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10 Jan 2016

IV VITAMIN C AND GSH INTERACTIONS WITH SODIUM THIOSULFATE USED FOR OTOPROTECTION Cont

QUESTION: Below is an oncologist’s receptive response to my patient’s mom (pt is a 4 y/o NED in maintenance therapy after dx with meduloblastoma) requesting to do IV Vitamin C and possibly glutathione after cisplatin. I am not familiar with any interaction with the drug in question sodium thiosulfate (STS) (giving it for otoprotection as stated below): “In reviewing what you sent, the only definite question that came to my mind is whether giving glutathione and/or ascorbic acid might diminish our desired hearing protection with sodium thiosulfate (STS) because I know glutathione is important in that cycle. We are off-roading a bit by using STS following cisplatin infusions, based on early data from the Children’s Oncology Group. I discussed with the otoprotection researcher here on campus, and he has directed me to one of the specialized pharmacists. But, it is his understanding that there is significant concern about timing and use of anything that can change the landscape of the free radicals. I’ll admit I don’t quite recall the biochemistry cycle in play, but it has something to do with scavenging free radicals at just the right time and if they aren’t available, that can be problematic. I have sent a message on to the pharmacist to learn more. With regard to other vitamins and minerals, I don’t have any obvious red flags that jump into mind, but I’ll admit here that I am not able to do a deep literature search to learn your field completely so it is hard for me to say it is definitely ok by me. However, I do trust and respect your expertise. If you have educated the mother and disclosed the uncertainties in pediatrics, and she wants to proceed, then I think our team is comfortable giving you access to the port. She does happen to be hypomagnesemic now (due to cisplatin), so is starting oral magnesium now. I will let you know what I learn about Vit C and glutathione and STS. Maybe there is a window between cisplatin cycles where we think it could be safe to give? I just have no idea what the timing should be.

ANSWER: I’m one of the few people alive using sodium thiosulfate, and who knows the biochemistry. In regard to this:

“But, it is his understanding that there is significant concern about timing and use of anything that can change the landscape of the free radicals. I’ll admit I don’t quite recall the biochemistry cycle in play, but it has something to do with scavenging free radicals at just the right time and if they aren’t available, that can be problematic.”

I think the pathway in question is: thiosulfate + 2 glutathione sulfite + glutathione disulfide + sulfide

One way to drive the glutathione cycle GSSGSSG is to add thiosulfate, and another is addition of IV GSH. (There are others but I’ll keep this short). Basically if the sodium thiosulfate and GSH were administered the same day there is no antagonistic effect. Likewise as long as a high dose ascorbate IV is administered on a different date from the sodium thiosulfate, as well as GSH, that has no antagonistic effect (keeps the antioxidant cycles supported and the ROS generating therapies separate. We have used IV sodium thiosulfate for about five years in the setting of oncologic quality of life and neuropathy as well as pathological calcification. We have also used it in combination with glutathione and (on a different day) high and low dose IV Ascorbate. As of yet, we have only seen positive outcome in proper combination for our neuropathic patients.