共查询到20条相似文献,搜索用时 31 毫秒
1.
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Shrestha SP Thompson JA Wempe MF Gu M Agarwal R Agarwal C 《Pharmaceutical research》2012,29(3):856-865
Purpose
The 3,3″-di-O-galloyl ester of procyanidin B2 (B2G2) is a component of grape seed extract that inhibits growth of human prostate carcinoma cell lines. In preparation for studies in mice, its hepatic metabolism was examined in vitro and compared to B2 and the corresponding monomers, epicatechin (EC) and 3-O-galloyl-epicatechin (ECG). 相似文献3.
β1- and β2-Adrenoceptors (AR) play a pivotal role in the regulation of cardiovascular function. Both β-AR subtypes are polymorphic: two single nucleotide polymorphisms (SNPs) have been described for the β1- (Ser49Gly, Arg389Gly) and four for the β2-AR (Arg-19Cys, Arg16Gly, Gln27Glu, Thr164Ile), and they are possibly of functional relevance. In recombinant cell systems, Gly49-β1-AR are more susceptible to agonist-promoted down-regulation than Ser49-β1-AR, whereas Arg389-β1-AR are three to four times more responsive to agonist-evoked stimulation than Gly389-β1-AR. With respect to β2-AR, the Cys-19 variant is associated with greater β2-AR expression than the Arg-19 variant; Gly16-β2-AR are more susceptible, whereas Glu27-β2-AR are almost resistant to agonist-promoted down-regulation; Thr164-β2-AR are three to four times more responsive to agonist-evoked stimulation than Ile164-β2-AR. Several studies addressed potential phenotypic consequences of these SNPs in vivo by influencing and/or contributing to the pathophysiology of cardiovascular/pulmonary diseases such as hypertension, congestive heart failure, arrhythmias or asthma. At present, it appears that these β-AR SNPs are very likely not disease-causing genes but possibly predictive for the responsiveness to agonists and antagonists. Patients carrying one or two alleles of the Gly389-β1-AR are poor or non-responders to agonists and antagonists, whereas patients homozygous for the Arg389-β1-AR are good responders. Subjects carrying the Ile164-β2-AR exhibit blunted responses to β2-AR stimulation. Asthma patients carrying the Arg16-Gln27-Thr164-β2-AR haplotype who receive regularly short- or long-acting β2-AR agonists are rather susceptible to agonist-induced desensitization and in consequence exhibit reduced bronchodilating and -protective effects and/or increased asthma exacerbations. The clinical relevance of these findings is still under debate. 相似文献
4.
Ochratoxin A (OTA) is a mycotoxin naturally occurring in different foods. OTA is arguably a risk factor for Balkan endemic nephropathy (BEN). The aims of this study are to (1) test the OTA-BEN association in BEN-groups and controls and (2) determine whether urine β2-microglobulin, a marker of impaired ability of the kidneys to re-absorb, is related to OTA. BEN patients had significantly higher OTA serum levels. Within the offspring, OTA was significantly related to higher β2-microglobulin excretion. OTA (2005/2006) was related to a higher incidence of BEN after 2008, providing further evidence that OTA is a risk factor for BEN. 相似文献
5.
《General pharmacology》1995,26(4):799-808
- 1.1. Effects of the enkephalins Met-enk (M) and Leu-enk (L), of two newly synthesized analogues—[Cys-(O2NH2)]2-Met-enk (CM) and [Cys-(O2 NH2)]2-Leu-enk (CL)-and of a hexapeptide—d-Ala2-Leu5-Arg6 (Dalargin; DL) on the spontaneous and electrically stimulated activity were examined with respect to their selectivity for the μ opioid receptors in the longitudinal layer of guinea pig ileum.
- 2.2. M and CM exerted relaxing and contractile effects on the spontaneous contractile activity while L, CL and DL produced only relaxation. The order of potency towards the relaxatory phase was DL > M > CM > L > CL and towards the contractile phase CM > M.
- 3.3. The effects of enkephalins on the spontaneous activity were naloxone and TTX sensitive except for the contractile phase of M and CM which persisted in the presence of TTX. NO was not involved in the neurotransmission of the relaxatory responses, while the blockade of α and β adrenoceptors showed the participation of adrenergic mechanisms. Relaxation and contraction induced by enkephalins could not be directly attributed to cholinergic neurotransmission.
