Interactive effect of carbendazim and imidacloprid on buffalo bone marrow derived mesenchymal stem cells: oxidative stress, cytotoxicity and genotoxicity.

The effect of a combination of two pesticides, carbendazim (CBZ) and imidacloprid (IMI), was investigated on mesenchymal stem cells derived from the bone marrow of buffalo (bMSCs). The bMSCs were exposed to the CBZ (2.25 µM, 4.49 µM, and 8.98 µM) and IMI (0.81 mM, 1.61 mM, and 3.22 mM) alone as well as in combinations. The bMSCs were found to be positive for the stem cell markers, AP, CD73, and OCT4. The bMSCs showed a significant reduction (p ≤ 0.05) in cell viability, and status of anti-oxidants while a significant increase (p ≤ 0.05) in the level of LDH, ALP, and CK-MB in CBZ and IMI-treated groups. A significant increase (p ≤ 0.05) was noticed in LPO, O2─ radical, total ROS, loss of ΔΨm, apoptotic index, and DNA damage in CBZ and IMI-treated groups. A low-dose combination group showed an elevated effect compared to the groups treated with the single pesticide. The interaction index was calculated for CBZ-IMI combined treatment groups on various parameters that showed the majority of antagonist effects. Present findings confirmed that CBZ and IMI-induced cytotoxicity in bMSCs was mediated via ROS production, altered ΔΨm and LPO along with depressed antioxidant status which was responsible for cell apoptosis and cell damage. This study suggested that CBZ and IMI had a dose-dependent toxic effect when the pesticides were used alone, while, co-exposure to both the pesticides simultaneously had an antagonist or non-additive effect on buffalo bMSCs at lower dose combinations and they induced a potentiating effect at high-dose combination.

Antioxidant status in oral subchronic toxicity of fipronil and fluoride co-exposure in buffalo calves.

The effects of fipronil and fluoride co-exposure were investigated on antioxidant status of buffalo calves. A total of 24 healthy male buffalo calves divided into 4 groups were treated for 98 consecutive days. Group I, receiving no treatment, served as the control. Animals of groups II and III were orally administered with fipronil at the dosage of 0.5 mg/kg/day and sodium fluoride (NaF) at the dosage of 6.67 mg/kg/day, respectively, for 98 days. Group IV was coadministered with fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced significant elevation in lipid peroxidation (LPO) and decrease in the levels of nonenzymatic antioxidant glutathione (GSH). However, it did not produce any significant effect on the activities of enzymatic antioxidants including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). NaF exposure led to enhanced oxidative stress as shown by significant increase in the LPO and SOD activities while GPx and CAT activities and GSH levels were significantly decreased. Co-exposure to fipronil and NaF showed additive effects on LPO, GPx activity, and GSH levels.

Pharmacokinetic profile of cefquinome after oral subchronic flubendiamide exposure and in vitro plasma protein binding in buffalo calves.

The disposition kinetics study of cefquinome was conducted following single intravenous (IV) administration of 2mg/kg bodyweight in buffalo calves after oral subchronic exposure to flubendiamide and to determine the in vitro plasma protein binding of cefquinome. Plasma concentrations of cefquinome were analyzed using reverse-phase high performance liquid chromatography (HPLC). The results were compared with our earlier study on the pharmacokinetics of cefquinome in untreated buffalo calves. Plasma concentration-time data for cefquinome following IV injection were best fit into a two-compartmental open model in flubendiamide-exposed buffalo calves. Following flubendiamide exposure, most of the pharmacokinetic parameters of cefquinome were significantly altered in buffalo calves. Cefquinome was bound to plasma proteins of buffalo calves to the extent of 11.4±0.66%. In flubendiamide-exposed animals an intravenous dose of 2mg/kg body weight would maintain the therapeutic plasma levels required to be effective against the bacterial pathogens with MIC values ≤0.39µg/mL for only 12h, whereas in untreated buffalo calves the same dose of 2mg/kg body weight would maintain the plasma levels up to 24h, The study revealed that subchronic flubendiamide exposure significantly alters the disposition of cefquinome in buffalo calves.

Pharmacokinetics of lincomycin following single intravenous administration in buffalo calves.

Lincomycin 10 mg kg(-1), IV in buffalo calves followed two-compartment open model with high distribution rate constant α (11.2 ± 0.42 h(-1)) and K 12/K 21 ratio (4.40 ± 0.10). Distribution half-life was 0.06 ± 0.01 h and AUC was 41.6 ± 1.73 µg mL(-1) h. Large Vdarea (1.15 ± 0.03 L kg(-1)) indicated good distribution of lincomycin in various body fluids and tissues. Peak plasma level of lincomycin (71.8 ± 1.83 µg mL(-1)) was observed at 1 min as expected by IV route. The elimination half-life and MRT of lincomycin were short (3.30 ± 0.08 and 4.32 ± 0.11 h, respectively). Lincomycin 10 mg kg(-1) IV at 12-h interval would be sufficient to maintain T > MIC above 60 % for bacteria with minimum inhibitory concentrations (MIC) values ≤1.6 µg mL(-1). Favourable pharmacokinetic profile in buffalo calves and a convenient dosing interval suggest that lincomycin may be an appropriate antibacterial in buffalo species for gram-positive and anaerobic bacterial pathogens susceptible to lincomycin.

Hematological Alterations on Sub-acute Exposure to Flubendiamide in Sprague Dawley Rats.

BACKGROUND: Pesticide poisoning is a common occurrence around the world. Pesticides can act on various body systems resulting in toxicity. Flubendiamide is a new generation pesticide, reported to have better activity against Lepidopteran insects. The present study was carried out with an objective to analyze the effects of flubendiamide sub-acute exposure on hematology of rats. MATERIALS AND METHODS: Male and female Sprague Dawley (SD) rats (9-11 weeks) were divided into five groups with six animals in each group. First group served as control, while the rest were exposed to ascending oral doses of flubendiamide (125, 250, 500 and 1000 mg/kg) for 28 days. After the trial period, blood was collected in heparinized vials and analyzed using Siemens ADVIA 2120(®) autoanalyzer. Various erythrocytic, platelet and leukocyte parameters were measured and analyzed using statistical tests by one-way analysis of variance (ANOVA) and t-test using Statistical Package for Social Sciences (SPSS)(®) 20 software. RESULTS: After processing the data through statistical analysis, it was observed that the effect of flubendiamide exposure on female rats was negligible. The only significant change observed in the female rats was that in total erythrocytic count, while rest of the parameters showed non-significant bidirectional changes. In males, many parameters viz., total leukocyte count (TLC), total erythrocyte count (TEC), packed cell volume (PCV), mean corpuscular volume (MCV), platelet count (PC), mean platelet volume (MPV), platelet distribution width (PDW), hemoglobin distribution width (HDW), large platelets (LPT) and plateletcrit (PCT) expressed significant difference when compared to control. CONCLUSION: Many of the changes were dose independent, but sex specific. This lead to the hypothesis that saturation toxicokinetics might be one of the reasons for this varied response, which can only be evaluated after further testing.

Effect of flubendiamide, lead and their combined exposure on erythrocytic indices in water buffalo calves.

This study evaluated the effect of flubendiamide, lead and their combined oral administration on erythrocytic indices in water buffalo calves. Exposure to flubendiamide alone resulted in non-significant decreases in Hemoglobin (Hb), packed cell volume (PCV), total erythrocyte count (TEC), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Lead acetate exposure resulted in significant declines in Hb, PCV and TEC. Combined exposure to flubendiamide and lead resulted in declines in Hb, TEC and PCV, but values did not differ significantly from corresponding values in the group treated with lead alone. Changes in MCV, MCHC and MCH were inconsistent. Plasma calcium concentration declined on day 90 in lead-exposed animals, but increased again on day 30 post-treatment. Results of the present study indicated that flubendiamide exposure results in marginal alterations in erythrocytic indices, but lead exposure caused significant declines in Hb, PCV and TEC. No interactive effects were observed for flubendiamide and lead on changes in erythrocytic indices.

Biochemical alterations induced by oral subchronic exposure to fipronil, fluoride and their combination in buffalo calves.

The effects of various pesticides and minerals on biochemical parameters have been explored in different species, but hardly any data exist regarding the combined toxicological effect of pesticides and minerals on these parameters in animals. The present study investigated the effects of fipronil and fluoride co-exposure on biochemical parameters in buffalo calves. Twenty-four healthy male buffalo calves divided into four groups were treated for 98 consecutive days. Group I, receiving no treatment served as the control. Animals of groups II and III were orally administered with fipronil @ 0.5mg/kg/day and sodium fluoride (NaF) @ 6.67 mg/kg/day, respectively, for 98 days. An additional group IV was co-administered fipronil and NaF at the same dosages as groups II and III. Administration of fipronil alone produced mild toxic signs, significant elevation in plasma proteins, blood glucose, blood urea nitrogen (BUN) and significant decline in the plasma cholesterol levels. NaF exposure produced toxic signs specifically of muscle weakness and brown and black discoloration of teeth. Significant elevation was seen in whole blood cholinesterase, BUN and creatinine levels. However, it produced significant decline in blood glucose, cholesterol and plasma protein levels. Combined exposure to fipronil and sodium fluoride produced toxic signs with greater intensity while biochemical alterations produced were similar to those that were produced by their individual exposures.

Pharmacokinetics following intravenous administration and pharmacodynamics of cefquinome in buffalo calves.

Disposition following single intravenous injection (2 mg/kg) and pharmacodynamics of cefquinome were investigated in buffalo calves 6-8 months of age. Drug levels in plasma were estimated by high-performance liquid chromatography. The plasma concentration-time profile following intravenous administration was best described by a two-compartment open model. Rapid distribution of cefquinome was evident from the short distribution half-life (t ½ α = 0.36 ± 0.01 h), and small apparent volume of distribution (Vd area = 0.31 ± 0.008 L/kg) indicated limited drug distribution in buffalo calves. The values of area under plasma concentration-time curve, elimination half-life (t ½ ß ), total body clearance (ClB), and mean residence time were 32.9 ± 0.56 µg · h/mL, 3.56 ± 0.05 h, 60.9 ± 1.09 mL/h/kg, and 4.24 ± 0.09 h, respectively. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration of cefquinome were 0.035-0.07 and 0.05-0.09 µg/mL, respectively. A single intravenous injection of 2 mg/kg may be effective to maintain the MIC up to 12 h in buffalo calves against the pathogens for which cefquinome is indicated.

Plasma levels, pharmacokinetics and dosage regimen of intravenously administered gatifloxacin in buffalo calves (Bubalus bubalis) on coadministration with meloxicam / Os níveis plasmáticos, farmacocinética e regime de dosagem de gatifloxacina administrado por via intravenosa em bezerros búfalos (Bubalus bubalis) na administração concomitante com meloxicam

The pharmacokinetics of intravenously administered gatifloxacin, upon concomitant administration with meloxicam was investigated in buffalo calves. Meloxicam was administered subcutaneously (0.5 mg.kg-1) immediately followed by intravenous administration of Gatifloxacin (4 mg.kg-1). The concentration of gatifloxacin was estimated in plasma by microbiological assay. Pharmacokinetic parameters were calculated and appropriate dosage schedule was computed. The therapeutic plasma drug concentration was maintained up to 12 h. Gatifloxacin was rapidly distributed from blood to tissue compartment, which was evident from the high values of distribution rate constant, α1 (11.9 ± 0.52 h-1) and the ratio of rate constant of transfer of drug from central to peripheral compartments and vice versa, K12/K21 (3.05 ± 0.36) and K13/K31 (2.04 ± 0.12). The area under the plasma drug concentration-time curve and apparent volume of distribution were 12.0 ± 0.68 µg.ml-1.h and 2.69 ± 0.14 L.kg-1, respectively. The elimination half-life (t1/2β), total body clearance (ClB) and the ratio of drug present in peripheral to central compartment (P/C) were 5.59 ± 0.40 h, 337.6 ± 19.9 ml.kg-1.h-1 and 8.04 ± 0.50, respectively. The present study revealed that the most suitable dosage regimen of gatifloxacin when concomitantly administered with meloxicam in buffalo calves would be 2.5 mg.kg-1 followed by 2.0 mg.kg-1 at 12 h intervals.

Investigou-se a farmacocinética da gatifloxacina, administrada por via intravenosa, concomitante à aplicação de meloxicam em bezerros búfalos. O meloxicam foi administrado por via subcutânea (0,5 mg.kg-1), imediatamente seguido pela administração intravenosa de gatifloxacina (4 mg.kg-1). A concentração plasmática de gatifloxacina foi estimada por ensaio microbiológico. Os parâmetros farmacocinéticos foram calculados e a posologia adequada foi computada. A concentração plasmática do fármaco-terapêutico foi mantida por 12 h. A gatifloxacina foi rapidamente distribuída a partir de sangue para o compartimento de tecido, o que ficou evidente a partir dos valores elevados da taxa constante de distribuição, α1 (11.9 ± 0.52 h-1) e a proporção de velocidade constante de transferência de droga a partir de centrais para os compartimentos periféricos e vice-versa, K12/K21 (3.05 ± 0.36) e K13/K31 (2.04 ± 0.12). A área sob a curva plasmática de concentração-tempo da droga e o volume aparente de distribuição foi de 12.0 ± 0.68 µg.ml-1.h e 2.69 ± 0.14 L.kg-1, respectivamente. A meia-vida (t1/2β), a depuração corporal total (ClB) e relação da droga presente no sangue periférico para o compartimento central (P/C) foram 5.59 ± 0.40 h, 337.6 ± 19.9 ml.kg-1.h-1 e 8.04 ± 0.50, respectivamente. O presente estudo revelou que o regime de dosagem mais adequado de gatifloxacina quando administrada concomitantemente com meloxicam em bezerros búfalos seria 2,5 mg.kg-1 seguida de 2,0 mg.kg-1 em intervalos de 12 h.

Disposition kinetics and urinary excretion of levofloxacin on concomitant administration with meloxicam in cross-bred calves.

The disposition kinetics and urinary excretion study of levofloxacin was conducted in 5 male cross-bred calves following its single intravenous administration (4mgkg(-1)) concurrently with meloxicam (0.5mgkg(-1)). Levofloxacin was estimated by microbiological assay. The drug levels above MIC(90) in plasma, were detected up to 10h. Disposition kinetic parameters were calculated by two-compartment open model. Rapid distribution of levofloxacin was evidenced by a small distribution half-life (0.13±0.01h) and high K(12)/K(21) ratio (2.21±0.15). High ratio of AUC/MIC (90.2±3.41) indicated good antibacterial activity of levofloxacin. The AUC, Vd(area), elimination half-life, MRT and total body clearance were 9.02±0.34µgml(-1)h, 1.38±0.05lkg(-)1, 2.16±0.08h, 2.58±0.11h and 0.45±0.02lkg(-1)h(-1), respectively. About 38.4% of the administered dose of levofloxacin was excreted in urine within 24h. A suitable intravenous dosage regimen for levofloxacin would be 1.8mgkg(-1) repeated at 8h intervals when prescribed with meloxicam in calves.

Influence of experimentally induced fever on the disposition of cefpirome in buffalo calves.

The influence of Escherichia coli endotoxin-induced fever on the disposition of cefpirome was investigated in five male buffalo calves following a single intravenous dose of 10mgkg(-1). Blood samples were collected from 1min to 24h of drug administration. The drug concentration in plasma was estimated by microbiological assay using E. coli as a test organism. The disposition of cefpirome followed two-compartment open model and the drug was detected above the minimum inhibitory concentration in plasma up to 12h. The Vd(area) and AUC were 0.75±0.01Lkg(-1) and 35.1±0.46µgml(-1)h, respectively. The elimination half-life of 1.81±0.009h and Cl(B) of 0.29±0.004Lkg(-1)h(-1) reflected rapid elimination and body clearance of cefpirome in febrile buffalo calves. Based on the results, a satisfactory dosage regimen of cefpirome in febrile buffalo calves was calculated to be 6mgkg(-1) to be repeated at 8h intervals.