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PubMed1988

Intraseptal microinjection of adrenocorticotropic hormone1-24 antagonizes pentobarbital-induced narcosis and depression of hippocampal cholinergic activity.

Intracerebroventricular or intraseptal microinjection of adrenocorticotropic hormone1-24 (ACTH1-24) to pentobarbital-anesthetized rats and rabbits produced shortening of the duration of narcosis. This analeptic effect was blocked by atropine, indicating the central cholinergic nature of the response. ACTH1-24 also increased hippocampal sodium-dependent high affinity choline uptake activity that had been depressed by the barbiturate. Naloxone-pretreatment also blocked the analeptic and cholinergic activating properties of ACTH1-24. These results suggest that intraseptal ACTH1-24 produces its analeptic effect by activating a hippocampal cholinergic arousal system.

Adrenocorticotropic Hormone↗
PubMed1990

Norvaline2-TRH: binding to TRH receptors in rat brain homogenates.

Norvaline2-thyrotropin-releasing hormone ([Nva2]TRH) has been described as a thyrotropin-releasing hormone (TRH) analog with no thyrotropin (TSH)-releasing capacity but enhanced analeptic activity compared with TRH, as shown by the reversal of haloperidol-induced catalepsy. We have evaluated the receptor-binding properties of [Nva2]TRH in homogenates of rat anterior pituitary, hypothalamus, brainstem and cortex tissue, using [3H]TRH and [3H][3-Me-His2]TRH as radioligands. Apparent Ki values at high affinity TRH-binding sites, labelled predominantly by [3H][3-Me-His2]TRH, ranged from 17.0 to 36.9 microM in all tested regions. Additionally, [Nva2]TRH was shown to compete with [3H]TRH at low affinity TRH-binding sites with similar affinities. It is concluded that the loss of TSH-releasing activity of [Nva2]TRH appears to be due to a drastic reduction in binding affinity to the high affinity TRH receptor subtype. Its analeptic activity, however, may be mediated by low affinity TRH binding sites which are predominantly labelled by [3H]TRH or by yet unidentified mechanisms.

Animals↗
PubMed1989

Mechanistic and functional divergence between thyrotropin-releasing hormone and RO 15-4513 interactions with ethanol.

Both thyrotropin-releasing hormone (TRH) and RO 15-4513 antagonize ethanol-induced depression, but this common property does not infer that both compounds share similar mechanisms of action. In the present studies, both TRH (30 mg/kg, i.p.) and RO 15-4513 (10 mg/kg, i.p.) reversed ethanol-induced depression of locomotor activity, in accord with previous reports. However, the benzodiazepine antagonist, RO 15-1788, blocked this action of RO 15-4513, while exerting no effect on the analeptic action of TRH. Using a model of seizure activity electrically elicited from the inferior colliculus, ethanol exerted a dose-related attenuation of seizure activity. This anticonvulsant action of ethanol was not altered by TRH (30 mg/kg, i.p.), but RO 15-4513 (3 mg/kg) reversed the effect of the 0.5, but not the 1.0 g/kg, dose of ethanol. In addition, pretreatment with RO 15-4513 (1 or 3 mg/kg, i.p.), but not TRH (30 mg/kg, i.p.), caused seizure generalization into the forebrain following inferior collicular stimulation, further verifying the proconvulsant properties of RO 15-4513. In conclusion, the analeptic action of TRH appears independent of benzodiazepine activity, and in contrast to RO 15-4513, TRH does not exhibit proconvulsant properties. Furthermore, because TRH did not antagonize both depressant actions of ethanol studied, it appears unlikely that TRH directly interacts with the molecular basis of ethanol action.

Animals↗
PubMed1993

Influence of thyrotropin-releasing hormone and catecholaminergic interactions on CNS ethanol sensitivity.

