Relationship Between Serum Concentration of the Active Metabolite and the Efficacy and Safety of Oxcarbazepine / 医药导报

Objective To investigate the relationship between serum 10-hydroxycarbazepine (MHD, the main active metabolite of oxcarbazepine) concentration and oxcarbazepine efficacy and safety, and to optimize rational use of oxcarbazepine. Methods A total of 553 patients were enrolled in a self-controlled and open-label trial to assess the efficacy and safety of oxcarbazepine as monotherapy. The steady state serum MHD trough concentrations after dose were determined by SPE-HPLC. The relationship between MHD level and efficacy were evaluated by logistic regression model and receiver operating characteristic (ROC) curve. Results A total of 498 patients (90.1%) were effective and 404 patients (73.1%) were seizure free after oxcarbazepine monotherapy in this study. The clinical therapeutic range of steady state serum MHD trough concentrations observed in this study was 5 - 20 mg ? L-1 , and the corresponding 95% distribution interval of oxcarbazepine daily dose was 9. 0 -34.5 mg?kg-1?d-1 . Logistic regression results indicated a positive correlation of antiepileptic efficacy with serum MHD trough concentration within 0.9-30.0 mg?L-1 . The ROC area (95% confidence interval) of MHD trough concentration as the predictor for efficacy was 0.964 (0.938- 0.990), which showed accurate predictions. Most of patients whould have good antiepileptic efficacy while the steady-state serum MHD trough concentration remains above 8 mg?L-1 . Adverse effects were observed in 104 patients (18.8%) during oxcarbazepine dose escalation phase, and 23 patients (4.2%) during maintenance phase. There were no severe adverse effects associated with oxcarbazepine in this study. Patients with serum MHD concentrations >20 mg?L-1 were at greater risk of developing adverse effects. Conclusion Oxcarbazepine therapeutic efficacy and safety are associated with MHD trough level closely, so it is necessary to monitor MHD concentration.

Pharmaceutical Care of a Neonate with Septicemia Based on Population Pharmacokinetics / 医药导报

Objective To introduce a pharmaceutical care method based on population pharmacokinetics(PPK)and Bayesian method. Methods A predictive model for individualized vancomycin dosing was established based on the JPKD-Bayesian software and a PPK model according to the intervenous drop infusion of vancomycin in Chinese children.Individualized dosage regimen of vancomycin was devised for a neonate with septicemia caused by methicillin-resistant staphylococcus epidermidis (MRSE)using the predictive model. Results The model prediction error of the trough concentration of vancomycin was 0.8 mg·L-1 ,and the weighted residual(WRES)was 8.7%,and thus the predictive accuracy of the model was satisfactory.The MRSE infection in this patient was effectively controlled following individualized vancomycin dosage regimen according to the model predicted results,and there were no vancomycin-caused adverse reactions. Conclusion Application of advanced pharmaceutical knowledge such as PPK contributes to clinical medication,and it can promote the quality of pharmaceutical care provided by clinical pharmacists.

Relationship between SLCO1B1 521T ＞ C genovariation and severe toxicity during high-dose methotrexate chemotherapy / 中华实用儿科临床杂志

Objective To investigate the relationship between severe toxicity during high-dose methotrexate (HD-MTX) chemotherapy and 29 related factors including SLCO1B1 521T ＞ C genovariation,and to enhance drug safety.Methods Eighty-two children with acute lymphoblastic leukemia (ALL) received HD-MTX chemotherapy.The regimen was MTX 3-5 g/m2 continuous infusion for 24 hours.The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the patients' genotypes of SLCO1B1 T521C polymorphism,which was the coding gene of organic anion transporting polypeptide 1 B1 (OATP1 B1).Haematological,gastrointestinal and hepatic toxicities in 1-10 days after HD-MTX administration were observed and graded according to Common Terminology Criteria for Adverse Events (CTCAE,version 4.02).The patients were divided into two groups based on toxicity grades:case group (grades Ⅲ-Ⅴ) and normal group (grades 0-]]).The differences of 29 variates including biology features,biochemical indicators,SLCO1B1 T521 C polymorphism and etc.were compared between the two groups by univariate analysis,and the significant factors were found out.The final predictive model of severe HD-MTX-related toxicity was set up through Logistic regression analysis.Receiver operating characteristic (ROC) curve of predictor was drawn based on final model in order to evaluate its predictive ability.Results There were only 4 significant different variates between case group and normal group (P ＜ 0.05),including SLCO1B1 T521C polymorphism,serum MTX concentrations at 72 hours after starting MTX infusion (C72h),the ratios of 7-hydroxy-MTX (the metabolin of MTX) to MTX concentrations at 48 hours (k48 h),and frequency of k48 h ≤2.Based on a multivariate logistic regression analysis,only SLCO1B1 521T＞ C genovariation (odds ratio 18.489,95％ confidence interval 5.413-63.157)was the significant independent predictor for severe HD-MTX-related toxicity.The area under ROC (95％ confidence interval) of SLCO1B1 521T ＞ C genovariation as the predictor for severe HD-MTX-related toxicity was 0.776 (0.653-0.899),which had significant diagnositic value (P ＜ 0.05).Conclusions There is higher risk of severe HD-MTX-related toxicity while patients having SLCO1B1 521T ＞ C genovariation.Clinician should consider it and take some protective measures.

