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1.
AAPS PharmSciTech ; 20(5): 196, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31123934

RESUMO

Undesired-burst release effect is observed in a freely water-soluble drug formulated into a gastro-floating formulation with effervescent (GFFE) delivery system. In order to address this limitation, interpolymer complex (IPC) of two swellable and non-soluble polymers, poly-ammonium methacrylate and poly-vinyl acetate, was incorporated into hydroxypropyl methyl cellulose (HPMC)-based matrix GFFE. This research studied the effect and interaction of the IPC-HPMC blending on the drug release of GFFE using a freely water-soluble drug, metformin HCl, under different threshold concentration levels and curing effect. The interaction between the IPC and HPMC was characterized using vibrational spectroscopy and thermal analyses under curing and swelling conditions. Anti-solvent followed by lyophilization had better physicochemical and physicomechanic properties than spray dying technique. The interaction was observed by a specific shifting of the vibrational peaks and alteration of the thermal behavior pattern. These effects altered the drug release behavior. Thereafter, the IPC reduced burst release effects in the initial time and during testing, and the IPC improved the HPMC matrix robustness under mechanical stress testing below threshold concentration of HPMC matrix formulated in the GFFE.


Assuntos
Fármacos Gastrointestinais/síntese química , Derivados da Hipromelose/síntese química , Polímeros/síntese química , Água/química , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Fármacos Gastrointestinais/farmacocinética , Derivados da Hipromelose/farmacocinética , Polímeros/farmacocinética , Solubilidade , Comprimidos
2.
AAPS PharmSciTech ; 20(4): 155, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30924008

RESUMO

In this paper, a novel formulation of dual-release dry suspension of mosapride citrate (DRDS-MC) was designed which can be quickly released in the stomach while having sustained-release effect. Co-grinding mixture of mosapride citrate (MC) together with L-HPC as hydrophilic excipient was prepared in order to improve the solubility of MC. The co-grinding mixture was characterized by solubility studies, DSC, X-RD, SEM, FTIR, and size distribution before the preparation of the DRDS-MC. Then, the co-grinding mixture was used to prepare DRDS-MC via wet granulation method. The evaluation of DRDS-MC was focused on physicochemical properties, intestinal absorption, and pharmacokinetics. The results of DSC, X-RD, SEM, FTIR, and size distribution indicated that MC resides in co-grinding mixture with no crystalline changes, hydrogen bonds made L-HPC greatly improving the solubility of MC. Then, the dissolution of DRDS-MC reached 70% in pH 1.2 within 2 h, and the 12-h dissolution of MC in pH 6.8 was nearly 80%. The sedimentation volume after 3 h was 0.94 and redispersibility was good. The linear regression equation between in vitro release of DRDS-MC and intestinal absorption fraction in rats was: Y = 29.215 + 47.535*X (r = 0.952). At last, pharmacokinetic studies in beagle dogs demonstrated that DRDS-MC has prolonged effect compared with commercial formulation Gasmotin as a reference. All results indicated that the DRDS-MC could be quickly released in the stomach while having sustained-release effect.


Assuntos
Benzamidas/síntese química , Benzamidas/farmacocinética , Absorção Gastrointestinal/efeitos dos fármacos , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacocinética , Morfolinas/síntese química , Morfolinas/farmacocinética , Animais , Estudos Cross-Over , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Excipientes/síntese química , Excipientes/farmacocinética , Absorção Gastrointestinal/fisiologia , Masculino , Distribuição Aleatória , Ratos , Solubilidade , Suspensões
3.
Future Med Chem ; 11(1): 21-32, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30526030

RESUMO

AIM: To synthesize the new bioactive metabolites of mosapride (R)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]-propyl-5-chlorine-4-amino-2-ethoxyben-zamide (R-isomer) and (S)-N-[2-hydroxy-3-(4-fluorobenzyl)amino]-propyl-5-chlorine-4-amino-2-ethoxybenzamide (S-isomer) and evaluate their in vitro and in vivo pharmacological and pharmacokinetic profiles. RESULTS: S-isomer as a gastroprokinetic agent showed significant pharmacological activities in vivo. Furthermore, compared with the EC50 values for R-isomer and mosapride, S-isomer was proven to generate the same 5-HT4 receptor agonistic activity with a smaller amount. S-isomer exhibited significant differences in the pharmacokinetic properties, which indicate that higher absorption rate and extent compared with R-isomer. CONCLUSION: S-isomer might have great potential as a safe and effective prokinetic agent capable of lessening gastrointestinal symptoms and increasing quality of life.


