Hypoxic ventilatory response after rocuronium-induced partial neuromuscular blockade in men with obstructive sleep apnoea.

Obstructive sleep apnoea and residual neuromuscular blockade are, independently, known to be risk factors for respiratory complications after major surgery. Residual effects of neuromuscular blocking agents are known to reduce the hypoxic ventilatory response in healthy volunteers. Patients with obstructive sleep apnoea have impaired control of breathing, but it is not known to what extent neuromuscular blocking agents interfere with the regulation of breathing in such patients. In a physiological study in 10 unsedated men with untreated obstructive sleep apnoea, we wished to examine if partial neuromuscular blockade had an effect on hypoxic ventilatory response (isocapnic hypoxia to oxygen saturation of 80%) and hypercapnic ventilatory response (normoxic inspired carbon dioxide 5%). The hypoxic ventilatory response was reduced by 32% (p = 0.016) during residual neuromuscular block (rocuronium to train-of-four ratio 0.7), but the hypercapnic ventilatory response was unaffected. We conclude that neuromuscular blockade specifically depresses peripheral chemosensitivity, and not respiratory muscle function since the hypercapnic ventilatory response was unaffected.

Separation distress call in the human neonate in the absence of maternal body contact.

Few studies have used the baby's cry as a means of evaluating the quality of neonatal care. In this randomized trial the newborn's cry was registered during the first 90 min after birth when infants were cared for either: (a) skin-to-skin with the mother; (b) in a cot; or (c) in a cot for the first 45 min of the 90-min observation period and then skin-to-skin with the mother. The results suggested that human infants recognize physical separation from their mothers and start to cry in pulses. Crying stops at reunion. The observed postnatal cry may be a human counterpart to the "separation distress call" which is a general phenomenon among several mammalian species, and serves to restore proximity to the mother. Our results suggest that in human newborns this cry is not dependent on earlier social experience and may be a genetically encoded reaction to separation. The findings are compatible with the opinion that the most appropriate position of the healthy full-term newborn baby after birth is in close body contact with the mother.

In the search for a novel class of antipsychotic drugs: preclinical pharmacology of FG5803, a 1-piperazinecarboxamide derivative.

Comparative studies of the 1-piperazinecarboxamide derivative 4-[3-(4-fluorobenzoyl)propyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride (FG5803) were made with clozapine and haloperidol. Receptor studies revealed that FG5803 potently and selectively bound to the serotonin type 2A receptors (Ki = 13 nM). FG5803 inhibited 5-hydroxytrophan- and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head twitches, which indicated potent in vivo serotonin type 2A receptor antagonism. FG5803 caused an acute activation of the tuberoinfundibular dopamine neurons and produced only a transient rise in plasma prolactin. In behavioral studies in rats, FG5803 showed strong antagonistic action on presynaptic dopaminergic autoreceptors but only weak postsynaptic dopamine D2 blockade. FG5803 was not cataleptogenic and did not antagonize amphetamine-induced stereotypies. FG5803 was active in the reduction of aggressive behavior and spontaneous exploratory behavior in mice and rats. Therefore, FG5803 is expected to constitute a promising approach in the search for a novel class of antipsychotic drugs that have a broader spectrum of activity and fewer adverse effects than the conventional, antidopaminergic antipsychotics.

Effects of amperozide in schizophrenia. An open study of a potent 5-HT2 receptor antagonist.

Ten male inpatients (aged 29 +/- 6 years) with a DSM-III diagnosis of schizophrenia participated in a 4-week open dose escalation study of amperozide, a novel 5-HT2 receptor antagonist. The maximum daily dose of amperozide was 20 mg. A close dose-plasma concentration relationship showed considerable interindividual variation in the steady-state plasma levels at a given dose. Approximately equal concentrations of amperozide and its metabolite, N-deethylated amperozide, were seen in plasma. The prolactin levels were not increased during amperozide treatment. No changes occurred in hematological or other laboratory parameters. ECG showed changes in T-wave morphology and a prolongation of the QTc time. One patient was withdrawn from the trial due to aggravation of psychotic symptoms, and two patients had a brief, temporary discontinuation of the drug due to somatic illness. Six patients were improved during amperozide treatment, as assessed by the Clinical Global Improvement Scale. Among the responders the total CPRS was reduced by a mean of 64% and total BPRS score by a mean of 46%. Mild tremor was a frequent side effect, but other extrapyramidal symptoms were rare. Nausea was seen in six patients and of a more pronounced character in one patient. In general, the severity of the side effects increased with increasing doses of amperozide.

Amperozide and emotional behaviour.

The new putatively antipsychotic drug amperozide is characterized pharmacologically by a specific limbic mode of action. Thus amperozide is a potent antagonist of muricidal behaviour (ED50 = 0.16 mg/kg) as well as aggression between isolated male mice. Although amperozide displays anxiolytic properties in Vogel's conflict test as well as an antidepressive effect in the despair test, the drug does not interfere with motor coordination or cause sedation (ED50 greater than 50 mg/kg). These results could make amperozide very interesting as an antipsychotic drug in the clinic, with effect on both positive and negative symptoms.

