The aim of this study was to delicately synthesize certain hybrid molecules bearing the mustard-derived and/or heterocyclic combretastain analogues to exploit new antitumor agents. Thus, a variety of heteroaromatic combretastatin analogues 8a-e were efficiently prepared and readily accessed to nitrogen mustard through an ester linkage. However, these delicately hybrid compounds were only shown moderate growth inhibitory potency with most IC50s at micromolar levels, which were much less potent than the natural CA-4 against the KB cells.
{"title":"Synthesis of Mustard-Derived and Heteroaromatic Combretastatin Analogues(superscript #)","authors":"Guan-Hon Chern, Ming‐Kuan Hu","doi":"10.7019/TPJ.200712.0195","DOIUrl":"https://doi.org/10.7019/TPJ.200712.0195","url":null,"abstract":"The aim of this study was to delicately synthesize certain hybrid molecules bearing the mustard-derived and/or heterocyclic combretastain analogues to exploit new antitumor agents. Thus, a variety of heteroaromatic combretastatin analogues 8a-e were efficiently prepared and readily accessed to nitrogen mustard through an ester linkage. However, these delicately hybrid compounds were only shown moderate growth inhibitory potency with most IC50s at micromolar levels, which were much less potent than the natural CA-4 against the KB cells.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"15 1","pages":"195-202"},"PeriodicalIF":0.0,"publicationDate":"2007-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82641785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phytosterols β-sitosterol (1) and stigmasterol (2) were extracted from Nigella sativa which were collected from Al Qaseem’s area in the Kingdom of Saudi Arabia. Steroidal sapogenin diosgenin (3) was extracted from Balanites aegyptiaca (Zygopyllaceae), which was collected from Khamis al Bahr in theKingdom of Saudi Arabia. They have been fully characterized. Stigmasterol (2) and diosgenin (3) were acetylated to give stigmasterol and diosgenin acetate derivatives 4 and 5. Epoxidation of 1-5 gave exo and endo epoxide derivatives 6a, b; 10a, b; 11a, b; 16a, b and 17a, b as precursors of the brassinosteroidal compounds. On the other hand, photooxygenation of 1-5 gave hydroperoxysitosterol derivatives 7 and 9, hydroperoxystigmasterol derivatives 12 and 13, hydroperoxystigmasterol acetate derivatives 14 and 15, hydroperoxydiosgenin derivatives 18 and 19, and hydroperoxydiosgenin acetate derivatives 20 and 21.
植物甾醇β-谷甾醇(1)和豆甾醇(2)是从采自沙特阿拉伯王国Al Qaseem地区的Nigella sativa中提取的。甾体皂苷元薯蓣皂苷元(3)是从沙特阿拉伯王国Khamis al Bahr的埃及巴兰(Balanites aegyptiaca, Zygopyllaceae)中提取的。它们已经被充分地描述过了。将豆甾醇(2)和薯蓣皂苷元(3)乙酰化，得到豆甾醇和薯蓣皂苷元乙酸酯衍生物4和5。1-5的环氧化反应得到外、内环氧衍生物6a, b;10 a, b;11 a, b;16a, b和17a, b是油菜素类固醇化合物的前体。另一方面，1-5光氧化得到氢过氧甾醇衍生物7和9，氢过氧豆甾醇衍生物12和13，氢过氧豆甾醇乙酸衍生物14和15，氢过氧薯蓣皂苷元衍生物18和19，氢过氧薯蓣皂苷元乙酸酯衍生物20和21。
{"title":"Thermal and Photooxidation Reactions of the Steroids : β-Sitosterol, Stigmasterol and Diosgenin","authors":"E. Elgendy, Huda Al-Ghamdy","doi":"10.7019/TPJ.200709.0113","DOIUrl":"https://doi.org/10.7019/TPJ.200709.0113","url":null,"abstract":"Phytosterols β-sitosterol (1) and stigmasterol (2) were extracted from Nigella sativa which were collected from Al Qaseem’s area in the Kingdom of Saudi Arabia. Steroidal sapogenin diosgenin (3) was extracted from Balanites aegyptiaca (Zygopyllaceae), which was collected from Khamis al Bahr in theKingdom of Saudi Arabia. They have been fully characterized. Stigmasterol (2) and diosgenin (3) were acetylated to give stigmasterol and diosgenin acetate derivatives 4 and 5. Epoxidation of 1-5 gave exo and endo epoxide derivatives 6a, b; 10a, b; 11a, b; 16a, b and 17a, b as precursors of the brassinosteroidal compounds. On the other hand, photooxygenation of 1-5 gave hydroperoxysitosterol derivatives 7 and 9, hydroperoxystigmasterol derivatives 12 and 13, hydroperoxystigmasterol acetate derivatives 14 and 15, hydroperoxydiosgenin derivatives 18 and 19, and hydroperoxydiosgenin acetate derivatives 20 and 21.