Anaesthetic complications in pigs undergoing MRI guided convection enhanced drug delivery to the brain: a case series

Jones, Alan J.; Bienemann, Alison; Barua, Neil; Murison, PJ; Gill, Steven

doi:10.1111/j.1467-2995.2012.00767.x

Cited by 4 publications

(1 citation statement)

References 15 publications

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“…A bespoke in-house-designed MRI-compatible head frame (Renishaw plc) was fixed to juvenile Large White-Landrace pigs under general anesthesia, as previously described. 1,4,15,30 A fiducial arc was then placed onto the frame, and the animal, while still under general anesthesia, was transferred to the MRI scanner (Philips field strength 1.5 T). Preoperative noncontrast T1 and T2 volume scans were obtained.…”

Section: Ced Procedures In Pigsmentioning

confidence: 99%

The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery

Singleton

Bienemann

Woolley

et al. 2018

Journal of Neurosurgery: Pediatrics

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OBJECTIVEThe pan–histone deacetylase inhibitor panobinostat has preclinical efficacy against diffuse intrinsic pontine glioma (DIPG), and the oral formulation has entered a Phase I clinical trial. However, panobinostat does not cross the blood-brain barrier in humans. Convection-enhanced delivery (CED) is a novel neurosurgical drug delivery technique that bypasses the blood-brain barrier and is of considerable clinical interest in the treatment of DIPG.METHODSThe authors investigated the toxicity, distribution, and clearance of a water-soluble formulation of panobinostat (MTX110) in a small- and large-animal model of CED. Juvenile male Wistar rats (n = 24) received panobinostat administered to the pons by CED at increasing concentrations and findings were compared to those in animals that received vehicle alone (n = 12). Clinical observation continued for 2 weeks. Animals were sacrificed at 72 hours or 2 weeks following treatment, and the brains were subjected to neuropathological analysis. A further 8 animals received panobinostat by CED to the striatum and were sacrificed 0, 2, 6, or 24 hours after infusion, and their brains explanted and snap-frozen. Tissue-drug concentration was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). Large-animal toxicity was investigated using a clinically relevant MRI-guided translational porcine model of CED in which a drug delivery system designed for humans was used. Panobinostat was administered at 30 μM to the ventral pons of 2 juvenile Large White–Landrace cross pigs. The animals were subjected to clinical and neuropathological analysis, and findings were compared to those obtained in controls after either 1 or 2 weeks. Drug distribution was determined by LC-MS/MS in porcine white and gray matter immediately after CED.RESULTSThere were no clinical or neuropathological signs of toxicity up to an infused concentration of 30 μM in both small- and large-animal models. The half-life of panobinostat in rat brain after CED was 2.9 hours, and the drug was observed to be distributed in porcine white and gray matter with a volume infusion/distribution ratio of 2 and 3, respectively.CONCLUSIONSCED of water-soluble panobinostat, up to a concentration of 30 μM, was not toxic and was distributed effectively in normal brain. CED of panobinostat warrants clinical investigation in patients with DIPG.

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Section: Ced Procedures In Pigsmentioning

confidence: 99%