First report of the lethal activity and synergism between deltamethrin, amitraz and piperonyl butoxide against susceptible and pyrethroid-resistant nymphs of Triatoma infestans.

In South America, Triatoma infestans (Hemiptera: Reduviidae) is the main vector of the parasite Trypanosoma cruzi, etiological agent of Chagas disease. The main strategy for vector control is to spray domestic structures with pyrethroids. Reports of populations of T. infestans with varying degrees of resistance to pyrethroids have made the search for alternative molecules for vector control necessary. In the first stage of this work we investigated the lethal activity of amitraz and deltamethrin against susceptible and pyrethroid-resistant nymphs of Triatoma infestans. Lethal dose at 50% (LD50) of susceptible nymphs were compared with those recorded in pyrethroid-resistant nymphs and the resistance ratio (RR50) was obtained. The RR50 of deltamethrin was approximately 300. In the case of amitraz, we observed similar triatomicidal activity in the two nymph populations (RR50: 0.7). In a second stage of the work, we determined the synergistic effect of amitraz and piperonyl butoxide (PBO) on the lethal activity of deltamethrin. The strong synergistic effect of PBO on the lethal activity of deltamethrin in resistant nymphs produced a decrease in RR50 to almost one third of the RR50 reported in absence of the synergist. Amitraz plus PBO lethal activity was similarly increased in pyrethroid susceptible and resistant nymphs. Our data indicate that deltamethrin synergism by amitraz was higher against resistant than to susceptible nymphs (Synergist ratio (SR50) of: 7.2- and 4.1-fold, respectively). In pyrethroid resistant nymphs, the highest level of synergism was obtained combining deltamethrin with amitraz and PBO (SR50: 26.7-fold). These results indicate that this combination could be considered an effective alternative for the control of T. infestans.

Pharmacokinetics of azithromycin in lactating dairy cows with subclinical mastitis caused by Staphylococcus aureus.

Azithromycin is a time-dependent antimicrobial with long persistence. The main characteristics of azithromycin suggest that it could be useful for treating bovine mastitis caused by Staphylococcus aureus. To investigate this possibility, its pharmacokinetic (PK) behavior was studied. Six Holstein lactating cows with subclinical mastitis were administered two 10 mg/kg intramuscular (i.m.) doses of azithromycin, with a 48-h interval. Milk and plasma concentrations were measured by microbiological assay. The MIC(90) was determined in 51 S. aureus isolations to calculate pharmacokinetic/pharmacodynamic (PK/PD) parameters. Milk maximal concentration (C(max)) was 7.76 +/- 1.76 microg/mL (16.67 h post-first administration) and 7.82 +/- 2.18 microg/mL (14 h post-2(nd) administration). In plasma C(max) was 0.18 +/- 0.03 microg/mL (2 h post-1(rst) administration) and 0.11 +/- 0.03 microg/mL (14 h post-2(nd) administration). Azithromycin was eliminated from the milk with a half-life (T(1/2)lambda) of 158.26 +/- 137.7 h after 2(nd) administration, meanwhile plasma T(1/2)lambda resulted shorter(13.97 +/- 11.1 h). The mean area under the concentration vs. time curve from 0 to 24 h (AUC(0-24h)) was 153.82 +/- 34.66 microg.h/mL in milk secretion and 2.61 +/- 0.59 microgxh/mL in plasma. Infection presence in the quarters had a significant effect (P < 0.05) on the area under the concentration vs. time curve from 0 to infinity (AUC(0-infinity)) and clearance from the mammary gland (Cl(mam)/F). Moreover, it had influence on milk bioavailability (F(milk)), T(1/2)lambda, AUC(0-infinity) and mean residence time (MRT) in milk, which values resulted increased in mastitic quarters. In this study, it was determined that the production level and the mammary health status have an influence on PK parameters of azithromycin treatments in bovine mastitis.

Pharmacokinetics of enrofloxacin after single intravenous administration in sheep.

