TMB-8抑制5-HT和KCl引起大鼠脑血流量减少

目的研究TMB-8对5-HT和KCl引起的大鼠脑血流量(CBF)减少的作用。方法用激光多普勒血流仪测量大鼠CBF,在人工脑脊液灌流液中加入TMB-8和工具药进行干预。结果12.5, 25和50 μmol·L^-1 TMB-8对大鼠CBF无明显影响,TMB-8可抑制5-HT引起的大鼠CBF减少。在1 μmol·L^-1 5-HT引起大鼠CBF持续下降的状态下,TMB-8可浓度依赖的增加大鼠CBF。TMB-8也可抑制KCl引起的大鼠CBF减少。在20 mmol·L^-1 KCl引起大鼠CBF持续下降的状态下,TMB-8可浓度依赖的增加大鼠CBF。结论TMB-8可抑制5-HT和KCl引起的大鼠CBF减少,也可浓度依赖的增加被5-HT和KCl所减少的大鼠CBF,改善大鼠缺血区脑血供。     

5-甲基-7,4’-二羟基异黄酮水溶性衍生物的合成及其抗缺氧活性

目的5-甲基-7,4’-二羟基异黄酮水溶性衍生物的合成及其抗缺氧活性的比较。方法三氟化硼-乙醚催化的“一锅法”工艺制备母体化合物1,并通过甲基化和磺化反应合成衍生物2～4,常压耐缺氧试验评价其活性。结果化合物3和4水溶性强,且抗缺氧作用等价于母体化合物。结论新合成的水溶性化合物3和4具有明显的抗缺氧活性。     

Synthesis of tritium labelled L783483 ‐ a PPARδ ligand

The potent peroxisome proliferator‐activated receptor (PPAR) δ ligand L783483 (3‐chloro‐4‐(3‐(7‐propyl‐3‐trifluoromethyl‐benzisoxazol‐6‐oxy)propylsulfanyl)phenylacetic acid) has been labelled with tritium via selective tritium/bromine exchange of 5‐bromo‐6‐(3‐bromopropyloxy)‐7‐propyl‐3‐trifluoromethyl‐benzisoxazole. [³H]‐L783483 had a specific activity of 529 GBq/mmol (14.3 Ci/mmol) and a radiochemical purity of 98%. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of [14C]ABT‐770, matrix metalloproteinase inhibitor (MMPI), labelled in the phenoxy ring

The MMPI [¹⁴C]ABT‐770 (1) , N‐[(1S)‐1‐[(4,4‐Dimethyl‐2,5‐dioxo‐1‐imi‐dazolidinyl)methyl]]‐2‐[[4′‐(trifluoromethoxy)[1,1′‐biphenyl]‐4‐yl]oxy]ethyl]‐N‐hydroxyformamide was synthesized in 8 steps using 4‐bromophenol‐UL‐¹⁴C (10) as a starting material. The Carbon‐14 label was introduced in one of the metabolically stable biphenyl rings. The key sequence of the synthesis was a three‐step one‐pot reaction in which the hydantoin moiety was introduced, the imine oxidized and further hydrolyzed to get the penultimate precursor to [¹⁴C]ABT‐770 (1) in 56% yield. Copyright © 2003 John Wiley & Sons, Ltd.     

Prostaglandin E2 Directly Inhibits Bone-Resorbing Activity of Isolated Mature Osteoclasts Mainly Through the EP4 Receptor

Prostaglandins (PGs) are well known to be important local factors in regulating bone formation and resorption. PGE₂ is a potent stimulator of bone resorption because of enhancing osteoclast formation by its indirect action through stromal cells. However, the direct action of PGE₂ on functionally mature osteoclasts is still controversial. In this study using highly purified rabbit mature osteoclasts, we examined the direct effect of PGE₂ on osteoclastic bone-resorbing activity and its mechanism. PGE₂ inhibited resorption pit formation on a dentine slice by the purified osteoclasts in a dose- and time-dependent manner. The inhibitory effect appeared as early as 4 hours after the PGE₂ addition. Forskolin and 12-0-tetradecanoyl phorbol-13-acetate (TPA), respective activators of adenylate cyclase and protein kinase C, also decreased the osteoclastic bone-resorbing activity. PGE₂ increased the content of intracellular cAMP in a dose range effective for the inhibition of bone resorption, whereas the prostanoid did not alter the intracellular level of inositol triphosphate. The inhibition of osteoclastic bone resorption by PGE₂ was amplified and diminished by a cAMP phosphodiesterase inhibitor (isobutyl methylxanthine) and a protein kinase A inhibitor (Rp-cAMP), respectively. Of four different subtypes of PGE₂ receptors (EPs), EP4 mRNA was predominantly expressed in isolated osteoclasts, whereas the other types of EP mRNA were detected in only small amounts. These results suggest that the PGE₂ inhibitory effect was mediated by an adenylate cyclase system coupled with EP4. This possible association of PGE₂ with EP4 in mature osteoclasts was supported by the finding that a specific agonist of EP4 (AE-604) inhibited the bone-resorbing activity and elevated the intracellular cAMP content. However, butaprost, a selective EP2 agonist, also mimicked the PGE₂ effects on isolated osteoclasts although EP2 mRNA expression was minimal. In conclusion, PGE₂ directly inhibits bone-resorbing activity of functionally mature osteoclasts by activation of the adenylate cyclase system, perhaps mainly through EP4. Received: 21 July 1999 / Accepted: 31 January 2000     

