Pre-clinical safety evaluation of pyrrolidine dithiocarbamate.

Pyrrolidine dithiocarbamate (PDTC) was examined for its potential in the intranasal treatment of human rhinovirus infections. Prior to clinical testing, a comprehensive non-clinical programme was performed to evaluate the general toxicity of PDTC. The animal experiments included investigations in rodents with study durations ranging from single dose to repeated dosing over a period of 28 days. The routes of administration were intranasal, inhalative, oral and intravenous for single-dose toxicity and pharmacokinetic studies, and intranasal for repeated dose studies. Blood and tissue samples were obtained from PDTC-treated rats to analyse pharmacokinetics and tissue distribution. Accumulation of selected metals due to PDTC treatment was examined in liver, brain, nerves and fat tissues.

Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans.

BACKGROUND: Humans are exposed to substantial quantities of isothiocyanates and glucosinolates from vegetables. Since dietary isothiocyanates are widely regarded as potentially important chemoprotectors against cancer, reliable methods for measuring the plasma and tissue pharmacokinetics of isothiocyanates and their dithiocarbamate metabolites are essential for defining dosing regimens. METHODS: Isothiocyanates (ITC) and dithiocarbamates (DTC) react quantitatively with 1,2-benzenedithiol to produce 1,3-benzodithiole-2-thione that can be quantified spectroscopically. Although this cyclocondensation reaction has been highly useful for analyzing plant material and urine samples, the determination of DTC/ITC (the total quantity of DTC and ITC components in a sample that react in the cyclocondensation reaction) in blood and tissues has been hampered by their low levels and the high concentrations of proteins that interfere with the cyclocondensation reaction. The protein content of blood and tissues was reduced by the precipitation with polyethylene glycol (PEG) or ultrafiltration, and the sensitivity of the method was increased substantially by the solid phase extraction of the cyclocondensation product. RESULTS: Pharmacokinetic measurements were made in four human volunteers who received single doses of about 200 micromol of broccoli sprout isothiocyanates (largely sulforaphane, with lesser amounts of iberin and erucin). Isothiocyanates were absorbed rapidly, reached peak concentrations of 0.943-2.27 micromol/l in plasma, serum and erythrocytes at 1 h after feeding and declined with first-order kinetics (half-life of 1.77+/-0.13 h). The cumulative excretion at 8 h was 58.3+/-2.8% of the dose. Clearance was 369+/-53 ml/min, indicating active renal tubular secretion. CONCLUSION: A sensitive and specific method for quantifying DTC levels in human plasma, serum, and erythrocytes has been devised. Determinations of ITC/DTC levels are important because: (i) dietary isothiocyanates are of potential value in reducing the risk of cancer, and (ii) humans are extensively exposed to DTC as fungicides, insecticides, pesticides and rubber vulcanization accelerators.

Strategies of cruciferous pathogenic fungi: detoxification of the phytoalexin cyclobrassinin by mimicry.

The remarkable metabolism of the cruciferous phytoalexin cyclobrassinin by the phytopathogenic root rot (Rhizoctonia solani Kuhn) and blackleg [Phoma lingam (Tode ex Fr.) Desm., asexual stage of Leptosphaeria maculans (Desm.) Ces. et de Not.] fungi is reported. It was established that R. solani metabolized and detoxified cyclobrassinin via the phytoalexin brassicanal A, which was further transformed into nontoxic products. Detoxification of cyclobrassinin in P. lingam avirulent isolate Unity occurred via the phytoalexin brassilexin, whereas the detoxification in P. lingam virulent isolate BJ 125 occurred via the phytoalexin dioxibrassinin. The chemistry involved in the structure determination of the intermediates of these three apparently different pathways and their antifungal activities are described. In addition, efficient syntheses of both phytoalexins brassicanal A and brassilexin by mimicry of the fungal biotransformation route are reported. Implications of these unprecedented transformations are discussed.

Comparative effects of diethyldithiocarbamate and N-benzyl-D-glucamine dithiocarbamate on cis-diamminedichloroplatinum-induced toxicity in kidney and gastrointestinal tract in rats.

Sodium diethyldithiocarbamate (DDTC) and sodium N-benzyl-D-glucamine dithiocarbamate (BGD) were compared for their protective effects against cis-diamminedichloroplatinum (DDP)-induced toxicity in kidney and gastrointestinal tract in rats. Rats were injected i.p. with the dithiocarbamates (2.0 mmol kg-1) immediately or 1 h after i.v. injection of DDP (20 mumol kg1). Treatment with BGD immediately or at 1 h after DDP injection effectively prevented the nephrotoxicity of DDP, but administration of DDTC immediately or 1 h after DDP afforded little protection. N-Benzyl-D-glucamine dithiocarbamte significantly reversed the reduction in maltase, sucrase and aminopeptidase activities of jejunal mucosa of rats treated with DDP, whereas treatment with DDTC concurrent with DDP could not reverse the reduction in disaccharidase activity following DDP injection. The platinum concentrations in liver and kidney were significantly decreased by treatment with BGD and DDTC. The treatment with DDTC at 1 h after DDP was more effective on the reduction of platinum concentrations in these tissues than that immediately after DDP. There was no difference between the renal and hepatic concentrations of platinum in two time intervals of BGD. The pharmacokinetic studies indicated that DDTC is more rapidly metabolized than BGD, resulting in larger total clearance and elimination rate constant values. These results reveal that the administration of BGD immediately and at 1 h after DDP can protect against the renal and gastrointestinal toxicities caused by DDP, whereas DDTC afforded little protection, and that the time interval between administration of DDP and DDTC greatly influences its protective effect on DDP-induced toxicity, indicating that the chelation therapy of BGD for DDP is superior to that of DDTC.

Optimal dithiocarbamate structure for immunomodulator action.

While the commercially available sodium diethyldithiocarbamate (DEDTC) has been used by several groups in the treatment of AIDS patients, chemical evidence suggests that other dithiocarbamates which are more stable at pH 7.4 might prove to be quite superior for this purpose. Of these other compounds, sodium pyrrolidinedithiocarbamate (PDTC) and sodium di-n-propyldithiocarbamate (DPDTC) which have much longer half lives at pH 7.4, are expected to exhibit similar lipophilicity to DEDTC but superior stability towards hydrolysis. They can be expected to be superior to DEDTC, especially for oral administration.