Assuntos
Benzamidas/metabolismo , Fármacos Gastrointestinais/síntese química , Morfolinas/metabolismo , Animais , Absorção Gastrointestinal , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/farmacologia , Masculino , Camundongos , Estrutura Molecular , Peristaltismo/efeitos dos fármacos , Agonistas do Receptor 5-HT4 de Serotonina/síntese química , Agonistas do Receptor 5-HT4 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia , Estereoisomerismo
4.
J Pept Sci ; 24(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29441631

RESUMO

The aim of present study was to develop a respirable powder (RP) of a shortened vasoactive intestinal peptide (VIP) analog for inhalation. VIP and C-terminally truncated VIP analogs were synthesized with a solid-phase method. A structure-activity relationship (SAR) study was carried out in terms with binding and relaxant activities of the peptides. Prepared RP formulation of a shortened VIP analog was physicochemically characterized by morphological, in vitro aerodynamic, and pharmacological assessments. The SAR study demonstrated that the N-terminal 23 amino acid residues were required for biological activity of VIP. Upon chemical modification of VIP(1-23), [R15, 20, 21 , L17 ]-VIP(1-23) was newly developed, which had higher binding activity in rat lung and smooth muscle relaxant effect in mouse stomach than VIP(1-23). The [R15, 20, 21 , L17 ]-VIP(1-23)-based RP, [R15, 20, 21 , L17 ]-VIP(1-23)/RP, exhibited fine in vitro inhalation performance. Airway inflammation evoked by sensitization of antigen in rats was attenuated by pre-treatment with the [R15, 20, 21 , L17 ]-VIP(1-23)/RP at a dose of 50 µg-[R15, 20, 21 , L17 ]-VIP(1-23)/rat as evidenced by a 70% reduction of recruited inflammatory cells in bronchoalveolar lavage fluid. On the basis of these results, [R15, 20, 21 , L17 ]-VIP(1-23)/RP might be a promising agent for treatment of airway inflammatory diseases.


Assuntos
Asma/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/síntese química , Peptídeo Intestinal Vasoativo/análogos & derivados , Administração por Inalação , Animais , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Fármacos Gastrointestinais/farmacologia , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Pós , Ratos , Estômago/efeitos dos fármacos , Relação Estrutura-Atividade , Peptídeo Intestinal Vasoativo/química
5.
J Biol Chem ; 292(24): 10288-10294, 2017 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-28473469

RESUMO

Inflammatory bowel diseases (IBDs) are a set of complex and debilitating diseases for which there is no satisfactory treatment. Recent studies have shown that small peptides show promise for reducing inflammation in models of IBD. However, these small peptides are likely to be unstable and rapidly cleared from the circulation, and therefore, if not modified for better stability, represent non-viable drug leads. We hypothesized that improving the stability of these peptides by grafting them into a stable cyclic peptide scaffold may enhance their therapeutic potential. Using this approach, we have designed a novel cyclic peptide that comprises a small bioactive peptide from the annexin A1 protein grafted into a sunflower trypsin inhibitor cyclic scaffold. We used native chemical ligation to synthesize the grafted cyclic peptide. This engineered cyclic peptide maintained the overall fold of the naturally occurring cyclic peptide, was more effective at reducing inflammation in a mouse model of acute colitis than the bioactive peptide alone, and showed enhanced stability in human serum. Our findings suggest that the use of cyclic peptides as structural backbones offers a promising approach for the treatment of IBD and potentially other chronic inflammatory conditions.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Modelos Animais de Doenças , Fármacos Gastrointestinais/uso terapêutico , Modelos Moleculares , Peptídeos Cíclicos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/imunologia , Colo/patologia , Desenho de Drogas , Estabilidade de Medicamentos , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/química , Humanos , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Conformação Proteica , Engenharia de Proteínas , Dobramento de Proteína , Estabilidade Proteica , Proteólise , Distribuição Aleatória , Soro/enzimologia , Organismos Livres de Patógenos Específicos
6.
J Med Chem ; 60(15): 6480-6515, 2017 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-28421763

