L. de Angelis

Comparative evaluation of the central nervous system activity of diazepam and its metabolites (demethyl-diazepam, methyl-oxazepam and oxazepam)

Summary The comparative profile of the central nervous system activities of diazepam and its three major metabolic derivatives (demethyl-diazepam, methyl-oxazepam, oxazepam) has been studied in mice. From the tests used (anti-metrazol and anti-strychnine activities, potentiation of narcosis, spontaneous motor activity evaluation, and muscle relaxant effect) it appears that the demethylation of diazepam causes, in general, an in=creased potency with respect to the parent compound. On the contrary, hydroxylation of diazepam induces an evident loss of activity. Oxazepam, which is the product of two biotransformations (demethylation and hydrox=ylation) results the least potent drug.

Effects of caffeine and chlor-desmethyldiazepam on fighting behavior of mice with different reactivity baselines

The effects of various doses of caffeine and of chlor-desmethyldiazepam on footshock-induced aggressive behavior were examined in mice with different baselines of aggressiveness. Caffeine significantly increased the number of fighting episodes with all the doses tested. This was more evident in mice with low rather than in those with high basal rates of agonistic response. Caffeine caused the appearance of minimal convulsive signs in mice subjected to a threshold electroshock which did not produce any seizure in the controls; it also increased metrazol toxicity. Chlor-desmethyldiazepam enhanced fighting behavior at doses of 0.04 and 0.08 mg/kg, but decreased it at 1.25 mg/kg. The first two doses produced the same effects as caffeine on electroshock test, but did not influence metrazol toxicity.

Absence of anxiolytic effects of calcium channel antagonists

The potential anxiolytic effects of some calcium channel antagonists (nifedipine, nicardipine, and ±verapamil) were investigated in the elevated plus‐maze test in mice. The acute effects of the above‐mentioned drugs were compared with those of phenobarbitone and ±propanolol. Results showed that control mice spent less time in the open than in the closed arms, reflecting increased anxiety. Both phenobarbitone (20 mg/kg i.p.) and ±propanolol (5 mg/kg i.p.) increased the percentage of entries into open arms as well as the time spent on the open arms. Nifedipine (2 and 4 mg/kg i.p.), nicardipine (0.5 and 1.0 mg/kg i.p.), and ±verapamil (5 and 10 mg/kg i.p.) failed to alter significantly the behavior of mice. In summary, although there have been some reports based on other tests that calcium antagonists may have potential anxiolytic properties, this conclusion has not been supported by our results from the elevated plus‐maze test.

Regional Distribution of High Affinity Binding of 3H-Adenosine in Rat Brain

The high and low affinity adenosine binding sites with Kd values ranging respectively from 0.8 to 1.65 microM and from 3.1 to 13.86 microM were demonstrated in the following rat brain areas: cortex, hippocampus, striatum, cerebellum, diencephalon, and pons-medulla. Adenosine receptors involved in the high affinity binding seem to be mainly Ra-type. The analysis of the regional distribution of 3H-Adenosine showed the highest levels of specific binding in striatum and hippocampus; somewhat smaller values in cortex, cerebellum, and diencephalon, and even lower in pons-medulla.

THE NOOTROPIC DRUGS PIRACETAM AND OXIRACETAM DO NOT REDUCE ANXIETY IN MICE DURING ELEVATED-X-MAZE TESTING

Abstract The behavioral effects of two nootropic drugs, piracetam and oxiracetam, were investigated on measures of anxiety in an elevated-x-maze test in mice. In this test, the acute effects of 250, 500, and 1,000 mg/kg intraperitoneal (IP) piracetam and 50, 100, and 200 mg/kg IP oxiracetam were compared with those of an established reference drug, lorazepam (0.025, 0.050, and 0.10 mg/kg IP). The putative anxiolytic effects of ± propranolol, a beta-blocker with 5HT1A and 5HT1B antagonistic properties, were also evaluated. Results showed that both piracetam and oxiracetam had no significant effect on the percentage of entries made onto the open arms or the percentage of time spent in the open arms or the total arm entries. A pronounced anxiolytic effect was evident after treatment with 0.050 and 0.10 mg/kg IP lorazepam or 5 and 10 mg/kg IP ± propranolol. In conclusion, our data show that two nootropic drugs, piracetam and oxiracetam, acutely administered in mice, are devoid of anxiolytic properties in the elevated-x-maze test of anxiety.

Tissue distribution of 14C-heteronium bromide: radioactivity levels at different time intervals after oral administration in the rat.

SummaryThe tissue distribution of radioactivity after oral administration to rats of 14C-heteronium bromide is measured by liquid scintillation counting and the results expressed as specific activity and percentage of administered radioactivity. From the data obtained in blood, liver, kidney, stomach, duodenum, cecum, large intestine and stool some conclusions can be drawn. Heteronium bromide undergoes a rapid systemic absorption, the radioactivity being present as early as 15 min from the administration, in all the tested organs. The blood levels show two peaks: one at 120 min and a second at 360 min. This diphasic behaviour can be explained either by the presence of an active enterohepatic circulation, as indirectly indicated by the data from liver and duodenum, or by a transient shift of the molecule from blood to other tissues, rich in polysulfuronic acids. The principal route of excretion is represented by the kidney, where consistent levels are reached at 120 min, while the intestinal route becomes evident at 240 min and reaches its maximum at 720 min. The complete metabolic cycle of the compound is long lasting, since in all the tested tissues, marked radioactivity levels are still present after 720 min. The pharmacokinetic profile obtained, suggesting a long persistence of the drug and/or of its metabolites in the organism, is in agreement with previous pharmacodynamic data showing a long lasting action for heteronium bromide.