Relationship between plasma risperidone concentrations and clinical features in chronic schizophrenic patients in China.

BACKGROUND: Prior studies have noted great variability in the plasma levels of risperidone (RIS). Plasma concentrations of RIS and its active moiety are highly variable and depend on absorption, metabolism, and other predictors of metabolic dysregulation; however, these factors are poorly understood and the association between metabolic change and change in psychopathology is uncertain. AIM: To ascertain the characteristics of chronic schizophrenic patients treated with RIS, and to assess their relationship with plasma RIS levels. METHODS: This was a descriptive cross-sectional study of 50 patients with a diagnosis of schizophrenic psychosis treated with RIS in a psychiatric service. The plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone were determined by high performance liquid chromatography. The patients' demographic and clinical characteristics, and psychopathologies were assessed, and the associations between clinical variables and plasma levels of RIS were explored. RESULTS: Male patients received higher doses of RIS than female ones, but plasma concentrations of RIS and risperidone + 9-hydroxyrisperidone (active moiety) were higher in female patients. Age and the mean scores of the general psychopathology subscale of the Positive and Negative Syndrome Scale (PANSS) were significantly positively correlated with plasma concentrations of risperidone + 9-hydroxyrisperidone adjusted for weight and dose in all 50 subjects. In male subjects, we found a statistically significant positive correlation between the concentrations of risperidone + 9-hydroxyrisperidone in plasma/(dose × kg) and age, mean PANSS negative subscale scores, mean PANSS general psychopathology subscale scores, and mean PANSS total scores. CONCLUSION: Long-term use of RIS should be closely monitored in older patients and females to minimize the risk of high concentrations which could induce side effects.

Therapeutic Drug Monitoring for Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma.

Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [Cmin], maximal plasma concentration [Cmax], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.

Simultaneous determination of colistin sulfate and tigecycline in human plasma by liquid chromatography-tandem mass spectrometry method.

OBJECTIVE: To establish a high-performance liquid chromatography-tandem mass spectrometry method (HPLC-MS/MS) to simultaneously determine colistin sulfate and tigecycline in human plasma. METHODS: Polymyxin B1 internal standard (20 µL) was added into 200 µL of plasma sample. The samples were treated with methanol-5% trichloroacetic acid (50:50, V/V) solution, and the protein precipitation method was adopted for post-injection analysis. The chromatographic column was a Dikma C18 (4.6 mm × 150 mm, 5 µm). For the mobile phase, 0.1% formic acid in aqueous solution was used for phase A, 0.1% formic acid in acetonitrile solution for phase B, and gradient elution was also applied. The flow rate was 0.8 mL/min, the column temperature was 40 °C, and the injection volume was 10 µL; Electrospray ionization and multiple reaction ion monitoring were adopted and scanned by the HPLC-MS/MS positive ion mode. RESULTS: The endogenous impurities in the plasma had no interference in the determination of the analytes. There existed a good linear relationship of colistin sulfate within the range of 0.1-10 µg/mL (R2 = 0.9986), with the lower limit of quantification (LLOQ) of 0.1 µg/mL. There existed a good linear relationship of tigecycline within the range of 0.05-5 µg/ mL (R2 = 0.9987), with the LLOQ of 0.05 µg/mL. The intra- and inter-day relative standard deviations of colistin sulfate and tigecycline were both less than 15%, and the accuracy was between 88.21% and 108.24%. The extraction had good stability, the extraction recovery rate was 87.75-91.22%, and the matrix effect was 99.40-105.26%. CONCLUSION: This study successfully established a method for simultaneously detecting colistin sulfate and tigecycline plasma concentrations. The method was simple, rapid, and highly sensitive and could be applied for therapeutic medication monitoring.

An adolescent boy with kleptomania and attention-deficit hyperactivity disorder treated with methylphenidate and guanfacine: A case report.

