山莨菪碱对乙酰胆碱和去甲肾上腺素引起的兔虹膜释放前列腺素的影响

本文研究了654-2对Ach及NE引起的兔虹膜释放PGE_2及6-keto-PGF_(1α)作用的影响。Ach及NE使虹膜释放PGs增加,654-2对Ach释放PGs的作用呈剂量依赖性抑制,当654-2浓度为3×10~(-5)mol/L时,Ach(5x10~(-5)mol/L)引起的PGE_2及6-keto-PGF_(1α)的释放量分别降低31%及30%。654-2浓度高于6x10~(-5)mol/L时显著抑制NE(5x10~(-5)mol/L)释放虹膜PGs的作用,当654-2浓度为3x10~(-4)mol/L时,使NE增加虹膜释放PGE:及6-keto-PGF_(1α)的量分别从62%及34%降至7.5%及4%(p<0.01)。654-2抑制PGs释放对其抗感染性休克等作用可能是有利的。     

非普拉宗对环氧酶活性的影响

目的　研究非普拉宗(feprazone, Fep)对环氧酶-1和环氧酶-2活性的影响。 方法　用放免法测定PGE2含量反映环氧酶-2活性,测定6-酮-前列腺素F_1α含量反映环氧酶-1活性。 结果　Fep在0.1,1.0,10.0 μmol.L^-1能剂量依赖性抑制小鼠腹腔巨噬细胞PGE₂生成,在相同浓度下对小牛主动脉内皮细胞6-keto-PGF_1α生成抑制作用较弱。结论　Fep显著抑制PGE₂生成,对PGI₂生成影响较小,提示其对环氧酶-2有较强的抑制作用。     

阿魏酸钠对花生四烯酸代谢的影响

利用放射薄层方法测定兔血小板花生四烯酸代谢产物TXB₂,PGE₂和PGF_2α。用放射免疫法测定兔血小板TXB₂及主动脉6-keto-PGF_1α。阿魏酸钠(SF,0.1～3.2 mmol/L),抑制¹⁴C-花生四烯酸转化为TXB₂,呈剂量效应关系,IC₅₀为0.762 mmol/L。SF在较高浓度(0.8～3.2mmol/L)时亦抑制PGE₂,PGF_2α的生成。用放免法观察到,SF对血小板TXB₂和动脉壁6-keto-PGF_1α的生成均有抑制作用,对TXB₂的作用较强。结果提示,SF可抑制兔血小板和动脉壁环氧酶活性。     

胸腺肽α1缓释注射微球的研究

制备胸腺肽α₁(Tα₁)的长效注射微球，并对微球的体外释放特性、体外活性及药效学进行考察。采用复乳法(W/O/W)制备了载Tα₁聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；采用CCK-8法评价微球制备工艺和体外释放过程中Tα₁的生物学活性；体内药效学研究中采用流式细胞仪检测免疫抑制模型大鼠给予Tα₁微球后所产生的CD₄⁺，CD₈⁺因子的量，根据CD₄⁺/CD₈⁺的比值变化评价体内药效。微球球形圆整，分散性好，两个优选处方(外水相中加入5%氯化钠和10%葡萄糖)的微球包封率分别为87.8%和90.2%；Tα₁微球1个月的体外累积释放可达90%以上。使用含10%葡萄糖的PVA溶液作为外水相，较好地保持了制备工艺过程中的Tα₁生物学活性，在体外释放过程中Tα₁的生物学活性略有下降；Tα₁微球可显著提高免疫抑制模型小鼠的免疫力。用可生物降解的聚合物PLGA作为载体材料，可以将Tα₁制备成缓释1个月的注射微球。     

四氢异喹啉类生物碱对大鼠脑内α肾上腺素受体的作用

应用放射受体结合法研究了近30种四氢异喹啉类(TIQs)生物碱对大鼠脑内α肾上腺素受体的作用。其中l-CBN,l-THC和l-STP对α₁受体亲和力最高,K_i值为～2.0×10^-7mol/L。其次是DHS,XLP和l-DCT,K_i值分别为4.7×10^-7,6.5×10^-7和7.6×10^-7mol/L。DHS对α₂受体亲和力最高(K_i=1.25×10^-6mol/L),l-REM次之。对α受体亚型亲和力选择比K_i(alpha-2)/Ki(alpha-1)最高的是l-STP(357) 和XLP(154),它们对α₂受体几无亲和力(K_i>10^-4mnl/L)。提示l-STP和XLP对α₁受体有较高的选择性。l-SPD和l-THP对α₁和α₂受体亲和力相近,均为中等强度。THJ,DRC及l-TTD等6种TIQs对α₁和α₂受体均无亲和力(K_i>10^-4mnl/L)。     

