他克莫司软膏的药理及临床评价

他克莫司软膏为大环内酯类免疫调节剂,是治疗特应性皮炎(AD)的非皮质类固醇类外用制剂,他克莫司可抑制钙调磷酸酶的活性及阻止多种细胞因子生成,从而抑制T淋巴细胞活化,发挥药理作用。临床用于治疗AD疗效确切,不良反应较少。本文对他克莫司软膏的药理特性、临床应用和不良反应进行概述,供临床合理应用参考。     

莫匹罗星软膏治疗脓疱疮的Meta分析

目的比较莫匹罗星软膏与安慰剂、其他局部抗菌药物、口服抗菌药物治疗脓疱疮的有效性与安全性。方法计算机检索Pub Med、Elsevier、Cochrane数据库、中国期刊全文数据库、万方、维普数据库(VIP)、中国生物医学文献数据库(CBM)等有关莫匹罗星软膏与安慰剂、其他局部抗菌药物或口服抗菌药物对比治疗脓疱疮的临床随机对照试验。采用Cochrane质量评价标准对纳入研究的方法学质量进行评价,采用Rev Man 5.1软件对入选资料进行Meta分析。结果共36篇文献,包含3 284例脓疱疮患者入选。Meta分析显示,莫匹罗星软膏的有效率显著高于安慰剂[RR=2.21,95%CI(1.59,3.05),P<0.000 01],与夫西地酸乳膏相比差异无显著意义[RR=1.01,95%CI(0.98,1.04),P=0.50],与利福霉素、新霉素、金霉素、杆菌素、新孢霉素无显著差异(P>0.05),显著优于四环素(P=0.000 4),显著优于口服红霉素[RR=1.07,95%CI(1.02,1.13),P=0.007],与双氯青霉素、头孢氨苄、氨苄西林无显著差异[RR=1.09,95%CI(0.94,1.28),P=0.25]。莫匹罗星软膏的不良反应发生率低于口服红霉素[RR=0.41,95%CI(0.25,0.69),P=0.000 7],高于夫西地酸乳膏[OR=5.27,95%CI(2.06,13.53),P=0.000 5]。在微生物学可评估患者中,莫匹罗星软膏对金黄色葡萄球菌的清除率与夫西地酸乳膏无显著差异,[RR=1.05,95%CI(0.99,1.12),P=0.09],显著高于四环素软膏[RR=1.16,95%CI(1.08,1.26),P=0.000 1]。结论莫匹罗星软膏治疗脓疱疮优于安慰剂、其他局部抗菌药物和口服红霉素,不良反应相对较少。     

Synthesis, formulation, and clinical pharmacological evaluation of hydralazine pyruvic acid hydrazone in two healthy volunteers

Hydralazine pyruvic acid hydrazone [2-(phthalazin-1-yl hydrazono)propionic acid; 1] is a major plasma metabolite of hydralazine in humans. A number of in vitro and animal studies have suggested that this hydrazone may have cardiovascular activity and could account for the prolonged antihypertensive effect of hydralazine in humans in the absence of detectable plasma levels of the parent drug. To study this possibility, the soluble sodium salt of hydralazine pyruvic acid hydrazone (2) was synthesized, its chemical purity and stability was checked, and an intravenous formulation was prepared. Isomeric forms were identified. Doses of 0.3, 0.6, and 1.1 mumol/kg of 2 were administered intravenously to one slow and one heterozygous fast acetylator of sulfamethazine. The slow acetylator received two additional doses of 0.06 and 0.14 mumol/kg. Peak plasma levels of 1 of 18 mumol/L were attained without tachycardia or hypotension in either subject. There was no evidence of nonlinearity in kinetics over the dose range studied and clearance remained constant in both subjects (0.517 +/- 0.033 mL/min/kg in the slow acetylator and 0.744 +/- 0.058 mL/min/kg in the fast acetylator). The distribution of 1 varied unpredictably with dose, and changes were reflected in the terminal half-life (3.47-5.97 h in the slow acetylator and 2.06-5.33 h in the fast acetylator). Only traces of the acetylated metabolite of hydralazine, 3-methyl-s-triazolo[3,4-a]phthalazine (3), were detected in the plasma of the subjects, suggesting that significant metabolism via this route was unlikely. An established and specific assay for hydralazine was further modified to allow measurement of levels as low as 1 nmol/L (0.2 ng/mL).(ABSTRACT TRUNCATED AT 250 WORDS)     

