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Author: SRIVIDYA, GULLAPUDI × End date: 2019 × Type: Thesis ×
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    ThesisItemOpen Access
    ROLE OF COMMON EFFLUX PROTEIN INHIBITORS ON PHARMACODYANMICS AND PHARMACOKINETICS OF ENROFLOXACIN IN BROILER CHICKEN
    (SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI - 517502. (A.P.) INDIA, 2019-11) SRIVIDYA, GULLAPUDI; SRINIVASA RAO, G (MAJOR); RAVIKUMAR, P; RAMA DEVI, V; MURALIDHAR, M
    Enrofloxacin, an antimicrobial fluoroquinolone is most commonly used against majority of gram negative bacterial and mycoplasma infections in majority of livestock including poultry. Due to indiscriminate usage of enrofloxacin in the poultry farming and clinical practice, resistance had been developed to this quinolne drug. Microbes develop resistance to antibiotics by various pathways. Among them, efflux pump mediated drug resistance is one of the important pathways identified in the recent past. Phytochemicals namely, theobromine, glycyrrhetenic acid and glycyrrhizic acid and capsaicin were identified as efflux pump inhibitors. It was described that phytochemicals which possess efflux pump inhibitory activity if combined with classical antimicrobial agents reduces the development of resistance and also improves their therapeutic efficacy. In the present study, pharmacokinetic and pharmacodynamic interaction between enrofloxacin, a fluoroquinolone antibacterial agent and efflux protein inhibitors capsaicin, theobromine, glycyrrhetenic acid and glycyrrhizic acid were investigated using chicken as model system. Broiler chickens weighing about 1.5-2.0 kg were randomly divided into six groups with six birds in each group. Group I birds did not receive any treatment and is primarily meant for standardization of HPLC assay for determination of enrofloxacin/ciprofloxacin in chicken plasma. Enrofloxacin alone (10 mg.kg-1, PO) was administered to birds in group II that served as control. Birds in groups III, IV, V and VI were received enrofloxacin (10 mg.kg-1, PO) after one hour of oral administration of efflux protein inhibitors, capsaicin (15 mg.kg-1), theobromine (125 mg.kg-1), glycyrrhetenic acid(100 mg.kg-1) and glycyrrhizic acid(100 mg.kg-1) respectively. Blood samples were collected from tarsal vein into heparinized tubes, at predetermined time intervals prior to and 0.166, 0.33, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24 and 48 h post-enrofloxacin administration. Plasma was separated and used for HPLC analysis to determine plasma concentrations of enrofloxacin. Based on plasma concentrations of enrofloxacin, pharmacokinetic parameters for enrofloxacin were determined using non-compartmental method. Detectable concentrations of enrofloxacin in birds persisted upto 48h in all groups. The mean Cmax, AUC(0-t), AUMC(0-t) , (Vd/F), MRT and (ClB/F) in enrofloxacin control group were 2.17 μg/ml, 36.28+4.80 μg.h.mL-1, 633.04+85.53 μg.h2.mL-1, 4.47+0.43 L.kg-1, 16.60+0.42 h and 0.28+0.03 L.kg-1.h-1. Results obtained from the study revealed that upon coadministration of theobromine, glycyrrhetenic acid and glycyrrhizic acid, the maximum plasma concentration (Cmax) increased to 2.62+0.14, 2.94+0.03 and 2.96+0.04 μg.mL-1 , area under the plasma drug concentration time profile (AUC0-t) enhanced to 48.93+1.29, 63.35+1.08 and 43.37+0.98 μg.h.mL-1, mean residence time (MRT) were increased significantly to 19.05+0.42, 17.70+0.25 and 17.27+0.69 h suggesting that enrofloxacin residence time was prolonged in birds. The phytochemical, capsaicin co-administration significantly shortened the half life and increased the elimination rate constant, tmax of enrofloxacin in chicken. Synergisitic interaction of efflux protein inhibitory phytochemicals capsaicin, theobromine, glycyrrhetenic acid and glycyrrhizic acid with enrofloxacin were noticed in minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values against S. aureus ATCC 25923, E.coli ATCC25922, K. pneumoniae ATCC700603 and P.aureginosa ATCC27853 in vitro. MIC (μg/ml) of enrofloxacin against E. coli, S. aureus, K. pneumoniae and P. aureginosa were 0.02, 0.20, 1.65 and 2.43 respectively. The MIC (μg/ml) of enrofloxacin in the presence of capsaicin was decreased to 0.090 (55%) against S.aureus, 0.012 (40%) against E.coli , 0.266 (84%) against K. pneumoniae, 0.404 (83%) against P. aureginosa. The MIC (μg/ml) of enrofloxacin in the presence of theobromine was reduced to 0.110 (45%) against S.aureus, 0.012 (66%) against E.coli, 0.258 (84%) against K. pneumoniae, 0.450 (81%) against P. aureginosa. The MIC (μg/ml) of enrofloxacin in the presence of glycyrrhetenic acid was reduced to 0.041(80%) against S. aureus, 0.012 (40%) against E. coli, 0.404 (76%) against K. pneumoniae, 0.450 (81%) against P. aureginosa. The MIC (μg/ml) of enrofloxacin in the presence of glycyrrhizic acid was reduced to 0.110 (45%) against S. aureus, 0.012 (40%) against E. coli, 0.404 (76%) against K. pneumoniae, 0.45 (81%) against P. aureginosa. In vitro results of revealed that efflux protein inhibitors potentiated the antibacterial activity of enrofloxacin against the selected bacterial strains. The PK-PD mathematical integration of pharmacokinetic and pharmacodynamic data obtained in the study was attempted. The surrogate markers commonly applied for optimization of the dose with pharmacokinetic and pharmacodynamic parameters were Cmax/MIC>10, AUC/MIC>125. The Cmax/MIC in group II, group III, group IV, group V and group VI against E.coli ATCC25922 were 86.92, 80.2, 104.72, 117.36, and 118.48 respectively. The Cmax/MIC in group II, group III, group IV, group V and group VI against S.aureus ATCC25923 were 10.86, 10.02, 13.09, 14.67, and 14.81 respectively. The Cmax/MIC in group II, group III, group IV, group V and group VI against K. pneumonia ATCC 700603 were 1.31, 1.21, 1.58, 1.77, 1.79 respectively. The Cmax/MIC in group II, group III, group IV, group V and group VI against P.aureginosa ATCC 27853 were 0.89, 0.82, 1.07, 1.20, 1.21 respectively. The ratio of AUC/MIC>125 will prevent the development of resistance against the antibacterial agent. The AUC/MIC in group II, group III, group IV, group V and group VI against E.coli ATCC25922 were 1813.93, 1859.15, 2446.45, 3167.30, and 2165.40 h respectively. The AUC/MIC in group II, group III, group IV, group V and group VI against S.aureus ATCC25923 were181.39, 185.91, 244.64, 316.73 and 216.54 h respectively. The AUC/MIC in group II, group III, group IV, group V and group VI against K. pneumoniae ATCC 700603 were 21.98, 22.53, 29.65, 38.39 and 26.24 h respectively. The AUC/MIC in group II, group III, group IV, group V and group VI against P.aureginosa ATCC 27853 were14.92, 15.30, 20.13, 26.06 and 17.82 h respectively. Based on the PK-PD integration values obtained in the present study it appears that enrofloxacin at the dose rate of 10 mg.Kg-1 is effective against E. coli and S. aureus but not effective against K. pneumoniae and P. aureginosa. Administration of efflux pump inhibitors namely theobromine, glycyrrhetenic acid and glycyrrhizic acid increases bioavailability, maximum plasma concentration of enrofloxacin whereas capsaicin significantly reduced the tmax and half life and increased the elimination rate constant in broiler chicken. The MIC, MBC which were used as indicators of antibacterial effect of enrofloxacin were significantly increased in the presence of efflux protein inhibitors.
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    ThesisItemOpen Access
    STUDIES ON ANTIHEPATOTOXIC POTENTIAL OF ACORUS CALAMUSRHIZOME EXTRACT IN RATS
    (SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI - 517 502. (A.P.) INDIA, 2007-01) SRIVIDYA, GULLAPUDI; VENKATESWARLU, U(MAJOR); ADILAXMAMMA, K; SRILATHA, Ch
    ABSTRACT: Hepatotoxicity is one of the major problem encountered in animals as well as in human beings, as the liver is the major target for metabolism of various xenobiotics. Herbal drugs are gaining importance now a clays, as reliable drugs in modem medicine are lacking. Acorus calamw is one of the important medicinal plant in traditional system of Indian medicine. The rhizomes of Acorus calamus possess various medicinal properties and antioxidant activity. The aqueous and alcoholic extracts of Acorus calumus were tssted for their antihepatotoxic potential in rats. Forty eight male wistar albino rats were divided into six groups having eight in each. Group I served ap control (WC) and group Il served as paracetam01 control. Group I1 to VI received paracetam01 @ 2 g w' b.wt. p.o on day one. Forty eight hours post administration of prmebnml, group II dved 0.5 per cent CMC for 10 9s. Gmup III and N received alcoholic d aqueous atracts @ 600 mg kg' b.wt. p.o for ten days, pup V and VI received silymarin and Vit.E @ 25 mg kg-' b.wt. and 30 mg kg" b.wt. p.o for ten days, respectively. Twenty four hours after last day of treatment the rats were sacrificed. The antihepatotoxic potential of Acorus calamus was compared with silymarin and Vit.E. Results obtained from the study revealed that paracetamol administration resulted in significant (P<0.01) reduction in GSH, GPx, GSH-R' and catalase in erythrocytes. It also resulted in significant (P<0.01) elevation of AST, ALT, ALP concentrations and hypoproteinemia in senun and elevation of TBARS in hepatic tissue. Treatment with Acorn calamus, silymarin and Vit.E prevented the above mentioned paracetamol induced changes. The biochemical alterations were correlated with the histopathological findings of liver sections