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Alcoholic extract of Tarantula cubensis induces apoptosis in MCF-7 cell line.
(ALLIED ACAD, 2017) Er, Ayse; Corum, Orhan; Corum, Duygu; Hitit, Mustafa; Donmez, Huseyin; Guzeloglu, Aydin
Tarantula cubensis Alcoholic Extract (TCAE) is a homeopathic agent used for treating many disorders. This study aimed to define the effects of TCAE on the breast carcinoma cell line (MCF-7). After various concentrations (10, 20, 40, 80 and 160 mu l/ml) of TCAE were applied to MCF-7 cells and the human embryonic kidney cell line (HEK293), the cells were incubated for 1, 3, 6, 9, 12, 24 and 48 h, followed by analysis by MTT assays. According to the results of the MTT assays, cells treated with 20 or 40 mu l/ml TCAE for 6 h were applied to apoptosis analysis by flow cytometry. Secreted levels of tumor necrosis factor alpha (TNF alpha), interleukin (IL)-1 beta, IL-6, IL-10, Interferon-gamma (IFN gamma), Transforming Growth Factor beta (TGF beta), and Nuclear Factor-kappa B (NF-kappa B) were measured using ELISAs. TNF alpha and TGF beta levels increased while IL-6 and IL-10 levels fluctuated in MCF-7 cells. In conclusion, our study suggests that TCAE may change the normal cancer physiology and lead to cell death by activating apoptosis in MCF-7 cells.
Amiodarone May Prevent the Tilmicosin-caused Lethal Toxicity
(UNIV FED RIO GRANDE DO SUL, 2014) Er, Ayse; Tras, Bunyamin; Cetin, Gul; Dik, Burak
Background: Tilmicosin is widely used in veterinary medicine and its accidental overdose by injection may cause death via causing negative inotropy and positive chronotropy in both the treated animal and the veterinarian. In addition, there is no any antidote against to tilmicosin-caused death. Amiodarone blocks some channels in the heart, but it has much complex effect including vagotonic, bradycardic etc on the heart. Considering vagotonic and bradycardic effects of amiodarone, it has been hypothesised that amiodarone may prevent tilmicosin-caused death. The aim of this study was to determine the effect of amiodarone on the survival rate of rats in tilmicosin-caused lethal toxicity. Materials, Methods & Results: Twenty female Wistar rats (body weight: 288 +/- 33.8 g, age: 7-8 months) were used in this study. The study protocol was approved by the Ethical Committee. Rats received food and water ad libitum. The rats were divided into two groups containing 10 rats each. Rats in Group 1 were administered 360 mg/kg of tilmicosin in a single subcutaneous injection. Rats in Group 2 were administered 25 mg/kg of amiodarone via the tail vein at 8. min after the single subcutaneous injection of tilmicosin in a dose of 360 mg/kg. After the injections, deaths were recorded at 0, 2, 6, 10, 12 and 24 h. At the end of the 24-h period, survival/death ratio was analysed by the Chi-square test. The level of statistical significance was set at P < 0.05. The survival rate of Group 2 (40%) was statistically significantly (P < 0.025) higher than that of Group 1 (0.0%). In control group all rats died at 10 h after subcutaneously tilmicosin injection. In Group 2 were administered 25 mg/kg of amiodarone (intravenously) at 8 min after the single subcutaneous injection of tilmicosin in a dose of 360 mg/kg, and 2 rats died at 2 h and 4 rats died at 12 h. At the end of the experiment, all rats died in tilmicosin injected group whereas 4 rats lived in amiodarone and tilmicosin administered group. Clinically tilmicosin administered rats were observed as worse than amiodarone and tilmicosin administered group. Observed clinical signs of toxicity were fluffed feathers, ataxia, weakness in the legs, hypoactivity, lethargy. Discussion: Tilmicosin, a macrolide antibiotic, is widely used in the therapy of respiratory system infections in cattle and sheep. However, tilmicosin has cause serious cardiac side effects, and after tilmicosin administration to animals or accidental self-exposure of this drug to humans, if may cause heart related side effects including chest pain, increased serum cardiac damage markers, changed electrocardiogram, and decreased antioxidant enzyme activities in the heart, serum potassium level and death, as well as. Tilmicosin causes negative inotropy and positive chronotropy. Although the mechanism of tilmicosin-induced cardiotoxicity is not fully known, the inhibitory effect of tilmicosin on the entry of calcium into the cell may cause this lethal effect. It can be speculated that the beneficial effect of amiodarone in tilmicosin toxicity may primarily depend on the potassium channel blocking, antiarrhythmic effect and other exactly not explained effects. Amiodarone may increase survival rate and may be beneficial in the treatment of tilmicosin-caused lethal toxicity. However, especially specific cellular target or other effects of amiodarone on the heart are needed to determine in the tilmicosin toxicity.
