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O A Stuart

Publications and source records attributed to O A Stuart.

24 records · Page 2Linked to original sources
PubMed1989

Synthesis of an actinomycin-related peptide lactone from the corresponding cyclic pentapeptide by N,O-acyl shift.

The N,O-acyl shift was investigated as a method for the synthesis of an O-peptide or peptide lactone from a linear or cyclic peptide respectively. Protected derivatives of glycyl-L-threonine could be converted to O-peptides by the action of HCl/dioxane at room temperature and N-acylated under conditions which precluded a reverse O,N-acyl shift. For effecting N,O-acyl shift in cyclo(Thr-D-Val-Pro-Sar-MeAla) this reagent was unsatisfactory and p-toluenesulfonic acid in dioxane at 80 degrees was used instead. The resulting crystalline peptide lactone p-toluenesulfonate salt was N-acylated with 3-benzyloxy-4-methyl-2-nitrobenzoyl chloride to afford a known intermediate in the synthesis of 5,5'-MeAla actinomycin D. This approach constitutes a novel synthetic route to actinomycins and potentially to other peptide lactone antibiotics.

Acylation↗
PubMed1987

Slow O,N-acyl shift in an actinomycin-related peptide lactone.

The pentapeptide lactone Cbz-(Thr-D-Val-Pro-Sar-MeAla-) was synthesized in order to observe the behavior of the unprotected lactone resulting from its hydrogenolytic deprotection. Closely related peptide lactones have been reported as intermediates in total syntheses of actinomycin D and its analogues, despite the fact that unprotected and unprotonated O-peptides of serine and threonine are known to undergo rapid O,N-acyl shift. In the present study the peptide lactone was seen to undergo a slow O,N-acyl shift, in a matter of hours, to the known cyclic pentapeptide. This contrasted with the rapid rearrangement of a model O-peptide, O-hippuryl-L-threonine methyl ester. This slowness of an O,N-acyl shift in a cyclic system presumably results from higher energy barriers of conformational origin. It explains the suitability of unprotected peptide lactones for the syntheses of actinomycins and other peptide lactone antibiotics which have appeared in the literature.

Acylation↗
PubMedDate not supplied

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies.

PURPOSE: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. METHODS: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. RESULTS: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. CONCLUSIONS: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Pharmacokinetics of intraperitoneal gemcitabine in a rat model.

BACKGROUND: Gemcitabine (2'-2' difluorodeoxycytidine) has been shown to possess a broad spectrum of antitumor activity against various malignancies, particularly pancreatic carcinoma. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal (i.p.) chemotherapy over intravenous (i.v.) chemotherapy is the high drug concentration that can be achieved locally. In addition, the cytotoxic effect of several anticancer agents can be enhanced by hyperthermia. Using a rat model, this study was designed to compare i.p. vs i.v. gemcitabine and to evaluate the effect of hyperthermia on i.p. gemcitabine. METHODS: In the first phase of this study, 18 Sprague Dawley rats were given a single dose of gemcitabine then randomized into three groups according to dose and route of delivery of chemotherapy (12.5 mg/kg--i.v., 12.5 mg/kg--i.p. or 125 mg/kg--i.p.). In a separate experiment (phase 2), 12 Sprague Dawley rats were given a continuous i.p. perfusion of gemcitabine (12.5 mg/kg in 150 mL total perfusate) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic or hyperthermic). During the course of both experiments, peritoneal fluid and blood were sampled using a standardized protocol. At the end of the procedure the rats were sacrificed and all urine was extracted. Selected tissue samples were taken from rats in the second phase of the study. The concentration of gemcitabine in all samples was determined by high performance liquid chromatography (HPLC). RESULTS: When gemcitabine was delivered at 12.5 mg/kg (phase 1) the area under the curve (AUC) was significantly higher with i.p. administration as compared to i.v. administration (P = 0.001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 12.5+/-3.2 for i.p. delivery as opposed to 0.2+/-0.2 for i.v. delivery (P = 0.0002). The AUC ratio for i.p. gemcitabine at 125 mg/kg was 26.8+/-5.8. Although there was no significant difference in drug concentrations between samples from the normothermic and hyperthermic groups, all tissue samples (except stomach) in the hyperthermic group exhibited increased gemcitabine concentrations. CONCLUSION: These experiments demonstrated that the exposure of peritoneal surfaces to gemcitabine is significantly increased with i.p. gemcitabine. Intraabdominal hyperthermia had no significant effect on the pharmacokinetics of i.p. gemcitabine but there was evidence of increased absorption of gemcitabine in most intraabdominal tissues. Due to the likelihood of a high incidence of microscopic residual disease after resection of a pancreatic carcinoma, clinical studies to evaluate i.p. hyperthermic gemcitabine may be indicated.

Animals↗