光照、加热对虾青素稳定性和抗氧化性的影响

目的考察光照、加热情况下虾青素的稳定性和抗氧化性的变化。方法配制一定浓度的虾青素溶液,分别经过阳光直射、紫外和加热处理,测定溶液中各虾青素异构体的浓度,并做1,1-二苯基-2-三硝基苯肼(DPPH)抗氧化性试验。结果在光照和加热条件下,减少的全反式虾青素转化为其顺式异构体,且主要转化为13-顺式异构体,对应的转化率分别为50%、100%。通过紫外照射试验发现,虾青素各异构体含量变化与光照相近,说明光照对虾青素的影响主要是由于其中的紫外光引起的。1,1-二苯基-2-三硝基苯肼清除试验表明,虾青素不止一种异构体有活性,且13-顺式异构体抗氧化性高于全反式。结论在光照和加热情况下虾青素容易发生降解以及异构体之间的转化。     

人血浆中全反式维甲酸、13-顺式维甲酸和9-顺式维甲酸浓度的监测

目的建立高效液相色谱法同时测定人血浆中全反式维甲酸、13-顺式维甲酸和9-顺式维甲酸浓度。方法色谱柱为KromasilC18柱(4.6mm×250mm,5μm);柱温为室温。流动相A:甲醇;流动相B:0.01mol/L醋酸钠缓冲液(pH=5.7),梯度洗脱,流速1ml/min;检测波长340nm。结果全反式维甲酸、13-顺式维甲酸和9-顺式维甲酸血药浓度在1～200ng/ml范围内,浓度与峰面积比有良好的线性关系,最低检测浓度为0.5ng/ml。全反式维甲酸方法回收率为97.22%～108.80%,日内RSD≤8.24%,日间RSD≤11.34%;13-顺式维甲酸方法回收率为98.62%～104.80%,日内RSD≤8.02%,日间RSD≤11.70%;9-顺式维甲酸方法回收率为97.74%～102.24%,日内RSD≤7.72%,日间RSD≤9.17%。结论本方法简单、快速、灵敏、重现性好,适用于全反式维甲酸、13-顺式维甲酸和9-顺式维甲酸临床血药浓度监测及人体药代动力学研究。     

高效液相色谱法同时检测人血清中全反式及13—顺式维甲酸浓度

目的 :建立高效液相色谱方法同时检测人血清中全反式及 13 -顺式维甲酸浓度。方法 :色谱柱 :μBondapakC18(3 9mm× 30 0mm) ,流动相 :甲醇 -醋酸铵缓冲液 (85∶15 ) ,流速 :0 8mL·min-1,紫外检测波长 :340nm ,柱温 :2 2℃ ,血清样品经乙醚 2次提取 ,按内标法定量 ,内标物选用对二甲氨基苯甲醛。结果 :全反式及 13-顺式维甲酸的线性范围分别在 0 8～ 112 0 μg·L-1和 0 82～ 1312 μg·L-1,最低检测浓度均为 0 6μg·L-1。全反式维甲酸测定的平均回收率为 98 86 %～ 10 5 2 % ,日内、日间精密度RSD为 0 84%～ 5 5 % ,13-顺式维甲酸测定的平均回收率为 10 1 6 %～ 10 1 8% ,日内、日间精密度RSD为 1 4%～ 5 7%。结论 :本方法灵敏、准确 ,样品处理简便易行 ,适用于全反式维甲酸的临床药动学研究     

反相高效液相色谱法测定格列美脲滴丸中顺式异构体

目的:建立反相高效液相色谱法测定格列美脲滴丸中顺式异构体的方法。方法:采用十八烷基硅烷键合硅胶色谱柱(4.6 mm×250 mm,5μm),以甲醇-乙腈-0.05 mol.L-1磷酸铵溶液(用磷酸调pH至4.0)=(30∶40∶30)为流动相;流速0.5ml.min-1;柱温25℃;检测波长为228 nm;进样量为10μl。结果:格列美脲峰与其顺式异构体峰分离度为1.75。3批样品中顺式异构体分别为0.034%,0.029%,0.027%,均符合规定。结论:本方法简便、灵敏、专属性强,可用于格列美脲滴丸中顺式异构体的检查。     

