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ABSTRACT: Aim:Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects.Methods:This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-∞ were calculated. Tolerance assessments were conducted throughout the study.Results:ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed.Conclusion:ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.
Acta Pharmacologica Sinica 04/2013; · 1.95 Impact Factor
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Jing-Ying Jia,
Lu-Nan Zhang,
You-Li Lu,
Meng-Qi Zhang,
Gang-Yi Liu,
Yan-Mei Liu,
Chuan Lu,
Shui-Jun Li,
Yi Lu,
Rui-Wen Zhang, Chen Yu
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ABSTRACT: The illegal use of clenbuterol has been an increasingly serious issue in today's livestock products industry. It becomes an important project to develop a reliable approach to detect its content in food animals. A simple and sensitive LC-MS/MS method was developed to detect clenbuterol residue in hair, with the low limit of quantitation (LLOQ) about 0.5ng/g. Hogs fed with 340µg/day of clenbuterol for 2 weeks were found a high clenbuterol residue in their hair approximately at 1-2 months after withdrawal. There remained 3.31ng/g clenbuterol in hog hair approximately 5 months after the last administration, focused on the tip of the hair (mainly in hogs with dark hair). An extensive contamination was observed in twenty investigated market hogs whose dark hair obviously had a higher clenbuterol residue than the light ones (p=0.017, t test). Volunteers (60.3 percent) from Xuhui district (Shanghai) were found to have a detectable amount of clenbuterol in their hair (>0.5ng/g). In conclusion, hair residue detection is a reliable method to evaluate the clenbuterol contamination in animals and humans. Meat supply in the Xuhui district might have serious potential safety risks which should be further investigated and discussed to determine the safety range of clenbuterol residue.
Ecotoxicology and Environmental Safety 04/2013; · 2.29 Impact Factor
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Yan-Mei Liu,
Kanyin E Zhang,
Yun Liu,
Hai-Chen Zhang,
Yun-Xiao Song,
Hua-Hua Pu,
Chuan Lu,
Gang-Yi Liu,
Jing-Ying Jia,
Qing-Si Zheng,
Jian-Min Zhu, Chen Yu
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ABSTRACT: BACKGROUND: Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe(®), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China. OBJECTIVE: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 × 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography-isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, and subject interviews on adverse events (AEs). RESULTS: Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0-168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%). CONCLUSIONS: The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated.
Clinical Therapeutics 10/2012; · 2.32 Impact Factor
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ABSTRACT: Aim:Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers.Methods:This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring.Results:For the 80, 160, and 320 mg dose groups, the mean C(max) were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC(0-12) were 6.18, 16.95, and 40.65 mg·L(-1)·h, respectively. DAS was rapidly cleared, with a mean T(max) of 0.94-1.0 h and a t(1/2) of approximately 1.51-1.89 h. Approximately 10.1%-15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported.Conclusion:This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens.
Acta Pharmacologica Sinica 08/2012; 33(10):1332-6. · 1.95 Impact Factor
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ABSTRACT: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to determine total N-acetylcysteine in human plasma. Mass spectrometric detection was achieved in positive electrospray ionization and multiple reaction monitoring mode. The mass transition pairs of N-acetylcysteine and the isotope-labeled internal standard d3-N-acetylcysteine were 164 → 122 and 167 → 123, respectively. The method was linear over the range of 10-5000 ng/mL in human plasma. The adoption of trichloroacetic acid significantly enhanced the extraction recovery. The blank matrix was screened to minimize the influence of endogenous N-acetylcysteine. After being fully validated, the method was successfully applied to the pharmacokinetic and bioequivalent study of N-acetylcysteine after oral administration of 600 mg tablets to 24 healthy Chinese volunteers.
Biomedical Chromatography 04/2011; 25(4):427-31. · 1.97 Impact Factor
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ABSTRACT: To evaluate human liver reserve function (LRF) by a simple and efficient method for measuring serum concentrations of phenacetin and its metabolites.
Overall 20 patients with liver cirrhosis (Child-Pugh score ≥ 7, aged 48-79 years), 30 healthy young volunteers (aged 18-40 years), and 20 healthy elderly volunteers (aged 61-80 years) were enrolled. All participants received a single oral dose of 0.5 g phenacetin. Liquid chromatography tandem mass spectrometry was used to determine the serum concentrations of phenacetin and its metabolites, including acetaminophen, acetaminophen glucuronide and acetaminophen sulfate.
The serum concentration of phenacetin was significantly higher in cirrhotic patients than those in either of the healthy volunteer groups (P < 0.001). It was higher in healthy elderly volunteers than that in healthy young ones but there was no statistically significant difference (P > 0.05) between them. The serum concentrations of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate were significantly lower in cirrhotic patients than in the healthy controls (P < 0.001). The serum concentrations of these three metabolites in healthy elderly volunteers were lower than those in healthy younger volunteers but again, there was no statistical significant difference (P > 0.05). The serum concentration of acetaminophen in healthy male volunteers was significantly higher than that in the women (P < 0.05).
Monitoring cytochrome P450 1A2 (CYP450 1A2)-mediated phenacetin metabolism is a simple and efficient method for evaluating human LRF. This method would warrant further validation in a large cohort clinical study.
Journal of Digestive Diseases 12/2010; 11(6):358-63. · 1.59 Impact Factor
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Yan-Mei Liu,
Yun Liu,
Chuan Lu,
Jing-Ying Jia,
Gang-Yi Liu,
Li-Ping Weng,
Jia-Yan Wang,
Guo-Xiu Li,
Wei Wang,
Shui-Jun Li, Chen Yu
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ABSTRACT: Acetylcysteine may be used as a muco- lytic agent for the treatment of chronic bronchitis, chronic obstructive pulmonary disease, and other pulmonary diseases complicated by the production of viscous mucus. However, little is known of its pharmacokinetic properties when given orally in healthy volunteers, particularly in a Chinese Han population. This study was conducted to provide support for the marketing of a generic product in China.
The purpose of this study was to compare the pharmacokinetics and relative bioavailability of a generic test formulation and a branded reference formulation of acetylcysteine in fasting healthy Chinese male volunteers.
A single-dose, open-label, randomized-sequence, 2-period crossover design with a 7-day washout period between doses was used in this study. Healthy Chinese male nonsmokers aged 18 to 40 years with a body mass index (BMI) of 19 to 25 kg/m(2) were selected. Eligible volunteers were randomly assigned to receive acetylcysteine 600 mg PO as either the test formulation (3 tablets of 200 mg each) or reference formulation (1 tablet of 600 mg) under fasting conditions. A total of 15 serial blood samples were collected over a 24-hour interval, and total plasma acetylcysteine concentrations were analyzed by a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters (C(max), T(max), t(½) AUC(0-t), and AUC(0-∞) were calculated and analyzed statistically. The 2 formulations were considered bioequivalent if the 90% CIs of the log-transformed ratios (test/reference) of C(max) and AUC were within the predetermined bioequivalence ranges (70%-143% for C(max); 80%-125% for AUC), as established by the State Food and Drug Administration of China. Tolerability was determined by vital signs, clinical laboratory tests, 12-lead ECGs, physical examinations, and interviews with the subjects about adverse events (AEs).
A total of 24 healthy Chinese Han male volunteers were enrolled in and completed the study (mean [SD] age, 25.0 [2.4] years; height, 173.0 [5.6] cm; weight, 65.9 [6.4] kg; BMI, 22.0 [1.7] kg/m(2)). No formulation, period, or sequence effects were observed. The 90% CIs for the log-transformed C(max), AUC(0-t), and AUC(0-∞) were 89.7% to 103.8%, 86.7% to 101.7%, and 87.7% to 102.4%, respectively, which met the predetermined criteria for assuming bioequivalence. Two subjects (8.3%) experienced 2 mild AEs (increase in total bile acid and prolongation of the QT interval), which were not considered to be related to study drug administration.
This single-dose study of acetylcysteine 600 mg PO found that the 3 tablets of the generic test formulation and 1 tablet of the branded reference formulation met the regulatory criteria for assuming bioequivalence in these fasting healthy Chinese male volunteers. Both formulations were generally well tolerated.
Clinical Therapeutics 11/2010; 32(12):2097-105. · 2.32 Impact Factor
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ABSTRACT: A LC-MS/MS method was developed and validated for the determination of dehydroandrographolide succinate (DAS), a traditional Chinese medicine derivative used for the treatment of pneumonia, upper respiratory tract infection, and chronic bronchitis. Following protein precipitation, DAS was detected by ion transition at m/z 531.2/99.0 in multiple reaction monitoring mode with negative electrospray ionization-tandem mass spectrometry. The limit of detection was 0.5ng/mL, and the lower limit of quantification was 10ng/mL in human plasma. Good linearity was maintained over the range of 10-5000ng/mL, and the correlation coefficient was better than 0.99. The accuracy ranged from 95.3% to 113%, RSD from 0.928% to 6.47%, for the within- and between-run analysis at all QC levels. The recovery ranged from 85.5% to 93.4% and the matrix effect from 107% to 119%. No significant carryover and good stability were found during method validation. The developed method was successfully applied to the determination of DAS in human plasma in a pharmacokinetic study following intravenous infusion of potassium sodium DAS to nine healthy volunteers.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 08/2010; 878(24):2274-9. · 2.78 Impact Factor
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ABSTRACT: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a useful inflammatory marker of cardiovascular risk, yet there are few reports on the prognostic significance of Lp-PLA2 as a risk factor for acute coronary syndrome (ACS). It is necessary to evaluate the association of Lp-PLA2 with major adverse cardiac events (MACE) in patients with ACS and assess its incremental value for risk discrimination over established risk factors and biomarkers.
One hundred fifty-two patients with ACS and 142 patients without coronary artery disease (CAD) from Shanghai Xuhui District, PRC (aged < 80 years) were enrolled from February 2007 to March 2008 and were followed for a median of 6 months (range, 4-10 months). Plasma Lp-PLA2 activity was measured at baseline with liquid chromatography tandem mass spectrometry. Its clinical significance was evaluated with existing risk indicators.
Lp-PLA2 activity was higher in patients with ACS than in patients without CAD (22.36 +/- 1.23 mg/mL vs 19.74 +/- 3.85 mg/mL; P = 0.027). During the follow-up period, 5 cases of cardiovascular death, 8 cases of nonfatal myocardial infarction, and 11 cases of target vessel revascularization occurred. Elevated Lp-PLA2 was associated with an increased risk of MACE (hazard ratio, 1.52; 95% confidence interval, 1.09-2.37; P = 0.033). The Lp-PLA2 activity level in incidental cases was higher than in nonincidental cases (P = 0.04).
In this community-based cohort of patients with ACS, Lp-PLA2 was strongly and independently associated with major adverse cardiac events and contributed incrementally to risk discrimination.
Postgraduate Medicine 07/2010; 122(4):200-5. · 1.78 Impact Factor
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Yan-Mei Liu,
Hua-Hua Pu,
Gang-Yi Liu,
Jing-Ying Jia,
Li-Ping Weng,
Rong-Jing Xu,
Guo-Xiu Li,
Wei Wang,
Meng-Qi Zhang,
Chuan Lu, Chen Yu
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ABSTRACT: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China.
The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers.
This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity)), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the log transformed ratios of AUC and C(max) of atorvastatin were within the predetermined bioequivalence range (0.80-1.25 for AUC and 0.70-1.43 for C(max)) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs).
A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m(2)) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m(2)) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C(max), AUC(0-t), and AUC(0-infinity)) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity)) of both atorvastatin (0.73-0.91, 0.92-1.02, and 0.91-1.01, respectively) and ortho-hydroxy-atorvastatin (0.83-1.05, 0.92-1.02, and 0.93-1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug.
This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.
Clinical Therapeutics 07/2010; 32(7):1396-407. · 2.32 Impact Factor
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ABSTRACT: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population.
To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers.
A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including C(max), AUC(0-36), and AUC(0-infinity), were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of C(max) was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China.
Twenty-seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20-29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m(2) [range, 20.0-25.0 kg/m(2)]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of C(max), AUC(0-36), and AUCAUC(0-infinity) were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of C(max), AUC(0-36), and AUCAUC(0-infinity) were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both C(max) and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174.
In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated.
Clinical Therapeutics 07/2010; 32(7):1387-95. · 2.32 Impact Factor
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Meng-Qi Zhang,
Jing-Ying Jia,
Chuan Lu,
Gang-Yi Liu,
Cheng-Yin Yu,
Yu-Zhou Gui,
Yun Liu,
Yan-Mei Liu,
Wei Wang,
Shui-Jun Li, Chen Yu
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ABSTRACT: A simple, reliable and sensitive liquid chromatography-isotope dilution mass spectrometry (LC-ID/MS) was developed and validated for quantification of olanzapine in human plasma. Plasma samples (50 microL) were extracted with tert-butyl methyl ether and isotope-labeled internal standard (olanzapine-D3) was used. The chromatographic separation was performed on XBridge Shield RP 18 (100 mm x 2.1 mm, 3.5 microm, Waters). An isocratic program was used at a flow rate of 0.4 m x min(-1) with mobile phase consisting of acetonitrile and ammonium buffer (pH 8). The protonated ions of analytes were detected in positive ionization by multiple reactions monitoring (MRM) mode. The plasma method, with a lower limit of quantification (LLOQ) of 0.1 ng x mL(-1), demonstrated good linearity over a range of 0.1 - 30 ng x mL(-1) of olanzapine. Specificity, linearity, accuracy, precision, recovery, matrix effect and stability were evaluated during method validation. The validated method was successfully applied to analyzing human plasma samples in bioavailability study.
Yao xue xue bao = Acta pharmaceutica Sinica 06/2010; 45(6):767-71.
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ABSTRACT: Glimepiride is an oral sulfonylurea antihyperglycemic agent indicated for the treatment of type 2 diabetes mellitus. Although there are reports in the literature regarding the pharmacokinetic (PK) characteristics of glimepiride, few data of PK parameters are available in a Chinese population; none are available regarding a recently developed generic formulation.
To meet the requirements for marketing a new generic product in China, the study was designed to compare the PK properties and bioequivalence of 2-mg tablets of glimepiride: the newly developed generic formulation (test) and a branded formulation (reference) in healthy Chinese male volunteers.
A single-dose, randomized-sequence, open-label, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected before study drug administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours after study drug administration. Concentrations in plasma of the parent glimepiride and its M1 metabolite were analyzed with a LC-MS/MS method. The formulations were considered bioequivalent if the 90% CIs for the log-transformed values were within the predetermined equivalence range (70%-143% for C(max) and 80%-125% for AUC), according to the guidelines of the State Food and Drug Administration (SFDA) of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, ECGs, and laboratory tests at baseline and completion of the study.
A total of 24 healthy Chinese male volunteers were enrolled and completed the study; however, only the data from 23 subjects were included (mean [SD] age, 23.6 [2.2] years [range, 18.6-26.9 years]; weight, 64.0 [8.4] kg [range, 52.0-82.0 kg]; and height, 172.3 [5.6] cm [range, 164.0-185.0 cm) in the PK and tolerability assessments due to a violation of the protocol. For parent glimepiride, the 90% CIs for the ratios of Cmax, AUC(0-t), and AUC(0-infinity) were 93.83% to 115.19%, 90.82% to 102.29%, and 92.22% to 103.78%, respectively. For the M1 metabolite, the 90% CIs were 91.71% to 110.79%, 91.33% to 101.76%, and 89.99% to 99.85%. Both met the predetermined criteria for bioequivalence. Four AEs (17.4%) were reported: hypertriglyceridemia (2 subjects [8.7%]; 1 each receiving the test and reference formulations); increase of red blood cells in urine (1 subject [4.3%] receiving the reference formulation); and hypoglycemia (1 subject [4.3%] receiving the test formulation). The incidence of hypoglycemia was the only AE considered probably related to study drug administration; all others were considered probably not related. All AEs were transient and considered by the investigators to be mild.
In this small study in fasted healthy Chinese male volunteers, a single 2-mg dose of the test formulation met the regulatory criteria to assume bioequivalence to the reference formulation based on the rate and extent of absorption. Both formulations were well tolerated. SFDA Registration No.: 2009L01033.
Clinical Therapeutics 05/2010; 32(5):986-95. · 2.32 Impact Factor
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Intelligent Virtual Agents, 10th International Conference, IVA 2010, Philadelphia, PA, USA, September 20-22, 2010. Proceedings; 01/2010
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ABSTRACT: Melamine was found to be the etiological factor for the urinary stones epidemic in infants and young children in China in 2008. Urine level of melamine and its analog cyanuric acid may be useful markers for the evaluation of toxic effects. Liquid chromatography tandem mass spectrometry methods for the individual determination of melamine and cyanuric acid in human urine are described. Using isotope labeled internal standards during liquid-liquid extraction, the method was fully validated by verifying specificity, linearity, LLOQ, intra- and inter-assay precision and accuracy, matrix effect, recovery and stability. Calibration curves with good linearity (r=0.9999) over the concentration range from 10 to 5000 ng/ml, intra-assay precision <10% and inter-assay precision <15%, accuracy between 93.0 and 111.6% were obtained with multiple reaction monitoring mode for melamine and cyanuric acid in human urine. The methods were successfully applied to the analysis of urine samples collected from 86 infants and 110 adults.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 01/2010; 878(9-10):758-62. · 2.78 Impact Factor
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ABSTRACT: Fentanyl is a potent analgesic drug in relieving chronic pain in patients. In this report, we present a simple, reliable and sensitive LC-ID/MS method for the quantification of fentanyl in human plasma. LC-ID/MS analysis was carried out on a triple quadrupole mass spectrometer operated in positive electrospray ionization multiple-reaction-monitoring using the transitions m/z 337.6 --> 187.9 for fentanyl and m/z 342.6 --> 187.9 for the internal standard (D5-fentanyl). The calibration curve covered the range 0.02-10 ng/mL. The intra- and inter-batch precision were less than 6.739 and 3.126% for fentanyl and IS, with accuracy from 94.16 to 102.0%. The lower limit of quantification was identifiable and reproducible at 0.02 ng/mL. The validated method offered increased sensitivity and wide linear concentration range. This method was successfully adopted for the evaluation of bioequivalence of two fentanyl transdermal preparations after single dose administration to 20 Chinese pain-patients.
Biomedical Chromatography 11/2009; 24(7):711-6. · 1.97 Impact Factor
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ABSTRACT: A simple, reliable and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) protocol was developed and validated for quantification of bisoprolol in human plasma. The sample was pretreated with a simple procedure of protein precipitation and an isotope-labeled d5-bisoprolol was used as internal standard. The chromatographic separation was performed on a Capcell Pak C(18) MG III column (100 mm x 2.0 mm, 5 microm). The protonated ion of the analyte was detected in positive ionization by multiple reaction monitoring mode. The mass transition pairs of m/z 326.3 --> 116.3 and m/z 331.3 --> 121.3 were used to detect bisoprolol and the internal standard, respectively. Linearity, accuracy, precision, recovery, matrix effect, dilution test and stability were evaluated during method validation over the range of 0.5-100 ng/mL. The validated method was successfully applied to analyze human plasma samples in a bisoprolol bioavailability study.
Biomedical Chromatography 10/2009; 24(6):574-80. · 1.97 Impact Factor
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ABSTRACT: Here we develop a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the determination of digoxin in serum.
The serum samples were extracted with methyl tert-butyl ether using an isotope-labeled digoxin-d3 as internal standard. The analyte was separated on a reverse phase Capcell C18 column and detected in positive electrospray ionization multiple reaction monitoring mass spectrometry.
The chromatographic analysis was carried out within 3 min, but the complete analysis took longer because of the liquid-liquid extraction. The lower limit of quantification was 0.1 ng/mL for digoxin. The intra- and inter-batch precisions were less than 12%, and the bias ranged from -9.1% to 10.7%. The external quality assessment (EQA) results obtained with the LC-MS/MS method were comparable to target values. Subsequently, this method has been applied to the therapeutic monitoring of digoxin in a clinical setting.
In this study, we have developed a rapid and reliable LC-MS/MS method for the therapeutic monitoring of digoxin in human serum.
Clinical biochemistry 10/2009; 43(3):307-13. · 2.02 Impact Factor
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ABSTRACT: A rapid and sensitive liquid chromatography-isotope dilution tandem mass spectrometry method was developed and validated for quantification of itraconazole (ITZ) and its active metabolite hydroxyitraconazole (OH-ITZ ) in human plasma. The plasma samples were extracted with tert-butyl methyl ether and two isotope-labeled internal standards (D5-itraconazole and D5-hydroxyitraconazole) were used. The chromatographic separation was performed on a Capcell Pak C(18) MG III (100 x 2 mm, 5 microm, Shiseido). The protonated ions of analytes were detected in positive ionization in multiple reaction monitoring mode. The plasma method has a lower limit of quantification of 1 ng/mL with a linearity range of 1-500 ng/mL for ITZ and OH-ITZ using 100 microL of plasma. The recoveries of the method were found to be 69.47-71.98% for ITZ and 75.68-82.52% for OH-ITZ. The intra- and inter-batch precision was less than 11% for all quality control samples at concentrations of 2.5, 200 and 400 ng/mL. These results indicate that the method was efficient with a short run time (4.5 min) and acceptable accuracy, precision and sensitivity.The validated method was successfully applied to analysis of human plasma samples in pharmacokinetics study.
Biomedical Chromatography 10/2009; 24(6):648-54. · 1.97 Impact Factor
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ABSTRACT: A sensitive and specific LC-CMS/MS method was developed for the quantification of changrolin, an anti-arrhythmic drug, in rat plasma using tiapride as internal standard. Liquid-liquid extraction was employed for sample preparation and analyzed using a multiple reaction monitoring mode with electrospray positive ionization source. The calibration curve for changrolin was linear over the range 5-1600 ng/mL with coefficients of correlation >0.99. The intra- and inter-batch precision was less than 8.6%, and accuracy ranged from 94.6% to 104.5%. This validated LC-MS/MS method was successfully applied to a bioavailability study of oral and intravenous administration of changrolin with 20mg/kg dosage in SD rats.
Journal of pharmaceutical and biomedical analysis 09/2009; 50(2):189-93. · 2.45 Impact Factor
