Pub Date : 2011-09-15DOI: 10.1002/9780470034590.EMRSTM1193
I. Wilson
The linking of NMR spectroscopy on-line with a separation technique, such as high performance liquid chromatography (HPLC or LC), provides many advantages for the structural characterization of unknowns present in mixtures. In particular, the use of this on-line technology can remove the need for the isolation of the analyte in a pure form, thus improving both speed and efficiency. Technical advances such as the implementation of capillary techniques, cryoflow probes, and on-line sample concentration via solid phase extraction have all contributed to increasing the sensitivity of LC-NMR, thereby making the technique increasingly useful in a range of application areas including pharmaceutical and environmental analysis, natural products research, and studies on drug and xenobiotic metabolism. The combination with on-line mass spectrometry (MS) to provide LC-NMR-MS systems enables even more information to be recovered from samples. Here, the methods employed in LC-NMR, and LC-NMR-MS, for the analysis of chromatographic eluents are described and illustrated with representative applications. Keywords: liquid chromatography; hyphenation; NMR spectroscopy; drug metabolites; natural products
{"title":"HPLC‐NMR Spectroscopy","authors":"I. Wilson","doi":"10.1002/9780470034590.EMRSTM1193","DOIUrl":"https://doi.org/10.1002/9780470034590.EMRSTM1193","url":null,"abstract":"The linking of NMR spectroscopy on-line with a separation technique, such as high performance liquid chromatography (HPLC or LC), provides many advantages for the structural characterization of unknowns present in mixtures. In particular, the use of this on-line technology can remove the need for the isolation of the analyte in a pure form, thus improving both speed and efficiency. Technical advances such as the implementation of capillary techniques, cryoflow probes, and on-line sample concentration via solid phase extraction have all contributed to increasing the sensitivity of LC-NMR, thereby making the technique increasingly useful in a range of application areas including pharmaceutical and environmental analysis, natural products research, and studies on drug and xenobiotic metabolism. The combination with on-line mass spectrometry (MS) to provide LC-NMR-MS systems enables even more information to be recovered from samples. Here, the methods employed in LC-NMR, and LC-NMR-MS, for the analysis of chromatographic eluents are described and illustrated with representative applications. \u0000 \u0000 \u0000Keywords: \u0000 \u0000liquid chromatography; \u0000hyphenation; \u0000NMR spectroscopy; \u0000drug metabolites; \u0000natural products","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86061189","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}
Pub Date : 2011-03-11DOI: 10.1111/J.2042-7158.1995.TB00381.X
B. Forbes, Clive G. Wilson, M. Gumbleton
Peptidases in the lung are well placed to have an important role in regulating levels of circulating endogenous and therapeutic peptides. They also present a first-pass metabolic barrier for peptides delivered to the lung for systemic absorption. The activities of five peptidases were surveyed in the pulmonary circulation of the asanguinous isolated perfused rat lung (IPRL) using synthetic substrates and selective inhibitors. Extraction ratios (ER) were calculated for the substrates of: aminopeptidase N (AMN), ER 0·37 ± 0·04; dipeptidyl peptidase IV (DPP), ER 0·69 ± 0·05; and angiotensin-converting enzyme (ACE), ER 0·40 ± 0·02. These activities were inhibited (> 95%) by the selective inhibitors bestatin, diprotin A, and captopril, respectively. Substrates for neutral endopeptidase 24.11 (NEP) and carboxypeptidase M (CPM) were minimally degraded with ER of 0·02 and 0·00, respectively. The low activity of NEP, a major membrane bound endopeptidase, indicates that the lungs may not contribute greatly to degradation of either systemic NEP substrates, or exopeptidase-resistant peptides absorbed from the peripheral lung. In contrast peptides susceptible to the exopeptidases AMN, DPP, and ACE, will be substantially degraded during passage through the lung. The absence of CPM activity in the pulmonary circulation of the asanguinous IPRL implies that basic carboxypeptidase activity in blood perfused lungs reported in the literature is more likely to be the result of plasma carboxypeptidase N activity.