The effect of amperozide on uptake and release of [3H]-dopamine in vitro from perfused rat striatal and limbic brain areas.

Amperozide, a putatively antipsychotic drug, was studied for its effects on uptake and release of [3H]-dopamine in rat brain in vitro. Amperozide inhibited uptake of [3H]-dopamine in striatal chopped tissue in vitro with an IC50 of 18 microM. It also increased basal release of [3H]-dopamine from perfused rat striatal and limbic tissue in vitro at concentrations above 5 microM. Release of [3H]-dopamine from perfused rat striatal and limbic tissue stimulated with 5 microM amphetamine, was inhibited by 1 microM amperozide to 46%. No significant difference was found for the effect of amperozide on in vitro release of [3H]-dopamine from corpus striatum compared to tissue from limbic brain regions; neither on basal release nor an amphetamine-stimulated release of dopamine.

Effects of amperozide on induced turning behaviour in 6-OHDA lesioned rats.

The effect of amperozide on DA synapses was studied in 6-OHDA lesioned rats exhibiting a specific turning behaviour in response to the DA agonists apomorphine and pergolide or indirectly acting stimulating agents like amphetamine. Amperozide, unlike classical neuroleptics, failed to antagonize apomorphine induced turning behaviour in a regular fashion, but showed pergolide antagonism within the D2 receptor selective dose range, suggesting a type of selective interference with dopaminergic nerve transmission which differs from that caused by classical neuroleptics. Furthermore, amperozide antagonized the turning behaviour induced by amphetamine, presumably by interfering with the availability of newly synthesized DA and NA suggesting a similar influence also on other DA releasing agents. Although amperozide potentiated the effects of alpha-MPT, the drug seemed not to influence the reserpine sensitive pool of DA.

Amperozide--a new putatively antipsychotic drug with a limbic mode of action on dopamine mediated behaviour.

Amperozide, a new putatively antipsychotic drug, was found to exert a functional selectivity for the limbic system of the brain. Thus, amperozide was as active as both classical and atypical neuroleptics on hypermotility induced by a low dose of amphetamine. On the other hand, amperozide did not produce catalepsy, nor did it reverse amphetamine-induced stereotypies. Moreover, amperozide inhibited exploratory behaviour in mice. The present results indicate an antipsychotic effect of amperozide, with a minimal risk for EPS when used in the clinic.

Amperozide and conditioned behaviour in rats: potentiation by classical neuroleptics and alpha-methylparatyrosine.

Amperozide, a new putatively antipsychotic compound, has been evaluated for its effect on conditioned avoidance response and food-reinforced lever-pressing. Given alone, amperozide was almost equipotent to clozapine, but less potent than haloperidol in both test models. It was found that there was a statistically significant synergism, in these two models, between amperozide and classical neuroleptics. Since amperozide is inactive in behavioural tests reflecting striatal dopaminergic mechanisms, the synergistic effect could be of great therapeutic value in the treatment of psychotic disorders.

Pharmacological data of the atypical neuroleptic compound melperone (Buronil).

Based on the non-cataleptic properties, the weak affinity for D2 receptors and the inability to induce DA receptor supersensitivity after both acute and repeated administration, melperone may be characterized as an atypical neuroleptic drug. This indicates a weak effect of melperone on striatal DA neurotransmission. On the other hand melperone is potent in blocking amphetamine induced locomotion, exploratory behaviour, L-Dopa induced jumping and aggression suggesting a limbic mode of action. The effect on limbic DA neurotransmission together with an antiadrenergic and 5-HT modulating action may explain the antipsychotic effect and the low incidence of extrapyramidal side effects observed during treatment with melperone.

Effects of amperozide on biting behavior and performance in restricted-fed pigs following regrouping.

Eight experiments were conducted to determine the effect of a single administration of amperozide on agonistic behavior and growth performance in newly mixed, restricted-fed pigs. Two hundred 12-wk-old pigs were used in a 4-wk trial (Exp. 1) to investigate the effect of amperozide on agonistic behavior and performance. The pigs were assigned to each pen on the basis of body weight and sex, ensuring that pigs in each pen were unacquainted. Each pig was weighed individually on d 3, 7 and 28. Agonistic behavior was quantified by counting bite and slash marks on each pig at 8, 26 and 48 h after penning. An i.m. injection of amperozide immediately before mixing the pigs reduced the physical damage (P less than .001) at each time point. There was no evidence of amperozide causing either sedation or motor disturbances. On the average, amperozide treatment improved (P less than .001) daily gain in the 4-wk study period by 70 g (17%). In Exp. 2 to 8, 1,648 pigs growing from approximately 20 to 100 kg body weight were used to determine the effect of amperozide on weight gain. Pigs were penned in groups of 9 to 11, randomly assigned to each pen on the basis of sex. Each pig was weighed individually after penning, on d 35 and at slaughter. Untreated control pigs had a poorer growth performance than did amperozide-treated pigs. During the first 5 wk postpenning average daily gain was improved (P less than .001) by 90 g (26%) in pigs receiving a single oral administration of amperozide at penning.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic effect of amperozide, a novel psychotropic compound with class III antiarrhythmic properties, on digoxin-induced arrhythmias in the guinea-pig.

