Fig 1.
Myelogram obtained during catheter implant at surgery.
1. The radiopaque catheter tip guides the positioning at the cervico-thoracic junction. Contrast agent is flushed through the pump access port to confirm correct positioning in the subdural space. The catheter tip is at C6: cervical vertebrae 6, T1-5: thoracic vertebrae 1–5.
Table 1.
Summary of riluzole IT formulations.
Table 2.
Studies summary.
Fig 2.
Study 1: Riluzole plasma concentrations.
Riluzole plasma concentrations were measured after oral administration (50 mg, single dose) and during continous IT infusion of riluzole at 0.2 mg/h for 128 hours in dogs from study 1. Data shown as means ± SEM (some error bars are shorter than the symbols and cannot be visualized). Data below the assay limit of quantitation (BLOQ) are reported at the BLOQ value (0.500 ng/mL).
Fig 3.
Study 2: Linear regression of riluzole plasma concentration measured during continuous intrathecal infusion at escalating doses of riluzole in dogs.
Plasma samples were taken on the fifth day of infusion at each dose, before increasing to the next dose. Regression: Y = 24.91*X + 0.01261 and R2 = 0.9943. Data shown as means ± SEM.
Fig 4.
Study 2: Mean plasma concentration of riluzole.
Dogs were treated with oral riluzole 50 mg BID for 14 days or IT infusion of riluzole at 0.25 mg/h for 5 days. Plasma samples were taken approximately 60 min after the last oral dose or before stopping IT infusion on day 5. Data shown as means ± SEM.
Fig 5.
Study 2: SC concentrations of riluzole at terminal necropsy.
Dogs were treated for 14 days with oral riluzole (50 mg BID) or continuous IT infusion of riluzole at 0.25 mg/h for 5 days. Tissue samples were taken approximately 60 min after the last oral dose or shortly after stopping IT infusion on day 5. The entire spinal cord was cut in 1 cm segments. The X-axis represents the distance (in cm) of each segment, measured for riluzole content, from the catheter tip location (0) noted at necropsy, or artificially set at T1 segment in non-implanted animals. Approximate anatomical position (sacral to cervical) is indicated. Y-axis is on a Log10 scale. Data shown as means ± SEM.
Fig 6.
Study 2: Correlation of plasma riluzole to mean riluzole concentrations in the SC.
Dogs were treated with oral riluzole at 50 mg BID for 14 days and plasma samples were taken approximately 60 min after the last oral dose. Animals were euthanatized and SC quickly removed thereafter. Data shown as averaged concentration of riluzole in all spinal cord analyzed segments and mean plasma concentrations (R2 = 0.9435, P = 0.029).
Fig 7.
Study 3: SC concentrations of riluzole at terminal necropsy.
Dogs were treated for 6-weeks with oral riluzole (50 mg BID) or a combination of oral and continuous IT infusion of riluzole at 0.05 mg/h, 0.1 mg/h or 0.2 mg/h. The entire spinal cord was cut in 1 cm segments. The X-axis represents the distance (in cm) of each segment, measured for riluzole content, from the catheter tip location (0) noted at necropsy, or artificially set at T1 segment in non-implanted animals. Approximate anatomical position (sacral to cervical) is indicated. Y-axis is on a Log10 scale. Data shown as means + SEM.
Fig 8.
Study 4: SC concentrations of riluzole at terminal necropsy.
Dogs were treated for 24-weeks with oral riluzole (50 mg BID) or a combination of oral and continuous IT infusion of riluzole at 0.1 mg/h, 0.2 mg/h or 0.4 mg/h. Dogs receiving IT infusion at 0.4 mg/h were necropsied at various stages of the study due to tolerability issues. The entire spinal cord was cut in 1 cm segments. The X-axis represents the distance (in cm) of each segment, measured for riluzole content, from the catheter tip location (0) noted at necropsy, or artificially set at T1 segment in non-implanted animals. Approximate anatomical position (sacral to cervical) is indicated. Y-axis is on a Log10 scale. Data shown as means + SEM.
Table 3.
Liver clinical chemistry values at end of Study 3 (Day 42).
Table 4.
Liver clinical chemistry values at end of Study 4 (Day 175).
Fig 9.
Microscopic images showing representative sections of SC tissue and catheter tracks stained with H&E from animals in Study 3 (6 weeks GLP).
Animals were treated with A: IT saline, B: IT vehicle, C: oral riluzole, D: oral + IT riluzole (0.05 mg/h), E: oral + IT riluzole (0.1 mg/h) and F: oral + IT riluzole (0.2 mg/h). Magnification as indicated. The cyclodextrin THPB-EC vehicle was associated with exacerbated catheter track inflammatory reactions as compared to the saline controls. The spinal cord of animals treated with oral riluzole only (C) were histologically within normal limits. Animals treated with IT riluzole showed equivocal, slight increases in SC degeneration (not visible here) compared to vehicle controls.
Fig 10.
Microscopic images showing representative sections of SC tissue and catheter tracks stained with H&E from animals in Study 4 (6 month GLP).
Animals were treated with A: IT saline, B: IT vehicle, C: oral riluzole, D: oral + IT riluzole (0.1 mg/h), E: oral + IT riluzole (0.2 mg/h) and F: oral + IT riluzole (0.4 mg/h). Magnification as indicated. The cyclodextrin THPB-EC vehicle was associated with exacerbated catheter track inflammatory reactions as compared to saline controls. The spinal cord of animals treated with oral riluzole only (C) were histologically within normal limits. Animals treated with 0.1 or 0.2 mg/h IT riluzole showed increases in SC degeneration (not visible here) compared to vehicle controls. Animals treated with 0.4 mg/h IT riluzole sowed additional exacerbations of catheter track inflammatory reactions and inflammatory changes in the parenchyma of the spinal cord (visible here).