极谱法研究辅酶Q10与β-环糊精的包结行为

目的研究辅酶Q_{10与β-环糊精(β-CD)的包结行为。方法用极谱法考察主体分子β-CD与电活性客体分子辅酶Q10发生包结反应时，包结物还原波峰电流随时间的变化，峰电位随β-CD浓度的变化，并在自然光照条件下分别考察辅酶Q10和包结物的还原波峰电流随时间的变化。结果在0.1 mol·L^-1 HAc/NaAc (pH 4.7)的乙醇-水(60∶40)介质中，辅酶Q10与β-CD形成1∶1的包结物，测得其包结常数kf为1.26×10⁴ L·mol^-1，包结反应的表观速率常数k为6.64×10^-2 min^-1。并测得辅酶Q10的光降解表观速率常数k为7.77×10^-3 min^-1，辅酶Q10-β-CD包结物的k为3.38×10^-3 min^-1。结论辅酶Q10和β-CD可形成包结物，并在一定程度上提高了辅酶Q10的光稳定性。}     

慢性孵育β-淀粉样肽(25-35)对培养大鼠海马神经元外向钾电流的影响

目的　研究慢性孵育β-淀粉样肽_(25-35) (β-AP_25-35)对海马神经元上瞬时外向钾电流(I_A)和延迟整流钾电流(I_K)的影响。方法　在培养的大鼠海马神经元上用膜片钳全细胞记录钾通道电流。结果　β-AP_25-35 3μmol·L^-1 孵育细胞24h ,I_K 电流幅度增加(44.3±5.4)% ,电流密度由(30.4±6.4)pA·PF^-1 增加至(43.8±4.7)pA·PF^-1 ;β-AP_25-3510μmol·L^-1 孵育12h ,I_K 电流幅度增加(69.8±4.1) % ,电流密度增加至(51.6±7.9)pA·PF^-1,呈浓度依赖性;β-AP_25-35引起的I_K 增加对TEA 5mmol·L^-1 敏感;β-AP_25-35上调I_K 的作用主要发生在β-AP_25-355用药后48h内。β-AP_25-35对I_A无显著性影响。结论　β-AP_25-35选择性地增加海马神经元上I_K,这一作用可能与β-AP的神经毒性有关     

某些四氢异喹啉类生物碱对大鼠脑内多巴胺和5-羟色胺受体的作用

本文报道十二种四氢异喹啉类生物碱对大鼠脑内D-2,5-HT₁和5-HT₂受体的结合特性。其中l-千金藤碱(l-STP)对这三种受体均有较高的亲和力,其Ki值分别为1.7×10^-7,9.4×10^-8和1.8×10^-7mol。l-莲碱(l-REM)对5-HT₂受体的亲和力与Z-STP相似(Ki=1.7×10^-7mol)。THB,THC和THJ对D-2受体的亲和力介于l-SPD和l-THP之间。本文报道的多数生物碱能同时影响两种或两种以上受体部位的结合特性,提示它们对单胺神经系统可能有复杂的相互作用。     

前列腺素E1经不同途径给药后的大鼠体内药效学比较

本文研究了前列腺素E₁(PGE₁)分别经不同途径给药后的大鼠体内药效学，旨在寻找目前PGE₁注射给药的替代途径。以PGE₁降压效应作为药效学指标，以静脉注射为对照，分别测定PGE₁经鼻腔、舌下、肌肉(im)、腹腔(ip)给药后的药效学参数，包括峰效应时间(Tmax)，血压下降最大百分数(Emax，%)，效应持续时间(T_d)以及血压下降百分数-时间曲线下面积(AUC，%·min)。研究结果表明，PGE₁经上述途径给药后，药效学参数Emax，T_d，AUC等均随给药剂量的增加而增大，提示存在明显的剂量-效应关系。根据所测Tmax值，推断上述给药途径其吸收速率的大小顺序为：鼻腔≈im>ip>舌下；依据所测药理生物利用度(PF)值，预测药物绝对生物利用度的顺序为：鼻腔>im≈ip>舌下。上述研究结果提示，PGE₁经鼻腔与舌下黏膜给药，有望替代目前的注射给药。     

乳香没药精油自微乳的制备与抗炎镇痛作用评价

目的 制备乳香没药精油（FMO）自微乳化给药系统（FMO-SMEDDSs）,并评价其抗炎镇痛效果。方法 水蒸气蒸馏法提取FMO,考察FMO与不同种类油相、乳化剂和助乳化剂的配伍相容性并确定了FMO-SMEDDSs的处方组成,最终根据伪三元相图法得到其处方配比;以热力学稳定性、动态光散射、透射电镜等实验手段评价FMO-SMEDDSs的理化性质。将 SD 大鼠随机分为 5 组 ：对照组、模型组、布洛芬（阳性药 ,20 mg·kg^-1）组、FMO（生药剂量 90 mg·kg^-1）组、FMOSMEDDSs （90 mg·kg^-1）组,每天ig给药2次,连续给药7 d,对照组与模型组ig生理盐水;除对照组外,其余4组大鼠均在右后足跖sc 40.0%甲醛溶液0.1 mL,6 h后用千分尺测量大鼠右后足厚度,并计算肿胀度和肿胀抑制率;ELISA试剂盒法分别检测致炎足足底组织中前列腺素E₂（PGE₂）水平,血清白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）水平。通过小鼠扭体法评价布洛芬（40 mg·kg^-1）组、FMO（180 mg·kg^-1）组、FMO-SMEDDSs（180 mg·kg^-1）的镇痛效果。结果 根据配伍相容性及伪三元相图结果,分别选择肉豆蔻酸异丙酯（IPM）、聚山梨酯 80 和异丙醇作为 FMO-SMEDDSs 的油相、乳化剂和助乳化剂,配比为 4∶4∶2;FMO-SMEDDSs形成的微乳平均粒径为（57.8±1.1）nm,PDI为（0.216±0.014）,Zeta电位为（-11.5±0.05）mV,在透射电镜下可观察到微乳呈球状,FMO-SMEDDSs热力学稳定性良好。与模型组比较,布洛芬、FMO、FMOSMEDDSs组大鼠的致炎足肿胀度及肿胀率均显著降低（P＜0.05）,PGE₂、TNF-α和IL-6水平显著降低（P＜0.05）;与FMO组比较,FMO-SMEDDSs组大鼠致炎足肿胀度及肿胀率进一步显著降低（P＜0.05）,PGE₂、TNF-α和IL-6水平进一步显著降低（P＜0.05）。与模型组比较,ig布洛芬、FMO以及FMO-SMEDDSs后均能显著延长小鼠扭体反应潜伏期,显著减少15 min内的扭体次数（P＜0.05）;相对于FMO组,FMO-SMEDDSs抑制小鼠扭体反应作用更明显。结论 成功制备FMO-SMEDDSs,其具有良好的抗炎镇痛的作用。     

Comparison of the effects of prostaglandins E2 and I2 on testicular nociceptor activities studied in vitro

Summary Effects of exogenous prostaglandin (PG) E₂ and PGI₂ on testicular polymodal receptor activities were compared in in vitro recordings of single- or multi-fiber discharges from canine testis-spermatic nerve preparations. PGI₂ up to 1.4×10^–6 mol/l (cumulative method) or 1.0×10^–5 mol/l (non-cumulative method) excited only weakly some of the receptors, and similar observations were made with PGE2. Both PGs applied cumulatively or non-cumulatively at concentrations above 1.4×10^–8 mol/l augmented the response to bradykinin (9.4×10^–8 mol/l) in more than half of the cases tested. The augmenting effect of PGE₂ lasted longer than that of PGI₂ both with the cumulative and the non-cumulative method. The degree of augmentation tended to increase dependent on concentration, but some cases showed no further increase or rather a decrease in augmentation by PGs at a ten times higher concentration, especially when PGs were applied cumulatively. A second challenge by PG after a short interval (2 min) did not induce augmentation. These phenomena were considered to be tachyphylaxis to PGs. Cross-tachyphylaxis to PGE₂ and PGI₂ was also observed. There was not much difference in excitatory and augmenting potencies between these two PGs, but there was a clear difference in the concentrations of the PGs necessary to induce excitation of polymodal receptors and to facilitate their response to bradykinin. Send offprint requests to T. Kumazawa at the above address     

Gn类化合物对小鼠腹腔巨噬细胞产生肿瘤坏死因子α的影响

目的　研究异单叶大黄素(isorhapotigenin, Gn-1), 白藜芦醇(resveratrol, Gn-2)和二苯乙烯低聚体(stilbene oligopolymer, Gn-3)等3种Gn类化合物对小鼠腹腔巨噬细胞产生肿瘤坏死因子α(TNF_α)的影响。 方法　用L929作为靶细胞的结晶紫染色法测定Gn类化合物对巨噬细胞经LPS或重组人白细胞介素-8(rhIL-8)产生TNF_α的影响。结果　Gn-1,Gn-2和Gn-3均能剂量依赖性地抑制巨噬细胞经LPS刺激产生的TNF_α,Gn-1和Gn-3均可剂量依赖性地抑制巨噬细胞经rhIL-8刺激产生TNF_α。结论　3种Gn类化合物可抑制小鼠腹腔巨噬细胞生成TNF_α,可能是它们抗炎作用的机制之一。     

