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Öğe 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, KamilThe 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.Öğe Biomarkers in premature calves with and without respiratory distress syndrome(Wiley, 2021) Ider, Merve; Naseri, Amir; Ok, Mahmut; Uney, Kamil; Erturk, Alper; Durgut, Murat K.; Parlak, Tugba M.Background Approaches to the evaluation of pulmonary arterial hypertension (PAH) in premature calves by using lung-specific epithelial and endothelial biomarkers are needed. Objective To investigate the evaluation of PAH in premature calves with and without respiratory distress syndrome (RDS) by using lung-specific epithelial and endothelial biomarkers and determine the prognostic value of these markers in premature calves. Animals Fifty premature calves with RDS, 20 non-RDS premature calves, and 10 healthy term calves. Methods Hypoxia, hypercapnia, and tachypnea were considered criteria for RDS. Arterial blood gases (PaO2, PaCO2, oxygen saturation [SO2], base excess [BE], and serum lactate concentration) were measured to assess hypoxia. Serum concentrations of lung-specific growth differentiation factor-15 (GDF-15), asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), and surfactant protein D (SP-D) were measured to assess PAH. Results Arterial blood pH, PaO2, SO2, and BE of premature calves with RDS were significantly lower and PaCO2 and lactate concentrations higher compared to non-RDS premature and healthy calves. The ADMA and SP-D concentrations of premature calves with RDS were lower and serum ET-1 concentrations higher than those of non-RDS premature and healthy calves. No statistical differences for GDF-15 and VEGF were found among groups. Conclusions and Clinical Importance Significant increases in serum ET-1 concentrations and decreases in ADMA and SP-D concentrations highlight the utility of these markers in the diagnosis of PAH in premature calves with RDS. Also, we found that ET-1 was a reliable diagnostic and prognostic biomarker for PAH and predicting mortality in premature calves.Öğe Comparative Pharmacokinetics of Intravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep(Bentham Science Publ Ltd, 2023) Coskun, Devran; Corum, Orhan; Corum, Duygu Durna; Uney, KamilBackground Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target-age animals. Objective To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. Methods The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC-UV and analyzed using a non-compartmental method. Results ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t(1/2 lambda z) and V-dss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC(0-infinity CIP)/AUC(0-infinity ENR) ratios were higher in one-month-old than in six- and twelve-months sheep. Conclusion The most important pharmacokinetic changes associated with aging in sheep are decreased V-dss and t(1/2 lambda z) of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC(0-24)/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (>125) with MIC of 0.37 mu g/mL and for S. aureus (>30) with MIC of 0.5 mu g/mL in all ages of sheep.Öğe Determination of temporal changes in hepatic drug-oxidizing capacity using plasma metabolite/caffeine ratios in non-pregnant and pregnant goats(Wiley, 2024) Altan, Feray; Cizmeci, Sakine Ulkum; Kose, Ayse Merve; Corum, Orhan; Uney, KamilCaffeine (CF) is a metabolic probe drug used in the determination of the hepatic drug-oxidizing capacity. The aim of this study was to investigate temporal changes in the hepatic drug-oxidizing capacity using plasma metabolite/CF ratios in non-pregnant goats (n = 11) and pregnant goats (n = 23). CF (5 mg/kg, intravenous) was administered in six periods (Period 1-6) with 45 days between two periods. The plasma levels of CF and its metabolites, theophylline (TP), theobromine (TB) and paraxanthine (PX), were determined by HPLC-UV. To evaluate hepatic drug-oxidizing capacity in terms of enzymes that play a role in CF metabolism, the plasma metabolic ratios including TB/CF, PX/CF, TP/CF and TB + PX + TP/CF were determined at 10 h following CF administration. Plasma metabolite/CF ratios were similar between non-pregnant and pregnant goats. However, plasma metabolite/CF ratios in Period 3 (45 days in pregnant goats) were significantly higher than those other periods in both pregnant and non-pregnant goats. The effect of pregnancy may not be observed on drugs that are substrates of enzymes involved in CF metabolism in goats.