石榴皮多酚有效部位单次给药毒性及对无水乙醇致大鼠胃溃疡的保护作用

目的研究石榴皮多酚有效部位对小鼠单次给药毒性,评价其安全性,为新药研发和临床用药提供理论依据。观察石榴皮多酚有效部位对无水乙醇致大鼠胃溃疡的保护作用。方法选择健康昆明种小鼠50只,随机分为5组,每组10只,分别灌胃给予不同剂量的石榴皮多酚有效部位,连续观察14 d,每日记录各组小鼠一般情况、毒性反应及死亡情况,采用Bliss法计算半数致死量。选择健康大鼠70只,随机分为:正常组、模型组(等体积生理盐水)、三九胃泰颗粒组(1 850 mg·kg-1)、枸橼酸铋钾组(33 mg·kg-1)和石榴皮多酚有效部位低、中、高剂量组(430、852、1 704 mg·kg-1),连续灌胃10 d;d 10,除正常组外,其余各组采用无水乙醇灌胃(每只1.5 m L)致大鼠胃溃疡;计算各组胃溃疡指数、溃疡抑制率、观察胃黏膜组织形态学改变、测定胃黏膜组织中PGE2、NO、SOD、MDA含量。结果石榴皮多酚有效部位的半数致死量(LD50)为8 520.9 mg·kg-1,其95%的可信限范围为(7 291.2~9 914.4)mg·kg-1;病理学显示,给药剂量为16 000 mg·kg-1的小鼠脏器有不同程度的损伤。实验表明,与模型组比较,石榴皮多酚有效部位对胃黏膜损伤有明显修复作用,且明显升高胃溃疡大鼠胃黏膜NO含量、提高胃溃疡大鼠胃黏膜SOD活性及降低MDA含量、增加PGE2含量。结论石榴皮多酚有效部位给药剂量为5 063mg·kg-1未出现死亡,随着石榴皮多酚有效部位给药剂量的增加,给药剂量为16 000 mg·kg-1可造成小鼠的心、肝、肺、肾脏有不同程度的损伤,甚至导致死亡。石榴皮多酚有效部位的LD50为8 520.9 mg·kg-1,其95%的可信限范围为(7291.2~9 914.4)mg·kg-1。石榴皮多酚有效部位对无水乙醇致大鼠胃溃疡具有良好的保护作用,这种作用可能与促进胃溃疡上皮细胞合成、提高再生黏膜功能、增强抗氧化能力和诱导、促进NO合成有关。     

水苏碱抗炎活性的研究

目的:研究水苏碱的抗炎活性及其相关作用机制。方法:通过二甲苯致小鼠耳廓肿胀法和棉球致大鼠肉芽肿实验考察水苏碱的抗炎作用;通过检测角叉菜胶致大鼠胸膜炎性渗出液中蛋白质含量和白细胞(WBC)数及前列腺素E(2PGE2)、白细胞介素1(IL-1)、肿瘤坏死因子α(TNF-α)、一氧化氮(NO)含量,结合血清中丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性测定,初步研究水苏碱抗炎有关的作用机制。结果:24、12mg.kg-1剂量下水苏碱可显著降低模型大鼠胸膜炎性渗出液中蛋白质含量和WBC数,降低炎症部位PGE2、IL-1、TNF-α含量,同时降低模型大鼠血清中MDA含量,提高血清SOD活性(P<0.01或P<0.05)。12mg.kg-1剂量下水苏碱可显著降低模型大鼠炎症部位NO含量(P<0.05)。结论:水苏碱在一定剂量内具有较强抗炎作用,其抗炎作用可能与改善细胞膜通透性、降低炎性因子水平、减少脂质过氧化反应等作用相关。     