SLCO1B1c. 521T>C gene polymorphisms are associated with high-dose methotrexate pharmacokinetics and clinical outcome of pediatric acute lymphoblastic leukemia / 中华儿科杂志

<p><b>OBJECTIVE</b>To provide guidance for the high-dose methotrexate (HD-MTX) treatment of pediatric acute lymphoblastic leukemia (ALL), and to understand the impact of SLCO1B1c.521T>C (rs4149056) variant on methotrexate (MTX) pharmacokinetics and clinical outcome in children with ALL.</p><p><b>METHOD</b>Eighty-two children with ALL in Division of Hematology of Wuhan Children's Hospital from January 2008 to February 2013 were enrolled. All patients were genotyped for rs4149056 single nucleotide polymorphism (SNP) into wild-type group (TT genotype) and variant group (TC/CC genotype). According to the ALL-BFM 2000 protocol, all patients received intravenous infusion of MTX every ten days at 3 to 5 g/m(2). Leucovorin rescue was performed after 36 hours of the MTX administration and its dose was adjusted according to the MTX plasma concentration at 48 hours. The concentrations of MTX and its metabolite at 24, 48 and 72 h were determined by high performance liquid chromatography with solid phase extraction. Population pharmacokinetic parameters were estimated by the NLME software. The pharmacokinetics, toxicity and leucovorin rescue was compared. The relapse rate within 5 years and event-free survival were followed up.</p><p><b>RESULT</b>Eighty-two pediatric patients were classified into two groups: variant group including 20 TC genotype carriers and one CC genotype carrier, wild-type group included 61 patients with TT genotype. Compared with wild-type group, plasma concentration of MTX at 48 and 72 h increased significantly [48 h: (1.00±1.41) vs.(0.34±0.17) µmol/L, t=2.131, P=0.046; 72 h: (0.31±0.26) vs.(0.08±0.04) µmol/L; t=3.995, P=0.001]. Area under the concentration time curve (AUC48-∝) of MTX significantly increased in variant group [(23.18±19.91) vs.(5.66±2.01) h·µmol/L] (t=4.025, P=0.001). Time above the MTX safety threshold (TC>0.1 µmol/L) increased significantly in variant group [(95.3±22.0) vs.(67.1±7.5) h, t=5.880, P<0.001]. Rescue dosage of leucovorin in variant group was higher than that in wild-type group [(312.7±287.8) vs.(140.6±27.5) mg/m2, t=2.614, P=0.017]. The children carrying rs4149056 C allele suffered from a higher frequency of serious adverse effect [gastrointestinal toxicity: 33% (7/21) vs. 5% (3/61);hepatic toxicity: 24% (5/21) vs. 2% (1/61)]. The difference was statistically significant (χ2=9.275, 8.289, all P<0.05). Hospital stay of variant group was significantly longer than that of wild-type [(4.95±1.43) vs. (4.05±0.22) d, t=2.881, P=0.009]. The relapse rate within 5 years of variant group and wild-type group were 9% (2/21) and 13% (8/61), respectively. There were no significant differences in the event-free survival between the two groups (χ2=0.001, P=0.971).</p><p><b>CONCLUSION</b>The SLCO1B1 c.521T>C variant was an important determinant of MTX pharmacokinetics. An appropriate leucovorin dose raise in variant group was beneficial to reducing the serious toxicity and did not affect the long-term clinical outcome.</p>