- 4.4. The naloxone-sensitive and concentration-dependent inhibitory effects of enkephalins and their analogues on the electrically stimulated cholinergic contractions were established. The order of the relative potency of opioids was: DL—3.8; M—1.0; L-0.4; CM-0.01; CL—0.005.
- 5.5. These data indicated that the D-Ala2 substitution and lengthening of the peptide chain by Arg6 in the molecule of L increased the potency at the μ opiate receptors, while the substitution in position 2 with Cys-(O2NH2) in the molecule of M and L yielded a less potent and selective μ agonists.
6.
Anne-Ulrike Trendelenburg Christian Andreas Wahl Klaus Starke 《Naunyn-Schmiedeberg's archives of pharmacology》1996,353(3):245-249
Four antagonists were examined for their ability to differentiate 2A from the orthologous 2Dadrenoceptors. The antagonists were (2S,12bS) 1, 3-di-methylspiro(1, 3, 4, 5, 6, 6, 7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinolizine)-2,4-pyrimidin-2-one (MK 912), 2-[2-(methoxy-1, 4-benzodioxanyl)imidazoline (RX 821002), efaroxan and benoxathian. The 2-autoreceptors in rabbit brain cortex were chosen as 2A- and the a2-autoreceptors in guinea-pig brain cortex as 2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, 2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK 14,304) was used as an 2-adrenoceptor agonist.UK 14, 304 decreased the stimulation-evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) 2D-adrenoceptors (pK
d values 10.0, 9.7 and 9.1, respectively) than for (rabbit) 2A-adrenoceptors (pK
d 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for 2A- (pK
d 7.4) than for 2D-adrenoceptors (pK
d 6.9). Ratios calculated from the K
d values of the four compounds differentiated between 2A and 2D up to 100 fold. It is concluded that MK 912, RX 821002, efaroxan and benoxathian are antagonists with high power to differentiate 2A- from 2D-adrenoceptors. 相似文献
7.
Pérez Piñero C Bruzzone A Sarappa MG Castillo LF Lüthy IA 《British journal of pharmacology》2012,166(2):721-736
BACKGROUND AND PURPOSE
β-Adrenoceptors are expressed in human and experimental animal breast cancer cells. However, the effect of the agonists and antagonists reported on cell proliferation and tumour growth was paradoxical, precluding their utilization as possible adjuvant therapy, mainly in the cases of refractory tumours.EXPERIMENTAL APPROACH
β-Adrenoceptor expression was analysed by immunofluorescence and RT-PCR. Cell proliferation was assessed by [3H]-thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting.KEY RESULTS
β2-Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α2-adrenoceptor action) and decreased in every tested cell line by the β-adrenoceptor agonist isoprenaline and the β2-adrenoceptor agonist salbutamol. Isoprenaline and salbutamol reduced tumour growth in every tumour tested (mouse C4-HD and CC4-3-HI and human IBH-4, IBH-6 and MDA-MB-231 cell lines growing as xenografts in nude mice). These effects were reversed by the β-adrenoceptor antagonist propranolol. The α2-adrenoceptor antagonist rauwolscine and the β2-adrenoceptor agonist salbutamol were equally effective in diminishing tumour growth. ERK 1/2 activation analysed in IBH-4 tumours correlated with tumour growth, with the β-adrenoceptor agonists decreasing its activation. Inhibition of ERK 1/2 phosphorylation in vitro was mainly mediated by the PKA pathway.CONCLUSIONS AND IMPLICATIONS
In our experimental models, the β-adrenoceptor agonists inhibited breast cancer cell proliferation and tumour growth, probably mediated by inhibition of ERK 1/2 phosphorylation. The β-adrenoceptor agonists were as effective as the α2-adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer. 相似文献8.
