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Plasma Concentration-time Curve (plasma + concentration-time_curve)
Selected AbstractsCLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source] Pharmacokinetics of mesalazine pellets in children with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2004Heleen Wiersma MD Abstract Mesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic data are scarce, and dosage recommendations are largely extrapolated from studies in adults. Aim of the study was to obtain the pharmacokinetic profile of a new mesalazine pellet formulation in children with ulcerative colitis and Crohn's colitis. A single oral dose of 20 mg/kg mesalazine was administered to 13 patients (age 6,16 years). Serial blood and urine sampling for determination of mesalazine and acetylmesalazine was performed before and during 24 hours following ingestion. Maximum plasma concentration of mesalazine (Cmax) was 1332 ng/mL (geometric mean, geometric coefficient of variation [CV]: 0.57), obtained 3.7 hours (tmax; CV: 0.31) after drug administration. Systemic exposure as determined by area under the plasma concentration-time curve (AUC0,, ) was 8712 ng/ml*h (CV: 0.44). Terminal half-life of elimination of mesalazine was 3.5 hours (t1/2; CV: 1.43). This study presents extensive pharmacokinetic data on mesalazine in children with mild-moderately active ulcerative colitis and Crohn's colitis. In comparison with previous experience in adults, pharmacokinetics of mesalazine administered as pellets appear to be similar in both populations. [source] The pharmacokinetics of antofloxacin in renally impaired ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2008X. Y. Pang Our aim was to investigate whether renal impairment induced by cisplatin altered the pharmacokinetics of antofloxacin. Antofloxacin (7.5 mg kg,1, i.v.) was given to normal or renally impaired rats (induced by cisplatin). Concentrations of antofloxacin in plasma and urine were measured using HPLC. Pharmacokinetic parameters were estimated. The plasma concentrations of antofloxacin in the renally impaired rats were significantly higher than those in the normal rats, accompanied by significant increase of the area under the plasma concentration-time curve (AUC) (968.78 ± 259.39 ,g min mL,1 versus 509.84 ± 46.19 ,g min mL,1 in normal rats P < 0.05). The system clearance (CL) and renal clearance (CLR) of antofloxacin decreased from 12.66 ± 1.15 mL kg,1 min,1 and 3.21 ± 1.80 mLkg,1 min,1 in normal rats, to 6.63 ± 2.82 mLkg,1 min,1 and 0.31 ± 0.15 mLkg,1 min,1, respectively. No differences between two treatments in half-life and mean residence time were found. We concluded that renal impairment induced by cisplatin significantly altered the pharmacokinetics of antofloxacin and resulted in decrease of the renal elimination. [source] Effects of cysteine on metformin pharmacokinetics in rats with protein-calorie malnutrition: partial restoration of some parameters to control levelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2008Young H. Choi Metformin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP)2C11, CYP2D1 and CYP3A1/2 in rats. The expression and mRNA levels of hepatic CYP2C11 and CYP3A1/2 are decreased in rats with protein-calorie malnutrition (PCM), but these levels are fully or partially restored to control levels in PMC rats by oral cysteine supplementation (PCMC rats). Thus, it would be expected that the pharmacokinetic parameters of metformin in PCM rats would be returned to control levels in PCMC rats. Metformin was administered i.v. (100 mg kg,1) and orally (100 mg kg,1) to control, CC (control rats with oral cysteine supplementation), PCM and PCMC rats. The following pharmacokinetic parameters of metformin following i.v. administration were restored from levels in PCM rats to levels in control rats in PCMC rats: intrinsic clearance (0.0350, 0.0309, 0.0253 and 0.0316 mL min,1 mg,1 protein for control, CC, PCM, and PCMC rats, respectively), total area under the plasma concentration-time curve from time zero to time infinity (AUC; 4110, 4290, 5540 and 4430 ,g min mL,1, respectively), and time-averaged non-renal clearance (8.12, 7.95, 5.94 and 8.17 mL min,1 kg,1, respectively). AUC values following oral administration were comparable between control and PCMC rats (1520, 1480, 2290 and 1680 ,g min mL,1, respectively). [source] Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Sandhya Ramanathan-Girish There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg,1 per week) or as a single dose injection (20 mg kg,1). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameter to correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin. [source] Pharmacokinetics of Dietary 13C-Labeled Docosahexaenoic Acid and Docosapentaenoic Acid in Red Sea Bream Chrysophrys majorJOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 2 2002Akio Tago The objectives of this study were to investigate: 1) the pharmacokinetics of dietary docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) using 13C-labeled fatty acids; 2) the interorgan transport of DHA in the red sea bream by monitoring the DHA level of several organs; and 3) the relationship between the plasma DHA level and optimum dietary DHA level in the plasma of the red sea bream Chrysophrys major. For this purpose, a mixture of 38.5% of [13C]DHA, 8.5% of [13C]DPA, and 4.2% of [13C]palmitic acid were given to the red sea bream at dose level of 8.0, 16.0, and 47.9 mg/kg by a single oral administration. For [13C]DHA, the maximum plasma concentration (tmax) occurred at 2.00,3.00 h after the oral administration. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve to 24 h (AUC0-24 for [13C]DHA level linearly increased with respect to dosage. [13C]DHA appeared in each organ (plasma, erythrocyte and the fat body of the orbit, liver, intestine, skin, brain, heart and muscle) at 0.5 h and was observed until 24 h. From the values determined for the pharmacokinetic parameters, the range of the effective plasma DHA level for normal growth of the red sea bream was suggested to be between 21.0 and 40.3 ,g/mL. For [13C]DPA, the AUC0-24 and Cmax values also linearly increased with the dosage, but tmax did not depend on it. [source] The effect of whole-body sunbed ultraviolet A exposure on the pharmacokinetics of the photolabile drug nifedipinePHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 3 2000H. S. Al-Ajmi The calcium antagonist nifedipine absorbs ultraviolet A (UVA) radiation and readily photodegrades in vitro to a toxic nitroso-pyridine photoproduct. We examined whether whole body exposure of normal subjects to sunbed UVA radiation would affect the pharmacokinetics of nifedipine. Eight healthy, male, Caucasian volunteers (phototypes I,III) participated in this ethically approved, randomised, cross-over study. Each subject attended on 2 occasions, one week apart, and on each occasion was given a single oral dose (10 mg) of nifedipine following which blood samples were collected at 0, 0.5, 1. 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 7 h. During one of the visits, 15 min after nifedipine ingestion, a whole-body UVA (sunbed comprising Philips R-UVA lamps) dose of 70% of the individual's predetermined minimal phototoxic dose was delivered over a period of 17,36 min. Plasma nifedipine levels were measured using a standard reverse-phase high-performance liquid chromatography method. The area under the plasma concentration-time curve (AUC) of nifedipine during the UVA irradiation session (median 206 ng,·,ml,1,·,h,1) was significantly higher than during the non-irradiation control session (median 174.5 ng,·,ml,1,·,h,1) (P=0.03; 95% C.I. for difference in medians 9.9 to 55.9 ng,·,ml,1,·,h,1). UVA irradiation did not significantly affect any of the other measured pharmacokinetic parameters (Cmax, t1/2, tmax). We demonstrate that sunbed UVA irradiation does not lead to in vivo photodegradation of nifedipine in healthy humans after a single dose. The apparent increase in AUC during UVA irradiation may be due to slightly slower metabolism of nifedipine in the presence of toxic photoproduct(s) or due to blood distribution changes affecting liver blood flow. [source] Prediction of herb,drug metabolic interactions: a simulation studyPHYTOTHERAPY RESEARCH, Issue 6 2005Shufeng Zhou Abstract In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb,drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb,drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright © 2005 John Wiley & Sons, Ltd. [source] Proposal for a standardised identification of the mono-exponential terminal phase for orally administered drugsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2008Christian Scheerans Abstract The area under the plasma concentration-time curve from time zero to infinity (AUC0,inf) is generally considered to be the most appropriate measure of total drug exposure for bioavailability/bioequivalence studies of orally administered drugs. However, the lack of a standardised method for identifying the mono-exponential terminal phase of the concentration-time curve causes variability for the estimated AUC0,inf. The present investigation introduces a simple method, called the two times tmax method (TTT method) to reliably identify the mono-exponential terminal phase in the case of oral administration. The new method was