Toxicity
Toxicity of ShK toxin in mice is quite low. The median paralytic dose is about 25 mg/kg bodyweight (which translates to 0.5 mg per 20 g mouse). In rats the therapeutic safety index was greater than 75-fold.
ShK-Dap22 is less toxic, even a dose of 1.0 mg dose did not cause hyperactivity, seizures or mortality. The median paralytic dose was 200 mg/kg body weight.
ShK-170 does not cause significant toxicity in vitro. The peptide was not toxic to human and rat lymphoid cells incubated for 48 h with 100 nM of ShK-170 (>1200 times greater than the Kv1.3 half-blocking dose). The same high concentration of ShK-170 was negative in the Ames test on tester strain TA97A, suggesting that it is not a mutagen. ShK-170 had no effect on heart rate or heart rate variability parameters in either the time or the frequency domain in rats. It does not block the hERG (Kv11.1) channel that is associated with drug-associated cardiac arrhythmias. Repeated daily administration of the peptide by subcutaneous injection (10 µg/kg/day) for 2 weeks to rats does not cause any changes in blood counts, blood chemistry or in the proportion of thymocyte or lymphocyte subsets. Furthermore, the rats administered the peptide gain weight normally.
ShK-186 is also safe. Repeated daily administration by subcutaneous injection of ShK-186 (100 µg/kg/day) for 4 weeks to rats does not cause any changes in blood counts, blood chemistry or histopathology. Furthermore, ShK-186 did not compromise the protective immune response to acute influenza viral infection or acute bacterial (Chlamydia) infection in rats at concentrations that were effective in ameliorating autoimmune diseases in rat models. Interestingly, rats repeatedly administered ShK-186 for a month by subcutaneous injection (500 µg/kg/day) developed low titer anti-ShK antibodies. The reason for the low immunogenicity of the peptide is not well understood. ShK-186 has completed GLP (Good Laboratory Practice) non-clinical safety studies in rodents and non-human primates, and ShK-186 is currently being evaluated in phase 1 human trials.
Many groups are developing Kv1.3 blockers for the treatment of autoimmune diseases.
Read more about this topic: Stichodactyla Toxin