Time Of Peak Concentration Research Articles

The Effect of Hydraulic Gradient and Pattern of Conduit Systems on Tracing Tests: Bench-Scale Modeling.

Tracer breakthrough curves provide valuable information about the traced media, especially in inherently heterogeneous karst aquifers. In order to study the effect of variations in hydraulic gradient and conduit systems on breakthrough curves, a bench scale karst model was constructed. The bench scale karst model contains both matrix and a conduit. Eight tracing tests were conducted under a wide range of hydraulic gradients from 1 to greater than 5 for branchwork and network-conduit systems. Sampling points at varying distances from the injection point were utilized. Results demonstrate that mean tracer velocities, tracer mass recovery and linear rising slope of the breakthrough curves were directly controlled by hydraulic gradient. As hydraulic gradient increased, both one half the time for peak concentration and one fifth the time for peak concentration decreased. The results demonstrate the variations in one half the time for peak concentration and one fifth the time for peak concentration of the descending limb for different sampling points under differing hydraulic gradients are mainly controlled by the interactions of advection with dispersion. The results are discussed from three perspectives: different conduit systems, different hydraulic-gradient conditions, and different sampling points. The research confirmed the undeniable role of hydrogeological setting (i.e., hydraulic gradient and conduit system) on the shape of the breakthrough curve. The extracted parameters (mobile-fluid velocity, tracer-mass recovery, linear rising limb, one half the time for peak concentration, and one fifth the time for peak concentration) allow for differentiating hydrogeological settings and enhance interpretations the tracing tests in karst aquifers.

Spatial and temporal variation of O3, NO and NO2 concentrations at rural and urban sites in Marmara Region of Turkey

The first continuous measurements of the hourly surface ozone (O3), nitric oxide (NO) and nitrogen dioxide (NO2) concentrations at 7 rural and 15 urban sites in Marmara Region of Turkey during the period from March 2013 to April 2016. The results indicate that surface O3 is an extensive problem throughout the Marmara Region. O3 levels have similar seasonal pattern in rural and urban sites by following the order of summer, spring, fall, and winter. The seasonal results showed an opposite behaviour among O3 and NOx (NO + NO2) in both rural and urban sites, marked by maximums (minimum NOx) of O3 in summer and minimums (maximum NOx) in fall and winter. The summer concentrations vary between 91.5 and 123.6 μg/m3 and 74.6–112.4 μg/m3 at rural and urban sites respectively. Furthermore, O3 peak concentration time in rural areas in O3 seasons (April–September) occurred at around 17:00–18:00 LST while in urban areas at around 15:00–16:00 LST, respectively. Air quality standards for O3 concentrations in Sile and Yalova rural sites were significantly exceeded during O3 season. This exceedance made a linkage between back trajectories and air masses with respect to the O3 levels. 72-hr back trajectories at an altitude of 500 m agl were computed by HYSPLIT model to assess the type of air masses which reach the area. AOT40 (accumulated exposure over a threshold of 40 ppb) index was performed for both vegetation and forestry standards and EU Directive were significantly exceeded at all rural stations.

Study of Pharmacodynamic and Pharmacokinetic Interaction of Bojungikki-Tang with Aspirin in Healthy Subjects and Ischemic Stroke Patients.

Background Bojungikki-tang (BJIKT) is a widely used traditional herbal formula in China, Japan, and Korea. There have been reports that several herbs among BJIKT have interactions with antiplatelet drugs, such as aspirin. This study aimed to assess whether BJIKT interacts with aspirin in terms of pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects and ischemic stroke patients. Methods The phase I interaction trial was a randomized, open-label, crossover study of 10 healthy male subjects, and the phase III interaction trial was a randomized, placebo-controlled, parallel study of 43 ischemic stroke patients. Each participant randomly received aspirin + BJIKT or aspirin + placebo. For PK analysis, plasma acetyl salicylic acid (ASA) and salicylic acid (SA) were evaluated, and, for PD analysis, platelet aggregation and plasma thromboxane B2 (TxB2) were measured. Results In the PK parameters, mean area under curve, maximum concertation, and peak concentration time of ASA and SA were not different between two groups in healthy subjects and ischemic stroke patients. In the PD profiles, TxB2 concentrations and platelet aggregation were not affected by coadministration of BJIKT in healthy subjects and ischemic stroke patients. Conclusions These results suggest that coadministration of BJIKT with aspirin may not result in herb-drug interaction.

