Phototoxic reaction and porphyrin fluorescence in skin after topical application of methyl aminolaevulinate

BACKGROUND: Photodynamic therapy using topical methyl aminolaevulinate (MAL) is a new treatment modality for skin disorders. MAL is metabolized into endogenous porphyrins, which act as photosensitizers when illuminated. OBJECTIVES: To evaluate the severity and duration of skin photosensitivity after MAL application, and to investigate its relation to the presence of endogenous porphyrins. METHODS: Placebo and 160 mg g(-1) MAL creams were randomly assigned to contralateral sites located at the forearms and fingertips of 16 healthy volunteers and were applied for 3 h. The porphyrin content in the skin was monitored by in situ fluorescence measurements following cream removal. Phototoxic reaction was evaluated after exposure to a high dose of red light. RESULTS: The porphyrin fluorescence in forearm skin peaked about 1 h after the cream removal, was halved after 8 h, and was reduced by > 90% within 24 h. Most forearm sites were photosensitive at 1 and 8 h following cream removal. Six subjects were still sensitive at 24 h, and at this time point the phototoxicity was coincidental with residual porphyrin fluorescence. In general, all reactions were mild or moderate, and included pain, erythema, oedema and transient hyperpigmentation. No photosensitivity or porphyrin fluorescence was detected at 48 h. At the fingertips photosensitivity was absent except for sporadic cases of mild pain. CONCLUSIONS: Topical MAL application and exposure to red light induced mild and moderate phototoxicity. The photosensitivity ceased within 24-48 h after cream removal, and its duration was associated with the degradation of porphyrins.     

Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study

BACKGROUND: There is a need for alternative treatments for moderate to severe acne vulgaris. Preliminary experience suggests that topical methyl aminolaevulinate photodynamic therapy (MAL-PDT) may have potential. OBJECTIVES: To investigate the efficacy and tolerability of MAL-PDT for treatment of moderate inflammatory facial acne. PATIENTS/METHODS: Thirty patients aged 15-28 years with moderate to severe acne were included in a blinded, prospective, randomized, placebo-controlled multicentre study. Each side of each patient's face was randomly assigned to treatment with MAL (160 mg g1) or placebo cream, applied for 3 h prior to illumination. A second treatment was given 2 weeks later. On each occasion, patients assessed the intensity of pain using a 10-cm visual analogue scale. Inflammatory and noninflammatory acne lesions were counted at baseline and 4 and 10 weeks after the last PDT treatment. The investigator assessed the global severity of acne at baseline (seven patients had severe acne on at least one side of the face) and each study visit using a six-point rating scale. Data were analysed on an intention-to-treat basis, including all 30 patients. RESULTS: There was a statistically significant greater reduction in the total inflammatory lesion count with MAL-PDT compared with placebo PDT at week 12; median reduction 54% [95% confidence interval (CI) 35-64%] vs. 20% (95% CI 8-50%), P = 0.0006. MAL-PDT was associated with more pain than placebo PDT, although intensity varied across centres and was reduced with repeated treatment. Local adverse events were consistent with this treatment modality. CONCLUSIONS: MAL-PDT is effective in the treatment of moderate to severe inflammatory facial acne. Further studies are warranted to optimize this promising procedure.     

Skin sensitization potency of methyl methacrylate in the local lymph node assay: comparisons with guinea-pig data and human experience

There is compelling evidence that contact allergens differ substantially (by 4 or 5 orders of magnitude) with respect to their inherent skin-sensitizing potency. Relative potency can now be measured effectively using the mouse local lymph node assay (LLNA) and such data form the basis of risk assessment and risk management strategies. Such determinations also facilitate distinctions being drawn between the prevalence of skin sensitization to a particular contact allergen and inherent potency. The distinction is important because chemicals that are implicated as common causes of contact allergy are not necessarily potent sensitizers. One example is provided by nickel that is undoubtedly a common cause of allergic contact dermatitis, but is a comparatively weak sensitizer in predictive tests. In an attempt to explore other examples of contact allergens where there may exist a discrepancy between prevalence and potency, we describe here analyses conducted with methyl methacrylate (MMA). Results of LLNA studies have been interpreted in the context of historical clinical data on occupational allergic contact dermatitis associated with exposure to MMA.     

