Dilek Aksit

Comparative plasma disposition, bioavailability and efficacy of ivermectin following oral and pour-on administrations in horses.

Pour-on formulations of endectocides decrease the risk of injury for both user and animal, and are particularly convenient for animal owners who can apply the product. This study was designed to investigate the plasma disposition and efficacy of ivermectin (IVM) following pour-on, per os and intravenous administrations. Eighteen female horses weighing 510-610 kg were used in this study. The animals were allocated into three groups (per os, pour-on and intravenous groups). The equine paste, bovine pour-on and bovine injectable formulations of IVM were administered orally, topically and intravenously at the dose rates of 0.2, 0.5 and 0.2mg/kg bodyweight, respectively. Heparinized blood samples and hair samples were collected at various times between 1h and 40 days. The samples were analysed by high performance liquid chromatography with fluorescence detector. Faecal strongyle egg counts (EPG) were performed by a modified McMasters technique before and at weekly intervals during 10 weeks after treatment. The results indicated that the plasma concentration and systemic availability of IVM was lower but the plasma persistence was prolonged after pour-on administration compared with per os route. IVM (paste) reduced the EPG by >95% for 10 weeks, whereas the reduction in pour-on group varied from 82 to 97%. EPG reduction in pour-on group was lower than that of per os group. Degradation on the application site, cutaneous biotransformation, binding of IVM to the haircoat and/or sebum are probably responsible for the relatively lower bioavailability of IVM in horses after pour-on administration. In conclusion, the poor plasma availability observed after pour-on administration could result in subtherapeutic plasma concentrations, which may promote the development of drug resistance in parasites.

Sex-related plasma disposition of ivermectin following pour-on administration in goats.

The effect of sex difference on the pharmacokinetic profiles of ivermectin (IVM) was investigated following pour-on administration in goats. A total of 12 (six males and six females) Kilis goats were allocated into two treatment groups with respect to sex. The pour-on formulation of IVM was administered topically (pour-on) at dose rate of 0.5mg/kg bodyweight. Blood samples were collected at various times between 1h and 40 days after treatment and the plasma samples were analysed by high-performance liquid chromatography (HPLC) using fluorescence detection. Substantial sex-related differences on the plasma disposition of IVM were observed between males and female goats following pour-on administration. The last detectable plasma concentration of IVM was significantly later in males (16.17 days) compared with female animals (10.67 days). There were no significant differences on C(max), t(max) and the area under the concentration-time curve-AUC values between male and female groups, respectively. However the terminal half-life (t(1/2lambdaz)) and mean plasma residence time (MRT) in male goats (2.35 days and 4.78 days, respectively) were significantly longer compared with female animals (1.42 days and 3.55 days, respectively) and this suggesting that the excretion patterns of IVM in male and female animals are probably different each other.

Breed-related plasma disposition of ivermectin following subcutaneous administration in Kilis and Damascus goats.

Many factors related with drug and animals affect the plasma disposition of endectocides including ivermectin (IVM). The aim of the present study was to investigate the breed differences in pharmacokinetics of IVM in goats following subcutaneous administration. Two different goat breeds (Kilis and Damascus goats) were allocated into two treatment groups with respect to breed. The injectable formulation of IVM was administered subcutaneously at a dose rate of 0.2 mg/kg bodyweight. Blood samples were collected before treatment and at various times between 1h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that the plasma disposition of IVM was substantially affected by breed differences following subcutaneous administration in goats. The last detectable plasma concentration (t(last)) of IVM was significantly later in Kilis goats (38.33 days) compared with Damascus goats (22.50 days). Although, there were no significant differences on C(max) (10.83 ng/ml vs. 10.15 ng/ml) and t(max) (2.75 days vs. 2.33 days) values; the area under the concentration-time curve-AUC (110.26 ng.d/ml vs. 73.38 ng.d/ml) the terminal half-life-t(1/2lambdaz) (5.65 days vs. 3.81 days) and the mean plasma residence time-MRT (9.31 days vs. 6.35 days) were significantly different in Kilis goats compared with Damascus goats, respectively. The breed-related difference observed on the plasma disposition of IVM between Kilis and Damascus goats could be attributable to different excretion pattern or specific anatomical and/or physiological characteristics such as body fat composition of each breed.

