Browsing by Author "Er A."

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A cardioprotective role of Nerium oleander with the expression of hypoxia inducible factor 2A mRNA by increasing antioxidant enzymes in rat heart tissue
(2018-01-01) Hitit M.; Corum O.; Corum D.D.; Donmez H.; Cetin G.; Dik B.; Er A.
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.
Pentoxifylline may restore kanamycin-induced renal damage in rats
(2018-01-01) Corum O.; Ozdemir O.; Hitit M.; Corum D.D.; Coskun D.; Er A.
Background: Kidney damage can be caused by many factors, such as using certain drugs in high doses or over the long term. The use of one such group of drugs, aminoglycosides, which act as Gram-negative antibacterial therapeutic agents, can lead to nephrotoxicity. It has been hypothesized that aminoglycoside-induced nephrotoxicity might be prevented by using pentoxifylline, which has antioxidant and anti-inflammatory effects and improves microcirculation. The objective of this present research was to determine the protective effects of pentoxifylline on kanamycin-induced kidney damage. Materials, Methods & Results: Thirty-two male Wistar rats were divided into four groups as follows: control, pentoxifylline, kanamycin, and kanamycin + pentoxifylline. The control group received intraperitoneal (IP) injections of 0.5 mL normal saline solution once a day (d) (SID) for 20 d; the pentoxifylline group received IP injections of 50 mg/kg pentoxifylline twice a day (BID) for 20 d, the kanamycin group received subcutaneous (SC) injections of 500 mg/kg kanamycin SID for 20 d, and the kanamycin + pentoxifylline group received both SC injections of 500 mg/kg kanamycin SID and IP injections of 50 mg/kg pentoxifylline BID for 20 d. At the end of 20 d, blood samples were taken from the heart by cardiac puncture under general anesthesia. After euthanizing the rats by cervical dislocation under anesthesia, the kidneys were immediately removed, relative kidney weights were calculated, and routine pathologic evaluations were conducted. Hemogram parameters were measured using a blood cell count apparatus and serum biochemical parameters were measured using an autoanalyzer. Kanamycin also caused (P < 0.05) tubular degeneration and tubular dilatation. Although pentoxifylline significantly reduced the level of kanamycin-induced tubular degeneration (P < 0.05), it did not significantly reduce tubular dilatation. Increases in relative kidney weights (P < 0.05) and in interstitial mononuclear cell (MNC) infiltrates were observed in the kanamycin and kanamycin + pentoxifylline groups compared to those in the control and pentoxifylline groups. Statistically significant changes were determined in the levels of some hemogram and biochemical parameters within reference ranges (P < 0.05). Discussion: In this study, both tubular degeneration and dilatation were observed in the kanamycin group. Pentoxifylline inhibited (P < 0.05) kanamycin-induced tubular degeneration and appeared to also reduce tubular dilatation, although this reduction was not significant. Tubular necrosis, epithelial edema of proximal tubules, tubular fibrosis, and perivascular inflammation might also be observed in aminoglycoside-induced nephrotoxicity. In current research, pentoxifylline prevented tubular damage induced by kanamycin, but did not inhibit infiltration by MNCs. Pentoxifylline also ameliorated amikacin- or gentamycin-induced histopathologic changes, especially those associated with tubular structures. The protective effects of pentoxifylline on kanamycin-induced tubular nephrotoxicity in this research might be a result of its stimulating the production of prostaglandin, a vasodilator, and of its improving microcirculation. Although the anti-inflammatory effects of pentoxifylline have been reported, these did not inhibit kanamycin-induced infiltration by interstitial MNCs in the present study. These results could indicate that the anti-inflammatory effects of pentoxifylline are not obvious and/or are dose dependent. Statistically significantly changes were determined in the levels of some hemogram and biochemical parameters in reference ranges. However, these changes were within the reference ranges for rats. These results suggested that kanamycin-induced tubular degeneration and dilatation might be prevented by administering pentoxifylline.
Pharmacokinetics and bioavailability of ceftriaxone in brown trout (Salmo trutta fario) after intravenous and intramuscular administration
(2019-02-01) Corum O.; Er A.; Durna Corum D.; Atik O.; Uney K.
