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991.
Segawa D Sjöquist PO Wang QD Gonon A Rydén L 《Journal of cardiovascular pharmacology》2002,40(3):339-345
The intracellular calcium level is increased during ischemia and early reperfusion. The aim of this study was to study the role of the calcium influx in the development of myocardial ischemic and reperfusion injury during the early and late phases of ischemia and during early reperfusion. An ultrashort-acting calcium antagonist, clevidipine, was used as a tool for this investigation. Pentobarbital-anesthetized pigs were subjected to 45 minutes of LAD occlusion followed by 240 minutes of reperfusion. In the first set of experiments, clevidipine (0.3 nmol/kg per minute) was infused over 5 minutes into the ischemic myocardium via a catheter in the LAD, starting at 5, 35, or 44 minutes following the onset of ischemia (n = 6 in each group). The area at risk and the infarct size were determined after 240 minutes of reperfusion by staining with Evans blue dye and triphenyl tetrazolium chloride (TTC), respectively. In a second set of experiments, two groups of animals (n = 6 in each) were subjected to the same periods of ischemia and reperfusion; one group received no infusion during ischemia, whereas the other group received vehicle infusion during a 5-minute period between 5 and 10 minutes of ischemia. In the first set of experiments, there were no significant differences between the groups with regard to hemodynamic variables. The area at risk expressed as a percentage of the left ventricle was of similar magnitude in all three clevidipine-treated groups (about 18%). The infarct size, expressed as a percentage of the area at risk, was significantly smaller in pigs given clevidipine after 5 minutes (58 +/- 17%; p < 0.01) and after 44 minutes (42 +/- 6%; p < 0.01) of ischemia than in pigs receiving clevidipine after 35 minutes of ischemia (85 +/- 4%). The difference in infarct size between pigs given clevidipine after 5 or 44 minutes of ischemia was not significant. In the second set of experiments, there was a similar area at risk and no significant difference in infarct size between the noninfusion group and the 5-minute vehicle infusion group, indicating that the LAD infusion per se did not affect infarct size. The present results demonstrate that blockade of calcium influx by the short-acting dihydropyridine calcium antagonist clevidipine during the early phase of ischemia and at the time of reperfusion, but not during a late phase of ischemia, limits infarct size induced by ischemia and reperfusion. This indicates that the pathophysiological importance of calcium influx varies according to the different phases of myocardial ischemia and reperfusion. 相似文献
992.
Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less. It is likely that many millions of chemically distinct molecules exist in nature but it is inconceivable that the number of different biological functions is near this number. This is corroborated by knowledge obtained from the genome sequences of an increasing number of species. It is unlikely that ligands for specific molecular targets are restricted to one species and even individual compounds are often found in more than one species. Important molecular mechanisms are likely to be ubiquitous and there are no a priori reasons to assume that some are restricted to, for example, tropical rainforests. Thus, there are no obvious advantages of "biodiversity prospecting", which will, possibly, endanger fragile ecosystems in the search for rare species. 相似文献
993.
Hägg M Bivén K Ueno T Rydlander L Björklund P Wiman KG Shoshan M Linder S 《Investigational new drugs》2002,20(3):253-259
Screening for anti-cancer substances iscommonly conducted using viability assays.An inherent problem with this approach isthat all compounds that are toxic andgrowth inhibitory, irrespective ofmechanism of action, will score positive.It would be beneficial to be able to screenfor compounds that specifically induceapoptosis. We here describe an ELISA-assaybased on a monoclonal antibody (M30) whichrecognizes a neo-epitope on cytokeratin 18exposed after cleavage by caspases duringapoptosis. We show that this assay detectsapoptosis in epithelial cells and that thesensitivity is sufficient for screening inthe 96-well format. We used the M30-ELISAassay to screen 500 low molecular weightcompounds from a chemical library from theNational Cancer Institute and identified 16drugs with strong pro-apoptotic activity,suggesting that the assay is a useful toolfor discovery of pro-apoptotic drugs. 相似文献
994.
Bendixen H Madsen J Bay-Hansen D Boesen U Ovesen LF Bartels EM Astrup A 《Obesity research》2002,10(9):911-922
OBJECTIVE: To elucidate how frequent weight-loss attempts are made, the methods used to achieve weight loss, and the extent to which the outcome is positive. RESEARCH METHODS AND PROCEDURES: Two independent interviews were conducted in 1992 and in 1998, each with 1200 randomly selected adult subjects. Each survey was designed to ensure an equal distribution of age, gender, and geographical regions in Denmark. RESULTS: The proportion of subjects having attempted weight loss did not change from 1992 to 1998, although the prevalence of overweight and obesity increased from 1992 (overweight, 30%; obesity, 6%) to 1998 (overweight, 35%; obesity, 8%). Almost twice as many women (61%) than men (32%) had attempted weight loss (p < 0.0001). Slimming occurred more often in subjects <50 years (51%) than >50 years (39%) (p < 0.0001), although overweight and obesity were more frequent in the elderly. Over-the-counter diet pills or meal replacements were associated with a negative outcome of slimming treatment (p < 0.0001). DISCUSSION: Approximately half of all adult Danes have attempted weight loss, particularly women and individuals <50 years. This finding is inconsistent with the fact that overweight and obesity are more prevalent in men and in individuals >50 years. Changes in habitual diet and increased physical activity are the most prevalent modes of slimming, whereas the use of over-the-counter diet pills or meal replacements has decreased from 1992 to 1998. This development may have a positive impact on future body- weight-management strategies. 相似文献
995.
