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Sepehr Sani, Tibor Boco, Steven L. Lewis, Elizabeth Cochran, Ajay J. Patel and Richard W. Byrne

Microfibrillar collagen hemostat, known by its trade name Avitene, has been used in neurosurgery for decades. Complications with this product have been documented in other surgical specialties and described as mostly immune-mediated foreign-body reactions that can lead to a granulomatous reaction. There has never been a case of disseminated encephalomyelitis associated with this topical hemostatic agent. In this report the authors present a case of postoperative acute disseminated encephalomyelitis after exposure to Avitene. Possible pathophysiological mechanisms are discussed and the pertinent literature is reviewed.

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William G. B. Singleton, Alison S. Bienemann, Max Woolley, David Johnson, Owen Lewis, Marcella J. Wyatt, Stephen J. P. Damment, Lisa J. Boulter, Clare L. Killick-Cole, Daniel J. Asby and Steven S. Gill

OBJECTIVE

The 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.

METHODS

The 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.

RESULTS

There 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.

CONCLUSIONS

CED 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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Oral Presentations

2010 AANS Annual Meeting Philadelphia, Pennsylvania May 1–5, 2010