The influence of rapid growth in broilers on florfenicol pharmacokinetics - allometric modelling of the pharmacokinetic and haemodynamic parameters.

1. The aim of this study was to determine if the pharmacokinetics (PK) of florfenicol (FF) undergo age-dependent changes in broilers. Since drug elimination depends on cardiovascular functions, a haemodynamic study was performed in parallel. 2. Broilers of 0.68, 1.27, 2.45 and 5.13 kg were administered FF in a single intravenous dose of 30 mg/kg body weight. Plasma drug concentrations were determined using high-performance liquid chromatography and PK parameters were calculated using a non-compartmental model. Echocardiography was used to measure haemodynamic functions. 3. During growth, the area under the drug concentration-time curve (AUCinf) increased from 25.7 ± 2.9 to 39.0 ± 8.0 mg h/l. Total body clearance (ClB) gradually decreased from 1.19 ± 0.14 to 0.80 ± 0.15 l/h/kg. Elimination half-life increased from 0.73 ± 0.08 to 1.07 ± 0.07 h, whereas volume of distribution (Vss) remained unchanged. Haemodynamic measurements revealed an increase in cardiac output, from 495 ± 65 to 1303 ± 306 ml/min, in the respective body weight groups. 4. Allometric models for PK and haemodynamic parameters were developed and validated. All models proved to be statistically significant; however, only models for ClB and Vss met stringent validation criteria. Model for ClB was used to calculate an optimal dose for a given age group that provides uniform AUCinf. 5. Age-dependent change in FF kinetics may cause variability in therapeutic response under clinical conditions. A novel approach to the dosing protocol was proposed as a means of optimising therapeutic efficacy.

Localized rotational activation in the left atrium during human atrial fibrillation: relationship to complex fractionated atrial electrograms and low-voltage zones.

BACKGROUND: In humans, the existence of rotors or reentrant sources maintaining atrial fibrillation (AF) and the underlying electroanatomic substrate has not been well defined. OBJECTIVE: Our aim was to determine the prevalence of localized rotational activation (RotA) in the left atrium (LA) during human AF and whether complex fractionated atrial electrograms (CFAEs) or low-voltage areas colocalize with RotA sites. METHODS: We prospectively studied 32 patients (mean age 57 ± 8 years; 88% with persistent AF) undergoing AF catheter ablation. Bipolar electrograms were recorded for 2.5 seconds during AF using a roving 20-pole circular catheter in the LA. RotA was defined as sequential temporal activation of bipoles around the circular catheter. Bipolar electrogram fractionation index and bipolar voltage were used to define CFAEs and low-voltage areas, respectively. RESULTS: In 21 (66%) patients, 47 RotA sites were identified. Few (9%) lasted 2.5 seconds (cycle length 183 ± 6 ms), while the majority (91%) were nonsustained (duration 610 ± 288 ms; cycle length 149 ± 11 ms). RotA was most common in the pulmonary vein antrum (71%) and posterior LA (25%). CFAEs were recorded from 18% ± 12% of LA area, and most (92% ± 7%) were not associated with RotA sites. However, 85% of RotA sites contained CFAEs. Very low voltage (<0.1 mV) areas comprised 12% ± 10% of LA area and were present in 23% of RotA sites. CONCLUSIONS: In patients with predominantly persistent AF, localized RotA is commonly present but tends to be transient (<1 second). Although most CFAEs do not colocalize with RotA sites, the high prevalence of CFAEs and very low voltages within RotA sites may indicate slow conduction in diseased myocardium necessary for their maintenance.

Influence of bestatin, an inhibitor of aminopeptidases, on T and B lymphocyte subsets in mice.

Bestatin, a low-molecular weight dipeptide, is a potent inhibitor of aminopeptidase N which has been demonstrated to have antitumor and immunomodulatory effects. The effects of bestatin (10, 1 and 0.1 mg/kg) administered intraperitoneally once, five or ten times to mice on the total number of lymphocytes in the thymus, spleen and mesenteric lymph nodes and the percentage and the absolute number of T cell subsets (CD4+CD8+, CD4-CD8-, CD4+, CD8+) in the thymus and T (CD3+, CD4+, CD8+) and B (CD19+) lymphocytes in the spleen and mesenteric lymph nodes were studied. It has been found that bestatin administered ten times at doses of 10, 1 and 0.1 mg/kg increased the total number of thymocytes, splenocytes and lymphocytes of mesenteric lymph nodes. Bestatin also changed the percentage and the absolute number of T cell subsets in the thymus and T and B lymphocytes in the peripheral lymphatic organs. Five and ten exposures to bestatin (10, 1 and 0.1 mg/kg) increased the absolute count of both immature CD4+CD8+ and CD4-CD8- thymic cells. Moreover, both a single and multiple administration of bestatin (1 and 0.1 mg/kg) decreased the percentage and absolute count of CD3+ splenocytes and mesenteric lymph node cells with corresponding decreases in the percentage and absolute count of CD4+ and CD8+ cells. Both a single and multiple administration of bestatin at all the doses under investigation augmented the percentage and the absolute count of CD19+ (B lymphocytes) in the peripheral lymphatic organs. The results of the study show that there is a relationship between the effect induced by bestatin and the dose of the drug as well as the number of doses applied. The strongest effect on the T and B lymphocyte subsets was noted after five injections of bestatin at doses of 1 and 0.1 mg/kg.

The effects of florfenicol on lymphocyte subsets and humoral immune response in mice.

Florfenicol is a broad-spectrum bacteriostatic antibiotic used in domestic animals. The aim of the study was to determine the effect of florfenicol on the total number of lymphocytes in the thymus, spleen and mesenteric lymph nodes and the percentage and the absolute number of T cell subsets (CD4+CD8+, CD4-CD8-, CD4+, CD8+) in the thymus and T (CD3+, CD4+, CD8+) and B (CD19+) lymphocytes in the peripheral lymphatic organs in non-immunized mice and humoral immune response in sheep red blood cells (SRBC)-immunized mice. Florfenicol was administered orally at a dose of 30 mg/kg six times at 24 h intervals to non-immunized mice and four or seven times at 24 h intervals to SRBC-immunized mice. SRBC was injected 2 hours prior to the first dose of the drug. Florfenicol increased the percentage of CD4CD8- thymocytes and the absolute number of CD4+ and CD8+ thymocytes on day 7. The increased percentage and absolute number of CD3+, CD4+ and CD8+ lymphocytes in mesenteric lymph nodes and decreased percentage of lymphocytes B were also observed 24 hours from the last administration of florfenicol. Florfenicol administered after SRBC immunization reduced the number of plaque forming cells (PFC) and the production of anti-SRBC antibodies on days 4 and 7 after priming.