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1.
Curr Pharm Des ; 4(1): 17-36, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10197031

RESUMO

Over 30 million people in the world take non-steroidal anti-inflammatory drugs (NSAID's). A large percentage of these individuals will develop gastric ulcers and related complications, a condition known as "NSAID gastropathy". NSAID gastropathy differs from classic peptic ulcer disease in many ways, and traditional peptic ulcer therapy is largely ineffective in preventing NSAID-induced gastropathy. The prostaglandin misoprostol has been shown to be effective and is approved for the prevention of NSAID gastropathy. However, misoprostol has side effects that limit its general use. For this reason, considerable effort throughout the 1990's has focused on the identification of new gastroprotective molecules. Some synthetic studies have been aimed at the preparation of new prostaglandins, prostacyclin mimetics, and thromboxane antagonists. New histamine H2 receptor antagonists have also been developed which, unlike cimetidine or ranitidine, now appear to couple true gastroprotective activity with antisecretory properties. One new H2 antagonist, ebrotidine, has shown clinical utility in preventing NSAID gastropathy. Many other types of structures (flavonoids, peptides, terpenoids, xanthines, others), as well as compounds displaying certain pharmacological actions (5-hydroxytryptamine receptor binding, adrenergic receptor binding, mast cell stabilization, others) have been linked in some way to gastroprotection. This article reviews many of these recent gastroprotection findings, with emphasis on those of potential use for prevention of NSAID gastropathy.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Animais , Antiulcerosos/farmacologia , Ensaios Clínicos como Assunto , Humanos
2.
Digestion ; 58(2): 147-54, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9144304

RESUMO

To elucidate the mechanisms of flavonoid-induced protection against nonsteroidal anti-inflammatory drug (indomethacin)-induced acute gastric damage, the effects of 5-methoxyflavone and 5-methoxyflavanone on the gastric vasculature were compared both in vivo (using laser Doppler flowmetry in anesthetized rats) and in vitro on rat superior mesenteric arteries. The effects of the compounds on indomethacin-induced leukocyte adherence to mesenteric venules were investigated by intravital videomicroscopy. Oral 5-methoxyflavone reduced indomethacin-induced macroscopic damage by 38 to 99% (ED50 = 5.5 mg/kg). Damage was not significantly reduced by 5-methoxyflavanone. Light microscopy studies also demonstrated a reduction in damage severity. 5-Methoxyflavone, but not 5-methoxyflavanone, increased the gastric conductance significantly. The effects on isolated mesenteric arteries correlated with the effects on in vivo conductance. Finally, indomethacin-induced leukocyte adherence was inhibited to a greater extent by 5-methoxyflavone than by 5-methoxyflavanone. In conclusion, the flavonoid 5-methoxyflavone provides gastroprotection against nonsteroidal anti-inflammatory drug-induced gastric damage. A structurally similar compound, 5-methoxyflavanone, demonstrated minimal gastroprotective activity, suggesting that the double bond of 5-methoxyflavone is required for biological activity. The finding that 5-methoxyflavone (but not 5-methoxyflavanone) significantly increased gastric vascular perfusion and reduced leukocyte adherence to mesenteric venules suggests that these mechanisms may contribute to the flavonoid's gastroprotective activity.


Assuntos
Flavonoides/farmacologia , Fármacos Gastrointestinais/farmacologia , Gastropatias/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Adesão Celular/efeitos dos fármacos , Modelos Animais de Doenças , Mucosa Gástrica/irrigação sanguínea , Técnicas In Vitro , Indometacina/administração & dosagem , Indometacina/farmacologia , Fluxometria por Laser-Doppler , Leucócitos/metabolismo , Masculino , Artérias Mesentéricas/fisiologia , Relaxamento Muscular/fisiologia , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo Regional/fisiologia
3.
J Med Chem ; 38(25): 4937-43, 1995 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-8523407

RESUMO

Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.


Assuntos
Flavonoides/síntese química , Flavonoides/farmacologia , Gastropatias/tratamento farmacológico , Animais , Citocromo P-450 CYP1A1 , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/metabolismo , Indução Enzimática/efeitos dos fármacos , Etanol , Indometacina/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Oxirredutases/biossíntese , Oxirredutases/metabolismo , Ratos , Ratos Sprague-Dawley , Gastropatias/induzido quimicamente , Relação Estrutura-Atividade
4.
J Med Chem ; 35(6): 1117-20, 1992 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-1552504

RESUMO

A series of 5-substituted-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid analogues have been examined as irreversible inhibitors of aldose reductase. The 5-alpha-bromoacetamide and 5-alpha-iodoacetamide analogues 5 and 6 gave irreversible inhibition of aldose reductase while the 5-alpha-chloroacetamide analogue 3 did not show this type of inhibition. Protection studies indicate that irreversible inhibitions are occurring at the inhibitor binding site. Comparative irreversible inhibition studies with rat lens aldose reductase (RLAR) and rat kidney aldehyde reductase (RKALR) indicate that 5-alpha-haloacetamide analogues 5 and 6 are much more effective inhibitors of RLAR.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Isoquinolinas/síntese química , Aldeído Redutase/isolamento & purificação , Animais , Sítios de Ligação/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Ratos
5.
Biochem Biophys Res Commun ; 142(3): 1064-71, 1987 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-3548714

RESUMO

Phenylisothiocyanate, enriched with 13C at the isothiocyanate carbon, has been synthesized and utilized as a 13C NMR probe of proteins for the first time. The reagent has been used to label the amino groups of oxidized glutathione, and the resulting 13C NMR spectrum shows a prominent thiocarbonyl peak after a single NMR scan. The reagent is also capable of differentiating amino groups on the insulin molecule with distinct peaks corresponding to the amino groups on the A and B chains of insulin. This study illustrates the potential of using a new 13C label to functionalize amino groups of proteins and to study the labeled proteins with 13C NMR.


Assuntos
Proteínas , Tiocianatos/síntese química , Isótopos de Carbono , Fenômenos Químicos , Química , Glutationa , Insulina , Isotiocianatos , Espectroscopia de Ressonância Magnética , Desnaturação Proteica
7.
J Med Chem ; 29(11): 2384-9, 1986 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3097318

RESUMO

5-Isothiocyanatoalrestatin (1b) and 5-azidoalrestatin (1c) were prepared synthetically and examined as potential affinity and photoaffinity inhibitors of rat lens aldose reductase. Both compound 1b and 1c under appropriate conditions at 10(-4) M produced a 70% irreversible inactivation of aldose reductase within 1 min. The enzyme could, in part, be protected by preincubation with sorbinil 2, a known potent inhibitor of aldose reductase.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Imidazolidinas , Isoquinolinas/síntese química , Desidrogenase do Álcool de Açúcar/antagonistas & inibidores , Marcadores de Afinidade , Animais , Relação Dose-Resposta a Droga , Imidazóis/farmacologia , Isoquinolinas/farmacologia , Ratos , Relação Estrutura-Atividade
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