We present the case of a patient, a boy of 16 years of age at initial presentation, with kleptomania, an impulse disorder characterized by an impulse to steal unneeded items, and attention-deficit hyperactivity disorder (ADHD). The patient's parents reported that he would frequently impulsively steal items and money that he did not need. Cognitive and physical assessments revealed no abnormalities, and the patient had no history of substance abuse. The patient was diagnosed with kleptomania and ADHD. The patient was started on Osmotic Release Oral System Methylphenidate (OROS-MPH), a medication commonly used to treat ADHD, and experienced improvement in ADHD symptoms and stealing behavior. At 19 years of age, it was discovered that the patient's behavioral symptoms were uncontrolled during times of the day when the blood concentration of MPH was likely to have waned. After starting an additional dose of guanfacine at night, his symptoms during these times of day improved. While existing research is not definitive, there may be a connection between ADHD and kleptomania. Further, there are some reports that treatment of ADHD with MPH also reduced stealing behavior, aligning with our present findings. We discuss the potential mechanisms behind these improvements and further present the first evidence of the efficacy of guanfacine in the treatment of kleptomania.

A liquid chromatography-tandem mass spectrometry method for simultaneous quantification of thirty-nine tyrosine kinase inhibitors in human plasma.

Currently, the use of targeted drugs such as tyrosine kinase inhibitors (TKIs) plays an important role in clinical therapy. As the number of approved TKIs continues to increase, existing analysis methods will not be able to meet the growing needs, and will hamper the development of therapeutic drug monitoring (TDM) of TKIs. Based on LC-MS/MS technology, this study tends to develop and validate a multi-component analysis method for simultaneous determination of the concentrations of 39 TKIs in plasma. Spiked plasma was blended with isotope labelled internal standards, and injected into the LC-MS/MS system after protein precipitation by acetonitrile. Chromatographic separation was achieved using an ODS-4 column with gradient elution of formic acid/water (1:1000; v/v) and acetonitrile. Analytes detection was conducted in positive ionisation mode using MRM. The total run time was 8 min. The method validation was conducted by assessing the following parameters: selectivity, linearity and the lower limit of qualification, accuracy and precision, stability, matrix effect and recovery. The concentrations of 39 TKIs showed good linearity within the range of their respective standard curves in plasma, the accuracy of all quality control samples ranged from 85.9% to 114.1%, and the precision was lower than 13.3%. The extraction recovery ranged from 92.6% to 114.7%, and the matrix effect of plasma was lower than 11.3%. This new method was successfully developed, can be used for the determination of drug concentrations in multiple patients with different kinds of TKIs, and will therefore be suitable for TDM of 39 TKIs.

Changes of anesthetic drug concentration in plasma during isolation of autologous blood with acute isovolumic hemodilution and its influence on anesthetic effect after reinfusion / 中国临床药理学与治疗学

To investigate the changes of anesthetic drug concentration in plasma during isolation of autologous blood with acute normovolemic hemodiluti-on and its influence on the depth of anesthesia, muscle relaxant effect and blood drug concentration after reinfusion. METHODS: Forty patients of both sexes, aged 20-60 yr, American Society of Anesthesiologists physical status or Ⅱ, hemoglobin (Hb) >120 g / L, hematocrit (Hct) >35%, undergoing eletive multilevel spinal surgery were included, were divided into 2 groups (n=20 each) using a random number table. ANH group (group A): ANH was performed after stable induction of anesthesia, the target Hct value was 28%-30%, and autologous blood was reinfused after the main operation steps. Control group (group C): routine transfusion and infusion treatment. The bispectral index (BIS) and Train-of-Four stimulation (TOF) were observed and recorded at the stable induction of anesthesia (T1), 30 minutes of stable induction (T2), the end of operation (T3), 30 minutes after the end of the operation (T4), 1 hour after the end of the operation (T5) and 2 hours after the end of the operation (T6). The concentrations of propofol and cisatracurium besylate in plasma at T1-T6, stored blood at 1 h (TS1), 2 h (TS2), and before reinfusion (TS3) were detected by Liquid Chromatography-tandem Mass Spectrometry. The extubation time and recovery score at T4-6 hours were recorded. RESULTS: There was no significant difference in propofol between the two groups at each time point (P > 0.05). The plasma concentration of cisatracurium besylate in group A was higher than that in group C at T3 (P0.05). The BIS value at T4 and TOF value at T3 in group A were significantly lower than those in group C. The recovery score of group A was lower than that of group C at T4 (P0.05). CONCLUSION: The plasma concentrations of propofol and cisatracurium besylate were basically unchanged during the in vitro isolation of ANH autologous blood. The plasma concentrations of cisatracurium besylate were only temporarily affected after the main operation steps, but the postoperative muscle relaxation recovery and recovery quality were not significantly affected.