The disposition of enrofloxacin in sheep was investigated after single-dose intravenous administration of 2.5 mg/kg body weight. Blood samples were drawn from the jugular vein at predetermined times after drug administration. Plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin were simultaneously determined by reverse-phase high performance liquid chromatography. The data collected were subjected to non-compartmental and compartmental kinetic analysis. Statistical model theory was used to determine non-compartmental pharmacokinetic parameters. Disposition of enrofloxacin was described by a three-compartment open model with elimination from the central compartment following intravascular administration. The elimination half-life, the volume of distribution, and the area under the concentration vs time curve (AUC) were 4.31 h, 1.10 l/kg and 9.24 microg x h/ml, respectively. Enrofloxacin was metabolised to ciprofloxacin and the ratio between the AUCs of ciprofloxacin and enrofloxacin was 0.26 after intravenous administration. With predictive models of efficacy (maximum plasma concentrations/minimum inhibitory concentrations [Cmax/MIC] and AUC/MIC ratios in plasma) for most of the sheep pathogen microorganisms, enrofloxacin produced scores higher than 15 and 50, respectively. After intravenous administration atthe dose of 2.5 mg/kg, enrofloxacin achieved concentrations several times above the MIC for major pathogen bacteria in plasma, and it may prove useful in the treatment of infectious diseases caused by sensitive pathogens in sheep.

Pharmacokinetic disposition of triclabendazole in cattle and sheep; discrimination of the order and the rate of the absorption process of its active metabolite triclabendazole sulfoxide.

A comparative pharmacokinetic study was conducted to determine the order and the rate of absorption of triclabendazole (TCBZ) in cattle and sheep. A commercial suspension of TCBZ (Biofasiolex, Biogénesis S.A., Argentina) was administered at a dose rate of 10 mg/kg by the oral route to six Holstein female calves and six Corriedale female sheep. The plasma concentration profiles of the metabolites triclabendazole sulfoxide (TCBZ-SO) and triclabendazole sulfone (TCBZ-SO(2)) were analysed by means of the non-compartmental method. The order of the absorption process of the active metabolite, TCBZ-SO, was determined by construction of curves of cumulative absorbed fraction of the drug by means of the Wagner-Nelson method. The appearance of TCBZ-SO in plasma of cattle and sheep resembles the entry of a constant quantity of drug into the organism per unit time. This is explained by the reservoir effect of the rumen, which acts as a biological slow-release system for TCBZ-SO and its precursor TCBZ to the posterior digestive tract where they are absorbed. The plasma concentration profiles of TCBZ-SO in both species were well described by a one-compartment open model with zero-order process of absorption and first-order process of elimination. The values of AUC(0-infinity) and C(max) of TCBZ-SO did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep. In the case of TCBZ-SO(2), t(max) was the only parameter that did not differ between species, while other kinetic parameters except for lambda(z) had higher values in calves than in sheep.

Pharmacokinetics and tissue residues of an oxytetracycline/diclofenac combination in cattle.

Eight male cattle were given a combined dose containing 20 mg/kg oxytetracycline and 0.5 mg/kg diclofenac intramuscularly. Blood samples were drawn at different times until 168 h after administration. Two experimental animals were slaughtered by humane means at weekly intervals up to 28 days after administration. Samples of muscle, injection zone tissue, liver, kidney and fat were obtained. Oxytetracycline and diclofenac concentrations were determined by high performance liquid chromatography. Kinetic analysis was performed by linear regression using the CSTRIP programme. Plasma oxytetracycline concentration showed a maximum (Cmax) of 3.89 +/- 1.48 microg/ml and a prolonged elimination half-life (T1/2beta: 47.73 +/- 18.33 h). The diclofenac plasma profile showed high Cmax (577.62 +/- 238.40 ng/ml), and its T1/2beta was also prolonged (30.48 +/- 9.42 h). Oxytetracycline concentrations were measurable in liver and adipose tissue until day 21 after administration, but all tissue samples were negative for diclofenac at 21 days. The long elimination half-life of diclofenac was an unexpected finding; its T1/2beta in humans is 1.1 h.

Pharmacokinetics of ricobendazole after its intravenous, intraruminal and subcutaneous administration in sheep.

Ricobendazole (RBZ) was administered in sheep at the dose rate of 5 mg/kg by intravenous (i.v.) route as a 10% experimental solution, by the intraruminal (i.r.) route as a 10% experimental suspension, and by the subcutaneous (s.c.) route as a 10% commercial formulation available in Argentina. Blood samples were drawn during a 60 h period. Plasma concentrations of RBZ and its inactive metabolite albendazole sulphone (ABZSO2) were determined by high-performance liquid chromatography. The pharmacokinetic parameters were determined by compartmental analysis. The fitting of the data was done by weighted least-squares non-linear regression analysis. The pharmacokinetic parameters were estimated for every animal by simultaneous fitting of the plasma concentrations profiles of RBZ obtained after its administration by the three routes. The kinetic analysis of ABZSO2 was performed by a statistical moment approach. Ricobendazole bioavailability was poor after i.r. administration, whereas high and sustained plasma concentrations and higher bioavailability were obtained after s.c. administration. A simple two-compartment open model explains in a mechanical sense the pharmacokinetic behaviour of RBZ in sheep and allows us to estimate the real first-order constant rate of absorption and the loss of drug from the absorption site after its administration by s.c. and i.r. routes.