银杏叶提取物对佐剂性关节炎大鼠血清抗氧化能力及肿瘤坏死因子含量的影响

目的:考察银杏叶提取物(EGb761)对佐剂性关节炎(AA)大鼠血清抗氧化能力及肿瘤坏死因子(TNF-α)含量的影响,初步探讨银杏叶提取物治疗佐剂性关节炎的作用机制。方法:雄性SD大鼠于右后足跖皮内注射弗氏完全佐剂(FCA)0.1 mL建立大鼠佐剂性关节炎模型。致炎第12天分别应用EGb761低、中、高剂量(50,100,200 mg.kg-1)灌胃对其进行治疗,连续给药16 d;并以雷公藤多苷(40 mg.kg-1)作为阳性对照。采用足容积法测量继发侧足肿胀度。致炎第28天处死大鼠,收集血清,检测血清中髓过氧化物酶(MPO)、超氧化物歧化酶(SOD)和一氧化氮合酶(iNOS)活力、丙二醛(MDA)、一氧化氮(NO)及TNF-α含量。结果:致炎后第12天,大鼠继发性关节炎出现,给予不同剂量的EGb761(50,100,200 mg.kg-1),从致炎后第20天开始,EGb761可明显减轻继发性AA大鼠足爪的肿胀度;与模型对照组比较,EGb761各剂量组大鼠血清中MPO、iNOS活力及MDA、NO和TNF-α含量均明显降低(P<0.05或P<0.01),而SOD含量明显升高(P<0.01)。结论:EGb761对AA大鼠继发性炎症具有显著的治疗作用,其作用机制可能与提高AA大鼠血清抗氧化能力,抑制致炎因子TNF-α生成有关。     

秋茄提取物抗大鼠实验性胃溃疡作用研究

目的探讨海洋红树林植物秋茄枝水提取物活性部分B部位(fraction B of stem aqueous extracts of kandelia candel,SAEKC)对实验性大鼠胃溃疡的作用及其作用机制。方法将大鼠随机分为正常对照组、模型对照组、给药组(480、240、60mg·kg-13个剂量组)和西咪替丁组。各组每天灌胃给药(赋形剂,SAEKCB和西咪替丁),连续3d。除正常对照组外,其余各组大鼠在最后一次给药后通过水应激18h建立水浸束缚应激型胃溃疡大鼠模型,测定溃疡指数(UI),计算溃疡抑制率;同时建立幽门结扎型胃溃疡大鼠模型,造模后17h测定溃疡指数,计算溃疡抑制率,检测胃液量、胃蛋白酶活性,血清和胃组织一氧化氮(NO)含量。结果SAEKCB的高、中、低3个剂量组能明显减轻应激型胃溃疡大鼠胃黏膜损伤的程度(P<0.01,P<0.01,0<0.05),溃疡抑制率分别为模型对照组的0.411、0.404、0.254;SAEKCB能明显减轻幽门结扎型胃溃疡大鼠胃黏膜损伤的程度(P均<0.01),溃疡抑制率分别为模型对照组的0.556、0.361、0.306。480、240mg·kg-1剂量组能明显降低胃蛋白酶活性和胃液量(P<0.01或P<0.05)。给药3个剂量组均能提高胃组织NO含量,其中240、60mg·kg-1剂量组能明显升高血清NO含量(P均<0.01)。结论SAEKCB有明显抗应激型和幽门结扎型大鼠胃溃疡的作用,其效应呈剂量依赖性。对于幽门结扎型大鼠其机制可能在于减少胃液分泌、降低胃蛋白酶活性、提高血清和胃组织中NO水平。     

呱氨托美丁及其代谢产物在大鼠体内药动学

目的:研究呱氨托美丁(MED-15)单剂量灌胃给药及静脉注射在SD大鼠体内的药动学。方法:12只大鼠随机分为2组,分别灌胃给药MED-15(100mg.kg-1)或静脉注射MED-15(8mg.kg-1),采用HPLC法测定给药后大鼠血浆内MED-15代谢产物托美丁-甘氨酰胺衍生物(MED-5)及托美丁的浓度,应用DAS2.0软件进行非房室模型拟合及参数计算。结果:血样中未检测到MED-15,只能检测到其代谢产物MED-5及托美丁。灌胃组大鼠托美丁的Cmax为(2.8±1.1)mg.L-1,tmax为(7.9±1.1)h,AUC为(20.2±7.0)mg.h.L-1,静脉注射组大鼠托美丁的Cmax为(17.0±1.2)mg.L-1,AUC为(59.9±4.2)mg.h.L-1。结论:原药MED-15在大鼠胃肠道内有较强的首过代谢,导致生物利用度低。     

