CN1107706A - 抑制皮脂溢和痤疮的方法 - Google Patents
抑制皮脂溢和痤疮的方法 Download PDFInfo
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- CN1107706A CN1107706A CN94119745A CN94119745A CN1107706A CN 1107706 A CN1107706 A CN 1107706A CN 94119745 A CN94119745 A CN 94119745A CN 94119745 A CN94119745 A CN 94119745A CN 1107706 A CN1107706 A CN 1107706A
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Abstract
Description
痤疮和皮脂溢是两类普遍的皮肤病,它们以皮肤中的皮脂腺的功能反常(通常是机能亢进)为特征。本发明的目的是抑制痤疮和皮脂溢的化合物的应用。
普通的痤疮是一种皮肤毛囊皮脂腺部位的疾病,实际上是慢性病和炎症。它以粉刺(黑头)、丘疹、脓疱、囊肿和小结为特征。人体最常见被其感染的部位是那些含皮脂腺最多的部位,即面部、颈部、背部和胸部。无论男女,痤疮是很普通的病,通常在青春期开始。虽然此病通常较轻而且大多数人到二十几岁时会自愈,但是它在很多情况下会损坏形象并造成巨大的生理上的苦恼,在某些极端的情况下,痤疮会引起严重的感染甚至危及生命。
此病的病原学和病理形成起因于粘合的角化过度,即角质化的细胞粘附并堵塞了位于皮脂腺和皮肤表面之间的囊管。受控于激素(睾酮和二氢睾酮)的皮脂腺刺激后变大并产生更多的皮脂分泌物(主要形式是三乙酰甘油)。这些皮脂分泌物堆积在堵塞的囊管并集结形成封闭的粉刺。在这个阶段,皮肤固有的并广泛存在的细菌(主要是粉刺丙酸菌(Propionibacterum Acnes))开始将三乙酰甘油代谢为游离的脂肪酸。而这些游离的脂肪酸是炎性的并导致丘疹的形成。丘疹通常增高并呈典型的炎症损害,即红、肿、痛。丘疹会继续扩张并胀破囊壁形成脓疱或囊肿。脓疱阶段很疼也不雅观,并经常成为受其它细菌(如Staphorius)二次感染的部位。在痤疮严重的情况下,脓疱和囊肿通常会结疤并破坏容貌。
治疗痤疮已有几种药物。在较轻的情况下,用过氧化苯甲酰通常适度有效。过氧化苯甲酰被认为通过抑制痤疮丙酸菌和粘合角化过度而起作用。尽管该药对轻度痤疮有效,但有几个缺点:第一,它必须局部用药不能一直渗透到痤疮起始损害的毛囊皮脂腺部位;第二,它会引起皮肤刺激,而这可能加剧病症。另一种中度有效的药物是维生素A(视黄酸,Retin-A),它也是局部用药。维生素A抑制粘合角化过度,然而作为一种局部用药制剂,它也具有象过氧化苯甲酰的某些缺点,此外若过量应用它会引起保护角质层损坏。常用来治疗痤疮的另一类药物是抗生素。它们可以局部或系统用药。最常用的抗生素是四环素和红霉素,范围略小的是二甲胺四环素、氨苄青霉素、氯林可霉素、三甲氧苄二氨嘧啶和磺胺甲基异噁唑。这些抗生素抑制痤疮丙酸菌和其它第二细菌感染。长期用抗生素治疗痤疮主要有2个缺点,第一,持续长期使用抗生素常导致皮肤和全身产生耐药性菌株;第二,连续应用抗生素可能导致病人对抗生素敏感。用于痤疮的一个新药是异维生素A酸。此药作用类似维生素A,但可系统用药。其常见的副作用是:唇炎、血清甘油三酯升高、提高沉积速度,最主要的是它还是人的致畸物,所以如果在治疗过程中有怀孕问题的话不宜使用。上述所有药物都对治疗痤疮的一定作用,但各自有其受限的副作用。
对妇女来说用激素疗法治疗痤疮也是有效的。在许多情况下,服用雌激素对治疗痤疮有效。雌激素抵消内源性雄激素的作用,以此降低皮脂分泌。然而,由于妇女对非对抗雌激素的摄入,其子宫面临产生子宫内膜癌的可能,所以治疗痤疮采用雌激素、孕激素循环疗法。一般地,规定妇女采用正规节育手段以进行痤疮治疗。虽然这些方法对痤疮有效,但在许多情况下,含大量孕激素的药物具有显著的雄激素活性。这些雄激素活性会使病情加剧。此外,众所周知孕激素药物可产生许多消极的心理副作用。显然,改进的激素药物会更好。
皮脂溢或脂溢性皮炎是另一类皮肤病,它们被认为与皮脂腺的异常功能有关。它发生在有大量皮脂腺的地方并以皮肤的鳞片以及红色轻度发炎的斑点为特征。皮脂溢常见于头发(一种头皮屑)、头皮边缘、眉毛、鼻唇沟、外耳道、耳后皱褶处以及胸部。总之,轻度皮脂溢可通过局部用药如糖皮质激素和Nivea油中的乳酸脱氢酶来控制。然而,较严重的情况则较难控制。
本发明提供抑制痤疮或皮脂溢的方法,包括给需要治疗的患者施用有效量的式Ⅰ化合物及其可药用盐和溶剂化物
