RESUMEN
BACKGROUND AND AIMS: Obesity-driven lipotoxicity is a risk factors for cardiovascular disease. The Farnesoid X Receptor (FXR) is a bile acids sensor and member of the nuclear receptor superfamily. Activation of FXR lowers plasma triacylglycerols and glucose levels through a mechanism that involves both the repression of key regulatory genes in the liver and the modulation of insulin sensitivity in peripheral tissues. In the present study we have investigated whether administering obese (fa/fa) Zucker rats, a genetic model of obesity associated with dyslipidemia and insulin resistance, with an FXR ligand protects against lipid-induced cardiomyopathy. METHODS AND RESULTS: FXR is expressed in neonatal cardiomyocytes and the treatment with FXR agonists, chenodeoxycholic acid (CDCA), and GW4064, increased the mRNA expression of FXR and its canonical target gene, the small heterodimer partner (SHP), as well as proliferator-activated receptor alpha PPARα, acyl-CoA oxidase (AOX) and pyruvate dehydrogenase kinase (PDK-4). Feeding obese fa/fa rats with CDCA, 12 weeks, reduced hyperinsulinemia and hyperlipidaemia. The histological-pathological analysis of hearts demonstrated that treatment with the FXR ligand reduced lipid heart content decreased the rate of apoptosis, fibrosis scores and restored heart insulin signalling. Chronic CDCA administration, in the heart, induced PPARα and PPARα-regulated genes involved in ß-oxidation. CONCLUSION: FXR agonism exerts beneficial effects in a genetic model of lipid-induced cardiomyopathy. The striking benefit of this therapy on cardiac function in this model warrants an effort to determine whether a counterpart of this activity translates in human settings.
Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Metabolismo de los Lípidos , Miocardio/metabolismo , Obesidad/fisiopatología , Receptores Citoplasmáticos y Nucleares/genética , Acil-CoA Oxidasa/genética , Acil-CoA Oxidasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Ácidos y Sales Biliares/metabolismo , Glucemia/análisis , Enfermedades Cardiovasculares/etiología , Ácido Quenodesoxicólico/farmacología , Dislipidemias/metabolismo , Dislipidemias/patología , Fibrosis/tratamiento farmacológico , Hiperinsulinismo/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Resistencia a la Insulina , Isoxazoles/farmacología , Hígado/metabolismo , Obesidad/complicaciones , PPAR alfa/genética , PPAR alfa/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Zucker , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Riesgo , Triglicéridos/sangreRESUMEN
BACKGROUND AND PURPOSE: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-to-moderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H(2)S-releasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. EXPERIMENTAL APPROACH: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. KEY RESULTS: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by approximately 70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFalpha, IFNgamma). Treatment with ADT-OH, the H(2)S-releasing moiety of ATB-429, did not affect severity of colitis. CONCLUSIONS AND IMPLICATIONS: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H(2)S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.
