Phase II/III randomized trial of TCH346 in patients with ALS.

BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine.

RATIONALE: Dopaminergic compounds have been targeted as potential treatments for cocaine abuse because of the known role of dopamine systems in drug reinforcement. Recent preclinical and human data have focused on the D1/5 antagonist, SCH 39166 (ecopipam), as a potential therapeutic agent. OBJECTIVES: The objective of the present study was to determine whether treatment with chronic ecopipam can blunt or block the subjective effects of cocaine in the absence of significant behavioral impairment or toxic physiological effects. METHODS: Four doses of ecopipam (0, 10, 25, and 100 mg p.o.) were administered daily for 1 week each in double-blind, random order to inpatient cocaine-dependent volunteers (n = 10). Cocaine challenge doses (0, 25, and 50 mg/70 kg i.v.) were administered on the 7th day in ascending order, 1 h apart. RESULTS: Ecopipam alone produced reliable dose-dependent deficits in performance on the digit symbol substitution task (DSST) and the circular lights task, but not a balance task. Impairment on the DSST waned with repeated dosing suggesting the development of tolerance. Ecopipam resulted in few direct subjective effects. Cocaine alone produced dose-dependent changes in prototypic subjective and physiological measures, however, ecopipam largely failed to alter either cocaine's direct effects or the desire for cocaine. CONCLUSIONS: Although the performance effects verify that these doses of ecopipam were behaviorally active, the absence of an attenuation of cocaine's effects of craving for cocaine in this chronic dosing paradigm suggests this compound is unlikely to be an effective pharmacotherapy for cocaine abuse.

Is caffeine a flavoring agent in cola soft drinks?

BACKGROUND: Concern has been expressed about the nutrition and health impact of high rates of soft drink consumption. Caffeine is an added ingredient in approximately 70% of soft drinks consumed in the United States. The soft drink manufacturers' justification to regulatory agencies and the public for adding caffeine to soft drinks is that caffeine is a flavoring agent. OBJECTIVE: To examine the claim that caffeine plays an integral role in the flavor profile of soft drinks, by examining the effect of caffeine on the threshold for detection of flavor differences in cola beverages. DESIGN: Double-blind crossover study starting November 1998 and ending July 1999. SETTING: An academic research center. PARTICIPANTS: Twenty-five adult regular consumers of cola soft drinks. Based on a screening session, all were able to detect a flavor difference between cola containing sugar and diet cola. INTERVENTION: A sensitive version of a forced-choice flavor-detection procedure was used to evaluate the effects of a wide range of caffeine concentrations (range, 0.05-1.6 mg/mL) on the ability to detect flavor differences between caffeinated and caffeine-free cola beverages. Repeated tests permitted determination of significant detection at each concentration in individual subjects. MAIN OUTCOME MEASURES: Percentage of subjects significantly detecting a flavor difference and mean percentage of trials correct at each caffeine concentration. RESULTS: Detection of flavor differences increased as a function of caffeine concentration. At the 0.1-mg/mL concentration, which is the approximate concentration in the majority of cola soft drink products, 2 subjects (8%) significantly detected a flavor difference and the mean percentage correct (53%) was at chance levels. CONCLUSIONS: The finding that only 8% of a group of regular cola soft drink consumers could detect the effect of the caffeine concentration found in most cola soft drinks is at variance with the claim made by soft drink manufacturers that caffeine is added to soft drinks because it plays an integral role in the flavor profile. It is valuable for the general public, the medical community, and regulatory agencies to recognize that the high rates of consumption of caffeinated soft drinks more likely reflect the mood-altering and physical dependence-producing effects of caffeine as a central nervous system-active drug than its subtle effects as a flavoring agent. Arch Fam Med. 2000;9:727-734

Microinfusion of cocaine into the medial preoptic area or nucleus accumbens transiently impairs maternal behavior in the rat.

Cocaine was microinfused bilaterally (50 microg/0.5 microl/side) into the medial preoptic area (MPOA) or nucleus accumbens (NA), 2 regions within the rat brain neural circuit known to mediate maternal behavior (MB). Additionally, 2 sites not involved in this neural circuit, the dorsal striatum and dorsal medial hippocampus, were used as control sites. Microinfusion of cocaine into the MPOA or NA impaired MB, whereas infusion into the control sites did not. MB impairment was not temporally coincident with the increased locomotor activity, also documented after cocaine infusion into the MPOA or NA, arguing strongly that impaired MB is a direct, specific effect of cocaine in these areas, not a derivative of increased motor activity. This is the first demonstration that cocaine action on single central nervous system (CNS) sites can impair MB to the same extent as systemic injections. Thus, cocaine's simultaneous effect on multiple CNS sites is not required for MB impairment.

Plasma cocaine levels and locomotor activity after systemic injection in virgin and in lactating maternal female rats.

We have determined the temporal pattern of plasma cocaine levels and increased activity that result from acute systemic injections of cocaine to female rats in two different endocrine and behavioral states, in nonmaternal virgins and in lactating maternal dams. Plasma levels of cocaine as well as ambulatory and rearing activity were determined every 30 min for a total of 300 min after subcutaneous injections of either 10, 20, or 40 mg/kg of cocaine. Virgin females had no prior drug history, whereas lactating, maternal dams had received two cocaine injections before activity testing. Within 30 min after an injection, cocaine in the plasma and activity were substantially elevated, and generally remained so for 270-300 min. Overall, plasma cocaine levels and activity were well correlated and followed a predictable dose-response pattern. The onset, peak, duration, and decline of activity corresponded generally to the onset, peak, duration, and decline of plasma cocaine. For virgins, mean ambulatory activity increased 2.5-4.0-fold over baseline, whereas in lactating females activity increased 5-11-fold over baseline. Stereotypy did not occur. Although the general responsivity of these females to cocaine was very similar to that reported for males, there are differences in the timing of peak activity and the return of activity to baseline when the virgins and the lactating dams are compared to each other and to reports by others on male rats. These data support the hypothesis that endocrine or behavioral state may influence the responsiveness of animals to cocaine.

Focal necrotizing panniculitis and vascular necrosis in rats given subcutaneous injections of cocaine hydrochloride.

Subcutaneous injections of cocaine hydrochloride in sterile physiological saline were administered to rats at a dosage of 20 or 40 mg.kg-1. Resultant skin lesions included focal areas of alopecia (within 1 to 2 days) which progressed to necrosis (within 2 to 7 days). Histologically, the skin lesions were characterized by necrotizing panniculitis and vascular necrosis, with only small numbers of inflammatory cells. The lesions may be ischemic in nature, and associated with cytotoxic properties of cocaine.

Cocaine transiently impairs maternal behavior in the rat.

This paradigm distinguished between two hypotheses not previously directly addressed. Do repeated exposures to cocaine at critical times during pregnancy, when the neural mechanisms that support maternal behavior are being read, alter some fundamental neural underpinning of maternal behavior in rats? Alternatively, does cocaine alter maternal behavior only when circulating? During the 4 hr after cocaine injection (20 or 40 mg/kg), there were significant deficits in maternal behavior. In contrast, 16 hr after cocaine injection, drug-injected females, in which plasma cocaine had fallen to nondetectable levels, showed the normal maternal behavior of saline-injected controls. This pattern of impaired maternal behavior after cocaine injection, followed by normal behavior as blood levels returned to zero, was replicated over 8 days. It was concluded that cocaine impairs maternal behavior only when circulating and does not have a residual effect in the transiently drug-free, chronically drug-treated dam.