Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The behavioural effects of selective serotonin reuptake inhibitors (paroxetine, sertraline, citalopram, fluvoxamine, fluoxetine) and reference compounds (N,N'-di(o-tolyl)guanidine, haloperidol, 3-(3-hydroxyphenyl)-N-(l-propyl)piperidine and chlorpromazine) were studied for their ability to produce dystonia and torticollis following direct micro injection into the left red nucleus of the rat, an area of the brain containing a high density of sigma2 receptors but relatively devoid of biogenic amine receptors. Each animal was monitored for abnormalities in posture and movement for a period of 30 min and then sacrificed 40 min following drug administation. Only fluvoxamine (100 nmol) and fluoxetine (100 nmol) elicited acute dystonic behaviour (1-5 min). The onset of dystonia was accompanied by facial spasticity, vacuous chewing movements and grooming behaviour which reflected the extent of dystonia. The dystonic behaviour following the direct intrarubal injection of fluvoxamine and fluoxetine suggest the possible activation of sigma2 receptors while citalopram, sertraline and paroxetine were without effect. The results of this study support the role of sigma2 receptors in the regulation and control of movement and coordination and provides preliminary evidence to suggest the in vivo activity of sigma receptors by fluoxetine and fluvoxamine.
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PMID:Behavioural effects of selective serotonin reuptake inhibitors following direct micro injection into the left red nucleus of the rat. 909 94

E2101 or N-methyl-[1-[1-(2-fluorophenethyl)piperidine-4-yl]-1H-indol-6-yl] acetamide, an antagonist of 5-hydroxytryptamine receptor subtypes 1A and 2, is currently under development for the potential treatment of skeletal muscle associated spasticity. Here we characterized the in vitro metabolism of E2101 using human liver enzymes including human liver microsomal preparations, human liver S9 fractions, and individual forms of recombinant cytochromes P450 (P450s). Our results showed that E2101 was metabolized by P450s to form monohydroxylated (M1 and M2), dihydroxylated (M3), and N-dealkylated metabolites (M4). The structures of these major microsomal metabolites were proposed based on LC/MS/MS analyses. All four metabolites, M1-M4, were formed by CYP3A4. Metabolites, M1, M2, and M4, were also formed by CYP2C19 and M2 and M3 by CYP2D6. The potential P450 inhibition and induction of E2101 were also evaluated. E2101 was determined to be a competitive inhibitor of CYP2C19 and CYP2D6 with K(i) of 15 and 48 microM, respectively, as determined by both Dixon plots and simultaneously nonlinear regression analyses. Induction of major P450 expression was not detected immunochemically after 72-h exposure to 10 or 50 microM E2101 in primary hepatocyte cultures obtained from three subjects. Taken together, E2101 is expected to metabolically interact with major human P450 enzymes including CYP2C19, CYP2D6, and CYP3A4, and a low risk of drug-drug interaction would be anticipated in clinical studies.
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PMID:In vitro interactions between a potential muscle relaxant E2101 and human cytochromes P450. 1206 39

Prostaglandin (PG) D2 is well known as a mediator of inflammation. Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD2 involved in inflammatory responses. Microglial activation and astrogliosis are commonly observed during neuroinflammation, including that which occurs during demyelination. Using the genetic demyelination mouse twitcher, a model of human Krabbe's disease, we discovered that activated microglia expressed HPGDS and activated astrocytes expressed the DP1 receptor for PGD2 in the brain of these mice. Cultured microglia actively produced PGD2 by the action of HPGDS. Cultured astrocytes expressed two types of PGD2 receptor, DP1 and DP2, and showed enhanced GFAP production after stimulation of either receptor with its respective agonist. These results suggest that PGD2 plays an important role in microglia/astrocyte interaction. We demonstrated that the blockade of the HPGDS/PGD2/DP signaling pathway using HPGDS- or DP1-null twitcher mice, and twitcher mice treated with an HPGDS inhibitor, HQL-79 (4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine), resulted in remarkable suppression of astrogliosis and demyelination, as well as a reduction in twitching and spasticity. Furthermore, we found that the degree of oligodendroglial apoptosis was also reduced in HPGDS-null and HQL-79-treated twitcher mice. These results suggest that PGD2 is the key neuroinflammatory molecule that heightens the pathological response to demyelination in twitcher mice.
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PMID:Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. 1662 58