(Ⅰ)
R2选自下列基团:吡咯烷基、六亚甲基亚氨基和哌啶子基。
本发明发现选自2-苯基-3-芳酰基苯并噻吩类(各种苯并噻吩)的式Ⅰ化合物适用于抑制痤疮或皮脂溢。本发明提供的治疗方法是:给需要治疗的患者服用抑制痤疮或皮脂溢有效剂量的式Ⅰ化合物及其可药用盐和溶剂化物。抑制这个词定义为包括其通常可接受的意义,即对尚未患有所述症状的人的预防性治疗以及控制和/或治疗现有病症。因此,本方法包括医疗和(适当的)预防性治疗。
本发明化合物雷洛昔芬,是式Ⅰ化合物的盐酸盐其中R1和R3是氢、R2是1-哌啶基,它是一个细胞核调节分子。雷洛昔芬已显示出能与雌激素受体结合,并且最初被认为是一种具有抗雌激素功能和药理作用的分子,即它阻断雌激素活化子宫组织的能力和依赖于雌激素的乳腺癌变。实际上,雷洛昔芬在某些细胞中阻断雌激素的作用,然而在其它各类细胞中,雷洛昔芬与雌激素产生相同的基因和显示相同的药理作用,(如骨质疏松症、高血脂)一样,雷洛昔芬激活同样的基因。因而雷洛昔芬被称做是具有兴奋-拮抗双重性能的一种抗雌激素。雷洛昔芬表现的不同于雌激素的独特作用目前认为是与雌激素-雌激素受体复合体对基因功能激活和/或抑制不同,由于雷洛昔芬-雌激素受体复合体对不同基因功能的独特激活和/或抑制造成的。因此,虽然使用雷洛昔芬和雌激素竞争相同的受体,但是这两者对基团调节的药理结果是难以预见的并且是彼此不同的。
通常,将该化合物与常用的赋形剂、稀释剂或载体一起配制,压制成片剂,或者配制成酏剂或溶液以便于口服,或者通过肌内或静脉内等途径给药。该化合物可以经皮肤给药,并可配制成缓释剂的形式及类似形式。
本发明方法中使用的化合物可以根据已确定的步骤制备,例如在美国专利4,133,814、4,418,068和4,380,635中详述的那些,这些专利均在本文中引用作为参考。一般来说,制备过程用一种有6-羟基和2-(4-羟基苯基)基团的苯并[b]噻吩开始。将此起始化合物保护、酰化和去保护,形成式Ⅰ化合物。在上述美国专利中提供了制备这类化合物的实例。取代的苯基包括用C1-C6烷基、C1-C4烷氧基、羟基、硝基、氯、氟或三(氯或氟)甲基取代一次或两次的苯基。
本发明方法中使用的化合物与许多种有机或无机酸和碱形成药学上可接受的酸和碱加成盐,包括在药物化学中经常使用的生理上可接受的盐。这些盐也构成本发明的一部分。用来形成这类盐的典型的无机酸包括盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸、连二磷酸等。也可以使用从有机酸衍生得到的盐,这些有机酸的实例有脂族单羧酸和二羧酸、苯基取代的链烷酸、羟基链烷酸和羟基链烷二酸、芳香酸、脂族和芳族磺酸等。因此,药学上可接受的盐包括乙酸盐、苯基乙酸盐、三氟乙酸盐、丙烯酸盐、抗坏血酸盐、苯甲酸盐、氯代苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、甲基苯甲酸盐、邻乙酰氧基苯甲酸盐、萘-2-苯甲酸盐、溴化物、异丁酸盐、苯基丁酸盐、β-羟基丁酸盐、丁炔-1,4-二酸盐、己炔-1,4-二酸盐、癸酸盐、辛酸盐、氯化物、肉桂酸盐、柠檬酸盐、甲酸盐、富马酸盐、乙醇酸盐、庚酸盐、马尿酸盐、乳酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、异烟酸盐、硝酸盐、草酸盐、邻苯二甲酸盐、对苯二酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、丙炔酸盐、丙酸盐、苯基丙酸盐、水杨酸盐、癸二酸盐、丁二酸盐、辛二酸盐、硫酸盐、硫酸氢盐、焦硫酸盐、亚硫酸盐、亚硫酸氢盐、磺酸盐、苯磺酸盐、对溴苯磺酸盐、氯苯磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、甲磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、酒石酸盐等。优选的盐是盐酸盐。
药学上可接受的酸加成盐通常由式Ⅰ化合物与等摩尔或过剩数量的酸反应形成。该反应物通常在一种互溶剂(例如乙醚或苯)中结合。盐一般在约1小时到10天内从溶液中沉淀出来,可以过滤分离,或者用常规方法脱除溶剂。
通常用来形成盐的碱包括氢氧化铵和碱金属及碱土金属氢氧化物,碳酸盐,以及脂族的伯胺、仲胺及叔胺,脂族二胺。特别适合制备加成盐的碱包括氢氧化铵、碳酸钾、甲胺、二乙胺、乙二胺和环己胺。
这些药学上可接受的盐一般比它们从中衍生的化合物有更高的溶解度。因此常常更适合于象液体或乳状液这类制剂。
