共查询到20条相似文献,搜索用时 15 毫秒
1.
The comparative in vivo pharmacology of mecamylamine and dihydro--erythroidine (DHE) in mice was studied. Modulation of the behavioral effects (antinociception, hypomotility, motor impairment and hypothermia) of nicotine in mice by DHE and mecamylamine were carried out. After SC administration, DHE and mecamylamine were nearly equipotent in blocking nicotine's effects except for antinociception, in which mecamylamine was clearly more potent. Intrathecal injection of DHE was also effective in blocking the antinociceptive effect of nicotine. In vivo interaction of DHE with calcium and calcium channels, involved in the central actions of nicotine, showed that intrathecal administration of DHE failed to reduce the antinociception induced by diverse drugs which increase intracellular calcium such as thapsigargin, (±)-BAYK 8644 and calcium, indicating that this antagonist does not affect calcium-dependent mechanisms involved in antinociception. On the other hand, mecamylamine blocked the antinociceptive effect of the calcium modulatory drugs, suggesting that it may be acting on calcium-dependent mechanisms involved in the intracellular signaling process. We conclude that DHE, a nicotinic neuromuscular antagonist, is able to block some of the central actions of nicotine after systemic and intrathecal administration. The mechanism of blockade is different from that of mecamylamine, a classical ganglionic antagonist, and may involve a direct action of DHE on nicotine receptor. 相似文献
2.
af Forselles KJ Root J Clarke T Davey D Aughton K Dack K Pullen N 《British journal of pharmacology》2011,164(7):1847-1856
BACKGROUND AND PURPOSE
Studies of the role of the prostaglandin EP2 receptor) have been limited by the availability of potent and selective antagonist tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP2 receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid).EXPERIMENTAL APPROACH
Functional antagonist potency was assessed in cell-based systems expressing human EP2 receptors and native tissue preparations from human, dog and mouse. The selectivity of PF-04418948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes. The ability of PF-04418948 to pharmacologically block EP2 receptor function in vivo was tested in rats.KEY RESULTS
PF-04418948 inhibited prostaglandin E2 (PGE2)-induced increase in cAMP in cells expressing EP2 receptors with a functional KB value of 1.8 nM. In human myometrium, PF-04418948 produced a parallel, rightward shift of the butaprost-induced inhibition of the contractions induced by electrical field stimulation with an apparent KB of 5.4 nM. In dog bronchiole and mouse trachea, PF-04418948 produced parallel rightward shifts of the PGE2-induced relaxation curve with a KB of 2.5 nM and an apparent KB of 1.3 nM respectively. Reversal of the PGE2-induced relaxation in the mouse trachea by PF-04418948 produced an IC50 value of 2.7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP2 receptors over homologous and unrelated receptors, enzymes and channels.CONCLUSIONS AND IMPLICATIONS
PF-04418948 is an orally active, potent and selective surmountable EP2 receptor antagonist that should aid further elaboration of EP2 receptor function.LINKED ARTICLE
This article is commented on by Birrell and Nials, pp. 1845–1846 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01494.x 相似文献3.
Y. Yamaguchi A. Touchi T. Baba T. Matsubara 《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(3):125-133
1.?The formation of β-oxidized metabolites from (+ )-S-145 [(+ )-(Z)-7-[(lR, IS, 3S, 4S)-3-(benzenesulphonamide)bicyclo-[2.2.l]-hept-2-yl]-5-heptenob acid] by liver homo- genates were compared between rat, dog and monkey. Species differences were found in hepatic β-oxidation capacities. The results agree with the qualitative and quantitative differences in β-oxidized metabolite proportions among these species observed in vivo.2.?The activities of microsomal (+ )-S-145-CoA synthesis, the initial step of the β- oxidation, were determined. Species differences in their intrinsic clearances primarily agreed with those of the β-oxidized metabolite formation.3.?(+ )-S-145-CoA oxidation activities towards (+ )-S-145-CoA by liver homogenates were much higher than the β-oxidized metabolite formation in all species, indicating that formed (+ )-S-145-CoA was immediately β-oxidized in peroxisomes. The species differences were inconsistent with those of β-oxidized metabolite formation in vitro.4.?Therefore, quantitative differences of hepatic (+ )-S-145 β-oxidation capacity in rat, dog and monkey were considered to be mainly due to the species difference in (+ )-S- 145-CoA formation. 相似文献
4.