灯盏乙素对异烟肼和利福平合用致小鼠肝损伤的保护作用

目的:观察灯盏乙素对异烟肼(INH)和利福平(RFP)合用致小鼠肝损伤的保护作用.方法:小鼠每天同时灌胃RFP和INH各100 mg·kg-1,2 h后灌胃灯盏乙素50,100,200 mg·kg-1,qd,连续给药10 d,末次给药16 h后,取血和各器官组织,测定肝、脾和胸腺指数、血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的活性、肝匀浆中超氧化物歧化酶(SOD)、脂质过氧化物丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-PX)以及一氧化氮(NO)的含量.结果:灯盏乙素能显著降低RFP和INH合用致肝损伤小鼠的肝指数、血清ALT和AST活性、肝匀浆中的MDA和NO含量,并能显著提高肝匀浆中的SOD和GSH-Px活性.结论:灯盏乙素对RFP和INH合用致小鼠肝损伤具有明显的保护作用,可能与其抗脂质过氧化及调节体内NO水平有关.     

南瓜多糖对链脲菌素诱导的大鼠胰岛损伤的保护作用

目的:观察南瓜多糖(PP)对链脲菌素诱导的大鼠胰岛损伤的影响。方法:建立链脲菌素性糖尿病模型,PP(150,300,600mg·kg-1)灌胃3周进行治疗。检测大鼠空腹血糖值、血清胰岛素含量以及血清中超氧化物歧化酶(SOD)、丙二酰二醛(MDA)、一氧化氮(NO)的水平;观察链脲菌素性糖尿病大鼠胰岛细胞的超微结构的变化。结果:PP(300,600mg·kg-1)能显著降低STZ诱导的糖尿病大鼠的空腹血糖值;PP(600mg·kg-1)能升高糖尿病大鼠血清中的胰岛素值;PP(300,600mg.kg-1)治疗后,糖尿病大鼠血清中SOD值明显增加,MDA、NO的含量显著减少;大鼠胰岛细胞的超微结构显示PP对STZ损伤的胰岛细胞具有保护作用。结论:PP对链脲菌素诱导的大鼠胰岛损伤具有保护作用。     

苯磺酰基呋咱氮氧化物与双氯芬酸偶联化合物的合成及抗炎活性

目的　研究高效低毒的双氯芬酸 (DC)偶联化合物。方法　以酯键或酰胺键将一氧化氮 (NO)供体 3 ,4 二苯磺酰基呋咱氮氧化物与DC偶联 ,观察偶联物对二甲苯致炎小鼠和角叉菜胶致炎大鼠的抗炎活性及对大鼠胃肠道反应 ,研究体内外偶联物的NO释放。结果　合成了 11个新化合物 (I1 - 1 1 ) ,其结构经MS ,IR ,1 HNMR和元素分析确证。I1 - 5,I9显示抗炎活性 ,其中I4 和I5活性与DC相当 ,胃肠道副作用显著小于DC ,体内外均释放NO。结论　苯磺酰基呋咱氮氧化物与DC偶联的化合物可保留DC抗炎活性 ,降低DC胃肠道不良反应。     

黄豆苷元对卡马西平及其代谢产物在大鼠体内药动学的影响

目的:研究黄豆苷元对卡马西平及其代谢产物10,11-环氧卡马西平(CBZ-E)在大鼠体内药动学的影响。方法:16只大鼠随机分为实验组和对照组,实验组大鼠连续10 d灌胃给予黄豆苷元100 mg.kg-1,对照组大鼠则灌胃给予等体积的生理盐水,两组大鼠第11天分别灌胃给予卡马西平10 mg.kg-1,于给药后不同时间点采血,采用HPLC法测定血浆中卡马西平及其代谢产物CBZ-E的浓度,计算药动学参数。结果:与对照组相比,实验组大鼠血浆中卡马西平的AUC0-24h、AUC0-∞、Cmax和t1/2显著增加(P<0.05),代谢产物CBZ-E的AUC0-24h、AUC0-∞和Cmax显著降低(P<0.05)。结论:黄豆苷元连续给药后改变了卡马西平在大鼠体内的药动学特征,可能与抑制CYP3A4的活性有关。     