药物制剂可以用工艺上已知的步骤制备。例如,这些化合物可以与常用的赋形剂、稀释剂或载体一起配制,形成片剂、胶囊剂、悬浮液、粉剂等。适合这些制剂的赋形剂、稀释剂和载体的实例包括以下物质:填料和增量剂(如淀粉、糖、甘露糖醇及硅酸衍生物);粘合剂(如羧甲基纤维素及其它纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮);增湿剂(如甘油);崩解剂(如碳酸钙和碳酸氢钠);延缓溶解剂(如石蜡);再吸收加速剂(如季铵化合物);表面活性剂(如十六烷醇、甘油单硬脂酸酯);吸附性载体(如高岭土和膨润土);以及润滑剂(如滑石、硬脂酸钙和镁以及固体的聚乙基乙二醇)。
这些化合物也可以配制成便于口服的酏剂或溶液,或是适合非肠道用药(例如肌内、皮下或静脉内)的溶液。另外,这些化合物很适合配制成缓释剂的剂量形式及类似形式。可能是在一段时间内。可以将制剂做成只在或者优选在肠道的特定部位释放出活性成分。涂层、被膜和保护基质可以由例如聚合物或蜡制成。
通过非局部用药以抑制痤疮或皮化脂的式Ⅰ化合物的特定剂量依本发明将取决于病症的严重程度、用药途径及有关因素,这些由主治医生决定。一般地,每日可接受的有效剂量约从0.1至约1000毫克,更具代表性的是每日约50到约200毫克。这样的剂量对需要治疗的患者每天用药1次至约3次,或者需要的话更多次用药以有效地治疗症状。
关于局部用药,本化合物可按已知工艺配制,直接用于患病区域。这类常用剂型包括软膏、洗液、糊剂、凝胶剂、喷雾剂和气溶胶。本发明的化合物在局部用药制剂中所占的重量百分比依赖于多种因素,但一般占制剂总重的0.5-95%,具代表性的是1-25%。
该组合物可采用以下形式:水溶液、无水溶液、胶体溶液或乳液、悬浮液。
这些组合物可含有现有技术已知的可药用赋形剂和辅助剂,例如用生理学可接受的一种或多种有机溶剂制备溶液,除选择水外还可选择例如丙酮、乙醇、异丙醇、如商品名“Dowanol”的乙二醇醚、聚乙二醇和聚氧乙烯、短链酸C1-C4烷基酯,优选乳酸乙酯或乳酸异丙酯、例如商品名为“Miglyol”的脂肪酸甘油三酯、肉豆蔻酸异内酯、动植物、矿物油及聚硅氧烷。
本发明化合物还可含有增稠剂,如纤维素和/或纤维素衍生物,也可含有黄原胶、瓜耳胶、角豆树胶、阿拉伯树胶或聚乙二醇、有机皂土和蒙脱土等等。
本发明的组合物可混合其它活性成分如视黄酸衍生物、抗菌素、抗炎药和类固醇如孕烯醇酮。这些试剂包括过氧化苯甲酰、四环素、红霉素、二甲胺四环素、氯林可霉素、氨苄青霉素、三甲氧苄二氨嘧啶、磺胺甲基异噁唑、维生素A和异维生素A酸;对皮脂溢则为Nivea油中的乳酸脱氢酶和糖皮质激素。
必要的话可添加选自下列的辅剂:抗氧化剂、表面活性剂、其它防腐剂、成膜剂、溶角蛋白剂或消粉刺剂、香料及着色剂。
例如,抗氧化剂中可以提到叔丁基氢醌,丁基化羟基茴香醚、丁基化羟基甲苯以及维生素E及其衍生物。
主要限于局部用药的盖仑制剂形式采用乳膏奶液、凝胶、胶体溶液或微乳液、或多或少加稠的洗液、浸渍垫、油膏或棒,或者为喷雾或泡沫形式的气雾剂,成为皂块。
制剂
下列制剂中,“活性成分”指式Ⅰ化合物。
制剂1:明胶胶囊
用以下组分配制硬明胶胶囊:
组分 数量(mg/胶囊)
活性组分 0.1-1000
淀粉(美国国家药典) 0-650
淀粉(可流动的粉末) 0-650
硅氧烷(350厘沲) 0-15
将各组分掺混,通过美国45目筛,装入硬明胶胶囊。
已制备的其中R2是哌啶子基的式Ⅰ化合物的特定胶囊制剂的实例包括如下所示那些。
制剂2:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 1
淀粉(美国国家药典) 112
淀粉(可流动的粉末) 225.3
硅氧烷(350厘沲) 1.7
制剂3:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 5
淀粉(美国国家药典) 108
淀粉(可流动的粉末) 225.3
硅氧烷流体(350厘沲) 1.7
制剂4:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 10
淀粉(美国国家药典) 103
淀粉(可流动的粉末) 225.3
硅氧烷流体(350厘沲) 1.7
制剂5:雷洛昔芬胶囊
组分 数量(mg/胶囊)
雷洛昔芬 50
淀粉(美国国家药典) 150
淀粉(可流动的粉末) 397
硅氧烷流体(350厘沲) 3.0
上述的具体配方可以根据所提供的合理变化量加以改变。
用以下组分制备片剂:
制剂6:片剂
组分 数量(mg/片)
活性组分 0.1-1000
微晶纤维素 0-650
煅制二氧化硅 0-650
