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[A comparison of the efficacy of aminophylline and doxapram in preventing idiopathic apnea in preterm newborn infants].

Doxapram is an analeptic of the respiratory system that has been used in the last few years for the treatment of idiopathic apnea spells in infants who show resistance to methylxantine. In this study we have compared the efficacy of aminophylline and doxapram for the prevention of idiopathic apnea spells in two groups of preterm infants comparable for gestational age, birthweight and postnatal age. The two drugs resulted to be effective in preventing the spells of apnea in 66% and 60% of the cases respectively. In the cases in which there was a partial or negative response, the association of the two substances resulted in a noticeable reduction of the apnea spells. The positive effect of the association of aminophylline and doxapram is probably due to the different action mechanism on the stimulation of the respiratory system.

Aminophylline↗

[Evaluation of the efficacy and tolerability of protirelin. Results of a multicenter study in Italy].

Controlled clinical trials demonstrated protireline tartrate (TRH-T) efficacy, with its analeptic, analgesic and arousing effects, in the treatment of neurological and functional impairment due to cerebrovascular accidents and head injuries. While the efficacy profile has been extensively studied, there isn't yet a completely satisfactory evaluation on TRH-T tolerability profile. We decided to perform, in Italy, a phase IV clinical trial on the efficacy-safety ratio of TRH-T, involving more than 170 centers spread in the whole country. The trial was an open study, with no control group, enrolling 2359 patients (M = 1405; F = 930; n.d. = 24), most aged between 50 and 80 years. About 52% of them had stroke sequelae, about 15% head injury, 11% a TIA and another 11% cerebral hemorrhage. The patients received TRH-T (4 mg/die) for a cycle of 14 days, by either intramuscular or intravenous routes (slow infusion). Drug efficacy was declared good in about 45% and excellent in about 18% of the patients with stroke. Two hundred twenty eight adverse events were found in 153 patients (M = 92; F = 61), namely with an incidence of 6.49%; they were more frequently detected in elderly patients and in those affected by cerebral hemorrhage or TIA. The most frequent adverse events concerned mucocutaneous, gastrointestinal, cardiovascular and central nervous systems; they were mostly considered light or moderate, and only one third of them required suspension of treatment. Drug-event causal relationship was judged, referring to the "Lasagna algorithm", as definite in 23.7% of the adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

[Sleep disturbances in multi-infarction dementia and trials of treatment with caffeine].

Atherosclerotic cerebrovascular lesions leading to repeated ischaemic strokes produce a wealth of clinical symptoms and signs with dementia. Sleep disturbances are frequent and take the form of difficult falling asleep and shifting of the sleep/waking rhythm to late night and morning hours. Hypnotic drugs produce often a paradoxical effect with complete reversal of the circadian sleep rhythm. These observations gave the inspiration to a trial of reversed treatment: with administration of analeptics in the evening and sedative drugs during the day. Sixteen patients with this dementia and pronounced disability were treated by this method. Before the treatment they spent most time in bed, their age was 51-81 years, 9 were males and 7 females. In 10 cases a significant improvement was obtained with shifting of the sleep rhythm by 4 hours on average towards normal rhythm. Further studies would be necessary for explaining this effect.

Aged↗

[Simultaneous coronary and carotid surgery: apropos of 73 cases].

A series of 73 simultaneous carotid and coronary revascularizations (Group I) is presented (January 1980-December 1988). Age, sex, risk factors, severity of angina, coronarography, neurological symptoms, angiographic carotid lesions and operative outcome of these 73 patients are compared with the aspects of 3544 coronary bypass patients (Group II) and 1001 carotid endarterectomized patients (Group III) during the same period. The angina in Group I is more severe, with 22% belonging to NYHA class IV and 26% having a stenosis of the left main coronary artery, vs 14% and 13% in Group II. Seventy percent of the carotid lesions in Group I are asymptomatic vs 33% in Group III. Group I patients had more problems in the perioperative period, with 16.4% needing prolonged high-doses analeptics and 5.4% intraaortic counterpulsation balloon. Operative mortality is higher (7%) in Group I compared with Group II (2.3%) and Group III (1.7%). These results permit to define a population of polyvascular patients with concomitant coronary and carotid disease, characterized by a more diffuse atherosclerosis and a higher operative risk. Operative morbidity and mortality after combined myocardial and cerebral revascularization remains nevertheless inferior to the cumulated surgical risk of the sequential procedures (74 patients with coexistant coronary and carotid lesions operated in two sessions before 1986).

Carotid Artery Diseases↗

[Vasodilating effects of etimizol in vitro and its relation to purinergic receptors].

The paper is concerned with the effect of the breath analeptic agent etimizole on the smooth muscle of vessels under in vitro conditions from the viewpoint of its assumed interaction with purinergic receptors. Isolated preparations of the coronary artery and a. dorsalis pedis of the dog served as experimental material. Etimizole administered in a cumulative manner in dependence on concentration decreases the strength of contraction of the preparations contracted with K+ ions. This relaxant effect, similarly as the effect of adenosine, is not affected by a removal of the endothelium, can be inhibited with theophylline and potentiated with dipyridamole. Etimizole in higher concentrations inhibits the response of vascular preparations to electrical stimulation. In the concentration of 10(-4) mol.l-1 it potentiates the relaxant effect of adenosine, the experimental effects not differing from the theoretical curve for the addition of effects. The obtained results support the assumption that the vasodilating effect of etimizole is mediated prevalently by P1 purinergic receptors.

Adenosine↗

[Pharmacologic control of breathing].

Recent advances in respiratory neuropharmacology and neurophysiology have allowed the assessment of the effects of different drugs on the control of the ventilation both qualitatively (alterations of ventilatory pattern) and quantitatively (size and duration of the ventilatory and haemogasometric alterations). In the control mechanism of ventilation, the pharmacological intervention can act both on the respiratory input (basal metabolism, peripheral chemo-receptors, pulmonary receptors, bulbar neurons, cortical nervous system) and on the respiratory output (respiratory muscles). Based on personal experience in this field and the recent literature, the Authors briefly discuss the seat and the mechanism of action of the drugs with stimulating effect (respiratory analeptics, almitrines, progesterone, acetazolamide, salicylates, protriptyline, theophylline) and depressing effect (narcotics and narcotic-antagonists, anaesthetics, barbiturates and benzodiazepines) on the ventilation, as well as the role of the neurotransmitters and modulators. The clinical (positive and negative) effects of these drugs, particularly related to the patients with chronic lung disease, are also illustrated.

Central Nervous System Stimulants↗

An EEG and behavioural study on the excitatory properties of caffeine in rabbits.

In the present work we have investigated some of the excitatory effects of caffeine in rabbits. Caffeine (5-50 mg/kg i.v.) elicited a cortical EEG desynchronization and an activation of the theta hippocampal rhythm but failed to affect the red nucleus activity. The EEG effects of caffeine were counteracted by L-PIA (1-3 mg/kg i.v.). Caffeine (25-50 mg/kg i.v.) completely reverted the EEG and motor effects due to L-PIA (1-5 mg/kg); the drug also counteracted the cortical and hippocampal EEG modifications elicited by diazepam (1-10 mg/kg), but failed to influence the diazepam-induced effects at the red nucleus level. In addition, caffeine (25 mg/kg) significantly increased the duration of the epileptiform EEG response (afterdischarge) elicited by electrical stimulation of the dorsal hippocampus. This caffeine-potentiating effect was reduced by administration of both L-PIA (0.05-2 mg/kg) and diazepam (1 mg/kg); Ro 15-1788 (1 mg/kg) was unable to affect it. Present data suggest that the analeptic action of caffeine is different from that of the drugs acting through the GABA-benzodiazepine system. Our results show the importance of the limbic system in the excitatory effects of caffeine and suggest that purinergic drugs may have a modulatory role in the control of limbic convulsions.

