Phase II study of intravenous melphalan (NSC-8806) in the treatment of patients with advanced squamous carcinoma of the head and neck

The Illinois Cancer Center entered 25 patients on a phase II trial of intravenous melphalan treating patients with recurrent, metastatic or locally advanced and inoperable squamous cell carcinoma of the head and neck. All patients had bi-dimensionally measurable disease, at least a sixty day life expectancy, and adequate performance status (ECOG scale 2). All patients except one had received prior radiotherapy, chemotherapy or both. Melphalan dosage was 30 mg/m² every three weeks. Twenty-four patients were evaluable for response. One patient with laryngeal carcinoma had a clinical complete response of a nodal metastasis. Four patients had stabilization of disease for one to three months. There was formidable toxicity, including neutropenia (ANC < 1000/l 36%), and thrombocytopenia (< 50,000/l 32%). There were no drug-related deaths. Melphalan administered intravenously does not appear to be efficacious therapy in patients with previously treated advanced head and neck squamous carcinomas.     

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer’s disease

To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease are warranted. Received: 27 February 1998/Final version: 9 September 1998     

Nebulization of Liposomes. II. The Effects of Size and Modeling of Solute Release Profiles

A series of carboxyfluorescein (CF)-containing multilamellar vesicle (MLV) dispersions was prepared and extruded through polycarbonate membranes ranging in size from 0.2 to 5 µm. Vesicle dispersions were nebulized for 80 min using a Collison nebulizer, and the release of CF was monitored during nebulization. Solute retention was dependent upon the size of the vesicles and leakage ranged from 7.9 ± 0.4% (N = 3) for vesicles extruded through 0.2-µm filters to 76.8 ± 5.9% (N = 3) for liposomes that were not filtered. Solute release profiles obtained over 420-min nebulization periods conformed to a two-compartment kinetic model and exhibited a fast initial phase (k _l = 0.052 ± 0.0043) followed by a slow terminal phase (k ₂ = 0.0034 ± 0.00018). The results show that CF retention can be increased by nebulizing small vesicles and modeling suggests that the rate of CF leakage from the bilayers is faster than from the core of the liposomes.     

An assessment of fructose-1,6-bisphosphate as an antimicrobial and anti-inflammatory agent in sepsis.

Tissue lesion mechanisms provoked by sepsis include the infectious process, inflammation, and cellular energy deficit. We chose to test fructose-1,6-bisphosphate (FBP) because of its possible anti-inflammatory and antimicrobial actions. Wistar rats were used and divided into three experimental groups: a control group (n=10), in which a capsule was introduced into the peritoneum of the animals; a septic group (n=10), in which a capsule containing non-sterile fecal matter was introduced together with Escherichia coli (1.5 x 10(9)CFU); and a septic group treated with FBP 500 mg/kg (n=10). The blood cell tests revealed that levels of leukocytes increased significantly in the septic group when compared to both the septic group treated with FBP and the control group. The blood cultures were 100% positive in both the septic group and the septic group treated with bisphosphorylated sugar. The antibiogram only revealed an inhibitory halo in the case of the antibiotic ampicillin, there was no such indication for FBP. The anti-inflammatory power of FBP remained at 60% for 5 h in the rats that received the carrageenan injection. What is more, the sugar reduced the levels of ionic calcium in relation to the control group. This data proves the validity of using FBP in the treatment of sepsis, possibly due to its anti-inflammatory rather than antimicrobial action.     

Effects of intermittent exposure to aflatoxin B1 on DNA and RNA adduct formation in rat liver: dose-response and temporal patterns.

We studied the effects of intermittent exposure to aflatoxin B1 (AFB1) on hepatic DNA and RNA adduct formation. Fisher-344 male rats were fed 0.01, 0.04, 0.4, or 1.6 ppm of AFB1 intermittently for 8, 12, 16, and 20 weeks, alternating with 4 weeks of dosing and 4 weeks of rest. Other groups of rats were fed 1.6 ppm of AFB1 continuously for 4, 8, 12, and 16 weeks. Control rats received AFB1-free NIH-31 meal diet. AFB1-DNA and -RNA adducts were measured by HPLC with fluorescence detection. The data are presented as total DNA or RNA adducts. The DNA and RNA adduct levels increased or decreased depending on the cycles of dosing and rest. Rats removed from treatment 1 month after 1 or 2 dosing cycles (8 and 16 weeks of intermittent exposure) showed approximately a twofold decrease in DNA adduct levels and a two- to elevenfold decrease in RNA adduct levels compared with rats euthanized immediately after the last dosing cycle (12 and 20 weeks of intermittent exposure). Our data indicate that DNA and RNA adducts increased linearly, from 0.01 ppm to 1.6 ppm of AFB1 after 12 and 20 weeks of intermittent treatment. A linear dose response was also apparent for DNA but not for RNA adducts after 8 and 16 weeks of treatment. As biomarkers of exposure, AFB1-RNA adducts were three to nine times more sensitive than AFB1-DNA adducts but showed greater variability. These results suggest that binding of AFB1 to hepatic DNA is a linear function of the dose, regardless of the way this is administered. The dose-response relationship for RNA adducts depends on the length of the no-dosing cycles and on the turnover rate of RNA.     

