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     

The characterization and localization of the glutamate receptor subunit GluR1 in the rat brain.

The cloning of cDNAs that encode functional glutamate receptors makes it possible to produce antibodies that can be used as high-affinity probes for the localization and characterization of these receptors in the mammalian brain. We have made antibodies to different regions of the first cloned member of this family, GluR1, using bacterially overproduced antigen. On Western blots, these antisera detect glycoprotein(s) of 105 kDa present in crude membranes of the hippocampus and cerebellum. The 105-kDa band is associated with postsynaptic densities, and it is observed in cultured cells upon transfection with the GluR1 cDNA. Although glutamate receptors are thought to be the most prevalent excitatory ligand-gated ion channel in the mammalian brain, immunohistochemistry reveals that the receptors recognized by these antisera are localized predominantly in neurons of the cerebellum and some structures of the limbic system, including the hippocampus, the central nucleus of the amygdala, and portions of the septum. This pattern of expression is, in general, consistent with the distribution of GluR1 mRNA as determined by in situ hybridization histochemistry. Our results suggest that glutamate excitatory circuits recognized by these antisera are predominantly found in regions of the limbic system that are reciprocally interconnected.     

Symptoms of tobacco withdrawal. A replication and extension

Smokers (n = 315) who wished to quit were randomly assigned in a double-blind manner to groups using either nicotine or placebo gum. Self-reported and observed symptoms of tobacco withdrawal were collected before cessation and at follow-ups of 1 to 2 weeks, 1 month, and 6 months. Self-reported and/or observed anger, anxiety, craving, difficulty concentrating, hunger, impatience, and restlessness were the most prominent symptoms of tobacco withdrawal. These symptoms had returned to precessation levels by 1 month except increased weight, hunger, and craving continued for 6 months in many smokers. Nicotine gum decreased most symptoms, including craving and hunger but not weight. Abstinent smokers with more intense withdrawal were not more likely to relapse. Abstinent smokers who gained more weight were less likely to relapse.     

The effect of atrial natriuretic peptide on human isolated resistance arteries.

1. The action of (1-28) alpha-human atrial natriuretic peptide (ANP) was studied on human isolated resistance arteries. 2. Renal, skeletal muscle, omental and subcutaneous resistance arteries were taken from tissue removed at surgery and isometric tension responses were measured with a myograph. 3. ANP (10(-9)-10(-6) M) relaxed precontracted segments of renal and skeletal muscle arteries in a concentration-dependent manner. ANP failed to relax isolated omental or subcutaneous arteries. 4. The effect of ANP on human isolated resistance arteries varies depending on the site of origin of the artery.     

Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine.

We explored the relationship between striatal dopamine-2 (D(2)) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5-45 mg/day olanzapine for at least 14 days. After that period, D(2) receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson-Angus Scale (SAS) and Barnes-Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28-50%, 10 mg to 40-68%, 15 mg to 69%, 20 mg to 57-66%, 30 mg to 66% and 45 mg to 80% D(2) receptor occupancy; and a significant correlation between plasma levels and occupancy (R(2)=.55, P=.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D(2) occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes.     

Successful treatment of OCD with a micronutrient formula following partial response to Cognitive Behavioral Therapy (CBT): A case study

Obsessive Compulsive Disorder (OCD) affects 0.5–2% of young people many of whom are resistant to conventional treatments. This case study describes an 18-year-old male with OCD who first underwent cognitive behavioral therapy (CBT) for a 1-year period with a modest response (his OCD had shifted from severe to moderate). Within a year, his anxiety had deteriorated back to the severe range and he now had major depression. He then entered an ABAB design trial using a nutritional formula consisting mainly of minerals and vitamins (together, known as micronutrients). After 8 weeks on the formula, his mood was stabilized, his anxiety reduced, and his obsessions were in remission. The treatment was then discontinued for 8 weeks, during which time his obsessions and anxiety worsened and his mood dropped. Reintroduction of the formula again improved the symptoms. This case illustrates the importance of considering the effect micronutrients have on mental illness.     

Remission and Recovery in the Treatment for Adolescents With Depression Study (TADS): Acute and Long-Term Outcomes

ObjectiveWe examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS).MethodThe TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive–behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission.ResultsAt week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive–behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36.ConclusionsMost depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment.