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R T Zera

Publications and source records attributed to R T Zera.

29 records · Page 2Linked to original sources
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↗
PubMed1984

2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity.

A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD90 doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl-, and 2(RS)-n- pentylthiazolidine -4(R)-carboxylic acids (compounds 1b,d,e, respectively) were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl-, and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c,f,g) were less protective. The enantiomer of 1b, viz., 2(RS)- methylthiazolidine -4(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase [Km = 1.1 x 10(-4) M; Vmax = 5.4 mumol min-1 (mg of protein)-1]. Compound 1b was not a substrate for proline oxidase but dissociated to L-cysteine in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D2O (k1 = 2.5 X 10(-5) s), suggesting that opening of the thiazolidine ring must have taken place. Indeed, 1b labeled with 14C in the 2 and methyl positions was rapidly metabolized by the rat to produce 14CO2, 80% of the dose being excreted in this form in the expired air after 24 h. It is suggested that these 2-substituted thiazolidine-4(R)-carboxylic acids are prodrugs of L-cysteine that liberate this sulfhydryl amino acid in vivo by nonenzymatic ring opening, followed by solvolysis.

Acetaminophen↗
PubMed1983

Enterocutaneous fistulas. Effects of total parenteral nutrition and surgery.

Fifty patients with 68 enterocutaneous fistulas were retrospectively reviewed at Hennepin County Medical Center from 1967 to June 1981. Eleven of 28 patients, treated with total parenteral nutrition (TPN) as the initial therapy for their fistulas, had spontaneous closure of 22 of 44 fistulas (three gastroduodenal, 17 small-bowel, two colonic fistulas). There were 35 operative procedures resulting in the closure of 26 fistulas, ten of which had failed to close with TPN (two gastroduodenal, ten small-bowel, and fourteen colonic fistulas). Overall mortality was 22 per cent, with five postoperative deaths and four deaths of patients treated with TPN. Aggressive use of TPN has not obviated the need for surgical closure in the authors' experience, particularly low in the gastrointestinal tract. Management should include TPN for up to four weeks and surgery if there has been no improvement with conservative therapy.

Adolescent↗
PubMed1981

Metabolism of paraldehyde to acetaldehyde by rat liver microsomes.

Paraldehyde (PAL) was shown to be metabolized to acetaldehyde (AcH) by rat liver microsomes in vitro only when the cofactors for the cytochrome P-450 system were present. Microsomes from phenobarbital treated rats significantly increased the amount of AcH produced from PAL. Attempts to inhibit this reaction by addition of SKF-525A to the incubation medium resulted in augmentation of the AcH generated, very likely due to the metabolic deethylation of SKF-525A itself to AcH. Rats pretreated with D-penicillamine and then given PAL excreted 2,5,5-trimethylthiazolidine-4-carboxylic acid (TTCA)-a condensation product of AcH and D-penicillamine-in the urine. These results strongly suggest that PAL is metabolized in vivo by the hepatic microsomal system giving rise to AcH as a metabolite.

Acetaldehyde↗
PubMed1980

N-Acetyl-DL-penicillamine and acetaminophen toxicity in mice.

N-Acetyl-DL-penicillamine (IIIb), a structural analog of N-acetyl-L-cysteine (IIIa), did not protect mice from lethal doses of acetaminophen (I), whereas IIIa offered protection. This lack of efficacy of IIIb probably is due to the decreased nucleophilicity of its sulfhydryl group compared to that of IIIa, the probable involvement of cysteine in and conjugate addition to the reactive intermediates of I, and the absence of metabolic conversion of IIIb to inorganic sulfate.

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↗
PubMedDate not supplied

Percutaneous endoscopic gastrostomy (PEG) in cancer patients.

Ninety-nine cancer patients underwent PEG placement attempt at Rosewell Park Cancer Institute between January 1, 1985, and December 1, 1987. Ninety-eight of these were successful and were retrospectively reviewed to determine if cancer patients constitute a high-risk group for PEG placement. Procedure-related mortality was 2% and morbidity was 19%. Morbidity of 17% was noted at less than 30 days and 2% had late complications. Six complications were considered serious with peritonitis in 3 and tube loss in 3 patients; an additional 4 patients had a failure of adequate GI tract decompression which was the indication for their PEG placement. Ascites was a major factor in morbidity with 4 of 5 patients with ascites having complications including the 2 deaths. Overall major morbidity was not increased in cancer patients without ascites including a group of patients with carcinomatosis (18 patients) and 22 patients requiring preoperative dilatation and/or tumor ablative procedures. We conclude that morbidity in cancer patients is not increased if one excludes those with ascites from the procedure.

Ascites↗
PubMedDate not supplied

Chemoprotection against cyclophosphamide-induced urotoxicity: comparison of nine thiol protective agents.

Nine thiol chemoprotective compounds were compared for their abilities to reduce the urotoxicity induced by a high dose (1.5 mmol/kg i.p.) of the cancer chemotherapeutic agent, cyclophosphamide (CTX) in male Swiss-Webster mice. Toxicity was assessed by the change in body weight at 48 h, as well as the relative bladder weight (rbw), both a macroscopic and a microscopic rating of bladder damage, and the glutathione (GSH) status of the bladder and the liver. In addition, the rbw, macroscopic assessment, and GSH measurements were also carried out at 4 h, the point of maximal damage and GSH depletion. The powerful effects of compounds with the D-configuration indicated that direct action by the thiols is their most likely mechanism of action. Indirect action through GSH is unlikely because the D-amino acid cannot support GSH's biosynthesis.

Acetylcysteine↗