肺中的肽酶在调节循环内源性和治疗性肽水平方面发挥着重要作用。它们也为输送到肺部供全身吸收的肽提供了第一道代谢屏障。采用合成底物和选择性抑制剂，研究了五种肽酶在大鼠血管离体灌注肺(IPRL)肺循环中的活性。计算底物的提取比(ER):氨基肽酶N (AMN)， ER为0·37±0·04;二肽基肽酶IV (DPP)， ER 0·69±0·05;血管紧张素转换酶(ACE) ER 0.40±0.02。这些活性分别被选择性抑制剂贝司他汀、双蛋白A和卡托普利抑制(> 95%)。中性内肽酶24.11 (NEP)和羧基肽酶M (CPM)底物分别在0·02和0·00的ER条件下被最低限度地降解。NEP是一种主要的膜结合内肽酶，其活性较低，表明肺部可能对全身NEP底物或外周肺吸收的外肽酶抗性肽的降解贡献不大。相反，易受外肽酶AMN、DPP和ACE影响的肽在通过肺部时将被大量降解。无痛性IPRL肺循环中CPM活性的缺失表明，文献报道的血灌注肺中碱性羧肽酶活性更可能是血浆羧肽酶N活性的结果。
{"title":"Extraction of Peptidase Substrates by the Isolated Perfused Rat Lung","authors":"B. Forbes, Clive G. Wilson, M. Gumbleton","doi":"10.1111/J.2042-7158.1995.TB00381.X","DOIUrl":"https://doi.org/10.1111/J.2042-7158.1995.TB00381.X","url":null,"abstract":"Peptidases in the lung are well placed to have an important role in regulating levels of circulating endogenous and therapeutic peptides. They also present a first-pass metabolic barrier for peptides delivered to the lung for systemic absorption. The activities of five peptidases were surveyed in the pulmonary circulation of the asanguinous isolated perfused rat lung (IPRL) using synthetic substrates and selective inhibitors. \u0000 \u0000 \u0000 \u0000Extraction ratios (ER) were calculated for the substrates of: aminopeptidase N (AMN), ER 0·37 ± 0·04; dipeptidyl peptidase IV (DPP), ER 0·69 ± 0·05; and angiotensin-converting enzyme (ACE), ER 0·40 ± 0·02. These activities were inhibited (> 95%) by the selective inhibitors bestatin, diprotin A, and captopril, respectively. Substrates for neutral endopeptidase 24.11 (NEP) and carboxypeptidase M (CPM) were minimally degraded with ER of 0·02 and 0·00, respectively. \u0000 \u0000 \u0000 \u0000The low activity of NEP, a major membrane bound endopeptidase, indicates that the lungs may not contribute greatly to degradation of either systemic NEP substrates, or exopeptidase-resistant peptides absorbed from the peripheral lung. In contrast peptides susceptible to the exopeptidases AMN, DPP, and ACE, will be substantially degraded during passage through the lung. The absence of CPM activity in the pulmonary circulation of the asanguinous IPRL implies that basic carboxypeptidase activity in blood perfused lungs reported in the literature is more likely to be the result of plasma carboxypeptidase N activity.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81726357","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735566
R. K. Bhardwaj, T. Velpandian, K. Kamal, S. Gupta
Liposomes interact with the stratum corneum and may be responsible for enhanced transdermal drug penetration. This study was carried out to compare the effect of liposomes on the permeation of diclofenac sodium with the conventionally available non-liposomal diclofenac gel. Preliminary in-vitro studies using fluorescein sodium as a marker showed 1.5- and 1.35- fold increased flux for small unilamellar vesicle and multilamillar vesicle liposome formulations, respectively, compared with non-liposomal fluorescein sodium. This was followed by diclofenac formulations, Lipogel-a (1% w/w diclofenac sodium), Lipogel-b (1.16% w/w diclofenac diethylammonium equiv. 1% w/w diclofenac sodium) and commercially available diclofenac gel. The Lipogel-a and Lipogel-b showed 2- and 1.5-times greater flux compared with conventional non-liposomal diclofenac gel. The pharmaco-kinetic profile in mice was studied as an experimental animal model and the drug concentration in blood was measured at various time points. Lipogel-a, Lipogel-b and conventional diclofenac gel were also compared for their anti-inflammatory activity using carrageenan and Freund's adjuvant models of inflammation. The significant pharmacokinetic profile and enhanced efficacy in pharmacodynamic parameters suggest that liposomes are responsible for enhanced drug penetration. Liposomes enhance drug penetration across the epidermis and thus could be used as alternative carriers to organic and inorganic penetration enhancers.
