Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.     

Using 3D animations to teach intracellular signal transduction mechanisms: taking the arrows out of cells

Traditional methods of teaching intracellular biological processes and pathways use figures or flowcharts with the names of molecules linked with arrows. Many veterinary students, presented with such material, simply memorize the names or chemical structures of the molecules and are then likely to forget the material once the examination is completed. To address this problem, the authors designed, created, and field-tested new teaching media that incorporate realistic three-dimensional (3D) animations depicting the dynamic changes that occur in intracellular molecules during cellular activation. Testing found that veterinary students taught using traditional teaching media (e.g., lectures, handouts, textbooks) are proficient in memorizing the names and order of intracellular molecules but unable to appreciate the interactions between these elements or their spatial relationships within cells. In contrast, more than 90% of veterinary students taught using 3D animations not only recall the facts about the intracellular elements but also develop accurate mental images of the interactions among these molecules and their spatial relationships. These findings strongly suggest that the comprehension of complex biological processes by veterinary students can be enhanced by the use of dynamic 3D depictions of these processes in the classroom.     

Hypoxaemia during anaesthesia in seven horses with colic

Anaesthetic records of horses with colic anaesthetised between June 1987 and May 1989 were reviewed. pH and blood gas analyses were performed during 157 operations from which the horses were allowed to recover. A PaO₂ of 8.0 kPa or less was measured during anaesthesia in seven of these horses. The horses were of different breeds, ages and sexes. Anaesthesia was induced with xylazine, guaifenesin and ketamine in four horses and with xylazine, guaifenesin and thiobarbiturate in three horses. Anaesthesia was maintained with inhalation anaesthetic agent and oxygen: isoflurane in five horses, halothane in one horse, and initially halothane but later isoflurane in one horse. Systolic arterial pressures during anaesthesia ranged from 80 to 150 mmHg, diastolic arterial pressures were between 60 and 128 mmHg, and heart rates were between 28 and 44 beats /min. Controlled ventilation was initiated at the start of anaesthesia. PaCO₂ exceeded 6.7 kPa in three horses but was subsequently decreased by adjustment of the ventilator. PaO₂ of 8.0 kPa or less was measured during early anaesthesia, with one exception, and persisted for the duration of anaesthesia. The horses' inspired air was supplemented with oxygen during recovery from anaesthesia, at which time measurement of blood gases in three horses revealed no increase in PaO₂. Recovery from anaesthesia was uneventful. The surgical problems involved primarily the large intestine in five horses and the small intestine in two horses. Six horses were discharged from the hospital alive; one horse was reanaesthetised later the same day and destroyed without regaining consciousness. We concluded that none of the objective values recorded during the pre-anaesthetic evaluation could have been used to predict the complication of intraoperative hypoxaemia. We observed that once hypoxaemia developed it persisted for the duration of anaesthesia and even into the recovery period when the horses were in lateral recumbency and regaining consciousness. We assume that the altered metabolism from anaesthetic agents and hypothermia combined with adequate peripheral perfusion contributed to the lack of adverse consequences in six of the horses. The contribution of hypoxaemia to the deteriorating condition of the seventh horse is speculative.     

光肩星天牛对损伤后复叶槭植株的行为反应

该文利用Y型玻璃嗅觉测定仪对光肩星天牛的趋性行为进行了研究 .诱源为受不同机械损伤和天牛咬食损伤处理后不同时间内整体复叶槭植株释放的挥发物 .结果表明 ,正常条件下生长的复叶槭对光肩星天牛具有明显的引诱作用 ,但经机械刻伤复叶槭木质部及损伤叶片、或天牛咬食复叶槭后 ,随着处理时间的增加 ,复叶槭对光肩星天牛的引诱作用逐渐减弱 ,驱避作用逐渐增强 .在咬食创伤 2 4h后复叶槭挥发物对天牛的驱避作用达到了差异显著的程度 ,48h后达到最大值 ,72h后驱避作用明显降低 .而叶片损伤处理 4h时 ,复叶槭就表现出较强的驱避作用 ;木质部刻伤引起的驱避作用则要于 4h后才出现 .     

Endocrine and gonadal changes during the annual reproductive cycle of the freshwater teleost,Stizostedion vitreum

The annual reproductive cycle of walleye (Stizostedion vitreum) was characterized by documenting changes in gonadal development and serum levels of estradiol-17β (E₂), testosterone (T), 17α,20β-dihydroxy-4-pregnen-3-one (17,20-P), and 11-ketotestosterone (11-KT) in wild fish captured from upper midwestern lakes and rivers throughout the year. Fish from the populations used in this study spawn annually in early- to mid-April. Walleye showed group synchronous ovarian development with exogenous vitellogenesis beginning in autumn. Oocyte diameters increased rapidly from ∼ 200 μm in October to ∼ 1,000 μm in November, and reached a maximum of 1,500 μm just prior to spawning. Changes in gonadosomatic indices (GSIs) paralleled changes in oocyte diameters. Serum E₂ levels in females increased rapidly from low values in October (< 0.1 ng ml⁻¹) to peak levels of 3.7 ng ml⁻¹ in November, coinciding with the period of the most rapid ovarian growth. Subsequently, E₂ levels decreased from December through spawning. Serum T levels exhibited a bimodal pattern, increasing to 1.6 ng ml⁻¹ in November, and peaking again at 3.3 ng ml⁻¹ just prior to spawning. We detected 11-KT in the serum of some females at concentrations up to 5.6 ng ml⁻¹, but no seasonal pattern was apparent. In this study (unlike our results in a related study) 17,20-P was not detected. In males, differentiation of spermatogonia began in late August, and by January the testes were filled (> 95% of germ cells) with spermatozoa. Mature spermatozoa could be expressed from males from January through April. GSIs ranged from 0.2% (post-spawn) to 3.2% (pre-spawn). Serum T levels rose from undetectable levels in post-spawn males to 1.6 ng ml⁻¹ by November, remained elevated throughout the winter, and peaked at 2.8 ng ml⁻¹ I prior to spawning. Levels of 11-KT in males remained low (< 10 ng ml⁻¹, from post-spawning through January, then increased significantly by March and peaked just prior to spawning at 39.7 ng ml⁻¹. Our results indicate that vitellogenesis and spermatogenesis are complete or nearly so, in walleye by early winter, and suggest that it may be possible to induce spawning in this species several months prior to the normal spawning season by subjecting fish to relatively simple environmental and hormonal treatments.     

Western blot detection of PrP Sc in archived paraffin-embedded brainstem from scrapie-affected sheep

Scrapie is a naturally occurring fatal neurodegenerative disease of adult sheep and goats, one of a group of mammalian diseases known as transmissible spongiform encephalopathies (TSE) or prion diseases. Immunoassays that identify disease-associated prion protein (PrP Sc) are integral to the diagnosis of scrapie and other prion diseases. Results obtained by either immunohistochemistry (IHC) or Western blot (WB) assay are generally adequate for the definitive diagnosis. Approved or accepted methods for WB diagnosis of TSEs requires the use of fresh or frozen nonfixed tissue samples, whereas formalin-fixed, paraffin-embedded tissue is required for the localization of PrP Sc by IHC. Because disparate processing methods are used for these accepted diagnostic techniques, separate tissue samples are collected from the same animal. Occasions arise in which there is either insufficient quantity of tissue available to complete analysis by both techniques or initial tissue processing is incompatible with one of the assays. Also, results between the assays may differ because of the vagaries of sampling, especially in case material that contains moderate-to-low levels of PrP Sc. The present article describes a method to conduct a WB assay from the same paraffin-embedded brainstem sample used for the IHC diagnosis of experimentally induced sheep scrapie.