Pharmacokinetics and distribution of voriconazole in body fluids of dogs after repeated oral dosing.

The goal of this project was to determine the pharmacokinetics of voriconazole and its concentration in cerebrospinal fluid (CSF), aqueous humor, and synovial fluid in five healthy dogs following once daily oral dose of 6 mg/kg for 2 weeks. Body fluid and plasma drug concentrations were determined by high-performance liquid chromatography (HPLC). Mild to moderate gastrointestinal adverse effects were seen. The mean AUC0-24 : minimum inhibitory concentration (MIC) ratio was 15.23 for a chosen MIC of 1 µg/mL, which is lower than the recommended target of 20-25 and also lower than previously reported in dogs, perhaps reflecting induction of metabolizing enzymes by multiple dosing. Voriconazole concentrations in the CSF, aqueous humor, and synovial fluid were only 13-30% the concurrent plasma concentration, which is lower than previously reported in other species. Results of this study suggest that twice daily, administration may be necessary to maintain therapeutic plasma concentrations in dogs but further studies are warranted.

Efficacy of gallium maltolate against Lawsonia intracellularis infection in a rabbit model.

Antimicrobial efficacy against Lawsonia intracellularis is difficult to evaluate in vitro, thus, the effects of gallium maltolate's (GaM) were investigated in a rabbit model for equine proliferative enteropathy (EPE). Juvenile (5-6-week-old) does were infected with 3.0 × 10(8) L. intracellularis/rabbit and allocated into three groups (n = 8). One week postinfection, one group was treated with GaM, 50 mg/kg; one, with doxycycline, 5 mg/kg; and one with a sham-treatment (control). Feces and blood were collected daily and weekly, respectively, to verify presence of L. intracellularis fecal shedding using qPCR, and seroconversion using immunoperoxidase monolayer assay. Rabbits were sacrificed after 1 week of treatment to collect intestinal tissues focusing on EPE-affected sections. Intestinal lesions were confirmed via immunohistochemistry. No difference was noted between treatments regarding EPE-lesions in jejunum (P = 0.51), ileum (P = 0.74), and cecum (P = 0.35), or in L. intracellularis fecal shedding (P = 0.64). GaM and doxycycline appear to have similar efficacy against EPE in infected rabbits.

Pharmacokinetics of gallium maltolate in Lawsonia intracellularis-infected and uninfected rabbits.

Oral gallium maltolate (GaM) pharmacokinetics (PK) and intestinal tissue (IT) concentrations of elemental gallium ([Ga]) and iron ([Fe]) were investigated in a rabbit model of equine proliferative enteropathy (EPE). New Zealand white does (uninfected controls and EPE-infected, n = 6/group) were given a single oral GaM dose (50 mg/kg). Serial blood samples were collected from 0 to 216 h post-treatment (PT) and IT samples after euthanasia. Serology, qPCR, and immunohistochemistry confirmed, or excluded, EPE. Blood and IT [Ga] and [Fe] were determined using inductively coupled plasma-mass spectrometry. PK parameters were estimated through noncompartmental approaches. For all statistical comparisons on [Ga] and [Fe] α = 5%. The Ga log-linear terminal phase rate constant was lower in EPE rabbits vs. uninfected controls [0.0116 ± 0.004 (SD) vs. 0.0171 ± 0.0028 per hour; P = 0.03]; but half-life (59.4 ± 24.0 vs. 39.4 ± 10.8 h; P = 0.12); Cmax (0.50 ± 0.21 vs. 0.59 ± 0.42 µg/mL; P = 0.45); tmax (1.75 ± 0.41 vs. 0.9 ± 0.37 h; P = 0.20); and oral clearance (6.743 ± 1.887 vs. 7.208 ± 2.565 L/h; P = 0.74) were not. IT's [Ga] and [Fe] were higher (P < 0.0001) in controls. In conclusion, although infection reduces IT [Ga] and [Fe], a 48 h GaM dosing interval is appropriate for multidose studies in EPE rabbits.

Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cows.

This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (+/-SD) were: C(max), 5.5 +/- 2.6 microg/mL; T(max), 0.75 +/- 0.27 h; AUC(0-infinity), 10.8 +/- 4.9 microg x h/mL; MRT, 2.2 +/- 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows.

Pharmacokinetics of tilmicosin in equine tissues and plasma.

The macrolide antibiotic tilmicosin has potential for treating bacterial respiratory tract infections in horses. A pharmacokinetic study evaluated the disposition of tilmicosin in the horse after oral (4 mg/kg) or subcutaneous (s.c.) (10 mg/kg) administration. Tilmicosin was not detected in equine plasma or tissues after oral administration at this dose. With s.c. injection, tilmicosin concentrations reached a maximum concentration of approximately 200 ng/mL in the plasma of the horses. Tilmicosin concentrations in plasma persisted with a mean residence time (MRT) of 19 h. Maximum tissue residue concentrations (C(max)) of tilmicosin measured in equine lung, kidney, liver and muscle tissues after s.c. administration were 2784, 4877, 1398, and 881 ng/g, respectively. The MRT of tilmicosin in these tissues was approximately 27 h. Subcutaneous administration of tilmicosin resulted in severe reactions at the injection sites.

Estimating the economic effects of cystic echinococcosis. Part 3: Jordan, a developing country with lower-middle income.

The economic costs of cystic echinococcosis (CE) in Jordan, a developing country of lower-middle income, were investigated. Initial cost-estimates for livestock were based on the published prevalences of Echinococcus granulosus infection in sheep and goats and the values of livestock-related products together with likely production losses. Likewise, the annual numbers of human cases of CE were estimated using published surgical incidences in man. The costs of surgery were estimated from hospital records and by costing out the procedures each patient received whilst undergoing treatment. After comparing the quality of life of patients treated for CE with that of case-matched controls, it appeared that the treated patients had some long-term morbidity caused either by the disease or the resulting treatment. A simple spreadsheet model was built up, to sum the individual cost items. Each cost item and each of the data related to prevalence and incidence was assigned a mathematical distribution and varied randomly, using Monte-Carlo techniques, throughout its range, over 10 000 simulations. The results of the study indicate that the most likely range of annual economic losses attributable to CE in Jordan (encompassing 95% confidence limits) is from U.S.$2 602 215-6533 661, with a median of U.S.$3 874 070.

Comparison of 2 techniques for regional antibiotic delivery to the equine forelimb: intraosseous perfusion vs. intravenous perfusion.

The purpose of this study was to compare the synovial fluid concentrations and pharmacokinetics of amikacin in the equine limb distal to the carpus following intraosseous and intravenous regional perfusion. The front limbs of 6 horses were randomly assigned to either intraosseous or intravenous perfusion. A tourniquet was placed distal to each carpus and the limb perfused with 500 mg of amikacin. Systemic blood samples and synovial fluid samples were collected over 70 min from the distal interphalangeal (DIP) joint, metacarpophalangeal joint, and digital flexor sheath. The tourniquet was removed following the 30 min sample collection. The mean peak amikacin concentration for the DIP joint was significantly higher with intravenous perfusion. There were no significant differences in time to peak concentration or elimination half-life between methods at each synovial structure. Each technique produced mean peak concentrations ranging from 5 to 50 times that of recommended peak serum concentrations for therapeutic efficacy.

Determination of flunixin residues in bovine muscle tissue by liquid chromatography with UV detection.

A new and sensitive liquid chromatography-ultra violet method with a detection limit of 6 ng/g (ppb) and a limit of quantification of 15 ng/g was developed for the determination of flunixin residues in bovine muscle tissue. Flunixin in homogenized animal tissue was extracted with acetonitrile after enzyme digestion. The tissue digest (extract) was then cleaned up on a solid-phase extraction cartridge and eluted with acidified hexane. After the eluate was evaporated to dryness under nitrogen at 55 degrees C, the residue was reconstituted in 1 mL mobile phase solution and analyzed by reversed-phase gradient chromatography with UV detection at 285 nm. The method was then applied in a survey study of slaughter animals to determine whether flunixin is being used in an off-label manner for veal and beef production in Canada.

Estimating the economic effects of cystic echinococcosis. Part 2: an endemic region in the United Kingdom, a wealthy, industrialized economy.