A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants.

This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of ≤50 mg or daily dosing of ≤10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and pharmacokinetics were not affected by administration with food or in otherwise healthy individuals with a cytochrome P450 2D6 poor metabolizer phenotype. (A Single and Multiple Ascending Dose Study of CK-3773274 in Health Adult Subjects; NCT03767855).

Pharmacokinetics and pharmacodynamics of once-weekly administration of JR-142, a long-acting albumin-fused human growth hormone: A rondemized, placebo-controlled phase 1 study.

OBJECTIVE: Under clinical development for patients with growth hormone deficiency, JR-142 is a long-acting growth hormone with a half-life extended by fusion with modified serum albumin. We conducted a Phase 1 study to investigate the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of once-weekly subcutaneous administrations of JR-142. The study consisted of two parts: an open-label single ascending dosing study (Part 1), and a randomized, placebo-controlled, assessor-blinded multiple ascending dosing study (Part 2). DESIGN: A total of 31 healthy Japanese male participants were enrolled. In Part 1, seven of them received a single subcutaneous injection of JR-142 each at dosages of 0.15 mg/kg (n = 1), 0.25 mg/kg (n = 2), 0.5 mg/kg (n = 2), or 1.0 mg/kg (n = 2). In Part 2, one weekly subcutaneous injection of JR-142 at 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg or a placebo were given for four weeks to each of the other 24 participants (six in each group). Plasma JR-142 and serum insulin-like growth factor-1 (IGF-1) concentrations were measured for PK and PD assessments. Safety was evaluated on the basis of adverse events (AEs), laboratory tests, and other measures. RESULTS: JR-142 induced dose-dependent increases in the maximum plasma JR-142 concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to τ (AUC0-τ). A similar dose-response relationship was observed in serum IGF-1 concentrations. All trough IGF-1 levels were well sustained one week after the final administrations of JR-142 at the three dosages, while the peak concentrations of IGF-1 remained mildly elevated. No serious AEs were observed, and laboratory tests, including assessment of anti-drug antibodies, uncovered no significant safety issues. CONCLUSIONS: Once-weekly subcutaneous injections of JR-142 produced positive dose-dependent PK and PD profiles over the dosage range. Drug accumulation was observed after the four-week administration period but did not raise safety concerns, indicating that JR-142 is well-tolerated in healthy participants. The PD profiles observed in terms of IGF-1 concentrations were also positive, and we believe the encouraging results of this study warrant substantiation in further clinical trials in patients with GHD. ETHICS: This clinical study was conducted at one investigational site in Osaka, Japan, where the clinical study and the non-clinical data of JR-142 were reviewed and approved by its Institutional Review Board on 9th May 2019. The study was conducted in compliance with the approved study protocol, the Declaration of Helsinki, 1964, as revised in 2013, and Good Clinical Practice.

Plasma Drug Concentration of Propranolol and Genetic Study in Chinese Han Patients With Infantile Haemangioma.

Background and Purpose: This study was conducted to explore the plasma drug concentration of propranolol in Chinese Han patients with infantile haemangioma (IH) and the influencing factors, as well as the relationship among plasma drug concentrations of propranolol, ß1-AR mutation and CYP2D6 188C>T, efficacy, and safety. Experimental Approach: From January 2018 to April 2019, 140 patients with IH who were admitted to the hospital for oral propranolol and agreed to have their plasma concentration of propranolol tested, including 112 patients with ß1-AR and CYP2D6 gene tested. Key Results and Conclusions and Implications: The mean peak blood levels of propranolol, 4-hydroxypropranolol (4-OH-P), and N-deisopropylpropranolol (NDP) were 60.35 ± 37.90, 1.90 ± 2.37, and 0.24 ± 0.18 ng/ml, respectively. The mean trough blood levels of propranolol, 4-OH-P, and NDP were 24.98 ± 17.68, 0.45 ± 0.52, and 0.05±0.05 ng/ml, respectively. The higher the dose of propranolol, the higher the plasma concentration of propranolol (p = 0.031). The plasma concentration of propranolol was not related to the treatment efficacy.

