Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0085631 (agitation)
 12,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sedative drugs are intended to cause various degrees of drowsiness. Animal experiments indicate that barbiturates induce these effects primarily by depression of the reticular activating system in the rostral brainstem. This in turn potentiates the thalamic recruiting system, thereby inducing 'barbiturate bursts' in the EEG. Anxiolytic drugs are intended to reduce anxiety or tension at doses which do not cause sedation or sleep. Propanediols may depress deactivating centers in the caudal brainstem, thereby releasing the activating centers in the rostral brainstem and depressing the thalamic recruiting response. These drugs may also act on the amygdala. Benzodiazepines have depressant effects on the amydala or hippocampus. These effects may release the reticular formation from inhibition. Enhanced activity of the activating and deactivating centers, to a different extent in different animals, would produce restlessness in some animals and sedation in others, accompanied by a mixture of fast and slow waves in the EEG. Sedative and anxiolytic agents also have central relaxant effects. The barbiturates act directly on the spinal cord, depressing both monosynaptic and polysynaptic reflexes. Propanediols and benzodiazepines act primarily on the descending facilitatory influence of the brainstem. Reduction of this influence depresses spinal polysynaptic but not monosynaptic reflexes. Biochemical studies suggest that barbiturates may act by antagonizing synaptic excitation induced by glutamate. Benzodiazepines may act by enhancing presynaptic inhibition mediated by GABA. The mechanism of action of propanediols is unknown.
 ...
PMID:Neuropharmacology of sedatives and anxiolytics. 3 29

Memantine is a 1-amino-adamantane derivative which has been proposed to be useful in the treatment of Parkinson's disease. Its beneficial effect has been related to its novel properties as an NMDA receptor blocker which can neutralize the effect of glutamate at striatal and subthalamic levels. In the present study, conducted in an open-fashion, 14 parkinsonian patients with motor fluctuations taking L-dopa, were given a supplement of memantine 30 mg/day. After one month, 10 patients completed the treatment (4 discontinued it due to abdominal pain, psychomotor agitation, confusion and dizziness). In 5 patients, the main parkinsonian features improved significantly (1 point or more on the Webster scale). In 6 patients, "off" episodes improved (from daily mean of 273 minutes, to 172 minutes). In summary, memantine addition to parkinsonian features, could form a basis for novel therapeutic strategies directed to neutralize the effects of glutamate at striatal and subthalamic levels.
 ...
PMID:Efficacy of memantine, an NMDA receptor antagonist, in the treatment of Parkinson's disease. 138 98

In late 1987 there was an outbreak in Canada of gastrointestinal and neurologic symptoms after the consumption of mussels found to be contaminated with domoic acid, which is structurally related to the excitatory neurotransmitter glutamate. We studied the neurologic manifestations in 14 of the more severely affected patients and assessed the neuropathological findings in 4 others who died within four months of ingesting the mussels. In the acute phase of mussel-induced intoxication, the patients had headache, seizures, hemiparesis, ophthalmoplegia, and abnormalities of arousal ranging from agitation to coma. On neuropsychological testing several months later, 12 of the patients had severe anterograde-memory deficits, with relative preservation of other cognitive functions. Eleven patients had clinical and electromyographic evidence of pure motor or sensorimotor neuronopathy or axonopathy. Positron-emission tomography of four patients showed decreased glucose metabolism in the medial temporal lobes. Neuropathological studies in the four patients who died after mussel-induced intoxication demonstrated neuronal necrosis and loss, predominantly in the hippocampus and amygdala, in a pattern similar to that observed experimentally in animals after the administration of kainic acid, which is also structurally similar to glutamate and domoic acid. We conclude that intoxication with domoic acid causes a novel and distinct clinicopathologic syndrome characterized initially by widespread neurologic dysfunction and then by chronic residual memory deficits and motor neuronopathy or axonopathy.
 ...
PMID:Neurologic sequelae of domoic acid intoxication due to the ingestion of contaminated mussels. 207 68

