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1.
Exp Dermatol ; 21(1): 32-7, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22151388

RESUMEN

The effects of the histamine H(4) receptor antagonist JNJ7777120 were evaluated in a model of acute skin inflammation induced by local application of croton oil. The influence of strain on the effect of JNJ7777120 was investigated in four different mouse strains (CD-1, NMRI, BALB/c and C57BL/6J). In CD-1 mice, JNJ777720 (30-100 mg/kg subcutaneously, s.c.) exerted a dose-dependent inhibition of croton oil-induced ear inflammation and polymorphonuclear leucocyte infiltration, as confirmed by histological evaluation of ear tissues. JNJ7777120 (30-100 mg/kg) did not reduce ear oedema in NMRI, BALB/c or C57BL/6J mice. The positive control, dexamethasone (2 mg/kg s.c.) induced significant anti-inflammatory effects only in CD-1 and NMRI mice. In these strains, also the histamine H(1) -receptor blocker pyrilamine (30 mg/kg s.c.) significantly reduced ear oedema at 2 h after croton oil challenge, being as effective as JNJ7777120 in CD-1 mice. Taken together, these data demonstrate that the H(4) receptor antagonist JNJ7777120 may reduce acute croton oil-induced skin inflammation as effectively as H(1) receptor blockade. However, present experiments evidenced for the first time marked strain-related differences in the JNJ7777120 pharmacological activity, which have to be carefully considered when using this ligand to characterize histamine H(4) receptor functions in murine models and translating preclinical data to clinical human settings.


Asunto(s)
Dermatitis/tratamiento farmacológico , Indoles/uso terapéutico , Piperazinas/uso terapéutico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Antiinflamatorios/uso terapéutico , Aceite de Crotón , Dermatitis/patología , Fármacos Dermatológicos , Dexametasona/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Oído Externo/patología , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Indoles/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Piperazinas/farmacología , Pirilamina/uso terapéutico , Receptores Histamínicos , Receptores Histamínicos H4
2.
Pharmacology ; 89(5-6): 287-94, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22538763

RESUMEN

AIM: In the present study we examined whether histamine H(4) receptors (H(4)Rs) have a role in gastric ulcerogenesis using a mouse model of gastric damage. METHODS: The H(4)R antagonist JNJ7777120 and the H(4)R agonists VUF8430 and VUF10460 were investigated in fasted CD-1 mice against the ulcerogenic effect induced by co-administration of indomethacin(IND, 30 mg/kg s.c.) and bethanechol (BET, 5 mg/kg i.p.). Both macroscopic and histologic lesions were examined. Strain-related differences were investigated by testing JNJ7777120 also in NMRI, BALB/c and C57BL/6J mice. RESULTS: Neither JNJ7777120 nor the H(4)R agonists displayed effects in the normal stomach at any dose tested (10 and 30 mg/kg s.c.). As expected, IND+BET provoked several lesions in the fundic mucosa, which were significantly reduced by JNJ7777120 (10 and 30 mg/kg s.c.). The gastroprotective effect of JNJ7777120 (10 and 30 mg/kg s.c.) was observed in CD-1, NMRI and BALB/c, but not in C57BL/6J, mice. In CD-1 mice, the H(4)R agonists VUF8430 and VUF10460 (both at 10 and 30 mg/kg s.c.) did not modify the damage induced by IND+BET, however VUF8430 (10 mg/kg s.c.) prevented the gastroprotection induced by JNJ7777120 (10 mg/kg s.c.). CONCLUSIONS: Data obtained with selective ligands suggest that the H(4)R may have a role in mouse gastric ulcerogenesis. If confirmed in humans, these data would emphasize the potential advantage of H(4)R blockers as gastrosparing anti-inflammatory drugs. The lack of effects of JNJ7777120 in C57BL/6J mice has to be carefully considered in the pharmacological characterization of H(4)R functions and/or new selective ligands.