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"1 1","pages":"113-132"},"PeriodicalIF":0.0,"publicationDate":"2007-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78527876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien-Lung Hsu, Cheng-Wei Chen, Bo Zheng, Jii Chen, Tianhui Zhou
This report describes the comparison of four pDNA quantitative methods including UV/Visible spectro-photometry, agarose gel electrophoresis, EtBr staining fluoro-photometry and HPLCSEC method. Finally, the HPLC-SEC method was used to evaluate the interaction of plasmid DNA (pCA-HA) and poly-L-lysine (PLL). In the pCA-HA concentrations ranged form 3.125 to 50 μg/mL, the standard curve of pCA-HA has good linearity, accuracy (CV%＜3%) and precision (Error%＜4%) by using UV/Visible spectro-photometry. But the sensitivity is not enough to evaluate less than 3 μg/mL of pDNA. The intensity of fluorescene emission of EtBr stained pCA-HA is not dose dependent by using EtBr staining fluoro-photometry. The agarose gel electrophoresis had a high sensitivity (ng/mL level), but the accuracy (CV%＞15%) and precision (Error%＞15%) were not good in the range of 0.048~0.760 μg/mL pCA-HA. The standard curve of pCA-HA had good linearity, accuracy (CV%＜3%) and precision (Error%＜5%) in the pCA-HA concentration ranges from 0.4 to 1.2 μg/mL by using the HPLC-SEC method. PLL, a positive charged peptide, was used to condense DNA and enhance the transfection of DNA in cell. We used the HPLC-SEC method to evaluate the interaction of pDNA and PLL. When the charge of pCA-HA and PLL were almost the same, the peak of pDNA disappeared from the HPLC chromatogram. It means that the charge ratio of pCA-HA/PLL is close to 1 in the complex.
{"title":"Quantification of Plasmid DNA in pCA-HA/poly-L-lysine Complex","authors":"Chien-Lung Hsu, Cheng-Wei Chen, Bo Zheng, Jii Chen, Tianhui Zhou","doi":"10.7019/TPJ.200709.0133","DOIUrl":"https://doi.org/10.7019/TPJ.200709.0133","url":null,"abstract":"This report describes the comparison of four pDNA quantitative methods including UV/Visible spectro-photometry, agarose gel electrophoresis, EtBr staining fluoro-photometry and HPLCSEC method. Finally, the HPLC-SEC method was used to evaluate the interaction of plasmid DNA (pCA-HA) and poly-L-lysine (PLL). In the pCA-HA concentrations ranged form 3.125 to 50 μg/mL, the standard curve of pCA-HA has good linearity, accuracy (CV%＜3%) and precision (Error%＜4%) by using UV/Visible spectro-photometry. But the sensitivity is not enough to evaluate less than 3 μg/mL of pDNA. The intensity of fluorescene emission of EtBr stained pCA-HA is not dose dependent by using EtBr staining fluoro-photometry. The agarose gel electrophoresis had a high sensitivity (ng/mL level), but the accuracy (CV%＞15%) and precision (Error%＞15%) were not good in the range of 0.048~0.760 μg/mL pCA-HA. The standard curve of pCA-HA had good linearity, accuracy (CV%＜3%) and precision (Error%＜5%) in the pCA-HA concentration ranges from 0.4 to 1.2 μg/mL by using the HPLC-SEC method. PLL, a positive charged peptide, was used to condense DNA and enhance the transfection of DNA in cell. We used the HPLC-SEC method to evaluate the interaction of pDNA and PLL. When the charge of pCA-HA and PLL were almost the same, the peak of pDNA disappeared from the HPLC chromatogram. It means that the charge ratio of pCA-HA/PLL is close to 1 in the complex.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"24 1","pages":"133-140"},"PeriodicalIF":0.0,"publicationDate":"2007-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87133105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien-Ming Huang, Y. Hsieh, Wen‐Hsin Huang, A. Lee
Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of 2-hydroxy-N-(4-substituted phenyl)nicotinamides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. 1 Currently, a series of compounds 5-13, which are alkyl substitution on phenylmoiety, mainly based on 2-hydroxy-N-(phenyl)nicotinamide 4 were further synthesized in high yields. After systematic pharmacological screenings of compounds 5-13, all compounds exhibited less potent anti-inflammatory activity comparable to leflunomide 1 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenan-induced paw edema assay.
来氟米特1及其非酶活性代谢物丙二硝基酰胺(MNA, 2)被临床用于治疗类风湿性关节炎(RA)。研究表明，丙二硝基酰胺2的免疫抑制作用完全由具有烯醛羟基的β-酮酰胺这一活性药效团导致水杨酰胺衍生物3的开发。在此之前，我们主要以水杨酰胺衍生物3为基础，对其β-羟基-酰胺部分进行了等构修饰，成功合成了一系列2-羟基- n -(4-取代苯基)烟酰胺。经过药理学筛选，含有4-Cl, 4-Br和4-NO2等吸电子基团的化合物显着显示出有效的抗炎活性。1目前，以2-羟基- n -(苯基)烟酰胺4为主要原料，进一步高收率合成了一系列苯基上的烷基取代化合物5-13。在脂多糖诱导的巨噬细胞Raw 264.7细胞和体内角叉菜胶诱导的足跖水肿实验中，通过对化合物5-13的系统药理学筛选，所有化合物的体外抑制一氧化氮(NO)产生的活性都不如来氟米特1和丙二硝基酰胺2。
{"title":"Anti-inflammatory Activity and Structure-activity Relationships of 2-Hydroxy-N-(alkylphenyl) Nicotinamides","authors":"Chien-Ming Huang, Y. Hsieh, Wen‐Hsin Huang, A. Lee","doi":"10.7019/TPJ.200709.0105","DOIUrl":"https://doi.org/10.7019/TPJ.200709.0105","url":null,"abstract":"Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of 2-hydroxy-N-(4-substituted phenyl)nicotinamides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. 1 Currently, a series of compounds 5-13, which are alkyl substitution on phenylmoiety, mainly based on 2-hydroxy-N-(phenyl)nicotinamide 4 were further synthesized in high yields. After systematic pharmacological screenings of compounds 5-13, all compounds exhibited less potent anti-inflammatory activity comparable to leflunomide 1 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenan-induced paw edema assay.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"1 1","pages":"105-112"},"PeriodicalIF":0.0,"publicationDate":"2007-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90060280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pochuen Shieh, Su-Shiang Cheng, D. Kuo, Wenyan Fu, M. Hsu, Fu-An Chen
Histidine (HID) is frequently compounded in pharmaceutical preparations for the treatment of gastrointestinal diseases. A simple and rapid liquid chromatographic method was developed and validated for the routine determination of HID in pharmaceutical preparations. The high-performance liquid chromatographic (HPLC) system consisted of an Purospher STAR RP18 endcapped column (4.6×250 mmi. d.) using amobile phase of 50 mMphosphate buffer with 3 mM sodium octanesulfonate: acetonitrile (95:5, v/v) with an ultraviolet/visible (UV/VIS) detector at 210 nm. The developed method satisfies the system suitability criteria and peak integrity for HID. The square of the correlation coefficient of the linear regression analysis was 0.9995. The relative standard deviations (RSDs) for intra- and inter-day tests were less than 2%. The recovery for 5 concentrations expressed as the closeness of the observed mean to the spiked concentration was 98.20%~101.02%. The limits of detection (LOD) and quantitation (LOQ) for HID were 2.2 and 7.3 μg/mL, respectively. The method was applied to quantitatively determine HID in 8 brands of HID-containing tablets on the Taiwanese market, and these were found to contain 100.59%±1.01% of the percentage claimed on the label. The results indicate that the established assay method is suitable for measuring HID in pharmaceutical preparations.
组氨酸(HID)常用于胃肠道疾病的药物制剂中。建立了一种简单、快速的液相色谱法常规测定药物制剂中HID的方法。高效液相色谱(HPLC)系统由Purospher STAR RP18端封柱(4.6×250 mmi)组成。d.)使用50mm磷酸盐缓冲液与3mm辛烷磺酸钠:乙腈(95:5,v/v)为流动相，在210 nm处使用紫外/可见(UV/VIS)检测器。所开发的方法满足HID的系统适用性和峰完整性标准。线性回归分析相关系数的平方为0.9995。日内、日间试验的相对标准偏差(rsd)均小于2%。5个浓度的回收率为98.20%~101.02%，表示为观测平均值与加标浓度的接近度。HID的检出限为2.2 μg/mL，定量限为7.3 μg/mL。将该方法应用于台湾市场上8个品牌含HID片剂的含量测定，发现其含量为标签所示含量的100.59%±1.01%。结果表明，所建立的测定方法适用于药物制剂中HID的测定。
{"title":"Simple and Rapid Liquid Chromatographic Method for Determination of Histidine HCl in Pharmaceutical Preparations","authors":"Pochuen Shieh, Su-Shiang Cheng, D. Kuo, Wenyan Fu, M. Hsu, Fu-An Chen","doi":"10.7019/TPJ.200709.0141","DOIUrl":"https://doi.org/10.7019/TPJ.200709.0141","url":null,"abstract":"Histidine (HID) is frequently compounded in pharmaceutical preparations for the treatment of gastrointestinal diseases. A simple and rapid liquid chromatographic method was developed and validated for the routine determination of HID in pharmaceutical preparations. The high-performance liquid chromatographic (HPLC) system consisted of an Purospher STAR RP18 endcapped column (4.6×250 mmi. d.) using amobile phase of 50 mMphosphate buffer with 3 mM sodium octanesulfonate: acetonitrile (95:5, v/v) with an ultraviolet/visible (UV/VIS) detector at 210 nm. The developed method satisfies the system suitability criteria and peak integrity for HID. The square of the correlation coefficient of the linear regression analysis was 0.9995. The relative standard deviations (RSDs) for intra- and inter-day tests were less than 2%. The recovery for 5 concentrations expressed as the closeness of the observed mean to the spiked concentration was 98.20%~101.02%. The limits of detection (LOD) and quantitation (LOQ) for HID were 2.2 and 7.3 μg/mL, respectively. The method was applied to quantitatively determine HID in 8 brands of HID-containing tablets on the Taiwanese market, and these were found to contain 100.59%±1.01% of the percentage claimed on the label. The results indicate that the established assay method is suitable for measuring HID in pharmaceutical preparations.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"25 4 1","pages":"141-148"},"PeriodicalIF":0.0,"publicationDate":"2007-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86054221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hang-Ching Lin, Sheng-Ming Pan, H. Ding, T. Chou, Wen-liang Chang
Leonurine (1) was simply isolated from the aerial part of Leonurus sibircus var. albiflora. Their structures were established on the basis of spectral evidence. Leonurine showed a significant inhibited rabbit platelet aggregation induced by thrombin, arachidonic acid, and collagen in vitro with an IC50 of 97.22 μM, 31.03 μM, and 44.48 μM, respectively.