ASSESSMENT OF THE CARDIOTOXICITY OF TULATHROMYCIN IN RABBITS
(AKADEMIAI KIADO ZRT, 2011) Er, Ayse; Altan, Feray; Cetin, Gul; Dik, Burak; Elmas, Muammer; Yazar, Enver
The aim of this study was to determine the cardiotoxic potency of tulathromycin. Tulathromycin (10 mg/kg, SC) was administered to ten adult male rabbits, and blood samples were obtained before and after drug administration (0 and 6 hours). Serum cardiac damage markers (troponin I, creatine kinase-MB, myoglobin, lactate dehydrogenase, aspartate aminotransferase), routine serum biochemical values (alkaline phosphatase, alanine aminotransferase, gammaglutamyltransferase, creatinine, blood urea nitrogen, cholesterol, triglyceride, high-density lipoprotein, amylase, total protein, albumin, glucose, calcium, ionised calcium, sodium, potassium), white blood cell (WBC) and red blood cell (RBC) counts, arterial blood gas parameters (pH, partial carbon dioxide pressure, partial oxygen pressure, actual bicarbonate, standard bicarbonate, total carbon dioxide, base excess in vivo, base excess in vitro, oxygen saturation, packed cell volume, haemoglobin) and serum oxidative status (malondialdehyde, nitric oxide, superoxide dismutase, retinol, beta-carotene) were measured. Increased levels of troponin I, creatine kinase-MB and creatinine, and decreased WBC counts, ionised calcium and potassium levels were observed after drug administration. Tulathromycin treatment may cause cardiotoxicity, but its effects may be less dramatic than those of other macrolide antibiotics frequently used in veterinary medicine.
Azithromycin Prevents Pregnancy Loss: Reducing the Level of Tumor Necrosis Factor-Alpha and Raising the Level of Interleukin-10 in Rats
(HINDAWI PUBLISHING CORPORATION, 2013) Er, Ayse
The aim of this study was to determine the effect of azithromycin on LPS-induced pregnancy loss. Thirty-six pregnant female Wistar rats were divided into 4 equal groups as follows: control group, where 0.3 mL of normal saline solution was administered intravenously on day 10 of pregnancy; azithromycin group, where azithromycin was administered orally at 350 mg kg(-1) day on days 9, 10, and 11 of pregnancy; lipopolysaccharide group, where LPS was administered intravenously via the tail vein at 160 mu g kg(-1) on day 10 of pregnancy; and the azithromycin + LPS group, where azithromycin was administered orally at 350 mg kg(-1) day on days 9, 10, and 11 of pregnancy and LPS was administered intravenously at 160 mu g kg(-1) on day 10 of pregnancy. Blood samples were obtained from the tail vein on day 10 of the experiment. Pregnancy rates were determined. Tumor necrosis factor-alpha (TNF-alpha) and interleukin( IL-10) levels were measured by ELISA. Azithromycin prevented (P < 0.05) LPS-induced pregnancy loss. Higher TNF-alpha and IL-10 levels were measured (P < 0.05) in the LPS and azithromycin + LPS groups, respectively. In conclusion, azithromycin may be useful in infection- or endotoxemia-dependent pregnancy loss.
Cardiac Safety of Diclofenac at a Single Dose in Ram
(HINDAWI LTD, 2013) Er, Ayse; Dik, Burak; Corum, Orhan; Cetin, Gul
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 (2.5mg/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), andmuscular (creatine kinase) damagemarkers 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.
