I should clarify this 2012 trial abstract cited in the earlier post was in blood cancers and cell penetration is not BBB penetration, although it may be a good indication. Here is some interesting background on SMON and CQ from the main text. With all that info on CQ toxicity in Japan, no one was able to identify the exact mechanism for the toxicity. I imagine it is quite difficult to provide that data for PBT2 which has not reached that toxicity in 8 trials. The IMAGINE extension trial did take the total dose way past the average of 136g where tox was seen in Japan with CQ.
"Most symptoms were reversible, but permanent disability was reported in approximately 10% of patients who developed the syndrome.
Notably, the reported neurological side effects after clioquinol use occurred almost exclusively in Japanese patients and usually after exposure to high cumulative doses of the drug.
Cases of SMON in patients outside of Japan were exceed-ingly rare and were primarily at the case report level despite the use of the drug in over 500 million doses in the rest of the world.
The encouraging preclinical activity of clioquinol in hematologic malignancies coupled with its novel mechanism of action supports its evaluation in clinical trials for patients with refractory hematologic malignancies. Here, we report a phase I study of escalating doses of clioquinol in patients with refractory hematologic malignancy. To our knowledge, this study represents the first clinical evaluation of clioquinol as an anticancer agent"
Looking at the findings below it is understandable giving a definitive answer to the FDA would be very difficult.
"Of note, in the patient who developed the grade 3 neuropathy, the intracellular level of clioquinol was 41.6 ⫾ 10.8 ng/1 ⫻ 10 cells.
However, the intracellular levels for this patient were not the highest among the cohort. A patient receiving 1200 mg clioquinol twice daily had an intracellular level of 79.6 ⫹ 2.3 ng/1 ⫻ 10 cells and experienced no toxicity."
"Notably, the patient with statically significant inhibition of the proteasome had the highest intracellular levels of clioquinol de-tected in the study (79.6 ⫾ 2.3 ng/1 ⫻ 10 cells)."
"When used as an antimicrobial before being withdrawn from the market, the therapeutic dose of clioquinol varied significantly. Patients received doses ranging from 250 mg per day to 3.5 g per day to treat or prevent a variety of parasitic infections.
However, most patients were treated with 750 to 1000 mg per day"
"In the Japanese patients with neurotoxicity, the average cumulative dose of clioquinol was 136 g and toxicity was seen across the spectrum of daily doses.(2yrs IMAGINE dosing at 250mg is about 180g with no neurotoxicity.)
The mechanism of neurotoxicity after clioquinol adminstration is unknown,"
"this patient had significant higher plasma levels of clioquinol with an AUC 2.7-fold higher than any other study patient. Moreover, the half-life of the drug was significantly longer than in all other patients in the trial. Thus, toxicity in this patient appeared related to drug exposure and plasma levels."
"As the intracellular levels did not correlate with plasma drug levels, the explanation must lie at the cellular level."
(20min delay)