Development of urban runoff model FFC-QUAL for first-flush water-quality analysis in urban drainage basins

An urban runoff model that is able to compute the runoff, the pollutant loadings, and the concentrations of water-quality constituents in urban drainages during the first flush was developed. This model, which is referred to as FFC-QUAL, was modified from the existing ILLUDAS model and added for use during the water-quality analysis process for dry and rainy periods. For the dry period, the specifications of the coefficients for the discharge and water quality were used. During rainfall, we used the Clark and time–area methods for the runoff analyses of pervious and impervious areas to consider the effects of the subbasin shape; moreover, four pollutant accumulation methods and the washoff equation for computing the water quality each time were used. According to the verification results, FFC-QUAL provides generally similar output as the measured data for the peak flow, total runoff volume, total loadings, peak concentration, and time of peak concentration for three rainfall events in the Gunja subbasin. In comparison with the ILLUDAS, SWMM, and MOUSE models, there is little difference between these models and the model developed in this study. The proposed model should be useful in urban watersheds because of its simplicity and its capacity to model common pollutants (e.g., biological oxygen demand, chemical oxygen demand, Escherichia coli, suspended solids, and total nitrogen and phosphorous) in runoff. The proposed model can also be used in design studies to determine how changes in infrastructure will affect the runoff and pollution loads.

Pudding products enriched with yellow mustard mucilage, fenugreek gum or flaxseed mucilage and matched for simulated intestinal viscosity significantly reduce postprandial peak glucose and insulin in adults at risk for type 2 diabetes

Soluble dietary fibre (DF) enrichment of carbohydrate-rich foods is one strategy to reduce type 2 diabetes (T2D) risk. However, glycemic response to specific soluble DF, and in particular, the contribution of soluble DF-induced viscosity, needs research. This study examined acute postprandial glycemic response of puddings containing agriculturally-derived soluble DF [yellow mustard mucilage (YMM), fenugreek gum (FG), flaxseed mucilage (FM)] matched for apparent viscosity under simulated small intestinal conditions (rather than concentration), in 15 adults at elevated T2D risk (age 55.1±12.0years; BMI 29.5±3.4kg/m2) using a randomized, double-blind, crossover design. Blood glucose and plasma insulin at peak concentration and specific time points were significantly decreased by all soluble DF puddings compared to a control pudding, but did not differ from each other. This study demonstrates that viscosity-matched soluble DF in a pudding matrix can reduce acute postprandial peak glucose and insulin, and T2D risk.

Effects on the QT Interval of a Gatifloxacin-Containing Regimen versus Standard Treatment of Pulmonary Tuberculosis.

ABSTRACTThe effects on ventricular repolarization—recorded on the electrocardiogram (ECG) as lengthening of the QT interval—of acute tuberculosis and those of standard and alternative antituberculosis regimens are underdocumented. A correction factor (QTc) is introduced to make the QT independent of the heart rate, translating into the slope of the regression line between QT and heart rate being close to zero. ECGs were performed predosing and 1 to 5 h postdosing (month 1, month 2, and end of treatment) around drugs' peak concentration time in tuberculosis patients treated with either the standard 6-month treatment (rifampin and isoniazid for 6 months and pyrazinamide and ethambutol for 2 months; “control”) or a test regimen with gatifloxacin, rifampin, and isoniazid given for 4 months (pyrazinamide for the first 2 months) as part of the OFLOTUB study, a randomized controlled trial conducted in five African countries. Drug levels were measured at steady state (month 1) in a subset of patients. We compared treatment effects on the QTc and modeled the effect of individual drugs' maximum concentrations of drug in serum (Cmax) on the Fridericia-corrected QT interval. A total of 1,686 patients were eligible for the correction factor analysis of QT at baseline (mean age, 30.7 years; 27% female). Median heart rate decreased from 96/min at baseline to 71/min at end of treatment, and body temperature decreased from 37.2 to 36.5°C. Pretreatment, the nonlinear model estimated the best correction factor at 0.4081 in between Bazett's (0.5) and Fridericia's (0.33) corrections. On treatment, Fridericia (QTcF) was the best correction factor. A total of 1,602 patients contributed to the analysis of QTcF by treatment arm. The peak QTcF value during follow-up was >480 ms for 21 patients (7 and 14 in the test and control arms, respectively) and >500 ms for 9 patients (5 and 4, respectively), corresponding to a risk difference of −0.9% (95% confidence interval [CI], −2.0% to 2.3%; P = 0.12) and 0.1% (95% CI, −0.6% to 0.9%; P = 0.75), respectively, between the test and control arms. One hundred six (6.6%) patients had a peak measurement change from baseline of >60 ms (adjusted between-arm difference, 0.8%; 95% CI, −1.4% to 3.1%; P = 0.47). No evidence was found of an association between Cmax of the antituberculosis drugs 1 month into treatment and the length of QTcF. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen appears to carry a sizable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. This is to date the largest data set studying the effects of antituberculosis regimens on the QT, both for the standard regimen and for a fluoroquinolone-containing regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT00216385.)

The Role of Segmental Analysis of Clonazepam in Hair in Drug Facilitated Cases

To infer the frequency of dosage and medication history investigate of the victims in drug facilitated cases by the segmental analysis of clonazepam in hair. Freezing milling under liquid nitrogen environment combined with ultrasonic bath was used as sample pretreatment in this study, and liquid chromatography-tandem mass spectrometry was used for the segmental analysis of the hair samples collected from 6 victims in different cases. The concentrations of clonazepam and 7-aminoclonazepam were detected in each hair section. Clonazepam and its metabolite 7-aminoclonazepam were detected in parts of hair sections from the 6 victims. The occurrence time of drug peak concentration was consistent with the intake timing provided by victims. Segmental analysis of hair can provide the information of frequency of dosage and intake timing, which shows an unique evidential value in drug facilitated crimes.

Prolonged targeted temperature management compromises thrombin generation: A randomised clinical trial

AimTo investigate whether prolonged compared with standard duration of targeted temperature management (TTM) compromises coagulation. MethodsComatose survivors after out-of-hospital cardiac arrest (n=82) were randomised to standard (24h) or prolonged (48h) duration of TTM at 33±1°C. Blood samples were drawn 22, 46 and 70h after attaining the target temperature. Samples were analysed for rotational thromboelastometry (ROTEM® (EXTEM®, INTEM®, FIBTEM® and HEPTEM®)) and thrombin generation using the Calibrated Automated Thrombogram® assay. ResultsWith the 22-h sample, we revealed no difference between groups in the ROTEM® and thrombin generation results beside a slightly higher EXTEM® and INTEM® maximum velocity in the prolonged group (p-values≤0.04). With the 46-h sample, ROTEM® showed no differences when using EXTEM®; however, 11% (p<0.01) longer clotting time and 12% (p<0.01) longer time to maximum velocity were evident in the prolonged group than in the standard group when using INTEM®. The prolonged group had reduced thrombin generation compared with the standard group as indicated by 30% longer lag time (p=0.04), 106nM decreased peak concentration (p<0.001), 36% longer time to peak (p=0.01) and 411 nM*minute decreased endogenous thrombin potential (p<0.001). With the 70-h sample, no differences in ROTEM® results were found between groups. However, the prolonged group had reduced thrombin generation indicated by longer lag time, decreased peak concentration and longer time to peak (all p-values≤0.02) compared with the standard group. ConclusionProlonged TTM in post-cardiac arrest patients impairs thrombin generation.ClinicalTrials.gov identifier: NCT02258360.