Asunto(s)
Antiinflamatorios/uso terapéutico , Agonistas de los Receptores Histamínicos/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Úlcera Gástrica/tratamiento farmacológico , Animales , Betanecol , Modelos Animales de Enfermedad , Guanidinas/uso terapéutico , Indoles/uso terapéutico , Indometacina , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H4 , Especificidad de la Especie , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/patología , Tiourea/análogos & derivados , Tiourea/uso terapéutico
3.
Bioorg Med Chem ; 19(19): 5852-60, 2011 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-21906954

RESUMEN

A new group of derivatives of salicylic acid containing NO-donor furoxans, and the related des-NO-furazans, were synthesized and evaluated as new aspirin-like molecules. Their stability was assessed in acid (pH 1) and physiological solutions (pH 7.4), and in human serum. No compound exhibited COX-inhibitory activity against COX-1 and COX-2 isoforms, when tested up to 100µM, respectively, on isolated platelets and on monocytes. Phenylsulfonyl- and cyano-substituted furoxans inhibited platelet aggregation induced by collagen in human platelet-rich plasma, through a cGMP dependent mechanism. Furoxan derivatives displayed cGMP-dependent vasodilator activities, tested on rat aorta strips precontracted with phenylephrine. All products showed anti-inflammatory activity similar to that of ASA, tested on rats by the carrageenan-induced paw edema assay. Unlike ASA, all products showed markedly reduced gastrotoxicity in a rat lesion model.


Asunto(s)
Antiinflamatorios/química , Aspirina/química , Donantes de Óxido Nítrico/química , Oxadiazoles/química , Ácido Salicílico/química , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Colágeno/química , Colágeno/metabolismo , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Concentración de Iones de Hidrógeno , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Vasodilatadores/síntesis química , Vasodilatadores/química , Vasodilatadores/farmacología
4.
Artículo en Inglés | MEDLINE | ID: mdl-20953425

RESUMEN

Pharmacological therapy of back pain with analgesics and anti-inflammatory drugs is frequently associated with adverse effects, particularly in the elderly. Aim of this study was to compare mesotherapic versus conventional systemic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in patients with acute low back pain. Eighty-four patients were randomized to receive anti-inflammatory therapy according to the following protocols: (a) mesotherapy group received the 1st and 4th day 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 40 mg (1 mL), then on 7th, 10th, and 13th day, 2% lidocaine (1 mL) + ketoprofen 160 mg (1 mL) + methylprednisolone 20 mg (1 mL) (b) conventional therapy group received ketoprofen 80 mg × 2/die and esomeprazole 20 mg/die orally for 12 days, methylprednisolone 40 mg/die intramuscularly for 4 days, followed by methylprednisolone 20 mg/die for 3 days, and thereafter, methylprednisolone 20 mg/die at alternate days. Pain intensity and functional disability were assessed at baseline (T0), at the end of treatment (T1), and 6 months thereafter (T2) by using visual analogic scale (VAS) and Roland-Morris disability questionnaire (RMDQ). In both groups, VAS and RMDQ values were significantly reduced at the end of drug treatment and after 6 months, in comparison with baseline. No significant differences were found between the two groups. This suggests that mesotherapy may be a valid alternative to conventional therapy in the treatment of acute low back pain with corticosteroids and NSAIDs.

5.
Pharmacology ; 85(3): 146-52, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20145426

RESUMEN

The effect of a chronic (4 weeks) administration of sulphurous thermal water on gastric acid secretion and mucosal defense was investigated in rats. Animals were randomized to receive daily intake of tap water or of thermal water obtained from a local spa center (Tabiano, Parma, Italy). Rats were followed for one month as for water and food consumption, body weight and general conditions. At the end of the watering period, the following study protocols were carried out: (a) study of basal and stimulated gastric acid secretion under general anesthesia, and (b) study of the gastric mucosal resistance against the damage induced by ethanol and indomethacin in conscious rats. Basal acid secretion and the acid response to pentagastrin or to histamine were similar in rats assuming ordinary drinking water or thermal water. As for resistance to gastric damage, histological, but not macroscopic, evaluation revealed that rats which assumed thermal water were slightly more resistant to the gastrolesive effect of ethanol (either absolute or diluted). Again, when indomethacin was used as a noxious stimulus, no difference was noted between the two groups as for macroscopic damage; only a nonsignificant reduction of damage was observed histologically in stomachs of rats assuming thermal water. In conclusion, these results indicate that chronic treatment of rats with thermal water, rich in sulphur compounds, may have only minimal effects on the rat gastric mucosa and did not significantly affect mucosal defense mechanisms. The observed tendency to gastroprotection would possibly need further investigation with longer periods of administration.


Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Aguas Minerales , Compuestos de Azufre/farmacología , Animales , Peso Corporal , Citoprotección , Relación Dosis-Respuesta a Droga , Etanol/toxicidad , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Histamina/metabolismo , Indometacina/toxicidad , Masculino , Pentagastrina/metabolismo , Ratas , Ratas Wistar , Factores de Tiempo
6.
Pharmacology ; 86(5-6): 259-66, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20975320

RESUMEN

In the present study, the effects of ghrelin against the gastric damage induced by intragastric administration of 0.6 N HCl and the involvement of histamine H3 receptors (H3Rs) were investigated in conscious rats with selective H3R ligands. Intraperitoneal (i.p.) injection of ghrelin (40 µg/kg) significantly reduced (43%) the gastric lesions caused by concentrated acid. The effect of ghrelin was prevented by prior administration of the ghrelin receptor antagonist [D-Lys³]-GHRP-6 (100 µg/kg i.p.) and by subcutaneous (s.c.) injection of the nonimidazole H3R antagonist UCL2138 (30 mg/kg). The selective H3R agonist immethridine (30 mg/kg s.c.) significantly inhibited (64.60%) the gastric lesions induced by 0.6 N HCl. The effect of immethridine was prevented by prior administration of UCL2138 (30 mg/kg s.c.), but not by [D-Lys³]-GHRP-6 (100 µg/kg i.p.). Neither [D-Lys³]-GHRP-6 nor UCL2138 modified HCl-induced gastric damage per se. These data enlarge previous studies showing protective effects of ghrelin against ulcerogenic stimuli; in addition, they clearly indicate that ghrelin-induced gastroprotection involves the release of histamine, which enhances gastric mucosal defense through the activation of histamine H3Rs.


Asunto(s)
Mucosa Gástrica/fisiología , Ghrelina/fisiología , Receptores Histamínicos H3/metabolismo , Animales , Mucosa Gástrica/patología , Histamina/metabolismo , Ácido Clorhídrico/toxicidad , Inyecciones Intraperitoneales , Masculino , Ratas , Ratas Wistar
7.
J Med Chem ; 51(6): 1894-903, 2008 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-18293898

RESUMEN

A new class of products in which the phenol group of salicylic acid is linked to alkanoyl moieties bearing nitrooxy functions has been synthesized and studied for their polyvalent actions. The products were stable in acid and neutral media, while they were hydrolyzed in human serum. Their half-lives were dependent upon the structure of alkanoyl moieties. The products showed anti-inflammatory activities similar to aspirin when tested in the carrageenan-induced paw edema assay in the rat. Interestingly, unlike aspirin, they showed reduced or no gastrotoxicity in a lesion model in rats at equimolar doses. A number of them were able to inhibit platelet aggregation induced by collagen in human platelet-rich plasma. All of the products were capable of relaxing rat aortic strips precontracted with phenylephrine in a concentration-dependent manner. Selected members of this new class of nonsteroidal anti-inflammatory drugs might represent possible safer alternatives to aspirin in different clinical settings.


Asunto(s)
Antiinflamatorios no Esteroideos/química , Donantes de Óxido Nítrico/química , Nitrocompuestos/química , Inhibidores de Agregación Plaquetaria/química , Ácido Salicílico/química , Vasodilatadores/química , Animales , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacología , Aorta Torácica/efectos de los fármacos , Aspirina/farmacología , Carragenina , Evaluación Preclínica de Medicamentos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Humanos , Hidrólisis , Masculino , Estructura Molecular , Donantes de Óxido Nítrico/clasificación , Donantes de Óxido Nítrico/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/clasificación , Inhibidores de Agregación Plaquetaria/farmacología , Ratas , Ratas Wistar , Ácido Salicílico/clasificación , Ácido Salicílico/farmacología , Soluciones/química , Estereoisomerismo , Vasodilatadores/clasificación , Vasodilatadores/farmacología , Agua/química
8.
J Med Chem ; 51(8): 2457-67, 2008 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-18357976