α(2)-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, α(2)-adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. α(2)-Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. α(2)-Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In addition to these presynaptic neuronal receptors, α(2)-adrenoceptors were also identified in many non-neuronal cell types of the body. Gene-targeting in mice provided a comprehensive assignment of the physiological and pharmacological functions of these receptors to specific α(2A)-, α(2B) - and α(2C)-adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype-specific α(2)-adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of α(2)-adrenoceptors in adrenergic neurons, that is, α(2)-autoreceptors, versus α(2)-adrenoceptors in non-adrenergic neurons, termed α(2)-heteroreceptors. α(2)-Autoreceptors are primarily required to limit release of noradrenaline from sympathetic nerves and adrenaline from adrenal chromaffin cells at rest. These receptors are desensitized upon chronic activation as it may for instance occur due to enhanced sympathetic activity during chronic heart failure. In contrast, pharmacological effects of acutely administered α(2)-adrenoceptor agonist drugs essentially require α(2)-heteroreceptors in non-adrenergic neurons, including analgesia, sedation, hypothermia and anaesthetic-sparing as well as bradycardia and hypotension. Thus a clear picture has emerged of the significance of auto- versus heteroreceptors in mediating the physiological functions of α(2)-adrenoceptors and the pharmacological functions of α(2)-adrenoceptor agonist drugs respectively. 相似文献
9.
《药学学报(英文版)》2022,12(5):2224-2238
Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα–FGF21–beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism. 相似文献
10.
Pharmacokinetics of flutamide and its metabolite 2-hydroxyflutamidein normal and hepatic injury rats
目的:建立一新的高压液相色谱法用来研究氟他胺(Flu)及其活性代谢产物2羟基氟他胺(HF)的药物动力学.方法:正常及肝损伤大鼠灌胃Flu50mg·kg-1.采用反相高压液相色谱法,以甲基睾丸素为内标,流动相为甲醇∶乙腈∶水∶乙醚=40∶20∶35∶1(体积比),检测波长为234nm.结果:Flu的K与Cl分别由062±016h-1及60±10L·kg-1·h-1减小到016±003h-1及063±029L·kg-1·h-1(P<001),AUC与Cmax分别由86±13mg·L-1·h及24±07mg·L-1增加到100±44mg·kg-1·h及67±28mg·L-1(P<001).HF的K(m)由007±001h-1减小到005±001h-1(P<001).结论:在肝损伤大鼠,Flu与HF消除受到显著抑制. 相似文献
11.
Huiqiang Zhou Dana P. Danger Steven T. Dock Lora Hawley Shane G. Roller Chari D. Smith Anthony L. Handlon 《ACS medicinal chemistry letters》2010,1(1):19-23
d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure−activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC50 of 10 nM. 相似文献
12.
A-J Chabot-Doré D J Schuster L S Stone G L Wilcox 《British journal of pharmacology》2015,172(2):388-402
Opioid and α2-adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co-administered. These supra-additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2-adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2-adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2-adrenoceptor agonists and that α2-adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid–adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 相似文献13.
14.
Brian D Hudson Terence E H��bert Melanie EM Kelly 《British journal of pharmacology》2010,160(3):627-642
Background and purpose:
The CB1 cannabinoid receptor and the β2-adrenoceptor are G protein-coupled receptors (GPCRs) co-expressed in many tissues. The present study examined physical and functional interactions between these receptors in a heterologous expression system and in primary human ocular cells.Experimental approach:
Physical interactions between CB1 receptors and β2-adrenoceptors were assessed using bioluminescence resonance energy transfer (BRET). Functional interactions between these receptors were evaluated by examining receptor trafficking, as well as extracellular signal-regulated kinase (ERK) and cyclic AMP response element binding protein (CREB) signalling.Key results:
Physical interactions between CB1 receptors and β2-adrenoceptors were demonstrated using BRET. In human embryonic kidney (HEK) 293H cells, co-expression of β2-adrenoceptors tempered the constitutive activity and increased cell surface expression of CB1 receptors. Co-expression altered the signalling properties of CB1receptors, resulting in increased Gαi-dependent ERK phosphorylation, but decreased non-Gαi-mediated CREB phosphorylation. The CB1 receptor inverse agonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) attenuated β2-adrenoceptor-pERK signalling in cells expressing both receptors, while the CB1 receptor neutral antagonist O-2050 ((6aR,10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran) did not. The actions of AM251 and O-2050 were further examined in primary human trabecular meshwork (HTM) cells, which are ocular cells endogenously co-expressing CB1 receptors and β2-adrenoceptors. In HTM cells, as in HEK 293H cells, AM251 but not O-2050, altered the β2-adrenoceptor–pERK response.Conclusion and implications:
A complex interaction was demonstrated between CB1 receptors and β2-adrenoceptors in HEK 293H cells. As similar functional interactions were also observed in HTM cells, such interactions may affect the pharmacology of these receptors in tissues where they are endogenously co-expressed.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x 相似文献15.