The role of catecholamine neuronal systems in mediating the analeptic and thermogenic effects of thyrotropin-releasing hormone (TRH) was examined in long-sleep (LS) and short-sleep (SS) mice. TRH [0.1 to 40 micrograms, intracerebroventricularly (icv)] was associated with a reduction in the sleep times of LS mice, but no dose of TRH had any effect on sleep times of SS mice. However, TRH (20 micrograms, icv) produced a 1.0 degree to 1.5 degrees C attenuation of the ethanol-induced hypothermia in both LS and SS mice. TRH did not change the rate of ethanol elimination in either line of mice, suggesting that the reduction in LS sleep times and attenuation of LS and SS hypothermia were due to decreased CNS ethanol sensitivity rather than an increase in the rate of ethanol metabolism. TRH (20 micrograms, icv) given alone produced an activation of central and peripheral catecholamine systems in LS, but not SS mice, as reflected by an increase in the in vivo tyrosine hydroxylase (TH) activity in the brain and adrenal gland. TRH, given with ethanol, prevented or attenuated ethanol-induced decreases in the brain and adrenal gland in vivo TH activity in LS mice but not SS mice. Thus, there was an association between the ability of TRH to produce an activation of catecholamine neuronal systems (increased rate of catecholamine biosynthesis) and the analeptic action of TRH to reduce the CNS depressant effects of ethanol (decreased sleep times).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic Intoxication↗
PubMed1964

ESERINE AND AMPHETAMINE: INTERACTIVE EFFECTS ON SLEEPING TIME IN MICE.

The sleeping time of mice given pentobarbital was found to be significantly shortened by the injection of eserine or amphetamine. When both eserine and amphetamine were given with pentobarbital the sleeping time, though much shortened, was significantly longer than with the addition of amphetamine alone. Though possessing an analeptic effect of its own, eserine appears to antagonize the analeptic effect of amphetamine.

Amphetamine↗
PubMed1970

Respiratory stimulants in treatment of perinatal asphyxia.

The effects of two analeptic drugs-taloximine and ethamivan-have been studied in asphyxiated fetal and newborn rabbits. In primary apnoea ethamivan reduced the time before the onset of gasping, while during gasping taloximine increased the gasp rate. In secondary apnoea neither drug initiated respiration, though most animals could be resuscitated by using intermittent positive pressure respiration. From these results it is suggested that analeptic drugs have no place in obstetric or neonatal departments.

Animals↗
PubMed1996

[Montirelin hydrate (NS-3), a TRH analog, improved the disturbance of consciousness caused by head concussion and pentobarbital in mice].

Effects of a novel TRH analog, montirelin hydrate (NS-3), on the coma caused by head concussion and narcosis induced by pentobarbital were compared with those of TRH in mice. Head concussion caused a behavioral comatose state with loss of the righting reflex and spontaneous motor activity. NS-3 shortened the latent periods to the recovery of the righting reflex (0.03-0.1 mg/kg, i.v.) and spontaneous motor activity (0.1 mg/kg, i.v.) following the head concussion. In the case of TRH, higher doses were needed to induce such effects. NS-3 (0.1-0.3 mg/kg, i.v.) reversed the pentobarbital-induced narcosis in a dose-dependent manner. A similar effect was elicited by 30- to 100-fold higher doses of TRH than NS-3. The analeptic effect of NS-3 in the pentobarbital-narcotized mice was antagonized by SCH23390, a dopamine D1 antagonist or by the combined treatment with prazosin and scopolamine, while neither prazosin nor scopolamine alone antagonized the analeptic effect of NS-3. Taken together with the finding that NS-3 did not bind to dopamine, adrenaline or muscarine receptors, it is suggested that NS-3 may restore the disturbance of consciousness by activating the brain dopamine, noradrenaline and acetylcholine neurons without stimulating these receptors directly.

Anesthesia↗
PubMed2005

A pyridinium-substituted analog of the TRH-like tripeptide pGlu-Glu-Pro-NH2 and its prodrugs as central nervous system agents.

A metabolically stable and centrally acting analog of pGlu-Glu-Pro-NH2 ([Glu2]TRH, a tripeptide structurally related to TRH (thyrotropin-releasing hormone)) was designed by replacing the amino-terminal pyroglutamyl residue with a pyridinium moiety. The analeptic action of the analog was used to optimize the efficacy of this novel CNS agent when administered intravenously in its CNS-permeable prodrug forms obtained via the reduction of the pyridinium moiety to the nonionic dihydropyridine and esterifying the central Glu with various alcohols. The maximum effect in antagonizing pentobarbital-induced narcosis in mice was achieved with the hexyl ester that was used subsequently for a comparative evaluation with a prodrug of the parent neuropeptide in the Porsolt swim test as a paradigm for antidepressant effect. The novel analog maintained its antidepressant potency but showed reduced analeptic action compared to [Glu2]TRH; thus, an increase in the selectivity of CNS-action was obtained by the incorporation of the pyridinium moiety.

Animals↗
PubMedDate not supplied

[Pharmacologic profile of protirelin tartrate].