苯磺酰基呋咱氮氧化物与双氯芬酸偶联化合物的合成及抗炎活性

目的　研究高效低毒的双氯芬酸(DC)偶联化合物。方法　以酯键或酰胺键将一氧化氮(NO)供体3 ,4-二苯磺酰基呋咱氮氧化物与DC偶联,观察偶联物对二甲苯致炎小鼠和角叉菜胶致炎大鼠的抗炎活性及对大鼠胃肠道反应,研究体内外偶联物的NO释放。结果　合成了11个新化合物(I_1-11) ,其结构经MS ,IR ,¹HNMR和元素分析确证。I_1-5,I₉显示抗炎活性,其中I₄ 和I₅活性与DC相当,胃肠道副作用显著小于DC ,体内外均释放NO。结论　苯磺酰基呋咱氮氧化物与DC偶联的化合物可保留DC抗炎活性,降低DC胃肠道不良反应。     

Characteristics of rofecoxib-polyethylene glycol 4000 solid dispersions and tablets based on solid dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion-based rofecoxib tablets by the direct compression method. Solid dispersion-based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion-based oral tablets.     

Characteristics of Rofecoxib-Polyethylene Glycol 4000 Solid Dispersions and Tablets Based on Solid Dispersions

The aim of this work was to report the properties of rofecoxib-PEG 4000 solid dispersions and tablets prepared using rofecoxib solid dispersions. Rofecoxib is a poorly water soluble nonsteroidal anti-inflammatory drug with a poor dissolution profile. This work investigated the possibility of developing rofecoxib tablets, allowing fast, reproducible, and complete rofecoxib dissolution, by using rofecoxib solid dispersion in polyethylene glycol (PEG) 4000. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to characterize the solid state of solid dispersions. The effect of PEG 4000 concentration on the dissolution rate of rofecoxib from its solid dispersions was investigated. The dissolution rate of rofecoxib from its solid dispersions increased with an increasing amount of PEG 4000. The extent of dissolution rate enhancement was estimated by calculating the mean dissolution time (MDT) values. The MDT of rofecoxib decreased significantly after preparing its solid dispersions with PEG 4000. The FTIR spectroscopic studies showed the stability of rofecoxib and absence of well-defined rofecoxib-PEG 4000 interaction. The DSC and XRD studies indicated the amorphous state of rofecoxib in solid dispersions of rofecoxib with PEG 4000. SEM pictures showed the formation of effective solid dispersions of rofecoxib with PEG 4000 since well-defined change in the surface nature of rofecoxib and solid dispersions were observed. Solid dispersions formulation with highest drug dissolution rate (rofecoxib: PEG 4000 1:10 ratio) was used for the preparation of solid dispersion–based rofecoxib tablets by the direct compression method. Solid dispersion–based rofecoxib tablets obtained by direct compression, with a hardness of 8.1 Kp exhibited rapid drug dissolution and produced quick anti-inflammatory activity when compared to conventional tablets containing pure rofecoxib at the same drug dosage. This indicated that the improved dissolution rate and quick anti-inflammatory activity of rofecoxib can be obtained from its solid dispersion–based oral tablets.     

