Pharmacokinetics of letrozole and effects of its increasing doses on gonadotropins in ewes during the breeding season.

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 (t1/2ʎz ) 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 (ClT ) 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 (C0.083h ) plasma concentration values between dose groups. The decreased ClT , prolonged t1/2ʎz, 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.

Pulse wave Doppler ultrasound of umbilical cord in experimentally induced pregnancy toxemia in sheep.

Contrary to its widespread use in human cases, the use of Doppler ultrasonography is only recently becoming prevalent in farm animals. This study aimed to determine the effects of maternal metabolic and clinical changes on fetal hemodynamics during pregnancy toxemia with the doppler examination of umbilical cord. In the study twenty ewes with a single healthy fetus were included in the study. At the end of the 120th day of pregnancy, 20 single-bearing pregnant ewes were randomly categorized into two groups. Ewes in the control group were fed to meet all nutritional requirements. On the other contrary, the experimental ewes were fed to meet equivalent to 50 % of the daily needs and then fasted for 96 h. Doppler ultrasonographic examinations of umbilical cord were performed once every two days and once a day during fasting. Beta hydroxybutyric acid (BHBA) concentration was measured by taking blood from sheep on examination days. Pulse systolic velocity (PSV), end diastolic velocity (EDV), PSV/EDV, pulsatility index (PI), resistance index (RI), and fetal heart rate (FHR) as well as BHBA values and how those parameters has changed over time (time by treatment effect) due to energy deprivation during pregnancy were evaluated using repeated measure analysis of variance. No clinical signs were observed in both toxemia and control groups during restricted feeding. BHBA concentration increased and there was a significant time, time by treatment and main effect of treatment effect between groups. No significant main effect of treatment and time by treatment interaction was observed in the changes of PI, RI, FHR, and systolic/diastolic velocity values over time in both groups. FHR was reduced over time, and there was a significant time effect in FHR in both groups. Although doppler indices didn't increase, both PSV and EDV values increased significantly in the pregnancy toxemia group compared with the controls (Time P = 0.03, time by treatment interaction P < 0.05) and the main effect of treatment P < 0.05). The marked increase in blood velocities (PSV and EDV) in the umbilical cord is probably due to the compensatory functioning for excessive energy deprivation of the fetus. Therefore, PSV and EDV might be a valuable indicator for evaluating the fetus's health status during the management of the PT.

Induction of ovulation using repeated doses of sulpiride, a dopamine antagonist, in ewe lambs.

This study aimed to test the hypothesis that sulpiride can increase the concentration of circulating gonadotropin that can promote puberty in pre-pubertal ewe lambs. Here, 12 1-3-year-old Merino rams and 60 7-9-month-old Merino sheep were included in the study. The sheep were randomly divided into sulpiride (n = 30) and control (n = 30) groups. The sulpiride group was subcutaneously injected with 0.6 mg/kg sulpiride twice daily (morning and evening) for 9 days. During these 9 days, blood samples were taken from the sheep before drug administration and at 4 h after every drug administration. The number of ovulating animals in the sulpiride group was significantly higher than that in the control group (90% vs. 32%). No oestrous signs were observed in either group during ram release. Further, there were no differences in the levels of mean follicle-stimulating hormone in the two groups based on treatment (p = .2), time (p = .3) or treatment-by-time interaction (p = .3). After sulpiride administration, the luteinizing hormone (LH) levels of the sulpiride group rapidly increased and remained stable for a long time, whereas physiological LH fluctuations in the control group remained unchanged. Within-group changes in terms of LH concentrations were significant for both groups (p < .001), whereas LH pulse frequency was significantly different between the sulpiride group (p = .03). Therefore, it is concluded that sulpiride can be used as a non-steroidal alternative to stimulate pre-pubertal ewe lambs and sheep during anoestrus.

The pharmacokinetics of letrozole and its effect on gonadotropins in anestrous ewes.

The aim of this study was to determine the pharmacokinetics of letrozole and its effect on FSH and LH concentrations after single (IV, IM, SC) and repeated IV doses in anestrous ewes. This study was conducted in experiments 1 and 2 by randomly dividing 24 healthy Akkaraman ewes in anestrus into two equal groups. In experiment 1, the pharmacokinetics of letrozole following single IV, IM, and SC administration at 1 mg/kg dose and its effect of a single IV dose on plasma FSH and LH concentration were determined. In experiment 2, the effect of repeated IV doses of letrozole on FSH and LH concentrations was established. Plasma concentration of letrozole was measured using high-performance liquid chromatography, and pharmacokinetic parameters were calculated by non-compartmental analysis. FSH and LH concentrations were quantified using ELISA. The elimination half-life (t1/2ʎz) for IV, IM, and SC routes were 9.94, 37.29, and 41.07 h, respectively. The IV route for letrozole had a total clearance of 0.11 L/h/kg and a volume of distribution at a steady state of 1.50 L/kg. The peak plasma concentration was 0.11 µg/mL for the IM route and 0.14 µg/mL for the SC routes. The bioavailability was 55.18% for the IM route and 75.34% for the SC route. Letrozole following single and repeated (every 24 h for 3 days) IV administrations at 1 mg/kg dose did not affect LH concentration in anestrous ewes but caused an increase in the FSH concentration. This increase in FSH concentration may create a potential for the use of letrozole in ovarian superstimulation protocols. Favorable pharmacokinetic properties (long t1/2ʎz and good bioavailability) of letrozole for IM and SC routes require further investigation before use in estrus induction or estrus synchronization protocols in sheep.