Effect of acute normovolemic hemodilution autologous blood transfusion on the EEG bispectral index and muscle relaxation in elderly patients undergoing orthopedic surgery / 中国临床药理学与治疗学

AIM: To observe the effect of acute normovolemic hemodilution (ANH) autologous blood transfusion on the EEG bispectral index and muscle relaxation in elderly patients undergoing orthopedic surgery to explore the influence of autologous blood transfusion containing anesthetic components on the quality and safety of postoperative anesthesia recovery. METHODS: Forty patients, aged 65-75, weighing 55-80 kg, ASA grade I-II, with an estimated intraoperative blood loss of more than 600 mL, were selected for elective orthopedic surgery. The patients were randomly divided into two groups (n=20): group A was given acute normovolemic hemodilution (ANH), and the target value of Hct was 28%-30% after induction of anesthesia; group B was the control group which was given routine fluid infusion during operation without ANH. Bispectral index (BIS), TOF values and plasma concentrations of propofol and cisatracurium were measured at the beginning of autotransfusion (T

Simultaneous determination of rosuvastatin, atorvastatin and their metabolites in human plasma by UPLC-MS/MS / 国际药学研究杂志

Objective: To develop a ultra performance liquid chromatography- tandem mass spectrometry(UPLC- MS/MS) method for the simultaneous determination of rosuvastatin(RT), atorvastatin(AT)and their metabolites, i.e., atorvastatin lactone (ATL), ortho- hydroxy-atorvastatin(O-AT)and para-hydroxy-atorvastatin(P-AT), in human plasma. Methods: Deuterium-labeled compounds, RT-d6, AT-d5 and P-AT-d5 were used as the internal standards(IS). The plasma samples were extracted with ethyl acetate. The chromatographic separation was achieved on a ACQUITY UPLCTM BEH C18 column(50 mm×2.1 mm, 1.7 μm)with the mobile phase of 0.2%(v/v)formic acid aqueous solution and methanol by gradient elution. The flow rate was 0.2 ml/min, and the column temperature was 40℃. Analytes were detected on a tandem mass spectrometer, equipped with an electrospray ionization source that was operated in the positive mode. The selectivity, standard curve, precision and accuracy, extraction recoveries, matrix effect, and stability were investigated. Results: The linear range of RT was 0.1-50 ng/ml with r2 =0.9977. The linear range for AT, ATL, O-AT and P-AT was 0.05-50 ng/ml with r2 =0.9997, 0.9988, 0.9923 and 0.9995, respectively. Conclusion: The established method is rapid, sensitive, accurate, specific and reliable, which is suitable for the simultaneous determination of RT, AT and their metabolites in human plasma.

[Effect of omeprazole on plasma concentration and adverse reactions of capecitabine in patients with colon cancer].

Objective: To investigate the effect of omeprazole on plasma concentration, efficacy and adverse reactions of capecitabine in patients with colon cancer. Methods: Seventy-two patients with colon cancer treated with capecitabine were analysed retrospective. The patients treated with capecitabine combined with omeprazole were identified as experimental group and the capecitabine treatment alone as control group.The differences of blood concentration and the side effects of capecitabine between these two groups were compared. Results: The plasma concentration of 5-Fluorouracilum in experimental group was (126.25±50.59) µg/ml, without significant difference of (123.09±56.70) µg/ml in control group (P=0.121). The incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and hand-foot syndrome in experimental group were 13.8%, 0%, 0% and 19.4%, respectively. In control group, the incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and the hand-foot syndrome were 11.1%, 0%, 0% and 19.4%, respectively, without significant difference of experimental group (P>0.05). The incidence of acid reflux and heartburn in the control group was 72.2%, significantly higher than 44.4% of the experimental group (P<0.05). The objective response rate (ORR) and progression-free survival time (PFS) in these two groups were 30.6% and 33.3%, and 8.0 month and 8.5 month, respectively, without significant difference (P>0.05). Conclusion: The intravenous omeprazole attenuates reflux and heartburn of colon cancer patients treated with capecitabine, without affecting its plasma concentration and side effects and has no impact on the PFS of these patients.

