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1. Plasma and Milk Pharmacokinetics and Estimated Milk Withdrawal Time of Tolfenamic Acid in Lactating Sheep.

Author

Corum, Orhan, Uney, Kamil, Coskun, Devran, Durna Corum, Duygu, Cetin, Gul, and Elmas, Muammer

Subjects
SHEEP milk, BLOOD volume, LIQUID chromatography, PHARMACOKINETICS, MILK
Abstract

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 (AUC0−∞, from 9.46 to 30.11 h µg/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 (Cmax) and AUC0−∞ values in milk were 0.26 µg/mL and 0.28 h µg/mL, respectively, for 2 mg/kg, and 0.43 µg/mL and 0.55 h µg/mL, respectively, for 4 mg/kg. Although the dose‐normalized Cmax of milk decreased depending on the dose, no difference was observed in dose‐normalized AUC0−∞. The AUC0−∞ milk/AUC0−∞ 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. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Pharmacokinetics and bioavailability of furosemide in sheep.

Author

Durna Corum, Duygu, Corum, Orhan, Atik, Orkun, Cetin, Gul, Zhunushova, Aidai, and Uney, Kamil

Subjects
BIOAVAILABILITY, SHEEP, HIGH performance liquid chromatography, FUROSEMIDE, INJECTIONS
Abstract

The pharmacokinetics and bioavailability of furosemide were determined following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at 2.5 mg/kg dose in sheep. The study was conducted on six healthy sheep in a three‐way, three‐period, crossover pharmacokinetic design with a 15‐day washout period. In first period, furosemide was randomly administered via IV to 2 sheep, IM to 2 sheep and SC to 2 sheep. In second and third periods, each sheep received furosemide via different routes of administration with the 15‐day washout period. Plasma concentrations were determined using a high‐performance liquid chromatography assay and analyzed by noncompartmental method. The mean total clearance and volume of distribution at steady state following IV administration were 0.24 L h‐1 kg‐1 and 0.17 L/kg, respectively. The elimination half‐life was similar for all administration routes. The mean peak plasma concentrations of IM and SC administration were 10.33 and 3.18 μg/ml at 0.33 and 0.42 hr, respectively. The mean bioavailability of IM and SC administration was 97.91% and 37.98%, respectively. The IM injection of furosemide may be the alternative routes in addition to IV. However, further research is required to determine the effect of dose and route of administration on the clinical efficacy of furosemide in sheep. [ABSTRACT FROM AUTHOR]

Published
2021
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10. Pharmacokinetics of meloxicam, carprofen, and tolfenamic acid after intramuscular and oral administration in Japanese quails (Coturnix coturnix japonica).

Author

Turk, Erdinc, Tekeli, Ibrahim Ozan, Corum, Orhan, Durna Corum, Duygu, Kirgiz, Fatma Ceren, Cetin, Gul, Arslan Atessahin, Dilek, and Uney, Kamil

Subjects
JAPANESE quail, QUAILS, ORAL drug administration, PHARMACOKINETICS
Abstract

The aim of this study was to determine the pharmacokinetics of meloxicam (MLX), carprofen (CRP), and tolfenamic acid (TA) in Japanese quails (Coturnix coturnix japonica) following intramuscular (IM) and oral administration at doses of 1, 10, and 2 mg/kg, respectively. A total of 72 quails were randomly divided into 3 equal groups as MLX, CRP, and TA. Each group was separated into two sub‐groups that received IM and oral administration of each drug. Plasma concentrations of MLX, CRP, and TA were determined using HPLC‐UV and analyzed by non‐compartmental method. The t1/2ʎz and MRT of MLX, CRP, and TA after oral administration were similar to those after IM administration. The Vdarea/F of MLX, CRP, and TA after IM administration was 0.28, 2.05, and 0.20 L/kg. The Cl/F of MLX, CRP, and TA after IM administration was 0.12, 0.19, and 0.09 L/h/kg. MLX, CRP, and TA after oral administration showed significantly lower Cmax and longer Tmax compared with IM administration. The relative bioavailability of MLX, CRP, and TA following oral administration in quails was 76.13%, 61.46%, and 57.32%, respectively. The IM and oral route of MLX, CRP, and TA can be used for the treatment of various conditions in quails. However, further research is necessary to determine the pharmacodynamics and safety of MLX, CRP, and TA before use in quails. [ABSTRACT FROM AUTHOR]