氯哌胺对15-甲基前列腺素F2α致泻和兴奋子宫作用的影响

氯哌胺(Loperamide)是一种新型止泻药,能拮抗15-M-PGF_2α引起的小鼠小肠内碳粉推进加速和腹泻,作用比吗啡和阿托品强,对离体大鼠回肠的抑制作用也比吗啡、阿托品强。氯哌胺能降低肠平滑肌张力,抑制离体大鼠回肠对15-M-PGF_2α的反应性,但却增强子宫平滑肌对15-M-PGF_2α的反应性。氯哌胺对离体大鼠子宫自发收缩活动低浓度兴奋、高浓度抑制。氯哌胺对15-M-PGF_2α促进大鼠空肠水和钠离子分泌也有拮抗作用,此作用不能被纳洛酮翻转。氯哌胺在小鼠的急性半数致死量为77.9 mg/kg。     

山莨菪碱对大鼠胸水中性白细胞花生四烯酸代谢的影响

本文研究了654-2对大鼠胸水中性白细胞代谢[1-¹⁴C]AA及内源性AA的影响。大鼠白细胞AA经5-LPO代谢途径形成的主要产物为LTB₄及5-HETE,经CO途径的主要产物为HHT及TXB₂。654-2对白细胞代谢[1-¹⁴C]AA无抑制作用,但显著减少白细胞从内源性AA形成的LTB₄,5-HETE,HHT及TXB₂。这种抑制作用与654-2呈剂量依赖关系。本实验结果表明,654-2抑制PG及LT的形成可能是影响了AA从胞膜的释放,而并非直接抑制CO及5-LPO。     

Effect of etodolac on the prostaglandin concentrations in the kidney of the normal rat

The effect of acute and subchronic dosing with etodolac on the renal PGE₂ and 6-keto-PGF_1α concentrations in the normal rat were studied. Etodolac and other nonsteroidal antiinflammatory drugs (NSAIDs) were administered orally, at equieffective antiinflammatory doses, to normal rats either as a single dose or as seven daily doses. Whole kidney prostaglandin (PG) concentrations were measured. In the acute study, etodolac (3 mg/kg) did not significantly lower the PGE₂ levels for up to 4 hr postdosing. In contrast, naproxen (3 mg/kg) and piroxicam (0.5 mg/kg) significantly decreased the PGE₂ levels to about 20% and 60% of control, respectively. Similar reductions in 6-keto-PGF_1α concentrations were observed. In the subchronic study, etodolac (3 mg/kg/day) did not lower either PGF₂ or 6-keto-PGF_1α concentrations whereas naproxen (3 mg/kg/day), piroxicam (0.5 mg/kg/day), indomethacin (1 mg/kg/day), and aspirin (300 mg/kg/day) significantlydecreased both PGs. In both studies, the effect of etodolac was significantly different from that of the NSAIDs. It is concluded that etodolac possesses only a very weak capacity to lower renal PGs, and therefore is unlikely to cause any renal complications related to PG biosynthesis inhibition.     