Cardiac safety of gamithromycin in ewes
(2016) Corum, Orhan; Dik, Burak; Bahcivan, Emre; Eser, Hatice; Er, Ayse; Yazar, Enver
Amaç: Bir makrolid antibiyotik olan gamitromisin sığırlarda pasteurellosis tedavisinde önerilmekle birlikte koyunlarda etiket dışı olarak kullanılmaktadır. Makrolid antibiyotiklerin kardiyotoksik etkileri bilinmektedir, ancak gamitromisinin koyunlarda kardiyak güvenilirliği ile ilgili bilgi bulunmamaktadır. Araştırmanın öncelikli amacı koyunlarda gamitromisinin kardiyak güvenilirliğini belirlemektir. Bunun yanı sıra karaciğer ve böbrek fonksiyonlarına ve hemogram parametrelerine etkisini tespit etmektir.Gereç ve Yöntem: Araştırmada 10 adet koyuna gamitromisin (6 mg/kg, SC) tek doz olarak uygulandı. Kan örnekleri uygulamadan önce (0. gün, kontrol) ve sonraki 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8 ve 9. günlerde alındı. Spesifik kalp hasar belirteçleri olan serum kreatin kinaz-MB kütle ve troponin I düzeyleri, karaciğer ile böbrek hasar belirteçleri ve hemogram parametreleri ölçüldü. Bulgular: Araştırmada troponin I düzeyinde birinci gün istatistiki olmayan yükselmeler belirlenirken, kreatin kinaz-MB kütle düzeyinde değişimler belirlenmedi. Total bilirubin, total protein, kreatinin ve akyuvar düzeyinde referans değerler arasında istatistiki değişimler belirlendi (P0.05).
A Cardioprotective Role of Nerium oleander with the Expression of Hypoxia Inducible Factor 2A mRNA by Increasing Antioxidant Enzymes in Rat Heart Tissue
(UNIV FED RIO GRANDE DO SUL, 2018) Hitit, Mustafa; Corum, Orhan; Corum, Duygu Durna; Donmez, Huseyin; Cetin, Gul; Dik, Burak; Er, Ayse
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.
Effect of Anti-TNF-alpha on the Development of Offspring and Pregnancy Loss During Pregnancy in Rats
(UNIV FED RIO GRANDE DO SUL, 2016) Er, Ayse; Aydin, Ibrahim; Dik, Burak
Background: Etanercept binds soluble tumor necrosis factor-alpha (TNF-alpha) and is classified as pregnancy risk category B. Increase in TNF-alpha level causes preterm labour or miscarriage. Lipopolysaccharides trigger preterm birth and abortion via producing of pro-inflammatory cytokines. Cytokines are divided into two groups as pro-inflammatory and anti-inflammatory. TNF-alpha is a pro-inflammatory cytokine, whereas interleukin (IL)-10 is an anti-inflammatory cytokine. IL-10 predominant in normal pregnancy while TNF-alpha characterize in abortion and recurrent abortion. The aim of this study was to determine the effect of etanercept on the development of offspring and lipopolysaccharide-induced pregnancy loss. Materials, Methods & Results: Twenty-eight female and 7 male Wistar rats (5-6 months old) were used in this study. The rats were fed a standard pelleted diet and tap water ad libitum. After female rats were caged with males for 1 day, the presence of a vaginal plug was designated as day 0 of pregnancy. Twenty-eight pregnant Wistar rats were divided into 4 equal groups, as follows: control (0.3 mL of Normal Saline Solution intravenously on day 10 of pregnancy); etanercept (0.8 mg kg(-1)/day intraperitoneally on days 9 and 10 of pregnancy); lipopolysaccharide (160 mu g kg(-1) intravenously on day 10 of pregnancy); and etanercept + lipopolysaccharide. Blood samples were obtained from the tail vein on day 10 of pregnancy (3 h after lipopolysaccharide administration). All animals were followed during pregnancy. Pregnancy rates and offspring characteristics were determined. TNF-alpha and IL-10 levels were measured using an ELISA reader. Etanercept alone did not have any negative effects, and etanercept did not prevent (P < 0.05) lipopolysaccharide-induced pregnancy loss. Higher TNF-alpha and IL-10 levels were measured (P < 0.05) in the etanercept + lipopolysaccharide group compared to other groups. Discussion: It is well known that use of etanercept does not increase pregnacy loss. In this study, higher pregnancy rates were determined in the control and etanercept groups than the lipopolysaccharide and etanercept + lipopolysaccharide groups. The proportion of fetal deaths in lipopolysaccharide administered pregnant subjects was decreased by the use of anti-TNF-alpha agents. While the concentrations of TNF-alpha are low in the onset of pregnancy period, the concentrations of TNF-alpha increases a peak level during the onset of labour. Embryonic resorption is affected by Th1 cytokines (TNF-alpha and lL-2) and low-dose lipopolysaccharide without any affecting mother survival, and in the early pregnancy term, the implantation area of embryo