The search for drugs of use in the treatment of age-associated memory impairment, multi-infarct dementia, and Alzheimer's disease is frustrated by the expense or inadequacy of animal models of these conditions. We hope that this critical review of existing models will stimulate the use and proper interpretation of the best of these models, and encourage thinking in devising new models.
{"title":"The validity of animal models in the search for drugs for the aging brain.","authors":"G Pepeu, I M Pepeu, F Casamenti","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The search for drugs of use in the treatment of age-associated memory impairment, multi-infarct dementia, and Alzheimer's disease is frustrated by the expense or inadequacy of animal models of these conditions. We hope that this critical review of existing models will stimulate the use and proper interpretation of the best of these models, and encourage thinking in devising new models.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"7 1","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"1990-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13251827","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}
Following previous studies in rats, the ability of two chemical delivery systems (CDSs) to deliver benzyl penicillin (1) to the central nervous system of rabbits and dogs was investigated. One of the systems (3) was a diester of methylene diol, and the other (5) a diester of ethylene 1,2-diol; in both, one hydroxyl group of the diol was esterified by the 3-carboxylic acid group of benzylpenicillin, and the other by the carboxy group of an N-methyldihydropyridine (dihydrotrigonelline). The basis of the system is the ability of the dihydropyridine components to undergo oxidation to quaternary pyridinium salts (2 from 3, and 4 from 5). In vitro relative stability studies were first performed in 10% rabbit brain homogenate, rabbit CSF and dog CSF. The results showed that the CDSs (3 and 5) were more stable than the corresponding quaternary salts (2 and 4). Hydrolysis of 2 and 3 resulted in the release of 1, whereas hydrolysis of 4 and 5 released both 1 and the hydroxyethyl ester (6) of 1. In vivo distribution studies were performed in rabbits and dogs. After i.v. administration of equimolar doses of 1 or the CDSs, levels of 1 in brain and CSF were substantially higher and more prolonged in the cases of the CDSs than in the case of 1 itself. Brain levels of 1 were lower following administration of 5, as compared with 3, due to the release of the intermediate compound, the hydroxyethyl ester (6) of 1, which was not hydrolyzed efficiently to 1 in rabbit or dog brain. The substantially increased and prolonged penicillin levels following administration of the CDSs arise as the result of improved penetration of the lipophilic CDSs across the blood-brain barrier, and a "lock-in" effect of the corresponding quaternary salts generated in situ.
{"title":"Brain and CSF specific chemical delivery systems for beta-lactam antibiotics. Study of two dihydropyridine derivatives of benzylpenicillin in rabbits and dogs.","authors":"W M Wu, E Pop, E Shek, R Clemmons, N Bodor","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Following previous studies in rats, the ability of two chemical delivery systems (CDSs) to deliver benzyl penicillin (1) to the central nervous system of rabbits and dogs was investigated. One of the systems (3) was a diester of methylene diol, and the other (5) a diester of ethylene 1,2-diol; in both, one hydroxyl group of the diol was esterified by the 3-carboxylic acid group of benzylpenicillin, and the other by the carboxy group of an N-methyldihydropyridine (dihydrotrigonelline). The basis of the system is the ability of the dihydropyridine components to undergo oxidation to quaternary pyridinium salts (2 from 3, and 4 from 5). In vitro relative stability studies were first performed in 10% rabbit brain homogenate, rabbit CSF and dog CSF. The results showed that the CDSs (3 and 5) were more stable than the corresponding quaternary salts (2 and 4). Hydrolysis of 2 and 3 resulted in the release of 1, whereas hydrolysis of 4 and 5 released both 1 and the hydroxyethyl ester (6) of 1. In vivo distribution studies were performed in rabbits and dogs. After i.v. administration of equimolar doses of 1 or the CDSs, levels of 1 in brain and CSF were substantially higher and more prolonged in the cases of the CDSs than in the case of 1 itself. Brain levels of 1 were lower following administration of 5, as compared with 3, due to the release of the intermediate compound, the hydroxyethyl ester (6) of 1, which was not hydrolyzed efficiently to 1 in rabbit or dog brain. The substantially increased and prolonged penicillin levels following administration of the CDSs arise as the result of improved penetration of the lipophilic CDSs across the blood-brain barrier, and a \"lock-in\" effect of the corresponding quaternary salts generated in situ.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"7 1","pages":"33-43"},"PeriodicalIF":0.0,"publicationDate":"1990-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13251829","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}
With the object of providing an oligomeric prodrug of 5-fluorouracil (5FU) with reduced side-effects, affinity for tumor cells and high antitumor activity, 5FU was covalently attached to three chito-oligosaccharides (COS) through hexamethylene spacer groups via carbamoyl bonds. The ability of these conjugates to prolong the life of lymphocytic leukemia mice (following their intraperitoneal administration) and their tumor-inhibitory effects on Meth-A fibrosarcoma or MH-134 hepatoma mice (following their subcutaneous administration) were assessed. The conjugates caused a significant increase in the survival time of the p-388 leukemia mice, and higher growth-inhibitory effects against the solid tumor than either 5FU, COS, or blends of 5FU and COS. At the highest dose levels, the conjugates did not cause acute toxicity, and did not cause rapid decrease in body weight.
{"title":"Synthesis and antitumor activity of conjugates of 5-fluorouracil and chito-oligosaccharides involving a hexamethylene spacer group and carbamoyl bonds.","authors":"T Ouchi, T Banba, T Matsumoto, S Suzuki, M Suzuki","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>With the object of providing an oligomeric prodrug of 5-fluorouracil (5FU) with reduced side-effects, affinity for tumor cells and high antitumor activity, 5FU was covalently attached to three chito-oligosaccharides (COS) through hexamethylene spacer groups via carbamoyl bonds. The ability of these conjugates to prolong the life of lymphocytic leukemia mice (following their intraperitoneal administration) and their tumor-inhibitory effects on Meth-A fibrosarcoma or MH-134 hepatoma mice (following their subcutaneous administration) were assessed. The conjugates caused a significant increase in the survival time of the p-388 leukemia mice, and higher growth-inhibitory effects against the solid tumor than either 5FU, COS, or blends of 5FU and COS. At the highest dose levels, the conjugates did not cause acute toxicity, and did not cause rapid decrease in body weight.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"281-7"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13237885","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}
D W Combs, M S Rampulla, R K Russell, R A Rampulla, D H Klaubert, D Ritchie, A S Meeks, T Kirchner
A synthetic program of rational drug design was undertaken to develop a series of quinazoline-3-oxides as pulmonary-selective inhibitors of ovalbumin-induced, leukotriene-mediated bronchoconstriction. The most active and selective compounds contained a methyl group at the 4-position, a medium sized branched alkyl group at the 2-position, and a small electron donating group on the phenyl ring. Significant enhancement in selectivity was observed in comparing the pulmonary versus cardiovascular effects of these new bronchodilators with the effects of theophylline.