Pharmacological interest in the tripeptide thyrotropin-releasing hormone (TRH) is due to the multiple effects it produces. In fact, apart from taking part in regulating the activity of the hypothalamo-pituitary-thyroid axis, TRH produces various neuropharmacological effects which indicate a biological role that is probably more important than that of a releasing hormone. Trials performed in animals have shown, for example, the dose-dependent capacity of TRH to induce analgesia, probably by interacting with the opioid peptide system. Motor activity is affected by TRH. In fact this tripeptide elicits an increase in spontaneous motor and explorative activities by interacting with the dopaminergic neurotransmitter system at the nucleus accumbens level. The neuropharmacological activities of TRH include an interesting arousal effect and an analeptic action on generalized depression of the CNS whether this depression is of natural origin, such as hibernation, or induced pharmacologically (barbiturates, ethanol) or of a traumatic origin (coma). This analeptic action is attributable to stimulation of cholinergic neurons in the septo-hippocampal area and to the presence of terminals containing TRH in the lateral septum and TRH receptors concentrated especially in the medial septum and diagonal band of Broca. It has also been suggested that TRH localized in the pineal gland has a part in activating the neuronal mechanisms of arousal. Associated with the arousal effect and especially evident in variously originated shock conditions are the activating effects of TRH on vegetative functions (body temperature, circulation, the gastrointestinal tract). These stimulatory activities on the CNS were the rationale for therapeutic use of TRH in the initial treatment of coma due to brain trauma and for the treatment of endogenous depression. A most interesting property of TRH is that of counteracting the neurological deficit due to experimental lesion of the spinal cord particularly with regard to spasticity and ataxia. Electrophysiological trials have shown that TRH depolarizes the motoneurons in frog spinal cord thereby increasing the monosynaptic reflex. Furthermore, TRH has recently been shown to have a trophic effect on cultures of rat fetus spinal cord. On this basis TRH has been used successfully for the treatment of amyotropic lateral sclerosis (Charcot's syndrome) and spinocerebellar degeneration. Further support for this therapeutic strategy is given by the demonstration that deafferentiation of rat spinal cord produces an increased density of TRH spinal receptors. Recent studies have also given encouraging results on the possible therapeutic use of TRH for the treatment of Alzheimer's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

[Acute poisoning. Apropos of 1200 cases].

The team studied 1 200 cases of acute intoxications both accidental and self inflicted, self inflicted poisonings are much more frequent than accidental ones and in general occur more often amongst the young and by women; the median age is about thirty. Barbituric are often the means. There is a progressive increase in the use of tranquilizers and of thymo-analeptics as their use becomes greater. A mixture of poisons increases the dangers because this frequently results in more rapid loss of consciousness; also more than one poison increases the risk of shock and of thermo-regulation, respiratory problems necessitate intubation and artificial respiration which both increase the risk of assification. The characteristics of certain poisons are stressed and in particular the thymo-analeptics; also the supervision of the patients in an intensive care unit.

Acid-Base Imbalance↗
PubMed1986

Antagonism of xylazine-induced depression of shuttle-avoidance responses in dogs by administration of 4-aminopyridine, doxapram, or yohimbine.

The effectiveness of 4-aminopyridine, doxapram, or yohimbine as antagonists against xylazine-induced CNS depression in dogs was evaluated and compared, using the 2-way shuttle-avoidance paradigm. All drugs were given IV to 5 male dogs trained to avoid mild shock by jumping over a hurdle within 10 s after initiation of an audible tone. At dosages of 1 and 2 mg/kg of body weight, xylazine abolished or significantly decreased the mean number of avoidance responses and significantly increased the mean latency of avoidance responses. The analeptic 4-aminopyridine (0.5 mg/kg) did not significantly antagonize xylazine in all dogs. One dog convulsed both times it was given xylazine followed by 4-aminopyridine, but did not convulse when given either drug alone. Doxapram (5.5 mg/kg), a short-acting analeptic and respiratory stimulant, was only partially effective in antagonizing xylazine, and its antagonistic actions were brief. Yohimbine (0.1 mg/kg), an alpha 2-adrenoreceptor-blocking agent, was superior to 4-aminopyridine and doxapram in its ability to antagonize xylazine-induced CNS depression. Yohimbine consistently increased the mean number of avoidance responses to the maximum of 8 and consistently decreased the mean latency of avoidance responses to control values in dogs given 1 or 2 mg of xylazine/kg. In dogs given 2 mg of xylazine/kg, yohimbine was significantly more effective than 4-aminopyridine or doxapram in its ability to increase the mean number of avoidance responses and decrease the mean latency of avoidance responses.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1987

Are nootropics a separate class of drugs? A differentiation in various models.

