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631.
CE Beyer Q Lin B Platt J Malberg G Hornby KM Sullivan DL Smith T Lock PJ Mitchell NT Hatzenbuhler DA Evrard BL Harrison R Magolda MN Pangalos LE Schechter S Rosenzweig-Lipson TH Andree 《British journal of pharmacology》2009,157(2):307-319
Background and purpose
As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT1A receptor antagonist activities, was evaluated in preclinical models.Experimental approach
Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models.Key results
WAY-211612 inhibited 5-HT reuptake (Ki = 1.5 nmol·L−1; KB = 17.7 nmol·L−1) and exhibited full 5-HT1A receptor antagonist activity (Ki = 1.2 nmol·L−1; KB = 6.3 nmol·L−1; Imax 100% in adenyl cyclase assays; KB = 19.8 nmol·L−1; Imax 100% in GTPγS). WAY-211612 (3 and 30 mg·kg−1, po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT1A receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3–30 mg·kg−1, po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg−1, s.c.) and a 5-HT1A antagonist (WAY-100635; 0.3 mg·kg−1, s.c). WAY-211612 (3.3–30 mg·kg−1, s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3–30 mg·kg−1, i.p. and 10–56 mg·kg−1, po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg·kg−1, i.p.) in the rat scheduled-induced polydipsia model.Conclusions and implications
These findings suggest that WAY-211612 may represent a novel antidepressant. 相似文献632.
T. TULASSAY W. RASCHER J. HAJDU R. E. LANG M. TÓTH I. SERI 《Acta paediatrica (Oslo, Norway : 1992)》1987,76(1):42-46
ABSTRACT. The role of dopamine (DA) in the activation and/or release of atrial natriuretic peptide (ANP) was investigated in 11 premature infants during the early postnatal period. Mean plasma concentration of ANP and free DA level before DA infusion was 252.6±210 fmol/ml, and 0.4±0.2 ng/ml, respectively. DA infusion in a dose of 2μg/kg/min caused a rise in plasma free DA level to 59.7±21.5 ng/ml and a significant increase in GFR, diuresis, sodium excretion and fractional sodium excretion. The plasma concentration of ANP, however, remained unchanged (252.6±210.0 vs. 213±143.0 fmol/ml). Thus, our data failed to demonstrate a stimulatory effect of DA on ANP release in premature infants. The role of the high plasma concentration of ANP in preterm neonates immediately after birth has to be clarified. 相似文献
633.
Serological confirmation of human T-lymphotropic virus type I infection in healthy blood and plasma donors 总被引:10,自引:0,他引:10
Anderson DW; Epstein JS; Lee TH; Lairmore MD; Saxinger C; Kalyanaraman VS; Slamon D; Parks W; Poiesz BJ; Pierik LT 《Blood》1989,74(7):2585-2591
We wished to develop criteria for serological confirmation of human T- lymphotropic virus type I (HTLV-I) infection in healthy donors. Selected serum or plasma samples reactive by HTLV-I enzyme immunosorbent assay or gel-agglutination assays with at least one viral- specific band on Western immunoblot (WIB) were tested in six laboratories by four WIBs and four radioimmunoprecipitation assays (RIPAs) for antibodies to HTLV-I proteins encoded by gag (p19 and p24), env (gp46 and/or gp61), and tax (p40x) genes. One hundred forty-two donor sera were obtained from 38 Japanese, 69 American, and 35 Caribbean blood or plasma donors. Among these samples, WIB assays appeared more sensitive to p24 antibodies, whereas RIPAs were significantly more sensitive to gp61 antibodies. All sera (137) with gp61 antibodies had p24 antibodies. Of the 137 sera positive for p24 and gp61 antibodies, p19 antibodies were detected in 129 sera, and p40x antibodies were detected in 108. In sera with p19 antibodies and antibodies to env- or tax-encoded proteins, p24 antibodies were always present. Antibodies to p40x were not found in the absence of gp61 antibodies. Virological evidence of infection was found in seven American donors by lymphocyte coculture (one HTLV-I, one HTLV-II) or by polymerase chain reaction (three HTLV-I, two HTLV-II). Sera from all seven donors showed p24 and gp46 and/or gp61 antibodies. We suggest that seroreactivity to both p24 and gp46 and/or gp61 by WIB or RIPA or both are suitable criteria to confirm but not to distinguish HTLV-I and HTLV-II infections. 相似文献
634.