The economic costs of cystic echinococcosis (CE) in Wales, which is part of one of the most highly developed, industrialized countries in the World, were evaluated. In this region, the disease in both sheep and humans causes financial losses. The sheep-related costs in the most highly endemic area, of southern and mid Wales, were estimated from recently published prevalences of the disease in local sheep. No relevant and recent data were available on the sheep in the rest of Wales but these animals were assumed to have lower prevalences, in line with historical data, and were ignored in the economic analysis. The costs of the disease in humans were based on published incidences of human cases treated surgically and the costs of surgery as estimated from hospital records and by costing out the procedures each patient received whilst undergoing treatment. The quality of life of patients treated for CE was also determined and compared with that of healthy, case-matched controls, using a standard health-survey questionnaire (SF-36). The results indicated that the treated patients suffered some long-term morbidity, caused by the disease itself, its treatment or both. Although accurate monetary values were not calculated for this decreased quality of life, the results indicate that the economic effects of human CE are greater than simply the cost of treatment. Assuming that the long-term morbidity demonstrated does have an economic effect, each year CE in Wales is probably costing the U.K. economy more than U.S.$1 million, and perhaps as much as U.S.$7.9 million.

A cross-sectional survey to analyse the risk factors associated with human cystic echinococcosis in an endemic area of mid-Wales.

In mid-Wales, the prevalence of cystic echinococcosis (hydatid disease) in humans and other animals has been well documented. A cross-sectional study was therefore undertaken to examine the associated demographic and environmental risk factors for the disease in humans, in Powys, mid-Wales. Overall, 223 fully completed questionnaires were returned from a postal survey. Eighteen of the respondents had been treated for cystic echinococcosis (CE). No significant association was found between many of the well-established risk factors, such as dog or farm ownership, and treatment for CE, although women were more likely to have been treated for the disease than men.

Determinants of the abundance of invasive annual weeds: community structure and non-equilibrium dynamics.

The dynamics of an annual pasture community are described from a five-year experimental and monitoring study. The community was dominated by two grasses (Lolium rigidum and Vulpia bromoides) and a legume (Trifolium subterraneum). Fits of population dynamic models to per capita rates of population change indicate that interactions between the grasses were generally strong, while interactions between the grasses and legumes were weaker. Most, but not all, of the net effects of competition on population growth could be attributed to interactions occurring during plant growth. Phase-plane analysis indicated that, for a constant environment, a joint equilibrium of the two grasses is unstable since interspecific competition between Lolium and Vulpia is stronger than intraspecific competition. Consequently, the community will tend to a mixture of only one or other of the grass species and T. subterraneum, depending on the founding composition of the pasture. Analysis of data taken from a year in which a drought occurred (1993-1994) demonstrated profound effects on all three species. Modelling of the long-term impacts of the effects of repeated droughts showed that disturbance of this form overrides the founder effect observed under constant conditions. Consequently, Vulpia is ultimately able to invade any mixture of the other species in environments where stochastic disturbances occur.

Risk factors associated with human cystic echinococcosis in Jordan: results of a case-control study.

The parasites causing cystic echinococcosis (CE) are transmitted to man and domestic animals either directly or indirectly from dogs. High levels of human infection have been frequently described in sheep-rearing areas of the world, where the infection cycles between dogs and sheep through the use of working dogs and the feeding of sheep offal to dogs. A case-control study was undertaken in northern Jordan to examine the epidemiological characteristics of echinococcosis in a Muslim community. Forty-four indigenous Jordanians who had been treated for CE between 1990 and 1996 were contacted and three controls for each case, matched for sex and age, were selected from the Jordanian population. The most important single factor associated with treatment for CE was the main source of domestic water; 42 (95%) of the cases but only 81 (61%) of the controls reported that they used a public, piped, water supply as their principal source of household water [odds ratio (OR) = 13.22; 95% confidence interval (CI) = 2.91-83.7]. The keeping of dogs or close association with dogs or farm animals was not associated with any increased risk of CE. However, individuals who grew their own vegetables had a significantly decreased risk of acquiring CE (OR = 0.30; CI = 0.08-0.98). There was evidence of widespread ignorance of the disease and how it is transmitted.

Clinical pharmacology of nervous system diseases.

The well-developed defense barriers of the CNS and the expense of drug therapy limit the pharmacologic options for the treatment of neurologic diseases in horses. New approaches to controlling inflammation in the CNS are improving the outcomes of bacterial meningitis. The appropriate treatment of EPM remains controversial. More research is needed to evaluate the pharmacokinetics and pharmacodynamics of drugs in the CNS of the horse. Behavioral pharmacology has become fashionable in human and small animal medicine, but it needs to be evaluated for the potential of unethical use in performance horses.