抗血吸虫病药物呋喃丙胺顺式异构体的研究

呋喃丙胺顺式异构体的合成,系按文献方法制备顺式β-(5-硝基-2-呋喃)-丙烯酸,然后于低温下与异丙胺经混合酸酐法,氨化为顺式与反式两种酰胺的混合物,再经分离获得顺式异构体。实验动物药理结果证明其生物活性与反式异构体相似。     

HPLC法测定盐酸曲普利啶中顺式异构体及其他杂质含量

目的建立HPLC法测定盐酸曲普利啶中顺式异构体及其他杂质含量的方法。方法采用Inertsil ODS-3(4.6 mm×250 mm,5μm)为色谱柱;以甲醇-醋酸铵溶液(取0.4%的醋酸铵溶液300 mL,加1 mL三乙胺,用冰醋酸调节pH值至5.5)(65∶35)为流动相;检测波长为254 nm。结果盐酸曲普利啶顺式异构体线性范围为0.000 1～0.039 0 mg/mL(r=0.999 9),定量限和检测限分别为4、0.8 ng,回收率为99.5%(n=9);测定结果重复性良好,盐酸曲普利啶顺式异构体、其他单个杂质、总杂的RSD(n=6)分别为1.95%、3.60%、1.92%。结论该方法灵敏、准确,专属性好,可用于测定盐酸曲普利啶中顺式异构体及其他杂质的含量。     

高效液相色谱法测定恩替卡韦分散片全反式异构体

目的建立测定恩替卡韦分散片全反式异构体的高效液相色谱法。方法采用Daicel Chiralcel AD H （4.6 mm×250 mm,5 μm）手性色谱柱;以无水乙醇（含0.1%三氟乙酸） 正己烷（40：60）为流动相;检测波长：254 nm;流速：0.8 mL•min 1。结果恩替卡韦与全反式异构体分离可在10 min内完成,分离度为5.0,异构体溶液浓度1.25～12.50 μg•mL 1范围内与峰面积呈较好线性关系,r＝0.999 9,定量限可达10.0 ng。结论该方法准确度高,专属性强,能有效分离恩替卡韦与其全反式异构体,可用于恩替卡韦分散片的全反式异构体检查。     

HPLC法测定盐酸曲马多中的顺式异构体

目的：用高效液相色谱法测定盐酸曲马多中的顺式异构体。方法：在ODS柱上,以1％三乙胺溶液－甲醇（65;35）为流动相,检测波长272nm。结果：盐酸曲马多马与其顺式异构体得到良好的,顺式异构体的最低检出量为6ng。结论：此方法可用于药品的质量控制。     

N-(顺式-4-异丙基环己基-1-甲酰基)-D-苯丙氨酸和N-(反式-4-异丙基环己基-1-甲酰基)-L-苯丙氨酸的合成

目的合成N-(顺式-4-异丙基环己基-1-甲酰基)-D-苯丙氨酸和N-(反式-4-异丙基环己基-1-甲酰基)-L-苯丙氨酸.方法以(4-异丙基)环己基甲酸为原料,在二环己基碳二亚胺(DCC)作用下,与N-羟基琥珀酰亚胺反应得到(4-异丙基)环己基甲酸琥珀酰亚胺酯(3),柱色谱分离化合物3得到顺式和反式异构体.顺式体与D-苯丙氨酸甲酯发生酰化反应,碱水解后即得到N-(顺式-4-异丙基环己基-1-甲酰)-D-苯丙氨酸;而反式体与L-苯丙氨酸甲酯发生酰化反应,水解后得到N-(反式-4-异丙基环己基-1-甲酰)-L-苯丙氨酸.结果与讨论成功合成了目标化合物,反应总收率分别为39%和31%.     