《药学学报(英文版)》2021,11(11):3508-3526
Given the opposing effects of Akt and AMP-activated protein kinase (AMPK) on metabolic homeostasis, this study examined the effects of deletion of Akt2 and AMPKα2 on fat diet-induced hepatic steatosis. Akt2–Ampkα2 double knockout (DKO) mice were placed on high fat diet for 5 months. Glucose metabolism, energy homeostasis, cardiac function, lipid accumulation, and hepatic steatosis were examined. DKO mice were lean without anthropometric defects. High fat intake led to adiposity and decreased respiratory exchange ratio (RER) in wild-type (WT) mice, which were ablated in DKO but not Akt2−/− and Ampkα2−/− mice. High fat intake increased blood and hepatic triglycerides and cholesterol, promoted hepatic steatosis and injury in WT mice. These effects were eliminated in DKO but not Akt2−/− and Ampkα2−/− mice. Fat diet promoted fat accumulation, and enlarged adipocyte size, the effect was negated in DKO mice. Fat intake elevated fatty acid synthase (FAS), carbohydrate-responsive element-binding protein (CHREBP), sterol regulatory element-binding protein 1 (SREBP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), peroxisome proliferator-activated receptor-α (PPARα), PPARγ, stearoyl-CoA desaturase 1 (SCD-1), phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase), and diglyceride O-acyltransferase 1 (DGAT1), the effect was absent in DKO but not Akt2−/− and Ampkα2−/− mice. Fat diet dampened mitophagy, promoted inflammation and phosphorylation of forkhead box protein O1 (FoxO1) and AMPKα1 (Ser485), the effects were eradicated by DKO. Deletion of Parkin effectively nullified DKO-induced metabolic benefits against high fat intake. Liver samples from obese humans displayed lowered microtubule-associated proteins 1A/1B light chain 3B (LC3B), Pink1, Parkin, as well as enhanced phosphorylation of Akt, AMPK (Ser485), and FoxO1, which were consolidated by RNA sequencing (RNAseq) and mass spectrometry analyses from rodent and human livers. These data suggest that concurrent deletion of Akt2 and AMPKα2 offers resilience to fat diet-induced obesity and hepatic steatosis, possibly through preservation of Parkin-mediated mitophagy and lipid metabolism. 相似文献
16.
Summary To find out whether, and which type of, adrenoceptors mediate prejunctional inhibition of sensory neurotransmitter release from trigeminal fibres, the modulation of twitch response to electrical field stimulation on rabbit isolated iris was investigated. Evoked iris sphincter contractions consisted of a minor fast cholinergic and a large slow component. The latter was unaffected by atropine and guanethidine, hence nonadrenergic noncholinergic in nature (NANC), but nearly completely abolished by capsaicin pretreatment and by the neurokinin receptor antagonist spantide. The response was probably not mediated by NK2 receptors as SR 48,968, an NK2 selective nonpeptide antagonist, failed to reduce the response to the release of the endogenous neurokinin(s) (and exogenous substance P), but in part due to NK1 receptor activation as shown by a reduction of response by CP 96,345, an NK1 selective non-peptide antagonist, and in part perhaps mediated by NK3 receptors. A small neurokinin receptor antagonist- and capsaicin-insensitive NANC contraction is probably not mediated by CGRP receptors.The 2-adrenoceptor agonist oxymetazoline inhibited the evoked NANC response (22 nmol/1, IC20; about 40%, maximum inhibition) without affecting the cholinergic response (up to 1 mol/1) or the postjunctional iris sensitivity to exogenous substance P. The inhibition was antagonized by rauwolscine (apparent -log KB 8.04) and by the relatively 2B-adrenoceptor selective antagonist ARC-239 (-log KB 8.51).The 2- and imidazoline receptor agonist aganodine inhibited the evoked NANC response (0.25 mol/l, IC20; about 30%, maximum inhibition) without affecting the postjunctional substance P responses. Rauwolscine 0.3 mol/l failed to antagonize this effect.It is concluded that the release of sensory neurotransmitter(s) from trigeminal fibres in the rabbit eye may be inhibited by 2B-adrenoceptors and by a non-2-receptor, perhaps an imidazoline receptor.This study was supported by the Deutsche Forschungsgemeinschaft (Fu 163/3)Correspondence to H. Fuder at the above address 相似文献
17.