is enormously sensitive to these molecules. In the current study, etanercept increased the concentration of TNF-alpha and the concentration of IL-10 when compared to the lipopolysaccharide group. IL-10 has a protective role, while TNF-alpha is an abortive factor during pregnancy. Thus, etanercept did not prevent pregnancy loss. This finding may have reflected an insufficient dose of etanercept. Adverse effects did not occur in the offspring of the etanercept or control groups, and there was no difference between the two groups statistically. Adverse pregnancy outcomes such as stillbirth, low birth weight, spontaneous abortion and herediter malformations are not associated with TNF-alpha inhibitors. In conclusion, etanercept does not pose a major teratogenic risk and has no preventive effects with respect to infection-dependent pregnancy loss.
Effect of Corynebacterium cutis Lysate on Serum Oxidative Stress and Plasma Prostaglandin F2 alpha Metabolite Levels
(UNIV FED RIO GRANDE DO SUL, 2014) Er, Ayse; Dik, Burak; Corum, Orhan
Background: The Corynebacterium cutis lysate is commercial product. Unbalance between oxidants and antioxidants cause oxidative stress and lipid peroxidation in the cell. Macrophages phagocytose large pieces of bacteria and synthesize cytokines. In addition to the benefi cial results of the drug have side effects. Since changes in biochemical parameters refl ect structural dysfunction in the organism, monitoring changes of these parameters is a way to keep track of side effects. The aim of this study was to determine the effect of Corynebacterium cutis lysate on serum thiobarbituric acid-reactive substances (TBARS) and plasma 13,14-dihydro-15-keto-prostaglandinF2a (PGM) levels in sheep. Materials, Methods & Results: Six Merino crossbred ewes (aged > 2 years, weight 40-60 kg) were used in this study. The procedures were approved by the Ethics Committee. A dose of 8 mg (0.4 mL) of commercial Corynebacterium cutis lysate was subcutaneously injected to each of the 6 Merino crossbred ewes. Blood specimens were taken from the sheep prior to injection (day 0, control) and after the injection on days 1, 2, 3, and 4. The levels of serum TBARS and plasma PGM were determined using an Enzyme Linked Immunosorbent Assay (ELISA) reader. The values of the hemogram [ white blood cells (WBC), red blood cells (RBC), platelets (PLT), hematocrit (HTC), and hemoglobin (HBG)] were assessed using a blood cell count apparatus. The levels of plasma creatine kinase-MB (CK-MB), serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine, and cholesterol were determined on an autoanalyzer. The data obtained were analyzed using ANOVA and Scheffe's test as a post hoc test (SPSS 19.0). A P < 0.05 value was taken as the cut-off value for statistical signifi cance. An increase (P < 0.05) in the levels of plasma PGM and serum cholesterol was detected when compared to the control samples, but there was no statistically signifi cant (P > 0.05) change in the other parameters. Discussion: The Corynebacterium cutis lysate is a commercial product and used in cattle, newborn calves, sheep, and poultry as an immunostimulant against infections and to increase body resistance in times of stress. Corynebacterium cutis lysate increased (P < 0.05) in plasma PGM and serum cholesterol levels compared to the control group. Detailed studies dealing with the effect of Corynebacterium cutis lysate on PGM and TBARS are not available in the literature. There is a balance between oxidants and antioxidants in the organism. Unbalance between oxidants and antioxidants caused by increased production of oxidizing species leads to oxidative stress and lipid peroxidation in the cells. The levels of TBARS or malondialdehyde are used in order to determine lipid peroxidation. The levels of serum TBARS, malondialdehyde and PGM increased in experimental infection models. Macrophages phagocytose large pieces of bacteria such as Corynebacterium cutis lysate and this case triggers the synthesis of cytokines by macrophages. Cholesterol metabolism may change in infections, and high levels of cholesterol were determined in test subjects after injection of LPS. Lipid metabolism may be affected by stimulants of the immune system, such as Corynebacterium cutis lysate. In conclusion, Corynebacterium cutis lysate has no effect on the oxidative status and number of blood cells and organ (heart, liver and kidney) damage markers in sheep and it may increase plasma PGM level by stimulating the immune system.
Effect of single dose dexamethasone (0.1 mg/kg) on white blood cell counts and serum glucose levels in healthy ewes
(2016) Corum, Orhan; Dik, Burak; Er, Ayse
Amaç: Araştırmanın öncelikli amacı sağlıklı koyunlara tek doz deksametazon (0.1 mg/kg, SC) uygulamasının akyuvar sayısı ve serum glikoz düzeyine etkisini belirlemektedir. Ay-rıca deksametazonun diğer bazı hemogram ve serum biyo-kimyasal parametrelere etkisi de değerlendirilmiştir. Gereç ve Yöntem: Araştırmada 8 adet sağlıklı Akkaraman koyuna 0.1 mg/kg (SC, tek doz) dozunda deksametazon uy-gulandı. Uygulamadan önce (0. saat, kontrol) ve sonraki 4, 8, 12, 24, 36, 48 ve 72. saatlerde kan örnekleri alındı. Akyuvar sayısı, alyuvar sayısı, platelet sayısı, hemogram ve hematok-rit değerleri kan hücresi sayım cihazında ölçülürken, serum glikoz, laktat dehidrogenaz, alkalin fosfataz, total bilirubin, alanin aminotransferaz, aspartat aminotransferaz, gamma glutamiltransferaz, total protein, albümin, kan üre nitrojen, kreatinin, kolesterol, trigliserit, yüksek yoğunluklu lipopro-tein ve düşük yoğunluklu lipoprotein düzeyleri otoanalizör-de ölçüldü. Bulgular: Kontrol (0. saat) zamanla karşılaştırıldığında, dek-sametazonun akyuvar sayısı ve serum glikoz düzeyini yük-selttiği (P0.05) belirlendi ve bu yüksek düzeylerin 48 saat süresince devam ettiği gözlendi. Ayrıca total bilirubin, trig-liserit ve kan üre nitrojen düzeylerinde istatistiki değişimler gözlendi, ancak bu değişimlerin referans aralıklar içinde ol-duğu tespit edildi. Öneri: Koyunlara deksametazon uygulamasının akyuvar sa-yısı ve serum glikoz düzeyini yükseltebileceği ve bu yüksek değerlerin 2-3 gün süresince belirlenebileceği ifade edilebilir.
Effect of Tilmicosin on Serum Cytokine Levels in the Endotoxemia
(MEDWELL ONLINE, 2009) Uney, Kamil; Er, Ayse; Avci, Gulcan Erbil; Bulbul, Aziz; Elmas, Muammer; Yazar, Enver
The effect of tilmicosin on serum cytokine concentrations were investigated in healthy and lipopolysaccharide-treated mice. The mice were divided into 3 groups. Lipopolysaccharide (250 mu g, Escherichia coli 0111:B4, intraperitoneally) was injected into the positive control group. The other 2 groups received tilmicosin (20 mg kg(-1), subcutaneously) concurrently without or with lipopolysaccharide. After treatment, serum samples were collected at 0, 1.5, 3, 6, 12 and 24 h. Serum tumor necrosis factor, interleukin-1 and interleukin-10 levels were determined by enzyme-linked immunosorbent assay. Lipopolysaccharide increased all cytokine levels in the healthy mice. Tilmicosin slightly induced interleukin-1 production in the healthy mice, while it had no effect on tumor necrosis factor or interleukin-10 productions. However, tilmicosin elevated (p<0.05) tumor necrosis factor, interleukin-1 and interleukin-10 levels in lipopolysaccharide-treated mice. In conclusion, these data suggest that tilmicosin stimulates both proinflammatory and antiinflammatory cytokines at the dose recommended for infection.