The protective effect of selenium in cisplatin-related retinotoxicity

Abstract Purpose: The aim of this study is to evaluate the retinal toxicity of cisplatin and neuroprotective effect of selenium in cisplatin-related retinal toxicity. Methods: Eighteen adult Wistar-Albino rats were divided into three groups. Group 1 (n = 6) received intraperitoneal (i.p.) injection of 2.5 ml physiologic saline for three days, group 2 (n = 6) received i.p. 16 mg/kg cisplatin for three days and group 3 (n = 6) received i.p. 16 mg/kg cisplatin for three days and 1.5 mg/kg twice daily selenium via gavage five days prior to cisplatin injection and for three days concomitantly with cisplatin injections. The total retinal thickness, outer nuclear layer (ONL), inner nuclear layer (INL) and inner plexiform layer (IPL) thicknesses were measured in hematoxylin/eosin and apoptotic index (AI) of ganglion cell layer (GCL) and INL was evaluated in TdT-mediated dUTP-biotin nick end labeling (TUNEL)-stained retina sections. Results: Selenium statistically succeeded to reduce total retinal thickness in cisplatin-toxicated retinas: from 210.17 ± 23.40 to 173.55 ± 20.43, ONL: 49.79 ± 5.32 to 41.87 ± 6.30, INL: 33.72 ± 7.93 to 25.06 ± 5.73 and IPL: 53.61 ± 8.63 to 45.61 ± 6.92 µm in hematoxylin/eosin-stained retina sections. The AI was also reduced in INL (30.10 ± 12.02 to 19.48 ± 12.99) and in GCL (37.59 ± 17.70 to 33.15 ± 13.78). However, statistical significance was present in only AI values of INL. Conclusions: Selenium limited edema due to the toxicity and reduced the retinal thickness and showed neuroprotection in cisplatin-induced retinotoxicity.

Plasma pharmacokinetics, faecal excretion and efficacy of pyrantel pamoate paste and granule formulations following per os administration in donkeys naturally infected with intestinal strongylidae

The plasma disposition, faecal excretion and efficacy of two formulations of pyrantel pamoate in donkeys were examined in a controlled trial. Three groups of seven donkeys received either no medication (control) or pyrantel paste or granule formulations at horse dosage of 20mg/kg B.W. (equals 6.94 mg/kg PYR base) of body weight. Heparinized blood and faecal samples were collected at various times between 1 and 144 h after treatment. The samples were analysed by high-performance liquid chromatography. The last detectable plasma concentration (tmax) of paste formulation was significantly earlier (36.00 h) compared with granule formulation (46.29 h). Although, there was no significant difference on terminal half lives (t1/2: 12.39 h vs. 14.86 h), tmax (14.86 h vs. 14.00) and MRT (24.80 h vs. 25.44 h) values; the Cmax (0.09 μg/ml) AUC (2.65 μgh/ml) values of paste formulation were significantly lower and smaller compared with those of granule formulation (0.21 μg/ml and 5.60 μgh/ml), respectively. The highest dry faecal concentrations were 710.46 μg/g and 537.21 μg/g and were determined at 48 h for both paste and granule formulation of PYR in donkeys, respectively. Pre-treatment EPG of 1104, 1061 and 1139 were observed for the control, PYR paste and PYR granule groups, respectively. Pre-treatment EPG were not significantly different (P>0.1) between groups. Post-treatment EPG for both PYR treatment groups were significantly different (P<0.001) from the control group until day 35. Following treatments the PYR formulations were efficient (>95% efficacy) until day 28. In all studied donkeys, coprocultures performed at day-3 revealed the presence of Cyathostomes, S. vulgaris. Faecal cultures performed on different days from C-group confirmed the presence of the same genera. Coprocultures from treated animals revealed the presence of few larvae of Cyathostomes.

Plasma disposition, milk excretion and parasitological efficacy of mebendazole in donkeys naturally infected by Cyathostominae.

Mebendazole (MBZ) has been licensed for use in horses and donkeys, however there are no data available in the literature regarding its pharmacokinetic disposition and efficacy in donkeys. This study was designed to determine the plasma disposition, milk excretion and anthelmintic efficacy of MBZ in donkeys naturally infected by Cyathostominae. The animals were allocated to three groups, each of six donkeys. One group was untreated control (C-group) and the others were treated using a paste formulation of MBZ administered per os at the manufacturers recommended horse dosage of 10 mg/kg body weight (MBZ 1) and at the double horse dosage 20 mg/kg body weight (MBZ 2). Blood and milk samples were collected at various times between 1h and 120 h post treatment and analyzed by high performance liquid chromatography with photodiode array detector. Individual FECs (Faecal Egg Counts) were performed on each animal before the treatment (day-3) and weekly from day 7 until day 56 post treatment using a modified McMaster technique. The plasma concentrations and systemic exposure of MBZ in donkeys were relatively lower compared with the other methylcarbamate benzimidazoles. Dose-dependent plasma dispositions of MBZ were observed at the increased dosage (10 mg/kg vs 20 mg/kg) in donkeys. MBZ was not detected in any milk samples at a dosage of 10 mg/kg. However, the parent drug reached 0.01 μg/ml peak milk concentration at 10.66 h and AUCmilk/AUCplasma value was 0.18 ± 0.02 at a dosage of 20 mg/kg bodyweight. This study indicated that per os administration of MBZ has a minimal disposition rate into the milk and may be used in lactating donkeys with zero milk-withdrawal period. The results of FECRT for both MBZ dosages were efficient (>95% efficacy) until day 28. This trial demonstrates that MBZ oral paste at horse dosage (10 mg/kg B.W.) was effective and safety for the treatment of Cyathostominae in donkeys. Therefore, similar dosage regimens of MBZ could be used for horses and donkeys.