RESUMO

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 29 new chemical entities (NCEs) that were approved for the first time in 2015.


Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/síntese química , Anti-Infecciosos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Antineoplásicos/síntese química , Fármacos Cardiovasculares/síntese química , Fármacos do Sistema Nervoso Central/síntese química , Técnicas de Química Sintética , Fármacos Gastrointestinais/síntese química , Hipoglicemiantes/síntese química , Receptores de Trombopoetina/agonistas
7.
AAPS PharmSciTech ; 18(6): 2026-2036, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27966176

RESUMO

The treatment of peptic ulcers induced by H. pylori remains challenging due to the deep mucous layer location of bacteria preventing antimicrobial drug access. The present work aimed to design and evaluate in vitro dual responsive (both pH and magnetic field-sensitive) polymeric magnetic particles loaded with amoxicillin as a smart drug carrier for deep mucous layer penetration and in situ drug release. Magnetite particles were produced by the co-precipitation method and subsequently coated with the Eudragit®S100 and amoxicillin by using the spray-drying technique. The physicochemical characterization of the obtained particles was carried out by optical and scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, nitrogen adsorption/desorption isotherms, and vibrating sample magnetometry. Additionally, drug release tests and antibacterial activity tests were evaluated in vitro. Microparticles presented 17.2 ± 0.4 µm in size and their final composition was 4.3 ± 1.5% of amoxicillin, 87.0 ± 2.3% of Eudragit, and 9.0 ± 0.3% of magnetite. They were both pH and magnetic field responsive while presenting antimicrobial activity. On one side, magnetic field responsiveness of particles is expected to prompt them to reach bacterium niche in deep mucous layer by means of magnetic forces. On the other side, pH responsiveness is expected to enable drug release in the neutral pH of the deep mucous layer, preventing undesired delivery in the acidic gastric lumen. Smart microparticles were designed presenting both pH and magnetic field responsiveness as well as antimicrobial activity. These may be promising assets for peptic ulcer treatment.


Assuntos
Amoxicilina/síntese química , Anti-Infecciosos/síntese química , Portadores de Fármacos/síntese química , Fármacos Gastrointestinais/síntese química , Fenômenos Magnéticos , Amoxicilina/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Portadores de Fármacos/farmacologia , Composição de Medicamentos/métodos , Fármacos Gastrointestinais/farmacologia , Helicobacter pylori/efeitos dos fármacos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodos
8.
Sci Rep ; 6: 29320, 2016 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-27381677

RESUMO

Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity.


Assuntos
Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/metabolismo , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Células HEK293 , Células Hep G2 , Humanos , Estrutura Molecular
10.
Peptides ; 74: 16-22, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26471904