{"title":"Effect of Liposomes on Permeation of Diclofenac Through Cadaver Skin: In‐vivo Evaluation Using Animal Models","authors":"R. K. Bhardwaj, T. Velpandian, K. Kamal, S. Gupta","doi":"10.1211/146080800128735566","DOIUrl":"https://doi.org/10.1211/146080800128735566","url":null,"abstract":"Liposomes interact with the stratum corneum and may be responsible for enhanced transdermal drug penetration. This study was carried out to compare the effect of liposomes on the permeation of diclofenac sodium with the conventionally available non-liposomal diclofenac gel. \u0000 \u0000Preliminary in-vitro studies using fluorescein sodium as a marker showed 1.5- and 1.35- fold increased flux for small unilamellar vesicle and multilamillar vesicle liposome formulations, respectively, compared with non-liposomal fluorescein sodium. This was followed by diclofenac formulations, Lipogel-a (1% w/w diclofenac sodium), Lipogel-b (1.16% w/w diclofenac diethylammonium equiv. 1% w/w diclofenac sodium) and commercially available diclofenac gel. The Lipogel-a and Lipogel-b showed 2- and 1.5-times greater flux compared with conventional non-liposomal diclofenac gel. The pharmaco-kinetic profile in mice was studied as an experimental animal model and the drug concentration in blood was measured at various time points. Lipogel-a, Lipogel-b and conventional diclofenac gel were also compared for their anti-inflammatory activity using carrageenan and Freund's adjuvant models of inflammation. The significant pharmacokinetic profile and enhanced efficacy in pharmacodynamic parameters suggest that liposomes are responsible for enhanced drug penetration. \u0000 \u0000Liposomes enhance drug penetration across the epidermis and thus could be used as alternative carriers to organic and inorganic penetration enhancers.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72660184","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735610
A. Veeranjaneyulu, N. Sridhar, R. J. Babu, C. Gupta, R. Malavika, S. Shobana
The aim of the study was to evaluate the role of 5-HT3 receptor ligands in animal models of gastric hypermotility and visceral hyperalgesia, symptoms associated with irritable bowel syndrome. The abrupt termination of sub-chronic morphine (in doses of 35, 70, 140 mg kg−1, i.p.) for four days by naloxone (43 mg kg−1 i.p., 3 h after the last morphine injection) results in withdrawal symptoms, of which diarrhoea and jumping behaviour are common in mice. The gastric hypermotility induced by morphine withdrawal is used as an animal model to evaluate 5-HT3 ligands. Acetic acid-induced abdominal constriction in mice serves as a model for visceral hyperalgesia. m-Chlorophenylbiguanide (mCPBG; 2 and 5 mg kg−1, i.p.) and ondansetron (3 and 6 mg kg−1, i.p.), 5-HT3 agonist and antagonist respectively, were used for the study. Ondansetron exhibited a dose-dependent inhibition of diarrhoea and significantly decreased the number of jumps. It also attenuated the abdominal constriction response induced by acetic acid in mice in a dose-dependent manner. mCPBG did not significantly alter diarrhoea or acetic acid-induced abdominal constriction. However mCPBG (5 mg kg−1, i.p) caused a significant increase in number of jumps. The results suggest that 5-HT3 receptor modulators can be used for the treatment of GI dysmotility and associated nociception, and the above models can be used to evaluate 5-HT3 ligands, especially antagonists, in treatment of irritable bowel syndrome.
本研究的目的是评估5-HT3受体配体在胃运动亢进和内脏痛觉过敏(肠易激综合征相关症状)动物模型中的作用。亚慢性吗啡(剂量分别为35、70、140 mg kg - 1, i.p)连续4天突然停用纳洛酮(43 mg kg - 1, i.p，最后一次吗啡注射后3小时)会导致戒断症状，其中腹泻和跳跃行为在小鼠中很常见。以吗啡戒断所致胃运动亢进为动物模型，对5-HT3配体进行评价。醋酸致小鼠腹部收缩可作为内脏痛觉过敏的模型。m-Chlorophenylbiguanide (mCPBG;研究中分别使用5- ht3激动剂和拮抗剂昂丹司琼(3和6 mg kg - 1, i.p)和2和5mg kg - 1。昂丹司琼表现出剂量依赖性的腹泻抑制作用，并显著减少跳跃次数。它还能以剂量依赖的方式减弱醋酸引起的小鼠腹部收缩反应。mCPBG没有显著改变腹泻或醋酸引起的腹部收缩。然而，mCPBG (5mg kg - 1, i.p)导致跳跃数量显著增加。结果提示，5-HT3受体调节剂可用于治疗胃肠道运动障碍及相关伤害感受，上述模型可用于评价5-HT3配体，特别是拮抗剂治疗肠易激综合征的作用。
{"title":"Morphine Withdrawal‐induced Diarrhoea and Acetic Acid‐induced Abdominal Constriction: Animal Models for the Evaluation of 5‐HT3 Ligands in the Treatment of Irritable Bowel Syndrome","authors":"A. Veeranjaneyulu, N. Sridhar, R. J. Babu, C. Gupta, R. Malavika, S. Shobana","doi":"10.1211/146080800128735610","DOIUrl":"https://doi.org/10.1211/146080800128735610","url":null,"abstract":"The aim of the study was to evaluate the role of 5-HT3 receptor ligands in animal models of gastric hypermotility and visceral hyperalgesia, symptoms associated with irritable bowel syndrome. \u0000 \u0000 \u0000 \u0000The abrupt termination of sub-chronic morphine (in doses of 35, 70, 140 mg kg−1, i.p.) for four days by naloxone (43 mg kg−1 i.p., 3 h after the last morphine injection) results in withdrawal symptoms, of which diarrhoea and jumping behaviour are common in mice. The gastric hypermotility induced by morphine withdrawal is used as an animal model to evaluate 5-HT3 ligands. Acetic acid-induced abdominal constriction in