Rosuvastatin and contrast-induced nephropathy in elective percutaneous coronary intervention: The randomized CLEAR-CIN-PCI sub study

Background: Statins may reduce the risk of contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary intervention (PCI). However, there is no knowledge that PCI performed at the same time of statin peak concentration in the blood, may cause additional benefit in renal protection. Methods: This study sought to determine whether PCI realized within the time of rosuvastatin peak concentration was associated with reduced in-hospital CIN compared with standard clinical practice. This single-center prospective, randomized, open-label, non-blinded clinical trial evaluated stable coronary artery disease patients taking chronic statin undergoing PCI. Patients were randomized to receive a loading dose of rosuvastatin (40mg within 2 to 6 hours before angioplasty) or to standard practice (without load dose of rosuvastatin). The pre-specified primary endpoint was the occurrence of CIN defined as an increase in the serum creatinine by {greater than or equal to} 0.3 mg/dl within 24 hours after intervention. Contrast-induced nephropathy after coronary angioplasty by creatinine-kinase measure. This trial is registered with (Creatine Leak After Rosuvastatin in Percutaneous Coronary Intervention [CLEAR-PCI]; (ClinicalTrials.gov number: NCT01968577). (J. Interven Cardiol 2015;28:339-347)@2015, Wiley Periodicals, Inc. Results: Of the 544 patients in the main trial, 528 participated in the CLEAR-CIN-PCI substudy, and 493 patients (244 in the rosuvastatin group and 249 in control) were analyzed. CIN occurred in 6 patients of the 244 patients (2.5%) treated with rosuvastatin compared with 9 of the 249 patients (3.6%) in control group (risk ratio, 0.80; 95% confidence interval [CI], 0.42 to 1.50; P=0.455). Conclusion: This result does not support the initiation of rosuvastatin before elective PCI to prevent CIN in patients taking chronic statin therapy.

Serum Bupivacaine Concentration After Periarticular Injection With a Mixture of Liposomal Bupivacaine and Bupivacaine HCl During Total Knee Arthroplasty.

A relatively new technique to reduce postoperative pain for total knee arthroplasty is to inject a mixture of 266 mg of liposomal bupivacaine and 125 mg of 0.25% bupivacaine HCl with epinephrine 1:300,000 around the knee joint at the time of surgery. Currently, no publications report serum bupivacaine concentrations over time after periarticular injection of liposomal mixed with free bupivacaine. This information is important to ensure safe serum bupivacaine concentrations are maintained especially when considering supplemental or rescue peripheral nerve blocks. A total of 40 subjects scheduled for primary unilateral total knee arthroplasty with intraoperative periarticular injection of the liposomal bupivacaine and bupivacaine HCl mixture were included. Total serum bupivacaine concentrations were measured after the last injection at selected time points and calculated by gas chromatography. Quantile regression techniques were used to analyze the data over time. This study is registered with ClinicalTrials.gov (ID NCT02626559). Peak serum concentration ranged from 0.17 to 1.2 μg/mL and occurred from 10 minutes to 48 hours. Across all time points, the 48-hour interval had the highest mean concentration of total serum bupivacaine at 0.55 μg/mL (SD, 0.27). Quantile regression showed total serum bupivacaine concentrations increased over the 48 hours measured. None of the participants demonstrated signs or symptoms of local anesthetic toxicity. Total serum concentrations of bupivacaine after periarticular administration of liposomal bupivacaine mixed with bupivacaine HCl remained below the described toxicity threshold (2.5 μg/mL) within the first 48 hours, and no patients demonstrated signs or symptoms of toxicity. However, peak serum concentration time was not achieved within the 48-hour interval. Additional studies are needed to describe the course of serum bupivacaine levels after 48 hours and to ascertain the risk of toxicity when combining this method of periarticular injection with peripheral nerve blocks.

A Comparative Analysis of Drainage Morphometry on Hydrologic Characteristics of Kereke and Ukoghor Basins on Flood Vulnerability in Makurdi Town, Nigeria

