Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults.

Modafinil is indicated for the management of excessive daytime sleepiness; however, recent studies have examined a broad range of potential uses. Given that clinical uses of modafinil may be expanding, this study compared modafinil and d-amphetamine effects on subjective and performance measures. Across 11 sessions, 11 healthy adults were tested after oral doses of placebo (5 sessions), modafinil (1.75 mg/kg, 3.50 mg/kg, or 7.00 mg/kg), and d-amphetamine (0.035 mg/kg, 0.070 mg/kg, 0.140 mg/kg) under double-blind, randomized conditions. Assessments of cognitive performance and subjective effects were completed before drug administration, 30 min after drug administration, and at hourly intervals after drug administration for 5 hr. Modafinil increased ratings on the Amphetamine and Morphine Benzedrine Group scales of the Addiction Research Center Inventory (ARCI) and increased ratings on the Vigor and Total Positive scales of the Profile of Mood States. d-Amphetamine increased visual analog ratings of feeling stimulated and liking the drug and increased ratings on the Morphine Benzedrine Group scale of the ARCI. Both medications significantly reduced visual analog scale ratings of feeling sleepy, and modafinil decreased ratings on the ARCI Pentobarbital-Chlorpromazine-Alcohol Group scale. Both medications sustained performance that deteriorated across time on the Sternberg Number Recognition Test. Modafinil also enhanced performance rate on the Digit-Symbol Substitution Task above baseline levels and increased response rate on the Repeated Acquisition of Response Sequences Task. These results suggest that modafinil engenders alerting effects and increases performance in healthy non-sleep-deprived individuals comparable with that of d-amphetamine.

Wake-promoting agents with different mechanisms of action: comparison of effects of modafinil and amphetamine on food intake and cardiovascular activity.

Despite efforts to achieve a desirable weight, two-thirds of the population has an elevated body weight. Medications are useful in supporting weight loss, but produce adverse effects. This study compared the effects of amphetamine and modafinil on food intake and cardiovascular activity in healthy men and women. Participants (n = 11) completed 11 sessions. In random order, participants received placebo on five separate sessions and single oral doses of modafinil (1.75, 3.5, or 7.0 mg/kg) and amphetamine (0.035, 0.07, 0.14 mg/kg). Free time between hourly performance testing intervals gave participants the opportunity to eat. Like amphetamine, modafinil reduced the amount of food consumed and decreased energy intake, without altering the proportion of macronutrients consumed. Although both medications significantly increase heart rate and blood pressure at higher doses, the dose of modafinil that was efficacious in decreasing food intake did not significantly increase heart rate. Modafinil may be well suited for the treatment of obesity, although further studies with repeated dosing in overweight populations are warranted. Modafinil may have less adverse health consequences than some anorectic agents and greater treatment efficacy.

Anti-TNF-alpha antibody normalizes serum leptin in IL-2 deficient mice.

OBJECTIVE: A recent study reports that the interleukin-2 deficient (IL-2(-/-)) mouse model of autoimmune and inflammatory bowel disease (IBD) with elevated pro-inflammatory cytokine production has elevated leptin concentrations during food deprivation. The objective of this study was to examine whether increased tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, contributes to the abnormally elevated leptin in IL-2(-/-) mice. METHODS: Eight week old, IL-2(-/-) and wild-type control (IL-2(+/+)), male mice were fed regular laboratory mouse food for two weeks. At the end of the study, blood was collected in the fed state, IL-2(-/-) and IL-2(+/+) mice were injected with either anti-TNF-alpha monoclonal antibody or normal saline, and blood was collected in the starved state. RESULTS: The IL-2(-/-) mice consumed less food and lost weight. Administration of anti-TNF-alpha antibody markedly reduced serum leptin concentrations in IL-2(-/-) and control mice after food deprivation. Serum leptin in the IL-2(-/-) mice not receiving anti-TNF-alpha antibody increased significantly in the starved state. Serum concentrations of TNF-alpha were higher in IL-2(-/-) mice compared to controls in both the fed and starved state. CONCLUSIONS: These results suggest that elevated TNF-alpha may be one mechanism for the sustained elevated leptin observed in IL-2(-/-) mice during food deprivation.

Decreased food intake rather than zinc deficiency is associated with changes in plasma leptin, metabolic rate, and activity levels in zinc deficient rats( small star, filled).

This study investigated the hypothesis that the reduced food intake and poor weight gain in zinc deficient rats is due to: increased plasma leptin concentration, increased physical activity and/or increased metabolic rate. Weanling rats were assigned to three groups: controls fed ad libitum (C), zinc deficient (ZD), and pair-fed controls (PF), and tested in a metabolic chamber and activity monitor at baseline and weekly for four weeks. At the end of the study, all groups were compared for differences in plasma leptin concentrations. ZD and PF animals had markedly reduced food intake and weight gain. ZD had reduced stereotypic and locomotor activity compared to PF animals and both groups demonstrated an abolished peri-nocturnal activity spike and were much less active than controls. This was associated with a reduced total metabolic rate by day 30: ZD (0.73 +/- 0.07 kcal/hr, p = 0.0001) and PF (0.83 +/- 0.06 kcal/hr, p = 0.0001) groups vs. controls (1.82 +/- 0.09 kcal/hr). Plasma leptin concentrations in ZD (1.55 +/- 0.06 &mgr;g/L) were lower than controls (2.01 +/- 0.18 &mgr;g/L, p < 0.03), but neither ZD nor controls were statistically different from PF (1.68 +/- 0.05 &mgr;g/L). Both low leptin concentrations and low metabolic rates in the ZD and PF rats were associated with decreased food intake rather than zinc deficiency. The reduced food intake and poor weight gain observed in zinc deficient rats could not be explained by elevated leptin concentrations, hypermetabolism, or increased activity. Low serum leptin concentrations, hypometabolism, and decreased activity are more likely the result of the anorexia of zinc deficiency.

The leptin defense against wasting is abolished in the IL-2-deficient mouse model of inflammatory bowel disease.

Anorexia is a major complication of inflammatory bowel disease (IBD). We postulated that chronic intestinal inflammation with increased proinflammatory cytokines elevates serum leptin concentration, thereby contributing to anorexia. This hypothesis was studied in interleukin-2-deficient (IL-2(-/-)) mice, a model of IBD with elevated proinflammatory cytokine production. IL-2(-/-), wild-type pair-fed and wild-type control male mice (8 wk old) were fed regular laboratory mouse food for 2 wk. The IL-2(-/-) and pair-fed groups consumed less food and lost weight. Serum leptin concentrations in the IL-2(-/-) mice in the fed state were lower than controls, but not different from pair-fed mice, and paradoxically increased in the starved state to levels significantly higher than both starved control and pair-fed groups. This result did not change when serum leptin was adjusted for amount of body fat. These data show abnormal leptin responses in IL-2(-/-) mice with increased leptin concentrations disproportionate to fat mass and prevention of the normal decline in leptin with food restriction.