硬脂酸 0-15
将各组分掺混并压制成片。
或者是,制备每片含0.1-1000mg活性组分的片剂如下:
制剂7:片剂
组分 数量(mg/片)
活性组分 0.1-1000
淀粉 45
微晶纤维素 35
聚乙烯吡咯烷酮(10%水溶液) 4
羧甲基纤维素钠 4.5
硬脂酸镁 0.5
滑石粉 1
将活性组分、淀粉和纤维素通过美国45目筛并充分混和。将聚乙烯吡咯烷酮溶液与所形成的粉末混合,然后通过美国14目筛。将这样制得的颗粒在50°-60℃下干燥并通过美国18目筛。将事先通过美国60目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加到上述颗粒中,混合后在压片机上压制成片剂。
每5ml中含0.1-1000mg药物的悬浮液制备如下:
制剂8:悬浮液
组分 数量(mg/5ml)
活性组分 0.1-1000mg
羧甲基纤维素钠 50mg
糖浆 1.25mg
苯甲酸溶液 0.10ml
香味剂 适量
着色剂 适量
加纯水至 5ml
使药物通过美国45目筛并与羧甲基纤维素钠和糖浆混合以形成均匀的浆体。用一些水将苯甲酸溶液、香味剂和着色剂稀释并在搅拌下加入,然后加入足量的水以达到所要求的体积。
配制下列组合物:
制剂9:
组分 数量(mg/5ml)
羟丙基纤维素 1.5g
活性组分 1.5-30g
异丙醇 加至 100g
制剂10:
制备下列组合物:
组分 数量(mg/5ml)
羟丙基纤维素 1.5g
乳酸乙酯 15.0g
活性组分 1.5-30g
异丙醇 加至 100g
制剂11:
制备下列组合物:
组分 数量(毫克/5毫升)
羟丙基纤维素 1.0g
丁基化羟基甲苯 0.02g
活性组分 1.5-25g
乙醇 加至 100g
制剂12:
制备下列组合物:
组分 数量(毫克/5毫升)
羟丙基纤维素 1.5g
丁基化羟基甲苯 0.01g
C8-C12脂肪酸甘油三酯 10.0g
活性组分 1.5-30g
异丙醇 加至 100g
制剂9-12采用凝胶形式,用于局部治疗痤疮。
制剂13:
制备下列组合物:
组分 数量(毫克/5毫升)
异丙醇 46.0g
活性组分 1.0-15g
C8-C12脂肪酸甘油三酯 49.0g
制剂14:
制备下列组合物:
组分 数量(毫克/5毫升)
乙醇 69.0g
乳酸乙酯 10.0g
活性组分 1.5-20g
C8-C12脂肪酸甘油三酯 30.0g
制剂15:
制备下列组合物:
组分 数量(毫克/5毫升)
异丙醇 47.0g
丙酮 10.0g
乳酸乙酯 10.0g
活性组分 1-15g
C8-C12脂肪酸甘油三酯 30.0g
制剂16:
制备下列组合物:
组分 数量(毫克/5毫升)
乙醇 95.08g
丁基化羟基甲苯 0.02g
活性组分 1.5-25g
制剂13、14、15、16为洗液。
制剂17:
制备下列组合物:
组分 数量(毫克/5毫升)
白凡士林 50.0g
液体石蜡 15.0g
精制石蜡 32.0g
活性组分 1-20g
制剂18:
制备下列组合物:
组分 数量(毫克/5毫升)
白凡士林 50.0g
液体石蜡 13.0g
精制石蜡 32.0g
活性组分 1-20g
制剂17和18为棒状。
试验
试验1
使进行临床评价的2到20个病人处在一种舒适的环境下,即舒适的温度、湿度、光照等。这些病人在评价前的12小时禁止激烈运动和吃辛辣食物。在人体被感染皮脂溢或痤疮、含有大量皮脂腺的区域,如前额,用一个纱布垫擦去积累的脂。在皮肤上用尺量出一块2.5cm×1.8cm的长方形,将一块面积为2.5cm×1.8cm的香烟纸或其它合适的吸收材料置于皮肤的被测区域上。吸收材料在放于被测区域之前必须先用乙醚脱脂以去除本底脂。该垫于患处用绷带固定。十五分钟后换一只新垫(测试垫)。这个步骤除去了皮肤的本底脂,所以可以测定由皮脂腺产生脂的真实速率。测试垫放3-6小时后移去。然后将测试垫用乙醚提取出酯,蒸发乙醚后,称量残余的脂。结果表示为每小时每10平方厘米的皮脂毫克数。然后病人每日口服30-400毫克活性组分,或每天局部用含5-20%活性组分的制剂,用药三至九周。上述测试垫方法在服用活性组分当中重复多次以检测进展。这项试验还可在动物身上进行以确证效用。阳性效果通过皮脂腺脂生成速度的降低而反应出来。
试验2
在此临床试验中招集2到20个病人,通过直接观察皮肤及其损伤作初步评价。这通过选择1cm2区域感染的皮肤并记录损伤的数目和类型(粉刺、皮脂损伤等)来进行。常用的区域是面颊、头皮或背。然后病人每天口服30-400mg活性组分或每天施用含5-20%(重量)活性组分的局部制剂,用药三到九周。在服药期间检查被测试的皮肤区域。必须注意评估相同的区域,以便作成小标记或用永久记号在皮肤上作标记。阳性结果通过皮肤被测区域上损伤程度和/或数目的减少反应出来。