{"title":"Design, synthesis and bronchodilatory activity of a series of quinazoline-3-oxides.","authors":"D W Combs, M S Rampulla, R K Russell, R A Rampulla, D H Klaubert, D Ritchie, A S Meeks, T Kirchner","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A synthetic program of rational drug design was undertaken to develop a series of quinazoline-3-oxides as pulmonary-selective inhibitors of ovalbumin-induced, leukotriene-mediated bronchoconstriction. The most active and selective compounds contained a methyl group at the 4-position, a medium sized branched alkyl group at the 2-position, and a small electron donating group on the phenyl ring. Significant enhancement in selectivity was observed in comparing the pulmonary versus cardiovascular effects of these new bronchodilators with the effects of theophylline.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"241-54"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13237883","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}
J R Best, R Cotton, A S Dutta, B Fleming, A Garner, J J Gormley, C F Hayward, P F McLachlan, P B Scholes
Analogues of gastrin releasing peptide (GRP) and bombesin based on His-Trp-Ala-Val-D-Ala-His-Leu, the 20-26 heptapeptide sequence of [D-Ala24]GRP, have been synthesized and tested in vitro for their ability to inhibit GRP (18-27)-induced mitogenesis in Swiss 3T3 cells. Compounds identified as potent antagonists in this test system were also tested in vivo for their ability to inhibit bombesin-induced amylase secretion in rats. The Trp-Ala-Val sequence was found to be a very important feature of the antagonist activity; most substitutions in this region led either to much less potent or inactive analogues. In contrast, amino acid replacements in other parts of the molecule were more tolerated and sometimes led to marked increases in the in vitro and in vivo activity. The most potent analogues were obtained by replacing Leu26 by MeLeu and His25 by Lys(X) where X = Z, PhCO, PhCH2CO or Ph(CH2)2CO. Thus 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)-Leu- NHMe (86) and 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-OMe (87) had IC50 values of less than 20 micrograms/kg s.c. in vivo, and their effects lasted for more than 3 hr.
基于[D-Ala24]GRP的20-26七肽序列His-Trp-Ala-Val-D-Ala-His-Leu的胃泌素释放肽(GRP)和bombesin的类似物已经合成,并在体外测试了它们抑制GRP(18-27)诱导的瑞士3T3细胞有丝分裂的能力。在该测试系统中被鉴定为强效拮抗剂的化合物也在体内测试了它们抑制炸弹素诱导的大鼠淀粉酶分泌的能力。发现Trp-Ala-Val序列是拮抗活性的一个重要特征;在这一区域的大多数替换要么导致效力低得多或无活性的类似物。相比之下,分子其他部分的氨基酸替换更耐受性,有时会导致体外和体内活性的显着增加。用MeLeu代替Leu26,用Lys(X) (X = Z)、PhCO、PhCH2CO或Ph(CH2)2CO代替His25,得到了最有效的类似物。因此,4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)- leu - NHMe(86)和4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)- meleu - ome(87)的体内IC50值小于20 μ g /kg s.c.,其作用持续时间超过3小时。
{"title":"Antagonists of bombesin/gastrin releasing peptide based on [D-Ala24]GRP(20-26)-heptapeptide. Modifications leading to potent analogues with prolonged duration of action.","authors":"J R Best, R Cotton, A S Dutta, B Fleming, A Garner, J J Gormley, C F Hayward, P F McLachlan, P B Scholes","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Analogues of gastrin releasing peptide (GRP) and bombesin based on His-Trp-Ala-Val-D-Ala-His-Leu, the 20-26 heptapeptide sequence of [D-Ala24]GRP, have been synthesized and tested in vitro for their ability to inhibit GRP (18-27)-induced mitogenesis in Swiss 3T3 cells. Compounds identified as potent antagonists in this test system were also tested in vivo for their ability to inhibit bombesin-induced amylase secretion in rats. The Trp-Ala-Val sequence was found to be a very important feature of the antagonist activity; most substitutions in this region led either to much less potent or inactive analogues. In contrast, amino acid replacements in other parts of the molecule were more tolerated and sometimes led to marked increases in the in vitro and in vivo activity. The most potent analogues were obtained by replacing Leu26 by MeLeu and His25 by Lys(X) where X = Z, PhCO, PhCH2CO or Ph(CH2)2CO. Thus 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(CO-CH2-CH2-Ph)-Leu- NHMe (86) and 4-pyridylcarbonyl-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-OMe (87) had IC50 values of less than 20 micrograms/kg s.c. in vivo, and their effects lasted for more than 3 hr.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"255-71"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12871086","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 promoting effect of cyclic monoterpenes on the percutaneous absorption of diclofenac sodium (DFS), a water-soluble drug, from gel ointments was investigated in rats. Of five cyclic monoterpenes examined, l-menthol was most effective. Plasma concentrations of diclofenac (DF) increased with increasing amounts of l-menthol in the gel ointment. L-menthol had no effect on the solubility and partition coefficient of DFS, suggesting that the thermodynamic nature of DFS in the formulation was not greatly affected. Plasma concentrations of DF arising from application of ointments containing varying amounts of the terpene were predicted from found pharmacokinetic parameters and the steady-state flux of DFS obtained from in vitro permeation experiments. Experimentally determined plasma concentration of DF agreed well with the predictions, indicating that steady-state flux in vitro well reflects percutaneous absorption in vivo.