Toxicity and carcinogenicity studies of nalidixic acid in rodents

Toxicity and carcinogenicity studies of nalidixic acid, an antimicrobial agent used to treat bacterial infections of the urinary tract, were conducted in F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. In the 13-week studies, nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. Body weights of both rats and mice were reduced in the groups receiving diet containing 8,000 and 16,000 ppm, and feed consumption of rats in the highest treatment groups was approximately two-thirds that of controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in either species. Two-year studies were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 rats and mice/sex/group. The average daily feed consumption was slightly reduced compared to control groups and resulted in approximate daily doses of 82 or 175 mg nalidixic acid/kg for low dose and high dose rats, and 220 or 475 mg/kg for low dose and high dose mice. Mean body weights of dosed rats and mice were lower than those of controls, except for groups of low dose female rats and male mice. The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly increased compared to those in controls; responses in low dose groups were similar to those in high dose groups. There were decreased incidences of leukemia and mammary gland neoplasms in dosed female rats and of pituitary gland neoplasms in dosed male rats. Subcutaneous tissue fibrosarcomas were marginally increased in dosed male mice. There were no increased incidences of neoplasms in dosed female mice. Under the conditions of these studies, the dietary administration of nalidixic acid was carcinogenic for rats, causing preputial gland or clitoral gland neoplasms in males and females, respectively. The association of subcutaneous neoplasms with administration of nalidixic acid to male mice was equivocal.     

盐酸达克罗宁软膏处方优化

目的优化复方达克罗宁软膏处方,考察软膏质量。方法采用单因素分析法,选择乳化剂;采用反射线直角单纯形法,考察软膏伸展性及稳定性,优化乳化剂和软膏基质十六醇的用量。结果选择乳化剂十二烷基硫酸钠-三乙醇胺-硬脂酸且用量为6.0%,十六醇用量为6.0%,软膏稳定,伸展性符合半流体软膏特性。结论该软膏处方合理,质量稳定。反射线直角单纯形法和单因素分析法,方法简单、实用,适合软膏剂处方优化。     

菌克软膏处方优化的研究

目的优化菌克软膏处方,提高质量稳定性。方法以外观性状、伸展性、离心、耐热及耐寒试验、含量为考察指标,对软膏剂的乳化剂进行筛选,对增稠剂的配比进行优化。结果选择复合乳化剂三乙醇胺+硬脂酸+十二烷基硫酸钠,白凡士林的用量为3%,十八醇用量为6%,液体石醋用量为6%,所制得乳膏质地均匀、细腻,色泽洁白;伸展性好,质量稳定,含量均匀。结论优化后的处方配伍合理,质量稳定,适合工业化生产。     

Color reactions for identification of nalidixic acid

Nalidixic acid (1) gives with 2-naphthol a yellow charge-transfer complex. The 7-methyl group of 1 condenses with vanillin (2) and Ehrlich's reagent (4) to the coloured (E)-benzylidene compounds 3 and 5. Treating 1 with thionyl chloride and subsequent reaction with aminopyrazolone (6) and sodium acetate leads to a mixture of trichloronalidixic acid (7) and its 3-carboxamide 8. The trichloromethyl group of 7 is converted with 6 in pyridine to form the amide 9. Nalidixic acid reacts with 1,3-dimethylbarbituric acid (10) in acetanhydride/acetic acid to yield the polymethine dyes 11-13, whose structures are confirmed by X-ray crystal structure analysis. The dyes 3 and 12 inhibit the growth of staphylococcus aureus and Escherichia coli, respectively.     