RESUMEN

Using a previously reported flexible alignment model we have designed, synthesized, and evaluated a series of compounds at the human histamine H 4 receptor (H 4R) from which 2-(4-methyl-piperazin-1-yl)-quinoxaline ( 3) was identified as a new lead structure for H 4R ligands. Exploration of the structure-activity relationship (SAR) of this scaffold led to the identification of 6,7-dichloro 3-(4-methylpiperazin-1-yl)quinoxalin-2(1 H)-one (VUF 10214, 57) and 2-benzyl-3-(4-methyl-piperazin-1-yl)quinoxaline (VUF 10148, 20) as potent H 4R ligands with nanomolar affinities. In vivo studies in the rat reveal that compound 57 has significant anti-inflammatory properties in the carrageenan-induced paw-edema model.


Asunto(s)
Antiinflamatorios/farmacología , Diseño de Fármacos , Receptores Histamínicos/efectos de los fármacos , Antiinflamatorios/química , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Receptores Histamínicos/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad
9.
Eur J Pharmacol ; 563(1-3): 240-4, 2007 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-17382315

RESUMEN

The effects of the highly selective histamine H4 receptor antagonists JNJ7777120 and VUF6002 were investigated on the carrageenan-induced inflammation and thermal hyperalgesia in rats. JNJ7777120 (10 and 30 mg/kg, s.c.) and VUF6002 (10 mg/kg, s.c.) significantly reduced paw edema and hyperalgesia provoked by subplantar injection of carrageenan; the effect was evident against the early (2 h) phase of inflammation. An inactive analog of VUF6002, VUF6007 (10 mg/kg, s.c.) slightly aggravated paw edema, while leaving unaltered carrageenan-induced nociception. These findings indicate that histamine H4 receptors participate in the early phase of acute inflammation induced by carrageenan in rats, influencing both edema and thermal hyperalgesia.


Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Bencimidazoles/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Hiperalgesia/prevención & control , Indoles/farmacología , Inflamación/prevención & control , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Carragenina , Modelos Animales de Enfermedad , Edema/metabolismo , Edema/prevención & control , Calor , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Inflamación/inducido químicamente , Inflamación/complicaciones , Inflamación/metabolismo , Masculino , Dimensión del Dolor , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H4 , Factores de Tiempo
10.
Naunyn Schmiedebergs Arch Pharmacol ; 374(4): 283-91, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17151854

RESUMEN

Proton pump inhibitors (PPIs) have been shown to be effective in preventing gastric and duodenal ulcers in high-risk patients taking nonsteroidal anti-inflammatory drugs (NSAIDs); by contrast, scarce information is available concerning the effects of PPIs on intestinal damage induced by NSAIDs in humans or in experimental animals. We examined the effects of lansoprazole and omeprazole on the intestinal injury induced by indomethacin in the conscious rat. PPIs were administered by the intragastric route at 30, 60 and 90 micromol/kg, 12 h and 30 min before and 6 h after indomethacin treatment. The effects of omeprazole and lansoprazole were evaluated on: (1) macroscopic and histologic damage; (2) mucosal polymorphonuclear cell infiltration; (3) oxidative tissue damage and (4) bacterial translocation from lumen into the intestinal mucosa. Lansoprazole and omeprazole (at 90 micromol/kg) significantly decreased (P<0.01) the macroscopic and histologic damage induced by indomethacin in the rat small intestine. Furthermore, both drugs greatly reduced (P<0.01) the associated increases in myeloperoxidase levels and lipid peroxidation induced by indomethacin, whereas they only moderately affected (P<0.05) the translocation of enterobacteria from lumen into the intestinal mucosa. These data demonstrate that omeprazole and lansoprazole can protect the small intestine from the damage induced by indomethacin in the conscious rat. The intestinal protection, possibly related to antioxidant and anti-inflammatory properties of these drugs, may suggest new therapeutic uses of PPIs in intestinal inflammatory diseases.


