Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-mortem brain regions of schizophrenics were investigated in comparison to matched controls regarding synaptosomal K(+)-stimulated [3H]DA release and its modulation by DA autoreceptors. Brain specimens were cryopreserved in liquid nitrogen until release experiments; synaptosomes from brain pieces preincubated with dimethylsulfoxide have unchanged ability for [3H]DA release and its autoreceptor-mediated inhibition after cryo-preservation. Release data were individually corrected for post-mortem delay back to the zero-time state based on [3H]DA release alterations after in situ preservation of rat heads. In schizophrenia, the K(+)-stimulated [3H]DA release from superfused synaptosomes of the nucleus (n.) accumbens and n. caudatus was diminished significantly. Furthermore, functional supersensitivity of the modulatory DA autoreceptors could be demonstrated in these regions. The alterations demonstrated seem not to be due primarily to medication since in neuroleptic-free patients similar changes were shown.
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PMID:Diminished synaptosomal dopamine (DA) release and DA autoreceptor supersensitivity in schizophrenia. 167 43

Ligands of various chemical classes (e.g., indoles, indazoles, benzamides, carbazoles, and quinolines) have demonstrated high affinity for the 5-HT3 receptor in radiolabeled ligand-binding studies, and have shown 5-HT3 receptor antagonistic activity in functional assays which utilize the excitatory effects of 5-HT on enteric neurons and autonomic afferents. Several 5-HT3 antagonists are currently being evaluated for potential use in the treatment of migraine, schizophrenia, and anxiety, and a few have already demonstrated high efficacy as antiemetics in cancer chemotherapy. The purpose of this presentation is to highlight the significant structure-affinity relationships (SAFIR) and common geometrical features among 5-HT3 receptor ligands, and to describe the three-dimensional pharmacophore for the 5-HT3 recognition site derived from computational techniques. The chemical template containing the recognition elements (functional groups) for the 5-HT3 receptor are: an aromatic or heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center, interrelated by well-defined distances. Two "binding shapes" or "active shapes" for 5-HT3 ligands have been identified from detailed conformational analyses.
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PMID:Molecular modeling of 5-HT3 receptor ligands. 181 57

This study examined the descriptive epidemiology of seizure disorder in 129 male residents of a Veterans Administration Nursing Home. Eighty-seven of the residents were institutionalized because of nonpsychiatric disorders (60 for chronic neurologic diseases, and 27 for other medical conditions). Forty-two were institutionalized because of a chronic psychosis (39 for schizophrenia, three for affective disorders). We determined for each resident an extensive clinical data base of 54 items including measures of hematologic, nutritional, metabolic and endocrine status, as well as continuing medications. In the nonpsychiatric group, 16 of the 87 men had a seizure disorder. In the psychiatric group, this proportion was only three of 42. The prevalence of epilepsy in the nonpsychiatric group was 20-40 times greater than in the aged-matched general population of men. In the nonpsychiatric group, the onset of seizures followed the onset of organic brain disease. Forty-five percent of seizure disorders occurred in men who had experienced a cerebrovascular accident, and 23% in men with other types of chronic brain disease. The seizures of the nonpsychiatric men had been observed to be generalized clonic-tonic in 45%, and partial complex in 22%. Ninety-four percent of the nonpsychiatric men with epilepsy received anticonvulsants, and none had experienced more than one seizure during the preceding year. Univariate statistical analysis of the 54 item data base showed that the occurrence of seizure disorder correlated inversely with age, blood urea nitrogen, serum creatinine and serum bilirubin, and directly with plasma testosterone, hemoglobin, use of anticonvulsants, and use of psychotherapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Seizure disorder in the men of a Veterans Administration nursing home. 328 Jul 35

Routine blood samples of 145 consecutive patients seen in the Los Angeles County Psychiatric Hospital Emergency Room during a 48-hour weekday period in June 1979 were examined for phencyclidine (PCP) using a sensitive and specific gas capillary gas chromatographic nitrogen detector (GC2-N) method. Of these 145 samples 63 (43.4%) were positive and PCP levels ranged 0.34 to 142.9 nanograms/ml (mean 14.6 ng/ml +/- 3.4 S.E.M.). An analysis of the records of these 63 patients revealed a wide variety of psychotic clinical pictures resembling mania, depression or schizophrenia with relatively few of the supposedly characteristic manifestations of PCP intoxication. Each of the 63 patients had at least one manifestation of toxic psychosis and/or acute delirium, in addition to the florid symptoms characteristic of functional states. PCP measurement, pharmacokinetics and the possible relationships of this intoxication to the psychiatric manifestations are discussed.
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PMID:The urban epidemic of phencyclidine (PCP) use: clinical and laboratory evidence from a public psychiatric hospital emergency service. 721 23

