Behavioral and neurochemical responses to cocaine in periadolescent and adult rats.

Although recreational drug use by human adolescents is a well-known and long-standing problem, relatively little is known regarding differences in behavioral and physiological responses to abused substances in adolescent vs adult animals. The present study compared effects of the psychomotor stimulant, cocaine, in periadolescent (postnatal days 37-52) and adult (postnatal days 75-90) male Wistar rats. Locomotion and motor stereotypy were recorded after acute and repeated cocaine injections (0, 10, or 20 mg/kg cocaine, intraperitoneal (i.p.), four injections spaced 5 days apart). Spontaneous acquisition of intravenous (i.v.) cocaine self-administration was investigated in two dose groups ( approximately 0.37 or 0.74 mg/kg/infusion) over 14 days. Dopamine levels in the nucleus accumbens were recorded under basal conditions (no net flux method) and after cocaine administration ( approximately 0.37, 0.74, and 2.92 mg/kg/i.v. infusion or 20 mg/kg i.p.) using in vivo microdialysis. The locomotor data are in partial agreement with previous reports of hyposensitivity to acute cocaine in periadolescent vs adult rats; periadolescents were less active overall than adults. Moreover, adult rats exhibited significant locomotor sensitization after repeated injection of 10 mg/kg cocaine, whereas periadolescents required the high dose of 20 mg/kg cocaine to demonstrate sensitization. Neither age group showed sensitization of motor stereotypies. No age-related difference was observed in acquisition of cocaine self-administration, or in basal or cocaine-stimulated nucleus accumbens dopamine. These experiments imply a developmental dissociation between the motor activating and reinforcing effects of cocaine. Similarities in dopamine levels across age groups suggest that age-specific motor responses to cocaine are not mediated by dopamine in the nucleus accumbens.     

A phase I study of bexarotene, a retinoic X receptor agonist, in non-M3 acute myeloid leukemia

PURPOSE: Bexarotene is a retinoic X receptor agonist that has been shown in vitro to inhibit growth and induce differentiation of myeloid leukemic cell lines. We therefore conducted a phase I dose escalation study to assess the maximum tolerated dose, toxicities, and activity of bexarotene in patients with non-M3 acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We enrolled patients with active non-M3 AML who had either relapsed or refractory disease or were not eligible for standard cytotoxic chemotherapy. Cohorts of three to six patients received escalating doses of daily oral bexarotene ranging from 100 to 400 mg/m(2) until evidence of disease progression or unacceptable adverse events occurred. RESULTS: Twenty-seven patients, with median age of 69 years (range, 51-82 years), were treated. Twenty-four (89%) patients had undergone prior chemotherapy. At the highest dose level tested (400 mg/m(2)), three of six patients had to reduce their dose of bexarotene due to grade 3 adverse events. The maximum tolerable dose of bexarotene was determined to be 300 mg/m(2). Clinical activity was manifested by 4 (15%) patients with reduction in bone marrow blasts to 1 year while taking bexarotene. Leukemic blast differentiation was suggested by the presence of the leukemic cytogenetic abnormality in mature circulating granulocytes and the occurrence of differentiation syndrome. CONCLUSIONS: The recommended dose of bexarotene for future studies is 300 mg/m(2)/d. Bexarotene is well tolerated in patients with non-M3 AML and has evidence of antileukemic activity.     

Exposure of Danish workers to trichloroethylene, 1947-1989

The aim of this study was to investigate the exposure of Danish workers to trichloroethylene (TCE) and the factors that affected such exposure. Data from Danish health authorities were evaluated for use in an epidemiological study of possible adverse health effects of TCE. The paper files relating to 1,075 air measurements taken between 1947 and 1989 at 150 companies were examined to extract information about calendar year, company, industry, type of measurement, and worker. Multiple regression models were used to analyze the effects of various factors on the concentration of TCE. TCE concentrations decreased over the four decades studied. The geometric mean was 329 mg/m3 for measurements taken 1947-1959, and 260 mg/m3, 53 mg/m3, and 23 mg/m3, respectively, for the three subsequent decades. Regression analyses showed that 1) TCE concentrations decreased on average 4 percent per year before 1964 and 15 percent per year afterward; 2) area and personal measurements gave similar concentrations (for the same calendar period, industry, and duration of measurement); 3) longer-duration measurements were associated with lower TCE concentrations; 4) high TCE concentrations occurred in the iron and metal industry; and, 5) in this industry men were exposed to concentrations two times those of women. Moreover, this study indicated that both the exposure level and the proportion of exposed workers in Danish companies increased with decreasing number of employees. Epidemiological studies of health effects of TCE may benefit from evaluating potential risk within different strata of calendar time, number of company employees, sex, and type of industry.