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sRecent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood–pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

In order to study the application of Internet of things energy system in complex fault risk dynamic assessment of transmission line. Firstly, the concept of power grid dynamic risk assessment is introduced, and the process of power grid dynamic risk assessment system based on Internet of things is designed. Then, it puts forward how to use the ubiquitous Internet of things multisource data to solve the key problems such as dynamic perception of fault probability, dynamic selection of fault set, dynamic generation of post fault state, and dynamic risk assessment of operation process. Finally, taking the maximum operation mode of a provincial power grid in summer 2013 as an example, this paper selects key 500 kV transmission lines for risk assessment, and the actual power grid example shows that. The power grid comprehensive risk assessment system considering the fault characteristics of transmission lines can effectively predict the fault probability of transmission lines; distinguish the two risks of high loss, low probability, and low loss and high probability; and provide guidance for operators. It is practical and effective.

In order to study the dynamic assessment system of composite fault risk of transmission line based on blockchain energy and in order to study the transmission line compound fault risk dynamic assessment system based on blockchain, firstly, according to the coupling relationship between power grid and natural disasters, the information resources such as data collected by power grid intelligent devices and natural meteorology are excavated, and the overall architecture of power grid disaster early warning and decision-making system supported by blockchain is built. Then, from the perspective of risk, combined with analytic hierarchy process, an index system for reasonable evaluation of distribution network fault benchmark risk is established. Quantitative assessment and risk classification shall be carried out for the failure probability, failure impact consequence, and comprehensive failure risk, so as to facilitate the adoption of risk response measures. Finally, taking several 220 kV lines in the northwest and central part of a city as examples, the icing prediction analysis verifies the feasibility and effectiveness of the proposed power grid disaster early warning decision system based on blockchain to predict the icing thickness. The experimental results show that taking the icing disaster as an example, the MPC method is used to modify the icing thickness prediction model, improve the accuracy of the icing prediction model, and verify the feasibility and effectiveness of the prediction and early warning system based on blockchain.

A novel and selective liquid chromatographic-mass spectrometric method (LC-MS/MS) has been established and validated for simultaneous determination of subutinib and active metabolite in human urine. Urine samples were extracted by liquid-liquid extraction with ethyl acetate and separated on a Wondasil C18 (150 × 2.1 mm, 3.5 µm), with methanol-0.2% formic acid solution (73:27, v/v) as mobile phase at flow rate of 0.2 mL/min. The linear range was 0.5000-200.0 ng/mL for subutinib and active metabolite, with a lower limit of quantitation of 0.5000 ng/mL. Intra- and inter-run precisions were all

Lapatinib, a tyrosine kinase inhibitor of HER2/EGFR, can inhibit the proliferation of HER2-positive breast cancer cells. Additionally, the combination of lapatinib and chemotherapy can markedly prolong patient survival time. However, the clinical therapeutic effect of lapatinib is severely limited by drug resistance. We previously found that brief treatment with lapatinib induced both apoptosis and autophagy in HER2-positive breast cancer cells. Additionally, the apoptosis induced by lapatinib was dependent on autophagy. In our current study, however, we used extended treatment of HER2-positive breast cancer cells with lapatinib to confirm the presence of protective autophagy in the previously established lapatinib-resistant cells. Specifically, we found that inhibition of autophagy could reduce the proliferation, DNA synthesis, and colony-forming capacity of resistant cells. Thus, autophagy is a potential novel therapeutic target for reversing lapatinib resistance of HER2-positive breast cancer cells. Our data provide clear, novel evidence of both anti-apoptotic and pro-apoptotic functions of autophagy in breast cancer during lapatinib treatment.