A series of biochemical determinations was performed on five cellular fractions obtained from the cerebellum of 8- to 14-day-old mice. Cerebellar tissue was dissociated by mild trypsinization and mechanical agitation. The dissociated cellular material was separated into five fractions using a series of continuous density gradients formed with Percoll. Three of the fractions were comprised primarily of cell bodies. One of these was dominated by cells having the size and morphological appearance of granule cells, and based on several criteria the other two were were enriched in astrocyte cell bodies. Morphological analysis indicated that the remaining two fractions were enriched, respectively, in nerve terminals and large nucleated cell bodies. The uptake of 12 amino acids and 4 other metabolites by these cellular fractions was examined, and Km and Vmax values were determined for 10 of the compounds studied. High affinity transport carriers (Km approximately 1 to 20 microM) for most of the compounds studied were evident in neuronal and astrocyte-enriched fractions; however, for glutamate and gamma-aminobutyric acid (GABA) additional carriers with higher substrate affinities (Km approximately 0.1 to 0.3 microM) were evident in the astrocyte-enriched fraction. The fraction enriched in granule cell bodies was distinguished by an exceptionally low uptake of GABA and citrate, and a comparatively low uptake of beta-alanine, taurine, alpha-ketoglutarate, and glutamate. An analysis of the content of nine amino acids in the five fractions revealed that only glutamate, aspartate, and GABA were concentrated in the fraction enriched in nerve terminals. GABA was concentrated also in the fraction enriched in large cell bodies and was present at a low concentration in the fraction enriched in granule cell bodies. The other amino acids measured were distributed nearly evenly among the five fractions. Several differences in metabolic activity among the five fractions were observed. Radiolabel from several precursors was incorporated into GABA preferentially in the fractions enriched in large cell bodies and nerve terminals. In contrast, the accumulation of label in glutamine occurred preferentially in the fractions enriched in astrocytes and granule cell bodies. Labeling of alanine from [14C]pyruvate and of proline from [14C]ornithine was most prominent in the fractions enriched in astrocytes and granule cell bodies.
 ...
PMID:Amino acid uptake, content, and metabolism by neuronal and glial enriched cellular fractions from mouse cerebellum. 669 46

Over fifty patients with severe head injury, and one hundred with stroke, have now been treated with the competitive NMDA antagonist CGS 19755 (selfotel). Preliminary analysis has shown possible evidence of benefit for both these clinical indications, and several other glutamate antagonists are now being evaluated for these indications in Phase II trials. The optimal dose of CGS 19755 (selfotel) for efficacy for severe head trauma has not yet been identified, but may be > 3 mg/kg, as at this dose there was evidence of an ICP lowering effect and improved CPP. For stroke, however, the maximal tolerated dose was 1.5 mg/kg, because these conscious patients developed hallucinations and agitation. There were no other significant drug-associated adverse events in either of these studies. It is difficult to determine the "neuroprotective" dose for this compound in humans. By extrapolating from animal studies the "best estimate" would be around 5 mg/kg in patients with severe head trauma. For stroke, behavioral side effects were the major limiting factor for dosing. Although several NMDA antagonists, including CGS 19755 (selfotel), are currently entering efficacy trials for stroke, based upon their tremendous potency in animal models, the problem of psychomimetic effects may necessitate the use of additional management strategies, e.g., more intensive monitoring and concomitant medications.
 ...
PMID:Strategies for neuroprotection with glutamate antagonists. Extrapolating from evidence taken from the first stroke and head injury studies. 748 13

Anticholinergic treatment of neuroleptic extrapyramidal movement disorders (EPS) has been associated with induction of tardive dyskinesia. Also an increasing abuse of anticholinergics by schizophrenic patients is noted. Since as early as 1976, positive effects of amantadine (AMA) on neuroleptic EPS have been described, therefore a controlled study of these reports seemed worthwhile. Forty-two schizophrenic patients (of which 7 were dropouts) of three centers entered the study and were treated for EPS in a double-blind design: 18 (11 m, 7 f) with AMA and 17 (8 m, 9 f) with biperiden (BIP). Identical preparations of AMA 100 mg, tid) and BIP (2 mg, tid) were used in treatment of haloperidol-induced EPS (AMA, mean 22.4 mg haloperidol; BIP, mean 19.6 mg haloperidol). Effects of treatment and possible side effects were rated: EPS for the intensity of EPS, BPRS for quantification of psychotic symptoms, FSUCL for rating the side effects and KUSTA to document patients' mood. Ratings were recorded on days 0, 3, 7, 14, 28 and at discontinuation, respectively. All patients were treated with haloperidol and levomepromazine (for tranquilization/sleep induction) and the respective antiparkinsonian agent for 14 days. Patient characteristics did not differ significantly in either groups. In the AMA treatment group, 2 patients dropped out for noncompliance, in the BIP group, 5 (3 no effect, 1 noncompliance, 1 agitation). All results as recorded with the different rating instruments showed a significant (p < 0.01) overall improvement, whereas no significant differences between treatment groups could be determined, notably the treatment effect of both drugs on EPS was similar. Thus, the application of AMA in cases of neuroleptic EPS seems justified and is a useful alternative of anticholinergic drugs. Certain advantageous aspects of AMA treatment of EPS with regard to the glutamate hypothesis of schizophrenia and tardive dyskinesia are discussed.
 ...
PMID:Amantadine versus biperiden: a double-blind study of treatment efficacy in neuroleptic extrapyramidal movement disorders. 892 33

