Effects of chronic treatment with atypical neuroleptics on the biosynthesis and release of opioid peptides in guinea-pig ileum.

The guinea-pig ileum myenteric plexus is known to contain opioid peptides, which can be released by electric stimulation at high frequency. Haloperidol, a classic neuroleptic drug, increases the biosynthesis and release of endogenous opioid peptides from the myenteric plexus. In the present work we have examined the effects of chronic treatment with sulpiride and clozapine, two atypical neuroleptics, on the release of these peptides in the myenteric plexus of guinea-pig ileum. Both neuroleptics, administered over a period of 7 days, produced an increase of the inhibitory response obtained by electrical stimulation at 10 Hz of the ileum myenteric plexus-longitudinal muscle preparation. The inhibitory response was reversed by the specific opioid antagonist naloxone, which suggest that the increase in the inhibitory response produced by blocking the dopaminergic receptors is mediated by an increase in the release of opioid peptides. When sulpiride- or clozapine-treated guinea-pigs received cycloheximide (an inhibitor of peptide biosynthesis) there was a significant decrease of the inhibitory response, which indicates that neuroleptics produced an increase of the synthesis of opioid peptides in the ileum myenteric plexus. These results reveal a possible influence of the dopaminergic system on the biological turnover of these peptides.

Mechanism of action of B-HT 933 (azepexole) in rat vas deferens and guinea-pig ileum.

The mechanism of action of B-HT 933 (azepexole) was studied on the rat vas deferens and myenteric plexus-longitudinal muscle (MP-LM) of the guinea-pig ileum. The drug caused a concentration-dependent inhibition of the twitch response in both preparations. The maximal inhibition in both preparations was 80-90%. B-HT 933 did not affect the cumulative dose-response curves of the vas deferens and of MP-LM to noradrenaline (NA) and acetylcholine (Ach) respectively. Yohimbine antagonized in a competitive way the twitch inhibitory effect of B-HT 933 on vas deferens and on MP-LM; the pA2 values were 8.62 and 8.5, respectively. The twitch inhibitory effects of B-HT 933 were not antagonized by propranolol. The results suggest that the action of B-HT 933 is mediated by stimulation of presynaptic alpha 2-receptors.

Fever, antipyretics and serum iron levels in rabbits.

The intracerebroventricular (i.c.v.) injection of bacterial endotoxin (Shigella dysenteriae) produces a rise in deep-body temperature in rabbits. The increase in body temperature was partially inhibited by polymyxin B (P), and completely suppressed by ketoprofen (K). The systemic injection of bacterial endotoxins (Shigella dysenteriae or Salmonella typhosa) elicited an elevation of body temperature in rabbits which was partially blocked by polymyxin B and completely antagonized by ketoprofen. Serum iron concentration fell in rabbits treated with Salmonella typhosa endotoxin and rose after injections of ketoprofen, polymyxin B, indomethacin and ketoprofen plus endotoxin (En). However, the total increases in serum iron levels were higher after antipyretics than after ketoprofen plus endotoxin treatment. These results show that the antipyretics antagonized the rise in body temperature and the fall in serum iron concentration induced by bacterial endotoxin and all the drugs used in this study to induce antipyresis increased serum iron levels.

ICV administration of CRF blocker (CRF9-41 delta helical) reduces morphine withdrawal in rats.

1. The effects of CRF9-41 delta helical on morphine withdrawal signs in rats were studied. 2. Intracerebroventricular administration of CRF9-41 delta helical 5 at 10 micrograms/kg reduced central and peripheral symptoms of the withdrawal syndrome, such as ptosis, jumping, wet dog shakes and teeth chattering; other signs remained unchanged. The effect were not dose dependent. 3. The hypothermi characteristic of the Withdrawal syndrome was reduced by CRF9-41 delta helical. 4. These results suggest that the hypothalamo pituitary adrenal(HPA) axis play an important role in the morphine withdrawal syndrome in rats.

Quantitative study on the uterus-inhibiting activity of sodium naproxen in rat isolated uterus.

Action of Sodium Naproxen on spontaneous and field stimulated motility of isolated rat uterus was studied. Sodium Naproxen inhibited both spontaneous and field stimulated motility. The IC50 on spontaneous motility was lower than the IC50 on stimulated motility. The inhibition produced on the field stimulated uterus was more regular in relationship to concentration used of Sodium Naproxen. The IC50 of Sodium Naproxen in these experimental conditions was 8.22 X 10(-4) M (pD2 = 3.09 +/- 0.02) and the maximum inhibitory effect was 100%. These results show that prostaglandin synthesis plays a necessary role in uterine contraction, spontaneous or induced by field stimulus.

[Speed of intubation using a new neuromuscular blocker. Rocuronium bromide (ORG 9426)]. / Rapidez de intubación de un nuevo bloqueador neuromuscular. Bromuro de rocuronio (ORG 9426).