本文所述化合物的效用通过上面一个或两个实验观察到的阳性结果而显示出来。
Claims (4)
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US170,970 | 1988-03-21 | ||
US08/170,970 US5439923A (en) | 1993-12-21 | 1993-12-21 | Method of inhibiting seborrhea and acne |
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CN1107706A true CN1107706A (zh) | 1995-09-06 |
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CN94119745A Pending CN1107706A (zh) | 1993-12-21 | 1994-12-19 | 抑制皮脂溢和痤疮的方法 |
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US (2) | US5439923A (zh) |
EP (1) | EP0659416B1 (zh) |
JP (1) | JPH07196497A (zh) |
KR (1) | KR950016731A (zh) |
CN (1) | CN1107706A (zh) |
AT (1) | ATE150307T1 (zh) |
AU (1) | AU8154794A (zh) |
CA (1) | CA2138491A1 (zh) |
CZ (1) | CZ321494A3 (zh) |
DE (1) | DE69402165T2 (zh) |
DK (1) | DK0659416T3 (zh) |
ES (1) | ES2101449T3 (zh) |
GR (1) | GR3023378T3 (zh) |
HU (1) | HUT71481A (zh) |
IL (1) | IL112042A0 (zh) |
NO (1) | NO311243B1 (zh) |
RU (1) | RU94044453A (zh) |
ZA (1) | ZA9410086B (zh) |
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US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5811447A (en) | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
US5595722A (en) | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
DE69435137D1 (de) * | 1993-05-13 | 2008-10-16 | Poniard Pharmaceuticals Inc | Prävention und behandlung von pathologien, die mit einer abnormalen proliferationglatter muskelzellen verbunden sind |
FR2728793A1 (fr) * | 1994-12-28 | 1996-07-05 | Oreal | Utilisation d'un antagoniste d'histamine, d'un antagoniste d'interleukine 1 et/ou d'un antagoniste de tnf-alpha dans une composition cosmetique, pharmaceutique ou dermatologique et composition obtenue |
CA2223595C (en) | 1995-06-07 | 2008-08-05 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies with tamoxifen analogues |
IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