{"title":"Effect of cyclic monoterpenes on percutaneous absorption in the case of a water-soluble drug (diclofenac sodium).","authors":"Y Obata, K Takayama, H Okabe, T Nagai","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The promoting effect of cyclic monoterpenes on the percutaneous absorption of diclofenac sodium (DFS), a water-soluble drug, from gel ointments was investigated in rats. Of five cyclic monoterpenes examined, l-menthol was most effective. Plasma concentrations of diclofenac (DF) increased with increasing amounts of l-menthol in the gel ointment. L-menthol had no effect on the solubility and partition coefficient of DFS, suggesting that the thermodynamic nature of DFS in the formulation was not greatly affected. Plasma concentrations of DF arising from application of ointments containing varying amounts of the terpene were predicted from found pharmacokinetic parameters and the steady-state flux of DFS obtained from in vitro permeation experiments. Experimentally determined plasma concentration of DF agreed well with the predictions, indicating that steady-state flux in vitro well reflects percutaneous absorption in vivo.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"319-28"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13238485","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 H+/K+ ATPase enzyme inhibitory activity of 2-[(2-benzimidazolylsulphinyl)methyl]anilines was found to be significantly correlated with hydrophobic, pi or van der Waals volume, Vw, electronic, sigma and molar refraction, MR parameters. The derived correlations support the concept that the basic centre of the anilines is involved in the rate of reaction of the compounds. Hydrophobic interaction of meta-substituents and the bulk of substituents on the benzimidazolyl moiety also contribute significantly in the realisation of enzyme inhibition.
{"title":"Quantitative structure-activity relationship study of 2-[(2-benzimidazolylsulphinyl)methyl]-aniline inhibitors of H+/K+ ATPase.","authors":"T N Ojha, R C Sharma, P Singh","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The H+/K+ ATPase enzyme inhibitory activity of 2-[(2-benzimidazolylsulphinyl)methyl]anilines was found to be significantly correlated with hydrophobic, pi or van der Waals volume, Vw, electronic, sigma and molar refraction, MR parameters. The derived correlations support the concept that the basic centre of the anilines is involved in the rate of reaction of the compounds. Hydrophobic interaction of meta-substituents and the bulk of substituents on the benzimidazolyl moiety also contribute significantly in the realisation of enzyme inhibition.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"289-96"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13122613","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}
By oxidation of dextran, and reduction of the Schiff bases formed by reaction of the oxidised dextran with diaminoalkanes, several diaminoalkane-introduced dextrans were prepared and evaluated as drug carriers. Conjugates between N4-(4-carboxyburyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C) and such drug carriers were prepared, and selected conjugates were tested in vivo, and investigated for inhibitory effects on cytidine deaminase. Ethylenediamine-introduced dextran prepared under 10% oxidation conditions was found to be most useful as a drug carrier from its chemical characteristics and toxicity evaluation in BDF1 mice. The conjugate obtained from glu-ara-C and ethylenediamine-introduced dextran 2000 showed high antitumor activity, significant at the relatively low dose of 100 mg equivalent ara-C/kg, in BDF1 mice bearing L1210 leukemia cells. Glu-ara-C and the conjugate were unaffected by cytidine deaminase under conditions in which 1-beta-D-arabinofuranosylcytosine was degraded rapidly to 1-beta-D-arabinofuranosyluracil.