The aim of this study is to investigate a food effect on the single-dose pharmacokinetics and tolerability of subutinib maleate capsules in healthy Chinese volunteers. The author evaluated the effect of being under a fasting or fed state at the time of drug intake on the single-dose of subutinib maleate capsules in a randomized, balanced, single-dose, 2-treatment (fasting and fed), 2-period design with a 3-week washout period. The end points were the maximum plasma drug concentration (Cmax) and areas under the plasma-concentration curve (AUC) for 336 h exposure (AUC0-336) and total exposure (AUC0-∞). All volunteers completed the whole study without side effects being observed. For subutinib, Cmax were 6.13 and 5.04 ng·mL(-1), and AUC0-336 were 278.4 and 304.5 h·ng·mL(-1) in the fasting and the fed state, respectively. For active metabolite, Cmax were 0.90 and 0.61 ng·mL(-1), and AUC0-336 were 65.5 and 56.4 h·ng·mL(-1) in the fasting and the fed state, respectively. The authors showed that food intake was associated with a slight increase in AUC values but decrease in Cmax of subutinib, and it was associated with a decrease both in AUC and Cmax of active metabolite.

Background and Objective: A new combination contraceptive tablet containing 0.02 mg ethinyl estradiol (EE) and 0.10 mg levonorgestrel (LNG) with potential advantages has been developed in China. This study was aimed to describe the pharmacokinetic characteristics of this new combination contraceptive tablet in female Chinese volunteers. Methods: This study was designed as phase I, open-label, and one-sequence clinical trial. 12 healthy nonpregnant female Chinese volunteers received a single dose (1 tablet) and multiple dose (1 tablet per day) administration for 21 consecutive days under fasting condition. Blood samples were analyzed with 2 validated LC-MS/MS methods for EE and LNG, respectively. Results and conclusion: After the single dose administration, the C max of EE and LNG were 44.76±18.64 pg/mL and 2.256±1.008 ng/mL, respectively. The steady-state condition of EE was achieved on the 6 th day after the beginning of the multiple dose administration, while the steady-state condition of LNG was achieved on the 21 st day. For EE, the mean MRT 0–72 and t 1/2 increased by 40.2 and 30.6%, meanwhile the mean Cl/F and Vd/F decreased by 18.5 and 29.1%, respectively from Day 1 to Day 24. For LNG, the mean MRT 0–72 increased by 27.1%, while the mean Cl/F and Vd/F decreased by 62.4 and 86.3%, respectively from Day 1 to Day 24. The t 1/2 remained unchanged for LNG. The exposure of LNG significantly increased with repeated dosing, but that of EE just slightly increased.

Objective The objective of this study was to evaluate the pharmacokinetic parameters of triflusal and its major active metabolite, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), following a single oral dose of 900 mg in healthy subjects under fed and fasting conditions. Methods The study participants (n=12) were randomized to receive one 900 mg triflusal capsule in a fasting condition (no food for 12 hours) or a fed condition (after a high-fat meal); after a 2-week washout period, participants received the same dose of triflusal capsule under the converse condition. Pharmacokinetic parameters were calculated using WinNonlin 6.2 software. Safety was evaluated through assessment of adverse events, standard laboratory evaluations, vital signs, and 12-lead electrocardiography. Results The mean Cmax of triflusal and HTB were 13.96, 110.2 ug/mL for the fasting state and 9.546, 97.15 ug/mL for the fed state, respectively. The AUC0-144 of triflusal and HTB were 19.66, 5,572 hxμg/mL for the fasting state and 22.20, 5,038 hxμg/mL for the fed state, the AUC0-∞ of triflusal and HTB were 19.79, 6,333 hxμg/mL for the fasting state and 22.44, 5,632 hxμg/mL for the fed state, respectively. The results showed that Cmax and AUCs for triflusal were outside the bioequivalency (BE) interval after food intake, but there was no statistically significant change for HTB. Conclusion High-fat food intake may affect the pharmacokinetics of triflusal capsule in healthy subjects.

