E. Yazar

Pharmacokinetics of flunixin after intravenous administration in healthy and endotoxaemic rabbits.

The pharmacokinetics of flunixin were determined after intravenous bolus injection at a single dose (2.2 mg/kg) in healthy rabbits and diseased rabbits with Escherichia coli lipopolysaccharide-induced septic shock. Six adult New Zealand White rabbits were used. Concentrations of drug in plasma were determined by HPLC. Pharmacokinetics were best described by a two-compartment open model. In healthy rabbits, there was a high plasma clearance (0.62 L/(h kg)), and a relatively short elimination half-life (1.19 h). In endotoxaemic rabbits, total plasma clearance (0.43 L/(h kg)) was significantly lower (p<0.05), and elimination half-life (1.90 h) and AUC0-∞ (5.29 (μg h)/ml) were significantly higher (p<0.05) than in healthy animals. The changes of pharmacokinetics of flunixin in rabbits with septic shock could be of clinical significance, and may require monitoring of plasma flunixin levels in endotoxaemic status.

Effects of drugs used in endotoxic shock on oxidative stress and organ damage markers.

Abstract The aim of this study was to determine the effects of enrofloxacin (ENR), flunixin meglumine (FM) and dexamethasone (DEX) on antioxidant status and organ damage markers in experimentally-induced endotoxemia. Rats were divided into three groups. To induce endotoxemia, lipopolysaccharide (LPS) was injected into all groups, including the positive control. The two other groups received the following drugs (simultaneously with LPS): ENR + FM + low-dose DEX and ENR + FM + high-dose DEX. After the treatments, blood samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 h. Oxidative stress parameters were determined by ELISA, while serum organ damage markers were measured by autoanalyser. LSP increased (p < 0.05) malondialdehyde, 13,14-dihydro-15-keto-prostaglandin F2α and nitric oxide, while LPS reduced vitamin C. These changes were especially inhibited (p < 0.05) by ENR + FM + high-dose DEX. LPS increased organ damages markers. Cardiac and hepatic damage was not completely inhibited by any treatment, whereas renal damage was inhibited by two treatments. This study suggested that ENR + FM + high-dose DEX is most effective in the LPS-caused oxidative stress and organ damages.

Acute-Phase Proteins, Oxidative Stress, and Enzyme Activities of Blood Serum and Peritoneal Fluid in Cattle with Abomasal Displacement

BACKGROUND Blood serum and peritoneal fluid acute-phase proteins, oxidative stress indicators, and some enzymes could be used for evaluation of abomasal tissue damage because of displacement in displaced abomasum (DA) cases. OBJECTIVES The aim of this study was to investigate the concentrations of acute-phase proteins, oxidative stress indicators, and activities of enzymes in blood serum and peritoneal fluid in cattle with right displaced abomasum (RDA) and left displaced abomasum (LDA) and in healthy cows. ANIMALS A total of 60 Holstein Friesian cows in early lactation were used, 31 with left and 9 with right displaced abomasum without volvulus diagnosis and no other postpartum disease, and 20 healthy cows as a control. MATERIALS AND METHODS DA diagnosis in dairy cows consisted of physical examination, laboratory, and specific DA tests. Acute-phase proteins, oxidative stress indicators, and enzyme activities were measured in blood serum and peritoneal fluid. RESULTS In the RDA group, serum haptoglobin (HPG), serum amyloid A (SAA), malondialdehyde (MDA), adenosine deaminase (ADA), myeleperoxidase (MPO), aspartate aminotransferase (AST), creatine kinase (CK, creatine kinase-MB (CK-MB), and gamma-glutamyl transferase (GGT) activity increased significantly, and serum HPG, MDA, ADA, and AST concentrations increased significantly in the LDA group (P < .05). Peritoneal fluid HPG, MDA, ADA, MPO, ALP, GGT, and LDH concentrations increased significantly, whereas NO concentrations reduced significantly in the RDA group, and HPG, MDA, ADA, and TP concentrations increased significantly, whereas concentrations of NO reduced significantly in the LDA group (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE There are acute-phase responses, oxidative stress, and abomasal tissue damage because of displacement in DA cases. Especially, HPG, MDA, ADA, and MPO concentrations can provide specific information to help in understanding these changes.

EFFECTS OF TYLOSIN ON SERUM CYTOKINE LEVELS IN HEALTHY AND LIPOPOLYSACCHARIDE-TREATED MICE

The effects of different doses of tylosin on serum cytokine concentrations were investigated in healthy and lipopolysaccharide-treated mice. The mice were divided into seven groups. Lipopolysaccharide (LPS) was injected into the positive control group. The other six groups received three different tylosin doses concurrently without or with LPS: 10 mg/kg, 100 mg/kg, 500 mg/kg, 10 mg/kg + LPS, 100 mg/kg + LPS and 500 mg/kg + LPS. After treatment, serum samples were collected at 0, 1, 2, 3, 6, 12 and 24 hours. Serum tumour necrosis factor alpha (TNFalpha), interleukin 1beta (IL1beta) and IL10 levels were determined by enzyme-linked immunosorbent assay (ELISA). Tylosin doses of 10 and 100 mg/kg induced no cytokine production in the healthy mice. Tylosin at 500 mg/kg had no effect on TNFalpha or IL1beta production, but it induced IL10 production in healthy mice. All doses of tylosin reduced the elevated TNFalpha and IL1beta in LPS-treated mice but increased their IL10 levels. In conclusion, these data suggest that tylosin has an immunomodulatory effect at the dose recommended for use against infection.

Effects of enrofloxacin, flunixin meglumine and dexamethasone on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activity in endotoxaemia in rats+

The aim of this study was to determine the effects of drugs used in the treatment of endotoxaemia on disseminated intravascular coagulation, cytokine levels and adenosine deaminase activities in endotoxaemic rats. Rats were divided into seven groups. Lipopolysaccharide (LPS) was injected into all groups, including the positive control group. The other six groups received the following drugs: enrofloxacin (ENR), flunixin meglumine (FM), low-dose dexamethasone (DEX), high-dose DEX, ENR + FM + low-dose DEX, and ENR + FM + high-dose DEX. After the treatments, serum and plasma samples were collected at 0, 1, 2, 4, 6, 8, 12, 24 and 48 hours (h). A coagulometer was used to determine the levels of coagulation values, while ELISA was used to assay serum cytokines and adenosine deaminase (ADA). Low-dose DEX alone and combined treatments depressed the levels of cytokines and ADA (from 371 to 70 IU/L at 6 h) significantly and inhibited the decrease of coagulation values (antithrombin from 67 to 140% at 6 h, fibrinogen from 54 to 252 mg/dL at 6 h). In summary, FM + high-dose DEX may be the preferred treatment of endotoxaemia because of its highest effectiveness. FM plus high-dose DEX may be a new therapy for endotoxaemic domestic animals.

Assessment of the cardiotoxicity of tulathromycin in rabbits.

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, gamma-glutamyltransferase, 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, β-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.

Effects of different doses of dexamethasone plus flunixin meglumine on survival rate in lethal endotoxemia.

Effects of different doses of dexamethasone plus flunixinmeglumine on survival rate were investigated in lethal endotoxemia. Atotal of 60 Balb/C female mice were divided into 4 equal groups. Lethalendotoxemia (80-100%) was induced by lipopolysaccharide injection(Group 1, 1 mg, intraperinoneally). At 4 hours after the lipopoly-saccharide injection; low-dose dexamethasone (0.6 mg/kg, SID, 5days, intramuscularly) + flunixin meglumine (2 mg/kg, SID, 5 days,subcutaneously), normal-dose dexamethasone (2 mg/kg, SID, 5 days,intramuscularly) + flunixin meglumine (2 mg/kg, SID, 5 days,subcutaneously) and high-dose dexamethasone (10 mg/kg, SID, 5days, intramuscularly) + flunixin meglumine (2 mg/kg, SID, 5 days,subcutaneously) were injected to Group 2, 3 and 4, respectively. Afterthe injections, survival was monitored at 7 days and 13.3%, 13.3%,33.3% and 73.3% survival rates were observed in Groups 1, 2, 3 and 4,respectively. As results, high-dose dexamethasone plus flunixinmeglumine may be the treatment of choice for endotoxaemia inanimals.Key words: lethal endotoxaemia, dexamethasone, flunixin,survival rate

Concentrations of sulfadoxine and trimethoprim in plasma, lymph fluids and some tissues 24 h after intramuscular administration to angora goats

This study was carried out to determine the concentrations of sulfadoxine and trimethoprim in plasma, lymph, and some tissues in goats after administration of a single recommended therapeutic dose. Five healthy, adult Angora goats were used. The drug combination, containing 200 mg sulfadoxine and 40 mg trimethoprim per millilitre, was given as a single IM injection at the recommended dose level, 15 mg/kg body weight for sulfadoxine and 3 mg/kg body weight for trimethoprim. The goats were slaughtered 24 hours after drug administration and samples were taken from liver, bone marrow, pelvic limb muscles, hepatic, thoracic duct, and the pelvic limb lymph fluids for analysis of drug concentrations by HPLC. The concentrations of trimethoprim in bone marrow, liver, pelvic limb muscles, hepatic lymph, the pelvic limb lymph, and thoracic duct lymph were found to be 6, 5, 4, 2, 5 and 15 times higher than those of plasma, respectively. Although the sulfadoxine concentrations in bone marrow, pelvic limb muscles, and liver were 2, 3 and 2 times higher than the plasma concentrations, respectively, the sulfadoxine concentrations in hepatic lymph, the pelvic limb lymph, and thoracic duct lymph were lower than those of plasma. The results show that the trimethoprim concentrations in lymph fluids were quite similar to those in tissues. However, the sulfadoxine concentrations in lymph fluids were different in each tissue.

Effects of tylosin, tilmicosin and tulathromycin on inflammatory mediators in bronchoalveolar lavage fluid of lipopolysaccharide-induced lung injury

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-1β, IL-6, IL-10 and 13,14-dihydro-15-keto-prostaglandin F2α (PGM) and C-reactive protein (CRP) were analysed. Area under the curve (AUC) and maximum plasma concentration (Cmax) 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 AUC0-24 level of TNF, while tilmicosin decreased the AUC0-24 level of IL-10. Tylosin and tulathromycin decreased the AUC0-24 of PGM, and all three macrolides decreased the AUC0-24 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.

Pharmacology: Investigation of biochemical and haematological side‐effects of cefquinome in healthy dogs

Summary In the present study, the effects of cefquinome, a 4 generation cephalosporin, on clinical, biochemical, haemato‐logical, and blood gas variables were investigated. Five healthy dogs were injected with cefquinome (1 mg/kg body weight, IM, daily) for 14 days. Negative effects of cefquinome on clinical, biochemical, and haematological variables were not observed, but it did change some blood gas variables.