The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission of their disease. Apparent steady state plasma levels of ara-C during 13 infusions averaged 115 +/- 32 microM. Upon cessation of the infusion, cytosine arabinoside (ara-C) was rapidly cleared from the plasma. The apparent postinfusion kinetics of ara-C were triexponential with a distribution half-life of 16 minutes and elimination half-lives of 1.8 hours and six hours. Total clearance averaged 86 L per hour and mean residence time averaged 0.47 hours. Disease status (relapse or remission) had no apparent effect on the pharmacokinetic characteristics of ara-C. Peak levels of ara-U averaged 310 microM and the metabolite had an average apparent elimination half-life of 3.75 hours. Despite the persistence of ara-U at about 100 microM at the time of administration of subsequent infusions of ara-C, there was no further accumulation of ara-U in the plasma with repetitive infusions of HiDAC. In vitro studies indicate that ara-U can exert an inhibitory effect on deoxycytidine (dCyd) deaminase activity. The ratio of the Ki of ara-U to the Km of ara-C for cytidine (Cyd)-dCyd deaminase is 40:1; however, during the gamma phase of ara-C elimination, the ratio of ara-U:ara-C in plasma is at least 100:1. Thus, a retardation of systemic catabolism of ara-C by ara-U is possible. Two to three hours after the termination of the HiDAC infusion, the ara-C cerebrospinal fluid: plasma ratio is 1-3:1, a feature of potential therapeutic significance. The slower elimination of ara-C from the CSF may also contribute to the plasma gamma half-life.

We have evaluated the efficacy of intravenous 2,5-diaziridinyl-3,6-biscarboethoxyamino-1,4-benzoquinone (diaziquone or AZQ, NSC-182986) in the treatment of recurrent primary anaplastic brain tumors. Three of 16 evaluable patients (18.8%) showed clinical and radiographic improvement that permitted discontinuation of corticosteroids, 4 patients (25%) showed either clinical or radiographic improvement and were considered partial responders, and 9 patients (56.2%) showed no effects after two courses of AZQ. The treatment was well tolerated, and hematologic toxicity was mild. Pharmacokinetic studies indicated rapid decay of the parent compound from plasma using two different infusion schedules. These results compare favorably with those obtained using the nitrosoureas or procarbazine as single agents.

The significance of baseline coagulation times and plasma concentrations of serine protease inhibitors as determinants of the relationship between heparin activity and its anticoagulant effect has been investigated in vitro. Citrated plasma was prepared from blood obtained from 20 normal subjects, and heparin added to yield concentrations ranging from 0.05 to 1.5 units/ml. The anticoagulant effect was determined by the activated partial thromboplastin time (APTT) and thrombin time (TT). An excellent linear relationship was observed between the natural logarithms (ln) of the coagulation times and heparin activity. Baseline APTT values ranged from 28.4 to 59.7 s and the slope values for the ln APTT vs heparin curves ranged from 1.488 to 3.427 ml/unit. Similar range was observed in the slope values for the ln TT vs heparin curves. There was a highly significant positive correlation between the ln APTT vs heparin slope values and the baseline APTT values (r: 0.905; p less than 0.001). There was also a weak but statistically significant positive correlation between plasma concentrations of alpha 2 macroglobulin and baseline APTT values (0.02 greater than 0 greater than 0.01) and slope values of the ln APTT vs heparin curves (0.02 greater than p greater than 0.01). Furthermore, there was a statistically significant positive correlation between plasma concentrations of alpha 1 antitrypsin and baseline TT values (0.05 greater than p greater than 0.02) and slope values of the 1n TT vs heparin (0.02 greater than p greater than 0.01). Neither baseline APTT and TT values nor slope values of the ln APTT and TT vs heparin curves were statistically significantly related to plasma concentrations of antithrombin III, fibrinogen, or alpha 1 acid glycoprotein. This study has demonstrated that baseline APTT is a major determinant of the anticoagulant response to heparin in vitro, as determined by that same coagulation test, and it illustrates that there is a wide intersubject variation in the anticoagulant response to heparin in vitro.

Eight chronic schizophrenic patients were maintained on a diet free of gluten, cereal grains, and milk (CM-F diet) and challenged in a double-blind manner with dietary wheat gluten and placebo. While on the CM-F diet, each patient received a daily challenge of 30 g of gluten for 5 weeks and a placebo challenge for 8 weeks. No deterioration in clinical status as measured by the BPRS was noted on gluten challenge. Serum alpha 1 acid glycoprotein measurement demonstrated no evidence of inflammatory response to gluten challenge. The data suggest that sensitivity to dietary gluten is not characteristic of young chronic schizophrenic patients.

No abstract