mice serves as a model for visceral hyperalgesia. m-Chlorophenylbiguanide (mCPBG; 2 and 5 mg kg−1, i.p.) and ondansetron (3 and 6 mg kg−1, i.p.), 5-HT3 agonist and antagonist respectively, were used for the study. Ondansetron exhibited a dose-dependent inhibition of diarrhoea and significantly decreased the number of jumps. It also attenuated the abdominal constriction response induced by acetic acid in mice in a dose-dependent manner. mCPBG did not significantly alter diarrhoea or acetic acid-induced abdominal constriction. However mCPBG (5 mg kg−1, i.p) caused a significant increase in number of jumps. \u0000 \u0000 \u0000 \u0000The results suggest that 5-HT3 receptor modulators can be used for the treatment of GI dysmotility and associated nociception, and the above models can be used to evaluate 5-HT3 ligands, especially antagonists, in treatment of irritable bowel syndrome.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82227116","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735629
S. Panda, A. Kar
The aim of this study was to determine the role of Rauwolfia serpentina root extract in the regulation of hyperthyroidism in mice. In L-thyroxine (50 μg/100 g for 30 days)-treated mice, an increase in serum concentrations of both thyroid hormones (thyroxine and triiodothyronine) and in hepatic glucose-6-phosphatase activity was observed. Daily administration of the plant extract (2.5 mg kg−1) either alone or with thyroxine for 30 days decreased concentrations of both thyroid hormones, indicating the possible regulation of hyperthyroidism by the plant extract. The plant extract also decreased hepatic lipid peroxidation and increased super-oxide dismutase and catalase activity in hyperthyroid mice without hepatotoxic effects. R. serpentina root extract might be a potentially effective treatment for hyperthyroidism.
{"title":"Regulation of Hyperthyroidism by Rauwolfia serpentina Root Extract in Mice","authors":"S. Panda, A. Kar","doi":"10.1211/146080800128735629","DOIUrl":"https://doi.org/10.1211/146080800128735629","url":null,"abstract":"The aim of this study was to determine the role of Rauwolfia serpentina root extract in the regulation of hyperthyroidism in mice. \u0000 \u0000 \u0000 \u0000In L-thyroxine (50 μg/100 g for 30 days)-treated mice, an increase in serum concentrations of both thyroid hormones (thyroxine and triiodothyronine) and in hepatic glucose-6-phosphatase activity was observed. Daily administration of the plant extract (2.5 mg kg−1) either alone or with thyroxine for 30 days decreased concentrations of both thyroid hormones, indicating the possible regulation of hyperthyroidism by the plant extract. The plant extract also decreased hepatic lipid peroxidation and increased super-oxide dismutase and catalase activity in hyperthyroid mice without hepatotoxic effects. \u0000 \u0000 \u0000 \u0000R. serpentina root extract might be a potentially effective treatment for hyperthyroidism.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75204260","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735584
H. Itoh, T. Nagano, Tetsuji Hayashi, M. Takeyama
The effect of the histamine H2 receptor antagonist, ranitidine, on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism, in five volunteers. Acetaminophen (1000 mg) together with ranitidine (300 mg), placebo or at 1 h after ranitidine (300 mg) was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. Plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were determined by HPLC. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves from each volunteer. The area under the plasma acetaminophen concentration-time curve from 0 to 3 h (AUC0–3) significantly (P < 0.01) increased from 13.03 ± 0.84 μg h mL−1 (placebo coadministration) to 21.30 ± 0.60 μg h mL−1 (ranitidine coadministration). The peak plasma acetaminophen concentration significantly (P < 0.01) increased from 18.30 ± 2.26 μg mL−1 (placebo coadministration) to 34.14 ± 1.07 μg mL−1 (ranitidine coadministration) 30 min after administration. Plasma acetaminophen concentrations with ranitidine were significantly increased at 15 to 120 min compared with placebo. Plasma acetaminophen glucuronide conjugate concentrations with ranitidine were significantly decreased at 15 to 45 min compared with placebo, whereas plasma acetaminophen sulphate conjugate concentrations were not significantly altered. Plasma acetaminophen and acetaminophen conjugate concentrations were not significantly different between placebo-coadministration and in the case where acetaminophen was orally administered 1 h after ranitidine. Coadministration of acetaminophen and ranitidine reduced plasma acetaminophen glucuronide concentrations and significantly increased plasma acetaminophen concentrations. The effects of ranitidine are as a result of the prevention of first-pass hepatic metabolism, by prevention of acetaminophen glucuronyltransferase. Thus care must be taken when acetaminophen and ranitidine are coadministered.