Delta sleep response to metyrapone in post-traumatic stress disorder.

Metyrapone blocks cortisol synthesis, which results in the stimulation of hypothalamic cortiocotropin-releasing factor (CRF) and a reduction in delta sleep. We examined the effect of metyrapone administration on endocrine and sleep measures in male subjects with and without chronic PTSD. We hypothesized that metyrapone would result in a decrease in delta sleep and that the magnitude of this decrease would be correlated with the endocrine response. Finally, we utilized the delta sleep response to metyrapone as an indirect measure of hypothalamic CRF activity and hypothesized that PTSD subjects would have decreased delta sleep at baseline and a greater decrease in delta sleep induced by metyrapone. Three nights of polysomnography were obtained in 24 male subjects with combat-related PTSD and 18 male combat-exposed normal controls. On day 3, metyrapone was administered during normal waking hours until habitual sleep onset preceding night 3. Endocrine responses to metyrapone were measured in plasma obtained the morning following sleep recordings, the day before and after administration. Repeated measures ANOVAs were conducted to compare the endocrine and sleep response to metyrapone in PTSD and controls. PTSD subjects had significantly less delta sleep as indexed by stages 3 and 4, and total delta integrated amplitude prior to metyrapone administration. There were no differences in premetyrapone cortisol or ACTH levels in PTSD vs controls. PTSD subjects had a significantly decreased ACTH response to metyrapone compared to controls. Metyrapone caused an increase in awakenings and a marked decrease in quantitative measures of delta sleep that was significantly greater in controls compared to PTSD. The decline in delta sleep was significantly associated with the magnitude of increase in both 11-deoxycortisol and ACTH. The results suggest that the delta sleep response to metyrapone is a measure of the brain response to increases in hypothalamic CRF. These data also suggest that the ACTH and sleep EEG response to hypothalamic CRF is decreased in PTSD.     

Direct and indirect acquisition of syringes from syringe exchange programmes in Baltimore, Maryland, USA

Syringe exchange programmes (SEPs) are a fundamental source of sterile syringes and other health services for injection drug users (IDUs). However, various obstacles prevent many individuals from obtaining syringes from this source. As a result, some IDUs acquire syringes from “secondary exchangers”. The current study assessed the acquisition of syringes from the Baltimore City Needle Exchange Program (BNEP) as well as factors associated with obtaining syringes from the BNEP. Participants were asked to identify the colour of the cap of the most recently obtained syringe (red or grey cap suggested BNEP origins). In addition, support and risk network variables were examined. Although 38% reported using a syringe with a grey or red cap, only 7% reported that the BNEP was their primary source of syringes. Multivariate analyses showed that reporting the most recent syringe cap as red or grey was associated with obtaining syringes from the BNEP, obtaining syringes from a spouse, obtaining syringes from friends/neighbours, and number of drug users in their network. Based on these findings, encouraging secondary exchange is an effective method of providing injectors with syringes.     

Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition.

PURPOSE: Gonadotropin-releasing hormone agonists decrease bone mineral density, lean mass, and muscle size and increase fat mass in men with prostate cancer. Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition. PATIENTS AND METHODS: In a 12-month, open-label study, we randomly assigned 52 men with prostate cancer and no bone metastases to receive either leuprolide or bicalutamide (150 mg by mouth daily). Bone mineral density and body composition were measured by dual energy x-ray absorptiometry and quantitative computed tomography. RESULTS: Mean (+/- standard error) bone mineral density of the posterior-anterior lumbar spine decreased by 2.5% +/- 0.5% in the leuprolide group and increased by 2.5 +/- 0.5 in the bicalutamide group from baseline to 12 months (P <.001). Mean changes in bone mineral density of the total body, total hip, femoral neck, and trabecular bone of the lumbar spine also differed significantly between groups (P < or =.003 for each comparison). Fat mass increased by 11.1% +/- 1.3% in the leuprolide group and by 6.4% +/- 1.1% in the bicalutamide group (P =.01). Changes in lean mass, muscle size, and muscle strength were similar between the groups. Breast tenderness and enlargement were more common in the bicalutamide group than in the leuprolide group. Fatigue, loss of sexual interest, and vasomotor flushing were less common in the bicalutamide group than in the leuprolide group. CONCLUSION: In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist.