[COMPARISON OF THE ANALEPTIC PROPERTIES OF ETEPHIL AND ETHYLNORANTIFEINE WITH THE WELL-KNOWN RESPIRATORY ANALEPTICS AFTER POISONING BY THIOPENTAL SODIUM AND MORPHINE].
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Anesthesia↗
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An electro-encephalographic study of the analeptic action of beta beta ethyl methyl glutarimide (megimide). I. Against several barbiturates and other hypnotics. II. Compared with other analeptics and convulsants.
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Barbiturates↗
Analeptic use in clinical toxicology: a historical appraisal.
BACKGROUND: The introduction and increasing popularity of the barbiturates during the first two decades of the 20th century was associated with a new life threatening toxicological problem: the barbiturate overdose. METHODS: This paper reviews the four major phases of analeptic use. As interest in the principles of physiologic antagonism between stimulants and depressants grew, analeptic agents were increasingly used to treat the obtundation and respiratory depression of barbiturate overdose. At first, naturally occurring stimulants such as camphor, strychnine, picrotoxin, and caffeine were used in desperate attempts to awaken patients. During the 1930s, and continuing at some centers into the 1960s, an increasing number of synthetic analeptics agents such as nikethamide, pentylenetetrazol, bemegride, amphetamine, and methylphenidate were enthusiastically recommended as barbiturate antidotes, often at very high doses. Unfortunately, utilizing generous amounts of multiple convulsants was not without its share of complications. Using this analeptic strategy the mortality rate after moderate to severe barbiturate overdose remained as high as 45%. Beginning in the mid-1940s a group of Scandinavian physicians pioneered a revolutionary approach to sedativehypnotic overdose that rejected the use of analeptics and relied on respiratory ventilation and supportive care. CONCLUSIONS: Although barbiturate overdose mortality decreased to less than 1% using this strategy, it would take another 20 years before this technique was universally adapted. While analeptic therapies for the treatment of drug overdose have now been abandoned, one of these analeptics, methylphenidate, currently enjoys wide use in the treatment of attention deficit hyperactivity disorder.
Barbiturates↗
The analeptic effect of methamphetamine in pentobarbital-narcotized rats is mediated via a dopaminergic-cholinergic mechanism.
Methamphetamine (MAP) administered in doses of 0.5 to 5 mg/kg i.p. to rats anesthetized with pentobarbital produced a shortening of the duration of loss of righting reflex. This analeptic effect of MAP was blocked by atropine but not by atropine methylbromide, indicating the central cholinergic nature of the response. This effect was also blocked by the D1 and D2 dopamine antagonists SCH 23390 (0.2 mg/kg) and raclopride (2 mg/kg), respectively. Pentobarbital decreased sodium-dependent high-affinity choline uptake (HACU) in frontal cortex and hippocampus as measured in synaptosomes from treated rats. MAP given to pentobarbital-narcotized rats restored HACU activity to nonanesthetized levels, but this restorative effect of MAP was blocked by SCH 23390 or raclopride. These data suggest that in addition to a cholinergic mechanism, the analeptic effect of MAP involves the dopamine system. alpha-Methyl-p-tyrosine, but not reserpine, pretreatment completely blocked the MAP analeptic response. In reserpinzed rats, MAP produced a markedly enhanced analeptic response. Studies of the effects of repeated administration of MAP on its analeptic activity were also undertaken in view of the well known sensitization to the locomotor and stereotypic effects of the amphetamines that occur with repeated intermittent administration. Rats pretreated daily with MAP (5 mg/kg) for 5 or 12 days showed neither tolerance nor sensitization to the analeptic effect of subsequent MAP administrations. 3H-quinuclidinyl benzilate-binding studies also showed no changes in muscarinic binding characteristics of membranes prepared from cortex or hippocampus of rats pretreated chronically with MAP. These and our earlier studies suggest that the analeptic effect of MAP is mediated via a dopaminergic-cholinergic mechanism.
Animals↗
D-1 agonist, SKF 38393, but not a D-2 agonist, produces a cholinergically mediated analeptic effect in rabbits.
SKF 38393 (2-15 mg/kg, IV), but not quinpirole, shortened the duration of loss of righting reflex produced in pentobarbital-narcotized rabbits. This effect was blocked by atropine (2-5 mg/kg, IV), but not by atropine methylbromide, suggesting that a central cholinergic mechanism was involved. The analeptic effect was also blocked by SCH 23390 (0.1 mg/kg, IV) or raclopride (5 mg/kg, IV). These results indicate that SKF 38393 activates central cholinergic neurons, which in turn initiate the analeptic effect. However, the fact that raclopride also blocked the SKF 38393 analeptic effect, but quinpirole did not exert any analeptic effect, suggests that a D-1/D-2 modulation of cholinergic systems may be involved in the SKF 38393-induced analeptic effect. These results also support our earlier findings and view that cocaine-induced analeptic activity is mediated by a dopaminergic-cholinergic mechanism.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Psychostimulants, analeptics, nootropics: an attempt to differentiate and assess drugs designed for the treatment of impaired brain functions.