Psychostimulants, analeptics, and nootropics are three classes of drugs that have been used with varying success in the treatment of impaired brain functions. They all produce an excitatory and disinhibitory effect on the CNS but can be distinguished through their characteristic properties. Psychostimulants are drugs that lead to a general, but nonphysiological activation, which is followed by a phase of inhibition. Analeptics are drugs that stimulate the CNS, in particular the respiratory and circulatory centers, and which in high doses lead to convulsions. Nootropics are drugs that (in impaired brain functions) lead to a physiological activation of adaptation.

Aged↗
PubMed1986

Haemodynamic and respiratory effects of post-operative doxapram and almitrine in patients following pneumonectomy.

Respiratory analeptics have been shown to give important increases in pulmonary vascular resistance and pulmonary arterial pressure in hypoxaemic respiratory failure patients, but no studies have been carried out in the post-operative recovery period. The aim of this study was to compare the haemodynamic and respiratory effects of doxapram and almitrine infusion given over 1 h in patients who had just undergone pneumonectomy. Two hours after the end of anaesthesia, three groups of randomly selected patients were therefore given 3 mg kg-1 doxapram (n = 10), 1 mg kg-1 almitrine (n = 10) or placebo (n = 10). Measurements were made before and 15, 30, 60, 90, 120 and 180 min after the beginning of the infusion. There was an immediate 15-20% fall (P less than 0.01) in PaCO2 and a 20% rise in PaO2 (P less than 0.005), identical for both drugs; the variations in the placebo group became significant only after 60 min. Heart rate and cardiac index did not change. Mean arterial pressure did not change with doxapram, but decreased by 20% during the infusion of almitrine (P less than 0.01), remaining low until the 90th min (P less than 0.05). This hypotension was due to a decrease in peripheral arterial resistance (P less than 0.05) and a small decrease in right atrial pressure (P less than 0.05). The mean pulmonary arterial and wedge pressures were increased before starting the infusion, and did not vary significantly. Pulmonary arterial resistance increased with both analeptics but only significantly with the doxapram (P less than 0.05) at 5, 60 and 90 min; however, there was no significant difference between doxapram and almitrine. The post-operative respiratory efficiency of these drugs has been confirmed, there being no difference between almitrine and doxapram. The haemodynamic effects were moderate, especially with almitrine. Both of these drugs, therefore, may be recommended for use after lung surgery.

Almitrine↗
PubMed1980

[Pharmacological studies of 2-methyl-3(2-phenyl-3-methyl-tetrahydrooxazino)-propiophenone hydrochloride and 1-phenoxycarboxy-1-phenyl-2-methyl-3(2-phenyl-3-methyl-tetrahydrooxazino)-propane hydrochloride compounds].

The authors used the compounds 2-methyl-3)2-phenyl-3-methyl tetrahydroxasino)-propiophenone hydrochloriad (code PsI) and 1-phenoxycarboxy-1-phenyl-2-methyl-3 (2-phenyl-3-methyl-tetrahydroxasino-propan hydrochlorid(code P3) and carried out the following studies: influence of tripamine, corasol and strichnine seizures 1-phenoxycarboxy--1-phenyl-2-methyl--3 (2-phenyl--3-methyl-tetrahydroxasino) propar hydrochlor (Code P8) in white mice, effect on the hypertensive action of reserpine in white rats, investigations on the analeptic action in urethanized cats as well as on the analgetic effect, examined both by the test of "hot plate" and the method of Hendreshot-Forsaith. The examined compounds, administered in a dose of 1/6 of LD50, showed analgetic effect weaker than that of the preparations Morphinum hydrochloricum and Analigin, but their analeptic effect was less manifested that of of corasol. Similar to MAO-inhibitor-oproniazid although in smaller degree the compound PS1 potentiated tripamine seizures and inverted the hypotensive effect of Reserpine into hypertensive.

Analgesics↗
PubMed1975

Thyrotropin-releasing hormone (TRH)-induced hyperthermia and behavioral excitation in rabbits.

The intraventricular administration of thyrotropin-releasing hormone (TRH) to conscious rabbits produces a dose-related increase in body temperature, a compulsive scratching syndrome, and behavioral excitation. These effects are not antagonized by most adrenergic or serotonergic blockers, amine depletors, or most depressants. Given to rabbits pretreated with anesthetic doses of barbiturates or high doses of other sedatives or neuroleptics, TRH exerts an analeptic effect. The duration of pentobarbital anesthesia is markedly shortened. Of all the depressants tested, only morphine was resistant to the analeptic effect of TRH, although the morphine-induced hypothermia was reversed.