The synergistic enforcement of the hydrographic behaviors of Kereke and Ukoghor river basins on the river Benue have been identified as the major contributors of the replete episodic flood hazard of Makurdi town. It is on this note that this study aims at analysing and comparing two categories of morphometric parameters; areal and linear/relief which influence runoff/discharge volumes and time lag of Kereke and Ukoghor river basins hydrograpghs respectively. This analysis provides a better understanding of their hydrographic characteristics and vulnerability to the flood hazard. The potential hydrographic variables examined include: runoff, peak flow, time to peak, infiltration, and overland flow. This was achieved using topographical maps of Makurdi sheet 251 NW and 251 SW on scale 1:50,000 published by Federal Survey of Nigeria (1965). These morphometric parameters were evaluated using ArcGIS 10.2 platform. Results indicated that both basins are 5th order basins with dendritic pattern. Kereke and Ukoghor basins have basin area 261.28 km2 94.82 km2, basin length 26 km/10.79 km, basin perimeter 76.28 km/40.15 km, bifurcation ratio 3.51/3.09, length of overland flow 0.56 km/ 0.42 km, form factor 0.39/0.85, circulatory ratio 0.56/0.70, relief ratio 0.45/0.91, drainage density 0.91/1.20, elongation ratio 0.40/ 0.60 and infiltration number 0.53/1.32 respectively. A comparison of the results of linear/relief parameters indicate that Okoghor drainage constitute fast peak flow and concentration time of shorter duration and hence higher flood vulnerability than Kereke drainage basin. On the other hand a comparison of areal aspects of morphometry Kereke river basin constitutes more vulnerability to flooding in Makurdi town than Ukoghor river basin with regards to hydrograph volume regimes. The outcome of the study is fundamental for prioritizing proactive and sustainable urban flood management, appropriate land use planning and zonation especially along their flood liable areas, storm water management and other general urban environmental degradation management.

The pharmacokinetics of Tiangou antihypertensive capsule in rat in vivo.

The aim of the study was to examine the effect of complex prescription on the pharmacokinetics of baicalin, rhynochophylline and gastrodin in Tiangou antihypertensive capsule. After administration, rat plasma was collected at different time-points. High-performance liquid chromatography was used to determine the content of baicalin, rhynochophylline and gastrodin in plasma. Two peaks occurred in the baicalin concentration-time curve. No significant difference was found for the peak concentration time (tmax) and area under concentration-time curve (AUC) of baicalin between the complex prescription and baicalin groups. The peak concentration (Cmax) of baicalin in the complex prescription group was significantly decreased, while no significant difference was found for the absorption factor (Ka) and AUC of baicalin between the complex prescription and gastrodin groups. The elimination factor (Ke) of gastrodin in the complex prescription group was significantly decreased, while the apparent volume of distribution (Vd) of gastrodin was significantly increased. No significant difference was found for AUC of baicalin between the complex prescription and rhynochophylline groups. Levels of Ka and Ke of rhynochophylline were lower in the complex prescription group while Vd was higher. Thus, complex prescription made plasma concentration-time curve more smooth. By contrast, the Tiangou antihypertensive capsule improved the distribution of baicalin, rhynochophylline and gastrodin in vivo.

Time and Magnitude of Peak Concentration of Reactive Groundwater Contaminants Discharged to a River.

An analytical solution for calculating the contaminant discharge rate in an aquifer following an instantaneous release of reactive contaminant mass to groundwater is used to derive relationships for the time and magnitude of peak concentration in a river receiving the transported material. Relationships are developed for the time of peak concentration relative to the time of travel for the contaminant, and the magnitude of peak concentration relative to the concentration calculated at the time of travel. Both quantities are found to be a function of two dimensionless parameters characterizing advective-dispersive-reactive transport-the Peclet number and the Damkohler number. It is shown that the time to peak concentration may occur before the time of travel, considering advection and retardation only, depending on the magnitudes of the Peclet and Damkohler numbers. Similarly, the magnitude of peak concentration may exceed the concentration calculated assuming that the time of peak concentration coincides with time of travel for the contaminant. For large Damkohler numbers, equating the time of peak concentration with the time of travel for the contaminant can significantly underestimate peak concentrations.

Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs

AIMS: To assess the effect of food intake on the pharmacokinetics of grapiprant administered orally at 2 mg/kg, and to estimate its oral bioavailability in dogs.METHODS: Eight healthy female Labrador Retriever dogs, aged 4–10 years were used. In the initial trial two dogs were administered a 0.5 mg/kg I/V bolus of grapiprant dissolved in ethanol. In the second trial, six dogs were assigned to two treatment groups, using a randomised cross-over design, and received 2 mg/kg of grapiprant orally, as pure powder, after fasting for 12 hours or after being fed. Blood samples were collected at preassigned times up to 36 hours after administration, and concentrations of grapiprant in plasma determined using validated high performance liquid chromatography.RESULTS: After I/V administration in the two dogs the terminal half life was 5.30 and 6.06 hours, clearance was 444 and 476 mL/hours/kg, and volume of distribution was 3,642 and 3,883 mL/kg. Compared with fasted dogs, oral administration in fed dogs resulted in reduced median peak concentrations in plasma (1,598 vs. 614 ng/mL) and delayed median time of peak concentration (1.0 vs. 3.0 hours). The estimated bioavailability in fasted and fed dogs was 111.9 and 59.1%, respectively. Concentrations of grapiprant in plasma following oral administration, in either fed or fasted dogs, remained higher than 164 ng/mL for up to 6 hours. This concentration has been estimated to be the minimal effective concentration required to control pain in dogs.CONCLUSION AND RELEVANCE: Oral administration of 2 mg/kg grapiprant in fed and fasted dogs resulted in different pharmacokinetics of the drug, but did not influence the length of time when concentrations in plasma exceeded theoretical effective concentrations. Further studies are necessary to verify these findings using pharmacokinetic-pharmacodynamic studies and in clinical subjects.

A real-time, rapid emergency control model for sudden water pollution accidents in long-distance water transfer projects

A real-time, rapid emergency control (EC) model is proposed to cope with sudden water pollution accidents in long-distance water transfer projects. The EC model outputs the method of EC based on pollutant properties. A generalized form of EC model is proposed and tested with a demonstrative project. The rapid prediction formulas of emergency control parameters (ECPs) are proposed under different states of water diversion. The closing times of check gates and the pollution range are calculated by the rapid prediction formulas of ECPs. A case study is examined under the scenario of a sucrose spill in a demonstrative project conducted in the Fangshui to Puyang channel of the Beijing–Shijiazhuang Emergency Water Supply Project in the middle route of the South-to-North Water Transfer Project. The relative errors of peak concentration and arrival time of peak concentration are less than 20%. However, we could not use an actual toxic soluble pollutant to validate the EC model, so we performed the experiment with sucrose to test the EC model based on its concentration variation. The final result shows that the model is able to play a fundamental role in the decisions involved in the Emergency Environmental Decision Support System.

Ratio of microRNA-122/155 in isoniazid-induced acute liver injury in mice

Liver injury is a major hindrance to the treatment of tuberculosis (TB) patients due to the primary side effects associated with anti-TB drugs. Several investigations have identified sensitive biomarkers for the early diagnosis of anti-TB drug-induced liver injury (ADLI), including the use of microRNAs (miRNAs/miRs). However, the association between miR-122/155 and ADLI remains unknown. Thus, the present study used reverse transcription-quantitative polymerase chain reaction to observe changes in tissue miR-122/155 expression levels during the course of liver injury in mice. Liver injury was induced by the administration of isoniazid (INH), a first-line anti-TB drug. miR-122/155 expression levels were quantified at seven time points throughout 1 day (0.25, 0.75, 1.5, 6, 12, 18 and 24 h) based on the pharmacokinetics of INH in mice. Notably, over the timecourse of INH-induced liver injury, the tissue miR-122 expression level significantly decreased at 0.25 h, which is the peak concentration time of INH, compared with the control group (P<0.05). The change was more rapid than that of the serum aminotransferase and miR-155, which were significantly increased at 0.75 h. In addition, the pathological score correlated with the ratio of miR-122/miR-155 (r=−0.779; P<0.01). In conclusion, the miR-122/155 ratio may be utilized as a sensitive biomarker for ADLI, which could contribute to the early diagnosis of patients following anti-TB treatment.