Asunto(s)
Antiinflamatorios/farmacología , Colitis/prevención & control , Colon/efectos de los fármacos , Disulfuros/farmacología , Fármacos Gastrointestinales/farmacología , Sulfuro de Hidrógeno/metabolismo , Mesalamina/farmacología , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/uso terapéutico , Quimiocinas/genética , Quimiocinas/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/patología , Colon/metabolismo , Colon/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Disulfuros/metabolismo , Disulfuros/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Fármacos Gastrointestinales/metabolismo , Fármacos Gastrointestinales/uso terapéutico , Expresión Génica/efectos de los fármacos , Granulocitos/efectos de los fármacos , Granulocitos/patología , Mesalamina/metabolismo , Mesalamina/uso terapéutico , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Ácido TrinitrobencenosulfónicoRESUMEN
Nonsteroidal anti-inflammatory drugs are widely prescribed for treatment of pain and inflammation, despite their association with gastrointestinal complications, including bleeding and perforation. Inhibition of cyclo-oxygenases, is the main mechanism of action of aspirin and nonsteroidal anti-inflammatory drugs. Non-selective nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase-1 and cyclo-oxygenase-2. Inhibition of cyclo-oxygenase-1 derived prostanoids in the stomach represent the underlying mechanism involved in development of gastric and duodenal ulcers in patients taking nonsteroidal anti-inflammatory drugs. Selective cyclo-oxygenases-2 inhibitor (coxibs) spare cyclo-oxygenase-1 show enhanced safety profile in the gastrointestinal tract, but increase the risk of heart attack and stroke. Spurred by these findings, two coxibs, rofecoxib and valdecoxib, were withdrawn from the market. In addition to prostanoids, two gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H(2)S) exert protective effects in gastric mucosa. The inhibitory effects of NO on nonsteroidal anti-inflammatory drugs-induced leukocyte adherence have been exploited in the development of NO-releasing nonsteroidal anti-inflammatory drugs, also indicated as cyclo-oxygenase-inhibiting NO-donating drugs. Despite its non-selective profile versus cyclo-oxygenase isoenzymes, naprocyclo-oxygenase-inhibiting NO-donating drugs, the prototype of this class of anti-inflammatory agents, reduces systemic blood pressure and might have enhanced cardiovascular safety than coxibs, while causing less gastrointestinal damage than its parent drug, the naproxen. H(2)S-releasing nonsteroidal anti-inflammatory drugs derivatives have been recently developed, based on the observed ability of this gaseous mediator to cause vasodilation and to prevent leukocyte adherence. In pre-clinical settings, H(2)S-releasing nonsteroidal anti-inflammatory drugs produce less gastric damage as compared to the parent drugs. Cyclo-oxygenases-inhibiting NO-donating drugs and H(2)S-releasing nonsteroidal anti-inflammatory drugs represent examples of new anti-inflammatory drugs created through the exploitation of the beneficial effects of endogenous gaseous mediators in the gastrointestinal and cardiovascular systems.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Inhibidores de la Ciclooxigenasa/efectos adversos , Mucosa Gástrica/efectos de los fármacos , Sulfuro de Hidrógeno/metabolismo , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico/metabolismo , Animales , Modelos Animales de Enfermedad , Úlcera Duodenal/inducido químicamente , Úlcera Duodenal/prevención & control , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , Humanos , Naproxeno/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & controlRESUMEN
The focus of management of gastrointestinal motility disorders should be to improve survival and quality of life. Some motor disorders are annoying, but are compatible with virtually normal activity and carry no significant life risk. Conversely, other motor disorders are highly incapacitating and may shorten life expectancy because of complications and nutritional impairment. Management is based first on establishing the correct diagnosis and prognosis; secondly, on adjusting therapy to the severity of illness; and thirdly, on preventing significant complications. Simple recommendations on appropriate changes in lifestyle and reassurance may suffice in mild cases. Pharmacological therapy and, exceptionally, surgical or nutritional measures may be required in other patients. Generally, pharmacological agents should be directed towards correcting specific pathophysiological abnormalities, but this is not always possible. Symptomatic relief may be achieved on an empirical basis. Long term treatment may often require the combination of different therapeutic approaches either sequentially or simultaneously.
