The partitioning of phosphoramide mustard and its aziridinium ions among alkylation and P-N bond hydrolysis reactions

NMR (1H and 31P) and HPLC techniques were used to study the partitioning of phosphoramide mustard (PM) and its aziridinium ions among alkylation and P-N bond hydrolysis reactions as a function of the concentration and strength of added nucleophiles at 37 degrees C and pH 7.4. With water as the nucleophile, bisalkylation accounted for only 10-13% of the product distribution given by PM. The remainder of the products resulted from P-N bond hydrolysis reactions. With 50 mM thiosulfate or 55-110 mM glutathione (GSH), bisalkylation by a strong nucleophile increased to 55-76%. The rest of the PM was lost to either HOH alkylation or P-N bond hydrolysis reactions. Strong experimental and theoretical evidence was obtained to support the hypothesis that the P-N bond scission observed at neutral pH does not occur in the parent PM to produce nornitrogen mustard; rather it is an aziridinium ion derived from PM which undergoes P-N bond hydrolysis to give chloroethylaziridine. In every buffer studied (bis-Tris, lutidine, triethanolamine, and Tris), the decomposition of PM (with and without GSH) gave rise to 31P NMR signals which could not be attributed to products of HOH or GSH alkylation or P-N bond hydrolysis. The intensities of these unidentified signals were dependent on the concentration of buffer.     

Novel high-performance liquid chromatographic assay using fluorescence detection for the quantitation of plasma gamma-methylene-10-deazaaminopterin and its major metabolite, 7-hydroxy-gamma-methylene-10-deazaaminopterin, in patients with solid cancers in a phase I trial

Gamma-methylene-10-deazaaminopterin (MDAM), a unique dihydrofolate reductase inhibitor, has demonstrated antitumor activity against a broad spectrum of human solid tumors in preclinical studies. A novel reversed-phase, ion-pair high-performance liquid chromatography (HPLC) assay that uses fluorescence detection has been developed to quantitate levels of MDAM and its major metabolite, 7-hydroxy-gamma-methylene-10-deazaaminopterin (7-OH-MDAM), in human plasma. The recovery of MDAM and 7-OH-MDAM from plasma was >97% by a simple one-step deproteinization process using tetrabutylammonium bromide (TBABr) and methanol. MDAM and 7-OH-MDAM remained stable in plasma over a 28-day test period at ambient temperatures, and neither compound was light-sensitive. The limit of quantitation was 0.005 microM for both MDAM and 7-OH-MDAM. This assay has been found to be simple, sensitive and reproducible in determining plasma concentrations of MDAM and 7-OH-MDAM in patients with solid cancers in a phase I trial.     

Circadian variations of the urinary excretion of catecholamines and electrolytes

Concomitant measurements of circadian variations in the urinary excretion of dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), epinephrine (E) as well as of creatinine, sodium and potassium under controlled dietary conditions during relative physical and emotional rest in 13 volunteers have shown that maximum excretion of all these substances occurred in the afternoon period between 14:30h and 18:00h, and minimum excretion in the morning between 4:00h and 5:00h. The changes were in some cases progressive from one collection period to the other, and synchronized for NE and E. DA and HVA excretions fluctuated from subject to subject. Excretory rhythms of sodium and potassium were found to be similar to those of the catecholamines. This can be explained by diurnal changes in renal blood flow and different renal excretory mechanisms of catecholamines. None of the catecholamines correlated with the urinary volume but urinary NE and E positively correlated with urinary creatinine, urinary NE and E with urinary DA and urinary sodium with urinary E. There are some common patterns in the diurnal rhythms of catecholamines and electrolytes but their interrelationship is different for individual catecholamines.     

Effect of morphine-diazepam on signs of anesthesia, awareness, and dreams of patients under N2O for cesarean section

Morphine (0.2 mg/kg) and diazepam (0.1 mg/kg) were injected IV after delivery of the fetus in 68 parturients undergoing cesarean section (CS). General anesthesia was with thiamylal-N2O-O2 (4:2) and muscle relaxant. Twenty-four to 36 hours postoperatively, 1 patient had recall, 1 had unpleasant dreams, and 2 had pleasant dreams. The incidence of recall and unpleasant dreams was 3.8 percent in elective CS and 0 percent in emergency cesareans. Morphine-diazepam combination caused anterograde and retrograde amnesia. During the cesarean, movement of patient, size of pupils, or changes in blood pressure were not indicative of awareness or dreams. During anesthesia, 33 percent O2 produced adequate oxygenation of mother and fetus.     

Acute myocardial infarction: prognosis after recovery

A prognostic index for 2-year survival after recovery from acute myocardial infarction was constructed from variables obtained during its course. One hundred ten of 143 patients survived 2 years, and 27 of 33 patients died of cardiac-related causes. Univariate analysis showed that 12 variables were significantly different between the surviving and nonsurviving groups. Discriminant analysis indicated five variables with meaningful predictive value to be included in a prognostic index: admission systolic blood pressure; highest blood urea nitrogen level in the cardiac care unit: atrial arrhythmias in the cardiac care unit; angina pectoris for more than 3 months or a previous myocardial infarction; and more than one ventricular ectopic beat per hour recorded on a dynamic electrocardiogram during the 17th to 24th hospital day. The prognostic index emphasizes the importance of extensive myocardial impairment and provides a means for identifying patients at risk of early mortality.