通过对右旋糖酐的氧化,以及氧化右旋糖酐与二氨基烷烃反应形成的希夫碱的还原,制备了几种引入二氨基烷烃的右旋糖酐,并对其作为药物载体进行了评价。制备了N4-(4-羧基buryryl)-1- β - d -阿拉伯糖醛酸胞嘧啶(glu-ara-C)与这些药物载体的偶联物,并对选定的偶联物进行了体内检测,考察了其对胞苷脱氨酶的抑制作用。通过对BDF1小鼠的化学特性和毒性评价,发现在10%氧化条件下制备的乙二胺引入葡聚糖是最有用的药物载体。从葡萄糖-ara-C和乙二胺引入的葡聚糖2000中获得的结合物在携带L1210白血病细胞的BDF1小鼠中显示出很高的抗肿瘤活性,在相对较低的剂量为100 mg当量ara-C/kg时显著。在1- β - d -阿拉伯糖醛酸胞嘧啶快速降解为1- β - d -阿拉伯糖醛酸胞嘧啶的条件下,葡萄糖-阿拉- c和缀合物不受胞苷脱氨酶的影响。
{"title":"Antitumor characteristics of the conjugate of N4-(4-carboxybutyryl)-ara-C with ethylenediamine-introduced dextran and its resistance to cytidine deaminase.","authors":"H Onishi, P Pithayanukul, T Nagai","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>By oxidation of dextran, and reduction of the Schiff bases formed by reaction of the oxidised dextran with diaminoalkanes, several diaminoalkane-introduced dextrans were prepared and evaluated as drug carriers. Conjugates between N4-(4-carboxyburyryl)-1-beta-D-arabinofuranosylcytosine (glu-ara-C) and such drug carriers were prepared, and selected conjugates were tested in vivo, and investigated for inhibitory effects on cytidine deaminase. Ethylenediamine-introduced dextran prepared under 10% oxidation conditions was found to be most useful as a drug carrier from its chemical characteristics and toxicity evaluation in BDF1 mice. The conjugate obtained from glu-ara-C and ethylenediamine-introduced dextran 2000 showed high antitumor activity, significant at the relatively low dose of 100 mg equivalent ara-C/kg, in BDF1 mice bearing L1210 leukemia cells. Glu-ara-C and the conjugate were unaffected by cytidine deaminase under conditions in which 1-beta-D-arabinofuranosylcytosine was degraded rapidly to 1-beta-D-arabinofuranosyluracil.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"273-80"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"12871516","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 effect of antibiotic pretreatment on the intestinal distribution and hydrolysis of the prodrug prednisolone-beta-D-glucoside was studied in rats. A combination of neomycin, lincomycin, and metronidazole was administered twice daily by gastric intubation for three days to young adult male rats. On the fourth day, prednisolone-beta-D-glucoside was administered intragastrically. The distribution of prodrug and drug in the intestinal contents was significantly altered by the antibiotic treatment. In comparison with untreated rats, stomach to cecum transit time appeared to be reduced, and more prodrug was hydrolyzed in the small intestine. In addition, an appreciable amount of the dose was retained longer in the small intestine of treated animals. The total recovery of prodrug and drug was unaltered by the pretreatment. Possible explanations for the observed results are presented.