The common characteristic properties of psychostimulants, analeptics, and nootropics are excitatory and disinhibitory effects on the central nervous system. The differences lie in the type of excitatory effect. Psychostimulants produce a general, yet nonphysiologic, activation with subsequent sedation. They generally act in a destabilising manner, disturbing the homoeostatic functions of centrally regulated reactions. Nootropics produce a physiological activation of disturbed or reduced adaptation functions. They have a stabilising effect, increasing the homoeostatic functions of the centrally regulated reactions that have become susceptible to disturbances. Analeptics differ from psychostimulants and nootropics. The effects of neuronal excitation or disinhibition are mainly restricted to the respiratory and circulatory systems. In high dosages they produce convulsions and corresponding motor reactions. No conclusive evidence for a general efficacy in the treatment of organic mental disorders has been furnished for any of the three drug classes. Yet there is sufficient proof that nootropics, unlike psychostimulants and analeptics, can produce therapeutic results in at least some patients, even if it is not yet clear under what conditions they can be meaningfully applied. There is a fundamental difference between the three groups with regard to the potential for abuse. While tolerance and extreme physiological dependence can occur rapidly under treatment with psychostimulants, such risks are not a typical feature of nootropics or analeptics.
Animals↗
[The place of respiratory analeptics in chronic respiratory failure (author's transl)].
The recent renewed interest in respiratory analeptic action in chronic respiratory failure raises the problem of the site of action and nature of these drugs. They lead to a direct or reflex increase in central nervous activity, which in consequence increases respiratory muscle activity. Indeed, patients with respiratory failure develop pressures two or three times greater than normal subjects to achieve adequate ventilation. During acute exacerbations the pressures generated are five or six times as large. This increase in pressure may risk precipitating fatigue. In general the anomalies of blood gases seem much more related to changes in ventilation-perfusion relationships than to global hypoventilation. Finally, a large increase in the force of muscular contraction may only have a minor effect on ventilation, given the alinear nature of the dynamic compliance curve. An increase of central respiratory activity may thus be ineffective and possibly even dangerous. In the overall assessment of drug considered as an analeptic one always ought to consider the possible non-analeptic actions on the bronchial calibre, the force of the respiratory muscles and the ventilation-perfusion relationships. Thus, it is possible that the therapeutic effects of certain analeptic drugs may be due to actions other than those of respiratory stimulation.
Central Nervous System↗
[Comparative evaluation of the antitoxic activity of central nervous system analeptics and their combinations in barbamyl poisoning].
Tests conducted on rats poisoned with increasingly lethal doses of sodium amytal demonstrated the antitoxic activity of an analeptic mixture to be superior to that of picrotoxin, strichnine, corasol and caffeine entering into its composition and also to the activity of bemegride. As to the degree of antitoxic activity in poisoning of mice with sodium amytal (one LD50) the CNS analeptics are arranged in the following descending oder of their action: analeptic mixture, picrotoxin, bemegride, corasol, strychnine. In poisoning with higher doses of sodium amytal (LD84) corasol, strychnine and caffeine are ineffective, the most productive being analeptic mixture and picrotoxin. Bemegride proves effective only in a single dose of 2.8 LD50 for intact animals.
Amobarbital↗
Analeptic effect of centrally administered histamine H2-receptor agonist dimaprit but not impromidine in urethane-anesthetized rats.
Intracerebroventricularly administered dimaprit decreased the depth of urethane anaesthesia. Ventilatory stimulation, positive corneal reflex and increased susceptibility to pain were observed. Furthermore, dimaprit decreased the lethal effect of large doses of urethane. The analeptic property of dimaprit was not shared by the potent H2-receptor agonist, impromidine, Histamine increased ventilatory tidal volume but no other stimulatory effects were observed. These findings suggest that the analeptic effects of dimaprit were not mediated by H2-receptors. Among the analeptic effects of dimaprit, only the protection against urethane toxicity was antagonized by metiamide. However, this phenomenon appeared to be due to the nonspecific interaction between the three bradypnoeic drugs metiamide, dimaprit and urethane. The histamine-induced increase in ventilatory tidal volume was not antagonized by diphenhydramine or metiamide, suggesting the existence of a novel histaminergic mechanism in the central nervous system.
