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91.
Z Xu G Mondal J P Song R E Purdy 《The Journal of pharmacology and experimental therapeutics》1990,253(2):668-675
The effect of ouabain on the rabbit ear artery response to serotonin was assessed in isolated vascular rings mounted in tissue baths for the measurement of isometric contractions and denervated with 6-hydroxydopamine in vitro. Ouabain, 1 and 10 microM, caused 5- and 6-fold shifts to the left of the serotonin concentration-response curve (CRC). However, 10 microM ouabain caused only a 1.6-fold shift to the left of the norepinephrine CRC. In the absence of ouabain, 0.01 microM ketanserin had little effect, whereas 0.1 microM prazosin caused a marked shift to the right of the serotonin CRC. In the presence of ouabain, prazosin exhibited little or no antagonism below 3 microM serotonin. Antagonism by ketanserin was increased by 1 and 10 microM ouabain, yielding 6.5- and 10.5-fold shifts to the right of the serotonin CRC, respectively. Benextramine pretreatment to inactivate alpha adrenoceptors nearly abolished the rabbit ear artery response to serotonin. However, in the presence of 10 microM ouabain, there was a substantial recovery of the response to serotonin, and this response was antagonized by ketanserin. These results are consistent with our hypothesis that serotonergic receptors are present in the smooth muscle cell membranes of the rabbit ear artery but are either uncoupled to the contractile mechanism or in a low efficacy state. In the presence of ouabain, these receptors either become coupled or convert to a high efficacy state and thereby contribute to the serotonin-induced contraction. Because the serotonin CRC was shifted to the left in the presence of ouabain, it is likely that most of the CRC was below the threshold concentration at which serotonin activates alpha adrenoceptors. Thus antagonism by prazosin was lost. 相似文献
92.
Goutam Banerjee Swapna Medda Mukul K. Basu 《Antimicrobial agents and chemotherapy》1998,42(2):348-351
The interaction of chemotactic peptide (e.g., fMet-Leu-Phe)-grafted liposomes with macrophages is noted to be rapid and specific. At a grafted peptide concentration of 100 nmol, internalization of the peptide-grafted liposomes by the macrophages is found to reach equilibrium in 30 min. The peptide alone and the peptide-grafted empty liposomes are found to show moderate antileishmanial activity in vitro. Primaquine, which is known to generate O2− in phagocytic cells, showed leishmanicidal properties when it was tested in vitro against parasite-infected macrophages over a certain range of concentrations. It showed much better efficacy against experimental leishmaniasis when it was used in the fMet-Leu-Phe-grafted liposomal form in comparison with its efficacy when it was either in the free form or encapsulated in ungrafted liposomes. The conventional toxicity parameters (e.g., blood pathology and tissue histology-specific enzyme levels related to normal liver function) are found to be very close to normal when fMet-Leu-Phe-grafted liposomal primaquine is used. The biodegradabilities of both the drug and the delivery systems are also found to be very satisfactory. Thus, this delivery system may have possible applications for the treatment of leishmaniasis as well as other macrophage-associated disorders. 相似文献
93.
Herman GA Mistry GC Yi B Bergman AJ Wang AQ Zeng W Chen L Snyder K Ruckle JL Larson PJ Davies MJ Langdon RB Gottesdiener KM Wagner JA 《British journal of clinical pharmacology》2011,71(3):429-436
AIMS
Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males.METHODS
In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20–46 years) in each panel received single oral doses of 5–400 mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0–48 h post dose and plasma DPP-4 inhibition from 0–24 h post dose. The results were compared with historical data from young, healthy non-Japanese males.RESULTS
Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2–6 h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9–14 h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73–1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50 mg resulted in weighted average DPP-4 inhibition from 0–24 h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia.CONCLUSIONS
The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes. 相似文献94.
95.
Yamazaki H Suemizu H Shimizu M Igaya S Shibata N Nakamura M Chowdhury G Guengerich FP 《Chemical research in toxicology》2012,25(2):274-276
The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with "humanized" liver: novel humanized TK-NOG mice were prepared by the introduction of thymidine kinase, followed by induction with ganciclovir, and human liver cells were transplanted. Following oral administration of racemic thalidomide (100 mg/kg), plasma concentrations of 5-hydroxy- and dihydroxythalidomide were higher in humanized mice than in controls. After administration of 5-hydroxythalidomide (10 mg/kg), higher concentrations of dihydroxythalidomide were detected. These results indicate that livers of humanized mice mediate thalidomide oxidation, leading to catechol and/or the GSH conjugate in vivo and suggest that thalidomide activation occurs. 相似文献
96.
