Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.16.2 (PCP)
 3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental evidence suggests that neuronal pharmacologic sites termed sigma (sigma) may be related, but not identical to PCP sites in the ion channel linked to NMDA excitatory receptors. These receptors may play a role in schizophreniform psychoses, and clinical trials of putative sigma-ligands have begun. Because of this, and because of the relationship of sigma-ligands to NMDA receptors, we studied the effect of the most selective presently available sigma-ligand on ischaemic neuronal death throughout the rat brain after transient forebrain ischaemia. Ventricular delivery of DTG at 0.5 mumol/h via an osmotic minipump was chosen to allow continuous access of the drug to brain tissue, control animals receiving artificial CSF. After one week survival, selective neuronal necrosis was reduced in the hippocampus, but not in the neocortex or striatum, contrasting with our previous findings in this model with pure NMDA antagonists. The results indicate that ischaemic neuronal necrosis in the hippocampus may be mitigated by sigma-agonists, possibly via an interaction with NMDA receptors.
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PMID:Intraventricular infusion of the selective sigma-agonist 1,3-di-ortho-tolylguanidine (DTG) mitigates ischaemic brain damage in the hippocampus. 168 37

By using receptor blockade, HPLC, destroying catecholaminergic nerve terminals by 6-OHDA, autoradiography, and other techniques, the relationship between effects of the spinal PCP receptor on cardiovascular function and noradrenergic system was studied. The main results were as following. Hypotension and bradycardia induced by ith PCP were significantly antagonized by prazosin and yohimbine; the MHPG levels in spinal CSF were significantly increased during the ith PCP induced hypotension and bradycardia; pretreatment with 6-OHDA to destroy NA terminals in the spinal cord significantly decreased the ith PCP induced hypotension and bradycardia, and the density of PCP receptors in the spinal cord. The results suggest that there are PCP receptors on the NA terminals in the spinal cord, which promoted the release of NA and/or inhibited the reuptake of NA. This may be a possible mechanism underlying the influence of spinal PCP receptors on cardiovascular function.
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PMID:[Relationship between spinal PCP receptor on cardiovascular effect and noradrenergic system]. 217 45

3'-azido-3'-deoxythymidine is a thymidine analogue with an in vitro as well as in vivo efficacy towards HIV-mediated infection. Zidovudine exerts its action, following an intracellular three-step phosphorylation, through viral reverse transcriptase inhibition. Its half-life is approximately one hour. Oral biodisponibility is 65%, and passage through blood-brain barrier results in therapeutic levels is CSF. Clinical evaluation has enabled demonstration of a beneficial effect on survival of stage IV AIDS patients, when treated after a PCP episode. In this setting, aggregate survival ratios reach 73% after one year of follow-up, and 41% after 2 years. In addition, zidovudine activity has been demonstrated in treatment of HIV-induced thrombopenias as well as HIV-related central nervous system disorders. Presently, zidovudine therapeutic evaluation proceeds through the following main axes: dosage tuning (either by lowering of standard dose, and/or dose interval modification); combination with other antiviral therapies; lastly, patient treatment et an early stage of disease.
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PMID:[Zidovudine. The current status of its evaluation]. 269 36

A fraction which potently and specifically competed with 3H-PCP binding to rat membranes was isolated from human CSF. This substance ran just before the salts in Sephadex G-25 column and was eluted with low concentrations of acetonitrile in reverse phase HPLC, predicating that it may be a small hydrophilic compound with a MW. of less than 1,000 daltons.
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PMID:An endogenous ligand from human CSE for the phencyclidine receptor. 282 64

A previously healthy 30-year-old black woman with no history of substance abuse was hospitalized after she attempted to drown her 4-year-old son. She had become progressively confused and delusional after a flu-like illness 2 weeks before. Serum and lumbar CSF samples assayed for phencyclidine (PCP) by gas chromatography-mass spectrometry with d5 PCP as an internal standard were positive. The patient recovered rapidly after treatment with haloperidol and acidification of her urine. Suspicion of PCP abuse should remain high among patients with psychosis, even for those with no history of substance abuse.
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PMID:Phencyclidine in CSF and serum: a case of attempted filicide by a mother without a history of substance abuse. 373 77