The Effects of Florfenicol on the Values of Serum Tumor Necrosis Factor-alpha and Other Biochemical Markers in Lipopolysaccharide-Induced Endotoxemia in Brown Trout
(HINDAWI LTD, 2014) Er, Ayse; Dik, Burak
The aim of the present study was to determine the effects of florfenicol on the expected changes in sTNF-alpha.,damagemarkers of the liver and kidney, and the lipid metabolism parameters in endotoxemic brown trout. Ninety-six brown trout were included in this study. After six of the fish were reserved as the control group, the remaining 90 fish were divided equally into 3 groups as follows: LPS ( 2mg/kg, IP), LPS (2mg/kg, IP) + florfenicol (40mg/kg, IM), and florfenicol (40mg/kg, IM). Blood samples were obtained from the tail of the fish at 1.5, 3, 6, 10, and 24 hours. The levels of sTNF-alpha were determined by ELISA and biochemical markers were evaluated with an autoanalyzer. A significant increase was observed in the values of sTNF-alpha in the LPS and LPS + florfenicol groups (P < 0.05). Significant increases were found in the kidney and liver damage determinants in the LPS and LPS + florfenicol groups (P < 0.05). Irregular changes in the lipid metabolism parameters were observed in all the subgroups. In conclusion, florfenicol does not affect the increases of sTNF-alpha caused by LPS and does not prevent liver or kidney damage; at least, it can be said that florfenicol does not have any evident positive effects on the acute endotoxemia of fish.
EFFECTS OF TYLOSIN, TILMICOSIN AND TULATHROMYCIN ON INFLAMMATORY MEDIATORS IN BRONCHOALVEOLAR LAVAGE FLUID OF LIPOPOLYSACCHARIDE-INDUCED LUNG INJURY
(AKADEMIAI KIADO ZRT, 2012) Er, Ayse; Yazar, Enver
The aim of this study was to determine the anti-inflammatory effects of macrolides through kinetic parameters in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide-induced lung injury. Rats were divided into four groups: lipopolysaccharide (LPS), LPS + tylosin, LPS + tilmicosin and LPS + tulathromycin. BALF samples were collected at sampling times. TNF, IL-1 beta, IL-6, IL-10 and 13,14-dihydro-15-keto-prostaglandin F-2 alpha (PGM) and C-reactive protein (CRP) were analysed. Area under the curve (AUC) and maximum plasma concentration (C-max) values of inflammatory mediators were determined by a pharmacokinetic computer programme. When inflammatory mediator concentrations were compared between the LPS group and other groups for each sampling time, the three macrolides had no pronounced depressor effect on cytokine levels, but they depressed PGM and CRP levels. In addition, tylosin and tilmicosin decreased the AUC(0-24) level of TNF, while tilmicosin decreased the AUC(0-24) level of IL-10. Tylosin and tulathromycin decreased the AUC(0-24) of PGM, and all three macrolides decreased the AUC(0-24) of CRP. Especially tylosin and tulathromycin may have more expressed anti-inflammatory effects than tilmicosin, via depressing the production of inflammatory mediators in the lung. The AUC may be used for determining the effects of drugs on inflammation. In this study, the antiinflammatory effects of these antibiotics were evaluated with kinetic parameters as a new and different approach.
Etanersept - endotoksemi tedavisinde kullanılabilir mi?