Published
2021
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11. A Cardioprotective Role of Nerium oleander with the Expression of Hypoxia Inducible Factor 2A mRNA by Increasing Antioxidant Enzymes in Rat Heart Tissue

Author

Hitit, Mustafa, Corum, Orhan, Corum, Duygu Durna, Donmez, Huseyin, Cetin, Gul, Dik, Burak, Er, Ayse, and EBYÜ, Eczacılık Fakültesi

Subjects
Tissue, Enzyme
Abstract

Background: Nerium oleander (NO) distillate is used to either protect heart cells against oxidative stress or reduce the risk of cardiovascular disease by regulating the production of reactive oxygen species. Hypoxia-inducible factors (HIFs) regulate cellular antioxidant defense mechanisms under hypoxic conditions in which heart cells survive; however, the key responsible mechanism of NO distillate for cardioprotection remains elusive. The objective of this study was to evaluate the effects on heart tissue at different time intervals after administering NO distillate intraperitoneally (IP) while considering the transcriptional regulation of HIFs and representative antioxidant enzymes. Materials, Methods & Results: The NO plant was chopped, and distillated water was added. The mixture was distilled, and the distillate separated and collected into tubes, after which it was lyophilized to obtain dry material. Twenty male Wistar albino rats (2-3 month-old, 250-300 g each) were used in the study. The rats were randomly divided into four groups. The control group (n = 5) received IP injections of saline; the remaining 15 rats received IP injections of a single dose of 7.5 mL NO distillate. The NO distillate injected rats were divided into three groups according to the time from injection to harvest the heart tissue samples. The tissues were collected at 0 h (control; n = 5), 2 h (group 2; n = 5), 4 h (group 3; n = 5), and 8 h (group 4; n = 5) after injection and under general anesthesia (60 mg/kg ketamine, IP + 10 mg/kg xylazine, IP). Quantitative polymerase chain reaction (qPCR) was used to assess the expression profiles of the genes of interest in the heart tissues. Hypoxanthine phosphoribosyltransferase was used as the reference gene. The expression of manganese superoxide dismutase (MnSOD) mRNA was in a steady state level between the control group and group 2 (P > 0.05); however, it significantly increased in group 3 and 4 compared with that in the control (P < 0.05). Expression of catalase (CAT) mRNA was significantly higher in group 2 than in the control group (P < 0.05) although it was lower in group 3 and 4 than in group 2 (P < 0.05); however, it appeared to be similar among the control group, group 3, and group 4 (P > 0.05). Copper (Cu) SOD mRNA was equally expressed in both the control group and group 2 (P > 0.05) but was lower in group 3 and 4 than in group 2 (P < 0.05). Expressions of HIF1A, HIF2A, and HIF3A mRNA were detected in the rat heart tissues in the control and 2, 4, and 8 h after administration of NO distillate. Expression of HIF1A mRNA was in a steady state and did not differ among groups 2, 3, and 4 (P > 0.05). Similarly, the expression of HIF2A mRNA did not change between the control group and group 2 (P > 0.05); however, it was higher in group 3 than in the control (P < 0.05) and tended to be higher in group 3 than in group 2 (P = 0.063). HIF3A mRNA expression did not change significantly in the heart tissue of any of the groups (P > 0.05). Discussion: The present study using rats determined that MnSOD, CAT, CuSOD, HIF1A, HIF2A, and HIF3A mRNA are expressed in the heart tissues after administration of NO distillate. The increased expression of HIF2A mRNA after 4 h in accordance with a rise in CAT mRNA after 2 h, and MnSOD mRNA after 4 and 8 h might confirm the role of HIF2A mRNA in oxidative stress defense by regulating antioxidant enzymes; consequently, this study may expand our understanding of uses of NO distillate with respect to molecular pathways.