Animals↗

Construction and reconstruction of memories.

1. Recent evidence suggests that treatments given after training may influence memory in two ways: by becoming themselves incorporated to the experience, or by altering post-training mechanisms involved in the storage of the experience. The two processes may be called consolidation. 2. Some endogenous substances that are normally released during or after training (brain beta-endorphin; the peripheral stress hormones, ACTH, epinephrine and vasopressin) appear to be of particular importance. Their effect may become incorporated to the experiences as a conditioned stimulus (CS), generating state dependency. The effect of beta-endorphin appears to be physiological, since the substance is released by novel experiences. 3. Post-event information provided by other training experiences, in rats, or by comments or leading words, in humans, may also incorporate to the experiences, altering their content qualitatively or quantitatively. 4. A variety of substances including the stress hormones at low doses and analeptic drugs may facilitate retention when given after training. In this case, the effect is best explained by an enhancement of the post-training strengthening of memory traces. 5. The reiteration of part of the experiences at the time of testing facilitates retrieval. This may be viewed as a reconstruction of consolidation at the time of retrieval, and may be obtained using cognitive material ("priming"), or neurohumoral stimuli (a beta-endorphin injection, or a presumable release of brain beta-endorphin by an interpolated novel experience). The effect can be seen in animals rendered amnestic by electroconvulsive shock, and in humans with amnesia of organic and non-organic nature. 6. The human amnesic syndrome seems, thus, largely explainable by a deficit of retrieval. It is possible that the stimulation of retrieval by priming, or by drugs, through the "reconstruction" of consolidation, may be useful for the relief or treatment of the human amnesic syndrome.

Amnesia, Retrograde↗

[Psychotropic drugs and pregnancy].

The multiplicity of psychotropic medications and their widespread prescription, justifies a review of the possible effect of psycholeptics and psycho-analeptics on the fetus in-utero, and on lactation. The authors attempt to differentiate between diverging if not conflicting opinions in most cases. They conclude that it is necessary to prescribe these products only with precise indications and after careful consideration.

Abnormalities, Drug-Induced↗

[Treatment of chronic respiratory insufficiency of pulmonary origin. Clinical considerations].

The key-points of the physiopathological treatment of chronic pneumogenous respiratory insufficiency are: correction of distribution defects, suitable local adjustment of the ventilation: perfusion ratio, and correction of obstacles to alveolocapillary diffusion. Many drugs can be used to obtain these results; bronchodilators, vasoactive drugs, cortisones, cardiokinetics, antibiotics, analeptics. Reference is also made to oxygen therapy, depletion management (bloodletting and-or diuretics, and their possible mechanisms. Lastly, attention is given to disturbances, in acid-base equilibrium in chronic respiratory insufficiency and their correction.

Adrenal Cortex Hormones↗

[A unique psychopharmacologic profile of adrafinil in mice].

The following psychopharmacological effects of adrafinil have been observed in mice: increase in locomotor activity (64-256 mg.kg-1), antagonism (16-128 mg.kg-1) of the hypnotic effects of barbitone but not of pentobarbitone, reduction of immobility duration in the forced swimming test (16-256 mg.kg-1); slight antagonism (256 mg.kg-1) of electroshock-induced convulsions; no modification of rectal temperature; no stereotyped or climbing behaviour; no increase in lethality in aggregated mice (LD50 isolated = 1022 mg.kg-1, LD50 aggregated = 859 mg.kg-1); lack of effects on the provisional tests for antidepressants: no interaction with reserpine-, oxotremorine-, or apomorphine-induced hypothermia but potentiation of yohimbine-induced toxicity; lack of peripheral sympathetic effects (no mydriasis, no salivation, no contraction of the pilomotor muscles, no antagonism of reserpine-induced ptosis); lack of peripheral anticholinergic effects (no mydriasis, no antagonism of oxotremorine-induced salivation or lacrimation). As compared to no analeptic, anticholinergic or antidepressant drugs, adrafinil shows a unique behavioural profile in mice defined on the one hand by a specific stimulant activity associated with antidepressant-like effects that do no seem related to a beta-adrenergic mechanism and on the other hand by a lack of dopaminergic effects. Most adrafinil-induced effects (increase in locomotor activity, reduction of immobility duration in the forced swimming test) may correspond to a central alpha 1-adrenergic stimulation, but the unexpected lack of peripheral sympathetic effects remains unexplained.

