossodonthina choui Jiang Zhang, 2012 and Lobellina yinae Jiang, Huang Luan, 2018 are also provided.
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http://dx.doi.org/10.11646/zootaxa.4712.1.5DOI Listing
December 2019

Familial Aggregation and Heritability of Aldosteronism with Cardiovascular Events.

J Clin Endocrinol Metab 2020 06;105(6)

Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Context: To date, the effect of positive family history as a risk factor of primary aldosteronism (PA) is largely unknown. Studies have failed to distinguish the heritability of PA as well as the associations between positive family history of PA and clinical outcomes.

Objectives: We quantified the prevalence, the extent of familial aggregation, the heritability of PA among family members of patients with PA, and the association between positive PA family history and major cardiovascular events (MACE).

Design And Settings: Using the Taiwan National Health Insurance Database, 30 245 077 National Health Insurance beneficiaries (both alive and those deceased between January 1, 1999, and December 31, 2015) were identified.

Results: We identified 7902 PA patients. Forty-four had PA (0.3%) among 10 234 individuals with affected parents, 2298 with affected offspring, 1924 with affected siblings, and 22 with affected twins. A positive family history was associated with the adjusted relative risk (RR) (95% confidence interval [CI]) of 11.60 (7.63-17.63) for PA in people with an affected first-degree relative. In subgroup analysis, the risk for PA across all relationships (parent, siblings, offspring, and spouse) showed highly significant differences to PA without family history. The accountability for phenotypic variance of PA was 51.0% for genetic factors, 24.9% for shared environmental factors, and 24.1% for nonshared environmental factors. PA patients with an affected first-degree relative were associated with an increased risk for composite major cardiovascular events (RR 1.31; 95% CI 1.24-1.40, P < .001) compared with PA patients without family history.

Conclusion: Familial clustering of PA exists among a population-based study, supporting a genetic susceptibility leading to PA. There is increased coaggregation of MACE in first-degree relatives of PA patients. Our findings suggest a strong genetic component in the susceptibility of PA, involving different kinships.
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http://dx.doi.org/10.1210/clinem/dgz257DOI Listing
June 2020

Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels.

Int Immunopharmacol 2020 Apr 10;81:106290. Epub 2020 Feb 10.

Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C values were 2-7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C/Dose ratio. The C/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C/Dose ratio in patients aged 1-≤6 and 6-≤12 years was significantly lower than that in patients aged 12-≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C/Dose ratio in younger children (1-≤6 years), rather than older children (6-≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C) of 2-7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.
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http://dx.doi.org/10.1016/j.intimp.2020.106290DOI Listing
April 2020

Research Progress of Mechanisms and Drug Therapy For Atherosclerosis on Toll-Like Receptor Pathway.

J Cardiovasc Pharmacol 2019 11;74(5):379-388

Department of Physiology, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.

Recent reports have established atherosclerosis (AS) as a major factor in the pathogenetic process of cardiovascular diseases such as ischemic stroke and coronary heart disease. Although the possible pathogenesis of AS remains to be elucidated, a large number of investigations strongly suggest that the inhibition of toll-like receptors (TLRs) alleviates the severity of AS to some extent by suppressing vascular inflammation and the formation of atherosclerotic plaques. As pattern recognition receptors, TLRs occupy a vital position in innate immunity, mediating various signaling pathways in infective and sterile inflammation. This review summarizes the available data on the research progress of AS and the latest antiatherosclerotic drugs associated with TLR pathway.
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http://dx.doi.org/10.1097/FJC.0000000000000738DOI Listing
November 2019

Transcriptome Sequencing of (Coleoptera: Coccinellidae) and Application of Two Assembled Unigenes.

G3 (Bethesda) 2020 01 7;10(1):247-254. Epub 2020 Jan 7.

Plant Protection Institute, Hunan Academy of Agricultural Science, Changsha, P.R. China, 410125.

The ladybird beetle is an important predator of whiteflies. Investigations of the molecular mechanisms of this predatory beetle have been hindered by the scarcity of gene sequence data. To obtain gene sequences for the ladybird beetle and determine differences in gene expression between the summer and winter seasons, paired-end sequencing was performed. Real-time PCR was used to validate differences in Krueppel homolog 1 gene () mRNA expression in summer winter samples. To determined the diversity of the population, annotated cytochrome c oxidase subunit I gene () gene fragments were amplified from several ladybird beetle populations. The analysis yielded 191,246 assembled unigenes, 127,016 of which (66.4%) were annotated. These functional annotations of gene sequences are currently available from the National Center for Biotechnology Information (NCBI), and will provide a basis for studying the molecular mechanisms underlying the biological characteristics of We found a change in expression of ribosome-associated genes across seasons, and postulate that this change is because of seasonal variation in temperature and photoperiod. The differential expression of suggests that can successfully overwinter because the adults enter diapause. To explain the effects of season on gene expression, we hypothesize a model in which that a short photoperiod affects the density of Ca, the subsequent activity of methyl farnesoate epoxidase and the synthesis of JH, and in turn gene expression. annotation was concordant with the morphological ID. The same sequence was found in the samples from several provinces in China. Therefore, the sequence is worth further study to distinguish beetle species and populations.
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http://dx.doi.org/10.1534/g3.119.400785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945030PMC
January 2020

Primary Aldosteronism and Obstructive Sleep Apnea: A Cross-Sectional Multi-Ethnic Study.