Diabetes is a major health problem worldwide, and metformin, a traditional oral anti-hyperglycemic drug, is now believed to be the most widely prescribed antidiabetic drug. Metformin acts primarily by inhibiting hepatic glucose production and improving insulin sensitivity. Metformin is absorbed predominately by the small intestine and excreted in an unaltered form in the urine. The pharmacokinetics of metformin is primarily determined by membrane transporters, including the plasma membrane monoamine transporter (PMAT), the organic cation transporters (OCTs), the multidrug and toxin extrusion (MATE) transporters, and the critical protein kinase AMPactivated protein kinase (AMPK). PMAT may play a role in the uptake of metformin from the gastrointestinal tract, while OCTs mediate the intestinal absorption, hepatic uptake, and renal excretion of metformin. MATEs are believed to contribute to the hepatic and renal excretion of the drug. The pharmacologic effects of metformin are primarily exerted in the liver, at least partly via the activation of AMPK and the subsequent inhibition of gluconeogenesis. A considerable amount of pharmacogenetic research has demonstrated that genetic variation is one of the major factors affecting metformin response. Moreover, it has become increasingly clear that membrane transporters are important determinants of the pharmacokinetics of metformin. In this review, we will discuss the genetic variants of major transporters that purportedly determine the pharmacokinetics of metformin in terms of drug bioavailability, distribution, and excretion, such as PMAT, OCTs, and MATEs. Understanding how genetic variation affects metformin response will help promote more effective use of the drug for the treatment of type 2 diabetes (T2D).

The aim of this study is to investigate a food effect on the single-dose pharmacokinetics and tolerability of clinofibrate tablets in 12 Chinese healthy volunteers. The authors evaluated the effect of being under a fasting or fed state at the time of drug intake on the single-dose of clinofibrate 400 mg tablets in a randomized, balanced, single-dose, two-treatment (fed and fasting), two-period, two-sequence study design with a 7-day washout period. The end points were the maximum plasma drug concentration (Cmax) and areas under the plasma-concentration curve (AUC) for 72 hours exposure (AUC0-72) and total exposure (AUC0-∞). All participants completed the whole study without side effects being observed. The Cmax mean of clinofibrate glucuronides and parent clinofibrate were 21.91, 17.85 μ/ml for the fasting state and 13.14, 11.25 μ/ml for the fed state, respectively. The AUC0-72 and AUC0-∞ of clinofibrate glucuronides and parent clinofibrate were 381.60, 307.07 μ/ ml and 404.55, 342.24 μ/ml for the fasting state and 379.02, 321.14 μ/ml and 432.24, 351.80 μ/ml for the fed state. The authors showed that food intake was associated with a significant decrease in Cmax, but no significant change in AUC values.

The present study was conducted to describe the pharmacokinetic profile of immediate-release compound omeprazole capsule and compare it with the enteric-coated formulation under fasting and fed condition. This study was designed to phase I, open-label, randomized, 3-part clinical trial. 12 subjects in part one received single doses (20 mg and 40 mg) and repeated doses (20 mg). Different 30 subjects in part 2 (fasting condition) and part 3 (fed condition) received either compound omeprazole capsule (40 mg) or delayed-release omeprazole (40 mg) separated by 7 days. Compound omeprazole capsule showed dose non-proportionality in the range from 20 mg to 40 mg. The AUC0–t of 20 mg omeprazole is 78% higher after repeated doses. The C max was higher and T max was lower for compound omeprazole capsule than delayed-release omeprazole. 90% CIs for AUC0–t of the 2 periods (test/reference) under fasting and fed conditions were 106.3% (102.2%~109.2%) and 104.1% (93.4%~109.6%), respectively. Presence of food reduced the rate (C max) and extent (AUC0–t) of systemic exposure of the test and reference formulations from 1 462 to 777 ng · mL−1, 1 055 to 602 ng · mL−1, 2 597 to 1 852 ng · h · mL−1 and 2 454 to 1 873 ng · h · mL−1, respectively. Exposed dose of omeprazole in subjects with compound omeprazole capsule was time- and dose-dependent. Compared with delayed-release omeprazole, compound omeprazole capsule had rapid but similar degree of absorption of omeprazole.

In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty-four healthy men were randomized to 4 treatments according to a crossover design with a 14-day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32-1.45) for the area under the concentration-time curve (AUC) for LEX and 1.27 (1.18-1.36) for the maximum concentration of drug in serum (C(max)) for LEX followed by AML versus alone. In contrast, no significant differences were found in the pharmacokinetic parameters of CXM between treatments (P < .05). They authors conclude that AML possesses an enhancement effect in β-lactam antibiotic bioavailability (in this case, LEX), and this interaction may be specific to the peptidomimetic β-lactam antibiotics.