EFFECTS OF NITRO-l-ARGININE ON ENDOTHELIUM-DEPENDENT RELAXATION OF CANINE CEREBRAL ARTERIES

1. The effect of N^G-nitro-l-arginine (NO₂Arg) on the relaxation of canine basilar artery was investigated and compared with those of middle cerebral and femoral arteries. 2. NO₂Arg (10^?7-3 × 10^?5 mol/L) inhibited the substance-P (Sub-P; 10^?12-10^?8 mol/L) induced relaxation in the basilar artery precontracted with prostaglandin F_2α (PGF_2α; 10^?5 mol/L) or KCl (10^?2 mol/L) in a concentration-dependent manner and a ratio of the maximum inhibition by NO₂Arg (3 × 10^?5 mol/L) was more than 90%. 3. The relaxation induced by A23187 (10^?9-3 × 10^?6) was also abolished by NO₂Arg (3 × 10^?5 mol/L), but that by glyceryl trinitrate (GTN; 10^?9-3 × 10^?5 mol/L) was not, in the basilar artery precontracted with PGF_2α (10^?5 mol/L). N^G-nitro-d-arginine (NO₂ArgD; 3 × 10^?5 mol/L) did not affect the relaxation induced by Sub-P (10^?12-10^?8 mol/L). 4. l-arginine (l-Arg; 3 × 10^?5-10^?4 mol/L) did not inhibit Sub-P (10^?12-10^?8 mol/L) induced relaxation in the basilar artery. Pretreatment of l-Arg (10^?4 mol/L) reversed the relaxation inhibited by NO₂Arg (3 × 10^?6 mol/L) in the arteries. 5. NO₂Arg (3 × 10^?5 mol/L) inhibited the Sub-P (10^?12-10^?8 mol/L) induced relaxation in the canine middle cerebral artery as much as in the basilar artery. NO₂Arg (3 × 10^?5 mol/L) also inhibited Sub-P (10^?12-10^?8 mol/L) induced relaxation in the femoral artery, but the degree of the inhibition was less than that in the basilar artery. 6. These results suggest that the endothelium-derived relaxing factor (EDRF) of canine basilar artery is mainly l-Arg derived nitric oxide which may play a more important role in the basilar artery than the femoral artery.     

Cytotoxic enzyme release and oxygen centered radical formation in human neutrophils are selectively inhibited by E-type prostaglandins but not by PGI2

Summary The action of PGE₁, PGE₂, PGI₂ and iloprost on superoxide anion generation, lysosomal enzyme release, and changes of Ca²⁺ fluxes in human polymorphonuclear leukocytes (PMN) was studied in vitro. Both PGE-type compounds were equipotent inhibitors of FMLP-and PAF-stimulated superoxide anion generation, -glucuronidase release (IC₅₀ 3–5 mol/l) and Ca²⁺ influx while PGI₂ and iloprost were ineffective at concentrations up to 10 mol/l. These inhibitory actions of PGE₁ and PGE₂ were paralleled by an increase in cAMP level of the PMN while no change occurred with PGI₂ and iloprost. None of the prostaglandins affected the initial intracellular Ca²⁺ liberation after challenge with FMLP or PAF. Preincubation of PMN with PGE₁ and PGE₂ but not with iloprost resulted in subsequent desensitization against a second administration of these compounds. None of the compounds affected PMN activation produced by arachidonic acid or calcimycin (A 23187).These data demonstrate that PGE-type compounds are effective inhibitors of receptor-mediated (PAF, FMLP) activation of human PMN while prostacyclins are considerably less potent. This suggests that the inhibitory prostaglandin receptor on human PMN belongs to the E-type being functionally different from the inhibitory prostaglandin receptor on human platelets. These results suggest that compounds, such as PGE₁ and PGE₂ might be superior to prostacyclins to prevent PMN-associated generation of reactive oxygen species and lysosomal enzyme release in situations with endogenous PMN activation, i. e. inflammatory reactions. Send offprint requests to K. Schrör at the above address     

Distinction of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition from cyclooxygenase-2 inhibition in cells using a novel, selective mPGES-1 inhibitor

Inflammation-induced microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme that synthesizes prostaglandin E₂ (PGE₂) downstream of cyclooxygenase-2 (COX-2). The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors in the treatment of the signs and symptoms of osteoarthritis, rheumatoid arthritis and inflammatory pain, largely attributed to the inhibition of PGE₂ synthesis, provides a rationale for exploring mPGES-1 inhibition as a potential novel therapy for these diseases. Toward this aim, we identified PF-9184 as a novel mPGES-1 inhibitor. PF-9184 potently inhibited recombinant human (rh) mPGES-1 (IC₅₀ = 16.5 ± 3.8 nM), and had no effect against rhCOX-1 and rhCOX-2 (>6500-fold selectivity). In inflammation and clinically relevant biological systems, mPGES-1 expression, like COX-2 expression was induced in cell context- and time-dependent manner, consistent with the kinetics of PGE₂ synthesis. In rationally designed cell systems ideal for determining direct effects of the inhibitors on mPGES-1 function, but not its expression, PF-9184 inhibited PGE₂ synthesis (IC₅₀ in the range of 0.5-5 μM in serum-free cell and human whole blood cultures, respectively) while sparing the synthesis of 6-keto-PGF_1α (PGF_1α) and PGF_2α. In contrast, as expected, the selective COX-2 inhibitor, SC-236, inhibited PGE₂, PGF_1α and PGF_2α synthesis. This profile of mPGES-1 inhibition, distinct from COX-2 inhibition in cells, validates mPGES-1 as an attractive target for therapeutic intervention.