Comparative persistent efficacy of doramectin, ivermectin and fenbendazole against natural nematode infections in cattle.

A study was conducted in Argentina, to investigate the period of protection of a single injection of doramectin administered subcutaneously (s.c.) at 200 micrograms kg-1 (1 ml/50 kg) compared with single treatments of ivermectin (200 micrograms kg-1 s.c.) and fenbendazole (5 mg kg-1 p.o.), against field infections of gastrointestinal parasites of cattle. Eighty-three animals were selected and ranked on the basis of serial fecal egg counts (e.p.g.'s). From this group, three animals were slaughtered before treatment and their lungs, abomasum, small and large intestines, were processed for parasite counts and identification. The remaining 80 animals were allocated in ranked groups of four to a control or one of three treated groups. Animals of the four groups were grazed together in the same pasture for the duration of the study. Treatments were administered on Day 0. Individual fecal samples were collected at weekly intervals for the first 49 days post-treatment and twice a week from Day 52 to Day 84 (end of study). At each collection day fecal samples were pooled for coprocultures. On Day 28 and 56, two animals from each group, previously identified on Day 0, were killed and their parasite burdens determined. The duration of protection of a single injection of doramectin was longer than ivermectin or fenbendazole treatment. On Day 56, the total number of parasites found in doramectin-treated animals was significantly (P < 0.05) lower than parasite burdens found in either ivermectin- or fenbendazole-treated animals. The longer persistent activity of doramectin was expressed by the lower number of adults and L4 stages of Ostertagia ostertagi. Data from this experiment demonstrated the limitations of using fecal egg counts to evaluate the persistent efficacy of anthelmintics. The duration of activity of doramectin was demonstrated more accurately by parasite counts in cattle from each group since decreasing e.p.g.'s were seen in non-medicated animals without changes in total parasite burdens.

Tissue concentrations of a long-acting oxytetracycline formulation after intramuscular administration in cattle.

The tissue distribution of a long-acting oxytetracycline formulation after intramuscular administration to calves at a dose rate of 20 mg/kg was studied. Oxytetracycline concentrations were determined in lung, bone marrow, mammary gland, uterus, uterine horn, ovary, liver, synovial fluid, joint tissue, kidney, spleen, brain, muscle, fat, urine, bile, saliva, ruminal content and serum. Observed concentrations were higher than the minimal inhibitory concentration for the majority of pathogens in all of the analysed tissues for at least 72 h post-injection. The shortest theoretical permanency time was 1.88 days (in saliva) and the longest was 19.06 days (in kidney). Taking the maximal permitted residue level as 0.1 microgram/g in muscle, 0.3 microgram/g in liver and 0.6 microgram/g in kidney, the calculated withdrawal time was 20 days.

A discriminatory study of a pharmacokinetic model for intramuscular gentamicin in sheep.

The resulting serum concentrations were measured in six ewes after intramuscular administration of 10 mg/kg of gentamicin. The model providing the best fit for the experimental data was determined both by linear regression analysis between the experimental and theoretical values and by means of the Minimum Akaike Information Criterion Estimation (MAICE) test. Linear regression analysis showed certain differences favouring the monocompartmental model although the advantage was not conclusive. The MAICE test, however, permitted a clear discrimination in favour of the same model. When linear regression analysis is not conclusive, the MAICE test represents a good alternative.

The pharmacokinetics of a slow-release theophylline preparation in horses after intravenous and oral administration.

The pharmacokinetics of a slow-release theophylline formulation was investigated following intravenous and oral administration at 10 mg/kg in horses. A tricompartmental model was selected to describe the intravenous plasma profile. The elimination half-life (t1/2 beta) was 16.91 +/- 0.93 h, the apparent volume of distribution (Vd) was 1.35 +/- 0.18 L/kg and the body clearance (ClB) was 0.061 +/- 0.009 L kg-1 h. After oral administration the half-life of absorption was 1.24 +/- 0.30 h, and the calculated bioavailability was above 100%. The t1/2 beta after oral administration was 18.51 +/- 1.75 h, only a little longer than that after intravenous administration. The slow release formulation did not exhibit any advantage in prolonging the t1/2 beta of theophylline in the horse.

The effects of the method of calculation on the evaluation of the pharmacokinetic parameters of oxytetracycline after intravenous administration to calves.

The aim of this study was to assess the differences in the values of the pharmacokinetic parameters attributable to the use of either linear or nonlinear regression analysis and to find the effect of weighting schemes on these differences. Six calves received 20 mg/kg oxytetracycline i.v. Blood samples were drawn during 72 h. The assay of the drug was performed microbiologically. A bicompartmental pharmacokinetic model was used, kinetic analysis being carried out by linear regression (LR) and by weighted least-squares nonlinear regression (WLSNLR). Statistical analysis included a test for normality, the Kruskall-Wallis test and ANOVA with log transformation. The A0, alpha and B0 did not show any statistically significant differences attributable to the mathematical method used. On the other hand, the statistically significant differences in the beta values found using the Kruskall-Wallis test and ANOVA with log transformation could be attributed to the different methods employed. ANOVA with log transformation determined statistically significant differences between the parameters obtained by linear analysis and those obtained by WLSNLR when the weighting (w) was 1. When weights were 1/x, 1/x2 or 1/square root of x, no statistically significant differences were found. The optimal weighting scheme was w = 1/x2 because of a more homogeneous scatter and random distribution of residuals about the abcissa axis in a plot of weighted residuals in the ordinate versus time in the abcissa. It was concluded that the use of these different procedures can give major variations in the apparent value of beta, the most important pharmacokinetic parameter. The correct selection of the weighting procedure is therefore fundamental in obtaining the best estimate of this pharmacokinetic parameter in WLSNLR.

The pharmacokinetics of thiamphenicol in lactating cows.

The pharmacokinetics of thiamphenicol were studied after intravenous and intramuscular administration of 25 mg/kg body weight in lactating cows. Distribution (t1/2 alpha) and elimination (t1/2 beta) half-lives of 6.10 +/- 1.39 min and 1.60 +/- 0.30 h, respectively, were obtained after intravenous administration. The body clearance was 3.9 +/- 0.077 ml/kg per min and the apparent volume of distribution was 1220.79 +/- 256.67 ml/kg. The rate at which thiamphenicol appeared in the milk, as indicated by the penetration half-life (t1/2P) (serum to quarters), was found to be 36.89 +/- 11.14 min. The equivalent elimination half-life (t1/2E) (quarters to serum) from the milk was 3.62 +/- 1.06 h and the peak thiamphenicol concentration in the milk was 23.09 +/- 3.42 micrograms/ml at 2.5 +/- 0.32 h. After intramuscular injection, the elimination half-life was 2.2 +/- 0.40 h, the absorption half-life was 4.02 +/- 1.72 min and the peak concentration in the serum was 30.90 +/- 5.24 micrograms/ml at 23 +/- 8.4 min. The bioavailability after intramuscular administration approached 100%. The penetration half-life was 50.59 +/- 6.87 min, the elimination half-life was 5.91 +/- 4.97 h and the mean peak concentration in the milk was 17.37 +/- 2.20 micrograms/ml at 3.4 +/- 0.22 h.

Chloramphenicol pharmacokinetics after intravenous and intramuscular administration in sheep.

The pharmacokinetics of chloramphenicol were studied after intravenous and intramuscular administration of 50 mg/kg body weight in Merino sheep. After intravenous administration, the drug was rapidly distributed extravascularly with a half-life of 10.5 +/- 8.83 min. Extensive distribution was confirmed by an apparent volume of distribution at steady state (1.5 +/- 0.43 1/kg). The elimination half-life was 3.24 +/- 0.60 h. After intramuscular injection, the absorption half-life was 44.33 +/- 19.21 min with a bioavailability of 65%. A maximum serum concentration of 15.57 +/- 3.95 micrograms/ml was determined 2 h after administration. Serum concentrations above 5 micrograms/ml were maintained for approximately 12 h with an elimination half-life of 5.75 +/- 1.25 h, longer than the half-life obtained after intravenous administration. In conclusion, the intramuscular administration of chloramphenical at a dose rate of 50 mg/kg permitted the maintenance of inhibitory concentrations of the antibiotic for the majority of Salmonella and Pasteurella isolates for at least 12 h.

Pharmacokinetics of neomycin in sheep after intravenous, intramuscular, subcutaneous and intratracheal administration.