1. 3-Ethyl-5-hydroxy-4,5-dimethyl-delta 3-pyrrolin-2-one (HPL, 'mauve factor') was determined quantitatively in the urine of schizophrenic, general medical and porphyric subjects by a sensitive gas/liquid-chromatographic method using a nitrogen-specific detector. 2. A comparative evaluation with previously used methods for HPL was made and some problems of specificity are discussed. 3. The concentration of HPL in early morning and spot smaples of urine from 146 subjects with schizophrenia was not greater than that in 42 general medical patients, contrary to previous reports. 4. Of the three patients with acute intermittent porphyria, two excreted HPL. One subject, studied over a 2 year period, did so intermittently in a manner unrelated to her attacks of porphyria. 5. It is concluded that the urine content of HPL is unlikely to be causally related to schizophrenia or to the clinical manifestations of acute intermittent porphyria.
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PMID:Urine concentration of 3-ethyl-5-hydroxy-4,5-dimethyl-delta 3-pyrrolin-2-one ('mauve factor') is not causally related to schizophrenia or to acute intermittent porphyria. 742 79

The recent finding that dendritic spines (on which 90% of all excitatory synapses on pyramidal cells are formed) are not permanent structures but are continually being formed and adsorbed has implications for the present theoretical basis of neurocomputation, which is largely based on the concept of fixed nerve nets. This evidence would tend to support the recent theories of Edelman, Freeman, Globus, Pribram and others that neuronal networks in the brain operate mainly as nonlinear dynamic, chaotic systems. This paper presents a hypothesis of a possible neurochemical mechanism underlying this synaptic plasticity based on reactive oxygen species and toxic 0-semiquinones derived from catecholamines (i) by the enzyme prostaglandin H synthetase induced by glutamatergic NMDA receptor activation and (ii) by reactive nitrogen species derived from nitric oxide in a low ascorbate environment. A key factor in this neuromodulation may be the fact that catecholamines are potent antioxidants and free radical scavengers and are thus able to affect the redox mediated balance at the glutamate receptors between synapse formation and synapse removal that may be a key factor in neurocomputational plasticity. But catecholamines are also easily oxidized to neurotoxic 0-semiquinones and this may be relevant to the pathology of several diseases including schizophrenia. The relationship between dopamine release and positive reinforcement is relevant to this hypothesis.
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PMID:The biochemical basis of synaptic plasticity and neurocomputation: a new theory. 914 26

Clozapine, an atypical antipsychotic used in the treatment of refractory schizophrenia, causes neutropenia and agranulocytosis in 3 and 0.8% of patients, respectively. Clozapine undergoes bioactivation to a chemically reactive nitrenium ion, which has been shown to cause neutrophil cytotoxicity. To define further the mechanism of cell death, we have investigated the toxicity of clozapine, its stable metabolites, and its chemically reactive nitrenium ion to neutrophils and lymphocytes. Clozapine was able to induce neutrophil apoptosis at therapeutic concentrations (1-3 microM) only when it was bioactivated to the nitrenium ion. The parent drug caused apoptosis at supratherapeutic concentrations (100-300 microM) only. Neutrophil apoptosis induced by the nitrenium ion, but not by the parent drug itself, was inhibited by antioxidants and genistein and was accompanied by cell surface haptenation (assessed by flow cytometry) and glutathione depletion. Dual-color flow cytometry showed that neutrophils that were haptenated were the same cells that underwent apoptosis. No apoptosis of lymphocytes was evident with the nitrenium ion or the parent drug, despite the fact that the former caused cell surface haptenation, glutathione depletion, and loss of membrane integrity. Demethylclozapine, the major stable metabolite in vivo, showed a profile that was similar to, although less marked than that observed with clozapine. N-oxidation of clozapine or replacement of the nitrogen (at position 5) by sulfur produced compounds that were entirely nontoxic to neutrophils. In conclusion, the findings of the study expand on potential mechanisms of clozapine-induced cytotoxicity, which may be of relevance to the major forms of toxicity encountered in patients taking this drug.
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PMID:Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. 1086 Sep 43

Olanzapine is a relatively new antipsychotic drug used in the United States for the treatment of schizophrenia. Since its release in the United States market in 1996, few cases of fatal acute intoxication have been reported in the literature. This article describes the case of a 25-year-old man found dead at home who had been prescribed olanzapine for schizophrenia. This case is unique because of the measurement of olanzapine in brain tissue obtained from seven regions in addition to the commonly collected biologic matrices. Olanzapine was detected and quantitated by basic liquid-liquid extraction followed by dual-column gas chromatographic analysis with nitrogen phosphorus detection. The assay had a limit of detection of 0.05 mg/L and an upper limit of linearity of 2 mg/L. The presence of olanzapine was confirmed by gas chromatography-mass spectrometry by use of electron impact ionization. The concentrations of olanzapine measured in this case were as follows (mg/L or mg/kg): 0.40 (heart blood), 0.27 (carotid blood), 0.35 (urine), 0.61 (liver), negative (cerebrospinal fluid), 0.33 mg in 50 ml (gastric contents). In the brain, the following distribution of olanzapine was determined (mg/kg): negative (cerebellum), 0.22 (hippocampus), 0.86 (midbrain), 0.16 (amygdala), 0.39 (caudate/putamen), 0.17 (left frontal cortex), and 0.37 (right frontal cortex). The cause of death was determined to be acute intoxication by olanzapine, and the manner of death was accidental.
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PMID:Tissue distribution of olanzapine in a postmortem case. 1156 38

Tricyclic psychotropic drugs (TDP) are used in the therapy of both schizophrenia and affective disturbances, especially depressive ones. They are a large group of compounds with a broadband spectrum, especially as an antipsychotic and antidepressant drugs. Phenothiazine derivatives distinguish themselves with a structure of triple cycles arrangement, composed of electrons such as a sulphur and nitrogen atoms. Among patients with schizophrenia there are many groups with different psychopathological symptoms, course of disease and neuroleptics drugs response. Affective disturbances occur particularly often in the course of schizophrenia. A higher incidence of depression in the course of schizophrenia has been observed during treatment with neuroleptics, especially in the late phase of treatment, particularly after using strong neuroleptics.
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PMID:[Application of pharmacotherapy with classic neuroleptics: phenothiazine derivatives in schizophrenia]. 1272 74

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed under physiological conditions in the human body and are removed by cellular antioxidant defense system. During oxidative stress their increased formation leads to tissue damage and cell death. This process may be especially important in the central nervous system (CNS) which is vulnerable to ROS and RNS damage as the result of the brain high O(2) consumption, high lipid content and the relatively low antioxidant defenses in brain, compared with other tissues. Recently there has been an increased number of reports suggesting the involvement of free radicals and their non-radical derivatives in a variety of pathological events and multistage disorders including neurotoxicity, apoptotic death of neurons and neural disorders: Alzheimer's (AD), Parkinson's disease (PD) and schizophrenia. Taking into consideration the basic molecular chemistry of ROS and RNS, their overall generation and location, in order to control or suppress their action it is essential to understand the fundamental aspects of this problem. In this presentation we review and summarize the basics of all the recently known and important properties, mechanisms, molecular targets, possible involvement in cellular (neural) degeneration and apoptotic death and in pathogenesis of AD, PD and schizophrenia. The aim of this article is to provide an overview of our current knowledge of this problem and to inspire experimental strategies for the evaluation of optimum innovative therapeutic trials. Another purpose of this work is to shed some light on one of the most exciting recent advances in our understanding of the CNS: the realisation that RNS pathway is highly relevant to normal brain metabolism and to neurologic disorders as well. The interactions of RNS and ROS, their interconversions and the ratio of RNS/ROS could be an important neural tissue injury mechanism(s) involved into etiology and pathogenesis of AD, PD and schizophrenia. It might be possible to direct therapeutic efforts at oxidative events in the pathway of neuron degeneration and apoptotic death. From reviewed data, no single substance can be recommended for use in human studies. Some of the recent therapeutic strategies and neuroprotective trials need further development particularly those of antioxidants enhancement. Such an approach should also consider using combinations of radical(s) scavengers rather than a single substance.
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PMID:Reactive oxygen species and reactive nitrogen species: relevance to cyto(neuro)toxic events and neurologic disorders. An overview. 1283 2


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