Öğe Effect of Xylazine on Pharmacokinetics and Physiological Efficacy of Intravenous Carprofen in Castrated Goats Kids(Mdpi, 2023) Uney, Kamil; Yuksel, Murat; Corum, Duygu Durna; Coskun, Devran; Turk, Erdinc; Dingil, Hasan Basri; Corum, OrhanCarprofen can be used in the castration process of male goats due to its low side effects, long elimination half-life, and long-term effect. However, no studies were found on the pharmacokinetics and physiological efficacy of carprofen when employed for castration in male goats. The aim of this study was to determine the effect of xylazine (0.05 mg/kg, intramuscular) on the pharmacokinetics and physiological efficacy following intravenous administration of carprofen (4 mg/kg, intravenous) in male goat kids castrated using the burdizzo method. Thirty male Kilis goat kids (5-6 months and 18-30 kg of body weight) were randomly assigned to five groups (n = 6) as follows: healthy control (HC), castration control (CAST), castration+carprofen (CAST+CRP), castration+xylazine (CAST+XYL), and castration+xylazine+carprofen (CAST+XYL+CRP). Plasma concentrations of carprofen were analyzed via a non-compartmental method. Physiological parameters including serum cortisol, scrotal temperature, rectal temperature, and scrotal circumference were determined. Xylazine caused a decrease in the volume of distribution and clearance and an increase in the area under the curve of carprofen in CAST+XYL+CRP group (p < 0.05). The mean cortisol concentrations in CAST+CRP and CAST+XYL remained lower compared to CAST (p < 0.05). The mean cortisol concentrations in CAST+XYL+CRP were lower than in CAST+CRP and CAST+XYL (p < 0.05). In addition, the effect of carprofen administration alone on reducing the initial cortisol response to castration was observed from 6 to 48 h, while in combination with xylazine, it was observed immediately up to 48 h. No treatment differences were observed in rectal temperature, scrotal temperature, and scrotal circumference (p > 0.05). Xylazine caused an increase in plasma concentration and a decrease in clearance of carprofen after co-administration. However, when the effect of the combined administration of carprofen with xylazine on cortisol is evaluated, their combined use in castration process may be beneficial.Öğe Pharmacokinetic behaviour and pharmacokinetic-pharmacodynamic integration of doxycycline in rainbow trout (Oncorhynchus mykiss) after intravascular, intramuscular and oral administrations(Wiley, 2024) Altan, Feray; Corum, Orhan; Corum, Duygu Durna; Uney, Kamil; Terzi, Ertugrul; Bilen, Soner; Sonmez, Adem YavuzObjective: Doxycycline (DO) has been used in fish for a long time, but there are some factors that have not yet been clarified regarding its pharmacokinetic (PK) and pharmacodynamic (PD) properties. Therefore, the aim of this study was to investigate the PK and PK/PD targets of DO after 20 mg/kg intravascular (IV), intramuscular (IM) and oral (OR) gavage administration in rainbow trout (Oncorhynchus mykiss). Methods: Plasma samples were collected at specific time points and subsequently analysed by HPLC-ultraviolet. The PK/PD indices were calculated based on the MIC90 (Aeromonas hydrophila and Aeromonas sobria) values obtained for the respective bacteria and the PK parameters obtained for DO following both IM and OR administration. Results: After IV administration, the elimination half-life (t(1/2 lambda z)), area under the concentration vs. time curve (AUC), apparent volume of distribution at steady-state and total body clearance of DO were 34.81 h, 723.82 h mu g/mL, 1.24 L/kg and 0.03 L/kg/h, respectively. The t(1/2 lambda z) of the DO was found to be 37.39 and 39.78 h after IM, and OR administration, respectively. The bioavailability was calculated 57.02% and 32.29%, respectively, after IM and OR administration. The MIC90 of DO against A. hydrophila and A. sobria was 4 mu g/mL. The PK/PD integration showed that DO (20 mg/kg dose) for A. hydrophila and A. sobria with MIC90 <= 4 mu g/mL achieved target AUC/MIC value after IM administration. Conclusions: These results suggest that when rainbow trout was treated with 20 mg/kg IV and IM administered DO, therapeutically effective concentrations were reached in the control of infections caused by A. hydrophila and A. sobria.