Ceftriaxone (CTX) is a third-generation cephalosporin that has proven to be effective in the treatment of infections caused by a wide range of gram-positive and gram-negative microorganisms. This study aimed to determine the plasma and muscle pharmacokinetics of CTX after its administration via the intravenous (IV) and intramuscular (IM) routes to brown trout (Salmo trutta fario) at temperatures of 10 °C–13 °C. In total, 140 healthy brown trout (body weight, 245 ± 38 g) were used. The brown trout received single IV and IM injections of CTX at 25 mg/kg. The IV doses were injected into the caudal vein, whereas the IM doses were injected into the right epaxial muscles. The plasma and muscle tissue concentrations of CTX were measured using high-performance liquid chromatography. Pharmacokinetic parameters were calculated using noncompartmental methods. Following the IV administration of CTX, the elimination half-life (t1/2ʎz), volume of distribution at steady state, total body clearance, and area under the concentration–time curve (AUC0–72) in plasma were 5.83 h, 0.09 L/kg, 0.02 L/h/kg, and 1079.46 h*μg/mL, respectively. After the IM administration of CTX, plasma t1/2ʎz, peak plasma concentration (Cmax), time to reach Cmax, and bioavailability were 22.78 h, 87.92 μg/mL, 0.5 h, and 27.19%, respectively. The AUCMuscle/AUCPlasma ratio following the IV administration was 0.02 and that following the IM administration was 0.04. CTX exhibited low bioavailability and prolonged t1/2ʎz after the IM administration. The prolonged t1/2ʎz of CTX could thus be beneficial in brown trout. Nevertheless, future studies that aim to determine the clinical efficacy and pharmacokinetics after repeated administration of CTX are warranted.
Pharmacokinetics and bioavailability of tolfenamic acid in sheep
(2018-12-01) Corum O.; Corum D.D.; Er A.; Yildiz R.; Uney K.
The pharmacokinetics, bioavailability, and tolerability of tolfenamic acid (TA) were determined after treating sheep with TA via different routes and doses. This crossover study was carried out with a washout period of 15 days. In the study, 16 clinically healthy sheep were randomly assigned to two equal groups. In the first group (n = 8), animals received TA by intravenous (IV), intramuscular (IM), subcutaneous (SC), or oral (OR) routes at 2 mg/kg. In the second group (n = 8), TA was administered intravenously to each sheep at 2, 4, 8, and 16 mg/kg. Plasma samples were analyzed with a high-performance liquid chromatography assay. Noncompartmental pharmacokinetic analyses were used to evaluate the data. The area under the concentration–time curves (AUC0−∞), elimination half-life (t1/2ʎz), and the mean residence time (MRT) significantly differed among the administration routes at 2 mg/kg of TA. Following IM, SC, and OR administrations, TA demonstrated different peak concentrations (Cmax) and time to reach Cmax (Tmax), with a bioavailability of 163%, 127%, and 107%, respectively. The dose-normalized AUC0−∞ revealed a significant difference among the dose groups; however, the relationship between dose and AUC0−∞ was linear. Both t1/2ʎz and MRT increased depending on the dose. Although the total clearance (ClT) decreased depending on dose, the volume of distribution at steady-state (Vss) increased. Tolfenamic acid indicated a long half-life and high bioavailability following IM, SC, and OR administrations at 2 mg/kg. TA exhibited linear kinetics and was well tolerated by the animals, except at 16 mg/kg. Thus, TA may be used in different routes and doses (≤8 mg/kg) in sheep; however, further studies are needed to determine the clinical efficacy of TA during the inflammatory and painful conditions and the pharmacokinetics and safety of repeated administration in sheep.
Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep
(2019-11-01) Corum O.; Corum D.D.; Er A.; Uney K.
The purpose of this study was to determine the pharmacokinetics of cefquinome (CFQ) following single and repeated subcutaneous (SC) administrations in sheep. Six clinically healthy, 1.5 ± 0.2 years sheep were used for the study. In pharmacokinetic study, the crossover design in three periods was performed. The withdrawal interval between the study periods was 15 days. In first period, CFQ (Cobactan, 2.5%) was administered by an intravenous (IV) bolus (3 sheep) and SC (3 sheep) injections at 2.5 mg/kg dose. In second period, the treatment administration was repeated via the opposite administration route. In third period, CFQ was administrated subcutaneously to each sheep (n = 6) at a dose of 2.5 mg/kg q. 24 hr for 5 days. Plasma concentrations of CFQ were measured using the HPLC-UV method. Pharmacokinetic parameters were calculated using non-compartmental methods. The elimination half-life and mean residence time of CFQ after the single SC administration were longer than IV administration (p < 0.05). Bioavailability (F%) of CFQ following the single SC administration was 123.51 ± 11.54%. The area under the curve (AUC0-∞) and peak concentration following repeated doses (last dose) were higher than those observed after the first dose (p < 0.05). CFQ accumulated after repeated SC doses. CFQ can be given via SC at a dose of 2.5 mg/kg every 24 hr for the treatment of infections caused by susceptible pathogens, which minimum inhibitory concentration is ≤1.0 μg/ml in sheep.