Anesthesia↗
Comparison of the analeptic potency of TRH, ACTH 4-10, LHRH, and related peptides.
Various peptide hormones appear to exert behavioral and pharmacologic effects apart from their classical endocrine actions. Thytrotopin-releasing hormone (TRH), for example, antagonizes the sedation and hypothermia produced by barbiturate and other depressant drugs and de Wied has shown that ACTH 4-10, TRH, LHRH and certain related substances show some activity in inhibition of extinction of a pole-jumping avoidance response in the rat. These data provided the impetus for screening ACTH 4-10, LHRH, and related peptides for analeptic activity. ACTH 4-10 and ACTH 4-7 were inactive in antagonizing pentobarbital whether administered peripherally or centrally. ACTH 4-7 amide and 4-Met(O2), 8-D-Lys,9-Phe-ACTH 4-9 were active regardless of route of administration LHRH and two tripeptide fragments (pGlu-His-Trp-NH, and pGlu-His-Phe-NH2) showed analeptic activity only after intracisternal administration. Thus, some peptide fragments related to ACTH 4-10 and LHRH were shown to share to some degree the analeptic properties previously demonstrated for TRH.
Adrenocorticotropic Hormone↗
Codeine produces a cholinergically mediated analeptic effect in rats and rabbits.
The intravenous administration of codeine to diazepam-narcotized rabbits resulted in a shortened duration of loss of righting reflex. Coadministration of naltrexone plus codeine enhanced this analeptic effect and was also effective in shortening the duration of pentobarbital narcosis. The analeptic effect was blocked by atropine, but not by methylatropine, indicating involvement of a central cholinergic mechanism. In rats the analeptic activity correlated with the reversal of the diazepam-induced fall in sodium dependent high affinity choline uptake in hippocampal and cortical synaptosomes. These findings may represent the pharmacological basis of the recently reported antinarcoleptic action of codeine in man.
Animals↗
Analeptic effect of opiate receptor agonists in rabbits.
Eight opiate agonists, administered by the intracerebroventricular (i.c.v.) route, were evaluated as analeptics in pentobarbital-anesthetized rabbits. Morphine, codeine, ethylketocyclazocine, N-allylnormetazocine, meperidine and methadone, but not etorphine or D-Ala2-Met-enkephalin, given i.c.v. 40 min after pentobarbital (30 mg/kg i.v.), produced significant shortening of the duration of anesthesia as determined by the loss of the righting reflex. No apparent relationship was found between this and analgesic potency, nor with the specific receptor subtypes with which these agonists are known to interact. With active compounds, such as morphine, codeine and methadone, producing narcotic sedation, it was necessary to pretreat the animals with naltrexone to unmask the analeptic effect. It is concluded that the analeptic effect produced by certain opiate drugs is not specifically related to any of the subtypes of opiate receptors thus far described.
Animals↗
[Effects of a respiratory analeptic with peripheral action-almitrine on ventilation immediately after surgery].
After a brief review of the advantages and disadvantages of the postoperative administration of a respiratory analeptic with a central action, the authors study the effects of almitrine (respiratory analeptic with a peripheral action) on alveolar ventilation following thoracic surgery. Two groups of 10 patients were distinguished: the patients of the first group received almitrine (1.5 mg/kg-1 over a period of one hour) thirty minutes after their return from the operating room, whilst those of the second group received no respiratory analeptic. Blood gases were measured 30 minutes after the return from the operating room (immediately before the start of the infusion of almitrine) then 1 hour, 2 hours and 3 hours later. The improvement in blood gases after almitrine was significant: whilst arterial pCO2 was a mean of 5.78 kPa (44.46 mmHg) in the control subjects, it fell 4.99 kPa (38.4 mmHg) by the end of the infusion in the tested subjects and subsequently remained at a mean of 5.04 kPa (38.79 mmHg). Arterial pO2 measured with FIO2 in all patients remained stable in the control subjects during the three hours postoperatively (mean = 15.11 kPa (116.26 mmHg). In the tested subjects, it improved progressively and significantly, rising from 11.08 kPa (85.2 mmHg) before almitrine to 14.05 kPa (108 mmHg) at the end of the infusion, then to 15.95 kPa (122.7 mmHg) 1 hour later and to 16.51 kPa (127 mmHg) 2 hours later. The authors concluded that almitrine is effective in the treatment of early alveolar hypoventilation after thoracic surgery in patients receiving moderate doses of oxygen (FIO2 = 0.40).
Adult↗
Role of TRH receptors as possible mediators of analeptic actions of TRH-like peptides.