RESUMO

Non-amidated gastrin peptides such as glycine-extended gastrin (Ggly) are biologically active in vitro and in vivo and have been implicated in the development of gastric and colonic cancers. Previous studies have shown that the truncated form of Ggly, the octapeptide LE5AY, was still biologically active in vitro, and that activity was dependent on ferric ion binding but independent of binding to the cholecystokinin 2 (CCK2) receptor. The present work was aimed at creating more stable gastrin-derived 'super agonists' using retro-inverso technology. The truncated LE5AY peptide was synthesized using end protecting groups in three forms with l-amino acids (GL), d-amino acids (GD) or retro-inverso (reverse order with d-amino acids; GRI). All of these peptides bound ferric ions with a 2:1 (Fe: peptide) ratio. As predicted, Ggly, GL and GRI were biologically active in vitro and increased cell proliferation in mouse gastric epithelial (IMGE-5) and human colorectal cancer (DLD-1) cell lines, and increased cell migration in DLD-1 cells. These activities were likely via the same mechanism as Ggly since no CCK1 or CCK2 binding was identified, and GD remained inactive in all assays. Surprisingly, unlike Ggly, GL and GRI were not active in vivo. While Ggly stimulated colonic crypt height and proliferation rates in gastrin knockout mice, GL and GRI did not. The apparent lack of activity may be due to rapid clearance of these smaller peptides. Nevertheless further work designing and testing retro-inverso gastrins is warranted, as it may lead to the generation of super agonists that could potentially be used to treat patients with gastrointestinal disorders with reduced mucosal function.


Assuntos
Gastrinas/química , Gastrinas/farmacologia , Fármacos Gastrointestinais/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sistema Digestório/efeitos dos fármacos , Sistema Digestório/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Gastrinas/síntese química , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacologia , Humanos , Íons/química , Ferro/química , Camundongos , Fragmentos de Peptídeos/síntese química
11.
Biochim Biophys Acta ; 1830(6): 3407-13, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23518200

RESUMO

BACKGROUND: Rapid enzymatic degradation of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), limits therapeutic use of the native peptide for diabetes. However, enzymatically stable analogues of GIP, such as (d-Ala(2))GIP, have been generated, but are still susceptible to renal filtration. METHODS: The present study examines the in vitro and in vivo biological actions of a novel, acylated GIP analogue, (d-Ala(2))GIP[Lys(37)PAL]. RESULTS: In BRIN-BD11 cells, (d-Ala(2))GIP[Lys(37)PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala(2))GIP[Lys(37)PAL] to normal mice 8h prior to a glucose load significantly reduced (p<0.05) the overall glycaemic excursion compared to controls, and increased (p<0.001) the insulinotropic response compared to (d-Ala(2))GIP and saline treated high fat control mice. Once daily administration of (d-Ala(2))GIP[Lys(37)PAL] for 21days in high fat fed mice did not affect energy intake, body weight or fat deposition. However, circulating blood glucose was significantly lower (p<0.05) accompanied by increased (p<0.05) insulin concentrations by day 21. In addition, (d-Ala(2))GIP[Lys(37)PAL] treatment significantly (p<0.01) reduced the overall glycaemic excursion and increased pancreatic insulin content (p<0.05) and the insulinotropic response (p<0.01) to an exogenous glucose challenge on day 21. Chronic treatment with (d-Ala(2))GIP[Lys(37)PAL] did not result in resistance to the metabolic effects of a bolus injection of native GIP. Finally, insulin sensitivity was significantly improved (p<0.001) in (d-Ala(2))GIP[Lys(37)PAL] treated mice compared to high fat controls. CONCLUSIONS: These data confirm that (d-Ala(2))GIP[Lys(37)PAL] is a stable, long-acting potent GIP agonist. GENERAL SIGNIFICANCE: (d-Ala(2))GIP[Lys(37)PAL] may be suitable for further evaluation and future clinical development.


Assuntos
Distribuição da Gordura Corporal , Diabetes Mellitus Experimental/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/análogos & derivados , Polipeptídeo Inibidor Gástrico/farmacologia , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Polipeptídeo Inibidor Gástrico/agonistas , Polipeptídeo Inibidor Gástrico/síntese química , Polipeptídeo Inibidor Gástrico/química , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacologia , Glucose/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Insulina/metabolismo , Masculino , Camundongos
12.
Amino Acids ; 43(5): 2073-85, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22526242