Pharmacokinetics of ceftriaxone following single ascending intravenous doses in sheep
(2018-12-01) Corum D.D.; Corum O.; Altan F.; Eser Faki H.; Bahcivan E.; Er A.; Uney K.
The objective of this study was to evaluate the pharmacokinetics of CTX following intravenous administration of ascending doses in sheep. In this study, six clinically healthy Akkaraman sheep (2.4 ± 0.4 years and 50 ± 3 kg of body weight) were used. CTX was administered intravenously to each sheep at 20, 40, and 80 mg/kg doses in a crossover design with a 15-day washout period. Plasma concentrations of CTX were measured using the high-performance liquid chromatography-UV method. Pharmacokinetic parameters were calculated by non-compartmental analysis. CTX was well tolerated following administration at 20, 40, and 80 mg/kg doses. The elimination half-life following administration of 40 and 80 mg/kg doses were significantly longer than that of 20 mg/kg dose (P < 0.05). The volume of distribution at steady state was similar among the groups (P > 0.05). When compared to 20 mg/kg, dose-normalized AUC0–∞ at the 80 mg/kg dose significantly increased (P < 0.05). The relation between dose and AUC0–∞ was linear. Our study showed that CTX can be used at 12-h intervals for 20, 40, and 80 mg/kg doses to maintain T > minimum inhibitory concentration (MIC) of >40% for the treatment of infections caused by bacteria with MIC values ≤2, ≤4, and ≤16 μg/mL, respectively. This information may be helpful in adjusting the dosage regimen, but there is a need for future work.
Pharmacokinetics of intravenous and intramuscular danofloxacin in red-eared slider turtles (Trachemys scripta elegans)
(2019-05-01) Corum O.; Corum D.D.; Altan F.; Er A.; Cetin G.; Uney K.
This study aimed to investigate the pharmacokinetics of danofloxacin in red-eared slider turtle (Trachemys scripta elegans) following a single intravenous (IV) and intramuscular (IM) administrations of 6 mg/kg, using a two-way crossover study with 30-day washout period. Eight clinically healthy red-eared slider turtle weighing 410-600 g (mean 490 g) were used for the study. Danofloxacin concentrations were measured using the reversed-phase high-performance liquid chromatography. The plasma concentration-time data were evaluated by a non-compartmental method. After IV administration, the elimination half-life (t1/2ʎz), mean residence time (MRT0-∞), area under the concentration-time curve (AUC0-∞), volume of distribution at steady state and total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr·μg/ml, 1.29 l/kg and 0.04 l/hr/kg, respectively. Following IM administration, t1/2ʎz, MRT0-∞AUC0-∞,peak concentration (Cmax), time to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr·μg/ml, 8.75 μg/ml, 1.5 hr and 139.89%, respectively. Danofloxacin has clinically superior pharmacokinetic properties, including the complete IM absorption, slow elimination and wide volume of distribution in redeared slider turtles. However, further pharmacokinetics/pharmacodynamics studies are necessary for the treatment of diseases caused by susceptible bacteria with known minimum inhibitory concentration values in red-eared slider turtles.
Pharmacokinetics of levamisole in the red-eared slider turtles (Trachemys scripta elegans)
(2019-11-01) Corum O.; Durna Corum D.; Atik O.; Altan F.; Er A.; Uney K.
The pharmacokinetics and bioavailability of levamisole were determined in red-eared slider turtles after single intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration. Nine turtles received levamisole (10 mg/kg) by each route in a three-way crossover design with a washout period of 30 days. Blood samples were collected at time 0 (pretreatment), and at 0.25, 0.5, 1, 1.5, 3, 6, 9, 12, 18, 24, 36, and 48 hr after drug administration. Plasma levamisole concentrations were determined by a high-performance liquid chromatography assay. Data were analyzed by noncompartmental methods. The mean elimination half-life was 5.00, 7.88, and 9.43 hr for IV, IM, and SC routes, respectively. The total clearance and volume of distribution at steady state for the IV route were 0.14 L hr−1 kg−1 and 0.81 L/kg, respectively. For the IM and SC routes, the peak plasma concentration was 9.63 and 10.51 μg/ml, respectively, with 0.5 hr of Tmax. The bioavailability was 93.03 and 115.25% for the IM and SC routes, respectively. The IM and SC route of levamisole, which showed the high bioavailability and long t1/2ʎz, can be recommended as an effective way for treating nematodes in turtles.
Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after intravenous administration of increasing doses to sheep
(2019-07-01) Corum O.; Corum D.D.; Atik O.; Er A.; Uney K.
OBJECTIVE To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. ANIMALS 6 healthy adult Merino sheep. PROCEDURES Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. RESULTS No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h.µg/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep. (Am J Vet Res 2019;80:702-708).
Pharmacokinetics of tolfenamic acid in red-eared slider turtles (Trachemys scripta elegans)
(2019-09-01) Corum O.; Atik O.; Durna Corum D.; Er A.; Uney K.
Objective: To determine the pharmacokinetics of tolfenamic acid (TA) after different routes of administration [intravenous (IV) and intramuscular (IM), 2 mg kg−1] and doses (IV, 2 and 4 mg kg−1) in red-eared slider turtles (Trachemys scripta elegans). Study design: Randomized experimental trial. Animals: Sixteen healthy red-eared slider turtles. Methods: Turtles were randomly assigned to two groups (n = 8 each). Group 1 received TA at a dose of 2 mg kg−1 IV and then IM, after a washout period of 30 days. Group 2 received 4 mg kg−1 TA IV. A noncompartmental analysis was used to calculate pharmacokinetic variables. Results: No local and/or systemic adverse drug effects were observed in any turtle. Elimination half-life and mean residence time following IM administration at 2 mg kg−1 were significantly longer than those following IV administration. The bioavailability following IM administration was complete. The area under the plasma concentration-time curve, elimination half-life, mean residence time and total clearance were significantly different between the dose groups. Conclusions and clinical relevance: The absence of adverse reactions in the turtles of the study of TA along with the favourable pharmacokinetic properties (the long half-life and the complete bioavailability) of TA administered at the single doses of 2 and 4 mg kg−1 suggest the possibility of its effective use in turtles. However, further studies are required to establish a multiple dosage regimen of TA and to evaluate the clinical efficacy of administering TA.
Plasma and tissue disposition of danofloxacin in brown trout (Salmo trutta fario) after intravenous and intramuscular administrations
(2018-12-02) Corum O.; Durna Corum D.; Er A.; Terzi E.; Uney K.
Plasma and muscle pharmacokinetics of danofloxacin were investigated after 10 mg/kg intravenous (IV, caudal vein) and intramuscular (IM, right epaxial muscles) administrations in 168 healthy brown trout (Salmo trutta fario) at 10°C–13°C. High-performance liquid chromatography was used to determine its plasma and muscle concentrations. Pharmacokinetic parameters were analysed with a non-compartmental model. After IV administration, elimination half-life (t 1/2ʎz ), area under the concentration–time curve (AUC 0–∞ ), mean residence time (MRT 0–∞ ), volume of distribution at steady state, total body clearance in plasma and AUC Muscle /AUC Plasma ratio were 22.22 h, 140.66 h*µg/mL, 23.15 h, 2.28 L/kg, 0.07 L/h/kg and 3.79, respectively. After IM administration, t 1/2ʎz , AUC 0–∞ , MRT 0–∞ , peak concentration (C max ), time to reach C max , bioavailability in plasma and AUC Muscle /AUC Plasma ratio were 28.28 h, 84.39 h*µg/mL, 37.31 h, 4.79 µg/mL, 1 h, 59.99% and 8.46, respectively. Danofloxacin exhibited long t 1/2ʎz and good bioavailability after IM administration. Therefore, 10 mg/kg IM administration of danofloxacin in brown trout can provide AUC 0–24 /MIC of > 125 and C max /MIC of > 10 to treat diseases caused by susceptible bacteria with ≤ 0.336 µg/mL MIC.
Predation efficacy of the predator Coccinella septempunctata L. on the Aphid species Macrosiphum rosae (L.) in Kastamonu Province, Turkey
(2017-01-01) Unal S.; Er A.; Akkuzu E.; Šálek L.
This study was conducted between the years 2013-2014 in order to determine the phenology of the predator Coccinella septempunctata Linnaeus (Coleoptera: Coccinellidae) and to evaluate its efficacy on Macrosiphum rosae (Linnaeus) (Hemiptera: Aphididae) in Kastamonu, Turkey. Rearing of C. septempunctata was carried out at 21.3±4.00°C and 78.8±9.44% relative humidity. The first, second, third and fourth larval instars of C. septempunctata consumed 20.3, 54.3, 108.2, and 232.7 M. rosea, respectively. The predation efficacy of the C. septempunctata was increased with the progress of the larval instars up to the fourth which was the most voracious.