(2013) Er, Ayse; Dık, Burak; Cetın, Gul; Altan, Feray; Uney, Kamil; Elmas, Muammer; Yazar, Enver
Araştırmanın amacı endotoksemide etanersept uygulamasının kan sitokinler, fibrinojen, antitrombin, 13,14-dihidro-15-keto prostaglandin F2? ve biyokimyasal parametrelere etkisini araştırmaktır. Erişkin 126 adet Sprague Dawley ırkı erkek rat 3 gruba ayrılarak; 1. Gruba lipopolisakkarit (4 mg, IP), 2. Gruba etanersept (8 mg/kg, IP) ve 3. Gruba lipopolisakkarit etanersept uygulamaları yapıldı. Uygulamalardan sonra 0., 1., 2., 4., 8., 12. ve 24. saatlerde kan örnekleri alındı. Serum tümör nekrozis faktör-?, interlöykin-1?, interlöykin-10 ve plazma 13,14-dihidro-15-keto-prostaglandin F2? düzeyleri ELISA okuyucusunda; sitratlı plazma antitrombin ve fibrinojen düzeyleri koagulometrede; serum biyokimyasal parametreleri otoanalizörde belirlendi. Etanerseptin fibrinojen düzeyinde düzensiz değişimlere ve 13,14-dihidro-15-keto-prostaglandin F2?, alkalen fosfataz ile alanin aminotransferaz düzeyinde yükselmelere neden olduğu belirlendi. Lipopolisakkarit uygulaması sitokinler, 13,14-dihidro-15-keto-prostaglandin F2?, fibrinojen, organ hasar belirteçleri ve trigliserit düzeylerinde yükselmelere neden olurken, antitrombin seviyesinde düzensiz değişimlere neden oldu. Lipopolisakkarit etanersept uygulanan grupta sitokinler, 13,14-dihidro-15-keto-prostaglandin F2? ve fibrinojen düzeyinde yükselmeler, antirombin düzeyinde düzensiz değişimler gözlendi. Lipopolisakkarit uygulaması ile yükselen kreatin kinaz-MB düzeyinin etanersept tarafından tamamen, tümör nekrozis faktör-? yükselmesinin kısmen engellendiği ancak kanda kalış süresini uzattığı ve interlöykin-10 düzeyini daha fazla yükselttiği belirlendi. Sonuç olarak endotoksemide etanerseptin kalp üzerindeki koruyucu etkisi ve interlöykin-10 düzeyini yükseltmesi nedeni ile tek doz uygulamasının veteriner sahada faydalı olabileceği belirlendi.
Investigation of the Effect of Tarantula cubensis Extract on Acute Phase Response
(UNIV FED RIO GRANDE DO SUL, 2016) Corum, Orhan; Er, Ayse; Dik, Burak
Background: Tarantula cubensis alcoholic extract is used to accelerate wound healing and to relieve edema in many animal species. In addition, it may be useful for many infectious diseases. Considering to these effects, it is believe that these effects may be on immune system. Cytokines (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10 and interferon gamma) secreted by immune cells and acute phase proteins (haptoglobin, alpha 1 acid glycoprotein, serum amyloid A) secreted by liver play role in acute phase response. The aim of the present study was to determine the effect of Tarantula cubensis alcoholic extract on cytokine and acute phase protein levels in sheep. Materials, Methods & Results: Tarantula cubensis alcoholic extract (6 mL/sheep, subcutaneously, single dose) was administered to 6 healthy sheep. Blood samples were obtained before (0 h) and after treatments at 2, 4, 8, 12, 24 and 48 h. Then, blood samples were centrifuged to obtain serum samples. Acute phase cytokines such as serum tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10, interferon gamma and acute phase proteins such as haptoglobin, alpha 1 acid glycoprotein and serum amyloid-A concentrations were determined with commercially available kits on ELISA reader. Administration of Tarantula cubensis alcoholic extract caused fluctuations in tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10, interferon gamma levels in sheep. In addition, levels of haptoglobin, alpha 1 acid glycoprotein, serum amyloid A showed fluctuations. But, these fluctuations in acute phase cytokines and acute phase proteins were not statistically significant (P > 0.05). Discussion: Tarantula cubensis alcoholic extract, homeopathic medicine, is used trauma, retentio secundinarium, tendinitis, bluetongue, foot and mouth, metritis and arthritis in many animal species including sheep. Cytokines, secreted against various stimulus including infectious diseases, play role in wound healing and in the regulation of the immune system. In current study, administration of Tarantula cubensis alcoholic extract lead to fluctuations in tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, interleukin-10 and interferon gamma levels, but these changes were not statistically significant (P > 0.05). Non-statistical fluctuations in cytokines result from inadequate immunological response of sheep against to Tarantula cubensis alcoholic extract. Also, use of molecular analysis techniques may be changed these results. Acute phase proteins are significantly secreted from the liver during the acute phase response. In current study, administration of Tarantula cubensis alcoholic extract in sheep caused non-statistifical fluctuations on haptoglobin, alpha 1 acid glycoprotein and serum amyloid A levels (P > 0.05). Tumor necrosis factor alpha and interleukin-1 beta stimulate synthesis of interleukin-6. Interleukin-6 provides synthesis of acute phase proteins in liver. Non-statistical fluctuations in acute phase proteins result from inadequate stimulus of IL-6. In conclusion, it may be stated that administration of Tarantula cubensis alcoholic extract has no distinctive effect on the acute phase response. However, when Tarantula cubensis alcoholic extract is administered repeated times or other acute phase parameters are evaluated, different results may be observed.