RESUMO

α-Aminoxy peptide AxyP1 has been reported to form synthetic chloride channel in living cells, thus it may have therapeutic potential for the treatment of diseases associated with chloride channel dysfunction. However, this study revealed significant gastrointestinal (GI) instability and extensive hepatic metabolism of AxyP1. To improve its GI and metabolic stability, structural modifications were conducted by replacing the isobutyl side chains of AxyP1 with methyl group (AxyP2), hydroxymethyl group (AxyP3), 4-aminobutyl group (AxyP4) and 3-carboxyl propyl group (AxyP5). Compared with AxyP1 (41 and 47 % degradation), GI stability of the modified peptides was significantly improved by 8-fold (AxyP2), 9-fold (AxyP3) and 12-fold (AxyP5) with no degradation for AxyP4 in simulated gastric fluid within 1 h, and by 12-fold (AxyP2) and 9-fold (AxyP3) with no degradation for AxyP4 and AxyP5 in simulated intestinal fluid within 3 h, respectively. The hepatic metabolic stability of the four modified peptides within 30 min in rat liver S9 preparation was also improved significantly with no metabolism of AxyP5 and threefold (AxyP2 and AxyP4) and eightfold (AxyP3) less metabolism compared with AxyP1 (39 % metabolism). Unlike hydrolysis as the major metabolism of peptides of natural α-amino acids, oxidation mediated by the cytochrome P450 enzymes, especially CYP3A subfamily, to form the corresponding mono-hydroxyl metabolites was the predominant hepatic metabolism of the five α-aminoxy peptides tested. The present findings demonstrate that structural modification can significantly improve the GI and metabolic stability of α-aminoxy peptides and thus increase their potential for therapeutic use in the treatment of chloride channel related diseases.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/metabolismo , Ionóforos/síntese química , Ionóforos/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Animais , Materiais Biomiméticos/química , Biotransformação , Cromatografia Líquida de Alta Pressão , Suco Gástrico/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estabilidade Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
13.
Arzneimittelforschung ; 60(9): 544-52, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21117497

RESUMO

Specific serotonin receptor agonists and antagonists are marketed with respect to various diseases, most prominently severe emesis. To identify new chemical classes with affinity for the serotonin 5-HT3 channel, several compounds were synthesized which can be structurally classified as arylalkylamines, azecines, quinolizines and beta-carbolines. These were tested in three models: (1) direct effect on ileum (overall model for contracting or relaxant effect), (2) antiserotoninergic effects on rat ileum (crude serotonin model), (3) inhibitory effect on the 5-HT, receptor channel complex expressed in N1E-115 cells (serotonin-induced [14C]guanidinium influx (specific model)). Key findings and conclusion: Several azecine-type compounds exhibit 5-HT3 receptor channel antagonistic properties at concentrations close to that of tropisetron (used as a positive control) and might serve as potential lead structures for the development of further 5-HT3 channel receptor antagonists.


Assuntos
Aminas/síntese química , Aminas/farmacologia , Carbolinas/síntese química , Carbolinas/farmacologia , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacologia , Quinolizinas/síntese química , Quinolizinas/farmacologia , Receptores 5-HT3 de Serotonina/efeitos dos fármacos , Serotoninérgicos/síntese química , Serotoninérgicos/farmacologia , Animais , Cátions/metabolismo , Linhagem Celular , Descoberta de Drogas , Feminino , Guanidina/metabolismo , Íleo/efeitos dos fármacos , Técnicas In Vitro , Indóis/farmacologia , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tropizetrona
14.
Acta Pharm ; 60(1): 89-97, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20228043

RESUMO

A biphasic gastroretentive drug delivery system of fenoverine was developed to maintain constant plasma concentration. The delivery system consisted of a loading-dose tablet and a floating multiple matrix tablet prepared by the direct compression process. The drug release from biphasic GRDDS in 0.1 mol L(-1) HCl and SGF (enzyme free) was sustained over 12 h with buoyant properties. Stability studies showed no significant change in dissolution profiles (f2 value > 50). Based on the release kinetics, it can be concluded that the floating multiple matrix tablet containing HPMC was a particularly suitable gastroretentive drug delivery system with a zero-order release profile.