97.
Wei H Zhang Z Saha A Peng S Chandra G Quezado Z Mukherjee AB 《Human molecular genetics》2011,20(6):1111-1121
The infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative lysosomal storage disease. Despite our knowledge that palmitoyl-protein thioesterase-1 (PPT1)-deficiency causes INCL, the molecular mechanism(s) of neurodegeneration and the drastically reduced lifespan of these patients remain poorly understood. Consequently, an effective treatment for this disease is currently unavailable. We previously reported that oxidative stress-mediated abnormality in mitochondria activates caspases-9 pathway of apoptosis in INCL fibroblasts and in neurons of Ppt1-knockout (Ppt1-KO) mice, which mimic INCL. Since mitochondria play critical roles in maintaining cellular energy homeostasis, we hypothesized that oxidative stress-mediated disruption of energy metabolism and homeostasis may contribute to INCL pathogenesis. We report here that, in cultured INCL fibroblasts and in the brain tissues of Ppt1-KO mice, the NAD(+)/NADH ratio, the levels of phosphorylated-AMPK (p-AMPK), peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α (PGC-1α) and Silent Information Regulator T1 (SIRT1) are markedly down-regulated. This suggested an abnormality in AMPK/SIRT1/PGC-1α signaling pathway of energy metabolism. Moreover, we found that, in INCL fibroblasts and in the Ppt1-KO mice, phosphorylated-S6K-1 (p-S6K1) levels, which inversely correlate with lifespan, are markedly elevated. Most importantly, resveratrol (RSV), an antioxidant polyphenol, elevated the NAD(+)/NADH ratio, levels of ATP, p-AMPK, PGC-1α and SIRT1 while decreasing the level of p-S6K1 in both INCL fibroblasts and in Ppt1-KO mice, which showed a modest increase in lifespan. Our results show that disruption of adaptive energy metabolism and increased levels of p-S6K1 are contributing factors in INCL pathogenesis and provide the proof of principle that small molecules such as RSV, which alleviate these abnormalities, may have therapeutic potential. 相似文献
98.
In the search of developing herbal acaricides, eight medicinal plants were screened for their efficacy against Boophilus microplus, the widely distributed tick species in India. Of the seven extracts screened, the extracts prepared from the Annona squamosa seed showed very high level of efficacy (70.8%) after 24 h of treatment. The effect of treatment on oviposition of the survived
ticks was also assessed, and a significant reduction (P < 0.05) in the reproductive index was noted in comparison to control. When efficacy of the in vitro optimized concentration
of A. squamosa was compared with previously tested extract of Azadirachta indica in in vivo model, it was observed that the extracts prepared from A. indica is more efficacious than the extracts of A. squamosa. A comparable efficacy against B. microplus fed on animals treated with herbal extracts and commonly used synthetic acaricide was noted. The possibility of using the
herbal extracts in IPM format for the management of ticks is discussed. 相似文献
99.
Kristine M. Peterson Jianfen Shu Priya Duggal Rashidul Haque Dinesh Mondal William A. Petri Jr 《The American journal of tropical medicine and hygiene》2010,82(4):620-625
An association between tumor necrosis factor α (TNF-α) and Entamoeba histolytica diarrhea was assessed in a cohort of 138 non-related Bangladeshi children who have been prospectively followed since 2001. Peripheral blood mononuclear cells (PBMCs) obtained at study entry were purified, cultured, and stimulated with soluble amebic antigen before cytokine measurement from supernatant. Higher levels of TNF-α were associated with increased risk of first (P = 0.01) and recurrent E. histolytica-related diarrheal episodes (P = 0.005). Children who developed E. histolytica diarrhea had significantly higher TNF-α protein levels than those who experienced asymptomatic E. histolytica infection (P value = 0.027) or no infection (P value = 0.017). Microarray studies performed using RNA isolated from acute and convalescent whole blood and colon biopsy samples revealed higher but non-significant TNF-α messenger RNA (mRNA) levels in subjects with acute E. histolytica diarrhea compared with convalescence. We conclude that there is an association between higher TNF-α production and E. histolytica diarrhea. 相似文献
100.
Banupriya C Ratnakar Doureradjou P Mondal N Vishnu B Koner BC 《Clinical biochemistry》2008,41(12):968-973