摘要:

AbstractAnalogues of the antitumour alkaloids fagaronine and nitidine have been synthesized to investigate their structure‐activity relationships against P388 leukaemia in mice. Bulky substituents at the 12‐position are well tolerated, whereas substituents larger than methoxy in the 2‐position result in total loss of activity.The effects of hydroxy groups in the 2‐ and 12‐positions, which are respectively potency‐enhancing and potency destroying, are rationalized in terms of their potential influence on bioavailability. Suitable choice of substituents may allow the production of more potent analogues with improved ability to penetrate lipi

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00607.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractWe have synthesized membranes based on gels by a simultaneously occurring process of radiation‐induced polymerization and cross‐linking ofN‐isopropylacrylamide in aqueous solution without any cross‐linking agent, to evaluate as a material for temperature‐modulation of drug delivery in the area of transdermal delivery systems.The permeation ofp‐nitrophenol as a model compound through the membrane obtained at a 30‐kGy irradiation was reached maximally at 30°C near a lower critical solution temperature of 32°C. The temperature required for the maximum permeation was shifted downwards by an increased dose.We suggest that this could be explained by the difference in microporous structure of the membrane, in association with both the thermo‐sensitive property and the degree

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00608.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractA matrix‐dispersion‐type transdermal drug delivery system of verapamil was designed and developed using different ratios of mixed polymeric grades of Eudragit. Formulations were selected on the basis of their drug release content and release pattern. These were evaluated for in‐vitro dissolution characteristics using a Cygnus sandwich patch holder.The release followed Higuchi kinetics (r = 0.972‐0.996;P<0.001). In‐vivo evaluation was carried out on healthy human volunteers (24.00 ± 0.82 y; 60.58 ± 6.29 kg). In‐vitro dissolution rate constant (K) and pharmacokinetic parameters generated from plasma and urine were evaluated by two‐way analysis of variance. Statistically excellent correlation was found between percentage of drug absorbed from patch vs Cmax, AUC0‐24, AUC0‐∞. The time at which maximum lowering of blood pressure was found coincided with the tmax. A highly significant difference (P<0.001) was observed when Cmaxand AUC0‐∞generated from plasma and urine data were compared but when k, t½e, ka, t½awere compared, the differences were not significant.We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00609.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractIn‐vitro percutaneous absorption of hydrophilic (water and mannitol) and moderately lipophilic (benzyl alcohol) solutes was investigated through pig ear epidermis and compared with the permeability of these solutes reported for human epidermis.Factors of difference in permeabilities of pig epidermis in comparison with human epidermis were 2.74, 1.2, and 0.58 for water, mannitol, and benzyl alcohol, respectively.An animal model may be predictive of human skin permeability if the factor of difference value between the species is less than 3. This suggests that pig ear skin can be used as a model for man for predicting percutaneous absorption of hydrophilic and moderately lipophilic solute

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00610.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractDrug‐cyclodextrin polymer co‐complexes increase the solubility of lipophilic drugs in aqueous solutions, such as eye‐drops, without affecting their lipophilicity. Also, the co‐complexes are able enhance the ocular availability of the drug after topical administration.The anhydrase inhibitor acetazolamide was solubilized in an aqueous eye‐drop formulation through formation of a co‐complex with 2‐hydroxypropyl‐β‐cyclodextrin and hydroxypropyl methylcellulose. The intraocular pressure (IOP)‐lowering activity of a 1% (w/v) acetazolamide eye‐drop solution was evaluated in nine ocular hypertensive patients. The patients were given the eye‐drops three times a day for 28 days. Maximum IOP lowering activity was observed at 9 a m, 2 h after installation of the drops, with a mean IOP‐lowering of 15.6 ± 8.9%.Through HP‐β‐CD‐HPMC co‐complex formation, it was possible to obtain a topically active aqueous acetazolamide eye‐drop solution. In man, the 1% (w/v) acetazolamide eye‐drop solution had less IOP‐lowering activity than an aque

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00611.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe ability of a novel co‐polymeric nanoparticulate delivery system, co‐polymerized peptide particles (CPP), to deliver a biologically active peptide via the oral route was investigated using the decapeptide luteinizing hormone releasing hormone (LHRH) as a model drug.Intact male Wistar rats (270 g, 9 weeks old) were orally dosed via gavage for 14 days with either the CPP delivery system (containing 1 mg LHRH/day), free LHRH in a buffer vehicle (1 mg LHRH/day) or saline. The seminal vesicle and prostate weights of rats dosed with the CPP system were approximately 50% of the weight of the same organs from rats dosed with saline or free LHRH. Repeated daily oral dosing with the CPP system also resulted in a statistically significant fall in serum testosterone concentrations (P<0.1), to approximately 55% of the control level.The results demonstrate that biologically active LHRH was absorbed after oral dosing with the CPP system, whereas the free peptide had no detectable biological activity. The chemical conjugation of LHRH within this co‐polymeric nanoparticulate delivery system represents a viable approach to promoting oral absor