Transfer of the experimental methodology described in the FDA guidance for corticosteroid bioequivalence testing to pharmacodynamic effects caused by nicotinates

Background The measurement of the pharmacodynamic response allows the noninvasive quantification of cutaneous drug penetration. Aims The objective of this study was to investigate whether the experimental methods described in the US Food and Drug Administration Guidance for Industry “Topical Dermatologic Corticosteroids: In vivo Bioequivalence” may be transferred to other response parameters such as skin redness and surface temperature. Methods Drug penetration experiments with methyl nicotinate in two different lipophilic vehicles were performed according to the FDA guidance for corticosteroid bioequivalence testing measuring the cutaneous erythema and skin temperature response. Results The guidance methodology was transferred to the response parameters redness and temperature. Bioequivalence testing was feasible with these response parameters. Conclusions An open one‐compartment model could only be confirmed for skin redness data by a compartmental analysis of response vs. time profiles. The obtained temperature data can neither be described by an open one‐compartment nor by a two‐compartment model. A correlation between skin color and skin surface temperature could not be found.     

N-甲基亚硝基脲诱发大白鼠膀胱肿瘤病理学动态观察

目的　研究N-甲基亚硝基脲(MNU)诱发大白鼠膀胱肿瘤的发生、发展过程。方法　以MNU为诱癌剂,进行大白鼠膀胱灌注,对其诱发的膀胱肿瘤过程的不同时期进行动态观察。结果　第1次MNU灌注后第2周8/10只出现单纯增生,第6周9/10只表现为乳头状肿瘤,第8周10/10只出现膀胱癌,主要为表浅膀胱癌,第10周6/10只为浸润癌。结论　MNU诱发的肿瘤发生、发展经历了从单纯增生→乳头状、结节状良性增生→乳头状肿瘤→非浸润癌→浸润癌这样一个典型病理过程。     

葡甲胺对顺铂所致大鼠肾毒性的预防作用

目的　研究葡甲胺 (N MG)对顺铂 (CDDP)所致大鼠肾毒性的预防作用及其可能机制。方法　大鼠1次腹腔注射 5mg/kgCDDP动物模型 ,于CDDP处理前 1h经口给予N MG预处理。检测指标包括血尿素氮BUN、尿蛋白、尿铂 (Pt) ,肾组织匀浆中NOS、NO、MDA、SOD及肾组织Pt含量 ,同时观察抗肿瘤活性。结果　给药后第 3、5天N MG预处理组可明显预防CDDP所致大鼠肾功能损害 ,降低肾组织中NOS、NO、及MDA含量 ,增加SOD活性 (P <0 0 5或P <0 0 1)。另外 ,给药后第 3天尿Pt(0 .42 5 μg/mgCr)排泄量非常显著地高于CDDP组(0 2 45 μg/mgCr,P <0 0 1) ,肾组织Pt含量于给药后第 3、5天显著低于CDDP组 (P <0 0 5 )。N MG预处理对荷瘤小鼠的肿瘤抑制率与CDDP组无显著性差异。结论　N MG预处理能明显预防CDDP所致大鼠的肾损害 ,其预防作用机制可能是N MG促进Pt经尿排出 ,并减少了肾组织Pt蓄积 ,从而CDDP产生的自由基减少 ,脂质过氧化程度减轻。N MG对CDDP抗肿瘤活性无明显影响。     

4—氨基—1—甲基—3—丙基吡唑—5—甲酰胺的合成

以２－戊酮和草酸二乙酯为起始原料,经缩合,环合、甲基化、水解、硝化、氨解、还原等７步反应合成了新型磷酸二酯酶５型（ＰＤＥ５）抑制剂西地那非的关键中间体－４－氨基－１－３－丙基吡唑－５－甲酰胺。     

N-甲基-D-天冬氨酸型受体亚单位-1在大鼠第三脑室室管膜细胞上的表达

目的　研究 N-甲基 - D-天冬氨酸型受体亚单位 - 1(NMDAR1)在大鼠第三脑室室管膜细胞上的表达。　方法　免疫组织化学技术。　结果　 (1) NMDAR1在第三脑室室管膜细胞中的表达呈强阳性 ;(2 ) NMDAR1阳性室管膜细胞的形态与分布 ,在雌、雄大鼠间不存在明显的性别差异。　结论　为脑脊液中的谷氨酸可通过 NM-DA受体介导调节室管膜细胞提供了形态学证据。     

亚硝基左旋精氨酸甲酯促进周围神经再生实验研究

目的 探索一氧化氮合成酶 (NOS)抑制剂对断裂周围神经再生的影响。方法 用 SD雄性大鼠 24只。在距梨状肌下缘 1cm处切断坐骨神经,远断端去除 4mm长,取硅胶管桥接两神经断端,并使其相距 4mm,随机分成硅胶管和腹腔注射两组。一组其右侧注入 10mg/kg亚硝基左旋精氨酸甲酯 (L-NAME),左侧注入等量生理盐水作对照。另组用同等剂量 L-NAME改为腹腔注射 10d。每组分成二半,分别于术后 1、 2月取材,作组织学检测。结果 发现 L-NAME对周围神经的再生有明显的促进作用,而局部注射药较腹腔注射给药神经再生优。结论 L-NAME能促进周围神经再生。