Relationship Between Serum Concentration at 48 h and Pharmacokinetic Characteristics and Toxic Reactions at Terminal Elimination Phase After Starting High Dose Methotrexate Infusion / 医药导报

Objective To recheck the reliability of methotrexate ( MTX) serum concentration at 48 h ( C48 h ) in predicting the pharmacokinetic characteristics and toxic reactions at terminal elimination phase after high dose MTX infusion and to provide a reference for determination of rational rescue regimen in clinic practice. Methods In total,114 cases of children with acute lymphoblastic leukemia (ALL) received 176 courses of high dose MTX chemotherapy treatment. The regimen was continuous infusion of MTX[3 -5 g·( m2 ) -1 ] in 24 h. Plasma samples were treated with solid phase extraction and serum concentrations of MTX were determined by HPLC at 24,48 and 72 h (C24 h ,C48 h and C72 h ) after starting MTX infusion. All data were divided into C48 h≥1 μmol·L-1 group and C48 h<1 μmol·L-1 group. The pharmacokinetic parameters of the two groups at elimination phase were estimated by residual method and the toxic reactions after MTX infusion of two groups were compared by Ridit analysis. Results The C72 h and AUC48-∞ were significantly higher in C48 h ≥1 μmol · L-1 group than in C48 h <1 μmol·L-1 group (P<0. 01). The MTX toxicities to the blood,digestive and hepatic systems were significantly higher in C48 h≥1 μmol·L-1 group than in C48 h < 1 μmol · L-1 group ( P < 0. 05). Conclusion C48 h can predict the pharmacokinetic characteristics and toxic reactions at ther terminal elimination phase. Therefore,C48 h≥1 μmol·L-1 can be used as a marker of MTX elimination delay event to guide later rescue regimen.

Investigation of Irrational Infusion Prescriptions for Outpatients from 2005 to 2007 in Wuhan Children's Hospital / 中国药房

OBJECTIVE: To investigate the irrational use of the infused drugs in our out-patient clinic.METHODS: In this retrospective study,the infusion prescriptions in our outpatient clinic from 2005 to 2007 were randomly selected for a statistical analysis of the irrational ones based on our knowledge on clinical pharmacology and literature.RESULTS: The problems manifested by the total 81 172 prescriptions were unsuitable solvent,improper dosage regimen,irrational drug combination and repeated drug of medicines etc.CONCLUSION: The use of infused antibiotics in our out-patient clinic were rational on the whole,however,there were some problems which remain to be solved and improved.

Determination of Vancomycin in Human Serum by HPLC / 中国药房

OBJECTIVE: To establish an HPLC method for the determination of the concentration of vancomycin in human serum. METHODS: Serum samples were centrifuged after serum protein was precipitated by 20% metaphosphoric acid. The separation was performed on Hypersil C18 column with mobile phase consisted of acetonitrile-0.012 5 mol?L-1 potassium dihydrogen phosphate buffer (10 ∶ 90) at flow rate of 0.8 mL?min-1. The detection wavelength was set at 236 nm and column temperature was set at 25 ℃. RESULTS: The average relative recovery rate of vancomycin in low, medium and high concentrations (2.5,30.8,150.4 mg?L-1) were 99.8%, 101.1% and 98.9% respectively. The inter-day and intra-day RSD were less than 2.5%(n=5). The limit detection of vancomycin in serum was 2.0 mg?L-1. The linear range was within 2.0～170.0 mg?L-1(r=0.999 8). CONCLUSION: The method is simple, accurate, and rapid for the monitoring and phamacokinetic studies of vancomycin in human serum.

Analysis on the Irrational Use of Drugs of the Transfusion Prescriptions in the Out-patient Clinic of Children's Hospital / 中国药房

OBJECTIVE:To ensure children's medication safety and to promote rational drug use.METHODS:33001ou_ t-patient transfusion prescriptions of12days in2004in our hospital were randomly sampled,in which,the irrational pre?scriptions were classified and analyzed statistically based on clinical pharmacological knowledge and literatures.RESULT:Of the total prescriptions investigated,60.56%of which were about the combined use of drugs;1354(4.10%of the total)involved irrational drug use like repeat drug application,improper combination of drugs,and improper application.CONCLUSION:To reduce the incidence of adverse drug reactions,clinicians should be provided with timely feedbacks on medication information.