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Type 1 Inhibitor (type 1 + inhibitor)
Selected AbstractsPhosphodiesterase Type 4 Inhibition Does Not Restore Ocular Dominance Plasticity in a Ferret Model of Fetal Alcohol Spectrum DisordersALCOHOLISM, Issue 3 2010Thomas E. Krahe Background:, There is growing evidence that deficits in neuronal plasticity account for some of the neurological problems observed in fetal alcohol spectrum disorders (FASD). Recently, we showed that early alcohol exposure results in a permanent impairment in visual cortex ocular dominance (OD) plasticity in a ferret model of FASD. This disruption can be reversed, however, by treating animals with a Phosphodiesterase (PDE) type 1 inhibitor long after the period of alcohol exposure. Aim:, Because the mammalian brain presents different types of PDE isoforms we tested here whether inhibition of PDE type 4 also ameliorates the effects of alcohol on OD plasticity. Material and Methods:, Ferrets received 3.5 g/Kg alcohol i.p. (25% in saline) or saline as control every other day between postnatal day (P) 10 to P30, which is roughly equivalent to the third trimester equivalent of human gestation. Following a prolonged alcohol-free period (10 to 15 days), ferrets had the lid of the right eye sutured closed for 4 days and were examined for ocular dominance changes at the end of the period of deprivation. Results:, Using in vivo electrophysiology we show that inhibition of PDE4 by rolipram does not restore OD plasticity in alcohol-treated ferrets. Conclusion:, This result suggests that contrary to PDE1, PDE4 inhibition does not play a role in the restoration of OD plasticity in the ferret model of FASD. [source] Complex of urokinase-type plasminogen activator with its type 1 inhibitor predicts poor outcome in 576 patients with lymph node,negative breast carcinomaCANCER, Issue 3 2004Peggy Manders M.Sc. Abstract BACKGROUND The ability of a solid tumor to grow and metastasize has a significant dependence on protease systems, such as the plasminogen activation system. The plasminogen activation system includes the urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1), among other molecules. Both uPA and PAI-1 are established prognostic factors for patients with breast carcinoma. In the current study, the authors investigated whether the complex of uPA with PAI-1 is also associated with the natural course of this malignancy. METHODS Cytosolic levels of uPA, PAI-1, and the uPA:PAI-1 complex were measured in tumor tissue from 576 patients with lymph node,negative invasive breast carcinoma using quantitative enzyme-linked immunosorbent assays. Patients did not receive adjuvant systemic therapy, and the median follow-up duration was 61 months (range, 2,187 months) after primary diagnosis. Correlations with well known clinicopathologic factors were assessed, and univariate and multivariate survival analyses were performed. RESULTS uPA:PAI-1 complex levels were positively associated with adverse histologic grade and inversely correlated with estrogen and progesterone receptor status. On univariate analysis, increased levels of the uPA:PAI-1 complex were found to be associated with reduced recurrence-free survival (RFS) and overall survival (OS) rates. On multivariate analysis, uPA:PAI-1 complex levels were found to be an independent predictor of OS (P = 0.039), but not RFS (P = 0.240). When uPA and PAI-1 levels were not included in the multivariate analysis, uPA:PAI-1 complex levels became a significant predictor of both RFS and OS (P = 0.029 and P = 0.007, respectively). CONCLUSIONS The results of the current study demonstrate that uPA:PAI-1 complex levels have prognostic value on univariate analysis. In addition, increased uPA:PAI-1 complex levels were significantly associated with poor OS on multivariate analysis. Increased uPA:PAI-1 complex levels were also significantly associated with reduced RFS rates after the exclusion of uPA and PAI-1 levels from the multivariate analysis model. Cancer 2004. © 2004 American Cancer Society. [source] New and emerging treatments in dermatology: acneDERMATOLOGIC THERAPY, Issue 2 2008A. Katsambas ABSTRACT:, Topical retinoids, benzoyl peroxide, azelaic acid, and topical and oral antibiotics remain the milestone of treatment for mild to moderate acne vulgaris. Oral isotretinoin is useful for the treatment of severe nodular acne, treatment-resistant acne, and acne with a risk of physical or psychological scarring. Hormonal treatment in female acne is useful in resistant or late-onset acne. With increasing concerns regarding teratogenicity of isotretinoin and increasing antibiotic resistance, there is a clear need for therapeutic alternatives to these long-used treatments. Research in the pathogenesis of acne has allowed for new therapies and future perspectives regarding acne to evolve. They include low-dose long-term isotretinoin regimens, insulin-sensitizing agents, 5,-reductase type 1 inhibitors, topical photodynamic therapy, new combination formulations, dietary interventions, and antiinflammatory agents such as lipoxygenase inhibitors. [source] Methyl esters of N -(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) as drugs and prodrugs: A new strategy for dual inhibition of 5,-reductase type 1 and type 2JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2005Martina Streiber Abstract Steroid 5,-reductase (5,R) inhibitory potency of three N -(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) and their corresponding methyl esters was monitored for type 2 isoenzyme in a benign prostatic hyperplasia cell free preparation and for type 1 isoenzyme in DU145 cells and in a cell free assay. The hydrolytic stability of the esters and their bioconversion to the corresponding acids was assessed in aqueous buffered solution (pH 7.4) and in selected biological media having measurable esterase activities. The carboxylic acids 1, 2, and 3 with high type 2 inhibitory potencies displayed only little type 1 inhibition. The esters 1a, 2a, and 3a, originally designed as prodrugs to enhance cell permeation, proved to be potent type 1 inhibitors and are therefore acting as drugs themselves. They are stable in buffered salt solution (pH 7.4), Caco-2 cells, and human plasma, whereas all esters are cleaved into the corresponding acids in benign prostatic hyperplasia tissue homogenate. Methyl esters, applied as hydrolytically stable precursor drugs to facilitate cell permeation, will yield the corresponding carboxylic acids as type 2 inhibitors after hydrolysis in the target organ. The esters themselves,stable in human plasma and Caco-2 cells,are acting as potent drugs toward 5,R type 1. Thus, dual inhibition of 5,R type 1 and type 2 can be achieved by applying a single parent compound. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:473,480, 2005 [source] | ||||||||||