The effect of protein kinase C (PKC) inhibitors on the induction of endothelin ET(B) receptors during organ culture was examined in isolated segments of the rat mesenteric artery. After 24 h of organ culture, the endothelin ET(B) receptor agonist sarafotoxin 6c (S6c) induced a strong contraction compared to fresh segments. The contractile response after 24-h organ culture to S6c was studied in presence (30-min preincubation) or absence, after 24-h treatment, of the PKC inhibitors staurosporine, K252a and Ro31-7549. Exposure to staurosporine or K252a in presence and after 24-h treatment reduced the S6c contraction. In contrast, presence of 2-1[1-3(aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide (Ro31-7549), did not affect the S6c-induced contraction, whereas 24-h treatment abolished the increase of contraction. The PKA inhibitor N-(2-[bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H89) did not affect the S6c responses. The mRNA expressions of endothelin ET(B) receptors (analysed with real-time PCR) were abolished after 24-h treatment with the PKC inhibitors. These results suggest that PKC is involved in the endothelin ET(B) receptor upregulation following organ culture. 相似文献
996.
Canan Koch SS Thoresen LH Tikhe JG Maegley KA Almassy RJ Li J Yu XH Zook SE Kumpf RA Zhang C Boritzki TJ Mansour RN Zhang KE Ekker A Calabrese CR Curtin NJ Kyle S Thomas HD Wang LZ Calvert AH Golding BT Griffin RJ Newell DR Webber SE Hostomsky Z 《Journal of medicinal chemistry》2002,45(23):4961-4974
A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines. 相似文献
997.
Jensen LH Renodon-Corniere A Wessel I Langer SW Søkilde B Carstensen EV Sehested M Jensen PB 《Molecular pharmacology》2002,61(5):1235-1243
Maleimide, N-ethyl-maleimide (NEM), and N-methyl-maleimide (NMM) were identified as potent catalytic inhibitors of purified human topoisomerase IIalpha, whereas the ring-saturated analog succinimide was completely inactive. Catalytic inhibition was not abrogated by topoisomerase II mutations that totally abolish the effect of bisdioxopiperazine compounds on catalytic inhibition, suggesting a different mode of action by these maleimides. Furthermore, in DNA cleavage assay maleimide and NEM could antagonize etoposide-induced DNA double-strand breaks. Consistently, maleimide could antagonize the effect of topoisomerase II poisons in three different in vivo assays: 1) In an alkaline elution assay maleimide protected against etoposide-induced DNA damage. 2) In a band depletion assay maleimide reduced etoposide-induced trapping of topoisomerase IIalpha and beta on DNA. 3) In a clonogenic assay maleimide antagonized the cytotoxicity of etoposide and daunorubicin on four different cell lines of human and murine origin. at-MDR cell lines with reduced nuclear topoisomerase IIalpha content are fully sensitive to maleimide, indicating that it is not a topoisomerase II poison in vivo. Our finding that topoisomerase II is sensitive to maleimide, NMM, and NEM but insensitive to succinimide demonstrates a strict requirement for the unsaturated ring bond for activity. We suggest that the observed antagonism in vitro and in vivo is caused by covalent modification of topoisomerase II cysteine residues reducing the amount of catalytically active enzyme sensitive to the action of topoisomerase II poisons. 相似文献
998.
