methylnaltrexone and Brain-Neoplasms

Methylnaltrexone (MNTX) was recently FDA approved to treat opiate induced constipation. It happens to also indirectly reduce Src activity. Src is a 54 kDa tyrosine kinase, crucial in signaling of, and link between, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Glioblastomas use both EGF and VEGF signaling to enhance growth and neo-angiogenesis. Stem cell sub-fractions of glioblastomas are enriched for high VEGF synthesizing cells so this is a particularly valuable adjunctive target during cytotoxic treatment with drugs like temozolomide. MNTX does not cross the blood-brain barrier (BBB). Methamphetamine (MA) temporarily opens the BBB and therefore may allow methylnaltrexone entry into glioblastoma tissue. MA is FDA approved, marketed to treat attention problems in children. MA-MNTX combination should be tested as glioblastoma treatment adjunct. Temozolomide CSF levels are 10-20% of blood levels. Thus MA may also allow greater brain tissue temozolomide levels yet with lower systemic exposure.

Topics: Brain Neoplasms; Central Nervous System Stimulants; Drug Approval; Drug Synergism; Glioblastoma; Humans; Methamphetamine; Naltrexone; Narcotic Antagonists; Neovascularization, Pathologic; Quaternary Ammonium Compounds; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A

Peripherally acting μ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor. This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms.. Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal.. Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Brain Neoplasms; Central Nervous System; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Naltrexone; Quaternary Ammonium Compounds

Topics: Analgesics, Opioid; Brain Neoplasms; Child; Constipation; Female; Humans; Morphine; Naltrexone; Narcotic Antagonists; Neuroblastoma; Pain; Quaternary Ammonium Compounds