Öğe Pharmacokinetics and bioavailability of meloxicam in Pekin ducks following intravenous, intramuscular and oral administration(Elsevier, 2023) Coskun, Devran; Corum, Orhan; Corum, Duygu Durna; Uney, KamilObjective To determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg(-1) in Pekin ducks.Study design Randomized experimental trial.Animals A total of 18 clinically healthy male Pekin ducks.Methods Pekin ducks were randomly assigned to three groups of six ducks: IV, IM and oral. Meloxicam (1.0 mg kg(-1)) was administered to each Pekin duck. A non-compartmental analysis was used to evaluate pharmacokinetic parameters.Results No local or systemic adverse effects were observed in any bird. Meloxicam was detected in the plasma up to 120 hours following IV, IM or oral administration. The elimination half-life of the IV route was slightly shorter than that of the IM and oral routes (p < 0.05). Following IV administration, volume of distribution at steady state and total clearance were 133.17 mL kg(-1) and 6.68 mL kg(-1) hour(-1), respectively. The mean absorption time was 2.29 hours for IM and 1.13 hours for oral route. There were significant differences between IM and oral administration for the peak plasma concentration (C-max), time to reach C-max and bioavailability (p < 0.05).Conclusions and clinical relevance Meloxicam showed long elimination half-life and high bioavailability following IM and oral administration. Meloxicam in Pekin ducks provided the effective therapeutic concentration indicated in other species for up to 48 hours. However, there is a need to determine the clinical efficacy of meloxicam in Pekin ducks.Öğe 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, KamilLetrozole 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.Öğe Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss)(Wiley, 2024) Corum, Orhan; Corum, Duygu Durna; Marin, Pedro; Acar, Omer Faruk; Aksoy, Mert; Uney, KamilBackground: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a nonsteroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. Objectives: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acidwere investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 +/- 0.5 degrees C. Methods: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. Results: The elimination half-life (t1/2 lambda z) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 mu g/mL, and 78.45% and 21.48%, respectively. Themean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. Conclusions: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.Öğe Pharmacokinetics, Tissue Residues, and Withdrawal Times of Oxytetracycline in Rainbow Trout (Oncorhynchus mykiss) after Single- and Multiple-Dose Oral Administration(Mdpi, 2023) Corum, Orhan; Durna Corum, Duygu; Terzi, Ertugrul; Uney, KamilSimple Summary: Determination of the pharmacokinetics of oxytetracycline (OTC) at single and multiple oral doses revealed its long half-life, very low bioavailability, and strong accumulation in rainbow trout. The withdrawal time (WT) for the safe consumption of rainbow trout muscle+skin varied according to the guidelines set by regulatory authorities in different countries. This study improves the establishment of the optimal dosing regimen following OTC multiple administration and the determination of the appropriate WT for the safety of rainbow trout consumption. The aim of this study was to compare the pharmacokinetics of oxytetracycline (OTC) following single- (60 mg/kg) and multiple-dose oral administrations (60 mg/kg, every 24 h for 7 days) in rainbow trout. It also aimed to determine bioavailability after a single dose and tissue residues and withdrawal times after multiple doses. This study was carried out on 420 rainbow trout at 9 +/- 0.8 degrees C. This study was carried out in two stages: single-dose (intravascular and oral) and multiple-dose treatment. The OTC concentrations in plasma and tissues were measured by high-performance liquid chromatography and analyzed by a non-compartmental method. The withdrawal time (WT) was estimated using the WT 1.4 software. OTC exhibited a long terminal elimination half-life (t(1/2 lambda z)) after IV and oral administration. The oral bioavailability of OTC was very low (2.80%). In multiple-dose treatment, tt(1/2 lambda z), the area under the plasma concentrationtime curve and peak plasma concentration increased significantly after the last day compared to the first day. OTC showed strong accumulation after multiple doses with a value of 5.33. OTC concentrations were obtained in the order liver > kidney > muscle+skin > plasma. At 9 +/- 0.8 degrees C, the WT calculated for muscle+skin was 56 days for Europe and 50 days for China, respectively. The t(1/2 lambda z) (68.94 h) and time (68 h) above the 1 mu g/mL MIC following a single OTC dose may support the extension of the 24 h dosing interval following multiple dosing. However, further studies are required to determine the optimal dosage regimen in multiple-dose OTC treatment in the treatment of infections caused by susceptible pathogens.