OBJECTIVES: To compare intubation conditions and neuromuscular parameters, patency time, maximum level of block, time and clinical duration of effect for rocuronium bromide 0.6 mg/kg (ORG 9426) versus equally potent doses of vecuronium and atracurium under similar experimental conditions. PATIENTS AND METHODS: Sixty patients were divided into three groups of twenty. Intubation conditions were scored on a scale of 3-12 points based on relaxation of the vocal cords, presence of cough and ease of laryngoscopy after 60 or 90 sec. Neuromuscular parameters were obtained by integrated electromyography of the thenar and hypothenar muscle structure, evoked by supramaximal stimuli of the cubital nerve in train of four (2 Hz in 2 sec). The shape of the electrocardiographic curve, heart rate and mean arterial pressure measured non-invasively were recorded throughout the surgical procedure. RESULTS: Means of onset times and times of effect for rocuronium (33 and 135 sec) were significantly lower than those obtained with vecuronium and atracurium. Clinical duration, free of hemodynamic changes, was similar in the three groups. Rocuronium produces excellent intubation conditions 60 sec after administration, although at this point peripheral muscle block was only partial. Rocuronium may be superior to other neuromuscular blockers available today as a result of the speed with which it affords excellent intubation conditions.

The beta-agonist drug tulobuterol decreases cardiac automaticity in the rat: comparison with isoproterenol.

The effect of the new beta-agonist drug tulobuterol, has been compared with isoproterenol in an experimental model of ectopic cardiac automaticity induced by local injury in the isolated right ventricle of the rat. Isoproterenol significantly increases ventricular automaticity even with the lowest concentrations tested (10(-9)M). Tulobuterol, at concentrations ranging from 10(-9)M to 10(-6)M do not induce any change on the automatic ventricular frequency. Nevertheless, at higher concentrations (10(-5) and 5 X 10(-5)M), tulobuterol decreases the experimentally induced ventricular automaticity. Our results suggest that the new beta-agonist drug tulobuterol does not increase ventricular automaticity but, in fact, decreases it.

[Difficulties of animal experiments in psychopharmacology. Punctual aspects of antidepressants]. / Dificultades que plantea la experimentación animal en psicofarmacología. Aspectos puntuales de los antidepresivos.

Animal psychopharmacological experimentation encounters great difficulty due to the lack of animal models for reproducing mental illness. This results from the greatly complex fashion of CNS, the lack of knowledge of biochemical and/or anatomical substrates of psychiatric pathology, and the difficulty in placing some CNS functions, such as memory and vice versa. The application of selective neurotoxins capable of specifically destroying a neuronal nucleus allows to advance in the knowledge of the CNS functions. Some easy experimental methods allow a quick investigation of certain pharmacological effects on CNS, though they have to be completed with more complex models. It is difficult to investigate the possible antidepressant effect because it is related to different mechanisms of action, it has an onset delay, and some trials which are positive to some drug with no antidepressant effect. In turn they have no right answer to other drugs with confirmed clinical efficacy. The forced swimming pool test that appears to be the most convenient for researching the possible antidepressant effect has been studied, although it should be completed with a spontaneous motility test.

Tulobuterol: a full beta-adrenoceptor agonist or a partial beta-agonist with membrane stabilizing activity?

1. The effects of tulobuterol on the atrial rate was compared with those of isoproterenol, pindolol and propranolol in spontaneously beating isolated right atria of the rat. 2. Isoproterenol markedly increased atrial rate. To the contrary, propranolol, pindolol and tulobuterol decreased atrial frequency. The chronotropic effect of tulobuterol was similar to that of pindolol but lower than that of propranolol. 3. Interactions between tulobuterol and isoproterenol showed that tulobuterol potentiated the chronotropic effect of low concentrations of isoproterenol but reduced the positive chronotropic response to higher concentrations of isoproterenol. 4. These results suggest that tulobuterol is a partial agonist on atrial beta-receptor but also seems to have another action (possibly a membrane stabilizing activity) which reduced the originally induced effect on beta-receptors as a non-competitive antagonist.

Pharmacokinetics and pharmacodynamics of rocuronium bromide in adult patients.

In seven patients (M/F: 4:3) rocuronium 0.6 mg kg-1 was given after the induction of anaesthesia with propofol, and during maintenance with N2O/O2, halothane 0.5% and alfentanil 60-90 micrograms kg-1 h-1. Intubation conditions were scored at 60 s and lag time, onset time, maximal block achieved, recovery to 25% of T1, and Recovery Index, were measured using a Relaxograph. Blood samples were taken over a 300 min period and analysed for rocuronium. Intubating conditions at 60 s were excellent in all patients. Mean clearance was 5.2 ml kg-1 min-1, the terminal half-life was 69 min and distribution volume at steady state was 0.22 litre kg-1. Cumulative urinary excretion was around 18% within 24 h.

[Pharmacological reactivity in cricetus aureus uterus (author's transl)]. / Reactividad farmacológica del útero de hamster

The motility of the isolated Cricetus auratus uterus was studied and compared to that of other species. Oxitocyn, epinephrine, norepinephrine, histamine, 5-hydroxy-tryptamine and acetylcholine were used as spasmogen agents. There was not contractil response with epinephrine or nor-epinephrine. Histamine reduced basal tonus. There was contraction with acetylcholine, oxytocin and 5-hydroxy-tryptamine. Cricetus auratus uterus appeared more sensitive when the contraction was registered by the isometric method. No taquifilaxy was produced by 5-hydroxy-tryptamine, as opposed to such effect in rat uterus. The Cricetus auratus uterus has, therefore, shown similar reactivity to that of rat, but different from rabbit and guinea-pig.