在5名志愿者中，研究了组胺H2受体拮抗剂雷尼替丁对对乙酰氨基酚血浆浓度的影响。对乙酰氨基酚(1000毫克)与雷尼替丁(300毫克)、安慰剂或在雷尼替丁(300毫克)后1小时口服给5名健康男性志愿者。给药前后分别取静脉血。用高效液相色谱法测定血浆中对乙酰氨基酚和对乙酰氨基酚偶联物(葡萄糖醛酸盐和硫酸盐)的含量。根据每位志愿者的血浆对乙酰氨基酚浓度-时间曲线计算药代动力学参数。0 ~ 3 h血浆对乙酰氨基酚浓度-时间曲线下面积(AUC0-3)由安慰剂组(13.03±0.84 μg h mL−1)显著增加至雷尼替丁组(21.30±0.60 μg h mL−1)(P < 0.01)。给药后30min对乙酰氨基酚峰浓度由安慰剂组18.30±2.26 μg mL−1升高至雷尼替丁组34.14±1.07 μg mL−1，差异有统计学意义(P < 0.01)。与安慰剂组相比，雷尼替丁组在15 ~ 120分钟时血浆对乙酰氨基酚浓度显著升高。与安慰剂相比，血浆对乙酰氨基酚葡萄糖醛酸盐与雷尼替丁结合的浓度在15至45分钟显著降低，而血浆对乙酰氨基酚硫酸盐结合的浓度没有显著改变。对乙酰氨基酚和对乙酰氨基酚偶联物的血浆浓度在安慰剂联合给药和在雷尼替丁后1小时口服对乙酰氨基酚的情况下没有显著差异。对乙酰氨基酚和雷尼替丁联合用药可降低血浆对乙酰氨基酚葡萄糖醛酸盐浓度，并显著增加血浆对乙酰氨基酚浓度。雷尼替丁的作用是通过预防对乙酰氨基酚葡萄糖醛酸转移酶来预防首过肝脏代谢。因此，当对乙酰氨基酚和雷尼替丁同时使用时，必须小心。
{"title":"Ranitidine Increases Bioavailability of Acetaminophen by Inhibiting First‐Pass Glucuronidation in Man","authors":"H. Itoh, T. Nagano, Tetsuji Hayashi, M. Takeyama","doi":"10.1211/146080800128735584","DOIUrl":"https://doi.org/10.1211/146080800128735584","url":null,"abstract":"The effect of the histamine H2 receptor antagonist, ranitidine, on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism, in five volunteers. Acetaminophen (1000 mg) together with ranitidine (300 mg), placebo or at 1 h after ranitidine (300 mg) was orally administered to five healthy male volunteers. Venous blood samples were taken before and after drug administration. Plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were determined by HPLC. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves from each volunteer. The area under the plasma acetaminophen concentration-time curve from 0 to 3 h (AUC0–3) significantly (P < 0.01) increased from 13.03 ± 0.84 μg h mL−1 (placebo coadministration) to 21.30 ± 0.60 μg h mL−1 (ranitidine coadministration). The peak plasma acetaminophen concentration significantly (P < 0.01) increased from 18.30 ± 2.26 μg mL−1 (placebo coadministration) to 34.14 ± 1.07 μg mL−1 (ranitidine coadministration) 30 min after administration. Plasma acetaminophen concentrations with ranitidine were significantly increased at 15 to 120 min compared with placebo. Plasma acetaminophen glucuronide conjugate concentrations with ranitidine were significantly decreased at 15 to 45 min compared with placebo, whereas plasma acetaminophen sulphate conjugate concentrations were not significantly altered. Plasma acetaminophen and acetaminophen conjugate concentrations were not significantly different between placebo-coadministration and in the case where acetaminophen was orally administered 1 h after ranitidine. \u0000 \u0000 \u0000 \u0000Coadministration of acetaminophen and ranitidine reduced plasma acetaminophen glucuronide concentrations and significantly increased plasma acetaminophen concentrations. The effects of ranitidine are as a result of the prevention of first-pass hepatic metabolism, by prevention of acetaminophen glucuronyltransferase. Thus care must be taken when acetaminophen and ranitidine are coadministered.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90699757","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735601
M. Schlitzer, I. Sattler