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00612.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractEnoxolone (18‐β‐glycyrrhetinic acid) has been widely used as a topical anti‐inflammatory compound. Due to its terpenoid chemical structure related to steroids, it has never been excluded that it could act at least in part, as a glucocorticoid‐like drug.In an animal model of inflammation, phorbol ester‐induced mouse ear oedema, enoxolone effects were not inhibited by treatment with RU38486, a glucocorticoid‐receptor antagonist whereas dexamethasone effects were inhibited by this agent.The results demonstrate that the enoxolone anti‐inflammatory mechanism of action is not related to glucocorticoid recept

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00613.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractA degree of structural similarity is sometimes apparent between molecules that induce or antagonize pharmacologic responses and those responsible for effector action. Ligands selective for histamine receptors, for example, relate to purine nucleotide structure. Furthermore, histamine shows structural similarity to the nitric oxide synthetase substrate, arginine. Acetylcholine also initiates cell responses by binding to a guanine nucleotide‐coupled receptor protein and activates the enzyme nitric oxide synthetase. Muscarinic receptor ligands are here compared with purine nucleotide and arginine structures.Relative configurations of acetylcholine, muscarinic agonists, muscarinic antagonists and guanosine triphosphate (GTP) show similarity in their relative configurations. The quaternary nitrogen, ester and carbonyl oxygen atoms in low‐energy conformers of acetylcholine, superimpose on primary nitrogen and oxygen atoms of the a‐phosphate group in GTP with a high degree of fit. The quaternary or tertiary nitrogen and negatively charged atoms in muscarinic agonists and antagonists show the same fit to the guanine nucleotide. In a similar low‐energy conformer of acetylcholine, the same atomic groups relate to the minimum energy conformer of arginine; oxygen atoms in acetylcholine superimpose on nitrogen atoms in the guanidinum group of arginine on the basis of charge.A pharmacophore common to acetylcholine and other muscarinic ligands relates to regulator and substrate molecules involved in signal transduction at muscarinic receptors and nitric oxide gen

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00614.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractOur previous studies have shown that the in‐vitro hepatic metabolism of quinine to form the major metabolite 3‐hydroxyquinine is catalysed by human P450IIIA (CYP3A). The present study was carried out to determine the capacity of liver CYP enzymes in three domestic animals, cow, pig and sheep, for the metabolism of quinine using in‐vitro hepatic microsomal preparations.In all animal species studied, quinine, after incubation with liver microsomes, is predominantly metabolized to 3‐hydroxyquinine. The apparent mean Vmaxvalues (n = 5‐6) for 3‐hydroxyquinine formation were 0.62±0.22; 0.54±0.19 and 11.6±4.9 μmol min−1mg−1for cow, pig and sheep liver microsomes, respectively. The mean values for apparent Kmfound in these species were 110±20; 128±6 and 76±10 μM for cow, pig and sheep liver microsomes, respectively. In liver microsomal preparations from all animals studied, the formation of 3‐hydroxyquinine was inhibited by the specific human CYP3A inhibitors, troleandomycin and midazolam.The present study suggests that the three domestic animals cow, pig and sheep are capable of metabolizing quinine to form 3‐hydroxyquinine and this reaction is catalysed by a liver CYP isoform tha

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00615.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe oxidative metabolism of dihydrocodeine to nordihydrocodeine and dihydromorphine was studied in liver microsomes of female Dark‐Agouti (cytochrome P450 2D1 (CYP2D1) deficient) and Sprague‐Dawley rats. Evaluation of microsomal metabolism in these two rat strains is a useful in‐vitro model to test possible substrates of polymorphic human cytochrome P450 2D6 (CYP2D6).Nordihydrocodeine formation rates were similar in both strains. Analysis of the Michaelis‐Menten kinetics of dihydromorphine formation showed a significant difference (P<0.05) between strains, with respect to Km(943 μM for Dark‐Agouti; 123 μM for Sprague‐Dawley), Vmax(0.925; 2.37 μmol min−1g−1) and intrinsic clearance (0.986; 19.5 mL min−1g−1). In Sprague‐Dawley liver microsomes, dihydromorphine formation was suppressed by the CYP2D1 inhibitors, quinine and quinidine, at concentrations which had no effect on nordihydrocodeine formation. These in‐vitro findings indicate that in rat liver microsomes the cytochrome P450 system is involved in dihydrocodeine metabolism to dihydromorphine and nordihydrocodeine and that CYP2D1 is involved in theO‐demethylation to dihydromorphine but not the Af‐demethylation to nordihydrocodeine.The results of this study are in agreement with recent in‐vivo studies of dihydrocodeine metabolism in man which indicate CYP2D6 is the predominant enzyme cata

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00616.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY