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Rilutsolin annostelua on kokeiltu aivan uudella tavalla - suun kautta annostelun sijasta selkäydinkanavaan. Kokeilu tehtiin minisioilla, joiden selkäydinkanavan rilutsolipitoisuus oli 10-kertainen suun kautta annosteltuihin kontrollipossuihin verrattuna. Lisäksi tällä annostelutavalla suun kautta antoon verrattuna periferaaliset sivuvaikutukset vältettiin. Voisi olettaa että myös ihmisillä tämä annostelutapa nostaisi lääkkeen tehoa ja pienentäisi sivuvaikutusten, kuten maksavaurion, riskiä.
http://www.ncbi.nlm.nih.gov/pubmed/27399519
Neurosurgery. 2016 Aug;63 Suppl 1:193. doi: 10.1227/01.neu.0000489810.52605.80.
321 Development of Intrathecal Riluzole: A New Route of Administration for the Treatment of Amyotrophic Lateral Sclerosis Patients.
Gutierrez J, Federici T, Peterson B, Bartus R, Betourne A, Boulis NM.
Abstract
INTRODUCTION:
Oral administration of riluzole is the only Food and Drug Administration-approved therapy for amyotrophic lateral sclerosis (ALS). However, per os riluzole therapy has shown modest efficacy and is limited by its negative impact on liver function. We hypothesize that intrathecal (IT) administration of riluzole will significantly improve drug efficacy by increasing local concentrations at targeted spinal cord segments, while circumventing peripheral toxicity.
METHODS:
A programmable infusion pump (SynchroMed II) connected to an IT catheter (Ascenda) was implanted into Göttingen minipigs to deliver a newly developed riluzole formulation. In group 1 (n = 2), drug levels in plasma, cerebrospinal fluid (CSF) and nervous tissue were analyzed after a single bolus infusion (1 hour; 1 and 3 mg). A control group (n = 4) received riluzole orally (single doses; 0.7 and 1.4 mg/kg). Group 2 (n = 4) received a chronic infusion of riluzole intrathecally (itRIL) following a dose-escalation scheme to delineate drug dose-range tolerability. The animals were monitored for signs of toxicity using a modified Tarlov Score. A third group (group 3, n = 4) received a continuous infusion of itRIL for 1 (n = 2) and 3 weeks (n = 2) to define the time course and levels of drug accumulation in the spinal cord.
RESULTS:
Analysis of riluzole pharmacokinetics after single-dose IT infusions revealed that itRIL enabled significantly higher CSF levels of riluzole while maintaining lower plasmatic levels compared with those achieved through oral administration (plasma Cmax, oral vs IT P < .01). Furthermore, the dose-escalation analysis of continuous itRIL infusion demonstrated that the formulation could be safely administered at a dose of up to 2.4 mg daily. Histology performed on nervous tissue showed that the IT route provides a 10-fold increase of riluzole concentrations in the spinal cord compared with the control group.
CONCLUSION:
Our results indicate that riluzole can be safely administered IT to provide higher drug levels in the spinal cord tissue while maintaining lower plasmatic levels, thereby circumventing peripheral side effects associated with the oral form.
http://www.ncbi.nlm.nih.gov/pubmed/27399519
Neurosurgery. 2016 Aug;63 Suppl 1:193. doi: 10.1227/01.neu.0000489810.52605.80.
321 Development of Intrathecal Riluzole: A New Route of Administration for the Treatment of Amyotrophic Lateral Sclerosis Patients.
Gutierrez J, Federici T, Peterson B, Bartus R, Betourne A, Boulis NM.
Abstract
INTRODUCTION:
Oral administration of riluzole is the only Food and Drug Administration-approved therapy for amyotrophic lateral sclerosis (ALS). However, per os riluzole therapy has shown modest efficacy and is limited by its negative impact on liver function. We hypothesize that intrathecal (IT) administration of riluzole will significantly improve drug efficacy by increasing local concentrations at targeted spinal cord segments, while circumventing peripheral toxicity.
METHODS:
A programmable infusion pump (SynchroMed II) connected to an IT catheter (Ascenda) was implanted into Göttingen minipigs to deliver a newly developed riluzole formulation. In group 1 (n = 2), drug levels in plasma, cerebrospinal fluid (CSF) and nervous tissue were analyzed after a single bolus infusion (1 hour; 1 and 3 mg). A control group (n = 4) received riluzole orally (single doses; 0.7 and 1.4 mg/kg). Group 2 (n = 4) received a chronic infusion of riluzole intrathecally (itRIL) following a dose-escalation scheme to delineate drug dose-range tolerability. The animals were monitored for signs of toxicity using a modified Tarlov Score. A third group (group 3, n = 4) received a continuous infusion of itRIL for 1 (n = 2) and 3 weeks (n = 2) to define the time course and levels of drug accumulation in the spinal cord.
RESULTS:
Analysis of riluzole pharmacokinetics after single-dose IT infusions revealed that itRIL enabled significantly higher CSF levels of riluzole while maintaining lower plasmatic levels compared with those achieved through oral administration (plasma Cmax, oral vs IT P < .01). Furthermore, the dose-escalation analysis of continuous itRIL infusion demonstrated that the formulation could be safely administered at a dose of up to 2.4 mg daily. Histology performed on nervous tissue showed that the IT route provides a 10-fold increase of riluzole concentrations in the spinal cord compared with the control group.
CONCLUSION:
Our results indicate that riluzole can be safely administered IT to provide higher drug levels in the spinal cord tissue while maintaining lower plasmatic levels, thereby circumventing peripheral side effects associated with the oral form.