Pentoxifylline May Restore Kanamycin-Induced Renal Damage in Rats
(UNIV FED RIO GRANDE DO SUL, 2018) Corum, Orhan; Ozdemir, Ozgur; Hitit, Mustafa; Corum, Duygu Durna; Coskun, Devran; Er, Ayse
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 of ceftiofur in healthy and lipopolysaccharide-induced endotoxemic newborn calves treated with single and combined therapy
(JAPAN SOC VET SCI, 2017) Altan, Feray; Uney, Kamil; Er, Ayse; Cetin, Gul; Dik, Burak; Yazar, Enver; Elmas, Muammer
The aim of this research was to compare plasma pharmacokinetics of ceftiofur sodium (CS) in healthy calves, and in calves with experimentally induced endotoxemia. Six calves received CS (2.2 mg/kg, IM) 2 hr after intravenous administration of 0.9% NaCl (Ceft group). After a washout period, the same 6 calves received CS 2 hr after intravenous injection of lipopolysaccharide (LPS+Ceft group). Another group of 6 calves received a combination of drug therapies that included CS 2 hr after administration of 0.9% NaCl (Comb group). A third group of 6 calves received the same combination therapy regimen 2 hr after intravenous injection of lipopolysaccharide (LPS+Comb group). Plasma concentrations of CS and all desfuroylceftiofurrelated metabolites were determined using HPLC, and its pharmacokinetic properties were determined based on a two-compartment model. The peak concentration of CS in the LPS+Comb group occurred the earliest, and the clearance rate of CS was the highest in the Comb and LPS+ Comb groups (P < 0.05). The elimination half-life of CS in the LPS+Ceft group was longer than that in the Ceft and Comb groups (P < 0.05). The results of this study indicate that combined therapies and endotoxemic status may alter the plasma pharmacokinetics of CS in calves.
Pharmacokinetics of ceftriaxone following single ascending intravenous doses in sheep
(ELSEVIER SCIENCE BV, 2018) Corum, Duygu Durna; Corum, Orhan; Altan, Feray; Faki, Hatice Eser; Bahcivan, Emre; Er, Ayse; Uney, Kamil
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 AUC(0-infinity) at the 80 mg/kg dose significantly increased (P < 0.05). The relation between dose and AUC(0-infinity) 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 mu g/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)
(JAPAN SOC VET SCI, 2019) Corum, Orhan; Corum, Duygu Durna; Altan, Feray; Er, Ayse; Cetin, Gul; Uney, Kamil
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 (t(1/2 lambda z)), mean residence time (MRT0-8), area under the concentration-time curve (AUC(0-infinity)), volume of distribution at steady state and total body clearance in plasma were 24.17 hr, 30.64 hr, 143.31 hr center dot mu g/ml, 1.29 l/kg and 0.04 l/hr/kg, respectively. Following IM administration, t1/2.z, MRT0-infinity, AUC(0-infinity), peak concentration (C-max), time to reach Cmax, and bioavailability in plasma were 32.00 hr, 41.15 hr, 198.23 hr center dot mu g/ml, 8.75 mu g/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)
(WILEY, 2019) Corum, Orhan; Durna Corum, Duygu; Atik, Orkun; Altan, Feray; Er, Ayse; Uney, Kamil
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 mu g/ml, respectively, with 0.5 hr of T-max. 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 t(1/2z), can be recommended as an effective way for treating nematodes in turtles.

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