Amperozide is a novel psychotropic compound with specific effect in limbic brain areas. Preliminary findings have also indicated an antiarrhythmic effect in-vitro. Injections of saline, amperozide, melperone, thioridazine, bretylium or lignocaine, were given i.p. to anaesthetized guinea-pigs, which 10 min later were given digoxin s.c. to induce arrhythmia. In a series of control experiments none of these compounds caused arrhythmia in combination with the vehicle of digoxin. The time to arrhythmia was significantly prolonged after treatment with amperozide, melperone and bretylium compared with saline, but there were no differences between the treatments. The digoxin concentrations in plasma at death varied considerably within the groups and no statistical significance was found.

Behavioral aspects of serotonin-dopamine interaction in the monkey.

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.

Methylphenidate, apomorphine, THIP, and diazepam in monkeys: dopamine-GABA behavior related to psychoses and tardive dyskinesia.

In eight monkeys (Cercopithecus aethiops), previously treated with haloperidol for 4-14 months, we have examined the behavioral effect of: (1) methylphenidate vs apomorphine; (2) 4,5,6,7-tetrahydroisoxazolo-(5,4-c)-pyridin-3-ol(THIP, a GABA agonist) vs diazepam; and (3) THIP and diazepam in methylphenidate-induced behavior. Methylphenidate (0.5-5.0 mg/kg) and apomorphine (0.1-0.5 mg/kg) both increased locomotion, but otherwise exhibited different behavioral profiles. Methylphenidate induced repetitive movements of head, limbs, and trunk, and hallucinatory-like behavior, but not oral hyperkinesia (licking and gnawing), whereas apomorphine preferentially caused oral hyperkinesia. THIP produced a syndrome of bradykinesia, dystonia, ataxia, myoclonus, sedation, and decreased responsiveness, whereas diazepam produced only bradykinesia, ataxia, sedation, and decreased responsiveness, but not dystonia and myoclonus. Methylphenidate-induced locomotion and repetitive movements were reduced by THIP and diazepam, whereas hallucinatory-like behavior was markedly aggravated by THIP, but not by diazepam.

Dopamine, acetylcholine, and GABA effects in acute dystonia in primates.

Neurological side effects associated with neuroleptic drugs result from a complex interaction of multiple neurotransmitters. To clarify the etiology of neuroleptic-induced acute dystonic reactions, monkeys (Cercopithecus aethiops) were treated with haloperidol at doses sufficient to evoke dystonia, and the effects of agents that influenced dopaminergic, cholinergic, or GABAergic neurotransmitters were evaluated. Apomorphine, a dopamine (DA) agonist, and biperiden, an acetylcholine (ACh) antagonist, decreased acute dystonia, whereas alpha-methyl-p-tyrosine (AMPT), an inhibitor of DA synthesis, and physostigmine, an ACh agonist, agonist, increased the symptoms. Muscimol, a GABA agonist, increased the dystonias in a dose-dependent way, and GABA inhibition with picrotoxin also aggravated dystonia, complicated by systemic intoxication and seizures. The reciprocal interaction between DA and ACh influences is consistent with clinical findings and animal models of dyskinesias. Dystonia may also be modulated by GABAergic substrates, but the results suggest complex interactions among DA, ACh, and GABA neurotransmission. Symptoms involving the orofacial, limb, and trunk regions, and purposeless overactivity are discussed in comparison with acute and tardive neuroleptic-induced movement disorders.

A double-blind study of melperone and placebo in hospitalized chronic alcoholics in postintoxication phase.

In a double-blind study in chronic alcoholics melperone (Buronil) was shown to significantly improve muscular and nervous tension, emotional lability, somatization, ability to sleep, anxiety, depression, paranoid ideation and presumed ability to work, but had no effect on alcoholic craving. The results received from three rating scales, and the theoretical aspects of alcoholism are discussed.

Increase in the amount of nuclear RNA in liver of ascites tumour-bearing mice.

The effect of tumour growth on the liver of the host was studied in the Ehrlich ascites tumour system. During the experimental period there was no infiltration of tumour cells in the liver, and the increase in the proliferation rate of Kupffer cells and parenchymal cells was only small. An increasing stability of the liver cell nuclei towards disruption during the isolation procedure was found to accompany the ascites tumour growth. In parallel, there was an increase in the amount of nuclear RNA and in the cellular speridine concentration. The major cause of these changes is probably an increasing demand on the liver by the growing tumour, illustrated by the fact that an amount of protein exceeding that of the whole liver accumulates in the ascites fluid during tumour growth. A hypothesis according to which the cellular accumulation of spermidine may be involved in the stabilization of cell nuclei and in the accumulation of nuclear RNA is advanced.