tested by Monte Carlo simulation in Excel and compared with the adjusted r squared algorithm (ARS algorithm) frequently used in pharmacokinetic software programs. Statistical diagnostics of three different scenarios, each with 10,000 hypothetical patients showed that the new method provided unbiased average AUC0,inf estimates for orally administered drugs with a monophasic concentration-time curve post maximum concentration. In addition, the TTT method generally provided more precise estimates for AUC0,inf compared with the ARS algorithm. It was concluded that the TTT method is a most reasonable tool to be used as a standardised method in pharmacokinetic analysis especially bioequivalence studies to reliably identify the mono-exponential terminal phase for orally administered drugs showing a monophasic concentration-time profile. Copyright © 2007 John Wiley & Sons, Ltd. [source] Decreased biliary excretion of tributylmethyl ammonium in cholestyramine pretreated rats due to reduced formation of ion-pair complexes with hepatic bile saltsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2007M. K. Choi Abstract The hypothesis that higher molecular weight (MW) quaternary ammoniums (QAs) form lipophilic ion-pair complexes with bile salts in the liver, and are subsequently excreted into bile via a canalicular transporter, P-gp, was re-examined in the present study for its validity. The biliary excretion of tributylmethyl ammonium (TBuMA), a QA with a MW of 200, in bile salt-depleted rats was determined. Depletion was induced by a daily oral administration of a resin, cholestyramine, at a dose of 0.5,g/kg for 2 consecutive weeks, which decreased the concentration of total bile salts in the liver by 38%. When TBuMA was administered intravenously (12,µmol/kg) to these rats, the plasma level, area under the plasma concentration-time curve (AUC), systemic clearance (CL) and volume of distribution (Vss) of the compound remained unchanged, whereas bile flow (23.03 vs 16.94,µl/min, p<0.05) and biliary clearance (CLbile, 12.75 vs 5.34,ml/min/kg, p<0.01) were decreased significantly. These results implied the biliary clearance of TBuMA in rats with bile salt depletion was significantly decreased as a result of decreased ion-pair complexation of TBuMA. The above results are consistent with our hypothesis and the existence of a MW threshold (i.e. 200±50 for rats) for the biliary excretion of QAs. Copyright © 2007 John Wiley & Sons, Ltd. [source] Liquid chromatographic,mass spectrometry analysis and pharmacokinetic studies of a novel rabeprazole formulation, sterile powder for injection, in dogs and ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2007Feng Shao Abstract Rabeprazole is among the most potent proton pump inhibitors (PPI) identified to date and it has been demonstrated that it is effective in such diseases as gastroesophageal reflux disease (GERD), duodenal ulcer and gastric ulcer. There is currently interest in developing a new formulation: rabeprazole sterile powder for injection (RSPI). This investigation was conducted to evaluate the preclinical pharmacokinetics of RSPI in rats and at the same time a comparative study was carried out in dogs between RSPI and Pariet® tablets using liquid chromatographic,mass spectrometry analysis. The liquid chromatographic,mass spectrometry method was first conducted and validated as being specific, and having accuracy, precision, sensitivity and a satisfactory recovery. After intravenous administration of RSPI (i.v.: 2, 6 and 18 mg/kg) to rats, no significant dose-dependency was found in the CL (4.20,5.72 l/h/kg), Varead (0.94,1.32 l/kg), dose-normalized AUC (197.20,245.82 µg/l*h based on 1 mg/kg) and t1/2 (p>0.05). In the dog, a randomized, open-label, crossover experiment was carried out to show that the mean area under the plasma concentration-time curve (AUC0,,) after i.v. administration of RSPI was at least four times larger than that following oral administration of Pariet® tablet at an equivalent dose but the elimination half-life of these two formulation was similar (p>0.05). The results showed that the pharmacokinetics of RSPI was linear (r2 = 0.98) in the dose range 2,18 mg/kg and the RSPI had a much higher AUC0,, and similar t1/2 values compared with the enteric-coated tablet. Copyright © 2007 John Wiley & Sons, Ltd. [source] In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humansBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001Noriko Hirota Abstract We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CLint) for 4-hydroxylation and CYP3A4 content and between the CLint for ,-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CLint for CYP3A4 was about 2-fold