Hypertension 2019 12 4;74(6):1532-1540. Epub 2019 Nov 4.

From the Division of Internal Medicine and Hypertension Unit, Department of Medical Sciences, University of Torino, Italy (F.B., S.M., J.P., F.V., P.M.).

The association between primary aldosteronism (PA) and obstructive sleep apnea (OSA) has been a matter of debate. 2016 Endocrine Society guideline recommends screening for PA all hypertensive patients with OSA. We designed a multicenter, multiethnic, cross-sectional study to evaluate the prevalence of PA in patients with OSA and the prevalence of OSA in unselected patients with PA. Two hundred and three patients with OSA (102 whites and 101 Chinese) were screened for PA, and 207 patients with PA (104 whites, 100 Chinese, and 3 of African descent) were screened for OSA by cardiorespiratory polygraphy. Eighteen patients with OSA (8.9%) had PA (11.8% of white and 5.9% of Chinese ethnicity). In patients without other indications for PA screening, the prevalence of PA dropped to 1.5%. The prevalence of OSA in patients with PA was 67.6%, consistent in both white and Chinese patients. A correlation between aldosterone levels and apnea/hypopnea index was observed in white patients with PA (=0.225, =0.016) but not in Chinese patients. Multinomial logistic regression confirmed a significant and independent association between plasma aldosterone levels and moderate to severe OSA diagnosis in white patients (odds ratio, 1.002; =0.002). In conclusion, aldosterone levels may contribute to the severity of OSA in white patients with hyperaldosteronism, but patients with OSA are not at high risk of PA. Results of the present study challenge the current recommendation of the Endocrine Society guideline that all patients with OSA should be screened for PA, irrespective of the grade of hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13833DOI Listing
December 2019

Adrenalectomy Completely Cured Hypertension in Patients With Familial Hyperaldosteronism Type I Who Had Somatic KCNJ5 Mutation.

J Clin Endocrinol Metab 2019 11;104(11):5462-5466

Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.

Context: Familial hyperaldosteronism type I (FH-I) or glucocorticoid-remediable aldosteronism (GRA) is caused by unequal crossing over of the steroid 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. Somatic KCNJ5 mutations have not been reported in patients with GRA; therefore, the appropriate treatment and prognosis of such concurrent cases remain unknown.

Case Description: Two siblings of a Taiwanese family with GRA were found to have adrenal adenomas and somatic KCNJ5 mutations. Complete clinical cure was achieved after unilateral adrenalectomy. Furthermore, the conversion site of the chimeric gene was identified by direct sequencing.

Conclusions: We report the coexistence of a somatic KCNJ5 mutation and GRA. Patients with GRA whose blood pressure management develops resistance to glucocorticoid treatment could therefore benefit from a lateralization test. The promising outcomes after unilateral adrenalectomy presented in this report offer new perspectives for further research into various PA subtypes.
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http://dx.doi.org/10.1210/jc.2019-00689DOI Listing
November 2019

Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update.

Curr Pharm Des 2019 ;25(3):343-351

Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, United States.

Background: Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed.

Methods: We searched in PubMed for manuscripts published in English, combining terms such as "Valproic acid", "hepatotoxicity", "liver injury", and "mechanisms". The data of screened papers were analyzed and summarized.

Results: The formation of VPA reactive metabolites, inhibition of fatty acid β-oxidation, excessive oxidative stress and genetic variants of some enzymes, such as CPS1, POLG, GSTs, SOD2, UGTs and CYPs genes, have been reported to be associated with VPA hepatotoxicity. Furthermore, carnitine supplementation and antioxidants administration proved to be positive treatment strategies for VPA-induced hepatotoxicity.

Conclusion: Therapeutic drug monitoring (TDM) and routine liver biochemistry monitoring during VPA-therapy, as well as genotype screening for certain patients before VPA administration, could improve the safety profile of this antiepileptic drug.
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http://dx.doi.org/10.2174/1381612825666190329145428DOI Listing
February 2020

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters.

Curr Pharm Des 2019 ;25(6):627-634

Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

Background: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment.