Few researches were conducted on the circadian variation of β-lactam antibiotics in humans. The aim of the present study was to determine whether circadian variation of cefalexin pharmacokinetics exists in postprandial or fasting male volunteers. Cefalexin was given orally to subjects under postprandial conditions or after an 8-h fast, at 08:00 or 20:00 h. In experiment 1, after the oral dose under postprandial conditions, time-dependent changes in cephalexin pharmacokinetics were significant. The elimination half-life (t 1/2) was prolonged obviously and thepeak serum concentration (C max) was higher after the 20:00 h compared to the 08:00 h administration. However, in experiment 2, no significant differences were found in the main pharmacokinetic parameters of cephalexin administered at two occasions after fasting. It is concluded that in this study, time of administration may affect the pharmacokinetics of cephalexin under the postprandial condition, and fasting may suppress the diurnal variations in ce...

Background Febuxostat is a novel non-purine selective inhibitor of xanthine oxidase developed for the management of hyperuricemia in patients with gout. Objective To investigate the pharmacokinetics and also evaluate the effects of gender and food on the pharmacokinetics of febuxostat in healthy Chinese volunteers. Methods A phase I, 3-period study was performed in healthy Chinese male and female subjects. Subjects either received single 40 mg, multiple 40 mg and single 80 mg doses of febuxostat under fasted conditions, or received single 80 mg doses under fed condition. Plasma concentrations of febuxostat were collected and determined at 14 time points over 48 h. Results After 40 mg and 80 mg single dose administration of febuxostat, the C max were 2.308±0.812 and 4.559±1.246 μg/mL, the T max were 1.6±0.6 and 2.1±1.0 h, the t 1/2 were 6.8±1.7 and 6.7±1.9 h, and the AUC0-∞ were 7.704±1.723 and 16.34±3.87 μg∙h/mL, respectively. In the multiple-dose study at 40 mg dose for 6 consecutive days, the mean (SD) steady-state pharmacokinetic parameters on day 8 were similar to those following a single dose of febuxostat on day 1. In addition, food caused a decrease of 33% for C max and a delay of 0.3 h for T max. Gender had no significant effect on the pharmacokinetics of febuxostat. Febuxostat was well tolerated over the investigated dose range. Conclusion Compared with the previous study, the pharmacokinetics of febuxostat appeared to be different between Chinese and other races.

Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new effective taxane with greater anticancer activity and less toxicity than docetaxel. Pharmacokinetic studies in animal models are the important components in clinical development of this agent. In this study, a rapid and sensitive analytical method based on high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed for the determination of felotaxel in tumor-bearing mice plasma, urine, feces and tissues (brain, heart, liver, lung and kidney and tumor). For all matrices, sample preparation involved liquid–liquid extraction with ethyl acetate. Calibration curves (1/x2 weighted) offered satisfactory linearity (r2 ≥ 0.995) within the test range. The lower limit of quantitation (LLOQ) for all matrices was 10 ng/ml except that for mouse plasma and brain LLOQ was 1 ng/ml. The accuracy and precision ranged from 86.1 to 107.2% and 1.1 to 9.2%, respectively. Recoveries (73.9–96.1%) and matrix effects (76.4–97.2%) were satisfactory in all the biological matrices examined. Stability studies (85.1–101.5%) showed that felotaxel was stable both during the assay procedure and long-term storage. The assay was successfully applied to plasma pharmacokinetics, tissue distribution and excretion study of mice. The pharmacokinetic parameters, such as half-life, mean residence time, maximum concentration were determined. The preclinical data are useful for the design of clinical trials of felotaxel.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Zinc supplementation is an important intervention against mortality from infectious disease. • Many patients using zinc supplementation will also be prescribed antimicrobials at some time. • Recently, an inhibitory effect of zinc on the absorption of β-lactam antibiotics has been demonstrated in animal studies, but there has been no clinical assessment of this drug–nutrient interaction. WHAT THIS STUDY ADDS • Zinc sulfate dosing significantly impaired the bioavailability and decreased T > MIC of cephalexin in healthy volunteers, which might lead to a clinical failure. • The dosing recommendation is that zinc sulfate can be safely administered 3 h after a cephalexin dose. AIMS To investigate the effect of zinc sulfate on pharmacokinetics of cephalexin when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction in healthy volunteers. METHODS In this study, all subjects (n= 12) were randomized to receive the following four treatments, separated by a wash-out period of 7 days: cephalexin 500 mg alone, concomitantly with zinc 250 mg, 3 h after zinc 250 mg or 3 h before zinc 250 mg. RESULTS All subjects completed the study safely. Zinc supplements administered concurrently with cephalexin significantly decreased the peak serum concentration (Cmax), area under the plasma concentration–time curve from zero to infinity (AUC0–∞) and the time for which the plasma concentration of the drug remained above the minimal inhibitory concentration of the pathogenic organism (T > MIC) of cephalexin [mean percentage decrease (95% confidence intervals) of 31.05% (22.09–40.01%), 27.40% (18.33–36.47%) and 22.33% (12.51–32.16%), respectively; P MIC of the drug compared with administration of cephalexin alone [mean percentage decrease (95% confidence intervals) of 11.48% (3.40–19.55%), 18.12% (9.63–26.60%) and 23.75% (14.30–33.20%), respectively; P 0.05). CONCLUSIONS The significant interaction between zinc and cephalexin might affect the clinical outcome of cephalexin therapy. The dosing recommendation is that zinc sulfate can be safely administered 3 h after a cephalexin dose.

A liquid chromatography/electrospray ionization mass spectrometry (LC/ESIMS) method for the determination of 4-(3-ethoxy-2-hydroxypropoxy) acrylanilide (M-1), the active metabolite of suplatast tosilate, in human plasma was established. Plasma samples were extracted with diethyl ether, separated on a C18 column with a mobile phase of acetonitrile–10 mm ammonium acetate solution containing 0.1% formic acid (28:72, v/v) and detected by ESIMS. The method was linear over the concentration range 0.15–60.0 ng/mL. The lowest limit of quantification was 0.15 ng/mL. The intra- and inter-run relative standard deviations obtained from three validation runs were all less than 8.6%, and the intra- and inter-run relative errors were all less than 3.1%. The method was successfully applied for the evaluation of pharmacokinetic profiles of M-1 in healthy volunteers. Copyright © 2007 John Wiley & Sons, Ltd.

Background The flowers of Gentiana macrophylla have been usually applied to cure the joint inflammation and rheumatoid arthritis in Traditional Chinese Medicine. Hypothesis/purpose This work aimed to investigate the anti-rheumatoid arthritic effect and possible mechanism of iridoid glycosides from G. macrophylla (GMI) using an animal model of collagen-induced rheumatoid arthritis (CIA) in rats. Study design All rats were randomly divided into five groups: normal control, CIA, dexamethasone, 15 mg/kg and 30 mg/kg GMI. Methods CIA was induced (day 0) in male Sprague-Dawley rats by intradermal injection of complete Bovine CII at the base of the tail. Dexamethasone was chosen as the positive drug. The administration of different drugs started from day 1 and continued for 28 days. Paw swelling, arthritis score and histopathological changes were examined to assess the severity of arthritis. In addition, the serum levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions in joint synovial tissues were detected. Results GMI reduced paw edema, arthritis scores and the index of spleen and thymus from day 7 to 21 after CIA compared with those in the CIA group. Our data also demonstrated that GMI inhibited pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, regulated the expression of iNOS and COX-2 compared with those in the CIA group. We also obtained four major components from GMI, identified as loganic acid, swertamarin, gentiopicroside and sweroside, and the contents of them were also calculated respectively. Conclusion Taken together, our results shed light on the therapeutic efficacy of GMI in rats rheumatoid arthritis model by reducing the levels of IL-1β, IL-6 and TNF-α in serum as well as down-regulating the levels of iNOS and COX-2. Therefore, GMI may be an effective therapy for the treatment of rheumatoid arthritis.

