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Summary: Background: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine‐treated horses. Objective: To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation. Study design: Experimental study. Methods: Drug plasma and urine concentrations following single intravenous administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 hours for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the international screening limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/mL, urine; 100 ng/mL). Results: For a regimen of 1.1 mg/kg BW q 24 hours, the IPC and IUC values were 2.0 and 73.0 ng/mL respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 hours after a single 1.1 mg/kg dose administration, 149 and 199 hours after multiple doses over 5 days at either 24‐ or 12‐hour intervals respectively. Corresponding detection times in urine were 46, 68 and 104 hours respectively. Main limitation: Only female horses were investigated. Conclusions: Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL. [ABSTRACT FROM AUTHOR]

This report describes 2 cases of dyskeratosis congenita in patients with progressive pulmonary diseases who required urgent living-donor lung transplantations. In the first case, a 13-year-old boy underwent bone marrow transplantation for aplastic anemia at age of 6 years. Severe pulmonary right-to-left shunting and fibrosis developed, and his condition deteriorated with acute fibrosis exacerbation and increased intrapulmonary shunt. He underwent lung transplantation and recovered uneventfully. In the second case, a 3-year-old girl with Revesz syndrome underwent bone marrow transplantation for refractory cytopenia. At 6 years of age, she had progressive hypoxia and a brain abscess. Her respiratory condition worsened, and she recovered uneventfully after urgent lung transplantation. [ABSTRACT FROM AUTHOR]

Objective: To clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis. Animals studied: Five healthy Thoroughbred horses. Procedures: Voriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography‐electrospray tandem‐mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle. Results: The mean maximum voriconazole concentrations in plasma and TF were 3.3 μg/mL at 1.5 h and 1.9 μg/mL at 1.6 h, respectively. Mean half‐life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC0–24 at steady state in TF (51.3 μg∙h/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively. Conclusions: This study demonstrated the detailed single‐dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK‐PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK‐PD analyses against pathogenic fungi in TF can be used to provide evidence‐based medicine for equine keratomycosis. [ABSTRACT FROM AUTHOR]

Measurement of progestines and estrogens in maternal plasma has been advocated as an indicator of foeto-placental function. The goals of the present study were as follows: to determine progestin and estrogen concentrations in mares with normal and abnormal pregnancies during late gestation, evaluate the diagnostic value of hormone concentrations, and investigate the relationship between hormone concentrations after treatment and the survival of foals. Blood samples were collected monthly from 459 pregnant mares between Day 201 of gestation and foaling. Progestin and estrogen concentrations were measured using a time-resolved fluoroimmunoassay with anti-progesterone and anti-17β-estradiol antibodies. The cutoff values of hormone concentrations that best discriminated between healthy foals and foal loss groups were determined using receiver-operating characteristic (ROC) curve analysis. Mares with compromised pregnancies are treated with progestins, tocolytics and antibiotics according to clinical signs, ultrasonographic examination and hormonal test. We investigated the relationship between the restoration of hormone concentrations after treatment and the survival rate of the foals of 62 compromised mares. Maternal serum progestin and estrogen concentrations on Days 241–320 of gestation differed significantly between healthy foals and foal loss of each group. Predictions of pregnancy outcomes were based on ROC curve analysis that established cutoff values of serum progestin and estrogen concentrations for each 20-day interval during gestation. All mares with improved concentrations of progestins or estrogens after treatment delivered healthy foals. When hormone concentrations got worse after treatment, the rate of loss was higher when treatment was administered during Days 201–290 of gestation than after Day 290. Mares with high progestin and low estrogen concentrations were likely to deliver aborted/dead foals during mid-to-late gestation. These results suggest that measurement of progestin and estrogen concentrations may be useful for diagnosing abnormal pregnancy and implementing early treatment strategies. [ABSTRACT FROM AUTHOR]

Gene doping is banned in human sports, horseracing, and equestrian sports. One possible form of gene doping is to administer exogenous genes, called transgenes. Several transgene detection methods based on quantitative PCR have been developed. In this study, we investigated the robustness of digital PCR and real-time PCR in transgene detection using primers and probes that matched (P-true) or incompletely matched (P-false) the template DNA. Fluorescence intensity was significantly reduced when substituted probes were used compared to that using the matched probe in both digital and real-time PCR assays. Digital PCR yielded a similar copy number regardless of the probe (P-true: 1230.7, P-false: 1229.7), whereas real-time PCR revealed a decrease in sensitivity based on C q values (P-true: 23.5, P-false: 29.7). When substituted primers were used, the detected copy number decreased in the digital PCR assay, and the C q value in real-time PCR was much higher. Interestingly, digital PCR copy numbers improved by performing PCR at a low annealing temperature, even if a substituted probe was used. Thus, when primer and probe sequences did not completely match the template transgene, digital PCR was relatively robust, but real-time PCR was less sensitive. Although PCR specificity may be reduced, PCR sensitivity can be improved by lowering the annealing temperature. If the target sequence is substituted to escape doping detection, it may be desirable to set the annealing temperature lower and use a more robust method, such as digital PCR, to increase the detection of positive cases, which will also result in fewer false-negative results.

The aim of this study was to investigate the pharmacokinetics of oseltamivir carboxylate (OC) in horses (n=6) after oral administration of its prodrug oseltamivir. The binding rate of OC to horse plasma proteins was negligible (<1%). Oral administration of oseltamivir of 2 mg/kg body weight of oseltamivir to horses provided a plasma concentration of OC (mean maximum concentration: 257.9 ng/ml) above the inhibitory concentrations against equine influenza A viruses determined in vitro. However, because OC is rapidly eliminated from horse plasma (mean elimination half-life: 2.5 hr), administration intervals should be less than 10 hr to retain a suitable concentration when using a single dose of 2 mg/kg oseltamivir.