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High-Dose MTX110 (Soluble Panobinostat) Safely Administered into the Fourth Ventricle in a Nonhuman Primate Model
Ist Teil von
Neurosurgery, 2020-12, Vol.67 (Supplement_1)
Ort / Verlag
Oxford: Oxford University Press
Erscheinungsjahr
2020
Link zum Volltext
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
INTRODUCTION New strategies are needed to treat medulloblastoma and other malignant tumors that originate in the posterior fossa in children. Systemic chemotherapy causes considerable toxicity and is often ineffective in a recurrent setting. Local delivery of chemotherapeutic agents directly into the fourth ventricle is a novel treatment approach. METHODS Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (short-term group, n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess cerebrospinal fluid (CSF) distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for five consecutive days. In Group II (long-term group, n = 2), fourth ventricle catheters were connected to a subcutaneously-placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions, were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and post-mortem histological analysis. RESULTS No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals. There were no MRI signal changes in the brain in any animals. Histologically, the cytoarchitecture of the brain was preserved with only focal mild post-surgical changes in all animals. Serum panobinostat levels at two and four hours after infusion were undetectable in both groups. In Group I (short-term group), the mean peak panobinostat level in fourth ventricle CSF (6242 ng/ml) exceeded that in lumbar CSF (9 ng/ml) by greater than 600-fold. In Group II (long-term group), mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than mean trough CSF level (33 ng/ml; P < .0001). CONCLUSION MTX110 (soluble panobinostat) can be safely infused in the fourth ventricle in non-human primates at high supra-therapeutic doses. Post-infusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. These results provide background data for a recently opened pilot clinical trial in patients with recurrent medulloblastoma.