Published
2018

13. Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

Author

CORUM, DUYGU DURNA, CORUM, ORHAN, YILDIZ, RAMAZAN, FAKI, HATICE ESER, IDER, MERVE, CETIN, GUL, and UNEY, KAMIL

Subjects
PHARMACOKINETICS, HIGH performance liquid chromatography, SHEEP, INTRAVENOUS therapy, ANALYTICAL mechanics
Abstract

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h x mg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep. [ABSTRACT FROM AUTHOR]

Published
2020
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15. Effects of bcrp and p-gp modulators on the penetration of aflatoxin b1 into the mouse brain

Author

Tras, Bunyamin, Cetin, Gul, Uney, Kamil, Dik, Burak, Corum, Orhan, Atalay, Sema, Selçuk Üniversitesi, Veteriner Fakültesi, Klinik Öncesi Bilimler Bölümü, Tras, Bunyamin, Uney, Kamil, and Dik, Burak

Subjects
Aflatoxin B-1, Modulation, Mice, Drug transporter proteins, Brain
Abstract

WOS: 000388115200013, This study was conducted to determine whether the plasma and brain concentrations of AFB(1) are affected by the modulation of P-gp and BCRP using zosuquidar (ZQR) and prazosin (PRZ), respectively. In this study, a total of 40 healthy adult male BALB/c mice (32 +/- 3.7 g) were used. The animals were randomly divided into 5 groups, with 8 animals per group. Group 1 was used for method validation. Group 2 (AF) received intraperitoneal AFB1 at a dose of 20 mg/kg of body weight. Groups 3 (AF+PRZ), 4 (AF+ZQR), and 5 (AF+PRZ+ZQR) received 20 mg/kg of AFB(1) intraperitoneally 30 min after the intraperitoneal administration of prazosin (0.3 mg/kg), zosuquidar (25 mg/kg), and prazosin+zosuquidar (0.3 mg/kg prazosin + 25 mg/kg zosuquidar), respectively. Six hours after the administration of AFB(1), blood and brain samples were collected from the animals in Groups 2 to 5. AFB(1) concentrations were determined using an HPLC system with fluorescence detection. Individual and simultaneous administration of prazosin and zosuquidar significantly reduced the brain concentrations of AFB(1) in comparison to a single administration of AFB(1) (P

Published
2017

18. Etanercept - can it be used in the treatment of endotoxemia?

Author

Cetin, Gul, Dik, Burak, Er, Ayse, Yazar, Enver, Altan, FERAY, Uney, Kamil, Elmas, Muammer, Selçuk Üniversitesi, Veteriner Fakültesi, Klinik Öncesi Bilimler Bölümü, Er, Ayse, Dik, Burak, Uney, Kamil, Elmas, Muammer, and Yazar, Enver

Subjects
Coagulation, Prostaglandin, Cytokines, Endotoxemia, Etanercept
Abstract

WOS: 000314082300023, Aim of this study was to investigate that effect of etanercept administration on the concentrations of cytokines, fibrinogen, antithrombin, 13,14-dihydro-15-keto-prostaglandin F-2 alpha and biochemical values in the endotoxemia. A totally male 126 Sprague Dawley rats were divided 3 equal groups; lipopolysaccharide (4 mg, IP), etanercept (8 mg/kg, IP) and lipopolysaccharide + etanercept were administered to Group 1, 2, and 3, respectively. Blood samples were collected at 0, 1, 2, 4, 8, 12 and 24th hours after treatments. Serum tumor necrosis factor-a, interleukin-1 beta, interleukin-10 and plasma 13,14-dihydro-15-keto-prostaglandin F-2 alpha levels were measured with ELISA reader, while antithrombin and fibrinogen levels were measured with coagulometer. Serum biochemical parameters were determined with auto-analyzer. Etanercept had irregular effect on the fibrinogen levels and it increased PGM, alkaline phosphatase and alanine aminotransferase activities. Lipopolysaccharide increased cytokines, PGM, fibrinogen, organ damage markers and triglyceride levels, and it had irregular effect on the antithrombin levels. Increased cytokines, PGM and fibrinogen levels were determined in lipopolysaccharide + etanercept group, but irregular changes were observed in antithrombin levels. Etanercept exactly depressed the increased creatine kinase-MB level and relatively depressed the increased tumor necrosis factor-a while it extended the presence of tumor necrosis factor-a, and it increased the elevated interleukin-10 levels by lipopolysaccharide. In conclusion, when protective effect of etanercept on the heart and increasing effect on the interleukin-10 levels in the endotoxennia is considered, single dose etanercept may be beneficial in the veterinary medicine.