A highly sensitive and rapid liquid chromatography-tandem mass spectrometry method was developed for the determination of clinofibrate in human urine. The analyte and IS were extracted through a simple protein precipitation by the mixture of acetonitrile and 1 mol/L hydrochloric acid (95:5, v/v) and separated on an Inspire C18 (150 mm x 4.6 mm I.D., 5 μm particle size) column using isocratic elution with methanol and water containing 0.1% formic acid and 10 mM ammonium acetate (90:10, v/v). Mass spectrometric detection was performed in electrospray positive ionization MRM mode. The mass transition was m/z 486.3--175.0 for clinofibrate and m/z 361.1--233.1 for IS, respectively. The flow rate was 0.6 mL/min and the column oven temperature was set at 35 °C. The total run time was 6.5 min. Good linear relationships were obtained for all analytes over the concentrations ranging of 0.1002-10.02 μg/mL (r2 = 0.9991) and the limit of quantification was 0.1002 μg/mL. The extraction recovery was larger than 87.4% and intra- and inter-batch precision and accuracy with RSD were all less than 6.5%. The total amount of unchanged clinofibrate excreted in urine was less than 0.34%. This method was successfully applied to the pharmacokinetic study of clinofibrate in human urine.

A selective liquid chromatographic-mass spectrometric method (LC-MS/MS) has been established and validated for simultaneous determination of subutinib and its active metabolite in human plasma. Plasma samples were extracted by liquid-liquid extraction with ethyl acetate and separated on a Wondasil C18 (150mm×2.1mm, 3.5μm), with methanol-0.2% formic acid solution (73:27, v/v) as mobile phase at flow rate of 0.2ml/min. The linear range was 0.25-100ng/mL for subutinib and 0.125-50.0ng/mL for its active metabolite, with lower limit of quantitation of 0.25ng/mL and 0.125ng/mL, respectively. Intra- and inter-run precision were within 7.0 and 13.1%, and the accuracies (relative errors) were

Pirfenidone is a promising antifibrotic agent with therapeutic potential for idiopathic pulmonary fibrosis. This study aimed to evaluate the pharmacokinetics and urinary excretion of pirfenidone and its major metabolite 5-carboxy-pirfenidone in healthy Chinese subjects under fed conditions. 20 healthy subjects of either sex were recruited in this randomized, single-center, and open-label, single ascending doses (200, 400, and 600 mg) and multiple doses (400 mg, 3 times daily) study. Safety was assessed by adverse events, ECGs, vital signs, and clinical laboratory parameters. Blood and urine samples were analyzed with a validated LC/MS method. Pirfenidone was safe and well tolerated. After single-dose administration, pirfenidone was rapidly absorbed with a mean Tmax of 1.8–2.2 h and a mean t1/2 of 2.1–2.4 h. 5-carboxy-pirfenidone was rapidly formed with a mean Tmax of 1.5–2.2 h and a mean t1/2 of 2.1–2.6 h. Cmax and AUC for both parent and metabolite were dose proportional over the 200–600 mg dose range. No gender effect was found. In the steady state, the accumulation index (R) estimated for the 3 dosing intervals ranged from 1.1 to 1.5 for both pirfenidone and 5-carboxy-pirfenidone, indicating that the exposure of pirfenidone and 5-carboxy-pirfenidone increased slightly with repeated dosing, but t1/2 and CL/F remained unchanged. Metabolism is the primary mechanism of drug clearance of pirfenidone. About 87.76% of the administered pirfenidone was excreted in urine in the form of 5-carboxy-pirfenidone, while only 0.6159% of the administered pirfenidone was detected as the unchanged form in urine.