A large family of TRH-like peptides in the limbic region of rat brain including pGlu-Glu-Pro-NH(2) (EEP), pGlu-Val-Pro-NH(2) (Val(2)-TRH), Leu(2)-TRH, Phe(2)-TRH and Tyr(2)-TRH has recently been discovered. TRH (pGlu-His-Pro-NH(2)) has antidepressant, neuroprotective, analeptic, anticonvulsant, antiamnesic and euphoric properties, and other TRH-like peptides such as EEP exert several of these effects. A new TRH receptor (TRHR2) has been reported which is highly expressed in regions of rat brain that regulate attention and learning, arousal, sleep and processing of sensory information. The TRHR1 predominates in limbic structures involved in regulation of mood and in pituitary. This study examined the possibility that some of the newly discovered TRH-like peptides bind with high affinity to TRHR2, and that this receptor acts as the transducer for some of the CNS effects of this new class of neuropeptides. EEP, Val(2)-TRH and Leu(2)-TRH were analeptics, like TRH, but Phe(2)-TRH and Tyr(2)-TRH were not. The affinity and efficacy of TRH-like peptides for TRHR1 and TRHR2 were measured in HEK293 cells stably expressing these receptors. The IC(50) values of TRH-like peptides for displacement of [3H]TRH from TRHR2 were TRH<<<(Leu(2)-, Phe(2)-TRH)<(Gln(2)-, Ser(2)-TRH)<<(Val(2)-, Tyr(2)-, Arg(2)-, Thr(2)-, and Glu(2)-TRH). The IC(50) for Leu(2)-TRH was about 100 times that for TRH. When tested at the calculated IC(50) values, TRH-like peptides stimulated calcium responses in cells expressing TRHR1 and TRHR2, indicating that the peptides act as weak agonists at both receptors. These results indicate that TRHR1 and TRHR2 do not mediate the behavioral effects of TRH-like peptides.
Amino Acid Sequence↗
Comparisons between the antianesthetic action of dibutyryl cyclic AMP and analeptic drugs on amobarbital-induced narcosis in the rat.
The dose-related antianesthetic and antidotal property of dibutyryl cyclic AMP, devoid of toxic effects, imparts uniqueness to the nucleotide as an arousal agent. Of the analeptic drugs studied (d-amphetamine, picrotoxin, pentylenetetrazol, caffeine, theophylline, strychnine, ethamivan and doxapram), only picrotoxin demonstrated antianesthetic properties. However, picrotoxin was associated with severe toxicity at all dose levels tested. No analeptic drug is effective in reversing the central nervous system depression produced by sedative, hypnotic or tranquilizer drug overdosage.
Amobarbital↗
Narcolepsy, paranoid psychosis, and analeptic abuse.
Analeptic-induced paranoid psychosis occasionally occurs in the treatment of narcolepsy. Two cases illustrate how analeptic abuse can contribute to the development of paranoid psychosis in narcolepsy and greatly complicate treatment.
Adult↗
[Effectiveness and current principles of pharmacologic diagnosis of epileptic focus using short- and ultrashort-acting analeptics and barbiturates].
An analysis of the results of examining 50 operated epileptic patients has shown that the use of short- and ultrashort-acting analeptics and barbiturates makes it possible to specify not only the location of the epileptic focus, but also to disclose the character of the interrelations between the elements of the epileptic system. Especially valuable data can be obtained with the use of brietal. The use of analeptics is the most promising in the course of operation, and, therefore, it should be limited to the preoperational period. It is suggested that the method of implanting permanent intracerebral electrodes acquires now not only diagnostic, but primarily therapeutic importance.
Amygdala↗
Antagonism of the analeptic activity of thyrotropin-releasing hormone (TRH) by agents which enhance GABA transmission.
Administration of 10 mg/kg TRH to mice was found to reduce the sleep and hypothermia induced by 4.7 g/kg ethanol. However, TRH did not reduce the sleep of mice that were given gamma-hydroxybutyric acid (GHBA), baclophen, or aminooxyacetic acid (AOAA) in combination with 3 g/kg/ ethanol. TRH also failed to reverse the hypothermia induced by the combination of ethanol and baclophen or GHBA, and the characteristic neurological effects of TRH e.g. tremor, increased muscle tone, and increased respiratory rate were reduced. In addition, TRH-induced locomotor stimulation was prevented by pretreatment with small doses of the GABA-ergic agents, and while 30 mg/kg TRH reduced the hypothermia produced by large doses of the GABA-ergic drugs, it did not antagonize the locomotor retardation produced by baclophen or GHBA. A hypothesis that the analeptic effects of TRH may be medicated via an inhibition of GABA systems is discussed.
Aminobutyrates↗