Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity.

INTRODUCTION: Cyclophosphamide (CP) is a potent anticancer agent; its clinical use is limited due to its marked cardiotoxicity. AIM: The present study was aimed at evaluating the cardioprotective effects of silymarin (SLY) and curcumin (CUR), which have strong antioxidant properties, against the toxic effects of high-dose CP on the heart of rats. MATERIALS AND METHODS: A total of 36 adult Wistar albino female rats were randomly divided into six groups. Group I (control group; nothing was administered), Group II (CP group; 30mg/kg/day CP was administered intraperitoneally to each animal for seven days), Group III (SLY group; 100mg/kg/day SLY by gavage for 14 days), Group IV (CUR group; 100mg/kg/day CUR by gavage for 14 days), Group V (SLY+CP group; 100mg/kg/day SLY by gavage for 14days plus 30mg/kg/day CP intraperitoneally starting from the seventh day) and Group VI (CUR+CP group; 100mg/kg/day CUR by gavage for 14days plus 30mg/kg/day CP intraperitoneally starting from the seventh day). Biochemical, histopathological and immunohistochemical methods were utilised for evaluation of the cardiotoxicity. RESULTS: The result showed that an increase in heart MDA and DNA fragmentation levels were detected while significant decreases were seen in SOD levels in CP alone group when compared to the other groups. CP caused severe damage in the histopathological status of heart tissue including intersititial oedema, haemorrhage, degeneration and necrosis in muscle fibrils and perinuclear vacuolization. A significant increase in the percentage of TUNEL-positive cells and γH2AX protein expression was detected in the CP-treated group compared to the control and other treated groups. There was significant increase in the percentage of caspase 3-positive cells and decrease in the percentage of Bcl-2 positive cells in the CP group compared to the control group and other treated groups. However, a significant decrease in the percentage of cTnI and cTnT immunoreactivity was also observed in the CP-treated group compared to the control and other treated groups. In the groups in which SLY and CUR were administered concurrently with CP, biochemical parameters, histopathological and immunohistochemical results were found to be significantly lower than in the CP-only group. CONCLUSIONS: These results lead to conclusion that the natural antioxidant SLY and CUR might have protective effects against CP-induced cardiotoxicity and oxidative stress in rats.

Pharmacokinetics of meloxicam in adult goats: a comparative study of subcutaneous, oral and intravenous administration.

AIMS: To determine the plasma disposition of meloxicam in goats following S/C, oral or I/V administration at a single dose of 0.5 mg/kg bodyweight. METHODS: Five healthy Saanen goats, aged 12-14 months and weighing 35-40 kg, were used for a three phase cross-over design with a 10-day washout period, with meloxicam administered I/V, then orally and S/C. Heparinised blood samples (5 mL) were collected from all animals prior to drug administration (0 hours) and subsequently up to 96 hours. Concentrations of meloxicam in plasma were measured using high performance liquid chromatography. Concentration-time curves were fitted and pharmacokinetic parameters were estimated for each administration group. RESULTS: Subcutaneous administration of meloxicam exhibited unique plasma distribution characteristics that differed from oral and I/V administration. Mean peak plasma concentrations were greater (1.91 (SD 0.39) vs. 0.71 (SD 0.17) µg/mL) and the time to reach them shorter (3.20 (SD 1.64) vs. 14.33 (SD 2.19) hours) following S/C compared with oral administration (p<0.05). The terminal half-life was longer (15.16 (SD 4.74) vs. 10.69 (SD 1.49) hours) and the MRT was shorter (15.67 (SD 2.37) vs. 24.33 (SD 3.12) hours) following S/C than oral administration (p<0.05), but bioavailability was similar (98.24 (SD 9.62) vs. 96.49 (SD 10.71)%). CONCLUSION AND CLINICAL RELEVANCE: Subcutaneous administration of meloxicam resulted in long-term presence of drug at high concentration in goat plasma. This unique plasma disposition characteristic may offer an advantage in some clinical cases towards potentially improving the treatment efficacy in goats.

Plasma disposition of enrofloxacin following intravenous and intramuscular administration in donkeys.

This study was designed to investigate the plasma disposition and systemic availability of enrofloxacin (ENR) following intramuscular and intravenous administrations. Six donkeys (Equus asinus) were used in this study. The animals were allocated into two groups (intramuscular and intravenous groups). After a 2-week washout period, the experiment was repeated with the groups reversed according to a two-phase crossover design. In phase I, group I received intravenously the commercially available injectable solution of ENR at the dose of 5 mg/kg and group II received intramuscularly the same ENR formulation at the same dose rate. Blood samples were collected 1 hour prior to drug administration and various times between 5 minutes and 48 hours post-treatments. The samples were analysed by high performance liquid chromatography with fluorescence detector. The half-life and mean residence time of ENR (12.08 hours and 17.85 hours) after intramuscular route were significantly longer compared with intravenous administration (9.54 hours and 7.46 hours, respectively) and these were associated with a flip-flop phenomenon. A marked proportion of ENR (20-21 per cent) was metabolised to ciprofloxacin (CPR) following both administration routes and the half-life of CPR paralleled that of the parent drug after intramuscular administration. Mean absorption time was relatively long (10.39 hours), and the bioavailability of ENR was 76.56 per cent after intramuscular route in the donkeys. The plasma concentration is lower after intramuscular administration at a dose rate of 5 mg/kg, and may need a higher dose to provide sufficient plasma concentration in donkeys compared with horses.