Asunto(s)
Indometacina/toxicidad , Intestino Delgado/efectos de los fármacos , Inhibidores de la Bomba de Protones , 2-Piridinilmetilsulfinilbencimidazoles/farmacología , Animales , Antiulcerosos/farmacología , Bacterias Aerobias/efectos de los fármacos , Bacterias Anaerobias/efectos de los fármacos , Traslocación Bacteriana/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indometacina/administración & dosificación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestino Delgado/microbiología , Intestino Delgado/patología , Intubación Gastrointestinal , Yeyuno/efectos de los fármacos , Yeyuno/microbiología , Yeyuno/patología , Lansoprazol , Masculino , Malondialdehído/metabolismo , Infiltración Neutrófila/efectos de los fármacos , Omeprazol/farmacología , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad
11.
Acta Biomed ; 78(2): 96-110, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17933277

RESUMEN

Nonsteroidal antiinflammatory drugs (NSAIDs) are frequently associated with adverse reactions, related to inhibition of cyclooxygenase (COX) in tissues where prostaglandins exert physiological effects, such as gastric mucosal defense and renal homeostasis. The discovery of two COX isoforms, namely COX-1 constitutively expressed in most tissues and COX-2 induced at sites of inflammation, led to the development of selective COX-2 inhibitors ("coxibs"), with the hope of significantly reducing the gastrointestinal toxicity associated with acute and chronic NSAID use. However, the increased knowledge of physiological roles of COX-2 enzyme in a variety of tissues, including stomach and kidney, together with the withdrawal from the market of rofecoxib and valdecoxib because of cardiovascular toxicity, have challenged the benefits of selective COX-2 inhibition. As a consequence, the interest for novel approaches has re-emerged; new therapeutic options, still under clinical evaluation, are represented by dual COX and 5-lipooxygenase (5-LOX) inhibitors, synthetic lipoxins, nitric oxide (NO)-releasing NSAIDs and, more recently, by NSAIDs releasing hydrogen sulphide (H2S). This review focuses upon the gastrointestinal (GI) safety of selective COX-2 inhibitors and of novel therapeutic strategies, in comparison with traditional NSAIDs.


Asunto(s)
Acetatos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Lipoxinas/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Pirroles/farmacología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Ensayos Clínicos como Asunto , Colon/efectos de los fármacos , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa , Mucosa Gástrica/efectos de los fármacos , Humanos , Sulfuro de Hidrógeno , Lipoxinas/síntesis química , Óxido Nítrico , Donantes de Óxido Nítrico/farmacología , Isoformas de Proteínas , Seguridad
12.
Eur J Pharmacol ; 552(1-3): 143-50, 2006 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-17069793

RESUMEN

It is now widely recognized that nonsteroidal anti-inflammatory drugs (NSAIDs) may cause extensive damage to the intestine. The pathogenesis of NSAID-induced intestinal injury, however, is still controversial and both local irritant actions and cyclooxygenase (COX) inhibition have been proposed as underlying mechanisms. In this study we investigated further on NSAID-induced intestinal damage by using nonselective (indomethacin and ibuprofen), COX-1 selective (SC-560) or COX-2 selective (celecoxib) inhibitors. NSAIDs were administered orally to conscious rats and small intestinal injury was evaluated 24 h afterwards in terms of macroscopic and microscopic alterations, myeloperoxidase activity, lipid peroxidation, number of enterobacteria in the mucosa and epithelial mucin content. Oral administration of indomethacin (20 mg/kg) induced macroscopic and microscopic damage to the small intestine, increased translocation of enterobacteria from lumen into the mucosa, myeloperoxidase activity and lipid peroxidation. Ibuprofen (120 mg/kg), SC-560 (20 mg/kg), celecoxib (60 mg/kg) or the combination of SC-560 plus celecoxib did not cause any intestinal injury nor modified the number of bacteria in mucosal homogenates. SC-560 significantly increased both myeloperoxidase activity and lipid peroxidation, whereas celecoxib significantly reduced myeloperoxidase levels, while leaving unaltered lipid peroxidation. Finally, all NSAIDs, mostly indomethacin, increased neutral mucins and decreased acidic mucins in the intestinal goblet cells. These results indicate that inhibition of cyclooxygenase, although variably influencing mucosal integrity homeostasis, is not sufficient to initiate acute intestinal damage in rats. Moreover, topical mucosal injury induced by the NSAID molecule seems to be a critical factor in the development of intestinal injury.