Pharmacokinetics of nalidixic acid in man: Hydroxylation and glucuronidation

Nalidixic acid is metabolized by hydroxylation to 7-hydroxymethylnalidixic acid and then by oxidation to 7-carboxynalidixic acid. The half-lives of the two elimination phases of nalidixic acid are 0.75 and 2.5 h. The apparent half-lives of the metabolite 7-hydroxymethylnalidixic acid are 2.5 and 5.5 h. Plasma protein binding of nalidixic acid is 95% and that of 7-hydroxymethylnalidixic acid 65%. The renal clearance of nalidixic acid varies between 2 and 25 ml/min and that of 7-hydroxymethylnalidixic acid between 37 and 162 ml/min. Of nalidixic acid 42% is glucuronidated and 40% hydroxylated. Of the hydroxy metabolite 57% is glucuronidated and 32% excreted unchanged. 7-Carboxynalidixic acid is excreted in the urine and is not glucuronidated. The variations in the glucuronidation/ hydroxylation ratio of nalidixic acid and the glucuronidation/renal excretion ratio of the 7-hydroxymethyl metabolite belong to a normal distribution.     

The human biotransformation of nalidixic acid.

Authors have developed new chemical methods for studying the human metabolism of nalidixic acid. The methods are suited for the quantitative determination of nalidixic acid, hydroxynalidixic acid, nalidixic acid glucuronide, hydroxynalidixic acid-glucuronide, and of free and total glucuronic acid excretion. The total urinary excretion of NA and its metabolites was found to be 50 to 100% of the ingested dose. The percentual distribution of the individual metabolites was as follows: NA 0,5-5, HNA2,5-6, NAG24-80, and HNAG11-26%. It was unanimously proved by enzymatic decomposition and specific chemical reactions that the excreted conjugates were monoglucuronides. The significance of individual differences, bilirubin metabolism, urinary pH and the pharmacokinetical behaviour of the individual metabolites is discussed from the therapeutic view.     

Nalidixic acid prodrugs: Amides from amino acid ester and nalidixic acid

Amides from amino acid ester and nalidixic acid were synthesized. The solubility characteristics and partition coefficient of the compounds were studied. The hydrolysis of the compounds was studied in the simulated gastric fluid and simulated intestinal fluid. Some compounds showed better antibacterial activity than nalidixic acid.     

Comparative controlled clinical trial of pivmecillinam and nalidixic acid in patients with acute simple urinary tract infections.

We performed a controlled double-blind clinical study with PMPC to investigate its therapeutic usefulness in acute simple cystitis in comparison with NA, with the results as follows: 1. In both treatment groups, PMPC proved to be remarkably more active (MIC) than NA against the bacterial isolates tested in vitro. 2. PMPC, administered in dosis (200 mg per day) one-tenth those of NA (2,000 mg per day), produced a greater improvement (therapeutic effects) than NA. 3. Side-effects were apparently less frequent with PMPC, as compared to NA. The results indicate a remarkable usefulness of PMPC in the treatment of acute simple cystitis.     

百多邦联合尤卓尔治疗脓疱疮的临床疗效评估

目的分析研究百多邦联合尤卓尔治疗脓疱疮的临床效果,以提高患者的生活质量。方法回顾性分析2011年6月至2012年6月期间在我院治疗的72例脓疱疮患者的临床资料。72例患者随机分为治疗组和对照组各36例,治疗组给予百多邦联合尤卓尔治疗,对照组单独使用百多邦治疗,疗程均为7d。观察2组临床疗效及不良反应。结果治疗组总有效率为97．22％,对照组总有效率为83．33％,两组比较差异有统计学意义（P〈0．05）;两组患者均无严重不良反应发生。结论百多邦联合尤卓尔治疗脓疱疮疗效显著,安全性好,值得临床推广应用。     

皮肤外用软膏基质变更的考虑要素

在皮肤科药品注册申请中,改变处方的补充申请较为多见,其中较有代表性的一类是基于临床应用顺应性而对软膏基质进行变更.尽管这种变更存在一定合理性,但经常会发现由于前期研究不足,导致多次补充资料的现象出现.为了更好地提高研发和评价效率,文中结合审评实际,对于此种基质改变的情况提出一些研究中应关注的考虑要素,以促进基质变更研究的合理性.