Oltipraz

[lexis]

http://link.springer.com/article/10.1007%2FBF02432270

 

[himsahimsa]

Looks like a good acute intervention but the toxicities don't look good for chronic use. What Oltipraz might be doing, is tricking the liver into thinking it has been poisoned and getting the detox enzymes flowing as the response. Maybe as an inducer at intervals of a week or so and maybe combined with a source of cysteine for raw materials it could radically boost the detox system (and slay parasites as a bonus).

This is related to the cysteine as substrate for glutathione issue. Low glutathione enzyme status is really bad. High glutathione enzyme status is really good.
I also raised this here --> http://www.raypeatforum.com/forum/viewtopic.php?f=10&t=3306#p38915

I have decided to handle this by taking 1.2 grams of N-Acetylcisteine morning and evening (=2.4g/D) on two consecutive days every two weeks. This will keep circulating cysteine down most of the time but still allow for repletion of glutathione reserves. Running chronically low on glutatione is just asking for trouble.
(I use NOW brand 600mg caps, thus 1.2, 2.4, ...)

A 2.4 gram dose of N-Acetylcisteine is used clinically as an antidote to acetaminophen poisoning by providing material (cysteine) for the liver to make the glutathione enzymes, which it immediately does, so it looks like single high doses do end up as intended.

Here is another study of Oltipraz

J Cell Biochem Suppl. 1993;17F:278-91.
Oltipraz: a laboratory and clinical review.
Benson AB 3rd.

Abstract

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; RP 35972] is a synthetic, substituted 1,2-dithiole-3-thione previously used in humans as an antischistosomal agent. Cruciferous vegetables (e.g., Brussels sprouts, cabbage) contain several agents, including dithiolethiones, which appear to inhibit carcinogenesis; however, it is unclear which dietary compounds produce the protective effects. Animal studies have demonstrated that oltipraz is a potent inducer of Phase II detoxification enzymes, most notably glutathione-S-transferase (GST). Laboratory evaluations have shown that dietary concentrations of oltipraz produce marked inhibition of aflatoxin B1-induced hepatic tumorigenesis in rats. Levels of hepatic aflatoxin-DNA adducts, urinary aflatoxin-N7-guanine, and serum aflatoxin-albumin adducts decreased when biliary elimination of aflatoxin-glutathione conjugants increased, thus providing predictive biomarkers that measured a chemopreventive effect. In other animal experiments, oltipraz was found to inhibit chemically induced carcinogenesis in bladder, colon, breast, stomach, and skin cancer models. In addition, oltipraz has been shown to be non-mutagenic, a radioprotector, and a chemoprotective agent against carbon tetrachloride and acetaminophen toxicity. More recent studies in rats suggest that unsubstituted 1,2-dithiole-3-thiones may more effectively inhibit aflatoxin-induced hepatic tumorigenesis and induce electrophile detoxification enzymes. Multiple human clinical trials have been conducted using 1.0-4.5 gram doses of oltipraz over 1-3 days for the treatment of schistosomiasis. Phototoxicity has precluded its use in tropical areas. More recently, a 6 month Phase I trial was completed in which patients with resected colon polyps, or females with first degree relatives with breast cancer, were given oral daily doses of oltipraz at 125 mg or 250 mg. The maximum tolerated dose of oltipraz was < or = 125 mg daily. Grade I/II toxicities included photosensitivity/heat intolerance, GI and neurologic toxicity. Peak plasma concentrations were analyzed by HPLC with wide variability. In another Phase I study, a single oral dose of oltipraz was given to normal volunteers at dose levels of 125, 250, 375, and 500 mg. There was no significant difference in half-life (t1/2) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak oltipraz levels > or = 1.0 microgram/mL were achievable with marked interpatient variability. A series of small trials evaluating single oral doses of oltipraz for up to 28 days (dosing range 1 mg/kg-3 mg/kg/day) also showed a short t1/2 (4.1-5.3 hours), a sustained steady state without variation after a loading dose, and increased serum and urine concentrations with consumption of a high-fat diet.(ABSTRACT TRUNCATED AT 400 WORDS)