We recently described non-peptidic, non-prenylic bisubstrate analogues as novel farnesyl-transferase inhibitors comprising three modules-a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. In this study, we replaced the originally used β-alanyl linker with aminomalonic, aspartic and glutamic acid, respectively, to introduce a second functional group capable of complexing the essential zinc ion, located in the active site of farnesyltransferase. Apart from aminomalonic acid, all moieties showed reduced inhibitory activity. Interestingly, the benzyl esters of the aspartic and glutamic acid derivatives were more active than the free acids. The results provide further evidence for an additional lipophilic binding cleft in the active site of farnesyltransferase.
{"title":"Non‐Peptidic, Non‐Prenylic Bisubstrate Farnesyltransferase Inhibitors. Effect of a Carboxyl Group at the Central Group on Farnesyltransferase Inhibitory Activity","authors":"M. Schlitzer, I. Sattler","doi":"10.1211/146080800128735601","DOIUrl":"https://doi.org/10.1211/146080800128735601","url":null,"abstract":"We recently described non-peptidic, non-prenylic bisubstrate analogues as novel farnesyl-transferase inhibitors comprising three modules-a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. In this study, we replaced the originally used β-alanyl linker with aminomalonic, aspartic and glutamic acid, respectively, to introduce a second functional group capable of complexing the essential zinc ion, located in the active site of farnesyltransferase. \u0000 \u0000 \u0000 \u0000Apart from aminomalonic acid, all moieties showed reduced inhibitory activity. Interestingly, the benzyl esters of the aspartic and glutamic acid derivatives were more active than the free acids. \u0000 \u0000 \u0000 \u0000The results provide further evidence for an additional lipophilic binding cleft in the active site of farnesyltransferase.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89503708","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735575
Saranjit Singh, T. Mariappan, N. Sharda, Baljinder Singh
This study was carried out to determine the extent of degradation of rifampicin, isoniazid and pyrazinamide from prepared mixtures and marketed preparations containing single, two, three and four drugs, under stomach conditions. Degradation studies were carried out in 0.1 M HC1 at 37°C for 50 min. A comparative study in simulated gastric fluid was also done. Under both conditions, rifampicin was decomposed by 17.8–24.4%, isoniazid to a lesser extent (3.2–4.7%), and pyrazinamide was stable. The decomposition of rifampicin was influenced by the presence of isoniazid but not by pyrazinamide or ethambutol. Compared with pure drugs and mixtures, wide variations in the decomposition of rifampicin (7.5–33.3%) and isoniazid (1.4–5.3%) were found in the marketed fixed-dose combinations, indicating the influence of formulation and storage conditions. The results suggest that the poor bioavailability of rifampicin might be in part due to the decomposition of the drug in the stomach. The recent WHO protocol suggests the comparison of the test fixed-dose combination preparations against a combination of separate formulations of two, three or four drugs. However, it may be more meaningful to carry out bioequivalence studies on fixed-dose combination formulations by comparing the test fixed-dose combination preparations with the standard formulations of individual drugs.
