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Aflatoksin b1'in fare beynine geçişi üzerine bcrp ve p-gp modülatörlerinin etkisi
(2017) Tras, Bunyamin; Cetın, Gul; Uney, Kamil; Dık, Burak; Corum, Orhan; Atalay, Sema
Çalışma, zosuquidar ve prazosin tarafından sırasıyla P-gp ve BCRP modülasyonunun AFB1'in plazma ve beyin konsantrasyonlarının etkileyip etkilemediğini belirlemek için gerçekleştirildi. Bu çalışmada, 40 adet sağlıklı, erkek BALB/c ırkı fare (323.7 g) kullanıldı. Hayvanlar her grupta 8 fare olacak şekilde rastgele 5 gruba ayrıldı. Grup 1, metod validasyon çalışmalarında kullanıldı. Grup 2 (AF)'ye AFB1 20 mg/kg dozda intraperitoneal yolla verildi. Grup 3 (AFPRZ), 4 (AFZQR) ve 5 (AFPRZZQR)'e ise sırasıyla intraperitoneal yolla prazosin (0.3 mg/kg), zosuquidar (25 mg/kg) ve prazosinzosuquidar (0.3 mg/kg prazosin 25 mg/kg zosuquidar) uygulamalarından 30 dk. sonra AFB1 20 mg/kg dozda intraperitoneal yolla uygulandı. Grup 2-5'de bulunan hayvanlardan AFB1 uygulamasından sonraki 6. saatte kan ve beyin örnekleri alındı. AFB1 düzeyleri fluoresans dedektör içeren HPLC sisteminde tayin edildi. Prazosin ve zosuquidarın tek ve eşzamanlı uygulanması AFB1'in beyin konsantrasyonlarında sadece AFB1uygulamasına göre önemli oranda azalmaya neden oldu (P0.05). AFB1 grubunda AFB1'in beyin/plazma oranı diğer gruplardan (AFPRZ, AFZQR, and AFPRZZQR) önemli oranda daha yüksekti (P0.05). Akut AFB1 zehirlenmelerinde özellikle BCRP gibi transmembran proteinlerin indüklenmesi hayatta kalma oranını artırabilir.
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.
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 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.
Effects of bcrp and p-gp modulators on the penetration of aflatoxin b1 into the mouse brain
(KAFKAS UNIV, VETERINER FAKULTESI DERGISI, 2017) Tras, Bunyamin; Cetin, Gul; Uney, Kamil; Dik, Burak; Corum, Orhan; Atalay, Sema
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<0.05). The brain/plasma ratio of the AF group was higher than that of the other groups (AF+PRZ, AF+ZQR, and AF+PRZ+ZQR) (P<0.05). Inducers of transmembrane proteins, especially BCRP, can be life saving during acute AFB(1) poisoning.
Halofuginone may suppresses azoxymethane-induced serum tumor necrosis factor-a synthesis and aberrant crypt foci progression in rat colon
(AGRICULTURAL RESEARCH COMMUNICATION CENTRE, 2017) Corum, Orhan; Ozdemir, Ozgur; Yazar, Enver
The aim of this research was to investigate the effect of halofuginone on the progression of azoxymethane-induced colon cancer in rats. A total of 38 male Wistar albino rats were divided into 4 groups: Control (n=8), Halofuginone (n= 10, 0.4 mg/kg, PO, SID), Cancer (n=10, azoxymethane, 15 mg/kg, IP, once a week for two weeks) and Cancer + Halofuginone (n=10). After 18 weeks, blood samples were taken under anesthesia and all animals were sacrificed. Aberrant crypt foci in the colon were stained with methylene blue. Blood cytokines, thiobarbituric acid reactive substances, 13,14-dihydro-15-ketoprostaglandin F2 alpha levels, hemogram and biochemical values were measured. The tumor necrosis factor-a level in the Cancer group was higher (P<0.05) than in other groups, while higher numbers of aberrant crypt foci were found in the Cancer group compared with the Cancer + Halofuginone group (P<0.05). In summary, it may be stated that halofuginone may warrant evaluation as a supportive drug in the treatment of colon cancer in the future.
Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep
(WILEY, 2019) Altan, Feray; Corum, Orhan; Yildiz, Ramazan; Faki, Hatice Eser; Ider, Merve; Ok, Mahmut; Uney, Kamil
In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined following a single intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 +/- 0.3 years and 53.5 +/- 5 kg of body weight) were used. A longitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the second and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxifloxacin was assayed by high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a two-compartment open pharmacokinetic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t(1/2 beta)), total body clearance (Cl-T), volume of distribution at steady state (V-dss) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h(-1) kg(-1), 1.66 L/kg and 8.91 hr*mu g/ml, respectively. While diclofenac and flunixin meglumine significantly increased the t(1/2 beta) and AUC of moxifloxacin, they significantly reduced the Cl-T and V-dss. These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics.
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 and bioavailability of marbofloxacin in lambs following administration of intravenous, intramuscular and subcutaneous
(ELSEVIER SCIENCE BV, 2018) Altan, Feray; Corum, Orhan; Corum, Duygu Durna; Atik, Orkun; Uney, Kamil
In this study, the pharmacokinetic disposition and bioavailability of marbofloxacin (MB) were determined in lambs after single intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 3 mg/kg. The plasma concentration of MB was measured using high-performance liquid chromatography-UV, and the pharmacokinetic parameters were analyzed using a non-compartmental analysis. Following IV, IM, and SC administrations, the mean terminal half-life (t(1/2 lambda z)) was 11.48, 12.64, and 24.86 h, respectively, and the mean residence time (MRT) was 7.27, 7.81, and 10.11 h, respectively. The bioavailability (F) was 96.01 and 126.39%, after IM and SC administration, respectively. This study showed that SC administration of MB at a dose of 3 mg/kg exhibited flip-flop pharmacokinetics in lambs. These results suggested that MB could be useful in the treatment of severe systemic infections, such as those with M. haemolytica (MIC = 0.035 mu g/mL), in lambs since high AUC(0.24)/MIC and C-max/MIC ratios were achieved after IV and IM administration at 3 mg/kg. However, MB administration (3 mg/kg) via the IV, IM, and SC routes might not be effective in the treatment of respiratory infections caused by organisms with MIC90 value in lambs.
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.
Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite following intravenous administration in cattle
(SPRINGER, 2019) Uney, Kamil; Tras, Bunyamin; Corum, Orhan; Yildiz, Ramazan; Maden, Mehmet
This study investigated the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after single-dose intravenous (IV) administration (10mg/kg) of PTX in six healthy cattle. The safety of PTX was evaluated by clinical observation and biochemical analysis. Plasma concentrations of PTX and M-I were simultaneously determined by reverse-phase high performance liquid chromatography. Pharmacokinetic parameters were calculated using non-compartmental methods. Salivation and discomfort were observed for 2h following the drug administration. Serum direct bilirubin, total bilirubin, and phosphorus levels at 24h following the drug administration were significantly different from the control values (0h) (P<0.05). Pharmacokinetic variables of PTX were characterized by a short terminal elimination half-life (1.05 +/- 0.19h), a large volume of distribution (6.30 +/- 1.76L/kg), and high total body clearance (5.31 +/- 1.27L/h/kg). The mean ratio between the area under the concentration-time curves of M-I and PTX was 1.34. These results indicate that single-dose administration of PTX at 10mg/kg IV in cattle resulted in therapeutic concentrations similar to those observed in humans and horse. However, further studies are necessary to determine the safety and pharmacokinetics following repeated administrations of PTX.

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