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R T Zera

Publications and source records attributed to R T Zera.

8 recordsLinked to original sources
PubMed1992

Protection against acetaminophen hepatotoxicity by ribose-cysteine (RibCys).

2(RS)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)thiazolidine-4(R)-carb oxylic acid (Ribose-Cysteine, RibCys), a latent form of L-cysteine, releases the sulfhydryl amino acid in vivo by non-enzymatic ring opening and solvolysis. The liberated L-cysteine then stimulates hepatic glutathione biosynthesis. In the present studies, the efficacy of hepatoprotection by RibCys was evaluated to explore its potential utility as an acetaminophen (APAP) antidote. Protection was evaluated in the Swiss-Webster mouse model both by survival data as well as by quantitative histological criteria of hepatic damage. A dose-response study showed increased protection with increased intraperitoneal doses of RibCys ranging from 0.5 to 8.0 mmol/kg. RibCys administration 30 min. prior to and up to four hours after the APAP dose showed varying degrees of protection; however, the best protection was seen when RibCys was given shortly after APAP administration. A single RibCys dose given by the intraperitoneal or intravenous route gave better protection than when administered orally; however, RibCys given in three doses, one hour apart, regardless of the mode of administration, offered the best protection after an LD90 dose of APAP. Overall, RibCys continues to exhibit promising protective capabilities against APAP hepatotoxicity, which may be capitalized upon in clinical overdose situations.

Acetaminophen↗
PubMed1991

L-cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity.

2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.

Animals↗
PubMed1987

Prodrugs of L-cysteine as protective agents against acetaminophen-induced hepatotoxicity. 2-(Polyhydroxyalkyl)- and 2-(polyacetoxyalkyl)thiazolidine-4(R)-carboxylic acids.

Eight prodrugs of L-cysteine (1a-h) were synthesized by the condensation of the sulfhydryl amino acid with naturally occurring aldose monosaccharides containing three, five, and six carbon atoms. The resulting 2-(polyhydroxyalkyl)thiazolidine-4(R)-carboxylic acids (TCAs) are capable of releasing L-cysteine and the sugars by nonenzymatic ring opening and hydrolysis. Thus, when added to rat hepatocyte preparations in vitro, these TCAs (1.0 mM) raised cellular glutathione (GSH) levels 1.2-2.1-fold relative to controls. On the basis of this finding, the cysteine prodrugs were tested as protective agents against acetaminophen-induced hepatotoxicity in a mouse model. The TCA derived from D-ribose and L-cysteine (RibCys, 1d) showed the greatest therapeutic promise of the series, with a 100% (12/12) survival profile compared to 17% without treatment. However, the degree of stimulation of GSH production in rat hepatocytes by these prodrugs did not correlate with the extent of protection afforded in mice, suggesting that pharmacokinetic parameters must supervene in vivo. To evaluate the effect of increased lipid solubility, we prepared prodrugs 2a-c by using peracetylated aldehydic sugars in the condensation reaction. These compounds, however, displayed acute toxicity to mice, possibly due to liberation of the acetylated sugars themselves. Nevertheless, the efficacy of the unacetylated TCAs, and RibCys (1d) in particular, suggests that the prodrug approach for the delivery of L-cysteine to the liver represents a viable means of augmenting existing detoxication mechanisms in protecting cells against xenobiotic substances that are bioactivated to toxic, reactive metabolites.

Acetaminophen↗
PubMedDate not supplied

Comparative surgical and colonoscopic appearance of colon anastomoses constructed with sutures, staples, and the biofragmentable anastomotic ring.

UNLABELLED: The following animal study was undertaken to compare and assess the endoscopic gross appearance and histology of colonic anastomoses constructed with sutures, staples, and the biofragmentable anastomotic ring (BAR). METHODS: Three anastomoses--1 BAR, 1 stapled, and 1 sutured--were placed in each of 48 dogs and colonoscopy and anastomotic evaluation were done. RESULTS: No leaks were found by air insufflation at surgery. Grossly, the BAR had serosal hematomas in 27/48 anastomoses vs 7/48 for stapled and 1/48 for sutured (BAR vs stapled P < 0.0005 and sutured vs stapled P = 0.07). Adhesions were significantly greater for BAR (35/36) and sutured (34/36) compared to stapled (26/36) (BAR vs stapled P = 0.01 and sutured vs. stapled P = 0.04). Colonoscopic exams at days 3, 7, and 28 showed no significant difference among groups with respect to bleeding, ulceration, necrosis, granulation, or contour. Sutured anastomoses were more stenotic (24/31) than stapled (4/31) or BAR (3/31) ones (BAR vs sutured and sutured vs stapled P < 0.005). At 28 days, 10/10 sutured vs 2/10 stapled vs 3/10 BAR were stenotic (BAR vs sutured P = 0.02, sutured vs stapled P = 0.01). Inflammation on histologic exam at 28 days was not significantly different: sutured (12/12), stapled (12/12), or BAR (9/12). Fibrosis was more prominent in sutured (12/12) than in stapled (5/12) or BAR (4/12) anastomoses (BAR vs sutured P = 0.001, sutured vs stapled P = 0.004, and BAR vs stapled P = 1.00). All anastomoses healed primarily without necrosis or obstruction. CONCLUSIONS: (1) Colonoscopy to evaluate anastomoses can be done safely even in the early post-operative period. (2) The BAR anastomoses had the most serosal hematomas; BAR and sutured had more adhesions than stapled anastomoses; and sutured anastomoses had the most stenosis and fibrosis. None of these differences was of clinical significance.

Anastomosis, Surgical↗