研究了抗生素预处理对大鼠肠道分布和前药强的松龙- d -葡萄糖苷水解的影响。新霉素、林可霉素和甲硝唑联合给予年轻成年雄性大鼠胃插管,每日2次,连续3天。第4天给予泼尼松- β - d -葡萄糖苷灌胃。抗生素治疗显著改变了肠内容物中前药和药物的分布。与未给药的大鼠相比,胃到盲肠的运输时间似乎缩短了,并且在小肠中水解了更多的前药。此外,相当数量的剂量在治疗动物的小肠中保留的时间更长。前药和药物的总回收率不受预处理的影响。对观测结果提出了可能的解释。
{"title":"Effect of antibiotic pretreatment on glycoside/glycosidase-based colonic drug delivery.","authors":"D R Friend, J J Chow, G W Chang","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The effect of antibiotic pretreatment on the intestinal distribution and hydrolysis of the prodrug prednisolone-beta-D-glucoside was studied in rats. A combination of neomycin, lincomycin, and metronidazole was administered twice daily by gastric intubation for three days to young adult male rats. On the fourth day, prednisolone-beta-D-glucoside was administered intragastrically. The distribution of prodrug and drug in the intestinal contents was significantly altered by the antibiotic treatment. In comparison with untreated rats, stomach to cecum transit time appeared to be reduced, and more prodrug was hydrolyzed in the small intestine. In addition, an appreciable amount of the dose was retained longer in the small intestine of treated animals. The total recovery of prodrug and drug was unaltered by the pretreatment. Possible explanations for the observed results are presented.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"311-8"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13237888","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 complex-forming abilities of 2,6-di-O-ethyl-beta-cyclodextrin (DE-beta-CD), and its effect on the release of nitroglycerin (TNG) from formulations of the compound, were studied and compared with corresponding properties of beta-cyclodextrin (beta-CD) and 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CD). Complex formation was confirmed by differential scanning calorimetry and infrared absorption spectroscopy. In an accelerator test involving temperature and reduced pressure, marked depression of the volatility of TNG was observed as a result of CD complex formation. Dissolution rates of TNG from powdery TNG/DE-beta-CD complex and its tablets were retarded in comparison with the rates from other CD complexes. The release rate of TNG from ointments was accelerated by complexation with DE-beta-CD, and retarded by complexation with beta-CD. To evaluate their in vivo percutaneous absorption, samples were applied to the inside tip of the cheek pouch of male golden hamsters. The amount of TNG remaining in the cheek pouch was lowest in the case of the TNG/DE-beta-CD complex ointment, and relatively high in the case of the TNG/beta-CD complex ointment, in agreement with the in vitro results. We suggest that the combination of DE-beta-CD complex and beta-CD complex might be applicable to sustained-release preparations for percutaneous administration.
{"title":"Effect of diethyl-beta-cyclodextrin on the release of nitroglycerin from formulations.","authors":"M Umemura, H Ueda, K Tomono, T Nagai","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The complex-forming abilities of 2,6-di-O-ethyl-beta-cyclodextrin (DE-beta-CD), and its effect on the release of nitroglycerin (TNG) from formulations of the compound, were studied and compared with corresponding properties of beta-cyclodextrin (beta-CD) and 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CD). Complex formation was confirmed by differential scanning calorimetry and infrared absorption spectroscopy. In an accelerator test involving temperature and reduced pressure, marked depression of the volatility of TNG was observed as a result of CD complex formation. Dissolution rates of TNG from powdery TNG/DE-beta-CD complex and its tablets were retarded in comparison with the rates from other CD complexes. The release rate of TNG from ointments was accelerated by complexation with DE-beta-CD, and retarded by complexation with beta-CD. To evaluate their in vivo percutaneous absorption, samples were applied to the inside tip of the cheek pouch of male golden hamsters. The amount of TNG remaining in the cheek pouch was lowest in the case of the TNG/DE-beta-CD complex ointment, and relatively high in the case of the TNG/beta-CD complex ointment, in agreement with the in vitro results. We suggest that the combination of DE-beta-CD complex and beta-CD complex might be applicable to sustained-release preparations for percutaneous administration.</p>","PeriodicalId":11271,"journal":{"name":"Drug design and delivery","volume":"6 4","pages":"297-310"},"PeriodicalIF":0.0,"publicationDate":"1990-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13282590","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}