An extended-release (ER) niacin and lovastatin fixed-dose combination has been developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The purpose of the present study was to examine the drug interaction between niacin and lovastatin after multi-dose oral administration of lovastatin/niacin ER combination in healthy Chinese volunteers. A single-center, randomized, open-label, 5-period crossover study was conducted in thirty healthy volunteers aged 18 to 45 years with a washout period of 8 days. Subjects were randomized to receive multiple doses of treatment A (1 500 mg niacin ER tablet), B (1 20 mg lovastatin tablet), C (1 20 mg lovastatin and 500 mg niacin-ER tablet), D (2 10 mg lovastatin and 350 mg niacin-ER tablets) or E (2 10 mg lovastatin and 500 mg niacin-ER tablets) in 1 of 5 sequences (ABCDE, BCDEA, CDEAB, DEABC, EABCD) per period. Lovastatin, niacin and its metabolites (nicotinuric acid and nicotinamide) were determined in plasma by LC/MS method. Pharmacokinetic parameters were calculated, and least square mean ratios and 90% confidence intervals for Cmax⁡ and AUC (0–24) were determined for lovastatin/niacin ER versus niacin ER or lovastatin. It revealed that the formulation had no potential drug interaction in healthy Chinese volunteers when the dosage was increased from 500 mg to 1000 mg.

In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty-four healthy men were randomized to 4 treatments according to a crossover design with a 14-day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32-1.45) for the area under the concentration-time curve (AUC) for LEX and 1.27 (1.18-1.36) for the maximum concentration of drug in serum (C(max)) for LEX followed by AML versus alone. In contrast, no significant differences were found in the pharmacokinetic parameters of CXM between treatments (P.05). They authors conclude that AML possesses an enhancement effect in β-lactam antibiotic bioavailability (in this case, LEX), and this interaction may be specific to the peptidomimetic β-lactam antibiotics.

A sensitive method using liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) was developed and validated for the analysis of antihistamine drug azatadine in human plasma. Loratadine was used as internal standard (IS). Analytes were extracted from human plasma by liquid/liquid extraction using ethyl acetate. The organic phase was reduced to dryness under a stream of nitrogen at 30 °C and the residue was reconstituted with the mobile phase. 5 μL of the resulting solution was injected onto the LC–MS/MS system. A 4.6 mm × 150 mm, I.D. 5 μm, Agilent TC-C18 column was used to perform the chromatographic analysis. The mobile phase consisted of ammonium formate buffer 0.010 M (adjusted to pH 4.3 with 1 M formic acid)/acetonitrile (20:80, v/v) The chromatographic run time was 5 min per injection and flow rate was 0.6 mL/min. The retention time was 2.4 and 4.4 min for azatadine and IS, respectively. The tandem mass spectrometric detection mode was achieved with electrospray ionization (ESI) iron source and the multiple reaction monitoring (MRM) (291.3 → 248.2 m/z for azatadine, 383.3 → 337.3 m/z for IS) was operated in positive ion modes. The low limit of quantitation (LLOQ) was 0.05 ng/mL. The intra-day and inter-day precision of the quality control (QC) samples was 8.93–11.57% relative standard deviation (RSD). The inter-day accuracy of the QC samples was 96.83–105.07% of the nominal values.

A sensitive and rapid LC–MS/MS method was developed and validated for the determination of levamisole in human plasma. The assay was based on liquid–liquid extraction of analytes from human plasma with ethyl ether. Chromatographic separation was carried on an Agilent HC-C 8 column (150 mm × 4.6 mm, 5 μm) at 40 °C, with a mobile phase consisting of acetonitrile—10 mM ammonium acetate (70:30, v/v), a flow rate of 0.5 mL/min and a total run time of 6 min. Detection and quantification were performed by mass spectrometry in the multiple reaction monitoring mode with positive electrospray ionization m / z at 205.1 → 178.2 for levamisole, and m / z 296.1 → 264.1 for mebendazole (internal standard). The assay was linear over a concentration range of 0.1–30 ng/mL with a lower limit of quantification of 0.1 ng/mL. The coefficient of variation of the assay precision was less than 8.5%. The assay was successfully used to analyze human plasma samples in a pharmacokinetic study where levamisole was administered as a liniment.

