里素劳撤市原因及对风险管理的思考

通过梳理酮康唑近年来国内外监管动态,从药品不良反应、临床使用情况、药品的治疗地位、风险管理以及药品受益-风险平衡等方面系统分析了里素劳（酮康唑片）的撤市原因,为进一步阐明药品的市场淘汰机制以及风险管理在药品生命周期中的作用提供了参考案例。     

酮康唑乳膏有关物质检查方法的试验研究

目的采用高效液相色谱法（HPLC法）测定酮康唑乳膏中的有关物质。方法色谱柱为十八烷基硅烷键合硅胶柱，甲醇-水（76：24）为流动相．流速为1．2mL／min，检测波长为239nm。结果酮康唑乳膏的有关物质限度为3．％。结论HPLC法简单、准确，适用于软膏制剂的有关物质检查。     

Study of ketoconazole toxiciy in rabbit cornea and conjuctiva

Ketoconazole, acetyl-dichlorophenyl-imidazole, when administered topically to the eyes of normal New Zealand white rabbits in concentrations of 1%, 3% and 5% in arachis oil has been shown to have no toxic effect to the conjunctival and corneal epithelium of these animals. No toxic effects were also noted on the iris sphincter and the crystalline lens of these animals. Five per cent ketoconazole in arachis oil showed some minimal conjunctival hyperaemia in two of the test eyes (33.3%) after two weeks of continuous administration. Arachis oil, the carrier for the test drug showed no ocular toxicity in all the rabbits tested.     

In vitro antifungal susceptibility testing of filamentous fungi with Sensititre Yeast One

Sensititre is a colorimetric microdilution method for in vitro antifungal susceptibility testing based on the M27-A document (National Committee for Clinical Laboratory Standards) for yeasts. Difference between both methods is the presence of Alamar-blue and RPMI 1640 (glucose 2%) as culture medium. Antifungal susceptibility to amphotericin B, fluconazole, itraconazole, ketoconazole and flucytosine, 100 opportunistic filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp.) obtained from pathological samples was determined by the Sensititre method. Induction to conidium and sporangiospore formation at 35 degrees C was used to get inoculum and plates were covered by 1 ml of saline and suspensions were made by gently probing by a sterile loop. Optical densities of the conidial suspensions were adjusted to 80-82% transmittance for Aspergillus spp. and 68-70% for the rest of strains tested. Final inoculum concentration size was 0.4 x 10(4)-5 x 10(4) CFU ml(-1). Readings were made at 72 h of incubation at 35 degrees C; amphotericin B and itraconazole was active against Aspergillus fumigatus with CMI90 1 and 0.5 microg ml(-1), respectively, opposite to Scedosporium prolificans and Scedosporium apiospermum. As it was expected, a CMI90 of 256 microg ml(-1) for fluconazole and CMI90 for flucytosine amounting to 64 g ml(-1) were obtained. Sensititre Yeast One is a useful method and an alternative to reference methods to determine antifungal susceptibility of filamentous fungi for clinical laboratory routine. Correlation with microdilution results is studied. New triazole derivatives should be included as soon as their clinical use will be feasible.     

Testotoxicosis: Report of Two Cases,One with a Novel Mutation in LHCGR Gene

Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic cases also may occur. Due to activating mutation in luteinizing hormone (LH))/choriogonadotropin receptor (LHCGR) gene, early virilization and advancement in bone age are common with increased serum testosterone levels above adult ranges, despite low LH and follicular-stimulating hormone (FSH) levels. There are different treatment regimens, such as combination of bicalutamide (antiandrogen agent) and a third-generation aromatase inhibitor, that are reported to be well-tolerated and successful in slowing bone age advancement and preventing progression of virilization. We report here two patients who presented with peripheral precocious puberty and an activating mutation in the LHCGR gene: one with a family history and previously determined mutation and the other without family history and with a novel mutation (c.830G>T). Combination of bicalutamide+anastrozole was ineffective in slowing pubertal progression and bone age. Short-term results were better with ketoconazole.     

Polymorphic behaviour of Compritol®888 ATO as bulk lipid and as SLN and NLC

Compritol®888 ATO (glycerol behenate) is widely used as a pharmaceutical excipient in the field of solid dosage forms due to its lubricating properties. It is an amphiphilic material with a high melting point (～70°C) and, therefore, it can also be used to prepare aqueous colloidal dispersions. The aim of this paper is to study the suitability of Compritol®888 ATO for the production of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the entrapment of a lipophilic model drug. This study assesses the crystalline structure of the bulk lipid, as well as the changes that occur in its crystal lattice with the addition of ‘impurities’, such as oil (α-tocopherol) and drug (ketoconazole), using DSC and X-ray diffraction analysis before and after thermal stress. Aqueous SLN and NLC dispersions were produced using an appropriate surfactant/co-surfactant system and their physicochemical stability was assessed by PCS, LD, DSC and by WAXS. It was found that the crystalline lattice of Compritol®888 ATO is composed of very small amounts of the unstable α polymorphic form characteristic of triacylglycerols, which disappears after thermal stress of bulk lipid. Mixing oils and drug molecules which are soluble in this lipid decreased its lattice organization and, thus, was revealed to be suitable for production of lipid nanoparticles containing ketoconazole. However, particle growth could not be avoided during shelf life.