新型含羟基E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物的合成及抗炎活性

目的寻找新的非甾体抗炎药物。方法利用羟醛缩合反应，合成了8个新型含羟基的E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物，通过¹H NMR，ESI-MS和元素分析对其结构进行表征。并测定了体外抗炎活性。结果体外抗炎活性测试结果表明，所有化合物都有一定程度的抗炎活性。结论其中化合物4d和4e具有较强的抗炎活性，其抗炎活性与白藜芦醇接近，值得进一步研究。     

Discovery and development of ML3000

NSAID management of the inflammatory process has focused on reducing the production of inflammatory prostaglandins by inhibiting the cyclooxygenase (COX) enzyme. However, blocking COX also reduces gastroprotective prostaglandins, causing the well-known gastrointestinal side effects. Furthermore, a shunting of arachidonic acid to the 5-lipoxygenase (5-LOX) pathway may also occur, causing an increase in leukotrienes and further GI damage. Several compounds, designed to block both COX and 5-LOX, have failed in clinical trials due to liver toxicity, related to their redox potential. ML3000 is a new pyrrolizine compound resulting from a systematic approach to design a non-redox substrate analog of arachidonic acid that inhibited both COX and 5-LOX. Pharmacodynamic studies determined that ML3000 is a dual inhibitor of COX and 5-LOX, with analgesic, anti-inflammatory, antipyretic, antiplatelet, and anti-bronchoconstrictive activity, and minimal gastrointestinal side effects. Clinical studies show efficacy in osteoarthritis and excellent gastrointestinal safety. ML3000 is now in phase III development.     

The pharmacological profile of ML3000: A new pyrrolizine derivative inhibiting the enzymes cyclo-oxygenase and 5-lipoxygenase

Since the discovery of aspirin about one century ago, many non-steroidal anti-inflammatory drugs (NSAIDs) have been used for the treatment of inflammatory states and pain. While the NSAIDs are generally safe and effective, common side effects frequently limit therapy. Typical mechanism-based side effects are gastrointestinal (GI)-related, ranging from GI upset and intolerance to ulceration and bleeding after long-term therapy. In order to overcome these side effects several strategies have been followed, among them the development of selective COX-2 inhibitors. Our strategy to find compounds that are active on the one hand and tolerated by the GI tract on the other hand, is based on the shunt to leukotrienes. This theory is founded upon the fact that NSAIDs, while inhibiting the cyclooxygenase branch of the arachidonic acid cascade, are able to increase the 5-lipoxygenase (5-LOX) branch of arachidonic acid metabolism. This shunt to the 5-LOX side leads to the increase in chemotactic LTB₄ and vasoconstrictive peptidoleukotrienes, the contributory effects of which to gastrointestinal disorders are widely accepted. Therefore, the design of anti-inflammatory compounds with 5-LOX inhibitory effects seems reasonable. With the compound ML3000, this theory has gained further evidence. ML3000 is an anti-inflammatory compound with potent activity in various animal experiments that represent models for acute and chronic inflammation, pain, fever and asthma. It is a balanced inhibitor of the enzymes 5-LOX and COX-1/2 in the submicromolar range. The compound demonstrates excellent gastrointestinal tolerance in various animal species. The preclinical profile of ML3000, which is currently in Phase III clinical development, is presented in this publication.     

4-Methoxylonchocarpin attenuates inflammation by inhibiting lipopolysaccharide binding to Toll-like receptor of macrophages and M1 macrophage polarization

The roots of Abrus precatorius (AP, Fabaceae) have traditionally been used in Vietnam and China for the treatment of inflammatory diseases such as stomatitis, asthma, bronchitis, and hepatitis. Therefore, in this study, we isolated 4-methoxylonchocarpin (ML), an anti-inflammatory compound present in AP, and studied its anti-inflammatory effects in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. In lipopolysaccharide (LPS)-stimulated macrophages, ML was found to inhibit nuclear factor (NF)-κB activation and tumor necrosis factor (TNF) and interleukin (IL)-6 expression by inhibiting LPS binding to Toll-like receptor 4 (TLR4) in vitro. Oral administration of ML in mice with TNBS-induced colitis suppressed colon shortening and colonic myeloperoxidase activity. ML treatment significantly inhibited the activation of nuclear factor (NF)-κB and phosphorylation of transforming growth factor β-activated kinase 1 in the colon. Treatment with ML also inhibited TNBS-induced expression of IL-1β, IL-17A, and TNF. While ML reduced the TNBS-induced expression of M1 macrophage markers such as arginase-2 and TNF, it was found to increase the expression of M2 macrophage markers such as arginase-1 and IL-10. In conclusion, oral administration of ML attenuated colitis in mice by inhibiting the binding of LPS to TLR4 on immune cells and increasing the polarization of M1 macrophages to M2 macrophages.     