TH.W.VAN DEN AKKER B. NAAFS A.H.J. KOLK E.DE GLOPPER-VAN DER VEER R.A.M. CHIN A LIEN TH.VAN JOOST 《The British journal of dermatology》1992,127(4):352-358
Eight out of 17 mouse anti-Mycobacterium leprae monoclonal antibodies (MAb) were previously observed to react with human nerve and skin antigenic determinants in cryostat sections, using an indirect immunoperoxidase technique. These observations suggested that antigenic mimicry may be involved in the development of the clinical manifestations of leprosy. In the present study we have extended our earlier findings by investigating sera from leprosy patients and MAb using Western blot technique. It was observed that 30 sera and their corresponding F(ab')2 fragments from isolated IgG fractions of both tuberculoid and lepromatous patients reacted with 40-50 epidermal proteins of molecular weights (MW) ranging from 10 to 130 kDa. Sera from 14 controls, however, showed similar reactivity patterns. Absorption of nine patient and control sera with M. tuberculosis, M. marinum and M. kansasii resulted in the removal of several components of different MW in nine, four and three cases, respectively. No consistent differences between sera from leprosy patients and controls were observed. Four out of eight MAb against M. leprae which reacted with determinants in human epidermis and/or dermis in skin cryostat sections reacted with epidermal proteins of MW higher than 39 kDa in Western blot. Four MAb which showed reactivity in cryostat sections did not react in Western blot. Another four MAb did react with human epidermal proteins in Western blot but did not react in cryostat sections, indicating that the MAb were reacting with different epitopes in the two systems. Five MAb did not react with human epidermal proteins either in cryostat sections or in Western blot.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
635.
OBJECTIVE: To examine the prevalence and pattern of neurodevelopmental handicap at 2 years of age in very low birth weight infants (VLBW) admitted in 1993 to a level 3 Malaysian nursery. METHODS: All VLBW babies born in the hospital or referred for neonatal care during 1993 were enrolled prospectively in the study. At 2 years of age development was assessed using the Griffiths mental scales. Neurological, hearing and visual assessments were graded into five groups according to functional handicap. Control infants were randomly selected during attendance at a primary health care clinic. RESULTS: One hundred and fifty VLBW infants were admitted and 82 (54.6%) survived to 2 years, of whom 77 (93.9%) were assessed. The mean General Quotient (GQ) on the Griffiths Scales was 94 (15.7) for the study group and 104 (8.3) for the 60 controls. For GQ, 21 (27.3%) of the study population were 1 or more SD below the mean (18 between 1 and 2 SD and 3 > 2 SD) compared with 1 (1.6%) of the controls who was 1-2 SD below the mean. Visual impairment occurred in 2 study infants and none of the controls. There was no hearing impairment in either group. Cerebral palsy occurred in 3 (1 mild and 2 moderate-severe) of the study group and none of the controls. Functionally 18 (23.3%) of the study group had mild handicap, 1 (1.3%) moderate, 2 (2.5%) severe, 2 (2.5%) multiply severe and 54 (70.2%) were normal. CONCLUSION: Although survival was low, overall rates of functional handicap were similar to those reported in developed countries but the proportion with moderate or severe handicap was low. 相似文献
636.
S. MENDELBOUM RAVIV A. HORVÁTH J. ARADI Z. BAGOLY F. FAZAKAS Z. BATTA L. MUSZBEK J. HÁRSFALVI 《Journal of thrombosis and haemostasis》2008,6(10):1764-1771
Summary. Background: The consensus thrombin aptamer C15‐mer is a single‐stranded DNA of 15 nucleotides [d(GGTTGGTGTGGTTGG)] that was identified by the selection of thrombin‐binding molecules from a large combinatorial library of oligonucleotides. It is capable of inhibiting thrombin at nanomolar concentrations through binding to a specific region within thrombin exosite 1. As has been shown in our earlier studies, the 4‐thio‐deoxyuridylate (s4dU)‐containing oligonucleotides have high affinity for a number of proteins, due to the reduced hydrophilic character of the modified oligonucleotide. Methods: Three different analogs of the original thrombin‐inhibiting sequence, in which some of the thymidylate residues were replaced by 4‐thio‐deoxyuridylates, were synthesized. The inhibitory effect of modified aptamers was tested on thrombin‐catalyzed fibrin clot formation and fibrinopeptide A release from fibrinogen, thrombin‐induced platelet aggregation/secretion, and the formation of thrombus on coverslips coated with human collagen type III, thrombin‐treated fibrinogen or subendothelial matrix of human microvascular endothelial cells. Results: As compared with the C15‐mer, the analog with the sequence GG(s4dU)TGG(s4dU)G(s4dU)GGT(s4dU)GG (UC15‐mer) showed a 2‐fold increased inhibition of thrombin‐catalyzed fibrin clot formation, fibrinopeptide A release, platelet aggregation and secretion in human plasma and thrombus formation on thrombin‐treated fibrinogen surfaces under flow conditions. Concerning the inhibition of thrombin‐induced fibrin formation from purified fibrinogen and activation of washed platelets, UC15‐mer was 3‐fold and twelve‐fold more effective than C15‐mer, respectively. Conclusion: The replacement of four thymidylate residues in C15‐mer by 4‐thio‐deoxyuridylate resulted in a new thrombin aptamer with increased anticoagulant and antithrombotic properties. 相似文献