Permeant lipophilicity and vehicle composition influence accumulation of dyes in hair follicles of human skin

In skin and hair research drug targeting to the hair follicle is of great interest. Therefore the influence of permeant lipophilicity and vehicle composition on local accumulation has been examined using confocal laser scanning microscopy (CLSM). Formulations saturated with either Oregon Green^® 488, Bodipy^® FL C₅ or Bodipy^® 564/570 C₅ were prepared. The dyes were applied in citric acid buffer, 8% (w/v) surfactants in citric acid buffer or 8% (w/v) surfactants/20% (w/v) propylene glycol in citric acid buffer. Flow-through diffusion experiments were performed with fresh human scalp skin, after which the skin was imaged using CLSM. Diffusion studies showed for Oregon Green^® 488 (low lipophilicity) a higher flux when applied in citric acid buffer compared to surfactants. In contrast the fluxes of the more lipophilic dyes (Bodipy^® FL C₅ and Bodipy^® 564/570 C₅) are highest when applied in surfactants/propylene glycol. CLSM studies revealed that follicular accumulation increased with (i) a lipophilic dye and (ii) application of lipophilic dyes in surfactants–propylene glycol. Therefore we conclude that targeting to the hair follicle can be increased by the use of lipophilic drugs in combination with surfactant solutions and propylene glycol.     

Development of fluridil,a topical suppressor of the androgen receptor in androgenetic alopecia

Nonsteroidal antiandrogens (AA) cannot be topically used for androgenetic alopecia (AGA) because of systemic resorption. A new class of androgen receptor (AR) suppressors designed for safe topical treatment of AGA was synthesized from (3‐amino‐2‐hydroxy‐2‐methyl‐N‐(4‐nitro‐3‐trifluoromethyl)phenyl) propanamide (BP‐34), to contain perfluoroalkyl moieties. The trifluoromethyl derivative (fluridil) at 10 μM decreased expression of the AR in LNCaP human cells by 95%, its serum half‐life was 6 h; it decomposes hydrolytically to BP‐34 and trifluoroacetic acid. Acute intraperitoneal maximum tolerated dose (MTD) of fluridil in mice is 270–300 mg/kg/d and the subacute MTD is 450 mg/kg/d. The oral LD₅₀ in mice was 2,872 mg/kg in males, 2,232 mg/kg in females, and >2,500 mg/kg in rats. Fluridil solution in isopropanol was not cutaneously absorbed in rabbits, did not sensitize or show any phototoxic or photoallergic effects on guinea pig skin, and demonstrated no skin irritation potential in rabbits and humans. Fluridil solid induced only slight and reversible eye irritancy in rabbits and displayed no cytotoxicity to rabbit corneal fibroblasts in vitro. Fluridil demonstrated no significant mutagenicity potential by Ames method. In a double‐blind study, 43 males with AGA, Norwood grade II to Va, used topical 2% fluridil in isopropanol or the vehicle daily for 12 months. Anagens (growing hairs) increased in the fluridil group from 76% to 89%. All hematological and biochemistry values remained within normal range, including testosterone, which varied but seasonally. No fluridil or its decomposition product (BP‐34) was detected in serum. No adverse side effects were reported. Drug Dev. Res. 59:292–306, 2003. © 2003 Wiley‐Liss, Inc.     

大鼠皮肤及毛囊骨桥蛋白研究

目的 对出生和出生后大鼠皮肤及毛囊的骨桥蛋白（ｏｓｔｅｏｐｏｎｔｉｎ）的ｍＲＮＡ进行研究。方法 确定妊齿１４～１８ｄ和出生后１～６１ｄ Ｗｉｓｔａｒ大鼠毛周期,用放性同位素标记的原位杂交法牟大鼠皮肤和毛囊骨桥蛋白ｍＲＮＡ的分布和含量进行研究。结果 骨桥蛋白ｍＲＮＡ在大鼠出生后第１８天首次在真皮乳头（ｄｅｒｍａｌｐａｐｉｌｌａ,ＤＰ）细胞中出现,在各毛发周期中骨桥蛋白ｍＲＮＡ信号均出现一毛囊退化期Ｄ     

条件声暴露后豚鼠耳埚外毛细胞F-激动蛋白的表达（英）

It has been found that in many mammalian animals,including mankind, non-traumatic"conditioning"noiseexposures can make the inner ear more resistant to trau-matic noise exposure. The possible mechanism underlyingthis phenomenon which is now known as"toughening",has been extensively studied . All the explanations aboutthis mechanism, however, have not been acceptable. Asa primary component of the structural filaments of the haircells and some supporting cells, filamentous actin (F-actin) are believed to be the basic unit in hair cell reac-tion. Furthermore, recent studies have shown that F-actinis involved in actin-mediated motile processes of the outerhair cells. Thus, F-actin may play an important role inthe process of"toughening". The present study is ①toobtain more information on the distribution of F-actin inthe guinea pig cochlea, ②to observe the effects of condi-tioning noise exposure on the expression of F-actin, and③to determine the relationship between the changes of F-actin expression in the outer hair cells (OHC) and the"toughening" phenomenon.     