Brachtendorf L Jetter A Beckurts KT Hölscher AH Fuhr U 《Pharmacology & toxicology》2002,90(3):144-149
From case reports of patients treated with the tetracyclic antidepressant drug maprotiline, it appears that this drug is subject to polymorphic metabolism. Thus, we studied formation of the major maprotiline metabolite desmethylmaprotiline to identify the human cytochrome P-450 enzymes (CYP) involved. In incubations with human liver microsomes from two different donors, the substrate maprotiline was used at five different concentrations (5 to 500 microM). For selective inhibition of CYPs, quinidine (0.5-50 microM; CYP2D6), furafylline (0.3-30 microM; CYP1A2), ketoconazole (0.2-20 microM; CYP3A4), mephenytoin (20-200 microM; CYP2C19), chlorzoxazone (1-100 microM; CYP2E1), sulphaphenazole (0.2-100 microM; CYP2C9) and coumarin (0.2-100 microM; CYP2A6) were used. Desmethylmaprotiline concentrations were measured by HPLC, and enzyme kinetic parameters were estimated using extended Michaelis-Menten equations with non-linear regression. Relevant inhibition of the desmethylmaprotiline formation rate was observed in incubations with quinidine, furafylline and ketoconazole only. Formation rates of desmethylmaprotiline were consistent with a two enzyme model with a high (K(M)=71 and 84 microM) and a low (K(M)=531 and 426 microM) affinity site for maprotiline in the two samples, respectively. The high affinity site was competitively inhibited by quinidine (K(i,nc) 0.13 and 0.61 microM), the low-affinity site was non-competitively inhibited by furafylline (K(i,nc) 0.11 and 1.3 microM). Thus it appears that CYP2D6 and CYPIA2 contribute to maprotiline demethylation. Based on the parameters obtained, for plasma concentrations of 1 microM 83% (mean) of desmethylmaprotiline formation in vivo is expected to be mediated by CYP2D6 while 17% only may be attributed to CYPIA2 activity. 相似文献
999.
Rydberg P Lüning B Wachtmeister CA Eriksson L Törnqvist M 《Chemical research in toxicology》2002,15(4):570-581
Adducts to N-terminal valine residues in hemoglobin (Hb) are used for monitoring in vivo doses of electrophiles and are quantitated by means of a modified Edman procedure, the "N-alkyl Edman procedure". In the reaction with pentafluorophenyl isothiocyanate, N-alkylated valines cyclize and detach from the protein as pentafluorophenylthiohydantoins (PFPTHs) much more efficiently than do unsubstituted N-terminal valine residues. The mechanisms of this reaction, and of possible degradation reactions, have been studied with model compounds using phenyl- and pentafluorophenyl isothiocyanate. The rapid cyclization to N-alkylvaline-PTHs occurs as a consequence of the influence of substituents on ring formation. This facilitated cyclization favors a direct attack by the thiocarbamoyl nitrogen atom on valine-C-1, and is also observed to occur slowly at unsubstituted N-terminal valines. Such cyclization is favored in protic solvents. Under alkaline conditions and in the presence of air, hydrolytic and oxidative processes give rise to degradation products. The PTH derivatives of N-alkylvaline are less apt to undergo such reactions than are the corresponding derivatives of unsubstituted valine. We conclude that the presence of an N-substituent exerts a greater influence on the cyclization process than the structure of the amino acid or of the Edman reagent. For adducts of different structures, the method has broad applicability, for which the limits, however, are not yet explored. The knowledge from the studies is valid not only for the N-alkyl Edman procedure, but also, to some extent, for the classical Edman degradation reaction. The oxidative side reaction gave rise to the invention of a novel synthesis route for insertion of nucleophiles at carbon-5 in thiohydantoins. The present investigation provides a basis for the N-alkyl Edman procedure, facilitating new toxicological applications. 相似文献
1000.
Aklillu E Herrlin K Gustafsson LL Bertilsson L Ingelman-Sundberg M 《Pharmacogenetics》2002,12(5):375-383
Black Africans show lower rates of CYP2D6- and CYP2C19-dependent drug metabolism compared to Caucasians of the same apparent genotype. To determine if environmental factors are responsible for this difference, the genotypes and phenotypes of CYP2D6 and CYP2C19 among Ethiopians living in Sweden (n = 70) were assessed and compared to our previously published data from Ethiopians living in Ethiopia (n = 114) and Swedish Caucasians (n = 134). There was no significant difference in CYP2C19 genotype or phenotype as assessed by mephenytoin between Ethiopians in Sweden or in Ethiopia. However, Swedes were significantly more rapid for CYP2C19 activity than both Ethiopian groups (P < 0.01). A comparison of the debrisoquine MR among individuals of the same CYP2D6 genotype revealed that Swedes exhibited the highest rate of debrisoquine metabolism, followed by Ethiopians in Sweden and Ethiopians in Ethiopia. The difference between the Ethiopian groups was significant (P < 0.02 using a univariate test ANOVA) and amounted to approximately 50% of the magnitude of the MR difference between Swedes and Ethiopians in Ethiopia. It is tempting to speculate that inhibitory dietary factors may explain the differences seen between the two Ethiopian groups and that these components in the past might have contributed to dietary stress-mediated selection of duplicated and multiduplicated active CYP2D6 genes, as frequently seen in Ethiopians. In conclusion, the results indicate a significant influence of environmental factors as an explanation for the difference in capacity for CYP2D6, but not CYP2C19 metabolism between Caucasians and Black Africans. Additional factors remain to be elucidated to fully explain the interethnic differences in CYP2D6 activity. 相似文献