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    Pharmacokinetics of letrozole and effects of its increasing doses on gonadotropins in ewes during the breeding season
    (Wiley, 2024) Kivrak, Mehmet Bugra; Corum, Orhan; Yuksel, Murat; Turk, Erdinc; Corum, Duygu Durna; Tekeli, Ibrahim Ozan; Uney, Kamil
    Letrozole is a non-steroidal, third-generation aromatase inhibitor used in humans. Although letrozole is not approved for use in animals, it is used off-label in cases of synchronization and infertility. The aim of this study was to determine the pharmacokinetics of letrozole after a single intravenous administration at three different doses in ewes during the breeding season and its effect on gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) at the beginning of proestrus. The study was carried out on 24 healthy Merino ewes. Ewes were randomly divided into four groups (n = 6) as control, 0.5, 1, and 2 mg/kg. Plasma concentrations of letrozole were measured using HPLC-UV and were analyzed by non-compartmental analysis. LH and FSH concentrations were measured with a commercial ELISA kit. The terminal elimination half-life (t(1/2 lambda z)) was significantly prolonged from 11.82 to 18.44 h in parallel with the dose increase. The dose-normalized area under the concentration-time curve (AUC) increased, and total body clearance (Cl-T) decreased at the 1 and 2 mg/kg doses (0.05 L/h/kg) compared with the 0.5 mg/kg dose (0.08 L/h/kg). There were no differences in the volume of distribution at steady-state and initial (C-0.083h) plasma concentration values between dose groups. The decreased ClT, prolonged t(1/2 lambda z), and increased AUC at increasing doses showed the nonlinear kinetic behavior of letrozole. Letrozole significantly reduced LH concentration without affecting FSH concentration at all doses. As a result, letrozole has the potential to be used in synchronization methods and manipulation of the follicular waves due to its effect on LH secretion.
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    Pharmacokinetics of meloxicam following intravenous administration at different doses in sheep
    (Wiley, 2024) Gungor, Huseyin; Corum, Orhan; Corum, Duygu Durna; Kumru, Alper Serhat; Yilmaz, Gokhan; Coskun, Devran; Coskun, Alparslan
    The aim of this study is to determine the pharmacokinetic change after intravenous administration of meloxicam at doses of 0.5, 1 and 2 mg/kg to sheep. The study was carried out on six Akkaraman sheep. Meloxicam was administered intravenously to each sheep at 0.5, 1, and 2 mg/kg doses in a longitudinal pharmacokinetic design with a 15-day washout period. Plasma concentrations of meloxicam were determined using the high performance liquid chromatography-ultraviolet, and pharmacokinetic parameters were evaluated by non-compartmental analysis. Meloxicam was detected up to 48 h in the 0.5 mg/kg dose and up to 96 h in the 1 and 2 mg/kg doses. As the dose increased from 0.5 to 2 mg/kg, terminal elimination half-life, and dose normalized area under the concentration versus time curve increased and total clearance decreased. Compared to the 1 mg/kg dose, it was determined that V(dss )decreased and C-0.083h increased in the 2 mg/kg dose. Meloxicam provided the therapeutic concentration of >0.39 mu g/mL reported in other species for 12, 48 and 96 h at 0.5, 1 and 2 mg/kg doses, respectively. These results show that meloxicam exhibits non-linear pharmacokinetics and will achieve unpredictable plasma concentrations when administered IV for a rapid effect at dose of >= 1 mg/kg in sheep.
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    The pharmacokinetics of sulpiride and its effect on sexual behaviours and LH concentrations in anestrous does (Capra hircus)
    (Elsevier, 2025) Yuksel, Murat; Corum, Orhan; Kivrak, Mehmet Bugra; Corum, Duygu Durna; Turk, Erdinc; Takci, Abdurrahman; Yardimci, Sara Busra
    The aim of this study was to investigate the pharmacokinetics of sulpiride and its effect on sexual behaviours and LH concentrations in anestrous does (Capra hircus). This study was carried out in two stages: pharmacokinetics (stage I) and effect on LH pulsatility, concentration, and estrus display (stage II). In the stage I, sulpiride was administered via intravenous (IV), intramuscular (IM), subcutaneous (SC) and oral routes to does at a dose of 0.6 mg/kg. In the stage II, sulpiride was administered intramuscularly at a dose of 0.6 mg/kg every 12 hours for 10 days. Plasma concentrations of sulpiride were measured using HPLC and pharmacokinetic parameters were calculated by non-compartmental analysis. LH concentrations were quantified using ELISA. The terminal elimination half-life, apparent volume of distribution, and total body clearance of sulpiride following IV administration were 1.76 h, 0.38 L/kg, and 0.15 L/h/kg, respectively. The peak plasma concentration of IM and SC administration was 1.39 and 0.83 mu g/mL at 0.53 and 0.78 h, respectively. The bioavailability of sulpiride was 103.30 % for the IM route and 72.21 % for the SC route. Sulpiride showed erratic and low absorption after oral administration. While LH concentrations decreased significantly after sulpiride administration, the LH plus frequency increased significantly. In conclusion, sulpiride with distinctive effect on LH pulse frequency has the potential to be used in protocols for hastening cyclicity. However, more studies are needed on the use of sulpiride in estrus induction protocols.