We hypothesized that therapy with granulocyte-macrophage colony stimulating factor (GM-CSF) would decrease intensity of murine Pneumocystis carinii pneumonia by upregulating alveolar macrophage function. Mice were depleted of CD4+ T lymphocytes and then inoculated intratracheally with P. carinii. Four weeks later, they received recombinant murine GM-CSF (rmGM-CSF) 5 micrograms/d subcutaneously for 7 and 14 d. At the end of therapy lung tissue was scored for intensity of P. carinii infection by silver methenamine stain and for inflammation by hematoxylin-eosin stain. We found that rmGM-CSF therapy significant decreased the intensity scores of PCP infection in comparison to control mice (1.88 +/- 0.47 vs 3.06 +/- 0.12, p < 0.001). Inflammation scores were not significantly different in the rmGM-CSF group compared with the control group (1.83 +/- 0.47 vs 2.83 +/- 0.67). Alveolar macrophages from mice treated with rmGM-CSF released significantly more tumor necrosis factor-alpha (TNF-alpha) than cells from control mice after in vitro stimulation with lipopolysaccharide (LPS) alone (2.65 +/- 0.30 vs 1.45 +/- 0.26 ng/ml, p = 0.01) or with LPS plus murine recombinant interferon-gamma (4.16 +/- 0.51 vs 2.25 +/- 0.34 ng/ml, p = 0.01). We conclude that GM-CSF therapy reduces the intensity of PCP and this effect is associated with an enhanced alveolar macrophage TNF-alpha production.
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PMID:Granulocyte-macrophage colony stimulating factor and Pneumocystis carinii pneumonia in mice. 769 58

In a multi-centre phase I study we investigated the possibility of reducing the interval between courses of standard CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mgs day 1, and prednisolone 40 mg/m2 days 1-8) from 21 days to 15 days and then 10 days using granulocyte colony stimulating factor (r-MetHuG-CSF (Amgen)-filgrastim) to accelerate neutrophil recovery. Patients received CHOP followed by G-CSF 5 micrograms/kg s.c. from day 2 to the day before the next course (e.g. days 2-14 for the 15-day interval). A total of 28 patients with newly diagnosed intermediate grade or high grade NHL were studied. Four patients were studied at a 21-day interval, six patients were treated at a 15-day interval and subsequently six patients at a 10-day interval. Following analysis of this initial cohort, a further 12 patients were evaluated; four at the 15-day interval, and eight at the 10-day interval. No dose-limiting toxicity was seen in the four patients receiving 21-day CHOP. Dose-limiting toxicity was seen in 4/10 patients treated at the 15-day interval (M:F 7:3, median age 55.5, range 39-67 years). This consisted of infection in two patients, recurrent infection and debility in a third, and mucositis in a fourth. Seven patients experienced one or more infectious episodes requiring antibiotics (median number of episodes: 2, range 1-4). Fourteen patients (M:F 4:3, median age 47.5, range 25-63 years) were treated at the 10-day interval. Dose-limiting toxicity was seen in six patients. This consisted of severe mucositis in three patients, neutropenia and thrombocytopenia on two separate occasions in one patient, and steroid-induced gastritis in two patients. Nine patients had one or more documented infections (median: 2, range 1-3) requiring antibiotics, of which six were severe (WHO grade 3 or 4). One patient died of Pneumocystis carinii (PCP) pneumonia. In summary, G-CSF (filgrastim) will facilitate the shortening of the dosage interval between cycles of CHOP chemotherapy due to accelerated hematological recovery. However, non-hematological toxicity due to the shorter dosage interval is increased and infective episodes are frequent.
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PMID:A phase I trial to assess the value of recombinant human granulocyte colony stimulating factor (R-MeTHuG-CSF, filgrastim) in accelerating the dose rate of chemotherapy for intermediate and high-grade non-Hodgkin's lymphoma (NHL). The Central Lymphoma Group. 926 65

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.
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PMID:Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis. 2681 Mar 16

Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Phencyclidine (PCP) is used as a validated model for schizophrenia, shown to reliably induce positive, negative and cognitive-like behaviors in rodents. It was previously shown in our lab that behavioral phenotypes of PCP-treated mice can be alleviated after intracranial transplantation of mesenchymal stem cells (MSC). Here, we assessed the feasibility of intranasal delivery of MSCs-derived-extracellular vesicles (EVs) to alleviate schizophrenia-like behaviors in a PCP model of schizophrenia. As MSCs-derived EVs were already shown to concentrate at the site of lesion in the brain, we determined that in PCP induced injury the EVs migrate to the prefrontal cortex (PFC) of treated mice, a most involved area of the brain in schizophrenia. We show that intranasal delivery of MSC-EVs improve social interaction and disruption in prepulse inhibition (PPI) seen in PCP-treated mice. In addition, immunohistochemical studies demonstrate that the EVs preserve the number of parvalbumin-positive GABAergic interneurons in the PFC of treated mice. Finally, MSCs-EVs reduced glutamate levels in the CSF of PCP-treated mice, which might explain the reduction of toxicity. In conclusion, we show that MSCs-EVs improve the core schizophrenia-like behavior and biochemical markers of schizophrenia and might be used as a novel treatment for this incurable disorder.
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PMID:Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia. 3302 83