Published
2013

21. Effects of drugs on kinetic values of cytokines, adenosine deaminase and 13,14-dihydro-15-keto-prostaglandin F 2α in endotoxemia: A different approach

Author

ALTAN, Feray, ELMAS, Muammer, ER, Ayse, UNEY, Kamil, CETİN, Gul, TRAS, Bunyamin, and YAZAR, Enver

Subjects
Enrofloksasin,fluniksin,deksametazon,kinetik,endotoksemi belirteçleri, Enrofloxacin,flunixin,dexamethasone,kinetic,endotoxemia markers
Abstract

Amaç: Lipopolisakkaritle (LPS) oluşturulan deneysel endotoksemide sitokinler, adenozin deaminaz (ADA) ve 13,14-dihidro-15-keto-prostaglandin F2α (PGM)’nın kinetik değerlerine tek başlarına ve/veya kombine uygulanan enrofloksasin (ENR), fluniksin meglumin (FM) ve deksametazonun (DEX) etkilerini belirlemektir. Gereç ve Yöntem: Araştırmada kullanılan ratlar 7 gruba ayrıldı. Deneysel endotoksemi oluşturmak için pozitif kontrol grubu dahil bütün gruplara LPS uygulandı. Diğer altı gruba ENR, FM, düşük doz DEX, yüksek doz DEX, ENR+FM+düşük doz DEX ve ENR+FM+yüksek doz DEX uygulandı. Uygulama sonrası 0, 1, 2, 4, 6, 8, 12, 24 ve 48. saatlerde kan örnekleri toplandı. Tümör nekroz faktör alfa (TNFα), interlökin-6 (IL6), interlökin-10 (IL-10), ADA ve PGM düzeyleri ELISA ile belirlendi. Eğri altında kalan alan farmakokinetik programla, plazma veya serum maksimum konsantrasyon (Cmax) ile maksimum konsantrasyona ulaşma zamanı (tmax) direk bakı yöntemiyle belirlendi. Bulgular: Pozitif kontrol (LPS) grubuyla kıyaslandığında EAA0-48 değerlerinin; ENR grubunda PGM için artarken (p, Aim: The objective of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on kinetic values of cytokines, adenosine deaminase (ADA) and 13,14-dihydro-15-keto-prostaglandin F2a (PGM) in lipopolysaccharide-induced endotoxemia. Materials and Methods: Rats were divided into seven groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The six other groups received the following drugs: ENR, FM, low-dose DEX, high-dose DEX, ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24, and 48 hours. Serum tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), ADA and plasma PGM levels were determined by ELISA. Area under the concentration time curve , maximal concentration in plasma or serum (Cmax) and time to reach (tmax) values were determined by pharmacokinetic computer program. Results: ENR increased (p

Published
2010

22. Effects of drugs on kinetic values of cytokines, adenosine deaminase and 13,14-dihydro-15-keto-prostaglandin F2α in endotoxemia: A different approach

Author

Altan,Feray, Cetin, Gul, Selçuk Üniversitesi, Veteriner Fakültesi, Klinik Öncesi Bilimler Bölümü, Elmas, Muammer, Er, Ayse, Uney, Kamil, Tras, Bunyamin, and Yazar, Enver

Subjects
fluniksin, deksametazon, Enrofloxacin, endotoksemi belirteçleri, kinetic, dexamethasone, Enrofloksasin, endotoxemia markers, flunixin, kinetik
Abstract