O. -E. Brodde M. Anlauf N. Graben K. D. Bock 《European journal of clinical pharmacology》1982,23(5):403-409
Summary The effect of clonidine on the number of
2-adrenoceptors in human platelet membranes, determined by3H-yohimbine binding, was investigatedin vitro andin vivo. Incubation of platelet membranes with clonidine (1–100 µM) for 16 h at 25 °C led to a concentration-dependent decrease in the number of3H-yohimbine binding sites of 10–25%; the affinity of3H-yohimbine to the sites was not changed (KD approximately 3–4 nM). In such desensitized membranes, inhibition of3H-yohimbine binding by clonidine resulted in steep, monophasic displacement curves, which in comparison to the curves from control membranes (IC50 for clonidine 90 nM), were shifted to the right (IC50: 321 nM) and were not affected by 10–4M guanosine-5-triphosphate (GTP).Treatment of 3 hypertensive patients with clonidine (3×150 µg/d for 7 days) reduced blood pressure and heart rate. Simultaneously, both3H-yohimbine binding sites on platelet membranes and plasma catecholamine levels decreased within three days and remained at a reduced level during treatment. After abrupt cessation of clonidine treatment, blood pressure, heart rate and plasma catecholamines rapidly increased, reaching values after two days similar to or higher than those before treatment.3H-yohimbine binding sites, however, initially decreased further before returning to control values. In platelet membranes derived from hypertensive patients treated with clonidine for at least three weeks, GTP (10–4M) had no influence on inhibition of3H-yohimbine binding by (—)-adrenaline and clonidine. It is concluded that clonidine desensitizes
2-adrenoceptors in human platelet membranesin vitro andin vivo. An important step in the desensitization process is the uncoupling of receptor occupancy by agonists and adenylate cyclase activity, as indicated by loss of the regulatory activity of GTP on desensitized membranes. The clonidine withdrawal syndrome may be caused by enhanced release of endogenous catecholamines not adequately regulated by presynaptic
2-adrenoceptors, which have become subsensitive after chronic clonidine treatment. 相似文献
5.
目的:研究普鲁卡因胺(PA)对凝血酶诱导血小板聚集和血栓素B2(TXB2)产生的影响.方法:用比浊法和放射免疫分析法.结果:普鲁卡因胺85,34,136和544μmol·L-1有明显抑制作用.抑制率分别为45%±37%,48%±32%,88%±23%,92%±15%和53%±24%,65%±26%,90%±6%,95%±6%.PA的浓度与血小板聚集和TXB2产生的抑制效力之间,以及血小板聚集抑制率和TXB2产生的抑制率之间均存在着正相关关系,三者的线性方程和主要参数为:^Y=02075X-49157,r=09985;^Y=09546X-346724,r=09921;^Y=08202X+197062,r=09921.结论:普鲁卡因胺抑制凝血酶诱导血小板聚集和TXB2产生. 相似文献
6.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(3):230-238
Abstract1. The metabolism and drug–drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs.2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1.3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1.4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency. 相似文献
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《International immunopharmacology》2009,9(9):1105-1109
The receptor activator of NF-κB ligand (RANKL) and its signal downstream nuclear factor-κB (NF-κB) are critical regulators for immune responses as well as bone remodeling. The present study aimed to examine the effects of erythromycin (EM) on the activation of RANKL, correlation with NF-κB expression, proliferation and apoptosis of human Jurkat T cells. Jurkat T cells were pretreated with 100 pmol/l tumor necrosis factor-alpha (TNF-α) for 1 h followed by various concentrations of EM for 24 h. The mRNA expressions of RANKL and NF-κB were examined by RT-PCR. The protein expression of NF-κB was analyzed by Western blot. The protein level of RANKL was examined by flow cytometry, immunofluorescence microscopy and Western blot analyses. We also examined proliferation of Jurkat T cells by MTT assay, apoptosis by flow cytometry analysis after staining with PI and morphological observation after AO/EB staining. The results showed that EM inhibited TNF-α-induced expressions of RANKL and NF-κB at both mRNA and protein levels in a concentration-dependent manner. The expression of RANKL was correlated with the expression of NF-κB. Moreover, EM influenced the proliferation and apoptosis of human Jurkat T cells. These data suggest that EM acts as an anti-inflammatory agent not only to interact with the expression of NF-κB and the proliferation of human Jurkat T cells, but also to reduce the level of RANKL. 相似文献
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10.
