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41.
Antidepressant-like effects of trazodone on a behavioral screen are mediated by trazodone, not the metabolite m-chlorophenylpiperazine 总被引:1,自引:0,他引:1
Trazodone is an atypical antidepressant drug (i.e. blocks neither monoamine uptake nor monoamine oxidase) which tests as an antidepressant drug on the differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule of reinforcement by increasing the reinforcement rate and decreasing the response rate. m-Chlorophenylpiperazine (m-CPP) is a 5-HT1B and 5-HT1C agonist, weak 5-HT2 antagonist, and trazodone metabolite. It has been suggested that formation of m-CPP is responsible for the antidepressant action of trazodone. Administration of m-CPP (1-10 mg/kg i.p.) 60, 30 or 10 min before the behavioral session did not mimic the reinforcement rate-increasing effects of trazodone (10-20 mg/kg i.p.) on rats performing under the DRL 72-s schedule of water reinforcement. Pretreatment with proadifen (50 mg/kg i.p.), an inhibitor of trazodone metabolism, caused a greater than 30-fold leftward shift in the dose-response curve for both the reinforcement rate and the response rate. These results suggest that the parent compound and not the trazodone metabolite m-CPP, mediates the antidepressant-like effects of trazodone on DRL 72-s behavior. 相似文献
42.
Leire García Maria Bu?uales Nejat Düzgüne? Conchita Tros de Ilarduya 《European journal of pharmaceutics and biopharmaceutics》2007,67(1):58-66
In this study, an efficient non-viral gene transfer system has been developed by employing polyethylenimine (PEI 800, 25 and 22kDa) and DOTAP and cholesterol (Chol) as lipids (lipopolyplex), at three different lipid/DNA molar ratios (2/1, 5/1 and 17/1) by using five different protocols of formulation. Condensation assays revealed that PEI of 800, 25 and 22kDa were very effective in condensing plasmid DNA, leading to a complete condensation at N/P ratios above 4. Addition of DOTAP/Chol liposomes did not further condense DNA. Increasing the molar ratio lipid/DNA in the complex resulted in higher positive values of the zeta-potential, while the particle size increased in some protocols, but not in others. High molecular weight PEI (800kDa) used in the formulation of lipopolyplexes lead to a bigger particle size, compared to that obtained with smaller PEI species, whether branched (25kDa) or linear (22kDa). These vectors were also highly effective in protecting DNA from attack by DNAse I. Transfection activity was maximal by using protocols 3 and 4 and a lipid/DNA molar ratio of 17/1. These complexes showed high efficiency in gene delivery of DNA to liver cancer cells, even in the presence of high concentration of serum (60% FBS). On the other hand, complexes formed with linear PEI (22kDa) were more effective than lipopolyplexes containing branched PEI (800 or 25kDa). The complexes resulted to be much more efficient than conventional lipoplexes (cationic lipid and DNA) and polyplexes (cationic polymer and DNA). The same behaviour was observed for complexes prepared in the presence of the therapeutic gene pCMVIL-12. Toxicity assays revealed a viability higher than 80% in all cases, independently of the protocol, molar ratio (lipid/DNA), molecular weight and type of PEI. 相似文献
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44.
Jean-Fran?ois Ghersi-Egea Nathalie Strazielle Audrey Murat Anne Jouvet Annie Buénerd Marie-Fran?oise Belin 《Journal of cerebral blood flow and metabolism》2006,26(9):1165-1175
The choroid plexuses (CPs) form a protective interface between the blood and the ventricular cerebrospinal fluid (CSF). To probe into the pathways by which CPs provide brain protection, we sought to evaluate the efficiency of glutathione conjugation in this barrier as a mechanism to prevent the entry of blood-borne electrophilic, potentially toxic compounds into the CSF, and we investigated the fate of the resulting metabolites. Rat CPs, as well as human CPs from both fetal and adult brains, displayed high glutathione-S-transferase activities. Using an in vitro model of the blood-CSF barrier consisting of choroidal epithelial cells cultured in a two-chambered device, we showed that glutathione conjugation can efficiently prevent the entry of 1-chloro-2,4-dinitrobenzene (CDNB) into the CSF, a model for electrophilic compounds. The duration of this enzymatic protection was set by the concentration of CDNB to which the epithelium was exposed, and this barrier effect was impaired only on severe epithelial intracellular glutathione and cysteine depletion. The conjugate was excreted from the choroidal cells in a polarized manner, mostly at the blood-facing membrane, via a high-capacity transport process, which is not a rate-limiting step in this detoxification pathway, and which may involve transporters of the ATP-binding cassette c(Abcc) and/or solute carrier 21 (Slc21) families. Supplying the choroidal epithelium at the blood-facing membrane with a therapeutically relevant concentration of N-acetylcysteine sustained this neuroprotective effect. Thus, glutathione conjugation at the CP epithelium coupled with the basolateral efflux of the resulting metabolites form an efficient blood-CSF enzymatic barrier, which can be enhanced by pharmacologically increasing glutathione synthesis within the epithelial cells. 相似文献
45.