Amaç: Lipopolisakkaritle (LPS) oluşturulan deneysel endotoksemide sitokinler, adenozin deaminaz (ADA) ve 13,14-dihidro-15-keto-prostaglandin F2α (PGM)’nın kinetik değerlerine tek başlarına ve/veya kombine uygulanan enrofloksasin (ENR), fluniksin meglumin (FM) ve deksametazonun (DEX) etkilerini belirlemektir. Gereç ve Yöntem: Araştırmada kullanılan ratlar 7 gruba ayrıldı. Deneysel endotoksemi oluşturmak için pozitif kontrol grubu dahil bütün gruplara LPS uygulandı. Diğer altı gruba ENR, FM, düşük doz DEX, yüksek doz DEX, ENR+FM+düşük doz DEX ve ENR+FM+yüksek doz DEX uygulandı. Uygulama sonrası 0, 1, 2, 4, 6, 8, 12, 24 ve 48. saatlerde kan örnekleri toplandı. Tümör nekroz faktör alfa (TNFα), interlökin-6 (IL6), interlökin-10 (IL-10), ADA ve PGM düzeyleri ELISA ile belirlendi. Eğri altında kalan alan (EAA0-48) farmakokinetik programla, plazma veya serum maksimum konsantrasyon (Cmax) ile maksimum konsantrasyona ulaşma zamanı (tmax) direk bakı yöntemiyle belirlendi. Bulgular: Pozitif kontrol (LPS) grubuyla kıyaslandığında EAA0-48 değerlerinin; ENR grubunda PGM için artarken (p, Aim: The objective of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on kinetic values of cytokines, adenosine deaminase (ADA) and 13,14-dihydro-15-keto-prostaglandin F2a (PGM) in lipopolysaccharide-induced endotoxemia. Materials and Methods: Rats were divided into seven groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The six other groups received the following drugs: ENR, FM, low-dose DEX, high-dose DEX, ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24, and 48 hours. Serum tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), ADA and plasma PGM levels were determined by ELISA. Area under the concentration time curve (AUC0-48), maximal concentration in plasma or serum (Cmax) and time to reach (tmax) values were determined by pharmacokinetic computer program. Results: ENR increased (p

Published
2010

24. Effects of BCRP and P-gp Modulators on the Penetration of Aflatoxin B1 into the Mouse Brain.

Author

TRAS, Bunyamin, UNEY, Kamil, DIK, Burak, CETIN, Gul, CORUM, Orhan, and ATALAY, Sema

Subjects
AFLATOXINS, FLUORIMETRY, PRAZOSIN, PROTEIN-drug interactions, LABORATORY rats
Abstract

Copyright of Kafkas Universitesi Veteriner Fakultesi Dergisi is the property of University of Kafkas, Faculty of Veterinary Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2017
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31. Cardiac safety of diclofenac at a single dose in ram.

Author

Er A, Dik B, Corum O, and Cetin G

Subjects
Animals, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Biomarkers, Blood Cells drug effects, Chemical and Drug Induced Liver Injury blood, Chemical and Drug Induced Liver Injury etiology, Diclofenac administration & dosage, Dose-Response Relationship, Drug, Heart drug effects, Heart Diseases blood, Heart Diseases chemically induced, Injections, Intramuscular, Kidney drug effects, Kidney Diseases blood, Kidney Diseases chemically induced, Liver drug effects, Male, Muscle, Skeletal drug effects, Sheep, Sheep Diseases blood, Species Specificity, Anti-Inflammatory Agents, Non-Steroidal toxicity, Chemical and Drug Induced Liver Injury veterinary, Diclofenac toxicity, Heart Diseases veterinary, Kidney Diseases veterinary, Sheep Diseases chemically induced
Abstract

Nonsteroidal anti-inflammatory drugs are frequently prescribed drug group in human and veterinary medicine. However, diclofenac, a traditional nonsteroidal anti-inflammatory drug, related to cardiotoxicity is reported, and blood cardiac damage markers may increase within the first hours after damage. The aim of the current research was to determine the effect of diclofenac on the blood cardiac damage markers. Single dose of diclofenac (2.5 mg/kg, IM) was injected to 6 rams. Blood samples were collected in before (0 hour, control) and 6 hours after injection. Specific (troponin I, and creatine kinase-MB) and nonspecific (lactate dehydrogenase, aspartate aminotransferase) blood cardiac damage marker concentrations, routine biochemical (hepatic damage, renal damage, lipid metabolism, glucose, and phosphorus) parameters, and hemogram values were measured. Diclofenac increased (P < 0.05) specific (troponin I) and nonspecific cardiac (lactate dehydrogenase, aspartate aminotransferase), hepatic (aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase), and muscular (creatine kinase) damage markers and high density lipoprotein level, while it decreased (P < 0.05) low density lipoprotein level. Moreover, diclofenac decreased (P < 0.05) white blood cell counts and increased (P < 0.05) red blood cell counts. In conclusion, it may be stated that diclofenac shows slight cardiotoxicity, whereas it may show potent hepatic and muscular damage effects at an intramuscularly single dose in sheep. Thereby, repeated injections of diclofenac may be more harmful in sheep.

Published
2013
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