Assuntos
Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Fármacos Gastrointestinais/administração & dosagem , Fenotiazinas/administração & dosagem , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Portadores de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacocinética , Fenotiazinas/síntese química , Fenotiazinas/farmacocinética , Comprimidos
15.
Steroids ; 75(6): 424-31, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20171237

RESUMO

The objective of this work was to study the effect of structure of bile acids on their membranolytic potential and extent of overlapping of the information about the membranolytic potential of bile acids and their physico-chemical parameters, namely: retention index R(M0) (as a measure of bile acid hydrophobicity, reversed-phase thin-layer chromatography (RPTLC)), lecithin solubilisation (measure of the interaction of bile acids with phospholipids) and critical micellar concentration (CMC). It was found that bile acid concentrations at 100% lysis of erythrocyte membranes is described best by their CMC values, whereas at 50% lysis the parameter used is lecithin solubilisation. This indicates that different mixed micelles are formed in the membrane lysis at lower and higher concentrations of bile acids. Replacement of the hydroxyl (OH) group in the bile acid molecule with an oxo group yields derivatives with lowered hydrophobicity, power of lecithin solubilisation, tendency for self-aggregation as well as the membranolytic activity.


Assuntos
Ácido Quenodesoxicólico , Ácido Cólico , Ácido Desoxicólico , Hemólise/efeitos dos fármacos , Animais , Ácido Quenodesoxicólico/síntese química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/farmacologia , Colagogos e Coleréticos/síntese química , Colagogos e Coleréticos/química , Colagogos e Coleréticos/farmacologia , Ácido Cólico/síntese química , Ácido Cólico/química , Ácido Cólico/farmacologia , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/química , Ácido Desoxicólico/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/química , Fármacos Gastrointestinais/farmacologia , Interações Hidrofóbicas e Hidrofílicas , Lecitinas/química , Modelos Moleculares , Estrutura Molecular , Coelhos
16.
J Med Chem ; 52(21): 6851-9, 2009 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-19821563

RESUMO

A series of 9-dihydro-9-acetamido-N-desmethyl-N-isopropyl erythromycin A analogues and related derivatives was generated as motilin agonists. The compounds were optimized for potency while showing both minimal antibacterial activity and hERG inhibition. As the substituent on the amide was increased in lipophilicity the potency and hERG inhibition increased, while polar groups lowered potency, without significantly impacting hERG inhibition. The N-methyl acetamide 7a showed the optimal in vitro profile and was probed further by varying the chain length to the macrocycle as well as changing the macrocycle scaffold. 7a remained the compound with the best in vitro properties.


Assuntos
Eritromicina/análogos & derivados , Eritromicina/síntese química , Fármacos Gastrointestinais/síntese química , Motilina/agonistas , Animais , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Linhagem Celular , Canal de Potássio ERG1 , Eritromicina/efeitos adversos , Eritromicina/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Humanos , Técnicas In Vitro , Intestinos/microbiologia , Testes de Sensibilidade Microbiana , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Coelhos , Estereoisomerismo , Relação Estrutura-Atividade , Taquifilaxia
17.
Eur J Med Chem ; 44(1): 332-44, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18406012