1. We have previously shown that chronic antagonism of group I metabotropic glutamate receptors (mGluRs), in the brain, attenuates the precipitated morphine withdrawal syndrome in rats. In the present investigation we assessed the effects of chronic antagonism of group II and III mGluRs on the severity of withdrawal symptoms in rats treated chronically with subcutaneous (s.c.) morphine. 2. Concurrently with s.c. morphine we infused intracerebroventricularly (i.c.v.) one of a series of phenylglycine derivatives selective for specific mGluR subtypes. Group II mGluRs (mGluR2,3), which are negatively coupled to adenosine 3':5'-cyclic monophosphate (cyclic AMP) production, were selectively antagonized with 2s, 1's, 2's-2-methyl-2-(2'-carboxycyclopropyl) glycine (MCCG). Group III mGluRs (mGluR4,6,7 and 8), which are also negatively linked to cyclic AMP production, were selectively antagonized with alpha-methyl-L-amino-4-phosphonobutanoate (MAP4). The effects of MCCG and MAP4 were compared with alpha-methyl-4-carboxyphenylglycine (MCPG), which non-selectively antagonizes group II mGluRs, as well as group I mGluRs (mGluR1,5) which are positively coupled to phosphatidylinositol (PI) hydrolysis. 3. Chronic i.c.v. administration of both MCCG and MAP4 significantly decreased the time spent in withdrawal, MCPG and MCCG reduced the frequency of jumps and wet dog shakes and attenuated the severity of agitation. 4. Acute i.c.v. injection of mGluR antagonists just before the precipitation of withdrawal failed to decrease the severity of abstinence symptoms. Rather, acute i.c.v. injection of MCCG significantly increased the time spent in withdrawal. 5. Our results suggest that the development of opioid dependence is affected by mGluR-mediated PI hydrolysis and mGluR-regulated cyclic AMP production.
 ...
PMID:Attenuation of morphine withdrawal symptoms by subtype-selective metabotropic glutamate receptor antagonists. 913 11

This single case reports an open trial of lamotrigine in the treatment of self-injurious behavior (SIB) and epilepsy in an 18-year-old female diagnosed with generalized seizure disorder, stereotypic movement disorder, and compulsive SIB in the context of profound mental retardation. Animal models of SIB suggest that the glutamate neurotransmitter systems, involved in the generation of epileptic seizures, may also have a role in the pathophysiology of SIB. Data suggesting that lamotrigine may decrease glutamate release encouraged an empirical trial of lamotrigine for treatment of SIB. After 4 weeks of treatment of lamotrigine 200 mg daily, decreases in agitation and fearfulness were clinically observed, along with a 50% reduction in the frequency of SIB as measured by standardized scales. Good seizure control was maintained throughout the trial. No significant adverse effects were observed. Positive effects persisted at 1-year follow-up. Symptoms of stereotypic movement disorder appeared unchanged. Because these findings are preliminary, no clinical recommendations for the treatment of SIB with lamotrigine can be made until controlled studies have been completed.
 ...
PMID:Open trial lamotrigine in the treatment of self-injurious behavior in an adolescent with profound mental retardation. 923 20

The Arabian Gulf catfish, Arius bilineatus (Valenciennes) secretes a proteinaceous epidermal secretion when threatened or injured. A toxic factor has been isolated and purified from the crude extract (crude skin toxin) of these secretions by a combination of gel filtration on Sephacryl S-300 and preparative discontinuous polyacrylamide gel electrophoresis. The purified skin toxin has a molecular weight of 39,000 Da and an isoelectric point (pI) of 5.45. Injection of the purified skin toxin into rabbits i.v. and determination of the LD50 indicated that the protein had been purified approximately 30 fold by these procedures. Injection of the purified skin toxin into rabbits caused agitation, convulsions and death within 5 min. Analysis of plasma levels of lactate dehydrogenase, glutamate-oxaloacetate transaminase and glutamate pyruvate transaminase in injected rabbits indicated that the skin toxin caused cardiac and liver damage to the animals.
 ...
PMID:Purification of a toxic factor from Arabian Gulf catfish epidermal secretions. 966 92

The temporolimbic structures of the brain that subserve emotional representation are highly epileptogenic and play an important role in the modulation of hormonal secretion and mediation of hormonal feedback. Estrogen is highly epileptogenic and exerts energizing and antidepressant effects. Excessive estrogen influence produces anxiety, agitation, irritability, and lability. It can promote the development of anxiety manifestations (e.g., panic, phobias, and obsessive-compulsive disorder). Progesterone and its metabolites inhibit kindling and seizure activity. They have potent anxiolytic effects, possibly by virtue of their GABAergic activity. Excessive progesterone influence produces sedation and depression. Testosterone has two major metabolites: estradiol, which can exacerbate seizures, and dihydrotestosterone, which blocks NMDA-type glutamate transmission and may be responsible for antiseizure effects. Testosterone has energizing effects and increases sexual desire in both men and women. In excess, however, it may promote aggressive, impulsive, and hypersexual behavior. Hormonal effects tend to be exaggerated or idiosyncratic in the setting of an abnormal or anomalous temporolimbic substrate, especially temporolimbic epilepsy. This may reflect altered neuronal responsivity to hormonal exposure perhaps by virtue of changes in the number of dendritic spines and receptors.
 ...
PMID:Psychoneuroendocrine aspects of temporolimbic epilepsy. Part I. Brain, reproductive steroids, and emotions. 1010 Apr 30


1 2 3 4 5 6 Next >>