Pharmacokinetics of enrofloxacin HCl-2H2 O (ENRO-C), PK/PD, and Monte Carlo modeling vs. Leptospira spp. in cows.

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl-2H2 O (Enro-C) and its reference preparation (Enro-R) were determined in cows. Fifty-four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro-C (Enro-C10 , Enro-C15 , Enro-C20 ) or Enro-R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (Cmax /MIC90 ) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC0-24 /MIC90 ). Monte Carlo simulations targeted Cmax /MIC = 10 and AUC0-24 /MIC = 125. Mean Cmax obtained were 6.17 and 2.46 µg/ml; 8.75 and 3.54 µg/ml; and 13.89 and 4.25 µg/ml, respectively for Enro-C and Enro-R. Cmax /MIC90 ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro-C and Enro-R, respectively. Monte Carlo simulations based on Cmax /MIC90  = 10 indicate that only Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC50  = 0.5 µg/ml, and ≥80% when MIC90  = 1.0 µg/ml. Although Enro-C15 and Enro-C20 may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.

Pharmacokinetics of enrofloxacin HCl-2H2O (Enro-C) in dogs and pharmacokinetic/pharmacodynamic Monte Carlo simulations against Leptospira spp.

Pharmacokinetic/pharmacodynamic (PK/PD) ratios of reference enrofloxacin (Enro-R) and enrofloxacin as HCl-2H2O (Enro-C), as well as Monte Carlo simulations based on composite MIC50 and MIC90 (MIC, minimum inhibitory concentration) vs. Leptospira spp., were carried out in dogs after their intramuscular (IM) or oral administration (10 mg/kg). Plasma determination of enrofloxacin was achieved by means of high-performance liquid chromatography. Maximum plasma concentration values after oral administration were 1.47 ± 0.19 µg/mL and 5.3 ± 0.84 µg/mL for Enro-R and Enro-C, respectively, and 1.6 ± 0.12 µg/mL and 7.6 ± 0.93 µg/mL, respectively, after IM administration. Areas under the plasma vs. time concentration curve in 24 h (AUC0-24) were 8.02 µg/mL/h and 36.2 µg/mL/h for Enro-Roral and Enro-Coral, respectively, and 8.55 ± 0.85 µg/mL/h and 56.4 ± 6.21 µg/mL/h after IM administration of Enro-R and Enro-C, respectively. The PK/PD ratios and Monte Carlo simulations obtained with Enro-C, not Enro-R, indicated that its IM administration to dogs will result in therapeutic concentrations appropriate for treating leptospirosis. This is the first time enrofloxacin has been recommended to treat this disease in dogs.

Assessment of acute respiratory and cardiovascular toxicity of casiopeinas in anaesthetized dogs.

The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas((R)) in dogs was calculated to be 200 mg/m(2) for casiopeina III-ia and 160 mg/m(2) for casiopeina IIgly. Considering therapeutic dose ranges from 3.6 to 18 mg/m(2) for the former and 1.2 to 3 mg/m(2) for the latter, true therapeutic margin of safety varies from 4.7 to 23.6 mg/m(2) and from 20 to 50 mg/m(2), respectively. For both casiopeinas intravenous administration of the corresponding lethal dose in 100 ml of 5% dextrose solution in a time period of 30 min. induced death after an almost uneventful latency time period of 30-50 min. Then, after an apparently sudden onset, changes in blood gases indicated respiratory distress (PO(2) from 82.5% to 26.5% for casiopeina III-ia and from 88.6% to 37.5% for casiopeina IIgly; end-tidal CO(2) from 38 to 8.1 mmHg for the first and from 35.1 to 11.2 mmHg for the second, this was almost simultaneously confirmed by the onset of tachypnoea (from 16 to almost 60 breaths/min. for both casiopeinas) and by a drop in arterial blood pressure (from 117 to 51 mmHg for casiopeina III-ia and from 108 to 49 mmHg for casiopeina IIgly). Reflex tachycardia occurs at the beginning of intravenous administration followed by bradycardia a few minutes later (from 158 to 63 beats/min. for casiopeina III-ia and from 148 to 56 beats/min. for casiopeina IIgly). Finally, cardiac arrest occurred no later than 25 min. towards the end of these events lung oedema appeared as fluid dripping from the endotracheal tube. Death occurred in a mean of 15 +/- 5 min. S.D. from the beginning of the end of the latency period. For both casiopeina's data allow the speculation that lung oedema is caused by a joined toxicity to the lung capillary bed, and particularly to the heart. Carvedilol premedication for 8 days delayed the outcome of lung oedema by approximately 8 hr but could not prevent it.