RESUMO

A series of arylalkanoic acid derivatives bearing methyl(phenethyl)amino groups were prepared and their inhibition of LTB(4) biosynthesis was evaluated. Regression analysis showed the slightly different parabolic dependences of this activity on lipophilicity of alpha-methyl and alpha-unsubstituted alkanoic acid derivatives. The relationship derived for alpha-unsubstituted alkanoic acids was extended by previously prepared group of similar derivatives of arylacetic acids without any change of regression coefficients and statistical criteria. It was concluded that the most active compounds belong to 2-arylpropanoic acid derivatives with lipophilicity close to logP(opt) (=6.97). But generally, the structural changes in the acidic part of compounds under study did not yield the substantial improvement of LTB(4) biosynthesis inhibition in comparison with the previously prepared series of derivatives IV. The anti-inflammatory effect of the compounds under study was evaluated in three animal models of inflammation and their possible utilization in the treatment of ulcerative colitis (UC) was followed. From 12 evaluated compounds, 4 compounds are more active in UC inhibition than the standard sulfasalazine but it can be stated that the change of connecting chain between aromatic ring and carboxyl did not bring about the important improvement of this activity in comparison with previous derivatives of arylacetic acids. Possible relation between LTB(4) biosynthesis inhibition and ulcerative colitis is seriously broken by the compound 8a with carbonyl as the additional functional group on the connecting chain between carboxyl and aromatic ring.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Hidrocarbonetos Aromáticos/síntese química , Receptores do Leucotrieno B4/antagonistas & inibidores , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Ácidos Carboxílicos , Células Cultivadas , Fármacos Gastrointestinais/síntese química , Fármacos Gastrointestinais/farmacologia , Hidrocarbonetos Aromáticos/farmacologia , Inflamação/tratamento farmacológico , Leucócitos , Relação Quantitativa Estrutura-Atividade , Ratos , Relação Estrutura-Atividade
19.
Neurogastroenterol Motil ; 20 Suppl 1: 130-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18402650

RESUMO

Functional gastrointestinal disorders (FGID) are common conditions seen in primary care and specialty practices but many affected individuals report a lack of satisfaction with available treatments. Despite the unmet need for more effective pharmacotherapy, drug development for these conditions can be challenging on many levels. This review will discuss the rationale and challenges of drug development for FGID. The reasons for engaging in drug development include that these conditions are highly prevalent, associated with a significant economic and healthcare burden, and associated with a lack of satisfaction with current therapies. The challenges include the lack of perception that FGID are legitimate disorders, the multidimensional and complex pathophysiology of FGID, the lack of a biological marker for diagnosis and treatment response, the heterogeneity of the patient population, the lack of consensus regarding the best outcome measures for clinical trials and the perceived increased risk-benefit ratio associated with drugs for FGID. Ongoing efforts are being taken to work towards a better understanding of pathophysiology, illness severity, patient-reported outcome measures, and benefit : risk assessment, and towards increasing education and communication amongst patients, clinicians, investigators, industry and regulatory agencies which will hopefully help optimize drug development strategies for FGID.


Assuntos
Desenho de Drogas , Fármacos Gastrointestinais/uso terapêutico , Gastroenteropatias/tratamento farmacológico , Tecnologia Farmacêutica/tendências , Animais , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/tendências , Fármacos Gastrointestinais/síntese química , Gastroenteropatias/fisiopatologia , Humanos , Tecnologia Farmacêutica/métodos
20.
Drug Deliv ; 15(1): 37-42, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18197522

RESUMO

N,N(')-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) was prepared by a simple synthetic route. 5-ASA-Cys was not degraded in pH 1.2 and 6.8 buffer solutions, and in the homogenates of the upper intestine. In marked contrast, 5-ASA-Cys was deconjugated extensively to liberate 5-ASA in the cecal contents. Upon oral administration of 5-ASA-Cys to rats, the plasma concentration of 5-ASA-Cys was extremely low and the urinary recovery of 5-ASA-Cys was approximately 10% of the dose. These results suggest that 5-ASA-Cys administered orally is delivered efficiently to the large intestine followed by deconjugation to liberate 5-ASA and cystine.


Assuntos
Ácidos Aminossalicílicos/farmacocinética , Anti-Inflamatórios/farmacocinética , Colo/metabolismo , Cistina/análogos & derivados , Fármacos Gastrointestinais/farmacocinética , Absorção Intestinal , Pró-Fármacos/síntese química , Administração Oral , Ácidos Aminossalicílicos/administração & dosagem , Ácidos Aminossalicílicos/síntese química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/síntese química , Biotransformação , Ceco/metabolismo , Cistina/administração & dosagem , Cistina/síntese química , Cistina/farmacocinética , Estabilidade de Medicamentos , Mucosa Gástrica/metabolismo , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/síntese química , Hipuratos/farmacocinética , Concentração de Íons de Hidrogênio , Intestino Delgado/metabolismo , Masculino , Pró-Fármacos/administração & dosagem , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley
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