Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies

Summary Cytosine arabinsodie (ara-C) and etoposide (VP-16) display synergy in the laboratory. Twenty-six patients participated in a phase I study of high-dose ara-C in combination with VP-16. The dose of VP-16 was held constant at 50 mg/m² as an intermittent infusion over 33 h; escalating doses of ara-C were given as infusions during hours 9–12 and 21–24. Myelosuppression was the dose-limiting toxicity and occurred with doses considerably less than those expected from studies of the two drugs as single agents. The suggested initial doses for phase II trials with this schedule are 750 mg/m²×2 doses of ara-C and 50 mg/m² of VP-16. Nonhematologic toxicity was minimal; therefore, further dose escalation is feasible in patients in whom myelosuppression is acceptable.Supported in part by grants from the National Cancer Institute (CA-12197 and CA-09422) and the American Cancer Society CF-85-182     

Spectral analysis of infant EEG and behavioral outcome at age five

Power spectral and discriminant analysis techniques were used to compare EEG records obtained at term and at 3 months past term from 5 groups of varying risk and developmental outcome. The groups were: healthy full-terms; healthy pre-terms with normal outcomes; sick pre-terms with normal outcomes; sick pre-terms with delayed development; sick pre-terms with later neurological problems. The EEG samples recorded at term were identified as belonging to the correct subject group at 52-70% accuracy, 20% being chance for 5 groups. The accuracy varied with the 4 classes of EEG patterns used. The individual subjects were also classified into their correct groups with few exceptions. Similar success was obtained with EEG samples selected from recording at 3 months past term. The predominant power spectral discriminating features were changes in intra- and inter-hemispheric coherence, and increased power, particularly in the middle and higher frequency range. Thus, computer analyses of EEG samples, using features not readily identified visually, differentiated risk from non-risk infants and also differentiated infants with substantial neonatal medical complications who have good or poor developmental outcomes.     

Inhibition and reversal of platelet-rich arterial thrombus in vivo: direct vs. indirect factor Xa inhibition

BACKGROUND/OBJECTIVE: The efficacy of a direct factor (F)Xa inhibitor, ZK-807834, was compared with indirect inhibition by enoxaparin for inhibition and deaggregation of acute platelet-rich thrombi in a well-characterized porcine carotid injury model. METHODS: A crush injury was performed on a randomly chosen carotid artery and the thrombus allowed to propagate for 30 min. Pigs then received intravenous drug for 35 min: ZK-807834-Dose 1 (40 microg kg(-1) bolus + 1.5 microg kg(-1) min(-1) infusion, n=6); ZK-807834-Dose 2 (20 microg kg(-1) bolus + 0.75 microg kg(-1) min(-1) infusion; n=6); enoxaparin (1 mg kg(-1) bolus; n=6); or saline (n=6). Five minutes after drug initiation, the contralateral artery was injured. Thrombus size was monitored by scintillation detection of autologous 111In-platelets. RESULTS: The prothrombin time ratio was 2.2 +/- 0.1; 1.4 +/- 0.3; 1.2 +/- 0.9 and 1.1 +/- 0.2, respectively. ZK-807834-Dose 1 significantly inhibited carotid platelet deposition (525 +/- 226 x 10(6) cm(-2); P = 0.008), whereas ZK-807834-Dose 2 (2325 +/- 768) and enoxaparin (1236 +/- 383) were not different from saline (2776 +/- 642). Thrombus deaggregation was greatest for animals receiving ZK-807834-Dose 1 (473 +/- 185). Neither ZK-807834-Dose 2 (1588 +/- 480) nor enoxaparin (1618 +/- 686) was different from saline control (2222 +/- 598). CONCLUSIONS: Direct FXa inhibition with ZK-807834, at a prothrombin time ratio of 2.2, effectively inhibits thrombosis and promptly deaggregates thrombi induced by arterial injury. In contrast, indirect FXa inhibition with enoxaparin was ineffective.     

Reproductive characteristics of a precocious vaccine line (Rt3+15) of Eimeria tenella in embryonating chicken eggs

Coccidiosis of chickens, caused by species of Eimeria (Protozoa, Apicomplexa), is an intestinal disease of major economic importance worldwide. In the present study, the reproductive characteristics of a precocious line (designated E. tenella Rt3+15) from Australia were investigated in chicken embryos and the implications of the findings briefly discussed.     

The effect of plasma solutes on total-body-water measurements via NMR.

Nuclear magnetic resonance (NMR) spectroscopy has been reported as an alternative method for quantitating deuterium oxide concentrations in the evaluation of total-body-water in humans. However, the presence of dissolved plasma proteins results in an underestimation of deuterium NMR (2H-NMR) intensity ratios, thereby causing an overestimation (5-6%) of total-body-water (TBW) values determined from nonsublimed patient plasma samples. We demonstrate that plasma samples must be corrected for the volume percentage of water in plasma. Correction of initial 2H-NMR intensity ratios with a factor of 0.93 results in intensity ratios comparable to those determined from plasma samples subjected to vacuum sublimation to remove all plasma solutes.     