Öğe Use of intestine-related biomarkers for detecting intestinal epithelial damage in neonatal calves with diarrhea(Amer Veterinary Medical Assoc, 2020) Ok, Mahmut; Yildiz, Ramazan; Hatipoglu, Fatih; Baspinar, Nuri; Ider, Merve; Uney, Kamil; Erturk, AlperOBJECTIVE To evaluate the usefulness of intestinal biomarkers in determining the presence of intestinal epithelial damage in neonatal calves with diarrhea caused by 4 etiologic agents. ANIMALS 40 neonatal calves that were healthy (n = 10) or had diarrhea (30). PROCEDURES The study was a cross-sectional study. Results of hematologic analyses and serum concentrations of intestinal fatty acid-binding protein (I-FABP), liver fatty acid-binding protein (L-FABP), trefoil factor 3 (TFF-3), Claudin-3 (CLDN-3), gamma-enteric smooth muscle actin (ACTG2), intestinal alkaline phosphatase (IAP), interleukin-8 (IL-8), platelet-activating factor (PAF), and leptin (LP) were compared among calves grouped according to whether they were healthy (control group; G-1) or had diarrhea caused by K99 Escherichia coli (G-2; n = 10), bovine rota-or coronavirus (G-3; 5 each), or Cryptosporidium spp (G-4; 10). RESULTS Across the 3 time points at which blood samples were obtained and evaluated, the groups of calves with diarrhea generally had markedly higher mean serum concentrations of L-FABP, TFF-3, IAP, IL-8, and LP, compared with the control group. In addition, G-2 also consistently had markedly higher mean serum concentrations of I-FAB and ACTG2 and lower mean serum concentrations of CLDN-3, compared with the control group. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that degree of intestinal epithelial damage differed among calves grouped by the etiologic agent of diarrhea and that such damage might have been more severe in calves with diarrhea caused by K99 E coli. Additionally, our results indicated that serum concentrations of I-FABP, L-FABP, TFF-3, IAP, IL-8, ACTG2, LP, and CLDN-3 were useful biomarkers of intestinal epithelial damage in calves of the present study.Öğe The Usefulness of Serum Brain Damage Biomarkers in Detection and Evaluation of Hypoxic Ischemic Encephalopathy in Calves with Perinatal Asphyxia(Mdpi, 2022) Ok, Mahmut; Naseri, Amir; Ates, Mehmet Burak; Ider, Merve; Uney, Kamil; Sevinc, Mutlu; Hatipoglu, FatihSimple Summary The objective of the present study was to determine hypoxic brain damage in calves with perinatal asphyxia using brain-specific damage biomarkers. Ten healthy calves and 25 calves with perinatal asphyxia were enrolled in the study. Consciousness evaluation and laboratory analyses were performed at admission, 24, 48, and 72 h. Serum concentrations of brain-related biomarkers were measured to assess brain injury. Moreover, histopathological and immunohistochemical examinations of the brain tissue were performed in 13 nonsurvivor calves. The consciousness level of the calves with asphyxia was significantly lower than the healthy calves. Mix metabolic-respiratory acidosis and hypoxemia were detected in calves with asphyxia. Serum UCHL1 and S100B concentrations were significantly increased, and NSE, ACTA, ADM, and CK-B were decreased in calves with asphyxia. Histopathological and immunohistochemical examination in nonsurvivor calves confirmed the development of mild to severe hypoxic-ischemic encephalopathy. In conclusion, asphyxia causes hypoxic ischemic encephalopathy in perinatal calves. UCHL1 and S100B were found to be useful markers of hypoxic-ischemic encephalopathy in calves with perinatal asphyxia. Neurological status scores and some blood gas parameters were helpful in mortality prediction. The purpose of the present study was to determine hypoxic brain damage in calves with perinatal asphyxia using brain-specific damage biomarkers. Ten healthy and 25 calves with perinatal asphyxia were enrolled in the study. Clinical examination, neurological status score, and laboratory analysis were performed at admission, 24, 48, and 72 h. Serum concentrations of ubiquitin carboxy-terminal hydrolysis 1 (UCHL1), calcium-binding protein B (S100B), adrenomodullin (ADM), activitin A (ACTA), neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP) and creatine kinase-brain (CK-B) were measured. Histopathological and immunohistochemical examinations of the brain tissue were performed in 13 nonsurvivor calves. The neurological status score of the calves with asphyxia was significantly (p < 0.05) lower. Mix metabolic-respiratory acidosis and hypoxemia were detected in calves with asphyxia. Serum UCHL1 and S100B were significantly (p < 0.05) increased, and NSE, ACTA, ADM, and CK-B were decreased (p < 0.05) in calves with asphyxia. Histopathological and immunohistochemical examinations confirmed the development of mild to severe hypoxic-ischemic encephalopathy. In conclusion, asphyxia and hypoxemia caused hypoxic-ischemic encephalopathy in perinatal calves. UCHL1 and S100B concentrations were found to be useful markers for the determination of hypoxic-ischemic encephalopathy in calves with perinatal asphyxia. Neurological status scores and some blood gas parameters were helpful in mortality prediction.