Animals↗

[Pharmacological correction of the acute effects of microwave irradiation in an experiment].

Possible ways of correction of acute effects developing in organism under the intensive microwave radiation (AMWE) are considered. The literature review demonstrates that the pharmacological preparations which cause stimulation of the supreme sections of the central nervous system (CNS) and breathing (analeptics, psychostimulants), an elevation of the vascular tone (adrenomimetics), an increase of the heart working capacity (cardiac glycosides) and an increase of energetic metabolism level (some hormones and vitamins) are suitable for the AMWE correction. For the AMWE prevention before radiation the drugs reducing excitability of CNS (sleeping draughts) oppressing the interoceptive reflexes (neuroplegic drugs) and antihypoxiac drugs can be used.

Acute Disease↗

Pharmacokinetics of prethcamide following rapid intravenous injection and oral administration in rabbits.

A simple gas chromatographic method for the quantitative determination of ethyl butamide and propyl butamide, the active constituents of the analeptic drug "Prethcamide", in whole blood and tissues has been developed. The method was used to study the disposition of the compounds after iv and po administration to rabbits. The course of changes of ethyl butamide and propyl butamide concentration following rapid intravenous injection and oral administration was described by the two-compartment and one-compartment open models, respectively. The mean half-life (t1/2 beta, min), the body clearance (Clb, 1/min), the mean absorption rate constant (ka, min1-) and tmax (min) values were, respectively: 43.07 +/- 10.54, 0.05 +/- 0.0125, 0.033 +/- 0.0073 and 30.0 +/- 5.0 for ethyl butamide and 30.0 +/- 4.13, 0.0962 +/- 0.0269, 0.0512 +/- 0.0328 and 30.0 +/- 5.0 for propyl butamide. The low bioavailability (F) of the compounds, in the range 24-32%, may be attributed to low absorption of the drugs from the gastro-intestinal tract, or the first-pass effect, or both. The drugs accumulate predominantly in the liver. The faster metabolism and elimination of propyl butamide is postulated.

Administration, Oral↗

Studies on the development of physical dependence on barbitone in the rat and rat atrium.

The mechanisms underlying the development of barbitone dependence have been studied in the rat and in atrial preparations removed from dependent animals. Long-term oral administration to the rat of barbitone, alone or together with the analeptics bemegride or pentylenetetrazol, has shown that the intensity of the withdrawal syndrome generally parallels the degree of associated CNS depression. In addition, the overall relationship between the spontaneous or evoked (chemical or audiogenic) responses of representative drug-withdrawn rats and the inotropic responses of corresponding withdrawn atria to supramaximal nerve stimulation, noradrenaline or Ca2+ was reasonably good. It is proposed that the rat atrial preparation may provide a suitable model system for the study of barbitone dependence in the rat, especially in relation to Ca2+-dependent mechanisms, and that selective calcium antagonists may prove helpful in the management of barbiturate and similar types of drug dependence. The barbitone withdrawal syndrome has been described in terms of a membrane phase distribution hypothesis of drug action.

Animals↗

[Shock during necrotic amoebic colitis (author's transl)].

Two varieties of conditions of shock may be isolated during necrotic amoebic colitis (13 cases). Eight patients present a simple hypovolemic shock secondary to wastage by diarrhea and perilesional oedema with globular, protein, alcaline and potassic deficiency. Its prognosis is relatively good, after vascular infilling and corrections of metabolic disorders. Five other patients present real toxi-infectious shock resulting from widespread tissue necrosis with auto-intoxication associated with septicemic complications. Its prognosis is frankly bad. The treatment is far more difficult. The use of cardiovascular analeptics, such as dopamine, after an infilling failure, is not always sufficient to re-establish the situation. The exeresis of necrotic tissues is an indispensable condition to remove the cause of the shock before septicaemic generalisation.

