Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors

Compounds that inhibit histone deacetylase may enable the re-expression of silenced regulatory genes in neoplastic cells, reversing the malignant phenotype. Although several molecules that inhibit histone deacetylase are undergoing preclinical development, butyric acid derivatives have undergone clinical investigation for several years, initially for non-malignant indications and more recently for the treatment of cancer. Of the butyric acid derivatives, sodium phenylbutyrate has undergone the most extensive systematic investigation. Administration of phenylbutyrate by iv. and oral routes is well-tolerated clinically at concentrations which effect acetylation of histones in vitro. Higher doses lead to reversible CNS depression. The studies presented to date have been Phase I studies and do not enable assessment of efficacy. However, current development of phenylbutyrate is proceeding in combination with other agents based on rational biologically-based in vitro studies. The parallel development of combination therapy including phenylbutyrate and early clinical development of other, more potent histone deacetylase inhibitors will hopefully lead to feasible, clinically tolerable strategies for altering the malignant phenotype of cancer cells.     

A study of potential skin atrophy following topical application of weak corticosteroids

Summary

A double-blind, half-side comparative dermal atrophy study of fluocortin butylester 0.75%, clobetasone butyrate 0.05%, hydrocortisone acetate 1% and placebo creams was carried out in 29 healthy human male volunteers. Skin thickness was measured by a modified radiographic technique before and after an 8-week application period of the test preparations. Significant skin thinning occurred in 3 of the 10 subjects treated with clobetasone butyrate and atrophy of marginal significance in 1 of the 29 subjects treated with fluocortin butylester. The results suggest that, compared with other fluorinated topical steroids, fluocortin butylester 0.75% is unlikely to produce significant dermal atrophy when used in the short and medium term.     

Phototherapy and photochemotherapy

The treatment of skin diseases with ultraviolet radiation represents an important therapeutic modality in clinical dermatology, and the number of skin diseases that improve under the phototherapeutic modalities of today is still growing. While clinical phototherapy was originally based on empirical observations, our present understanding of the underlying mechanisms has improved substantially due to important progress in photobiological science. The better understanding of this scientific basis of treatment allows to both choose the correct phototherapeutic modality and determine the most effective treatment regimen. The aim of this article is to discuss the appropriate indications for phototherapy as well as its safe and effective employment, providing practical help in daily clinical phototherapeutic practice.     

散瘀止痛巴布膏对大鼠试验性炎症和疼痛药效学研究

目的研究散瘀止痛巴布膏对大鼠试验模型的抗炎和镇痛作用。方法通过对二甲苯致小鼠耳肿胀和角叉菜引起的大鼠足趾肿胀的作用观察抗炎作用;通过对醋酸引起的扭体反应的影响及热板法观察镇痛作用。结果散瘀止痛巴布膏对角叉菜胶致大鼠足肿胀和二甲苯致耳肿胀有显著的抑制作用;能明显抑制由醋酸引起的小鼠扭体次数,显著提高小鼠的痛阈值。结论散瘀止痛巴布膏具有显著的消肿抗炎、镇痛作用。     

丁酸钠诱导Raji细胞基因表达的变化

 目的 分析丁酸钠诱导Raji细胞的基因表达变化,探讨丁酸钠诱导凋亡作用机制。方法 限制性显示PCR技术（Restriction Display PCR,RD-PCR）分析基因表达变化,利用互联网提供的GenBank核酸数据库分析比对获得的差异表达序列。结果 获得14条差异表达序列,其中6条是对照组高表达序列,8条是实验组高表达序列。结论 采用RD-PCR技术可以快速简便地分析药物诱导基因表达变化。分析表达差异的序列发现,丁酸钠可诱导促进细胞凋亡的基因表达,降低肿瘤细胞高表达的基因表达。     