HPLC测定格列美脲顺式异构体的方法改进

目的:改进并建立测定格列美脲顺式异构体的高效液相色谱法。方法:采用二醇基硅胶色谱柱(250 mm×4.6 mm,5μm),以冰醋酸-正庚烷-无水乙醇(1∶900∶100)为流动相,流速1.0 mL·min-1,检测波长为228 nm。结果:在上述色谱条件下,格列美脲与顺式异构体分离度良好,顺式异构体的定量限为8 ng,在0.001～0.01 mg·mL-1范围内线性关系良好(r=0.9999)。顺式异构体相对于格列美脲的相对保留时间为0.9,校正因子为1.0。结论:可用不加校正因子的主成分自身对照法测定格列美脲中顺式异构体的含量。     

核磁共振法测定13-顺阿维A

目的建立核磁共振法测定13-顺阿维A。方法采用1H-NMR测定13-顺阿维A,通过样品与内标物质响应峰面积比较计算样品的质量分数以及其中残留溶剂。结果以δ5.64处定量峰和δ8.45处内标峰面积比值与13-顺阿维A和1,4-对硝基苯质量比进行线性回归,线性关系良好。13-顺阿维A的质量分数为98.5%,RSD值为1.5%(n=3),重复性良好,与质量平衡法测定结果一致;样品中残留溶剂为四氢呋喃,其质量分数为1.0%。结论核磁共振法测定13-顺阿维A快速、准确、方便,结果可靠,可以用来进行标准物质的测定。     

Glutathione catalysis of interconversion of acitretin and its 13-cis isomer isoacitretin

The ability of glutathione to catalyze the cis-trans isomerization of acitretin and isoacitretin was explored. Glutathione catalyzed the isomerization reaction in both directions; the reaction rate varied with glutathione concentration, atmospheric exposure condition, and identity of starting isomer. The ability of this widely distributed molecule to catalyze this interconversion nonenzymatically may contribute to the presence of both isomers in vivo after administration of either isomer.     

Synthesis and potent antitumor activities of novel 1,3,5-cis,cis-triaminocyclohexane N-pyridyl derivatives

The iron chelator N,N',N' '-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr) was recently reported to display potent antitumor activity. The present study was focused on identifying an adequate bifunctional version of tachpyr as a lead compound for use in antibody-targeted iron depletion tumor therapy. Preparation of tachpyr derivatives having a side chain is reported, and their cytotoxic activity is evaluated in the HeLa cell line. The observed cytotoxity appears dependent on the functionalization site of the tachpyr employed for introducing the protein conjugation. Tachpyr derivatives 14 and 15 having a side chain introduced into the 5-position of the pyridyl ring display more potent cytotoxicity than tachpyr derivatives 7 and 8 having a side chain introduced onto one of the secondary amines. BOC-protected tachpyr derivative 14 exhibited the most potent cytotoxicity against this cancer cell line, which was reasonably comparable to the parent tachpyr. Tachpyr derivative 14 was further converted into bifunctional tachpyr 17 possessing a maleimide linker for conjugation with thiolated monoclonal antibodies (mAbs).     

Pharmacokinetics of acitretin and its 13-cis metabolite in patients on haemodialysis.

1. Plasma concentrations of acitretin and its metabolite (13-cis acitretin) were measured in six patients on haemodialysis and six subjects without renal failure following a single oral dose of 50 mg of acitretin. 2. The mean areas under the plasma concentration vs time curves of acitretin and its metabolite were about 50% lower in patients on haemodialysis. 3. No retinoids were detectable in the dialysate.     