Leonurine(1)是从益母草(Leonurus sibircus var. albiflora)的地上部分简单分离得到的。它们的结构是根据光谱证据确定的。Leonurine对凝血酶、花生四烯酸和胶原诱导的兔血小板聚集有明显的抑制作用，IC50分别为97.22 μM、31.03 μM和44.48 μM。
{"title":"Antiplatelet Effect of Leonurine from Leonurus sibiricus","authors":"Hang-Ching Lin, Sheng-Ming Pan, H. Ding, T. Chou, Wen-liang Chang","doi":"10.7019/TPJ.200709.0149","DOIUrl":"https://doi.org/10.7019/TPJ.200709.0149","url":null,"abstract":"Leonurine (1) was simply isolated from the aerial part of Leonurus sibircus var. albiflora. Their structures were established on the basis of spectral evidence. Leonurine showed a significant inhibited rabbit platelet aggregation induced by thrombin, arachidonic acid, and collagen in vitro with an IC50 of 97.22 μM, 31.03 μM, and 44.48 μM, respectively.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"2 1","pages":"149-152"},"PeriodicalIF":0.0,"publicationDate":"2007-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88810502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The in vitro metabolism of etoperidone (Et), an antidepressant drug, was conducted after 30 and 60 min incubations with rat hepatic S9 fraction, and 60 and 90 min incubations with human hepatic S9 fraction, respectively, in the presence of an NADPH-generating system. Unchanged Et (35% of the sample in rat, 46% in human) plus 8 phase I metabolites from the 60 min rat incubation, and 9 phase I metabolites from the 90 min human incubation, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of Et metaboiltes are via the following three metabolic pathways: 1. alkyl oxidation, 2. phenyl oxidation, and 3. oxidative N-dealkylation, Pathways 1 and 2 formed 2 major metabolites [OH-ethyl Et (M1): 18-21% of the sample; OH-Ph Et (M2): 14-32%] and 3 minor metabolites [oxo-ethyl Et (M3): 1-3%; OH-ethyl-OH-Ph Et (M4): 3-5%; oxo-ethyl-OH-Ph Et (M5): 1-3%] in all species, and pathway 3 in conjunction with phenyl oxidation led to the production of 3 minor metabolites, triazole propyl aldehyde (M6), triazole propionic acid (M7) and OH-Ph-MCPP (M9) with each ≤ 1-2% of the sample, and a moderate metabolite, MCPP (M8, 1-8%) in all species. In general, both rat and human appeared to metabolize Et extensively in this hepatic system.
在nadph生成系统存在的情况下，研究抗抑郁药物依哌啶酮(Et)与大鼠肝脏S9组分分别孵育30和60 min，与人肝脏S9组分孵育60和90 min后的体外代谢。在API-MS和MS/MS数据的基础上，对Unchanged Et(大鼠体内35%的样品，人体内46%的样品)加上大鼠孵育60分钟的8个I期代谢物和人孵育90分钟的9个I期代谢物进行了分析、定量和初步鉴定。Et代谢物的形成通过以下三种代谢途径:1。烷基氧化，2。苯基氧化，3。氧化n -脱烷基，途径1和途径2形成2个主要代谢物[OH-ethyl Et (M1)]:占样品的18-21%;OH-Ph Et (M2): 14-32%]和3个次要代谢物[氧乙基Et (M3): 1-3%;oh -乙基- oh - ph Et (M4): 3-5%;途径3与苯基氧化相结合，在所有物种中产生3种次要代谢物，三唑丙醛(M6)、三唑丙酸(M7)和OH-Ph-MCPP (M9)，各≤样品的1-2%，以及一种中等代谢物MCPP (M8, 1-8%)。总的来说，大鼠和人类似乎都在这个肝脏系统中广泛代谢Et。
{"title":"Hepatic in Vitro Metabolism of Etoperidone, an Antidepressant Drug, in the Rat and Human","authors":"W. Wu, L. A. Mckown","doi":"10.7019/CPJ.200702.0031","DOIUrl":"https://doi.org/10.7019/CPJ.200702.0031","url":null,"abstract":"The in vitro metabolism of etoperidone (Et), an antidepressant drug, was conducted after 30 and 60 min incubations with rat hepatic S9 fraction, and 60 and 90 min incubations with human hepatic S9 fraction, respectively, in the presence of an NADPH-generating system. Unchanged Et (35% of the sample in rat, 46% in human) plus 8 phase I metabolites from the 60 min rat incubation, and 9 phase I metabolites from the 90 min human incubation, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of Et metaboiltes are via the following three metabolic pathways: 1. alkyl oxidation, 2. phenyl oxidation, and 3. oxidative N-dealkylation, Pathways 1 and 2 formed 2 major metabolites [OH-ethyl Et (M1): 18-21% of the sample; OH-Ph Et (M2): 14-32%] and 3 minor metabolites [oxo-ethyl Et (M3): 1-3%; OH-ethyl-OH-Ph Et (M4): 3-5%; oxo-ethyl-OH-Ph Et (M5): 1-3%] in all species, and pathway 3 in conjunction with phenyl oxidation led to the production of 3 minor metabolites, triazole propyl aldehyde (M6), triazole propionic acid (M7) and OH-Ph-MCPP (M9) with each ≤ 1-2% of the sample, and a moderate metabolite, MCPP (M8, 1-8%) in all species. In general, both rat and human appeared to metabolize Et extensively in this hepatic system.