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    Age-related changes in the pharmacokinetics of meloxicam after intravenous administration in sheep
    (Wiley, 2023) Coskun, Devran; Corum, Orhan; Corum, Duygu Durna; Cetin, Gul; Irmak, Mehmet; Ceyhan, Hatice Rumeysa; Uney, Kamil
    The pharmacokinetics of meloxicam was studied in 1-, 6-, and 12-month- old sheep following a single intravenous (i.v.) dose of 1 mg/kg. The experiments were carried out when the Romanov sheep were 1 month old (7.93 +/- 0.91 kg), 6 months old (27.47 +/- 4.91 kg), and 12 months old (37.10 +/- 3.64 kg). Meloxicam concentration in plasma was determined by high-performance liquid chromatography and the data collected were evaluated by non-compartmental kinetic analysis. Meloxicam was detected in the plasma up to 72 h following i.v. administration in all age groups. The volume of distribution at steady state (Vdss) and total body clearance (ClT) were significantly higher in 1- month- old (304.87 mL/kg and 16.57 mL/h/kg) than in 12- month- old (193.43 mL/kg and 10.50 mL/h/kg) sheep. The area under the concentration- time curve from 0 to 72 h value of meloxicam was lower in 1- month- old (58.51 h*mu g/mL) compared to 12- month- old (92.59 h*mu g/mL) sheep. There was no difference in t1/ 2.z value in different age groups. The body extraction ratio values for meloxicam ranged from 0.0186 to 0.0719 after i.v. administration in all age groups. Meloxicam showed an increase in plasma concentration and a decrease in Vdss and ClT in 12- month- old compared to 1- month- old sheep. Compared to 1- month- old and 12- month- old sheep, there was no difference in these parameters in 6- month- old sheep. Because the age of sheep has an influence on the pharmacokinetics of meloxicam, dosage apparently may need to be adjusted for age.
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    Effect of ketoprofen and tolfenamic acid on intravenous pharmacokinetics of ceftriaxone in sheep
    (Wiley, 2021) Cetin, Gul; Durna Corum, Duygu; Corum, Orhan; Atik, Orkun; Coskun, Devran; Uney, Kamil
    In this study, the pharmacokinetics of ceftriaxone (40 mg/kg) was determined following a single intravenous (IV) administration of ceftriaxone alone and co-administration with ketoprofen (3 mg/kg) or tolfenamic acid (2 mg/kg) in sheep. Eight healthy Akkaraman sheep (2.4 +/- 0.3 years and 44 +/- 4 kg of body weight) were used. The study was carried out according to the longitudinal design in three periods with a 15-day washout period between administrations. In the first period, sheep received ceftriaxone alone via an IV injection. In the second and third periods, the same sheep received ceftriaxone in combination with ketoprofen and tolfenamic acid, respectively. Plasma concentrations of ceftriaxone were assayed by high-performance liquid chromatography and analyzed using non-compartmental analysis. Following the administration of ceftriaxone alone, the elimination half-life (t(1/2 lambda z)), area under the plasma concentration-time curve from zero (0) hours to infinity (infinity) (AUC(0-infinity)), total clearance (Cl-T), and volume of distribution at steady state were 1.42 h, 182.41 h*mu g/ml, 0.22 L/h/kg, and 0.17 L/kg, respectively. While ketoprofen and tolfenamic acid significantly increased the t(1/2 lambda z) and AUC(0-infinity) of ceftriaxone, they significantly reduced the Cl-T. Ceftriaxone (40 mg/kg, IV) in concurrent use with ketoprofen and tolfenamic acid can be administrated at the 12 h dosing intervals to maintain T> minimum inhibitory concentration (MIC) values above 60% in the treatment of infections caused by susceptible pathogens with the MIC value of <= 0.75 and <= 1 mu g/mL, respectively, in sheep with an inflammatory condition.
