Non-Human Primate Husbandry and Impact on Non-Human Primates Health: Outcomes From an IQ DruSafe/3RS Industrial Benchmark Survey.

The presence of health issues (diarrhea, poor body condition) in non-human primates can impact animal welfare, confound toxicity study data, and lead to animal exclusion from studies. A working group cosponsored by DruSafe and 3Rs Translational and Predictive Sciences Leadership Groups of the IQ Consortium conducted a survey to benchmark quarantine, pre-study screening, husbandry, and veterinary care practices and their impact on NHP health. Nineteen companies participated in the survey providing separate responses for studies conducted in-house and at Contract Research Organizations from 3 regions (North America (NA), Europe and Asia) for an aggregate of 33 responses. A majority of responding companies conducted studies at North America CROs (39%) or in-house (36%) using primarily Chinese (33%) or Cambodian (27%) and to a lesser extent Vietnam (18%) or Mauritian (15%) origin NHPs. Forty-Five percent of responses had pre-study health issues (fecal abnormalities, etc.) on ≥ 1 studies with the highest incidence observed in Vietnam origin NHPs (80%). The survey suggested variable pre-screening and quarantine practices across facilities. Husbandry practices including behavioral assessments, environmental enrichment and consistent diets were associated with a lower incidence of health issues. The survey also benchmarked approaches used to diagnose and manage abnormal feces in NHPs and has provided strategies to minimize impact on NHP health. The survey highlighted opportunities for harmonizing screening criteria across industry and for improving tracking and sharing of health screening results, leading to further refinement of NHP veterinary care practices, higher quality studies, and reduced NHP use.

A chronic bile duct and intravenous cannulation model in conscious rabbits for pharmacokinetic studies.

In the development of novel pharmaceutical compounds, pharmacokinetic parameters, such as the extent of biliary excretion, must be characterized. Pharmacokinetic studies in nonrodent species, typically dogs, are generally required for new drug approvals. However, in some cases, rabbits may be a more desirable model. We developed a surgical procedure for the intermittent or continuous collection of bile for long-term use. This surgery involves the removal of the gallbladder and cannulation of the proximal and distal aspects of the common bile duct using a 40 cm flexible surgical-grade cannula. The cannula loop is passed subcutaneously and exteriorized between the scapulae to divert bile flow. During use, the proximal cannula segment is attached to a collection container placed in a nylon torso jacket worn by the animal, and the distal segment of catheter is sealed with a stainless-steel adapter. An auricular catheter, secured by ligatures, is placed aseptically into the lateral ear vein and the tip is advanced to the cranial vena cava for serial blood collection. Daily infusions of a heparinized saline "lock" ensure patency. These procedures have been used in 18 rabbits for up to 1 month without clinical complications. Complete blood counts, biochemical profiles, body weights, and bile flow were monitored weekly and reflected normal enterohepatic circulation.

Chronic lumbar intrathecal catheterization for the collection of cerebrospinal fluid in the canine.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by an excessive production of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. Studies have shown that concentrations of tau and amyloid protein (ß-amyloid (Aß)) are altered in the cerebrospinal fluid (CSF) of patients with AD. In an effort to support the investigation of specialized CSF biomarkers, a reliable and reproducible chronic system was developed to collect lumbar CSF from conscious dogs. Several nonsurgical and surgical procedures have been published for accessing lumbar CSF. We elected to use a lumbar catheter with a vascular access port to collect lumbar CSF. Although the surgical model is not novel, we evaluated various modifications to the procedure and maintenance to increase patency of chronic indwelling lumbar CSF catheters. Different types of catheters were evaluated, and for our purposes a 3.5 Fr open-ended polyurethane catheter was selected. With our final modified surgical procedure and catheter maintenance program, 67% remained patent for longer than 30 days for the first surgery and 86% remained patent for longer than 30 days if a repair or replacement surgery was performed. Based on the results of the proof of concept studies, our model proved to be useful for single and multiple dose pharmacokinetic studies in a search for effective Alzheimer's disease treatment.

Development of a dog microdialysis model for determining synovial fluid pharmacokinetics of anti-arthritis compounds exemplified by methotrexate.

PURPOSE: The purpose of this study was to develop and validate an animal model of drug disposition in synovial fluid (SF) by comparing microdialysis with arthrocentesis using the anti-arthritic drug methotrexate (MTX). METHODS: Microdialysis probes were calibrated in vitro with the no net flux method using dog synovial fluid. The probes were implanted surgically into the stifle joint space of four dogs and were dialyzed overnight using a portable microinfusion pump. The membrane integrity of the probes was monitored by retrodialysis using an internal standard. After an intravenous bolus of 2.5 mg/kg of MTX, unbound concentrations in synovial fluid, as well as total plasma concentrations, were measured by liquid chromatography tandam mass spectrometer (LC/MS/MS) in samples collected from 0 to 48 h postdose. RESULTS: The probe membrane remained intact at least 48 h after implantation. The mean probe recovery and unbound fraction of MTX in SF were 46.8% and 44.8%, respectively. The unbound fraction of MTX was 44% in synovial fluid. MTX penetrated into the joint space rapidly, with maximal concentrations of 6.6 microM reached at approximately 1 h postdose. The unbound MTX area under the curve in SF was approximately 40% of the total area under the curve in plasma. These data agree well with the previous data obtained for MTX using arthrocentesis. CONCLUSION: In contrast with arthrocentesis, microdialysis enables the collection of multiple serial SF samples from individual animals with minimal trauma and potential blood contamination. This animal model should prove valuable for studying the disposition of new antiarthritis compounds or biomarkers in SF.