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"44 26","pages":"31-38"},"PeriodicalIF":0.0,"publicationDate":"2007-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91538969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chien-Ming Huang, Y. Hsieh, Wen‐Hsin Huang, A. Lee
Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of N-(4-substituted phenyl)-2-hydroxynicotinanilides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. Currently, a series of compounds 5-14, which are the chloro variants on phenyl moiety, mainly based on N-(substituted phenyl)-2-hydroxynicotin-anilide 4-14 were further synthesized in high yields. After systematic pharmacological screenings of compounds 4-14 and controls, compound 14 exhibited potent in-vivo anti-inflammatory activity comparable to that of compound 5 and Leflunomide 1, whereas the other compounds have comparable activity to compound 4 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenaninduced paw edema assay, except for compounds 8 and 11.
{"title":"Synthesis of N-(chlorophenyl ) -2 -hydroxynicotinanilides as potential anti-inflammatory agents","authors":"Chien-Ming Huang, Y. Hsieh, Wen‐Hsin Huang, A. Lee","doi":"10.7019/CPJ.200702.0039","DOIUrl":"https://doi.org/10.7019/CPJ.200702.0039","url":null,"abstract":"Leflunomide 1 and its non-enzymically active metabolite, malononitrilamide (MNA, 2) are clinical use for treating rheumatoid arthritis (RA). Study indicated that the active pharmacophore, a β-keto amide with the enolic hydroxyl group, was fully responsible for the immunosuppressive effects of malononitrilamide 2 leading a salicylamide derivative 3 developed. Previously, we have conducted isosterically structural modification mainly based on salicylamide derivative 3, which β-hydroxy-enamide-containing portion remains untouched, to successfully synthesize a series of N-(4-substituted phenyl)-2-hydroxynicotinanilides. After pharmacological screenings, compounds bearing electron-withdrawing groups such as 4-Cl, 4-Br, and 4-NO2 significantly showed potent anti-inflammatory activity. Currently, a series of compounds 5-14, which are the chloro variants on phenyl moiety, mainly based on N-(substituted phenyl)-2-hydroxynicotin-anilide 4-14 were further synthesized in high yields. After systematic pharmacological screenings of compounds 4-14 and controls, compound 14 exhibited potent in-vivo anti-inflammatory activity comparable to that of compound 5 and Leflunomide 1, whereas the other compounds have comparable activity to compound 4 and malononitrilamide 2 by both in vitro suppressing nitric oxide (NO) production under the LPS-elicited macrophage Raw 264.7 cell and the in-vivo carrageenaninduced paw edema assay, except for compounds 8 and 11.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"26 1","pages":"39-45"},"PeriodicalIF":0.0,"publicationDate":"2007-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89573764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li-Ying Huang, Chun-yu Wang, T. Jang, Hseng-Long Yeh
Background and Purpose: Vancomycin and teicoplanin are considered first line medications for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but these agents are also associated with the side-effect of nephrotoxicity. This study investigated the association between treatment with vancomycin monotherapy, teicoplanin monotherapy and combinations of these drugs with aminoglycoside antibiotics, and the occurrence of nephrotoxicity. Methods: Patients treated with vancomycin or teicoplanin, either alone or in combination with an aminoglycoside antibiotic from June to December 2003 were included. Data analyzed included age, gender, renal function (before and after drug administration), days of antibiotics administration, location of infection, other antibiotics used in combination factors affecting renal function. Results: A total of 96 patients, comprising 50 males and 46 females, with a mean age of 67.97±13.43 years were included. Multivariate logistic regression analysis revealed no association between treatment with vancomycin or teicoplanin and gender, chronic renal function impairment, dialysis treatment, diabetes, hypertension, mean age, combination with an aminoglycoside, or treatment in the ICU. Among the 28 courses of vancomycin treatment for which there were adequate serum concentration monitoring data, 16 (57.1%) courses resulted in high trough vancomycin concentration, 8 (28.6%) courses were in the normal range, and 4 (14.3%) courses were low trough concentration. Vancomycin trough serum concentrations were significantly higher in ICU patients (p=0.003). Conclusion: There was no significant difference (p＞0.05) in nephrotoxicity among patients treated with vancomycin or teicoplanin alone or in combination with an aminoglycoside. Vancomycin trough serum concentrations were highest in critically ill patients. Additional serum concentration monitoring in ICU patients was therefore advised after the use of vancomycin, in order to make necessary dosage adjustment. This can avoid unnecessary drug expenditure and reduce the likelihood of side-effects.
{"title":"Nephrotoxicity of Vancomycin and Teicoplanin Alone and in Combination with an Aminoglycoside","authors":"Li-Ying Huang, Chun-yu Wang, T. Jang, Hseng-Long Yeh","doi":"10.7019/CPJ.200702.0001","DOIUrl":"https://doi.org/10.7019/CPJ.200702.0001","url":null,"abstract":"Background and Purpose: Vancomycin and teicoplanin are considered first line medications for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections but these agents are also associated with the side-effect of nephrotoxicity. This study investigated the association between treatment with vancomycin monotherapy, teicoplanin monotherapy and combinations of these drugs with aminoglycoside antibiotics, and the occurrence of nephrotoxicity. Methods: Patients treated with vancomycin or teicoplanin, either alone or in combination with an aminoglycoside antibiotic from June to December 2003 were included. Data analyzed included age, gender, renal function (before and after drug administration), days of antibiotics administration, location of infection, other antibiotics used in combination factors affecting renal function. Results: A total of 96 patients, comprising 50 males and 46 females, with a mean age of 67.97±13.43 years were included. Multivariate logistic regression analysis revealed no association between treatment with vancomycin or teicoplanin and gender, chronic renal function impairment, dialysis treatment, diabetes, hypertension, mean age, combination with an aminoglycoside, or treatment in the ICU. Among the 28 courses of vancomycin treatment for which there were adequate serum concentration monitoring data, 16 (57.1%) courses resulted in high trough vancomycin concentration, 8 (28.6%) courses were in the normal range, and 4 (14.3%) courses were low trough concentration. Vancomycin trough serum concentrations were significantly higher in ICU patients (p=0.003). Conclusion: There was no significant difference (p＞0.05) in nephrotoxicity among patients treated with vancomycin or teicoplanin alone or in combination with an aminoglycoside. Vancomycin trough serum concentrations were highest in critically ill patients. Additional serum concentration monitoring in ICU patients was therefore advised after the use of vancomycin, in order to make necessary dosage adjustment. This can avoid unnecessary drug expenditure and reduce the likelihood of side-effects.