Asunto(s)
Antiinflamatorios no Esteroideos/toxicidad , Inhibidores de la Ciclooxigenasa/toxicidad , Intestino Delgado/efectos de los fármacos , Administración Oral , Análisis de Varianza , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Celecoxib , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/administración & dosificación , Enterobacteriaceae/citología , Enterobacteriaceae/crecimiento & desarrollo , Ibuprofeno/administración & dosificación , Ibuprofeno/toxicidad , Indometacina/administración & dosificación , Indometacina/toxicidad , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Intestino Delgado/metabolismo , Intestino Delgado/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Mucinas/metabolismo , Peroxidasa/metabolismo , Pirazoles/administración & dosificación , Pirazoles/toxicidad , Ratas , Ratas Wistar , Sulfonamidas/administración & dosificación , Sulfonamidas/toxicidad
13.
J Med Chem ; 48(6): 2100-7, 2005 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-15771452

RESUMEN

In this study, we continue our efforts toward the development of potent and highly selective histamine H(3) receptor agonists. We introduced various alkyl or aryl alkyl groups on the piperidine nitrogen of the known H(3)/H(4) agonist immepip and its analogues (1-3a). We observed that N-methyl-substituted immepip (methimepip) exhibits high affinity and agonist activity at the human histamine H(3) receptor (pK(i) = 9.0 and pEC(50) = 9.5) with a 2000-fold selectivity at the human H(3) receptor over the human H(4) receptor and more than a 10000-fold selectivity over the human histamine H(1) and H(2) receptors. Methimepip was also very effective as an H(3) receptor agonist at the guinea pig ileum (pD(2) = 8.26). Moreover, in vivo microdialysis (in rat brain) showed that methimepip reduces the basal level of brain histamine to about 25% after a 5 mg/kg intraperitoneal administration.


Asunto(s)
Agonistas de los Receptores Histamínicos/síntesis química , Imidazoles/síntesis química , Piperidinas/síntesis química , Receptores Histamínicos H3/efectos de los fármacos , Animales , Unión Competitiva , Línea Celular , Chlorocebus aethiops , Cricetinae , Cricetulus , Estimulación Eléctrica , Cobayas , Histamina/metabolismo , Agonistas de los Receptores Histamínicos/química , Agonistas de los Receptores Histamínicos/farmacología , Humanos , Hipotálamo/metabolismo , Íleon/efectos de los fármacos , Íleon/fisiología , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Microdiálisis , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Piperidinas/química , Piperidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Wistar
14.
J Med Chem ; 46(5): 747-54, 2003 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-12593655

RESUMEN

A new series of NSAIDs in which aspirin is joined by an ester linkage to furoxan moieties, with different ability to release NO, were synthesized and tested for NO-releasing, antiinflammatory, antiaggregatory, and ulcerogenic properties. Related furazan derivatives, aspirin, its propyl ester, and its gamma-nitrooxypropyl ester were taken as references. All the products described present an antiinflammatory trend, maximized in derivatives 12, 16, and 17, they are devoid of acute gastrotoxicity, principally due to their ester nature, and show an antiplatelet activity primarily determined by their ability to release NO. They do not behave as aspirin prodrugs in human serum.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Aspirina/análogos & derivados , Aspirina/síntesis química , Donantes de Óxido Nítrico/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Aspirina/farmacología , Aspirina/toxicidad , Edema/tratamiento farmacológico , Ésteres , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Técnicas In Vitro , Masculino , Necrosis , Óxido Nítrico/sangre , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/toxicidad , Úlcera Péptica/inducido químicamente , Úlcera Péptica/patología , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/toxicidad , Ratas , Ratas Wistar
15.
Br J Pharmacol ; 135(7): 1598-606, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11934799