C. Chiung Chang M. Jai Su J. Don Lee David Eaker 《Naunyn-Schmiedeberg's archives of pharmacology》1977,299(2):155-161
1.beta-Bungarotoxin, crotoxin and taipoxin, presynaptic neurotoxins of snake venom origin, have about the same phospholipid-splitting activities as a much less toxic cobra phospholipase A2 in the presence of Ca2+ and deoxycholate. 2. Sr2+ was a much less effective activator of the enzymes than is Ca2+, the activation by Sr2+ being only 3-6% for beta-bungarotoxin and crotoxin and 12% for taipoxin. 3. Sr2+ also inhibited the Ca2+ -activated enzymes by 80% in the cases of beta-bungarotoxin and crotoxin, but only 16% in the case of taipoxin. 4. Mg2" had no significant effect on beta-bungarotoxin or crotoxin, but activated taipoxin in the presence or absence of Ca2". 5. In Sr2+ -Tyrode lacking Ca2+ all three toxins exhibited the same immediate depression followed by facilitation in the rat and mouse diaphragms, but the final blocking activity was only 3-10% with beta-bungarotoxin and crotoxin and was 30% with taipoxin. 6. In Sr2+ -Tyrode, increasing in the rate of nerve stimulation had less accelerating effect on the development of neuromuscular block than in Ca2+ -Tyrode for any of the toxins. 7. Removal of Mg2+ from Sr2+ -Tyrode did not diminish the potency of taipoxin in blocking neuromuscular transmission, suggesting that enzyme activity at the outer surface of the axolemma does not contribute to the neuromuscular blocking action. 8. All of the results indicate that there are close correlations between the presynaptic activities of these toxins and their phospholipid-splitting activities in the cationic environment prevailing in the axoplasm. Apparently the final blocking effect of these toxins is due to phospholipase A action within the nerve terminal. 相似文献
18.
《Expert opinion on investigational drugs》2013,22(10):1521-1536
Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are beneficial in the treatment and prevention of Alzheimer’s disease (AD). NSAIDs act by inhibiting cyclooxygenase, an enzyme that occurs in constitutive and inducible isoforms, known respectively as COX-1 and COX-2. Recognition that COX-2 plays a key role in inflammation led to the hypothesis that COX-2 might represent the primary target for NSAIDs in AD, consistent with inflammatory processes occurring in AD brain. This review highlights recently gathered evidence leading to a more complex view of the role of COX-2 in AD, including evidence that COX-2 directly contributes to neuronal vulnerability. Consideration of these roles is critical for the rational implementation of NSAID therapy in AD. 相似文献
19.
Lee BJ Choi HG Kim CK Parrott KA Ayres JW Sack RL 《Archives of pharmacal research》1997,20(6):560-565
The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9+/-0.24 degrees C and 7249+/-217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees C. In HCl-NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPbetaCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT. 相似文献
20.
Xin X Higai K Imaizumi Y Suzuki C Ito K Itoh A Matsumoto S Azuma Y Matsumoto K 《Biological & pharmaceutical bulletin》2011,34(4):480-485
Killer lectin-like receptors on natural killer (NK) cells mediate cytotoxicity through glycans on target cells. We prepared recombinant glutathione S-transferase-fused extracellular lectin-like domains (AA 94-231) of natural killer group 2A (NKG2A) (rGST-NKG2A) and NKG2C (rGST-NKG2C) and determined the binding of these receptors to plates coated with heparin-conjugated bovine serum albumin (heparin-BSA) and glycoproteins. rGST-NKG2A and rGST-NKG2C directly bound to heparin-BSA with K(d) values of 20 and 40 nM, respectively. Binding of rGST-NKG2A and rGST-NKG2C to heparin-BSA was suppressed in the presence of soluble heparin, heparan sulfate, fucoidan, λ-carrageenan, and dextran sulfate. 2-O-Sulfate residues in heparin were essential for the binding of rGST-NKG2A and rGST-NKG2C. Moreover, rGST-NKG2A and rGST-NKG2C bound to multimeric sialyl Lewis X expressing transferrin secreted by HepG2 cells with K(d) values of 80 and 114 nM, respectively. This is the first report showing that NKG2A and NKG2C bind to heparin and α2,3-NeuAc-containing glycoproteins. 相似文献