TW442286B (en) * | 1996-02-28 | 2001-06-23 | Pfizer | New therapeutic uses of estrogen agonists |
GR1002807B (el) * | 1996-06-20 | 1997-11-13 | Lavipharm A.E. | Συστημα για την τοπικη θεραπεια της ακμης και μεθοδος παραγωγης του |
US6117911A (en) * | 1997-04-11 | 2000-09-12 | Neorx Corporation | Compounds and therapies for the prevention of vascular and non-vascular pathologies |
US6187777B1 (en) | 1998-02-06 | 2001-02-13 | Amgen Inc. | Compounds and methods which modulate feeding behavior and related diseases |
WO1999064081A1 (en) * | 1998-06-08 | 1999-12-16 | Ferris Corporation | Analgesic and antinociceptive methods |
HUP0200871A3 (en) | 1999-05-04 | 2004-04-28 | Strakan Int Ltd | Androgen glycosides and androgenic activity thereof |
FR2804865B1 (fr) * | 2000-02-15 | 2003-11-28 | Oreal | Utilisation des corps gras particuliers permettant de modifier les proprietes physio-chimiques de la peau et/ou des muqueuses en tant qu'agents empechant ou diminuant l'adhesion des micro-organismes sur ces dernieres |
US6495158B1 (en) | 2001-01-19 | 2002-12-17 | Lec Tec Corporation | Acne patch |
US8048919B2 (en) * | 2004-06-28 | 2011-11-01 | Archer Daniels Midland Company | Use of ethyl lactate as an excipient for pharmaceutical compositions |
JP2008521913A (ja) * | 2004-12-03 | 2008-06-26 | ニュー‐ティーン カンパニー,インク. | キサントフィル類を用いて皮膚疾患を治療する方法 |
FR2953832B1 (fr) | 2009-12-10 | 2012-01-13 | Galderma Res & Dev | Derives de nouveaux peroxydes, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique pour le traitement ou la prevention de l'acne |
FR2953833B1 (fr) | 2009-12-10 | 2012-01-13 | Galderma Res & Dev | Derives de nouveaux peroxydes, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique pour le traitement ou la prevention de l'acne |
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US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
US4859585A (en) * | 1986-04-17 | 1989-08-22 | Trustees Of Tufts College | In-vitro methods for identifying compositions which are agonists and antagonists of estrogens |
