Implications for dosing regimen of enrofloxacin administered concurrently with dexamethasone in febrile buffalo calves.

The objective of the study was to determine the influence of dexamethasone (DXM) on pharmacokinetics (PK) and pharmacodynamics (PD) of enrofloxacin (ENR) for dosage optimization following concurrent administration of ENR and DXM in febrile buffalo calves. A 2 µg/kg intravenous dosage of lipopolysaccharide derived from Escherichia coli was used to induce fever in calves. After inducing fever, ENR was administered at the dose rate of 12 mg/kg, IM followed by IM injection of DXM (0.05 mg/kg) in calves. Minor alterations in PK of ENR were observed following the administration of ENR + DXM. The PK parameters were t1/2K10 = 6.34 h, Cl/F = 0.729 L/kg/h, and MRT0-∞ = 10.5 h. Antibacterial activity (MIC, MBC, ex vivo time-kill kinetics) of ENR for P. multocida was not affected by DXM. But MPC of ENR against P. multocida was lessened in presence of DXM. Using PK-PD-modeled AUC0-24h/MIC values for bactericidal effect against P. multocida, daily dosages of ENR administered in combination with DXM were 4.02 mg/kg and 16.1 mg/kg, respectively, for MIC90s of 0.125 µg/ml and 0.50 µg/ml. A dose of 5.38 mg/kg was determined for ENR for frequently occurring P. multocida infections having ≤ MIC90 of 0.125 µg/ml and PK-PD modeled dose was comparable with the recommended ENR dose of 5 mg/kg for bovines for mild infections. It is suggested that a recommended dosage of 5-12.5 mg/kg of ENR can be used effectively in combination with DXM to treat P. multocida associated infections in buffalo calves without any risk of resistance amplification.

Pharmacokinetic-pharmacodynamic relationship of marbofloxacin for Escherichia coli and Pasturella multocida following repeated intramuscular administration in goats.

The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin (MBF) were determined in six healthy female goats of age 1.00-1.25 years after repeated administration of MBF. The MBF was administered intramuscularly (IM) at 2 mg kg-1  day-1 for 5 days. Plasma concentrations of MBF were determined by high-performance liquid chromatography, and PK parameters were obtained using noncompartmental analysis. The MBF concentrations peaked at 1 hr, and peak concentration (Cmax ) was 1.760 µg/ml on day 1 and 1.817 µg/ml on day 5. Repeated dosing of MBF caused no significant change in PK parameters except area under curve (AUC) between day 1 (AUC0-∞ D1 = 7.67 ± 0.719 µg × hr/ml) and day 5 (AUC0-∞ D5 = 8.70 ± 0.857 µg × hr/ml). A slight difference in mean residence time between 1st and 5th day of administration and accumulation index (AI = 1.13 ± 0.017) suggested lack of drug accumulation following repeated IM administration up to 5 days. Minimum inhibitory concentration (MIC) demonstrated that Escherichia coli (MIC = 0.04 µg/ml) and Pasturella multocida (MIC = 0.05 µg/ml) were highly sensitive to MBF. Time-kill kinetics demonstrated rapid and concentration-dependent activity of MBF against these pathogens. PK/PD integration of data for E. coli and P. multocida, using efficacy indices: Cmax /MIC and AUC0-24hr /MIC, suggested that IM administration of MBF at a dose of 2 mg kg-1  day-1 is appropriate to treat infections caused by E. coli. However, a dose of 5 mg kg-1  day-1 is recommended to treat pneumonia caused by P. multocida in goats. The study indicated that MBF can be used repeatedly at dosage of 2 mg/kg in goats without risk of drug accumulation up to 5 days.

Rosuvastatin and retinoic acid may act as 'pleiotropic agents' against ß-adrenergic agonist-induced acute myocardial injury through modulation of multiple signalling pathways.

Cardiovascular disorders constitute the principal cause of deaths worldwide and will continue as the major disease-burden by the year 2060. A significant proportion of heart failures occur because of use and misuse of drugs and most of the investigational agents fail to achieve any clinical relevance. Here, we investigated rosuvastatin and retinoic acid for their "pharmacological pleiotropy" against high dose ß-adrenergic agonist (isoproterenol)-induced acute myocardial insult. Rats were pretreated with rosuvastatin and/or retinoic acid for seven days and the myocardial injury was induced by administering isoproterenol on the seventh and eighth day. After induction, rats were anaesthetized for electrocardiography, then sacrificed and different samples were collected/stored for various downstream assays. Myocardial injury with isoproterenol resulted in increased cardiac mass, decreased R-wave amplitude, increased QRS and QT durations; elevated levels of cardiac markers like cTnI, CK-MB, ALT and AST; increased lipid peroxidation, protein carbonylation and tissue nitric oxide levels; decreased endogenous antioxidants like SOD, CAT, GR, GST, GPx and total antioxidant activity; increased inflammatory markers like TNF-α and IL-6; decreased the mRNA expression of Nrf2 and Bcl-2; increased the mRNA expression of Bax, eNOS and iNOS genes. Pretreatment with rosuvastatin and/or retinoic acid mitigated many of the above biochemical and pathological alterations. Our results demonstrate that rosuvastatin and retinoic acid exert cardioprotective effects and may act as potential agents in the prevention of ß-adrenergic agonist-induced acute myocardial injury in rats. Cardioprotective potential of rosuvastatin and retinoic acid could be attributed to their influence on the redox pathways, immunomodulation, membrane stability, Nrf2 preservation, iNOS and Bax expression levels. Thus, they may act directly or indirectly at various steps, the breakpoints, in the pathophysiological cascade responsible for cardiac injury. Our study gives insights about the pharmacological pleiotropism of rosuvastatin and retinoic acid.

Maturation arrest of neutrophils-a possible reason for the leucopenia in sodium selenite induced sub-chronic selenosis in cow calves.

The effect of long-term administration of sodium selenite on leucocyte indices of peripheral blood of calves was determined. Nine calves, 9-12 months old, with an average body weight of 104kg were divided into three groups. Calves of groups 2 and 3 were administered with sodium selenite at 0.1 and 0.25mg/kg body weight for 98 consecutive days. The clinical signs characteristic of selenosis viz. alopecia, cracking of hooves, intradigital lesions and discoloration of hard palate, started appearing from 45 to 60 days onwards with high dose, whereas only subtle indications of toxicosis were observed in the low-dose group. The prolonged administration of sodium selenite produced a progressive and dose-dependent decline in the circulating leucocyte count with concomitant decline in the circulating neutrophil count. There was a high negative correlation (0.94) between blood selenium levels and neutrophils. Granulocyte/agranulocyte ratio was also significantly reduced in the treated animals. Evaluation of bone marrow smears revealed a decline in the myeloid to erythroid ratio. In addition, there was also maturation arrest of neutrophils at promyelocyte or myelocyte level as shown by differential granulocyte count in the bone marrow. The results indicated that host's immune response may be adversely affected.

Effect of levofloxacin, pazufloxacin, enrofloxacin, and meloxicam on the immunolocalization of ABCG-2 transporter protein in rabbit retina.

Adenosine triphosphate-binding cassette (ABC) sub-family G member-2 (ABCG-2) is a transporter protein, implicated for multi-drug efflux from tissues. This study evaluated the effect of fluoroquinolones; levofloxacin, pazufloxacin and enrofloxacin, and non-steroidal anti-inflammatory drug, meloxicam; on the immunolocalization of ABCG-2 transporter protein of rabbit retinas. Thirty-two male rabbits were randomly divided in to eight groups. Control group was gavaged, 2% benzyl alcohol in 5% dextrose since these chemicals are excipients of the drug preparations used in the treatment groups of this study. Four groups were exclusively gavaged, levofloxacin hemihydrate (10 mg/kg body weight b.i.d 12 h), pazufloxacin mesylate (10 mg/kg body weight b.i.d 12 h), enrofloxacin (20 mg/kg body weight o.d.), and meloxicam (0.2 mg/kg body weight o.d.), respectively. Three other groups were co-gavaged meloxicam with above fluoroquinolones, respectively. These drugs were administered for 21 days. ABCG-2 immunolocalization was mild in the retinas of control and levofloxacin-alone-treated groups. The immunolocalization intensity was significantly higher in meloxicam-alone-treated group when compared to control and levofloxacin-alone-treated groups. Immunolocalization of this transporter increased in the levofloxacin-meloxicam co-treated group when compared to the levofloxacin-alone-treated group. Highest immunolocalization was observed in the enrofloxacin-meloxicam co-treated group although the immunolocalization of all treatment groups, except the levofloxacin-alone-treated group, was significantly higher than the control and levofloxacin-alone-treated groups.

Effect of repeated oral administration of levofloxacin, enrofloxacin, and meloxicam on antioxidant parameters and lipid peroxidation in rabbits.

The effect of 21 days of repeated oral administration of levofloxacin and enrofloxacin both alone and in combination with meloxicam, on the oxidative balance in blood was evaluated in rabbits. Rabbits were randomly allocated to six groups of four animals each. Control group was gavaged 5% dextrose and 2% benzyl alcohol. Three groups were exclusively gavaged meloxicam (0.2 mg/kg body weight o.d.), levofloxacin hemihydrate (10 mg/kg body weight b.i.d 12 h), and enrofloxacin (20 mg/kg body weight o.d.), respectively. Two other groups were co-gavaged meloxicam with levofloxacin hemihydrate and enrofloxacin, respectively. A reduction ( p < 0.05) of reduced glutathione levels was observed in groups treated with meloxicam both alone and in combination with levofloxacin, whereas an increase ( p < 0.01) in the levels of this antioxidant was observed in the groups treated with enrofloxacin. The activities of enzymes, glutathione peroxidase and superoxide dismutase, were induced ( p < 0.05) in levofloxacin-alone treated group. Superoxide dismutase was also induced ( p < 0.05) in meloxicam-alone treated group and inhibited ( p < 0.05) in enrofloxacin-meloxicam co-treated group. The activity of catalase was non-significantly different between various groups. Enrofloxacin-treated groups had higher ( p < 0.01) lipid peroxidation than control and levofloxacin-alone treated groups. Elevated lipid peroxidation was also observed in the groups treated with meloxicam both alone and in combination with levofloxacin ( p < 0.05). In conclusion, these drugs have potential to induce oxidative imbalance, however, compared to levofloxacin, more oxidative damage is produced by enrofloxacin and meloxicam.

Evaluation of ameliorative potential of supranutritional selenium on enrofloxacin-induced testicular toxicity.

The study was designed to assess the ameliorative potential of selenium (Se) on enrofloxacin-induced testicular toxicity in rats. There was a significant decrease in body weight and non-significant decrease in mean testicular weight of enrofloxacin treated rats. In enrofloxacin treated rats, total sperm count and viability decreased where as sperm abnormalities increased. Testicular histopathology revealed dose dependent dysregulation of spermatogenesis and presence of necrotic debris in seminiferous tubules which was marginally improved with Se. Enrofloxacin also produced a dose dependent decrease in testosterone level. The activity of testicular antioxidant enzymes decreased where as lipid peroxidation increased in a dose-dependent manner. Se supplementation partially restored oxidative stress and sperm damage and did not affect the plasma concentrations of enrofloxacin or ciprofloxacain. The results indicate that enrofloxacin produces a dose-dependent testicular toxicity in rats that is moderately ameliorated with supranutritional Se.

Comparative mutant prevention concentration and antibacterial activity of fluoroquinolones against Escherichia coli in diarrheic buffalo calves.

Owing to emerging threat of antimicrobial resistance, mutant prevention concentration (MPC) is considered as an important parameter to evaluate the antimicrobials for their capacity to restrict/allow the emergence of resistant mutants. Therefore, MPCs of ciprofloxacin, enrofloxacin, levofloxacin, moxifloxacin, and norfloxacin were determined against Escherichia coli isolates of diarrheic buffalo calves. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were also established. The MICs of ciprofloxacin, enrofloxacin, levofloxacin, moxifloxacin and norfloxacin were 0·009, 0·022, 0·024, 0·028, and 0·036 µg/ml, respectively. The MBCs obtained were very close to the MICs of respective drugs that suggested a bactericidal mode of action of antimicrobials. The MPCs (µg/ml) of ciprofloxacin (4·2×MIC), moxifloxacin (4·8×MIC), and norfloxacin (5·1×MIC) were approximately equal but slightly lower than enrofloxacin (7·6×MIC) and levofloxacin (8·5×MIC) against clinical isolates of E. coli. The MPC data suggested that enrofloxacin has the potential for restricting the selection of E. coli mutants during treatment at appropriate dosing.

Effects of repeated oral administration of pazufloxacin mesylate and meloxicam on the antioxidant status in rabbits.

Prolonged antibiotic and antiinflammatory therapy for complicated infections exposes the body to xenobiotics that can produce several adverse effects for which oxidative damage is the proposed underlying mechanism. In this context, we evaluated the effect of pazufloxacin, a fluoroquinolone antimicrobial, and meloxicam, a nonsteroidal antiinflammatory drug, on antioxidant parameters and lipid peroxidation in rabbits after oral administration for 21 d. Reduced glutathione levels were significantly decreased in rabbits (n = 4 per group) given pazufloxacin, meloxicam, or their combination. In addition, glutathione peroxidase activity was induced in the rabbits treated with pazufloxacin only. Administration of pazufloxacin and meloxicam, as single agents as well as in combination, produced significant lipid peroxidation compared with levels in untreated controls. In conclusion, both pazufloxacin and meloxicam potentially can induce oxidative damage in rabbits.

Effect of sub-chronic selenium toxicosis on lipid peroxidation, glutathione redox cycle and antioxidant enzymes in calves.

The present investigation reports the effect of sodium selenite-induced sub-chronic toxicity in crossbred cow calves on various antioxidant enzymes. Sodium selenite (0.25 mg/kg for 16 w) resulted in characteristic signs of sub-chronic selenosis, ie alopecia, cracking and enlargement of hooves, interdigital lesions, ring formation on the coronet region, and gangrene at tip of the tail. The sodium selenite resulted in significant rise of blood selenium levels and concurrent increase in erythrocytic glutathione peroxidase (GPx) activity. Blood selenium levels and GPx activity had a high positive correlation (r = 0.97). Blood glutathione levels were lowered from 211.1 +/- 13.4 to 95.56 +/- 11.8 microg/ml. Selenosis caused oxidative stress as evidenced by a 3-fold increase in lipid peroxidation: activities of glutathione-S-transferase, glutathione reductase, superoxide dismutase and catalase were significantly increased. These findings support the hypothesis that the pro-oxidant attributes of selenium play important roles in its toxicity.