α-取代的对甲磺酰基苯丙烯酰胺的合成及抗炎活性

目的寻找高效低毒的非甾体抗炎药。方法合成α-取代的对甲磺酰基苯丙烯酰胺，评价其抗炎活性，并考察连续经口给药对大鼠胃肠道（GI）的影响。结果合成了25个新化合物（II1-25），其结构经IR、¹H NMR、MS和元素分析确证。角叉菜胶致大鼠足跖肿胀模型试验结果显示，12个化合物(II1,3,5,7,8,10-12,17,18,20,23)的抗炎活性与双氯芬酸钠（DC）和罗非昔布（RC）相当（P>0.05）。其中II3,8,10,11,18,20的GI副作用均显著小于DC(P<0.01)，与RC和羧甲基纤继素钠(CMC-Na)无明显差别(P>0.05)。结论α-取代的对甲磺酰基苯丙烯酰胺抗炎活性强，GI不良反应低，值得深入研究。     

Cancer chemopreventive in vitro activities of isoflavones isolated from Iris germanica

Six known isoflavones were isolated from the rhizomes of Iris germanica, and were established by UV, MS and NMR techniques as irisolidone (1), irisolidone 7-O-alpha-D-glucoside (1a), irigenin (2), irilone (3), iriflogenin (4), and iriskashmirianin (5). These compounds were examined for their cancer chemopreventive potential. They were shown to be potent inhibitors of cytochrome P450 1A activity with IC 50 values in the range 0.25-4.9 microM. The isoflavones 2, 3 and 5 displayed moderate activity as inducers of NAD(P)H:quinone reductase (QR) in cultured mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 3.5-16.7 microM, whereas weak activity was observed with compounds 4 and 5 in the radical (DPPH) scavenging bioassay (IC 50 values 89.6 and 120.3 microM, respectively). With respect to anti-tumor promoting potential based on anti-inflammatory mechanisms, none of the compounds demonstrated significant activity in the concentration range tested.     

Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide. They are anti-inflammatory, antipyretic, and analgesic and are prescribed as first choice for the treatment of rheumatic disorders and, in general, inflammation. The main limitation in using NSAIDs consists in their side-effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase (COX), and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). Arachidonic acid can also be converted to leukotrienes (LTs) by the action of 5-lipoxygenase (5-LOX). LTC(4,) LTD(4,) and LTE(4) are potent bronchoconstrictors, whereas LTB(4) is chemotactic for leukocytes and plays an important role in the development of gastrointestinal ulcers by contributing to the inflammatory process. Thus, developing dual inhibitor compounds that will simultaneously inhibit COX and 5-LOX could enhance their individual anti-inflammatory effects and reduce the undesirable side-effects associated with NSAIDs, especially of the gastrointestinal tract. The most promising COX/5-LOX inhibitor is ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid), now in Phase III clinical trials. This new approach will certainly help to unravel the mechanisms at the root of the undesirable effects of NSAIDs and to develop safer NSAIDs.     

Preparation of meloxicam–β-cyclodextrin–polyethylene glycol 6000 ternary system: characterization,in vitro and in vivo bioavailability

Ternary complexes of meloxicam (ML), a poorly water-soluble anti-inflammatory drug, with β-cyclodextrin (βCD) and polyethylene glycol (PEG) 6000 were prepared from an equimolar (ML–βCD) and 10% of PEG. Characterization of the ternary complex was carried out by differential scanning calorimetry and X-ray diffractometry. The solubility of ML increased as a function of increasing the concentration of βCD and PEG 6000. Ternary system increased significantly ML solubility in water. Ternary complexes improved drug release compared with ML and ML–βCD. The oral bioavailability of ML–βCD–PEG was investigated by administration to rat and compared with ML and ML–βCD. The results confirmed that the oral bioavailability of ML was significantly improved by complexation with βCD in the presence of PEG.