Schaller S Henriksen K Hoegh-Andersen P Søndergaard BC Sumer EU Tanko LB Qvist P Karsdal MA 《Assay and drug development technologies》2005,3(5):553-580
Although our approach to the clinical management of osteoporosis (OP) and degenerative joint diseases (DJD)-major causes of disability and morbidity in the elderly-has greatly advanced in the past decades, curative treatments that could bring ultimate solutions have yet to be found or developed. Effective and timely development of candidate drugs is a critical function of the availability of sensitive and accurate methodological arsenal enabling the recognition and quantification of pharmacodynamic effects. The established concept that both OP and DJD arise from an imbalance in processes of tissue formation and degradation draws attention to need of establishing in vitro, ex vivo, and in vivo experimental settings, which allow obtaining insights into the mechanisms driving increased bone and cartilage degradation at cellular, organ, and organism levels. When addressing changes in bone or cartilage turnover at the organ or organism level, monitoring tools adequately reflecting the outcome of tissue homeostasis become particularly critical. In this context, bioassays targeting the quantification of various degradation and formation products of bone and cartilage matrix elements represent a useful approach. In this review, a comprehensive overview of widely used and recently established in vitro, ex vivo, and in vivo set-ups is provided, which in many cases effectively take advantage of the potentials of biomarkers. In addition to describing and discussing the advantages and limitations of each assay and their methods of evaluation, we added experimental and clinical data illustrating the utility of biomarkers for these methodological approaches. 相似文献
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目的:研究5HT对STA2血小板聚集和释放反应的影响及可能的分子机制.方法:以透光法,介质中ATP含量及荧光图像法评价血小板变形,聚集反应和[Ca2]i水平.结果:(1)5HT预处理可消除STA2的血小板变形,STA203μmol·L-1的聚集增强,l-3μmol·L-1的聚集不变,释放反应抑制.(2)5HT预处理增加STA203μmol·L-1的[Ca2+]i,降低3μmol·L-1的[Ca2+]i降低.(3)延长加入5HT和STA2的间隔,STA203μmol·L-1的聚集增强,3μmol·L-1的聚集不变,释放反应抑制.结论:5HT对STA2介导的聚集和释放反应有双重影响.对STA2[Ca2+]i的调节可能是上述反应的分子机制. 相似文献
13.
Sandri G Bonferoni MC Gökçe EH Ferrari F Rossi S Patrini M Caramella C 《Journal of microencapsulation》2010,27(8):735-746
The aim of this study was to develop cyclosporine A (CsA) loaded solid lipid nanoparticles (SLN) associated with chitosan (CS), to improve interaction and internalization in corneal cells. The SLN were prepared using high shear homogenization and ultrasound methods with CS in the aqueous phase. The lipid phase was based on Compritol or Precirol. The SLN were characterized for particle size, polydispersity index, morphology, zeta potential and encapsulation efficiency. The systems were freeze-dried to increase physical stability and trehalose was used as a cryo/lyo-protector to stabilize the SLN. The penetration and permeation properties of the SLN were assessed in?vitro (cell culture) and ex vivo (excised pig cornea). The cell uptake of SLN was studied by means of confocal laser scanning microscopy. CS-associated SLN based on Compritol were biocompatible and enhanced the permeation/penetration of CsA along with a possible mechanism of internalization/uptake of the nanoparticles both in?vitro and ex vivo. 相似文献
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《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(5):539-549
Abstract1. Metabolites isolated from the urine of rats after oral administration of β-myrcene (I) were: 10-hydroxylinalool (II), 7-methyl-3-methylene-oct-6-ene-1,2-diol (IV), 1-hydroxymethyl-4-isopropenyl cyclohexanol (VI), 10-carboxylinalool (III) and 2-hydroxy-7-methyl-3-methylene-oct-6-enoic acid (V).2. Liver microsomes prepared from phenobarbital-treated rats convert β-myrcene (I) to 10-hydroxylinalool (II) in the presence of NADPH and oxygen. NADH neither supported this reaction nor did it show any synergistic effect. The rate of conversion was significantly greater in microsomes prepared from phenobarbital-treated rats than from 3-methylcholanthrene-treated or control microsomal preparations. The formation of 10-hydroxylinalool (II) was inhibited by metyrapone, carbon monoxide, SKF-525A, p-chloromercuric benzoate (p-CMB) and cytochrome c.3. Titration of phenobarbital-induced liver microsomes with β-myrcene (I) produced a series of type I difference spectra with peaks around 387–390?nm and troughs around 421–425?nm. The Ks for β-myrcene was 10.6 μM.4. Administration (four days) of β-myrcene (I) to rats did not result in any significant effect on the hepatic drug-metabolizing enzymes. 相似文献
16.
Smith AP Wilson SJ Glue P Nutt DJ 《Journal of psychopharmacology (Oxford, England)》1992,6(3):376-381
Idazoxan, an α( 2)-adrenoceptor antagonist, is an effective antidepressant with a mode of action different from that of conventional antidepressants. As it is used as an antidepressant it is important to know whether there are any unwanted CNS side effects. Study of its effects will also provide information on the relationship between noradrenergic function and mood and performance. Twelve normal male volunteers who were given the drug (40 mg orally three times daily for 21 days) were compared with 12 matched controls. A computerized test battery was used to assess mood and various aspects of memory and attention. Many of the tests of memory and attention in the battery have been widely used over the last 20 years, and in addition two new selective attention tasks were included. The subjects were tested 3 days before starting the drug, on days 3 and 17 while on the drug, and after they had stopped taking the drug (4 days after and 24 days after). Control subjects followed a similar testing schedule. The results showed that the drug had no effect on mood, logical reasoning, retrieval from semantic memory or sustained attention. However, the drug did improve one aspect of selective attention (the place repetition effect), although this effect was only observed on the third day on the drug. Overall, the results suggest that idazoxan produces selective performance improvements, and that the measures of selective attention used here may be more sensitive indicators of drug effects than some of the traditional tasks currently in use. 相似文献
17.
In vitro effects of brominated flame retardants and metabolites on CYP17 catalytic activity: a novel mechanism of action? 总被引:4,自引:0,他引:4
Cantón RF Sanderson JT Nijmeijer S Bergman A Letcher RJ van den Berg M 《Toxicology and applied pharmacology》2006,216(2):274-281
Fire incidents have decreased significantly over the last 20 years due, in part, to regulations requiring addition of flame retardants (FRs) to consumer products. Five major classes of brominated flame retardants (BFRs) are hexabromocyclododecane isomers (HBCDs), tetrabromobisphenol-A (TBBPA) and three commercial mixtures of penta-, octa- and deca-polybrominated diphenyl ether (PBDE) congeners, which are used extensively as commercial FR additives. Furthermore, concentrations of PBDEs have been rapidly increasing during the 1999s in human breast milk and a number of endocrine effects have been reported. We used the H295R human adrenocortical carcinoma cell line to assess possible effects of some of these BFRs (PBDEs and several of their hydroxylated (OH) and methoxylated (CH(3)O) metabolites or analogues), TBBPA and brominated phenols (BPs) on the combined 17alpha-hydroxylase and 17,20-lyase activities of CYP17. CYP17 enzyme catalyzes an important step in sex steroidogenesis and is responsible for the biosynthesis of dehydroepiandrosterone (DHEA) and androstenedione in the adrenals. In order to study possible interactions with BFRs, a novel enzymatic method was developed. The precursor substrate of CYP17, pregnenolone, was added to control and exposed H295R cells, and enzymatic production of DHEA was measured using a radioimmunoassay. In order to avoid pregnenolone metabolism via different pathways, specific chemical inhibitor compounds were used. None of the parent/precursor BFRs had a significant effect (P < 0.05) on CYP17 activity except for BDE-183, which showed significant inhibition of CYP17 activity at the highest concentration tested (10 muM), with no signs of cytotoxicity as measured by mitochondrial toxicity tests (MTT). A strong inhibition of CYP17 activity was found for 6-OH-2,2',4,4'-tetrabromoDE (6-OH-BDE47) with a concentration-dependent decrease of almost 90% at 10 muM, but with a concurrent decrease in cell viability at the higher concentrations. Replacement of the 6-OH group by a 6-CH(3)O group eliminated this cytotoxic effect, but CYP17 activity measured as DHEA production was still significantly inhibited. Other OH- or CH(3)O-PBDE analogues were used to elucidate possible structural properties behind this CYP17 inhibition and associated cytotoxicity, but no distinct structure activity relationship could be determined. These in vitro results indicate that OH and CH(3)O-PBDEs have potential to interfere with CYP17 activity for which the in vivo relevance still has to be adequately determined. 相似文献
18.
Effects of cadmium on in vitro and in vivo cholinesterase (ChE) activities of brain and muscle tissues of Oreochromis niloticus fingerlings were evaluated, considering its potential use in biomonitoring tropical water pollution. Results show that in vitro
ChE activities were depressed significantly by millimolar concentration ranges of Cd2+. The IC50 values of Cd2+ on in vitro ChE activity in brain and muscle tissues were 1.56 and 4.31 mM, respectively. Exposure of fish to environmentally
relevant concentrations of Cd2+ (5–30 μg l−l) for 28 days evoked only a transient inhibition (21–34%) of in vivo ChE activities. Prior exposure and co-exposure of fish
to 15 μg l−1 of Cd2+ enhanced the extent of inhibition of ChE levels induced by the organophosphorous insecticide chlorpyrifos. As high concentrations
of cadmium have the potential to depress ChE activities, monitoring of metal levels in water bodies with suspected high levels
of metal inputs is necessary to accurately interpret the fish ChE inhibition data in relation to insecticide contaminations. 相似文献
19.
Context Pueraria lobata (Leguminoseae) shows cytotoxic effects against cancer cells; however, its active components remain unclear.Objective This study investigated the antitumour activity of puerarin 6″-O-xyloside (POS) on the human lung carcinoma A549 cell line.Materials and methods The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxicity of POS (at 10, 20 and 40?μM) in vitro, and xenograft nude mice were established to evaluate the antitumour effect of POS (at 40?mg/kg/d) in vivo by 15 days intraperitoneal injection (ip). To explore its mechanism of action, flow cytometry was performed to determine the pro-apoptotic effect of POS (at 10, 20 and 40?μM). Subsequently, the expression of caspase-3, caspase-7, caspase-9, Bcl-2 and Bax in A549 cells were determined.Results POS showed significant cytotoxicity toward A549 cells (p?<?0.05) by inducing apoptosis. Treatment with POS significantly upregulated the levels of caspase-3 (p?<?0.01), caspase-7 (p?<?0.01), caspase-9 (p?<?0.01) and Bax (p?<?0.01) in A549 cells, and Bcl-2 was downregulated (p?<?0.01). Additionally, the in vivo animal study showed that POS significantly inhibited tumour growth in A549 cells (p?<?0.01).Conclusion Our study demonstrated the POS has significant antitumour activities. The mechanisms are related to increased levels of caspase-3, caspase-7, caspase-9 and Bax, and reduced levels Bcl-2. 相似文献
20.
Wattanachai N Polasek TM Heath TM Uchaipichat V Tassaneeyakul W Tassaneeyakul W Miners JO 《European journal of clinical pharmacology》2011,67(8):815-824