Effect of meloxicam and its combination with levofloxacin , pazufloxacin , and enrofloxacin on the plasma antioxidative activity and the body weight of rabbits

Aim: Evaluation of meloxicam, levofloxacin, pazufloxacin, and enrofloxacin for their effect on the plasma antioxidative activity (AOA) and the body weight in rabbits. Materials and Methods: Thirty two male Soviet Chinchilla rabbits were divided to eight groups of four rabbits each. Group A, serving as control, was administered 5 % dextrose. Group B, C, E and G were gavaged meloxicam, levofloxacin, pazufloxacin and enrofloxacin, respectively, in 5% dextrose. Levofloxacin and pazufloxacin were administered at the dose rate of 10 mg/kg body weight b.i.d 12h, whereas the meloxicam and enrofloxacin were administered at 0.2mg/kg body weight o.i.d and 20 mg/kg body weight, respectively. Groups D, F and H were co-gavaged meloxicam with levofloxacin, pazufloxacin, and enrofloxacin, respectively, at the above dose rates. All these drugs were administered for 21 consecutive days. The plasma AOA and body weight was determined on 0, 7, 14, and 21 day of treatment. th Results: The plasma AOA of meloxicam treated group was significantly lower than the control from 7 day of treatment. On th the 14 day of treatment, the levofloxacin treated group had values significantly higher than the enrofloxacin-meloxicam cotreated group. Except for the levofloxacin treated group, a significant decrease in the antioxidative activity was observed in all st treatment groups when compared to the control group on 21 day of treatment. The body weight of all groups differed nonsignificantly throughout the study period. Conclusion: The results from this study indicate that although these drugs have no effect on the body weight, a decrease in the plasma AOA is observed, especially when the duration of treatment is increased.


Introduction
microbial drugs [2].Despite the basic similarity in the core structure of these molecules, their physiochemical Non-steroidal anti-inflammatory drugs (NSAIDs) properties, pharmacokinetic characteristics, and antiare widely used drugs in both veterinary and human microbial activities vary markedly across compounds medicine for various inflammatory conditions of [3].Levofloxacin, the active L-isomer of the racemate infectious or non-infectious origin [1].NSAIDs act by ofloxacin, has nearly 100% oral bioavailability and is inhibiting the pro-prostaglandin enzymes, cyclooxythus preferred over FQs that have broad spectrum of genase-2 (COX-2), and cyclooxygenase-1(COX-1).
activities, but limited oral bioavailability [4].It is used The COX-2 inhibition is considered to mediate the alone or in combination with other antibacterial drugs therapeutic actions of NSAIDs, while the COX-1 to treat certain bacterial infections, including inhibition usually results in unwanted side-effects, pneumonia, urinary tract infections, and abdominal particularly in the gastrointestinal tract [1].Meloxicam infections.Pazufloxacin, a fused tricyclic quinolone, is a NSAID that has an apparently greater selectivity has a 1-aminocyclopropyl substituent at C-10 position, towards inhibition of inducible COX-2 isoform, than a unique feature of the molecule contributing the potent the constitutive isoform COX-1 [1].
broad spectrum activity to this drug [5].It may be used Fluoroquinolones (FQs) are the quinolones with as the drug of choice in community acquired infections, fluorine atom attached to the central ring system, acute exacerbation of chronic bronchitis and posttypically at the C-6 position or C-7 position.These are abdominal infection sepsis [6].Enrofloxacin, a 6bactericidal drugs that inhibit the bacterial enzymes fluoro-7-piperazinyl-4-quinolone approved for DNA gyrase and topoisomerase IV and possess a broad veterinary use, has been evaluated as a method to spectrum of anti-bacterial activity against a range of eliminate Salmonella infections in cattle and poultry bacteria, including the ones resistant to other antiand manage several bacterial diseases in lagomorphs, from Pasteurella multocida to Mycoplasma spp.Experimental design: Rabbits were randomly divided all of the FQs, about irreversible peripheral neuropathy, to eight groups of four rabbits each.Group A, serving rhabdomyolysis, tendon damage, pseudomembranous as control, was administered 5 % dextrose.Group B, C, colitis, heart problems (prolonged QT Interval/ Torsades de pointes), Stevens -Johnson syndrome, as well as E and G were gavaged meloxicam, levofloxacin, concurrent usage of NSAIDs contributing to the severity pazufloxacin, and enrofloxacin, respectively, in 5% of these reactions [9].Some of the side effects of FQs, dextrose.Levofloxacin and pazufloxacin were adminilike phototoxicity [10] and cartilage defects [11] have stered at the dose rate of 10 mg/kg body weight b.i.d been incriminated to the production of reactive oxygen 12h, that was extrapolated from the therapeutic dose in species (ROS) [12].Although, NSAIDs including humans [6,25], whereas the meloxicam (0.2mg/Kg meloxicam improve oxidative imbalance [1, 13, 14], body weight o.i.d.) and enrofloxacin (20 mg/kg body alteration of antioxidant levels has been reported with weight o.i.d.) were used at their recommended theraseveral NSAIDs [15] with studies demonstrating peutic doses in rabbits [26,27].Groups D, F and H were oxidative stress as the mechanism of their toxicity [16, co-gavaged meloxicam with levofloxacin, pazufloxacin, 17].An imbalance between the pro-oxidant and and enrofloxacin, respectively, at the above dose rates.antioxidant moieties represents oxidative imbalance/ ® Drugs: The drugs used were meloxicam (Melonex stress.Complete antioxidant profile of body fluids Intas Pharma, India), levofloxacin hemihydrate cannot be fully reflected by any single component of ® (Levoflox , Cipla Pharma, India) pazufloxacin antioxidant complex, due to interactions that occur in ® mesylate (Pazumac , Macleoids Pharma, India) and vivo among different antioxidant components [18].

TM enrofloxacin (Enrocin , Pfizer Animal Health, India). Total antioxi-dative activity (AOA) considers the cumulative effect of all antioxidants present in body
Disclaimer about the drugs: The drugs used in the fluids [19].It could be used to assess the real change in study are for information purpose only.Authors or antioxidant status in patients with severe infection and institute of authors do not recommend the use of these can thus make the treatment effective [20].Complicated drugs.infections require weeks of antibiotic therapy and Plasma antioxidant activity analysis: Blood samples protracted course of NSAIDs to manage various were collected from the ear vein of these animals in associated inflammatory conditions like pyrexia and heparinized vials on 0, 7, 14 and 21 day of treatment.pain [21,22].Taking the above facts into consideration The plasma AOA was determined by the method of and the lack of sufficient toxicological data regarding Koracevic et al. [28] based on the principle that a the simultaneous exposure of FQs and NSAIDs, we standardized solution of Fe-EDTA complex reacts with evaluated meloxicam, levo-floxacin, pazufloxacin and hydrogen peroxide by a Fenton-type reaction, leading enrofloxacin for their effect on the plasma AOA that to the formation of hydroxyl radicals that degrade could give some insight of their basic toxicological benzoate, resulting in the release of thio-barbituric acid profile.Since prolonged treatment of some drugs reactive substances (TBARS).Antioxidants from the (zonisamide, topiramate, caffeine, etc) leads to body added plasma suppress TBARS production.This weight loss, drugs like antipsycotics, on the other hand, reaction was measured spectrophotometrically and the produce obesity in humans [23,24].The assessment of inhibition of color development is defined as the total body weight parameter would indicate general impact antioxidant activity.on metabolism in addition to generating data regarding the above cited effects of drugs on the body weight.
Body weight: Body weight was determined with an This will also help in considering dosage corrections of electronic weighing balance at 0, 7, 14 and 21 days of these drugs when used for prolonged durations.
treatment.These weekly body weight values were also The availability of data on body weight with the used to make the necessary corrections in dose of the co-administration of NSAIDs and FQs is also lacking.above drugs administered.The weekly determined Thus, we also evaluated the effect of these drugs on body weight of each animal was expressed as the body weight and correlated the body weight with AOA percentage of its zero day body weight to determine the to determine any relation between the two parameters.
trend in the body weight pattern.

Materials and Methods
Statistical analysis: All these results were subjected to analysis of variance carried in completely randomized Animals: Thirty two male adult Soviet Chinchilla design, and the significance was tested using Duncan's rabbits of 6 months of age, weighing around 3 Kg, were multiple range test [29].The results for AOA were of small number of electrons to oxygen forms reactive correlated with body weight with Pearson's correlation.
mitochondrial ROS production and its potential These statistical calculations were carried out with involvement in physiological (signal transduction) SPSS 16.0 software.
versus pathological processes (oxidative stress induced disorders) depends on the balance between

Results and Discussion
their production and detoxification [36].Plasma AOA The results for the effect of meloxicam, levofloxacin, includes both enzymatic and nonenzymatic antioxidant pazufloxacin and enrofloxacin on the plasma systems [37], the measurement of which provides a antioxidative activity in rabbits are presented in the holistic picture of antioxidant status than the Table-1.On the day 7 of treatment, the AOA of group B measurement of individual antioxidant indices and is was significantly lower than the groups A, G and H thus considered as a better marker of antioxidant status with group G having significantly higher values [36,38] that could also help in assessment of oxidative compared to groups C, D and E and group H having status in vivo [39].significantly higher values than the group C. The An initial response of body to ROS is the values of group B were significantly lower than the expression of Nrf-2, a transcription factor that increases th groups A, C and F on the 14 day of treatment, with the expression of genes mediating antioxidant response group C also having the values significantly higher [40].The significantly higher values of AOA in some than the group H.When compared to the two nonof the treatment groups (group G versus groups B, C, D significantly different groups, A and C, a significant and E on day 7 of treatment and group C versus groups decrease in the AOA was observed in the other B and D on day 14 of treatment) could be attributed to st this mechanism.However, consistently increasing treatment groups on the 21 day of treatment.However, exposure of pro-oxidative xenobiotics overwhelms the the AOA values of group C differed non-significantly antioxidant status, by inhibiting the activity or from the group D. The alterations in various parameters sufficient synthesis of antioxidants, predisposing the of antioxidant status/oxidative stress have been cells to oxidative damage [41].This might be reported with FQs [30][31][32] or NSAIDs [15], although incriminated as a reason for the significantly decreased only a few studies are available about the effect of these levels of AOA observed in this study, especially at the drugs on AOA [15,33,34].There are paucity of literature st 21 day of treatment when all treated groups, except on the concurrent exposure of FQs and NSAIDs.group C, had significantly lower levels of AOA Elimination of xenobiotic requires ATP as the compared to the control group.energy source.During the ATP synthesis from mito- The results for the effect of meloxicam and the chondrial electron transport chain, a premature leakage

Table - 1
. Effect of meloxicam (group B), levofloxacin (group C), levofloxacin+meloxicam (group D), pazufloxacin (group E), pazufloxacin+meloxicam (group F), enrofloxacin (group G) and enrofloxacin+meloxicam (group H) on the plasma antioxidant activity (mmol/L) in rabbits.Values given are mean ± standard error of mean for 4 animals Means, in a column, with one common superscript do not differ significantly