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The validity of animal models in the search for drugs for the aging brain. 动物模型在寻找抗脑衰老药物中的有效性。
Drug design and delivery Pub Date : 1990-12-01
G Pepeu, I M Pepeu, F Casamenti
{"title":"The validity of animal models in the search for drugs for the aging brain.","authors":"G Pepeu,&nbsp;I M Pepeu,&nbsp;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}
引用次数: 0
Brain and CSF specific chemical delivery systems for beta-lactam antibiotics. Study of two dihydropyridine derivatives of benzylpenicillin in rabbits and dogs. -内酰胺类抗生素的脑和脑脊液特异性化学传递系统。青霉素两种二氢吡啶衍生物在家兔和狗体内的研究。
Drug design and delivery Pub Date : 1990-12-01
W M Wu, E Pop, E Shek, R Clemmons, N Bodor
{"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,&nbsp;E Pop,&nbsp;E Shek,&nbsp;R Clemmons,&nbsp;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}
引用次数: 0
Synthesis and antitumor activity of conjugates of 5-fluorouracil and chito-oligosaccharides involving a hexamethylene spacer group and carbamoyl bonds. 含六亚甲基间隔基和氨基甲酰键的5-氟尿嘧啶和壳寡糖缀合物的合成及其抗肿瘤活性。
Drug design and delivery Pub Date : 1990-10-01
T Ouchi, T Banba, T Matsumoto, S Suzuki, M Suzuki
{"title":"Synthesis and antitumor activity of conjugates of 5-fluorouracil and chito-oligosaccharides involving a hexamethylene spacer group and carbamoyl bonds.","authors":"T Ouchi,&nbsp;T Banba,&nbsp;T Matsumoto,&nbsp;S Suzuki,&nbsp;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}
引用次数: 0
Design, synthesis and bronchodilatory activity of a series of quinazoline-3-oxides. 一系列喹唑啉-3氧化物的设计、合成及其支气管扩张活性。
Drug design and delivery Pub Date : 1990-10-01
D W Combs, M S Rampulla, R K Russell, R A Rampulla, D H Klaubert, D Ritchie, A S Meeks, T Kirchner
{"title":"Design, synthesis and bronchodilatory activity of a series of quinazoline-3-oxides.","authors":"D W Combs,&nbsp;M S Rampulla,&nbsp;R K Russell,&nbsp;R A Rampulla,&nbsp;D H Klaubert,&nbsp;D Ritchie,&nbsp;A S Meeks,&nbsp;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}
引用次数: 0
Antagonists of bombesin/gastrin releasing peptide based on [D-Ala24]GRP(20-26)-heptapeptide. Modifications leading to potent analogues with prolonged duration of action. 基于[D-Ala24]GRP(20-26)-七肽的bombesin/胃泌素释放肽拮抗剂。修改导致有效的类似物与延长的作用时间。
Drug design and delivery Pub Date : 1990-10-01
J R Best, R Cotton, A S Dutta, B Fleming, A Garner, J J Gormley, C F Hayward, P F McLachlan, P B Scholes
{"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,&nbsp;R Cotton,&nbsp;A S Dutta,&nbsp;B Fleming,&nbsp;A Garner,&nbsp;J J Gormley,&nbsp;C F Hayward,&nbsp;P F McLachlan,&nbsp;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}
引用次数: 0
Effect of cyclic monoterpenes on percutaneous absorption in the case of a water-soluble drug (diclofenac sodium). 环单萜烯对水溶性药物(双氯芬酸钠)经皮吸收的影响。
Drug design and delivery Pub Date : 1990-10-01
Y Obata, K Takayama, H Okabe, T Nagai
{"title":"Effect of cyclic monoterpenes on percutaneous absorption in the case of a water-soluble drug (diclofenac sodium).","authors":"Y Obata,&nbsp;K Takayama,&nbsp;H Okabe,&nbsp;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}
引用次数: 0
Quantitative structure-activity relationship study of 2-[(2-benzimidazolylsulphinyl)methyl]-aniline inhibitors of H+/K+ ATPase. H+/K+ atp酶2-[(2-苯并咪唑基磺胺基)甲基]-苯胺抑制剂的定量构效关系研究。
Drug design and delivery Pub Date : 1990-10-01
T N Ojha, R C Sharma, P Singh
{"title":"Quantitative structure-activity relationship study of 2-[(2-benzimidazolylsulphinyl)methyl]-aniline inhibitors of H+/K+ ATPase.","authors":"T N Ojha,&nbsp;R C Sharma,&nbsp;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}
引用次数: 0
Antitumor characteristics of the conjugate of N4-(4-carboxybutyryl)-ara-C with ethylenediamine-introduced dextran and its resistance to cytidine deaminase. N4-(4-羧基丁基)- α -c与乙二胺引入的葡聚糖缀合物的抗肿瘤特性及其对胞苷脱氨酶的抗性。
Drug design and delivery Pub Date : 1990-10-01
H Onishi, P Pithayanukul, T Nagai
{"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,&nbsp;P Pithayanukul,&nbsp;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}
引用次数: 0
Effect of antibiotic pretreatment on glycoside/glycosidase-based colonic drug delivery. 抗生素预处理对基于糖苷/糖苷酶的结肠给药的影响。
Drug design and delivery Pub Date : 1990-10-01
D R Friend, J J Chow, G W Chang
{"title":"Effect of antibiotic pretreatment on glycoside/glycosidase-based colonic drug delivery.","authors":"D R Friend,&nbsp;J J Chow,&nbsp;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}
引用次数: 0
Effect of diethyl-beta-cyclodextrin on the release of nitroglycerin from formulations. 二乙基- β -环糊精对配方中硝酸甘油释放的影响。
Drug design and delivery Pub Date : 1990-10-01
M Umemura, H Ueda, K Tomono, T Nagai
{"title":"Effect of diethyl-beta-cyclodextrin on the release of nitroglycerin from formulations.","authors":"M Umemura,&nbsp;H Ueda,&nbsp;K Tomono,&nbsp;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}
引用次数: 0
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