RESUMEN

1. The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. 2. In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 - 4.00 micromol kg(-1), i.v.) and the selective CB(1)-receptor agonist HU-210 (0.03 - 1.50 micromol kg(-1), i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg(-1) h(-1)) and 2-deoxy-D-glucose (1.25 mmol kg(-1), i.v.). By contrast, neither WIN 55,212-2 (1 - 4 micromol kg(-1), i.v.) nor HU-210 (0.03 - 1.50 micromol kg(-1), i.v.) did modify histamine-induced acid secretion (20 micromol kg(-1) h(-1)). The selective CB(2)-receptor agonist JWH-015 (3 - 10 micromol kg(-1), i.v.) was ineffective. 3. The gastric antisecretory effects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB(1)-receptor antagonist SR141716A (0.65 micromol kg(-1), i.v.) and unaffected by the selective CB(2)-receptor antagonist SR144528 (0.65 - 2 micromol kg(-1), i.v.). 4. Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg(-1), i.v., followed by continuous infusion of 10 mg kg(-1) h(-1)) significantly reduced, but not abolished, the maximal inhibitory effect of HU-210 (0.3 micromol kg(-1), i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg(-1), i.v.) did not modify the antisecretory effect of HU-210. 5. Immunoreactivity to the CB(1) receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB(2) receptor-like immunoreactivity was not observed. 6. These results indicate that gastric antisecretory effects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB(1) receptors, located on pre- and postganglionic cholinergic pathways. However, the ineffectiveness of atropine in reducing the effect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB(1) receptors.


Asunto(s)
Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Receptor Cannabinoide CB2 , Receptores de Droga/metabolismo , Animales , Atropina/farmacología , Cannabinoides/farmacología , Dronabinol/análogos & derivados , Dronabinol/farmacología , Hexametonio/farmacología , Inmunohistoquímica , Masculino , Antagonistas Muscarínicos/farmacología , Antagonistas Nicotínicos/farmacología , Pentagastrina/farmacología , Ratas , Ratas Wistar , Receptores de Cannabinoides , Receptores de Droga/fisiología , Vagotomía
16.
Brain Res Bull ; 64(4): 357-61, 2004 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-15561471

RESUMEN

Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 microg/kg) and HU-210 (25, 50 and 100 microg/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 microg/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 microg/kg) or HU-210 (10-100 microg/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB(1)-receptor antagonist SR141716A (1000 microg/kg, i.v.). These results show that CB(1)-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.


Asunto(s)
Cannabinoides/farmacología , Dronabinol/análogos & derivados , Ácido Gástrico/metabolismo , Estómago/efectos de los fármacos , Análisis de Varianza , Animales , Área Bajo la Curva , Benzoxazinas , Bloqueadores de los Canales de Calcio/administración & dosificación , Cannabinoides/síntesis química , Relación Dosis-Respuesta a Droga , Dronabinol/administración & dosificación , Vías de Administración de Medicamentos , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Mucosa Gástrica/metabolismo , Inyecciones Intravenosas/métodos , Inyecciones Intraventriculares/métodos , Masculino , Morfolinas/administración & dosificación , Naftalenos/administración & dosificación , Pentagastrina/farmacología , Ratas , Ratas Wistar
17.
Front Biosci (Schol Ed) ; 4(1): 226-39, 2012 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-22202056

RESUMEN

The location and functional role of histamine H4 receptors (H4Rs) in the gastrointestinal tract (GI) is reviewed, with particular reference to their involvement in the regulation of gastric acid secretion, gastric mucosal defense, intestinal motility and secretion, visceral sensitivity, inflammation, immunity and carcinogenesis. H4Rs have been detected in different cell types of the gut, including immune cells, paracrine cells, endocrine cells and neurons; moreover, H4R expression was reported in human colorectal cancer specimens. Functional studies with selective H4R ligands demonstrated protective effects in several experimental models of gastric mucosal damage and intestinal inflammation, suggesting a potential therapeutic role of drugs targeting this new receptor subtype in GI disorders, such as allergic enteropathy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and cancer.