Electron microscopic localization of nitric oxide I synthase in the organ of Corti of the guinea pig

Nitric oxide synthase (NOS) activity has been detected previously in the mammalian cochlea at a light microscopic level. Here we present results of electron microscopic analysis for post-embedding immunoreactivity of neural-type NOS I in the cochlea of the guinea pig. Strong enzyme immunoreactivity was identified in the cytoplasm of inner and outer hair cells. Gold-labeled NOS I antibodies were mainly located in electron-dense areas of the cytoplasm, whereas electron-lucent regions of the receptor cells were nearly free from any immunoreactivity. In both types of hair cells anti-NOS I antibodies were also visible in the cuticular plates, hair bundles and nuclei. Further ultrastructural analysis revealed that the submembranous cisternae of the outer hair cells were nearly free from any reaction product, demonstrating that the whole cytoplasm of this hair cell was not immunoreactive. Other NOS I immunoreactivity was identified in the cuticular plates of the inner and outer pillar cells and in the cytoskeletal elements located in the apical parts of Deiter cells, forming the lamina reticularis or in cytoskeletal-containing regions in basal Deiter cells. Anti-NOS antibodies were visible in the nuclei of various cell types. Our findings suggest that nitric oxide produced by NO I synthase in the organ of Corti may act as a modulator of hair cell physiology during the processes of signal transduction with frequence selectivity.     

Alteration of loosely bound calcium in the guinea pig organ of Corti after treatment with diltiazem as calcium channel blocker

After oral administration of the organic calcium channel blocker diltiazem to guinea pigs for 7 days, calcium ions were precipitated with potassium antimonate in the cochleae. The spatial distribution of the precipitates was studied by energy-filtering transmission electron microscopy and the amount of the ultrastructural reaction products formed was determined semiquantitatively by an image processing system. Compared with untreated control ears, the number of the formed precipitates was reduced drastically in the inner hair cells after diltiazem treatment. In addition, electron microscopic analysis revealed that the number of calcium precipitates attached at the basolateral membrane of the outer hair cells was clearly reduced when compared with untreated control specimens. A large number of histochemical reaction products could be identified in the basilar membrane and were also observed in the untreated control specimens. The spatial distribution of the calcium precipitates in the lamina reticularis was not affected by diltiazem treatment and calcium precipitates could be identified within different cell membranes. The technique used was considered to be helpful for identifying calcium channels ultrastructurally in intact undissected tissues and to support light microscopic analyses and patch-clamp electrophysiological measurements.     

高渗透压对豚鼠耳蜗离体外毛细胞膜电位的影响

为了解高渗透压对豚鼠耳蜗离体活外毛细胞膜电位及细胞长度的影响。我们运用粘附式细胞仪和膜电位敏感针ＤｉＢＡＣ，对豚鼠耳蜗离体外细胞在高渗环境中的膜电位相对值及细胞长度的变化进行了动态测定。     

Complete Removal of Colloid Cyst via CT-Guided Stereotactic Biportal Neuroendoscopy

Four patients harbouring a colloid cyst of the 3rd ventricle were operated on endoscopically. With the "classical" monoportal technique, through a precoronal burr hole only partial removal could be achieved in the first case. As the crucial point of the procedure is the safe dissection of the cyst from the thela chorioidea and from the internal cerebral veins, adequate control of the posterior rim of the foramen of Monro and the roof of the 3rd ventricle is mandatory. Accordingly in other three cases a CT-guided biportal endoscopic technique was applied, which permitted radical removal of the entire cyst with maximum safety. CT-guidance is essential for optimal planning after careful study of the individual anatomy. In this way the rigid scopes are moved exclusively along their own axes throughout the procedure, the resulting brain damage thereby being minimal. With regard to all circumstances of the procedure, the use of flexible endoscopes appears to be inappropriate and biportal endoscopy offers itself as the method of choice.     

环境危险因素和代谢酶基因多态性与白血病关系的研究

[目的]研究环境危险因素和代谢酶基因多态性及其交互作用与白血病发生的关系。[方法]通过1：1配对病例-对照研究，对用药史、家居附近三废污染、职业暴露史、家居装潢史、吸烟史、染发史等相关因素进行调查；同时运用PCR技术，检测病例与对照的CYP1A1、GSTT1、GSTM1基因型，并分析基因．环境之间的交互作用。[结果]暴露染发年限(OR：2．182，95％CI：1．224～3．828)和装修后入住间隔(OR：1．665，95％CI：1．069～2．529)是白血病发生的危险因素；CYP1A1突变型(P=0．0235)与GSTT1缺失型基因(P=0．0042)可能增加患白血病的危险，而且与染发史或装修史存在交互作用。[结论]暴露干染发或装修，同时存在CYP1A1突变型基因或GSTT1缺失型基因可能增加白血病发生的危险性。     

83例硅油取出时机及并发症的临床分析

目的 分析硅油充填的时间与视网膜复位的关系及硅油在眼内存留时间和硅油并发症产生的关系。方法 回顾分析83例(83只眼)行硅油取出术患者的临床资料及随访记录。结果 行硅油取出的时间为3～13个月，平均8个月。在无发生硅油相关的并发症的条件下，78例在取出硅油之后，视力无明显改变或稍有提高。角膜变性的病例，在硅油取出之后，其混浊情况无明显改变。11例青光眼在硅油取出之后眼压恢复正常者8例，5例在硅油取出之发生了复发性视网膜脱离。结论 硅油取出的最佳时机是3～6个月。硅油取出可以缓解硅油并发症的发展。硅油取出术的并发症主要为复发性视网膜脱离、脉络膜出血、脉络膜脱离、视网膜出血及低眼压。