Modified peptide nucleic acid compositions
a technology of peptide nucleic acid and composition, which is applied in the field of neurodegenerative genetics, can solve the problems of no treatment for hd that can slow or stop the progression of the disease, and the loss of neurons in the brain of hd
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example 1
Plasma Protein Binding of Compound 1 in Mouse, Dog, Minipig, Sheep, Monkey, and Human
[0509]This study was designed to determine the in vitro binding of Compound 1 to plasma proteins in C57BL6J mouse, Beagle dog, Gottingen minipig, sheep, Cynomolgus monkey, and human. Plasma Protein Binding (PPB) was assessed in pooled male plasma at nominal Compound 1 concentrations of 1, 10, and 50 μg / mL. The assay was performed using the ultrafiltration technique and the concentrations of Compound 1 were determined by LC MS / MS analysis. Warfarin was used as positive control to validate each ultrafiltration run.
[0510]Using Busher's classification, Compound 1 binding to plasma proteins was ranked as high-to-very high (PPB>85.0%) at 1 μg / mL and high (85.0%≤PPB≤98.0%) at both 10 and 50 μg / mL. A slight concentration dependence was observed over the concentration range investigated, suggesting the tendency of PPB to become non-linear with increasing Compound 1 concentration. This trend was more evidentl...
example 2
stribution of Total Radioactivity in the Cynomolgus Monkey Following Single Intravenous Bolus Administration of Compound 1
[0573]The objective of this study was to assess tissue distribution, disposition, and pharmacokinetics (PK) of [14C]-Compound 1 drug related material following a single intravenous (IV) administration to the male cynomolgus (Macaca fascicularis) monkeys at the target dose level of 5 mg / kg using quantitative whole-body autoradiography (QWBA). The cynomolgus monkey is representative of the distribution and excretion in a human. Three animals were placed into metabolism cages after dosing and kept up to 4, 12, and 168 h post dose, respectively.
[0574]Disposition of [14C]-Compound 1 was investigated in one animal only (No. 103, 168h). Total radioactivity was measured in urine, feces, and cage rinse.
[0575]Pharmacokinetic profiles were obtained in blood and plasma collected from each animal at selected timepoints post-dose up to the terminal timepoint.
[0576]Following eu...
example 3
harmacokinetic and Tissue Distribution Study Following Single Intracerebroventricular Administration of Compound 1 in Male and Female C57BL6J Mouse
[0691]The objective of this study was to assess the pharmacokinetics and tissue distribution of Compound 1 in male and female C57BL6J mice following single intracerebroventricular (ICV) administration at 0.6, 1, and 2 mg / kg. One-hundred male and ninety-six female naïve C57BL6J mice received Compound 1 at 0.3 mg / kg, (n=24 males and 32 females) or at 0.6 mg / kg (n=32 males and 32 females) or at 1 mg / kg (n=32 males and 32 females) or at 2 mg / kg (n=12 males).
[0692]One-hundred male and ninety-six female naïve C57BL6J mice received Compound 1 at 0.3 mg / kg, (n=24 males and 32 females) or at 0.6 mg / kg (n=32 males and 32 females) or at 1 mg / kg (n=32 males and 32 females) or at 2 mg / kg (n=12 males).
[0693]Due to severe clinical signs observed in males dosed at 2 mg / kg, the treatment was stopped after the dosing of 12 males (4 for each timepoint up to...
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