犬海水中火器伤后早期血流动力学变化 总被引:3,自引:0,他引:3
Hui Meng Hong Shen Gao-wang Liu Tian-ling Zhu Jun-xin Zhang Zeng-rong Wu Hai-ji Bu 《第一军医大学学报》2004,24(5):493-496
OBJECTIVE: To investigate the hemodynamic changes in the early stages of gunshot wound of dogs in seawater for exploring early treatment protocol. METHOD: Fourteen conventional Beagles models undergoing gunshot wound in seawater were used along with another 2 dogs receiving the wound on land to serve as control. After the dogs were rescued from the seawater, the respiration (R), heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), central venous pressure (CVP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were measured continuously in the early stages of the wound (53.62+/-12.19 min following injury), followed by statistical analysis of the results. RESULTS: Compared with the control group, the hemodynamic disturbance of the dogs receiving the wound in seawater was relatively severe during the first 15 min of the wound. The mortality tended to descend relevant to the position of the wounds, in the order of the head, chest, abdomen and limbs. CONCLUSIONS: Gunshot wound in seawater may cause severe hemodynamic changes, resulting in progressive dysfunction of circulation and high mortality rate. Early treatment should be targeted at hemodynamic stabilization in accordance to the characteristic changes during the early stages of the wound. 相似文献
46.
Blanka Ríhová Jirí Strohalm Jana Prausová Katerina Kubácková Markéta Jelínková Lad'ka Rozprimová Milada Sírová Dana Plocová Tomás Etrych Vladimír Subr Tomás Mrkvan Marek Kovár Karel Ulbrich 《Journal of controlled release》2003,91(1-2):1-16
An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing doxorubicin and human immunoglobulin as an actively/passively targeting moiety was used in four patients with generalized breast cancer resistant to standard cytotoxic chemotherapy. The dose and time schedule were deduced from a Phase I clinical trial in which doxorubicin bound to HPMA copolymer carrier (PK1) was tested. It was confirmed that the Dox-HPMA-HuIg conjugate is stable and doxorubicin remains in the peripheral blood with a small amount also in the urine, mostly in its polymer-bound form. More than 116 biochemical, immunological and hematological parameters were determined for blood samples taken from patients 24 h, 48 h, 72 h and 1 to 11 weeks after treatment. Depending on the patient, some parameters decreased permanently or temporarily to the normal level (CRP, C3, CA 72-4, beta(2)-microglobulin, ferritin, CEA, CA 125, CD4, CD8, CE19, CD16(+)56(+), leu, ery) and some moved markedly towards physiological values (AST, ALT, ALP, GMT, CA 15-3, NSE, AFP). While the number of peripheral blood reticulocytes was significantly decreased after treatment with the classical free drug, their number was not affected or was even elevated after treatment with Dox-HPMA-HuIg. Increased absolute numbers of CD16(+)56(+) and CD4(+) cells in the peripheral blood and activation of NK and LAK cells in all patients support data obtained in experimental animals, pointing to a dual, i.e. cytostatic and immunomobilizing character of Dox-HPMA conjugates containing a targeting immunoglobulin moiety. 相似文献
47.
Bošnjaković Petar Ivković Tomislav Ilić Miodrag Aracki Snežana 《Cardiovascular and interventional radiology》1992,15(4):217-220
Flexible tantalum stents (Strecker) were used as an adjunct to percutaneous transluminal angioplasty (PTA) in the treatment
of stenotic arterial or venous limbs of Brescia-Cimino hemodialysis fistulas. The diagnostic procedure was performed using
retrograde fistulography. After PTA with unsatisfactory results, stents were placed in 5 patients with significant residual
stenoses and poor fistula function. Within the mean follow-up period of 6.4 months (range 3–10 months) all fistulas were functioning.
We conclude that Strecker stent is useful in the treatment of stenotic hemodialysis arteriovenous fistulas as an adjunct to
PTA. 相似文献
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