Postprandial Cranberry Flavonol Glycoside Bioavailability in Human Urine

Cranberry health benefits for prevention of urinary tract infections have been linked to proanthocyanidins even though their bioavailability is questionable. Protection could also be dependent upon the bioavailability of cranberry flavonol glycosides, which have not been previously characterized in urine postprandially. Healthy women (n=10; 19.5 ± 1.1 years; 22.5 ± 2.0 BMI) ingested low‐acidity 27% v/v cranberry juice (CBJ) from Demoranville cranberries sweetened with sucrose (74 Cal/240 ml), or an isocaloric control (74 Calories sucrose/240 ml). Midstream urine was collected at baseline (0), then 90, 225, and 360 minutes postprandially. UHPLC‐ESI‐MS‐MS methods were developed to identify flavonol glycosides in CBJ and urine. CBJ quercetin‐3‐galactoside (Q‐3‐gal), quercetin‐3‐arabinoside (Q‐3‐ara), myricetin‐3‐galactoside (M‐3‐gal), quercetin‐3‐rhamnoside (Q‐3‐rha), and myricetin‐3‐arabinoside (M‐3‐ara) concentrations were 1.8, 0.5, 0.5, 0.3, and 0.2 mg/240ml. Postprandial peak concentration times in urine were 114.5 ± 12.1, 237.2 ± 12.1, 90.0 ± 12.1, 151.4 ± 12.1 and 104.4 ± 12.8 min, respectively. These flavonol glycosides were not detected in control (0 min) urine. Following CBJ ingestion, Q‐3‐gal/mg creatinine was the most abundant flavonol glycoside at 1298 ± 421, 302 ± 85, 74 ± 59 (ng/mg creatinine) at 90, 225 and 360 min. Q‐3‐rha was 597 ± 206, 444 ± 142, and 122 ± 66. Q‐3‐ara was 36 ± 20, 337 ± 92, and 226 ± 96. M‐3‐ara was 270 ± 102, 56 ± 23, and 19 ± 15. M‐3‐gal was 169 ± 28, 8 ± 28 and 5 ± 28. This is the first study demonstrating that CBJ flavonol glycosides occur in urine postprandially. Sugar conjugate specificity at the 3‐linkage appears to affect flavonol glycoside bioavailability. Future studies should consider whether Q‐3‐gal or other flavonol glycosides may be responsible for UTI protection.

Capillary electrophoresis with end-column electrochemiluminescence for ultrasensitive determination of urapidil hydrochloride in rat plasma and its application to pharmacokinetics study.

A simple, sensitive and selective method for determination of urapidil hydrochloride was developed using capillary electrophoresis with electrochemiluminescence (CE-ECL) technique for the first time. Under the optimized experimental conditions, the ECL intensity was linear with the concentration of urapidil hydrochloride in the range from 0.050 to 50.0ng/mL and the detection limit was 0.014ng/mL (S/N=3). The proposed method was used for studying pharmacokinetics of urapidil hydrochloride in rat plasma and the main pharmacokinetic parameters of the peak concentration (Cmax), half life time (T1/2) and peak concentration time (Tmax) were 240.45±21.15ng/mL, 0.58±0.16h and 1.08±0.13h, respectively. The recoveries of urapidil hydrochloride in the diluted extracts of rat plasma samples ranged from 96.68 to 98.82%. The RSD was lower than 3%.

Pharmacokinetic interaction of Acacia catechu with CYP1A substrate theophylline in rabbits

ObjectiveTo investigate the effect of black catechu (BC) on the pharmacokinetics of theophylline (CYP1A2 substrate, with narrow therapeutic index) in rabbits. MethodsIn the present investigation the effect of BC on the pharmacokinetics of theophylline, a CYP1A2 substrate was determined. In the study, BC (264 mg/kg, p. o.) or saline (control group) was given to rabbits for 7 consecutive days and on the 8th day theophylline (16 mg/kg) was administered orally one hour after BC or saline treatment. Blood samples were withdrawn at different time intervals (0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 h) from the marginal ear vein. ResultsThe pretreatment of rabbits with BC resulted in a significant increase in maximum blood concentration, time of peak concentration and area under the concentration time profile curve until last observation which was about 41.32%, 35.71% and 15.03%, respectively. While decreases in clearance, volume of distribution, and half-life were observed. It is suggested that BC pretreatment decreases the CYP1A metabolic activity leading to increase in bioavailability and decrease in oral clearance of theophylline, which may be due to inhibition of CYP1A. ConclusionBC can significantly alter theophylline pharmacokinetics in vivo possibly due to inhibition of CYP1A and P-glycoprotein activity. Based on these results, precaution should be exercised when administering BC with CYP1A substrate.

Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency.

BackgroundTV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy.ObjectiveTo assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers.MethodsSubjects (n=56) were assigned to one of seven ascending dose groups (3–100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection.ResultsEighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23–35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose.ConclusionSingle administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD.