High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model Article Swipe
David I. Sandberg
,
Natasha Kharas
,
Bangning Yu
,
Christopher F. Janssen
,
Amanda Trimble
,
Leomar Y. Ballester
,
Rajan Patel
,
Afroz S. Mohammad
,
William F. Elmquist
,
Rachael W. Sirianni
·
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.3171/2020.2.peds19786
YOU?
·
· 2020
· Open Access
·
· DOI: https://doi.org/10.3171/2020.2.peds19786
OBJECTIVE Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates. METHODS Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (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 (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses. RESULTS No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001). CONCLUSIONS MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.
Related Topics
Concepts
Medicine
Fourth ventricle
Ventricle
Third ventricle
Carcinosis
Panobinostat
Catheter
Lumbar
Cerebral ventricle
Anesthesia
Surgery
Internal medicine
Cancer
Gene
Colorectal cancer
Chemistry
Histone deacetylase
Peritoneal carcinomatosis
Histone
Biochemistry
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.3171/2020.2.peds19786
- https://thejns.org/downloadpdf/journals/j-neurosurg-pediatr/26/2/article-p127.pdf
- OA Status
- bronze
- Cited By
- 11
- References
- 12
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W3023317523
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W3023317523Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.3171/2020.2.peds19786Digital Object Identifier
- Title
-
High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate modelWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2020Year of publication
- Publication date
-
2020-05-01Full publication date if available
- Authors
-
David I. Sandberg, Natasha Kharas, Bangning Yu, Christopher F. Janssen, Amanda Trimble, Leomar Y. Ballester, Rajan Patel, Afroz S. Mohammad, William F. Elmquist, Rachael W. SirianniList of authors in order
- Landing page
-
https://doi.org/10.3171/2020.2.peds19786Publisher landing page
- PDF URL
-
https://thejns.org/downloadpdf/journals/j-neurosurg-pediatr/26/2/article-p127.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
-
https://thejns.org/downloadpdf/journals/j-neurosurg-pediatr/26/2/article-p127.pdfDirect OA link when available
- Concepts
-
Medicine, Fourth ventricle, Ventricle, Third ventricle, Carcinosis, Panobinostat, Catheter, Lumbar, Cerebral ventricle, Anesthesia, Surgery, Internal medicine, Cancer, Gene, Colorectal cancer, Chemistry, Histone deacetylase, Peritoneal carcinomatosis, Histone, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
11Total citation count in OpenAlex
- Citations by year (recent)
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2025: 2, 2024: 1, 2023: 5, 2022: 2, 2020: 1Per-year citation counts (last 5 years)
- References (count)
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12Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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