流通池法测定复方酮康唑乳膏释放度的方法研究

目的:建立适用于复方酮康唑乳膏的释放度检查方法。方法:采用流通池法测定复方酮康唑乳膏的释放度,释放介质为0.01 mol·L~(-1)盐酸溶液,流速为8 mL·min~(-1);以 HPLC 测定释放量,使用 Symmetry C_(18)柱(3.9 mm×150 mm,5 μm),流动相0.02 mol·L~(-1)磷酸氢二钠溶液-甲醇(25:75,用磷酸调节 pH 至6.9±0.1),流速1 mL·min~(-1);检测波长为225 nm。结果:酮康唑在0.3～18μg·mL~(-1)浓度范围内线性良好(r=0.9999);平均回收率(n=9)为99.8%,RSD 为0.67%。同一厂家的复方酮康唑乳膏释放曲线稳定,在24 h 内释放药物超过65%;不同厂家的复方酮康唑乳膏释放曲线不同。结论:本方法可用于复方酮康唑乳膏的释放度检查,对于药物乳膏的质量控制具有指导意义。     

毛细管气相色谱法测定无极膏中薄荷脑、樟脑、水杨酸甲酯、冰片及麝香草酚的含量

目的:建立 GC 法测定无极膏中薄荷脑、樟脑、水杨酸甲酯、冰片及麝香草酚含量的方法。方法:采用 HP-5弹性石英毛细管柱程序升温的方法测定。结果:5组分 GC 法测定的分离度和线性关系良好,薄荷脑、樟脑、水杨酸甲酯、冰片、麝香草酚线性范围分别为132.4～1324.0μg·mL~(-1),243.9-2439.0μg·mL~(-1),132.0～1320.0μg·mL~(-1),20.0～200.0μg·mL~(-1),10.1～101.3μg·mL~(-1);平均回收率分别为99.8%(RSD=0.9%),99.5%(RSD=1.2%),98.7%(RSD=0.9%),99.5%(RSD=1.2%),100.8%(RSD=1.6%)。结论:本法准确、灵敏,可用于该制剂的质量控制。     

芦荟冰片烧伤膏的生肌、镇痛及抗炎作用

目的：研究芦荟冰片烧伤膏生肌、镇痛与抗炎作用。方法：分别采用小鼠浅Ⅱ度烫伤模型、热板试验及二甲苯所致小鼠耳廓肿胀模型进行芦荟冰片烧伤膏的药效学研究。结果：芦荟冰片烧伤膏对浅Ⅱ度烫伤小鼠伤口愈合有明显的促进作用，在给药后90min内有显著的镇痛作用，对二甲苯所致小鼠耳廓肿胀有消炎效果。结论：芦荟冰片烧伤膏具有去腐生肌、镇痛和抗炎作用，可望用于临床浅Ⅱ度烧烫伤的治疗。     

肾囊内注射氢化可的松琥珀酸钠治疗肾病综合征的临床应用研究

目的为了减轻糖皮质类固醇激素的不良反应,观察了一种新的给药方式—肾脏脂肪囊内氢化可的松琥珀酸钠治疗肾病综合征的临床治疗效果。方法216例经肾活检证实为原发及继发肾小球肾炎患者,B超引导下向每侧肾脂肪囊内注射氢化可的松琥珀酸钠200mg,2次/周,共16次,治疗前后观察患者的尿蛋白、血压、体质量、血清尿素氮、血浆白蛋白及肌酐变化。结果216例患者中200例患者尿蛋白明显减少或转阴(P<0·005),未发现糖皮质类固醇激素的不良反应。结论肾囊内注射氢化可的松琥珀酸钠为有效的治疗肾病综合征的方法,且避免了毒副作用。     

复方甲硝唑乳膏的制备及质量控制

目的:制备复方甲硝唑乳膏并建立其质量控制方法。方法:以甘油、硬脂酸等为基质制备乳膏;采用高效液相色谱法测定其中主药含量。结果:制备的乳膏性状、鉴别、检查等均符合2005年版《中国药典》相关规定;甲硝唑、氯霉素检测浓度线性范围分别为10·16～101·60(r=0·9995,n=6)、10·02～100·20mg·L-1(r=0·9999,n=6);平均回收率分别为96·82%(RSD=0·94%,n=6)、98·11%(RSD=0·85%,n=6)。结论:本制剂组方合理,制备工艺简便可行,质量稳定可控。