The effect of fasting on the plasma disposition of triclabendazole following oral administration in goats

This study was designed to investigate the effect of feeding on the plasma disposition of triclabendazole (TCBZ) in goats following oral administration. A total of eight goats, aged 14-16 months and weighing 20-30 kg were used in this study. The animals were allocated into two groups (fasted and fed groups) of four animals each. The goats in fed group were fed ad libitum but the animals in fasted group were not fed 24 h before and 6 h after drug administration. Commercial oral drench formulation of TCBZ (Endex-K, 5%) was administered orally to animals in two groups at dose of 10mg/kg bodyweight. Heparinized blood samples were collected between 1 and 192 h after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) for TCBZ, TCBZ sulphoxide (TCBZ-SO), and TCBZ sulphone (TCBZ-SO(2)). Relatively very low concentration of TCBZ parent drug was detected between 2 and 48 h, but TCBZ-SO and TCBZ-SO(2) metabolites were present between 2 and 192 h in the plasma samples of fed and fasted animals. Fasting significantly enhanced the plasma concentration of TCBZ and its metabolites. The availability of TCBZ, TCBZ-SO and TCBZ-SO(2) in the plasma samples of fasted goats were markedly greater compared to those of fed goats. It was concluded that fasting decreases the digesta flow rate and prolongs the retention of the drug into the gastrointestinal tract, resulting in enhanced quantitative gastrointestinal absorption or systemic availability of TCBZ and its metabolites in fasted goats.

The effects of simulated rain and sun exposure on the plasma disposition of ivermectin following pour-on administration in heifers

Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey; Department ofParasitology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey; Department of Animal Nutrition and NutritionDiseases, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey

Does protocatechuic acid, a natural antioxidant, reduce renal ischemia reperfusion injury in rats?

BACKGROUND Protocatechuic acid (PCA), which has antioxidant property, is a simple phenolic compound commonly found in many plants, vegetables, and fruits, notably in green tea and almonds. Present study was an investigation of the effects of PCA on rat kidney with ischemia/reperfusion (IR) injury. METHODS Sprague-Dawley rats were randomly divided into 4 groups: (1) Sham, (2) Renal IR, (3) Renal IR+Vehicle, and (4) Renal IR+PCA. Renal reperfusion injury was induced by clamping renal pedicle for 45 minutes after right nephrectomy was performed, followed by reperfusion for 3 hours. Dose of 80 mg/kg PCA was intraperitoneally administered to 1 group immediately before renal ischemia; 33% polyethylene glycol was used as vehicle. Total antioxidant status (TAS), malondialdehyde (MDA), superoxide dismutase (SOD), tumor necrosis factor alpha (TNF-α), and interleukin-6 levels were measured in blood and kidney tissue samples taken from sacrificed rats. Kidney tissue samples were examined and scored histopathologically. Terminal deoxynucleotidyltransferase-mediated dUTP digoxigenin nick end labeling assay method was used to detect apoptotic cells. RESULTS It was found that PCA significantly reduced serum MDA, TNF-α, and kidney MDA levels, while it increased serum and kidney TAS and SOD levels. Histopathological scores were significantly higher for the group given PCA. CONCLUSION PCA reduced oxidative stress and can be used as an effective agent in treatment of renal IR injury.

Effects of selenium on ischaemia–reperfusion injury in a rat testis model

Selenium is shown to have beneficial effects on ischaemia–reperfusion (IR) injury. Our aim was to assess the effects of selenium on IR‐induced testicular damage in terms of biochemical and histopathological evaluation. A total of 32 rats were randomised into four groups: control, IR, IR + selenium (IR + S) and S. Detorsion was applied after 3 h of torsion. Testicular tissue superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), total antioxidant capacity (TAC) and DNA fragmentation levels were determined. Testicular tissue samples were examined by histopathological examination and terminal deoxynucleotidyl transferase dUTP nick end‐labelling staining. The control, IR and IR + S groups had higher SOD values compared with the S group; SOD levels of the control and IR + S groups were higher than those of the IR group (P < 0.05). Further, MDA levels of the IR group were higher than those in the other three groups (P < 0.05). The IR group revealed lower TAC levels than the three groups (P < 0.05 for all). GSH levels of the IR group were significantly lower than those in the other three groups (P < 0.05 for all). In contrast, GSH levels of the IR + S group increased compared with those of the S group. The IR group had more DNA fragmentation than the control and S groups (P < 0.05). It is concluded that selenium possibly reduces oxidative stress and apoptosis caused by testicular IR injury in rats. The testicular protective effect of selenium appears to be mediated through its anti‐apoptotic and antioxidative effects. However, selenium does not affect DNA fragmentation.