Medical Research Council leukaemia trial--UKALL V: an attempt to reduce the immunosuppressive effects of therapy in childhood acute lymphoblastic leukemia. Report to the Council by the Working Party on Leukaemia in Childhood

The Medical Research Council UKALL V trial for children with standard-risk acute lymphoblastic leukemia (ALL) (aged 1 to 14 years, leucocyte count less than 20 X 10(9)/L) was designed to determine whether the immunosuppressive effects of treatment could be reduced without sacrifice of antileukemic effect by alterations in the type of continuing therapy or in fractionation of cranial irradiation. Remission was achieved in 496 children on standard induction therapy, and 309 children received 24 Gy of cranial irradiation in ten to 16 fractions over 21 days, and 174 received 21 Gy in five to nine fractions over 21 days. The type of radiotherapy administered had no influence on relapse at any site or rate of death in remission. All 496 children were randomized to receive chemotherapy for 2 or 3 years with 6-mercaptopurine and methotrexate either as a continuous (group C) or a semicontinuous (group G) regimen or as a five-day pulse every 3 weeks (group I). All groups also received vincristine and prednisolone every 6 weeks. With a minimum follow-up of almost 7 years, patients in group I had significantly fewer remission deaths (P = .025) but a much higher rate of bone marrow relapse than those in group C or G (P = .002). There was an overall benefit for 3 years of chemotherapy compared with 2 years, which in contrast to previous studies, was more apparent in girls and in patients in groups C and G. Testicular relapse occurred in 37 boys, including 19 patients off therapy, with a previously negative biopsy. The overall results confirmed the prognostic significance of initial leucocyte count, even among these standard-risk patients, while girls had a superior rate of disease-free survival, but not of hematologic remission. It is concluded that, even among standard-risk patients, the prognosis is influenced by the height of the initial leukocyte count. While alterations in the fractionation of cranial irradiation do not appear to have influenced disease-free survival, intermittent continuing chemotherapy, although less immunosuppressive, is less effective than conventional continuous therapy in the treatment of ALL. In this study, 3 years of chemotherapy appeared superior to 2 years.     

Developmental Toxicity of Dimethylacetamide by Inhalation in the Rat

Developmental Toxicity of Dimethylacetamide by Inhalation inthe Rat. SOLOMON, H. M., FERENZ, R. L., KENNEDY, G. L., ANDSTAPLES, R. E. (1991). Fundam. Appl. Toxicol. 16, 414–422.Dimethylacetamide (DMAC) is a widely used industrial solvent.It has been reported to be teratogenic when given to rats byinjection or following dermal application. Most of these studiesemployed large single doses and did not examine both the fetaland the maternal response. In this study, groups of pregnantCrl:CD rats were exposed to 32, 100, or 282 ppm DMAC by inhalationfor 6 hr/day from Days 6 through 15 of gestation (day on whichcopulation plug was detected was termed Day 1G). A control groupof chambered pregnant rats was exposed simultaneously to aironly. All female rats were euthanized on Day 21G. At 282 ppm,both maternal weight gain during the exposure period and fetalweight were significantly decreased and accompanied by a significantdose-response trend. These effects were not seen in rats inhalingeither 32 or 100 ppm. Fetal resorptions were not increased inany of the groups exposed to DMAC. Fetal incidences of external,visceral, or skeletal variations and malformations were similarbetween the test and control groups. Therefore, both fetal andmaternal toxicity were noted at 282 ppm and the no-observedadverse-effect level under these experimental conditions was100 ppm for both the dam and the conceptus. DMAC was not demonstratedto produce malformations in the rat fetus even at a level thatwas toxic to the dam.     

The usefulness of small-bowel manometry in the diagnosis of gastrointestinal motility disorders

Motility disorders of the gastrointestinal (GI) tract have traditionally been diagnosed by excluding mechanical small-bowel obstruction. In order to diagnose GI motility disorders in a positive fashion, small-bowel manometry was performed on 15 patients who were referred to the authors with intestinal motility disorders. Intestinal manometry was performed after first positioning a 200-cm multilumen tube into the small intestine. Ports located at 10-cm intervals were perfused with sterile water and connected to pressure transducers to record intraluminal pressures with a multichannel chart recorder. This low compliance water perfusion manometry system allowed examination of both fasting and postprandial motility. Intestinal manometry was able to assist in the diagnosis of two patients that had true mechanical small-bowel obstruction. One patient had a stenosis of the gastrojejunostomy and three patients had a functional gastric outlet obstruction secondary to a motility disorder in the Roux limb. One patient had a functional obstruction from a reversed jejunal loop and eight patients were identified as having intestinal pseudo-obstruction. We found intestinal manometry was a helpful adjunct in the diagnosis of GI motility disorders.