Methods: We searched PubMed for citations published in English using the terms "methotrexate", "transporter", "acute lymphoblastic leukemia", "polymorphisms", and "therapeutic drug monitoring". The retrieval papers were critically reviewed and summarized according to the aims of this mini-review.

Results: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied.

Conclusion: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.
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http://dx.doi.org/10.2174/1381612825666190329141003DOI Listing
February 2020

Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis.

Eur J Clin Pharmacol 2019 Apr 27;75(4):591-593. Epub 2018 Nov 27.

Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China.

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http://dx.doi.org/10.1007/s00228-018-2604-4DOI Listing
April 2019

Risk of severe erectile dysfunction in primary hyperaldosteronism: A population-based propensity score matching cohort study.

Surgery 2019 03 23;165(3):622-628. Epub 2018 Nov 23.

Taiwan Primary Aldosteronism Investigation (TAIPAI) Study Group, Taipei; Division of Urology, Department of Surgery, Taipei Tzu Chi Hospital, The Buddhist Medical Foundation, New Taipei City, Taiwan. Electronic address:

Background: An elevated plasma aldosterone level has been reported as an independent risk factor for severe erectile dysfunction in men. The aim of this study was to explore whether primary hyperaldosteronism patients experience erectile dysfunction after targeted treatment.

Methods: We conducted a population-based cohort study of men with newly identified primary hyperaldosteronism/aldosterone-producing adenoma from January 1, 1997, to December 31, 2009. Men with essential hypertension and normotension were matched to the primary hyperaldosteronism group according to propensity score matching.

Results: We identified 1,067 men with primary hyperaldosteronism (mean age, 46.7 ± 12.8 years) and matched them with the same number of men with essential hypertension or normotension. During the mean follow-up interval of 5.4 years, the incident rates of total erectile dysfunction were 5.7, 3.9, and 3.1 per 1,000 person-years for the primary hyperaldosteronism, essential hypertension, and normotension groups, respectively. Men with primary hyperaldosteronism exhibited a higher risk of erectile dysfunction compared with men with normotension (competing risks hazard ratio, 1.83), and no difference was seen in comparison with men who have essential hypertension. After adrenalectomy, men who have primary hyperaldosteronism had a higher risk of exhibiting severe erectile dysfunction compared with men who have essential hypertension (competing risks hazard ratio, 2.44) or normotension (competing risks hazard ratio, 2.90).

Conclusion: Men with primary hyperaldosteronism reported a higher incidence of severe erectile dysfunction than normotension controls despite targeted treatment. The risk of severe erectile dysfunction increased after men who have primary hyperaldosteronism underwent adrenalectomy. This result raises the possibility of severe erectile dysfunction after adrenalectomy and calls for a prospective large-scale study of men who have aldosterone-producing adenoma regarding their erectile function both before and after adrenalectomy.
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http://dx.doi.org/10.1016/j.surg.2018.08.020DOI Listing
March 2019

Risk of sepsis in patients with primary aldosteronism.

Crit Care 2018 11 21;22(1):313. Epub 2018 Nov 21.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: The interaction between hyperaldosteronism and immune dysfunction has been reported and glucocorticoid co-secretion is frequently found in primary aldosteronism (PA). The aforementioned conditions raise the possibility of the infection risk; however, clinical episodes of sepsis have not been reported in PA.

Methods: Using Taiwan's National Health Insurance Research Database between 1997 and 2009, we identified PA and aldosterone-producing adenoma (APA) matched with essential hypertension (EH) at a 1:1 ratio by propensity scores. The incidences of sepsis and mortality after the index date were evaluated, and the risk factors of outcomes were identified using adjusted Cox proportional hazards models and taking mortality as a competing risk.

Results: We enrolled 2448 patients with PA (male, 46.08%; mean age, 48.4 years). There were 875 patients who could be ascertained as APA. Taking mortality as the competing risk, APA patients had a lower incidence of sepsis than their matched EH patients (hazard ratio (HR) 0.29; P < 0.001) after target treatments. Patients receiving adrenalectomy showed a benefit of decreasing the risk of sepsis (PA vs EH, HR 0.14, P = 0.001; APA vs EH, HR 0.16, P = 0.003), but mineralocorticoid receptor antagonist treatment may differ. Compared with matched control cohorts, patients with APA had a lower risk of all-cause mortality (PA, adjusted HR 0.84, P = 0.050; APA, adjusted HR 0.31, P < 0.001) after target treatments.

Conclusions: Our study demonstrated that patients with PA/APA who underwent adrenalectomy could attenuate the risk of sepsis compared with their matched EH patients. We further found that APA patients with target treatments could decrease all-cause mortality compared with EH patients.
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http://dx.doi.org/10.1186/s13054-018-2239-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249889PMC
November 2018
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