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"12 1","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2007-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84820493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oral microencapsulated controlled release preparations of tizanidine hydrochloride (TIZ) were prepared by modified solvent evaporation technique using different proportions of ethyl cellulose as the retardant material. The microcapsules (TIZ1, TIZ2 and TIZ3) were compressed in to tablets (T-TIZ1, T-TIZ2 and T-TIZ3) for oral delivery. The prepared microcapsules were white, free flowing and spherical in shape, with the particle size varying from 215.38 ± 11.52 to 227.36 ± 12.89 μm and shows good drug entrapment efficiency. The 60% of TI2 release from microcapsules were found to be 2.15 ± 0.6, 2.98 ± 0.6 and 4.55 ± 0.8 h respectively for formulation TIZ1, TIZ2 and TIZ3 while their tablets i.e., T-TIZ1, T-TIZ2 and T-TIZ3 releases in 7.49 ± 1.2, 8.69 ± 0.6 and 15.24 ± 0.3 h respectively indicating more extension of time in tablet than microcapsules. The mechanism of drug release from tizanidine hydrochloride microcapsules and their tablets were studied by using Higuchi and Korsmeyer-Peppas models. The r-value for TIZ1, TIZ2 and TIZ3 indicates diffusion controlled with first order kinetic. The value of exponent coefficient (n) for T-TIZ1, T-TIZ2 and T-TIZ3 were found to be 0.874, 0.902 and 0.913 indicating anamolous, case-Ⅱ and case-Ⅱ transport release mechanism respectively.
{"title":"Preparation and In-vitro Characterization of Tizanidine Controlled-Release Microcapsular Matrices","authors":"K. Dashora, S. Saraf, S. Saraf","doi":"10.7019/CPJ.200702.0017","DOIUrl":"https://doi.org/10.7019/CPJ.200702.0017","url":null,"abstract":"Oral microencapsulated controlled release preparations of tizanidine hydrochloride (TIZ) were prepared by modified solvent evaporation technique using different proportions of ethyl cellulose as the retardant material. The microcapsules (TIZ1, TIZ2 and TIZ3) were compressed in to tablets (T-TIZ1, T-TIZ2 and T-TIZ3) for oral delivery. The prepared microcapsules were white, free flowing and spherical in shape, with the particle size varying from 215.38 ± 11.52 to 227.36 ± 12.89 μm and shows good drug entrapment efficiency. The 60% of TI2 release from microcapsules were found to be 2.15 ± 0.6, 2.98 ± 0.6 and 4.55 ± 0.8 h respectively for formulation TIZ1, TIZ2 and TIZ3 while their tablets i.e., T-TIZ1, T-TIZ2 and T-TIZ3 releases in 7.49 ± 1.2, 8.69 ± 0.6 and 15.24 ± 0.3 h respectively indicating more extension of time in tablet than microcapsules. The mechanism of drug release from tizanidine hydrochloride microcapsules and their tablets were studied by using Higuchi and Korsmeyer-Peppas models. The r-value for TIZ1, TIZ2 and TIZ3 indicates diffusion controlled with first order kinetic. The value of exponent coefficient (n) for T-TIZ1, T-TIZ2 and T-TIZ3 were found to be 0.874, 0.902 and 0.913 indicating anamolous, case-Ⅱ and case-Ⅱ transport release mechanism respectively.","PeriodicalId":22409,"journal":{"name":"The Chinese Pharmaceutical Journal","volume":"14 1","pages":"17-24"},"PeriodicalIF":0.0,"publicationDate":"2007-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76193534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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