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    Pharmacokinetics of cefquinome in rainbow trout (Oncorhynchus mykiss) after intravascular, intraperitoneal, and oral administrations
    (Wiley, 2022) Corum, Duygu Durna; Corum, Orhan; Terzi, Ertugrul; Coskun, Devran; Bilen, Soner; Cetin, Gul; Uney, Kamil
    This study aimed to determine the pharmacokinetics and bioavailability of cefquinome in rainbow trout (Oncorhynchus mykiss) following intravascular (IV), intraperitoneal (IP), and oral (PO) administrations at 14 +/- 1 degrees C. In this study, three hundred and six clinically healthy rainbow trout (110-140 g) were used. The fish received single IV, IP, and PO injections of cefquinome at 10 mg/kg dose. The plasma concentrations of cefquinome were measured using HPLC-UV and were evaluated using non-compartmental analysis. Cefquinome was measured up to 96 h for PO route and 144 h for IV and IP routes in plasma. Following IV administration, t(1/2 lambda z), Cl-T, and V-dss were 18.85 h, 0.037 L/h/kg, and 0.84 L/kg, respectively. The C-max of IP and PO routes was 9.75 and 1.64 mu g/ml, respectively. The bioavailability following IP and PO administrations was 59.46% and 12.33%, respectively. Cefquinome at 10 mg/kg dose may maintain T > MIC above 40% at 72 and 96 h intervals, respectively, following the IP and IV routes for bacteria with MIC values of <= 2 mu g/ml and at 24 h intervals following the PO route for bacteria with MIC value of <= 0.75 mu g/ml. However, further studies are needed to determine in vitro and in vivo antibacterial efficacy and multiple dosage regimens of cefquinome against pathogens isolated from rainbow trout.
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    Plasma and Milk Pharmacokinetics and Estimated Milk Withdrawal Time of Tolfenamic Acid in Lactating Sheep
    (Wiley, 2024) Corum, Orhan; Uney, Kamil; Coskun, Devran; Durna Corum, Duygu; Cetin, Gul; Elmas, Muammer
    Objective: This study aimed to investigate the plasma and milk pharmacokinetics, as well as the withdrawal time (WT) from milk of tolfenamic acid (2 and 4 mg/kg) following intravenous (IV) administration to eight healthy lactating Akkaraman sheep. Methods: The trial was conducted in two periods in accordance with a crossover pharmacokinetic design. The concentrations of tolfenamic acid in the plasma and milk were determined using high-pressure liquid chromatography and evaluated using non- compartmental analysis. The WT of tolfenamic acid in milk was calculated using the WT 1.4 software. Results: Compared to the 2 mg/kg dose, plasma volume of distribution at steady state (from 0.43 to 0.50 L/kg), terminal elimination half-life (from 2.41 to 4.14 h) and dose-normalized area under the plasma concentration-time curve (AUC(0-infinity), from 9.46 to 30.11 h mu g/mL) increased, whereas total body clearance (from 0.21 to 0.13 L/h/kg) decreased at the 4 mg/kg dose. The peak milk concentration (C-max) and AUC(0-infinity) values in milk were 0.26 mu g/mL and 0.28 h mu g/mL, respectively, for 2 mg/kg, and 0.43 mu g/mL and 0.55 h mu g/mL, respectively, for 4 mg/kg. Although the dose-normalized C-max of milk decreased depending on the dose, no difference was observed in dose-normalized AUC(0-infinity). The AUC(0-infinity milk)/AUC(0-infinity plasma) ratio was 0.03 for 2 mg/kg and 0.02 for 4 mg/kg. The WT values calculated for milk at dosages of 2 and 4 mg/kg were 3 and 4 h, respectively. Conclusions: A decrease in plasma elimination and an increase in plasma concentration of tolfenamic acid were observed depending on the dose. Tolfenamic acid lowly passed into sheep's milk at 2 and 4 mg/kg doses. This study may provide valuable information for clinicians' decision-making processes.