Simultaneous Pharmacokinetic Model for Rolofylline and both M1-trans and M1-cis Metabolites

Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites (metabolites) by cytochrome P450 (CYP) 3A4. The aim of this investigation was to provide a pharmacokinetic (PK) model for rolofylline and metabolites following intravenous administration to healthy volunteers. Data included for this investigation came from a randomized, double-blind, dose-escalation trial in four groups of healthy volunteers (N = 36) where single doses of rolofylline, spanning 1 to 60 mg ,were infused over 1–2 h. The rolofylline and metabolite data were analyzed simultaneously using NONMEM. The simultaneous PK model comprised, in part, a two-compartment linear PK model for rolofylline, with estimates of clearance and volume of distribution at steady-state of 24.4 L/h and 239 L, respectively. In addition, the final PK model contained provisions for both conversion of rolofylline to metabolites and stereochemical conversion of M1-trans to M1-cis. Accordingly, the final model captured known aspects of rolofylline metabolism and was capable of simultaneously describing the PK of rolofylline and metabolites in healthy volunteers.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-012-9443-5) contains supplementary material, which is available to authorized users.KEY WORDS: adenosine A1 receptor antagonist, pharmacokinetics, rolofylline     

Practical implications for the administration of 13-cis retinoic acid in pediatric oncology

Children with high-risk neuroblastoma are treated with polychemotherapy, surgery, radiotherapy and even autologous stem-cell transplantation. On top of this complex treatment, most children also receive 13-cis retinoic acid as differentiation agent. As no suitable pharmaceutical formulation is available so far, there are often problems with the administration of the product in children. The present report describes some practical recommendations for the administration of isotretinoin in children treated for high-risk neuroblastoma.     

9-顺维甲酸对肺鳞癌细胞生物学特性的影响

目的　探讨 9 顺维甲酸 ( 9 cis RA)对肺鳞癌细胞的生物学作用。方法　对应用 9 cis RA处理后L78和A2 两肺鳞癌细胞株的生长、分化和凋亡等特性进行检测观察。结果　① 9 cis RA对两肺癌细胞株的生长产生明显的抑制作用 ;②应用 9 cis RA后 ,两株细胞分化特征明显 ;③经 9 cis RA处理后的两肺鳞癌细胞凋亡率明显高于对照组。结论　 9 cis RA具有抑制肺鳞癌细胞的生长、诱导其分化和凋亡等生物学作用。     

Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin,carbamazepine and valproate

All-trans retinoic acid deficiency resulting from ethanol’s interference with the synthesis of all-trans retinoic acid from retinol was recently suggested to cause the malformations of the fetal alcohol syndrome. Phenytoin, carbamazepine and valproate, might be teratogenic because they lower the concentration of all-trans retinoic acid in serum, by inducing the enzyme systems in the liver responsible for the metabolism of the all-trans retinoic acid, or by other mechanisms. Here we show, that in patients given therapeutic doses of phenytoin, carbamazepine and valproate, serum all-trans and 13-cis retinoic acid concentrations are indeed significantly lowered. We propose that drugs with this ability should be considered as potential teratogens.     

Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of Rat.

We have measured the pharmacokinetics of three retinoids, all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain [especially white matter (WM) and gray matter (GM)] to help select retinoids for treating human malignant glioma. All-trans retinoic acid permeated well into the WM, giving peak concentration in WM of 25.7 microg/g, 6 to 7 times higher than the peak serum concentration. There was less 13-cis retinoic acid in WM: area under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) serum = 18.00 microg ml(-1) h/32.67 microg ml(-1) h. The ratio WM/GM was over 1 for these two compounds, but the half-lives were short in the serum and cerebral tissue (0.57-1.02 h). Fenretinide had different pharmacokinetics: the peak concentrations were in serum (1.7 microg/ml) and WM (1.2 microg/ml)-low, but the AUC(0-->infinity) was large (25.55 microg ml(-1) in serum and 57.53 microg ml(-1) in WM) due to its long elimination half-life (13.78 h in serum and 17.77 h in WM). These findings provide information that may be used to select a retinoid and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.     

The Requirement for a Retinoic Acid Lactone of 11-cis, 13-cis-Stereochemistry for Topical Dermatologic Activity

Pharmaceutical Research -