US5075321A (en) * | 1987-03-24 | 1991-12-24 | University Of Pennsylvania | Methods of treating diseases characterized by interactions of IgG-containing immune complexes with macrophage Fc receptors using antiestrogenic benzothiophenes |
US5395842A (en) * | 1988-10-31 | 1995-03-07 | Endorecherche Inc. | Anti-estrogenic compounds and compositions |
IL95584A (en) * | 1989-09-07 | 1995-03-15 | Abbott Lab | Indole-, benzoporene- and benzothiophene compounds including lipoxygenase-inhibiting compounds and pharmaceutical compounds containing them |
JP3157882B2 (ja) * | 1991-11-15 | 2001-04-16 | 帝国臓器製薬株式会社 | 新規なベンゾチオフエン誘導体 |
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- 1994-12-19 AU AU81547/94A patent/AU8154794A/en not_active Abandoned
- 1994-12-19 CN CN94119745A patent/CN1107706A/zh active Pending
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- 1994-12-19 ES ES94309474T patent/ES2101449T3/es not_active Expired - Lifetime
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- 1994-12-19 KR KR1019940034922A patent/KR950016731A/ko not_active Application Discontinuation
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JPH07196497A (ja) | 1995-08-01 |
CZ321494A3 (en) | 1995-09-13 |
CA2138491A1 (en) | 1995-06-22 |
US5439923A (en) | 1995-08-08 |
NO311243B1 (no) | 2001-11-05 |
HUT71481A (en) | 1995-11-28 |
RU94044453A (ru) | 1996-10-10 |
EP0659416A3 (en) | 1995-09-06 |
DE69402165T2 (de) | 1997-07-17 |
ATE150307T1 (de) | 1997-04-15 |
KR950016731A (ko) | 1995-07-20 |
EP0659416A2 (en) | 1995-06-28 |
IL112042A0 (en) | 1995-03-15 |
NO944918L (no) | 1995-06-22 |
US5688812A (en) | 1997-11-18 |
ES2101449T3 (es) | 1997-07-01 |
GR3023378T3 (en) | 1997-08-29 |
NO944918D0 (no) | 1994-12-19 |
DE69402165D1 (de) | 1997-04-24 |
AU8154794A (en) | 1995-06-29 |
DK0659416T3 (da) | 1997-08-18 |
HU9403667D0 (en) | 1995-02-28 |
ZA9410086B (en) | 1996-06-19 |
EP0659416B1 (en) | 1997-03-19 |
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