Evaluation of analgesic agents in recurring headache compared with other clinical pain models.

The efficacy of three preparations (placebo, analgesic agent, and analgesic plus antihistaminic agent) were compared in a double-blind crossover study in subjects with recurring headaches. It was confirmed that headache as a pain model does not show the usual return of pain with as the effects of a single analgesic dose wear off. Consequently, there is no "peak effect," and the rationale for comparing treatments by "area under the curve" calculations is weakened. Greater efficacy was demonstrated for the analgesic over the placebo and for the analgesic and antihistaminic combined over the analgesic alone in several parameters. Slopes of straight lines derived as a quadratic function of pain versus time data proved to be a more effective discriminator between treatments than area under the curve calculations from the same data.

Residual effects of chronic cannabis treatment on behavior in mature rats.

Mature rats (starting weight at least 270 g) were treated daily with cannabis extract (daily THC dose 20 mg/kg) for 3 months. After a 1- to 4-month drug-free period, residual effects on a variety of behaviors were studied. No residual effects were found in learning of an eight-arm radial maze task, nor on a differential reinforcement of low-rate responding (DRL-20) task, nor on open field activity. On the other hand, two-way shuttle box avoidance learning was facilitated by previous cannabis treatment, since cannabis-treated rats exhibited shorter mean latencies to avoid footshock than vehicle controls. The findings indicate greater vulnerability of immature organisms (previous studies) than mature organisms (the present study) to long-term effects of chronic cannabis administration.

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats.

Chronic oral administration of cannabis extract to rats (daily delta 9-tetrahydrocannabinol dose 20 mg/kg) was examined for its residual effect on open field activity and DRL (differential reinforcement of low-rat responding) performance, following a 2-3 month drug-free period. Locomotor activity during the latter part of an open field test was markedly increased in rats previously treated for either 6 months or 3 months with the drug. The same treatments also produced a significant impairment on a DRL-20 task relative to control subjects' performance. These and other findings (impaired maze learning and facilitated two-way shuttle box avoidance) might mean that cannabis produces long-lasting hippocampal dysfunction in rats.

Learning impairment in the radial-arm maze following prolonged cannabis treatment in rats.

Chronic oral administration of cannabis extract to rats (daily delta 9-tetrahydrocannabinol dose 20 mg/kg) was examined in three experiments for its residual effect on radial-arm maze learning following a 1-month drug-free period. Learning a simple eight-arm maze was significantly impaired in rats treated for either 6 months (Experiment I) or 3 months (Experiment II) with the drug. In Experiment III, animals that received the extract for 3 months exhibited significant learning deficits on a much more difficult 12-arm radial maze. The results demonstrate that the deleterious effects of cannabis on radial-arm maze learning are probably due to a tendency toward increased vigilance and perseveration, possibly combined with an impaired utilization of spatial cues.

Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat.

Rats treated chronically with delta 9-tetrahydrocannabinol (THC, daily oral dose 20 mg/kg) were examined for residual effects on a variety of behaviors following a 1-4-month drug-free period. Learning a 12-arm radial maze and a differential reinforcement of low-rate responding (DRL-20) task was significantly retarded in THC-treated animals, although performance reached control levels by the end of testing. Learning two-way shuttle box avoidance was slightly facilitated in the drug-treated subjects. In open field tests THC-treated rats displayed an initial hypoactivity, followed by hyperactivity, but these changes were not significant. Most of the effects of THC resemble, but are weaker than those of chronic treatment with cannabis extract in a dose containing the same amount of THC. The findings are discussed in terms of the role of other constituents of cannabis that may add to, or potentiate the effects of THC itself.

Residual effects of prolonged cannabis treatment on shuttle-box avoidance in the rat.

Chronic oral administration of cannabis extract to rats was examined for its residual effects on shuttle-box avoidance learning. In experiment 1 avoidance learning was assessed in rats that had been tested previously on other behavioral tests. Chronic treatment (3 months) facilitated the learning of shuttle-box avoidance in cannabis-treated animals relative to vehicle controls. In experiment 2 very similar results were obtained in naive rats. These and other residual effects of chronic cannabis treatment are similar to the effects of hippocampal lesions.

Effects of lesions of various medial forebrain bundle components on lateral hypothalamic self-stimulation.

Unilateral lesions of various medial forebrain bundle components were assessed for their effects on lateral hypothalamic self-stimulation. Damage of areas containig nigrostriatal dopaminergic or ascending noradrenergic neurons had negligible effects on bar pressing, tail moving and alley running for hypothalamic stimulation. Lesions which appeared to destroy most or all of the catecholaminergic fibers in the posterior medial forebrain bundle virtually eliminated reinforced bar pressing and tail moving, but only partially suppressed alley running. The results suggest that brain stimulation reinforcement of the bar press and tail movement tasks depends upon the integrity of neural tissue in the area of the catecholaminergic pathways of the medial forebrain bundle, but not upon specific dopaminergic or noradrenergic systems. The data further suggest that the reinforcement of alley running is at least partially mediated by different neural tissue (possibly non-catecholaminergic) at the level of the posterior medial forebrain bundle lesions.

Bismuth-based triple therapy with bismuth subcitrate, metronidazole and tetracycline in the eradication of Helicobacter pylori: a randomized, placebo controlled, double-blind study.

OBJECTIVE: To determine the rate of Helicobacter pylori eradication following bismuth-based triple therapy with colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole. PATIENTS AND METHODS: One hundred and eleven patients were randomly assigned, in a two to one ratio, to colloidal bismuth subcitrate 120 mg qid plus metronidazole 250 mg qid plus tetracycline 500 mg qid (Gastrostat), or matching placebo tablets and capsules for 14 days. Presence or absence of H pylori was documented by histology at entry and at least 28 days after treatment. Patients had dyspeptic symptoms with or without a history of peptic ulcer. Patients with any previous attempt(s) at eradication of H pylori, who used bismuth, antibiotics, H2 receptor antagonists or proton pump inhibitors in the previous four weeks were excluded. RESULTS: Fifty-three of 59 (90%) patients on bismuth-based treatment and only one of 35 (3%) on placebo achieved eradication by per protocol analysis. Fifty-three of 65 (82%) patients on bismuth-based treatment achieved eradication, while only two of 34 (5%) achieved eradication on placebo by intention to treat analysis. Eradication rates for bismuth-based treatment across sites ranged from 83% to 100%. Only two patients in the bismuth-based treatment group (4%) and one in the placebo group (3%) discontinued treatment because of adverse events. CONCLUSIONS: Colloidal bismuth subcitrate plus metronidazole plus tetracycline, given in the doses studied for 14 days, is safe and highly effective against H pylori infection and would be appropriate as a first-line therapy for eradication.

Increase in ethanol consumption in rats due to caloric deficit.

Naive food-restricted and food-satiated rats were given a choice between ethanol (8%, 16%, or 32%) and water for 22 hours/day over 14 days. On all days and at all concentrations, intakes of ethanol were significantly higher in the food-restricted animals. Doses consumed by these animals were highest when 32% ethanol was used, with a mean daily intake of 6.83 g/kg. Preference scores, calculated as the percent of total fluid intake as ethanol, were also much higher in the food-restricted animals. These findings demonstrate that the caloric value of ethanol may be an important factor in ethanol self-administration, but they do not rule out the possible importance of pharmacological effects.