针刺对实验性变态反应性神经炎TNF-α和IL-4的影响

目的 探讨肿瘤坏死因子-α(TNF-α)和白细胞介素-4(IL-4)与实验性变态反应性神经炎(EAN)发病的关系，从细胞因子水平研究针刺疗法对本病的免疫调节作用。方法 40只大鼠分为正常对照组、模型组、针刺组、药物组，建立大鼠EAN动物模型，观察大鼠发病率及致病程度，针刺组取腰。夹脊、足三里、悬钟穴，药物组用泼尼松灌胃给药。采用双抗体夹心ELISA法，检测大鼠血清的TNF-αa和IL-4的含量变化。结果 模型组TNF-α含量较正常组明显升高。针刺组和药物组均能降低TNF-α的含量，使其水平接近正常，尤以药物组抑制作用明显。IL-4的含量各组间均无明显差异。结论 提示本病存在Th1／Th2细胞因子间的失衡，其中以Th1型细胞占优势。针刺主要是通过抑制TNF-α等Th1细胞，来重建细胞因子间的平衡。     

A chimeric opioid peptide with mixed μ agonist/δ antagonist properties

Abstract: There is evidence to indicate that opioid compounds with mixed μ agonist/δ antagonist properties are analgesics with low propensity to produce tolerance and physical dependence. A chimeric peptide containing the potent and selective μ agonist H‐Dmt‐D‐Arg‐Phe‐Lys‐NH₂ ([Dmt¹]DALDA) (Dmt = 2′,6′‐dimethyltyrosine) and the potent and selective δ antagonist H‐Tyr‐TicΨ[CH₂‐NH]Cha‐Phe‐OH (TICP[Ψ]) (Cha = cyclohexylalanine), connected ‘tail‐to‐tail’ via a short linker, was synthesized using a combination of solid‐phase and solution techniques. The resulting peptide, H‐Dmt→D‐Arg→Phe→Lys‐NH‐CH₂‐CH₂‐NH‐Phe←Cha[NH‐CH₂]ΨTic←Tyr‐H, showed the expected μ agonist/δ antagonist profile in the guinea‐pig ileum and mouse vas deferens assays. Its μ and δ receptor binding affinities were in the low nanomolar range, as determined in rat brain membrane binding assays.     

Study and development of encapsulated forms of 4, 5′, 8‐Trimethylpsoralen for topical drug delivery

Trimethylpsoralen (TMP) is often used to treat skin diseases (i.e., psoriasis, vitiligo, etc.). This drug permeates moderately the skin barrier. In the present study, we investigated the effect of formulation on the improvement of TMP skin bioavailability. Three formulations were performed. Each form (liposomes, nanospheres, and EtOH solution) contained 0.05% of TMP. For each preparation, the quantity deposited on the skin surface was 250 µg (Q₀). The TMP percutaneous penetration through ex‐vivo human skin was processed by Franz^® cells (n=4) using a human albumin solution (1.4% w/v) as receiver medium. The percentages of the extracted TMP that permeated through the skin and that were retained in the skin over 24 h, were calculated with respect to Q₀. The values obtained were reported, respectively, as follows: EtOH solution (1.33 vs. 0.08%), liposomes (0.93 vs. 0.93%), and PLG‐nanospheres (0.79 vs. 3.01%). So, considering the correlation between the cumulated amounts of TMP permeated through the skin and the TMP stocked in the skin, the nanosphere form showed the higher quantity of TMP accumulated in the skin structures. On the other hand, the maximum value of the flux (ng/cm²/h) in the steady state of TMP incorporated in each formulation was at 6 h for all formulations: 173.5±1.06 (EtOH solution) > 120.4±1.06 (liposomes) > 93.82±0.88 (PLG‐nanospheres). These results indicate that the controlled release of TMP by incorporation in PLG‐nanospheres may increase drug content in the skin, while maintaining a minimal percutaneous absorption. Finally, this work shows that the PLG‐nanospheres could constitute a promising approach for controlling TMP release in order to maintain its topical activity. Drug Dev. Res. 61:86–94, 2004. © 2004 Wiley‐Liss, Inc.     

鼻咽癌面颈联合野放疗对唾液腺功能影响的临床分析

目的 :利用放射性核素99mTcO4-动态显像唾液腺定量测定鼻咽癌面颈联合野放疗前、中、后唾液腺功能的变化并探讨与放疗剂量之间的关系。方法 :2 0 0 3年 2月 1日～ 2 0 0 3年 10月 3 1日 ,分别对 2 0例鼻咽癌面颈联合野放疗患者于放疗前、放疗至 10、3 6～ 40、70Gy时进行99mTcO4-动态显像定量测定其唾液腺(腮腺、颌下腺 )摄锝率 (UR)、泌锝率 (ER)变化 ,同时观察其口干程度进行临床分级。结果 :2 0例鼻咽癌面颈联合野放疗剂量为 10和3 6～ 40Gy时 ,其泌锝率明显低于放疗前 ,P <0 0 5 ,在放疗 70Gy时降到最低 ,P <0 0 1。与临床观察到的口干严重程度一致 ,而其摄锝率在 3 6～ 40Gy照射以前变化不明显 ,无统计学意义。结论 :鼻咽癌面颈联合野照射患者放疗前无明显唾液腺功能障碍 ,随着放疗剂量的增加 ,唾液腺功能明显下降 ,其ER较UR下降明显 ,在确保患者放疗疗效的同时 ,应尽可能提高放疗技术 ,减少唾液腺照射剂量和放疗体积 ,保护唾液腺功能 ,以提高患者的生活质量。