A rapid, simple and sensitive LC-MS/MS method was developed for simultaneous determination of amoxicillin and ambroxol in human plasma using clenbuterol as internal standard (IS). The plasma samples were subjected to a simple protein precipitation with methanol. Separation was achieved on a Lichrospher C(18) column (150 mm x 4.6mm ID, dp 5 microm) using methanol (containing 0.2% of formic acid) and water (containing 0.2% of formic acid) as a mobile phase by gradient elution at a flow rate of 1.0 mL/min. Detection was performed using electrospray ionization in positive ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 365.9-->348.9 (amoxicillin), m/z 378.9-->263.6 (ambroxol) and m/z 277.0-->203.0 (IS). Calibration curves were linear in the concentration range of 5-20,000 ng/mL for amoxicillin, and 1-200 ng/mL for ambroxol, with the intra- and inter-run precisions of

A sensitive and specific method was developed and validated for the determination of mitiglinide in human plasma using liquid chromatographic separation with electrospray ionization tandem mass spectrometric detection. Acidified plasma samples were extracted with ethyl acetate. The chromatographic separation was performed on an Agilent Zorbax Eclipse Plus C18 column with a mobile phase of methanol–10 mm ammonium acetate solution at a flow rate of 0.3 mL/min. Analytes were detected with an Agilent 6410 Triple qudrupole mass spectrometer equipped with an electrospray ionization source in positive multiple reaction monitoring mode: m/z 316.2 (precursor ion) to 298.2 (product ion) for mitiglinide and m/z 318.2 (precursor ion) to 120.2 (product ion) for the internal standard. This method was validated over a linear range of 0.5–4000 ng/mL for mitiglinide in human plasma. The lower limit of quantification (LLOQ) was 0.5 ng/mL, while a relative standard deviation (RSD) was less than 3.9%. The intra- and inter-run precision (as RSD, %) obtained from three validation runs were all less than 15%. The validated method was successfully used to analyze human plasma samples for application in pharmacokinetic studies. Copyright © 2008 John Wiley & Sons, Ltd.

A sensitive, specific and rapid liquid chromatographic/tandem mass spectrometric (LC/MS/MS) assay for the determination of allylestrenol in human plasma was established. Plasma samples were extracted by tert -butyl ether and separated by LC/MS/MS using a Phenomenex Curosil-PFP column (250 mm × 4.6 mm ID, dp 5 μm) with a mobile phase of methanol–water (95:5, v/v). The analytes were monitored with atmospheric pressure chemical ionization (APCI) by selected reaction monitoring (SRM) mode. The linear calibration curves covered a concentration range of 0.04–20.0 ng/mL with lower limit of quantification (LLOQ) at 0.04 ng/mL. The mean extraction recovery of allylestrenol was greater than 81.8%. The intra- and inter-day precisions were less than 1.3% and 3.1% respectively, determined from quality control (QC) samples of three representative concentrations. The method has been successfully applied to determining the plasma concentration of allylestrenol and a clinical pharmacokinetics study in healthy Chinese female volunteers.

This paper reports the development and validation of an assay for ifenprodil based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) and its application to a pharmacokinetic study involving single and multiple intravenous infusions to healthy Chinese volunteers. After sample preparation of plasma by liquid–liquid extraction with ethyl acetate, the analyte and internal standard, urapidil, were separated by reversed phase chromatography in a run time of 4 min and detected by positive ion electrospray ionization followed by multiple reaction monitoring of the precursor-to-product ion transitions at m/z 326.2→308.1 for ifenprodil and m/z 388.4→205.3 for IS. The assay was linear in the concentration range 0.2–50.0 ng/mL with recovery >76.4%. In the pharmacokinetic study of single intravenous infusions of 5, 10 and 15 mg ifenprodil, peak plasma concentrations and areas under the plasma concentration–time curve were both linearly related to dose. In the pharmacokinetic study of multiple once daily intravenous infusions of 10 mg ifenprodil for 7 days, pharmacokinetic parameters were similar to those after the single dose showing that ifenprodil does not accumulate on repeated administration.