Adult↗

[Ventilation and gas-dynamic work of breathing during CO2 stimulation in patients with airways obstruction prior to and following bronchodilation with reproterol (author's transl)].

A new, non-invasive method for measuring chemo-sensitivity of the respiratory center is described, one that may sensibly be applied in patients with airways obstruction. It is used for measurement of ventilation and gas-dynamic work of breathing in body plethysmography during a modified unsteady state of CO2 rebreathing technique. In 9 patients suffering from chronic obstructive bronchitis, a linear correlation between the end-expiratory CO2 partial pressure and the respiratory work rate vs. the airways resistance was established while between the end-expiratory PCO2 and the respiratory minute volume as well as the respiratory minute volume and the respiratory work rate vs. airways resistance, a non-linear correlation exists. In tests with 7-(3[2-(3 5-dihydroxyphenyl)-2-hydroxy-ethyl-amino]-propyl)-theophylline (reproterol, Bronchospasmin), a beta-phenylethyl-amino alkylxanthine, with known bronchodilating effects and a preparation for which pharmacological considerations of central-analeptic effects cannot definitely be excluded, this method revealed in patients with airways obstruction no breathing stimulation. In contrast, however, specific airways resistance in patients afflicted with bronchitis was statistically significantly reduced.

Adult↗

Xylazine-induced prolongation of gastrointestinal transit in dogs: reversal by yohimbine and potentiation by doxapram.

The effects of yohimbine and doxapram on xylazine-induced prolongation of gastroduodenal transit of barium sulfate were studied in 5 dogs. Base-line transit time was determined while the dogs were non-sedated and undisturbed; the time for barium sulfate to move from the stomach to the duodenojejunal junction was 5.6 +/- 4.0 minutes (mean +/- SD). An IV injection of xylazine (1 mg/kg) prolonged the transit time to 95.0 +/- 14.6 minutes. During the xylazine-induced prolongation of gastroduodenal transit, there were no vigorous gastric or intestinal peristaltic contractions for at least 60 minutes. Yohimbine, an alpha 2-adrenergic blocking agent, given IV at a dosage of 0.1 mg/kg, reversed the gastrointestinal and sedative effects of xylazine. Doxapram hydrochloride, an analeptic, given IV at a dosage of 5.5 mg/kg, prolonged the transit time to 43.0 +/- 22.8 minutes. When doxapram was given in combination with xylazine, it potentiated the gastrointestinal effect of xylazine, and further prolonged the transit time to 148.0 +/- 32.7 minutes. It was concluded that yohimbine is effective as an antidote to reverse the xylazine-induced prolongation of gastrointestinal transit, whereas doxapram has no value in this respect.

Animals↗

Thyrotropin-releasing hormone: neurogenesis of actions in the pentobarbital narcotized rat.

Possible neuroanatomical substrates mediating some of the effects seen with thyrotropin-releasing hormone (TRH) in the pentobarbital (PB) narcotized rat were examined. This was accomplished by microinjecting picomole concentrations of TRH into 20 different brain sites. The behavioural effects examined were the capacity of TRH to antagonize PB-induced narcosis and hypothermia as well as TRH-induced shaking behavior. Microinjection of TRH into the septum was found to be significantly more effective in the reversal of PB narcosis than any other site examined. In contrast, the temperature and shaking response were evoked with approximately equal efficacy by TRH microinjection into a number of brain sites; including the preoptic/anterior hypothalamus, medial thalamus, thalamic, periventricular gray, interpeduncular nucleus and locus ceruleus. These results demonstrate the septal region to be the site of action for TRH reversal of PB narcosis and suggest the involvement of the septohippocampal system. In addition, they indicate that the neurogenesis of the shaking response is similar to that of the temperature response and that this differs from the neurogenesis of the analeptic response.

Animals↗