Effect of omeprazole on plasma concentration and adverse reactions of capecitabine in patients with colon cancer / 中华肿瘤杂志

Objective@#To investigate the effect of omeprazole on plasma concentration, efficacy and adverse reactions of capecitabine in patients with colon cancer.@*Methods@#Seventy-two patients with colon cancer treated with capecitabine were analysed retrospective. The patients treated with capecitabine combined with omeprazole were identified as experimental group and the capecitabine treatment alone as control group.The differences of blood concentration and the side effects of capecitabine between these two groups were compared.@*Results@#The plasma concentration of 5-Fluorouracilum in experimental group was (126.25±50.59) μg/ml, without significant difference of (123.09±56.70) μg/ml in control group (P=0.121). The incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and hand-foot syndrome in experimental group were 13.8%, 0%, 0% and 19.4%, respectively. In control group, the incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and the hand-foot syndrome were 11.1%, 0%, 0% and 19.4%, respectively, without significant difference of experimental group (P>0.05). The incidence of acid reflux and heartburn in the control group was 72.2%, significantly higher than 44.4% of the experimental group (P<0.05). The objective response rate (ORR) and progression-free survival time (PFS) in these two groups were 30.6% and 33.3%, and 8.0 month and 8.5 month, respectively, without significant difference (P>0.05).@*Conclusion@#The intravenous omeprazole attenuates reflux and heartburn of colon cancer patients treated with capecitabine, without affecting its plasma concentration and side effects and has no impact on the PFS of these patients.

Methadone Dosage and Plasma Levels, SNPs of OPRM1 Gene and Age of First Drug Use Were Associated With Outcomes of Methadone Maintenance Treatment.

Objective: To explore the association between methadone dosage, plasma drug concentration, SNPs of µ-opioid receptor gene (OPRM1), ATP-binding cassette subfamily B member 1 gene (ABCB1), and methadone maintenance treatment (MMT) response. Method: A total of 240 Chinese Han participants receiving MMT were recruited from Shanghai. Nine single nucleotide polymorphisms (SNPs) of the OPRM1 gene and three SNPs of the ABCB1 gene were genotyped, plasma methadone concentration was detected, and a morphine urine test was taken from all subjects. Results: Methadone dosage, plasma methadone concentration, and negative rate of morphine urine test of retention participants were significantly higher, although the addiction severity index (ASI) was not significantly different between the two groups. A allele and AA genotype carriers of rs562859 (OPRM1 gene) had better compliance of MMT, and AA genotype carriers had a higher negative rate of morphine urine test. However, the difference was not significant after adjusting influence factors (age, sex, and methadone dosage). GG genotype carriers of rs3192723 (OPRM1 gene) had a significantly lower negative rate of morphine urine test, and the difference was still significant after adjusting influence factors. Logistic regression analysis showed that methadone-free trough concentration (OR = 0.910, p = 0.023) and AA genotype of rs526859 (OR = 0.580, p = 0.037) were associated with better compliance of MMT. After Bonferroni correction, only free trough concentration of methadone was negatively correlated with MMT compliance. The SNPs rs6912029 (OR = 0.021, p = 0.066) and rs6902403 (OR = 0.910, p = 0.007) of the OPRM1 gene, age at first use (OR = 1.118, p = 0.005), and average methadone dosage (OR = 1.033, p = 0.045) were associated with MMT effect. After Bonferroni correction, average methadone dosage was no longer correlated with MMT effect. Conclusion: Dosage of methadone, plasma methadone concentration, several SNPs (rs3192723, rs6912029, rs6902403) of the OPRM1 gene, and age of first drug use were associated with better MMT outcomes.

Influence of Glimepiride on Plasma Concentrations and Antihypertensive Effects of Losartan and Losartan Carboxylic Acid in the Patients with Type 2 Diabetes Mellitus Complicated with Hypertension / 中国药师

Objective:To assess the influence of glimepiride on the plasma concentrations and antihypertensive effects of losartan and its active metabolite losartan carboxylic acid(E-3174) in the patients with type 2 diabetes mellitus and hypertension. Methods:Pragmatic randomized controlled trial was used in the clinical study. Forty-five patients were enrolled and randomized into glimepiride group and the control group. Losartan was used as the antihypertensive drug in the two groups. After two-week interference,the plasma concentrations of losartan and its active metabolite E-3174 were determined using an LC-MS/MS method and the reduction of hyperten-sion was measured. Results:The plasma trough concentrations of losartan in glimepiride group was not higher than those in the control group,and those of E-3174 in glimepiride group was not lower than those in the control group. Additionally,the reduction of hyperten-sion was similar in the two groups. Conclusion: Glimepiride does not influence the plasma concentrations and the antihypertensive effects of losartan and its active metabolite E-3174 in the patients with type 2 diabetes mellitus and hypertension, suggesting no drug-drug interactions between them. Owing to the small sample,large clinical trial should be performed to confirm the above conclusion.

Propofol in combination with remifentanil for cesarean section: Placental transfer and effect on mothers and newborns at different induction to delivery intervals.

OBJECTIVE: This study aims to describe the administration of propofol in combination with remifentanil for the induction of general anesthesia during cesarean section (CS). Our aim was to evaluate its impact on the drug concentrations of the maternal and neonatal blood at different induction of anesthesia to delivery (I-D) intervals as well as its effect on newborns. MATERIALS AND METHODS: In this double-blind randomized controlled study, patients undergoing elective CS were administered anesthesia at short (n = 20) or long (n = 20) I-D intervals. Anesthesia was induced with 1 mg/kg propofol and 1 µg/kg remifentanil and maintained by continuous infusion of 3 mg/kg/h propofol and 7 µg/kg/h remifentanil. RESULTS: The mean plasma propofol concentrations at delivery in the maternal arterial (MA) blood and the fetal umbilical arterial (UA) and venous (UV) blood in the short I-D interval group were 1.91, 1.17, and 0.51 µg/mL, respectively, while those in the long I-D interval group were 1.57, 1.07, and 0.61 µg/mL, respectively. The mean plasma remifentanil concentrations at delivery in the MA, UA, and UV in the short I-D interval group were 2.25, 1.43, and 0.65 ng/mL, respectively, and those in the long I-D interval group were 1.96, 1.25, and 0.75 ng/mL, respectively. There were no statistically significant differences in the neonatal Apgar scores and neurological adaptive capacity scores between the two groups. CONCLUSIONS: It is safe to administer propofol in combination with remifentanil by continuous infusion after the bolus dose for the induction of anesthesia during cesarean section. Prolonging the I-D interval within a certain limit will not have any significant influence on the fetus.

Establishment of Plasma Concentration Detection Method for 5-Fluorouracil and its Clinical Application / 中国药师

Objective:To establish a liquid chromatography tandem mass spectrometry ( LC-MS/MS) method for the determination of 5-fluorouracil (5-Fu) in patient’s plasma and apply it in clinics patients validation. Methods:5-Fu was analyzed on an Agela Inno-val NH2 (2. 1 mm × 50 mm, 5 μm) column. Methanol:ultra pure water (2 ∶98) was used as the mobile phase with isocratic elution. The flow rate was 0. 3 ml ·min-1 and the column temperature was set at 40℃. The ion transitions with electrospray ionization negative model were m/z 128. 8→42. 1 and m/z 188. 6→42. 1 for 5-Fu and 5-bromouracil (the internal standard), respectively. The LC-MS/MS method was verified according to the guideline of quantitative analysis validation of biological samples ( Chinese Pharmacopoeia, 2015 edition, the fourth part) . Results:The calibration curve of 5-Fu was linear within the range of 10-1 000 ng · ml-1 . The lower limit of quantification was 10 ng · ml-1 . The precision, accuracy, matrix effect and stability within the linear range were all in line with the requirements of method validation. Conclusion:The LC-MS/MS method developed in the study for the determination of 5-Fu is simple, rapid, accurate and reproducible, which can be used for the plasma concentration detection of 5-Fu in patients.

Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens.

Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009-2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.

Therapeutic Dose Monitoring for Linezolid in a Patient with MRSA Pneumonia with Bacteremia in Diabetes Insipidus.

INTRODUCTION: Few studies have investigated the effect of increased creatinine clearance (CrCl) on linezolid (LZD) concentration. Herein, we report the pharmacokinetic/pharmacodynamic (PK/PD) profile of LZD used in the management of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia with concomitant bacteremia in a patient with high CrCl caused by diabetes insipidus (DI). CASE REPORT: A 19-year-old man was admitted to the intensive care unit following a traumatic brain injury. After admission, he underwent a craniotomy for the severe brain injury. However, he developed DI after the operation. Despite treatment with vasopressin, his urine output reached 5-6 L/day as a result of the DI, and his CrCl increased to 180-278 mL/min. We were required to administer 6-7 L of fluid a day to compensate for the high urinary fluid output. On day 55, MRSA pneumonia with sepsis was suspected and, consequently, LZD was administrated intravenously (600 mg every 12 h). He was treated with LZD for 14 days. The patient has since successfully recovered from MRSA pneumonia with concomitant bacteremia, and was transferred to the general ward on day 82. Blood LZD levels from days 60-68, which were measured after the patient's transfer to the general ward, showed that the trough levels were lower than the threshold level of detection. The blood 24-h area under the plasma LZD concentration-time curve (AUC)24/minimum inhibitory concentration (MIC) was 69.3. CONCLUSION: In spite of the low level of LZD AUC24/MIC caused by the high CrCl with DI, MRSA pneumonia with concomitant bacteremia was successfully treated with LZD.

Effect of CYP2C19 polymorphism on Voriconazole Cmin in children with hematological malignancies compli-cated with invasive fungal infection / 中华实用儿科临床杂志

Objective To explore the effect of CYP2C19 polymorphism on plasma minimum concentration of Voriconazole in children with hematological malignancies complicated with invasive fungal infection.Methods Twenty children with hematological malignancies complicated with invasive fungal infection were selected from the Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University were selected,and 5 mL venous blood for each was extracted.CYP2C19 genotypes of the whole blood of all patients were detected by using the method of polymerase chain-reaction restriction -fragment length polymorphism(PCR -RFLP).All the patients were treated with Voriconazole at the same time and by the same way.Plasma concentration of Voriconazole was measured by the method of fluo rescence polarization immunoassay.The impact of CYP2C19 genotypes on plasma minimum concentration of voriconazole was analyzed by using the rank sum test.Results Typing results showed that the incidence of iuhomozygous extensive me-tabolizers (EM)genotype (CYP2C19* 1 /*1 )was 30%(6 /20 cases);the incidence of mixed sub extensive metaboli-zers (IM)genotype (CYP2C19*1 /*2 or CYP2C19*1 /*3)was 45%(9/20 cases),among which ,CYP2C19*1 /*2 was in 4 cases,CYP2C1 9*1 /*3 was in 5 cases;and that of poor metabolizer (PM)genotype (CYP2C1 9*2 /*2 or CYP2C1 9*2 /*3 or CYP2C1 9*3 /*3)was 25%(5 /20 cases),among which,CYP2C1 9*2 /*2 was in 3 cases, CYP2C1 9*2 /*3 was in 1 case,and CYP2C1 9*3 /*3 was in 1 case.The serum trough concentration of Voriconazole in EMgroup,IMgroup and PMgroup was(2.30 ±0.50)mg/L,(3.23 ±0.71 )mg/L,(4.84 ±0.29)mg/L,respec-tively.There was a statistically significant relationship between CYP2C19 genotype and plasma minimum concentration of Voriconazole (F =26.99,P =0.032).Conclusions CYP2C19 polymorphism has a significant effect on the mini-mum concentration of Voriconazole in children with hematological malignancies complicated with invasive fungal infec-tion,which indicates that administration of Voriconazole for clinical treatment should be based on individual CYP2C19 genotype.