{"title":"Degradation of Rifampicin, Isoniazid and Pyrazinamide from Prepared Mixtures and Marketed Single and Combination Products Under Acid Conditions","authors":"Saranjit Singh, T. Mariappan, N. Sharda, Baljinder Singh","doi":"10.1211/146080800128735575","DOIUrl":"https://doi.org/10.1211/146080800128735575","url":null,"abstract":"This study was carried out to determine the extent of degradation of rifampicin, isoniazid and pyrazinamide from prepared mixtures and marketed preparations containing single, two, three and four drugs, under stomach conditions. \u0000 \u0000Degradation studies were carried out in 0.1 M HC1 at 37°C for 50 min. A comparative study in simulated gastric fluid was also done. Under both conditions, rifampicin was decomposed by 17.8–24.4%, isoniazid to a lesser extent (3.2–4.7%), and pyrazinamide was stable. The decomposition of rifampicin was influenced by the presence of isoniazid but not by pyrazinamide or ethambutol. Compared with pure drugs and mixtures, wide variations in the decomposition of rifampicin (7.5–33.3%) and isoniazid (1.4–5.3%) were found in the marketed fixed-dose combinations, indicating the influence of formulation and storage conditions. \u0000 \u0000The results suggest that the poor bioavailability of rifampicin might be in part due to the decomposition of the drug in the stomach. The recent WHO protocol suggests the comparison of the test fixed-dose combination preparations against a combination of separate formulations of two, three or four drugs. However, it may be more meaningful to carry out bioequivalence studies on fixed-dose combination formulations by comparing the test fixed-dose combination preparations with the standard formulations of individual drugs.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82264863","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735593
N. Shibata, A. Kitamura, Y. Yoshikawa, T. Inoue, T. Bamba, K. Takada
In this study, we developed a simultaneous determination of the antiviral drugs, aciclovir and ganciclovir, in patient and rat plasma. We also confirmed any potent pharmacokinetic interactions between these two drugs. Precipitation and extraction of aciclovir, ganciclovir, and an internal standard (5-fluoro-2′-deoxyuridine) was achieved by adding 12.5% trichloroacetic acid solution. Separation of the three compounds was performed by a reversed-phase liquid chromatography, and the peaks of compounds were detected spectrophotometerically at 280 nm. The working curves by a least-squares linear regression over the range 0.1–10 μg ML−1 passed through the origin with a correlation coefficient of 0.999 or better, and the results of within-day and between-day precisions were adequate for clinical use. The therapeutic windows of aciclovir and ganciclovir (from the lower to the upper quartile), estimated by measuring clinical plasma samples, were from 0.40 to 0.63 μg mL−1 and from 0.29 to 0.51 μg mL−1, respectively. The trough plasma concentrations of ganciclovir from patients with bone marrow transplants increased significantly when aciclovir was co-administered, and the area under the concentration-time curve of ganciclovir and aciclovir after intravenous coadministration of these drugs in rats showed approximately 2.4- and 1.5-fold increase, respectively, suggesting the existence of some drug interaction between aciclovir and ganciclovir. The HPLC assay method developed here could be used for the rapid pharmacokinetic study in rats and the clinical monitoring of the concentrations of aciclovir and ganciclovir in human plasma with a minimum sample volume of 100 μL.
在这项研究中，我们开发了同时测定患者和大鼠血浆中抗病毒药物阿昔洛韦和更昔洛韦的方法。我们还证实了这两种药物之间存在有效的药代动力学相互作用。采用12.5%三氯乙酸溶液沉淀提取阿昔洛韦、更昔洛韦和内标(5-氟-2′-脱氧尿苷)。采用反相液相色谱法对3种化合物进行分离，并在280 nm处进行分光光度检测。在0.1 ~ 10 μ ML−1范围内，经最小二乘线性回归的工作曲线通过原点，相关系数在0.999以上，日内、日间精密度均可满足临床使用。通过测量临床血浆样本，估计阿昔洛韦和更昔洛韦的治疗窗口(从下到上四分位数)分别为0.40至0.63 μ mL - 1和0.29至0.51 μ mL - 1。与阿昔洛韦联合给药时，骨髓移植患者更昔洛韦的血药谷浓度显著升高，大鼠静脉联合给药后更昔洛韦与阿昔洛韦的浓度-时间曲线下面积分别增加约2.4倍和1.5倍，提示阿昔洛韦与更昔洛韦存在一定的药物相互作用。该方法可用于大鼠体内快速药代动力学研究和临床监测阿昔洛韦和更昔洛韦在人血浆中的浓度，最小样本量为100 μL。