higher than the CLint for CYP3A5 in the case of 4-hydroxylation. However, the CLint for CYP3A5 was about 3-fold higher than the CLint for CYP3A4 in the case of ,-hydroxylation. The metabolic rates for 4- and ,-hydroxylation increased as the added amount of cytochrome b5 increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b5. The values of CLint, in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CLint value (sum of 4- and ,-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitroKi values and reported pharmacokinetic parameters of ketoconazole was 2.30,2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73,1.79 vs 1.58,1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants. Copyright © 2001 John Wiley & Sons, Ltd. [source] Plasma concentrations of fluticasone propionate and budesonide following inhalation: effect of induced bronchoconstrictionBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2007Kevin J. Mortimer What is already known about this subject ,,All inhaled corticosteroids are absorbed into the systemic circulation and hence have the potential to cause adverse systemic effects. ,,Plasma drug concentrations following inhalation of 1000 µg fluticasone are considerably lower in people with airflow obstruction than in healthy volunteers but this is not the case for budesonide. What this study adds ,,This is the first study to determine whether changes in airflow obstruction within an individual affect the systemic absorption of inhaled fluticasone and budesonide; ,,Plasma concentrations of fluticasone and, to a lesser extent, those of budesonide were lower when the drugs were inhaled following induced bronchoconstriction; ,,The lower plasma concentrations of corticosteroids seen when the drugs were inhaled following induced bronchoconstriction is likely to reflect variations that will occur with fluctuations in airway caliber in asthma. Aims To determine whether and to what extent bronchoconstriction affects plasma concentrations of fluticasone and budesonide following inhalation. Methods Twenty people with mild asthma inhaled 1000 µg fluticasone (Accuhaler®) plus 800 µg budesonide (Turbohaler®) on two visits. On one occasion, prior to drug inhalation, FEV1 was decreased by at least 25% using inhaled methacholine. Plasma drug concentrations were measured for each drug over 5 h and area under the plasma concentration-time curve (AUC(0,5 h)) compared between visits. Results The mean difference in FEV1 prior to drug inhalation on the 2 days was 33%. AUC(0,5 h) values for fluticasone and budesonide were lower by a median of 60% (IQR 36,75) and 29% (IQR 2,44), respectively, when administered following bronchoconstriction; the reduction was greater for fluticasone than for budesonide, P = 0.007. Conclusions The lower plasma concentrations of fluticasone and, to a lesser extent, budesonide seen when the drugs were inhaled following induced bronchoconstriction, is likely to reflect variations that will occur with fluctuations in airway caliber in asthma. [source] Influence of rabeprazole and lansoprazole on the pharmacokinetics of tacrolimus in relation to CYP2C19, CYP3A5 and MDR1 polymorphisms in renal transplant recipientsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2007Masatomo Miura Abstract The objective of this study was to evaluate whether genetic polymorphisms of CYP2C19, CYP3A5 and MDR1 significantly impact the interaction between tacrolimus and rabeprazole or lansoprazole. Seventy-three recipients were randomly assigned after renal transplantation to receive repeated doses of tacrolimus for 28 days with a regimen of either 20 mg of rabeprazole or 30 mg of lansoprazole. Blood concentrations of tacrolimus were measured by microparticle enzyme immunoassay. The mean daily dose and the dose-adjusted area under the plasma concentration-time curves from 0 to 12 h (AUC0,12) of tacrolimus coadministered with rabeprazole or lansoprazole were the lowest and highest, respectively, in CYP2C19 poor metabolizers (PMs) having the CYP3A5*3/*3 genotype (0.084 and 0.112 mg/kg/day and 1.269 and 1.033 ng·h/ml/mg/kg, respectively). On the other hand, the mean dose-adjusted AUC0,12 of tacrolimus coadministered with rabeprazole or lansoprazole were the highest in CYP2C19 PMs having the MDR13435CC+CT genotype, but not significantly. The present study indicates that there are significant interactions between tacrolimus and rabeprazole or lansoprazole in CYP2C19 PM renal transplant recipients bearing the CYP3A5*3/*3 genotypes. For recipients having these genetic polymorphisms, lower dosages of tacrolimus are required to achieve the target therapeutic index. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||