The pharmacokinetics and bioavailability of neomycin in sheep were investigated following intravenous, intramuscular, subcutaneous and intratracheal administration of 10 mg/kg. A rapid distribution phase (t 1/2 alpha, 3.16 min) was followed by a slower elimination phase (t1/2 beta, 1.98 h). The apparent volume of distribution was 304.69 ml/kg. Absorption half-lives were 18.62, 21.22 and 40.83 min and elimination half-lives 2.68, 2.82 and 2.55 h after IM, SC and IT administration, respectively. Bioavailabilities between 0.74 and 0.85 were obtained for the three routes of administration. Based on the bioavailability and disposition kinetics of neomycin, a twice daily IM dosage regimen should both be practical and adequate to maintain plasma neomycin concentrations within the pharmacologically active but nontoxic range.

Some dynamic and toxic effects of theophylline in horses.

A single intravenous administration of theophylline as aminophylline at 10 mg/kg to four mares induced a diuresis in which maximal urine production was more than seven times the control volume. The diuretic effect was maximal within the first hour post-administration, and lasted approximately 6 h. Theophylline resulted in dose-related tachycardia, polypnoea and nervous symptoms (tactile, visual and auditory hypersensitivity, muscle tremor, sweating) in normal mares, but had only minor effects on arterial and central venous blood pressures, intrapleural pressure, red blood cell variables and plasma proteins. The upper limit of safe plasma theophylline concentration in horses is approximately 15 micrograms/ml. Whenever feasible, the oral or intragastric route of administration should be used as it is safer than the intravenous route.

Pharmacokinetics of cefoperazone in horses.

The pharmacokinetics and bioavailability of cefoperazone (CPZ) were studied following intravenous (IV) and intramuscular (IM) administration of single doses (30 mg/kg) to horses. Concentrations in serum, urine and synovial fluid samples were measured following IV administration. CPZ concentrations in serum, synovial fluid and spongy bone samples were measured following IM administration. After IV administration a rapid distribution phase (t1/2 (alpha): 4.22 +/- 2.73 min) was followed by a slower elimination phase (t1/2(beta) 0.77 +/- 0.19 h). The apparent volume of distribution was 0.68 +/- 0.10 L/kg. Mean synovial fluid peak concentration was 5.76 +/- 0.74 microgram/mliter. After IM administration a bioavailability of 42.00 +/- 5.33% was obtained. Half-life of absorption was 2.51 +/- 0.72 min and t1/2(beta) was 1.52 +/- 0.15 h. The mean synovial fluid and spongy bone peak concentrations at 2 h after IM administration were 2.91 +/- 0.85 microgram/mliter and 5.56 +/- 0.70 microgram/mliter, respectively.

Pharmacokinetics of ricobendazole in calves.

The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen.

Pharmacokinetics of amoxycillin in normal horses and horses with experimental arthritis.

The serum and synovial pharmacokinetics of amoxycillin (AMX) were studied after i.v. administration at a dosage of 40 mg/kg to normal horses and horses with induced aseptic carpal arthritis. The best estimates of serum and synovial pharmacokinetic parameters were calculated by mono or bivariable non-linear regression analysis. A biexponential equation was used to describe the concentration vs. time profiles in both normal and arthritic horses. There were no serum kinetic differences between normal and arthritic horses. There were, however, major synovial kinetic changes between these groups. The rate of penetration from serum to synovial fluid was larger in arthritic animals, indicating better penetration in this case. On the other hand, the rate of disappearance from synovial fluid was larger in normal horses, indicating more persistence of the drug in the diseased joint. Synovial AMX availability increased from 21% in normal horses to 79% in arthritic horses. These findings support the use of AMX for the treatment of infectious synovial joint disease produced by susceptible organisms in horses.

Pharmacokinetics and bioavailability of theophylline in horses.

The pharmacokinetics and bioavailability of theophylline in horses were investigated following both intravenous and intragastric administration of aminophylline solutions at doses corresponding to 15 and 10 mg/kg theophylline base. A rapid distributive phase with a half-life of approximately 15-30 min was followed by a slower elimination half-life averaging 15-17 h. The apparent volume of distribution averaged 850-900 ml/kg. Theophylline, administered as aminophylline solution, was both rapidly and completely absorbed from the equine digestive tract. Based on the bioavailability and disposition kinetics of theophylline, an intragastric dosage regimen for aminophylline consisting of the administration of 5 mg/kg at 12 h intervals would be expected to maintain plasma theophylline concentrations within the therapeutic range.