Animals↗
PubMed1963

The use of ethamivan in the treatment of barbiturate poisoning.

Ethamivan was used as a respiratory analeptic in the treatment of nine cases of severe barbiturate poisoning. Initial intravenous injections of 100 to 150 mg. of ethamivan increased the depth of respirations within a minute. Prolonged respiratory stimulation was achieved by a continuous intravenous infusion of 500 to 3000 mg. of ethamivan per litre of fluid. If hypotension occurred, an intravenous drip of noradrenaline was used; fluid overloading was avoided by adjusting the concentrations of drugs given, so that no more than a total of 125 c.c. of fluid per hour was administered. The chief side effect of overdosage of ethamivan was muscular twitching. This did not prove to be a problem and was of some value in determining the amount of drug given. The nine patients survived. It was concluded that ethamivan is a useful agent in the treatment of barbiturate poisoning.

Barbiturates↗
PubMed2003

Antitumor and antimetastatic activities of Angelica keiskei roots, part 1: Isolation of an active substance, xanthoangelol.

The roots of Angelica keiskei Koizumi have traditionally been used as a health food, with diuretic, laxative, analeptic and galactagogic effects. It has been thought that the roots and leaves of A. keiskei have preventive effects against coronary heart disease, hypertension and cancer. In the present study, we examined the antitumor and antimetastatic activities of various fractions isolated from a 50% ethanol extract of A. keiskei roots. The ethyl acetate-soluble fraction of the 50% ethanol extract inhibited tumor growth in LLC-bearing mice at a daily dose of 100 mg/kg prolonged survival time and inhibited metastasis to the lung after surgical removal of primary tumors. Two active substances were isolated from fractions 1 and 2: compound 1 was identified as xanthoangelol based on the data of the (1)H- and (13)C-NMR spectra. Xanthoangelol inhibited tumor growth in LLC-bearing mice as well as lung metastasis and prolonged survival time in carcinectomized mice at a daily dose of 50 mg per kg. Furthermore, xanthoangelol (50 or 100 mg per kg daily) inhibited liver metastasis and the growth of metastasized tumor cells in the livers of mice with intrasplenically implanted LLC. Xanthoangelol inhibited DNA synthesis in LLC cells at concentrations of 10 and 100 microM, but it had no effect on DNA synthesis in HUVECs or on the adherence of LLC cells to HUVECs. Xanthoangelol inhibited tumor-induced neovascularization (in vivo) at doses of 10 and 20 mg per kg, and it inhibited the Matrigel-induced formation of capillary-like tubes by HUVECs at concentrations of 1-100 microM. Furthermore, xanthoangelol inhibited the binding of VEGF to HUVECs at concentrations of 1-100 microM. These results indicate that the antitumor and/or antimetastatic activities of xanthoangelol may be due to inhibition of DNA synthesis in LLC cells and of tumor-induced neovascularization through inhibition of the formation of capillary-like tubes by vascular endothelial cells and inhibition of the binding of VEGF to vascular endothelial cells.

Acetates↗
PubMed2005

TRH-like antidepressant peptide, pyroglutamyltyroslyprolineamide, occurs in rat brain.

We have previously reported the occurrence of pGlu-Glu-Pro-NH(2)(Glu-TRH, EEP), Val-TRH, Tyr-TRH, Leu-TRH, Phe-TRH, and Trp-TRH in rat brain using a combination of HPLC and radioimmunoassays with antibodies that cross-react with the general structure pGlu-X-Pro-NH(2) where 'X' maybe any amino acid residue (Peptides 2004; 25 : 647). This new family of TRH-like peptides, along with TRH (pGlu-His-Pro-NH(2)), has neuroprotective, anticonvulsant, antidepressant, euphoric, anti-amnesic, and analeptic effects. We now report that a combination of affinity chromatography using a rabbit antibody specific for Tyr-TRH and Phe-TRH, along with HPLC and tandem mass spectrometry operating in the multiple reaction monitoring (MRM) mode, provide conclusive evidence for the presence of Tyr-TRH in rat brain. Furthermore, synthetic Tyr-TRH is active in the Porsolt Swim Test suggesting that it is a fourth member of this family of in vivo neuroregulatory agents that have psychopharmacotherapeutic properties.

Animals↗