{"title":"Simultaneous Determination of Aciclovir and Ganciclovir in Plasma by HPLC and Pharmacokinetic Interactions","authors":"N. Shibata, A. Kitamura, Y. Yoshikawa, T. Inoue, T. Bamba, K. Takada","doi":"10.1211/146080800128735593","DOIUrl":"https://doi.org/10.1211/146080800128735593","url":null,"abstract":"In this study, we developed a simultaneous determination of the antiviral drugs, aciclovir and ganciclovir, in patient and rat plasma. We also confirmed any potent pharmacokinetic interactions between these two drugs. \u0000 \u0000 \u0000 \u0000Precipitation and extraction of aciclovir, ganciclovir, and an internal standard (5-fluoro-2′-deoxyuridine) was achieved by adding 12.5% trichloroacetic acid solution. Separation of the three compounds was performed by a reversed-phase liquid chromatography, and the peaks of compounds were detected spectrophotometerically at 280 nm. The working curves by a least-squares linear regression over the range 0.1–10 μg ML−1 passed through the origin with a correlation coefficient of 0.999 or better, and the results of within-day and between-day precisions were adequate for clinical use. The therapeutic windows of aciclovir and ganciclovir (from the lower to the upper quartile), estimated by measuring clinical plasma samples, were from 0.40 to 0.63 μg mL−1 and from 0.29 to 0.51 μg mL−1, respectively. The trough plasma concentrations of ganciclovir from patients with bone marrow transplants increased significantly when aciclovir was co-administered, and the area under the concentration-time curve of ganciclovir and aciclovir after intravenous coadministration of these drugs in rats showed approximately 2.4- and 1.5-fold increase, respectively, suggesting the existence of some drug interaction between aciclovir and ganciclovir. \u0000 \u0000 \u0000 \u0000The HPLC assay method developed here could be used for the rapid pharmacokinetic study in rats and the clinical monitoring of the concentrations of aciclovir and ganciclovir in human plasma with a minimum sample volume of 100 μL.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80583582","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}
Pub Date : 2000-11-01DOI: 10.1211/146080800128735557
G. Rao, R. Murthy
Hydroxypropyl methylcellulose (HPMC) K4M gels containing free flucinolone acetonide, liposomal-encapsulated flucinolone acetonide and physical mixture of the drug and lipids were prepared and evaluated in in-vitro drug release studies using rat skin to determine diffusion parameters. Data were analysed to calculate the quantity of the drug remaining in the skin (Qm) and in the blood (Csf) and the ratio of Qm to Csf. The in-vivo skin blanching assay performed with these formulations in human volunteers showed low blanching scores for liposomal gel formulations indicating low absorption of the liposomal-encapsulated drug into the blood stream and leading to the accumulation of the drug in the skin. This result is in agreement with the high Qm/Csf ratios obtained in the in-vitro experiments. Of all the formulations, gels containing liposomal-encapsulated flucinolone acetonide, prepared with drug, phosphatidyl choline and cholesterol in the ratio of 4:8:1, had the highest Qm/Csf ratio and minimum blanching score. The results indicate the potential of topical preparations containing liposomal-encapsulated drugs for selective accumulation of the drug in the skin.
{"title":"Preparation and Evaluation of Liposomal Flucinolone Acetonide Gel for Intradermal Delivery","authors":"G. Rao, R. Murthy","doi":"10.1211/146080800128735557","DOIUrl":"https://doi.org/10.1211/146080800128735557","url":null,"abstract":"Hydroxypropyl methylcellulose (HPMC) K4M gels containing free flucinolone acetonide, liposomal-encapsulated flucinolone acetonide and physical mixture of the drug and lipids were prepared and evaluated in in-vitro drug release studies using rat skin to determine diffusion parameters. \u0000 \u0000Data were analysed to calculate the quantity of the drug remaining in the skin (Qm) and in the blood (Csf) and the ratio of Qm to Csf. The in-vivo skin blanching assay performed with these formulations in human volunteers showed low blanching scores for liposomal gel formulations indicating low absorption of the liposomal-encapsulated drug into the blood stream and leading to the accumulation of the drug in the skin. This result is in agreement with the high Qm/Csf ratios obtained in the in-vitro experiments. \u0000 \u0000Of all the formulations, gels containing liposomal-encapsulated flucinolone acetonide, prepared with drug, phosphatidyl choline and cholesterol in the ratio of 4:8:1, had the highest Qm/Csf ratio and minimum blanching score. The results indicate the potential of topical preparations containing liposomal-encapsulated drugs for selective accumulation of the drug in the skin.","PeriodicalId":19946,"journal":{"name":"Pharmacy and Pharmacology Communications","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2000-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75327684","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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