Asunto(s)
Tracto Gastrointestinal/metabolismo , Receptores Histamínicos/metabolismo , Animales , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/metabolismo , Motilidad Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/fisiología , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Terapia Molecular Dirigida
18.
Eur J Pharmacol ; 669(1-3): 121-7, 2011 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-21839070

RESUMEN

The present study investigated the role of histamine H(3) and H(4) receptors in gastric mucosal defense, by the use of selective ligands. Firstly, the affinities of several histaminergic agonists for the rat histamine H(3) and H(4) receptors were checked in HEK 293T cells transfected with either receptor subtype. Next, functional activities were determined in conscious rat against the ulcerogenic effect of 0.6N HCl. Radioligand binding studies showed that immethridine and methimepip were the most selective agonists at rat H(3) receptors, whereas VUF10460 displayed approximately a 50-fold selectivity for the rat H(4) receptor over the H(3) receptor. In conscious rats, immethridine and methimepip significantly reduced (66% and 48% inhibition, respectively) the gastric lesions induced by HCl; the effect of immethridine was antagonized by the H(3) receptor antagonist A-331440, but not by the H(4) receptor antagonist JNJ7777120. The mixed H(3)/H(4) receptor agonist immepip induced a significant aggravation of HCl damage, which was prevented by JNJ7777120; HCl-induced lesions were also significantly enhanced by the H(4) receptor agonists VUF10460 and VUF8430; however, this effect was not modified by JNJ7777120. Overall, this study indicates that, whereas the histamine H(3) receptor is involved in the protection of rat stomach against concentrated HCl, the functional role of the H(4) receptor is still to be defined, although selective agonists induce proulcerogenic effects under HCl challenge. Finally, the species-dependent variations in affinity and receptor selectivity observed for most ligands need to be carefully addressed in the pharmacological characterization of histamine H(3) and H(4) receptor functions in vivo.


Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos/metabolismo , Úlcera Gástrica/tratamiento farmacológico , Animales , Células HEK293 , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Ácido Clorhídrico , Masculino , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/genética , Receptores Histamínicos H3/genética , Receptores Histamínicos H4 , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Transfección
19.
Curr Protoc Toxicol ; Chapter 21: Unit 21.1, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20967743

RESUMEN

The gastrointestinal (GI) tract has the unique feature of having a huge area for exposure to potentially harmful agents, including concentrated acid, food, chemicals, and pathogens. Research over the past decades has identified some of the key events that are involved in mucosal damage and defense. The enteric nervous system, immune system, and a variety of endocrine and paracrine mediators act in concert to endure mucosal barrier integrity and gut homeostasis. Disruptors of mucosal defense mechanisms include drugs, food allergens and contaminants, metals, chemicals, radiation, and pathogens. A variety of animal experimental models have been set up to detect possible deleterious effects to the GI tract and the potential risk in humans.


Asunto(s)
Enfermedades Gastrointestinales/inducido químicamente , Tracto Gastrointestinal/efectos de los fármacos , Animales , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/microbiología , Mucosa Gástrica/fisiología , Mucosa Gástrica/fisiopatología , Enfermedades Gastrointestinales/microbiología , Enfermedades Gastrointestinales/fisiopatología , Tracto Gastrointestinal/fisiología , Tracto Gastrointestinal/fisiopatología , Tracto Gastrointestinal/efectos de la radiación , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/fisiología , Mucosa Intestinal/fisiopatología
20.
Curr Protoc Toxicol ; Chapter 21: Unit 21.5, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20967747

RESUMEN

The protocols described in this unit are designed to assess the effects of substances on gastric acid secretion by the rat stomach, with the animal under general anesthesia. Both stimulatory and inhibitory effects of compounds can be evaluated and specific mechanisms of action can also be investigated. Acid secretion is induced by substances that directly activate parietal cell receptors (histamine and bethanechol), by indirect stimuli, like 2-deoxy-D-glucose, by electrical stimulation of vagal nerves, or by the peptide pentagastrin. Reference antisecretory drugs are represented by histamine H(2) receptor antagonists and proton pump inhibitors. This model allows the evaluation of complete dose-response curves together with a time-course of the secretory/antisecretory effects. Indirect effects involving activation or inhibition of vagal pathways are evaluated in intact animals by means of electrical vagal stimulation or in vagotomized animals.


Asunto(s)
Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Estómago/fisiología , Animales , Animales de Laboratorio , Determinación de la Acidez Gástrica , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inervación , Farmacología/métodos , Ratas , Estómago/efectos de los fármacos , Estómago/inervación , Toxicología/métodos , Vagotomía , Estimulación del Nervio Vago
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