Asunto(s)
Trastornos de la Motilidad Esofágica/tratamiento farmacológico , Motilidad Gastrointestinal/efectos de los fármacos , Gastroparesia/tratamiento farmacológico , Seudoobstrucción Intestinal/tratamiento farmacológico , Agonistas Adrenérgicos/administración & dosificación , Agonistas Adrenérgicos/farmacología , Agonistas Adrenérgicos/uso terapéutico , Antiinfecciosos/administración & dosificación , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Calcio/antagonistas & inhibidores , Dolor en el Pecho/tratamiento farmacológico , Dolor en el Pecho/etiología , Ensayos Clínicos como Asunto , Terapia Combinada , Endoscopía , Trastornos de la Motilidad Esofágica/etiología , Gastroparesia/etiología , Humanos , Seudoobstrucción Intestinal/etiología , Seudoobstrucción Intestinal/terapia , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/uso terapéutico , Inhibidores de la Bomba de ProtonesRESUMEN
BACKGROUND: Altered visceral perception is common in functional dyspepsia (FD). Dopaminergic pathways control gastrointestinal motility, but whether they modulate visceral sensitivity is unknown. AIM: To investigate whether levosulpiride, a D2 antagonist, modulates gastric sensitivity and compliance in dyspeptic patients. METHODS: Eight healthy subjects and 16 dyspeptic patients underwent graded gastric distensions using a tensostat. In dyspeptic patients the same isotonic distensions were repeated during either levosulpiride or saline administration. Eight FD patients were evaluated after 4-week treatment with oral levosulpiride. Gastrointestinal symptoms were evaluated using a 100 mm visual analogue score. Perception was scored on a scale of 0 to 6. RESULTS: Although healthy subjects and FD patients had similar gastric compliance, FD patients tolerated lower tension levels. At the same distending tension levels, levosulpiride decreased gastric compliance and perception score (14 +/- 6% and 38 +/- 10% change, respectively; P < 0.05 vs. saline) only in FD patients. Isotonic distensions exhibited very reproducible perception. Chronic levosulpiride administration significantly reduced dyspeptic symptoms and increased discomfort threshold. CONCLUSIONS: Compared with healthy subjects, FD patients show marked gastric hypersensitivity. In FD patients levosulpiride decreased the perception of gastric distension with an action unrelated to change of gastric tone. Chronic levosulpiride administration significantly ameliorates gastrointestinal symptoms and increases the discomfort threshold.
Asunto(s)
Dispepsia/fisiopatología , Vaciamiento Gástrico/efectos de los fármacos , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacología , Estómago/efectos de los fármacos , Sulpirida/análogos & derivados , Sulpirida/administración & dosificación , Sulpirida/farmacología , Adulto , Método Doble Ciego , Esquema de Medicación , Dispepsia/tratamiento farmacológico , Femenino , Vaciamiento Gástrico/fisiología , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Humanos , Persona de Mediana Edad , Tono Muscular/efectos de los fármacos , Presión , Reproducibilidad de los Resultados , Estómago/fisiopatología , Sulpirida/efectos adversos , Sulpirida/uso terapéutico , Encuestas y CuestionariosRESUMEN
BACKGROUND: Nitric oxide (NO)-releasing NSAIDs are a new class of NSAID derivatives with markedly reduced gastrointestinal toxicity. Although it has been demonstrated that NO-NSAIDs spare gastric mucosal blood flow, molecular determinants involved in this effect are unknown. AIM: To investigate the effect of aspirin, naproxen and flurbiprofen, and their NO-derivatives, on gastric apoptosis and endothelial cell damage induced by tumour necrosis factor-alpha (TNFalpha). In other systems, TNFalpha-induced apoptosis is mediated by caspases, a growing family of cysteine proteases similar to the IL-1beta converting enzyme (ICE), and so we have investigated whether NO-NSAIDs modulate ICE-like endopeptidases. METHODS: Rats were treated orally with aspirin, naproxen and flurbiprofen, or their NO-releasing derivatives in equimolar doses, and were killed 3 h later to assess mucosal damage and caspase activity. Endothelial cells (HUVECs) were obtained from human umbilical cord by enzymatic digestion. Caspase 1 and 3 activities were measured by a fluorimetric assay using selective peptides as substrates and inhibitors. Apoptosis was quantified by ELISA specific for histone-associated DNA fragments and by the terminal transferase nick-end translation method (TUNEL). RESULTS: In vivo NSAID administration caused a time-dependent increase in gastric mucosal damage and caspase activity. NCX-4016, NO-naproxen and NO-flurbiprofen did not cause any mucosal damage and prevented cysteine protease activation. NSAIDs and NO-NSAIDs stimulated TNFalpha release. Exposure to TNFalpha resulted in a time- and concentration-dependent HUVEC apoptosis, an effect that was prevented by pretreating the cells with NCX-4016, NO-naproxen, NO-flurbiprofen, SNP or Z-VAD.FMK, a pan-caspase inhibitor. The activation of ICE-like cysteine proteases was required to mediate TNFalpha-induced apoptosis of HUVECs. Exogenous NO donors inhibited TNFalpha-induced cysteine protease activation. Inhibition of caspase activity was due to S-nitrosylation of ICE/CPP32-like proteases. NO-NSAIDs prevented IL-1beta release from endotoxin-stimulated macrophages. CONCLUSIONS: NO-releasing NSAIDs are a new class of non-peptide caspase inhibitors. Inhibition of ICE-like cysteine proteases prevents endothelial cell damage induced by pro-inflammatory agents and might contribute to the gastro-protective effects of NO-NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas , Inhibidores de Cisteína Proteinasa/farmacología , Mucosa Gástrica/citología , Óxido Nítrico/metabolismo , Animales , Aspirina/análogos & derivados , Aspirina/farmacología , Línea Celular , Fragmentación del ADN/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Flurbiprofeno/análogos & derivados , Flurbiprofeno/farmacología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/enzimología , Humanos , Etiquetado Corte-Fin in Situ , Masculino , Ratones , Naproxeno/análogos & derivados , Naproxeno/farmacología , Óxido Nítrico/farmacología , Peroxidasa/antagonistas & inhibidores , Peroxidasa/metabolismo , Ratas , Ratas WistarRESUMEN
BACKGROUND: The aim of as study was to ascertain whether the association of interferon alpha-2a and ursodeoxycholic acid (IFN+UDCA) was more efficacious in ameliorating liver parameters than interferon (IFN) alone in patients with chronic hepatitis C. METHODS: Forty-one chronic hepatitis C patients, who had at least twice the normal value of one transaminase, were randomly assigned to treatment with IFN + UDCA (n = 21) or IFN alone (n = 20). IFN was administered subcutaneously at a dose of 3 MU thrice weekly, UDCA orally at 10 mg/kg bw/day. IFN therapy was terminated 6 months later and the responders (normalized transaminases) of both groups were treated with UDCA alone for a further 12 months. RESULTS: In the IFN + UDCA group there were 2 drop-outs from therapy and 11 responders, while in the IFN group they were, respectively, 3 and 10. Transaminases normalized after the first month of treatment in 7/11 responders with IFN + UDCA compared with 3/10 in the IFN responders group. The trend to normalization was more rapid with IFN + UDCA than with IFN alone (chi 2t = 3.95; p < 0.05). Disease relapse (defined as at least one transaminase > x 1.5 the normal value) was 3/11 in the IFN + UDCA group and 4/10 in the IFN group. 2/11 responders in the IFN + UDCA and 1/10 in the IFN group were HCV RNA negative by PCR. The total Knodell histological score decreased more in the IFN+UDCA than in the IFN group (-2.67 +/- 3.44. vs -1.67 +/- 2.16, mean +/- SD). CONCLUSIONS: The administration of UDCA determine an earlier normalization-time of transaminases in the patients responders to IFN therapy and could be useful to reduce the relapse into disease after the IFN therapy.
Asunto(s)
Antivirales/uso terapéutico , Colagogos y Coleréticos/uso terapéutico , Hepatitis C/terapia , Interferón-alfa/uso terapéutico , Ácido Ursodesoxicólico/uso terapéutico , Adolescente , Adulto , Anciano , Enfermedad Crónica , Quimioterapia Combinada , Femenino , Hepatitis C/sangre , Hepatitis C/patología , Humanos , Interferón alfa-2 , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , RecurrenciaRESUMEN
The effectiveness of oral bile acid therapy with ursodeoxycholic acid (10 mg/kg/day) was investigated in a 10 year old boy affected by Alagille's Syndrome, a chronic cholestatic disorder due to congenital hypoplasia of the intrahepatic biliary ducts. Cholestatic and hepatonecrotic indices were measured before and during ursodeoxycholic acid therapy and 1 month after stopping and 36 months after restarting the treatment. Ursodeoxycholic acid led to a marked improvement in the cholestatic and hepatonecrotic parameters which was maintained during all the treatment phase. Pruritus and steatorrhea disappeared during the treatment with ursodeoxycholic acid. Histological examination of the liver biopsy after the treatment revealed a disappearance of the biliary plugs but without increasing he intrahepatic bile ducts. The results suggest that ursodeoxycholic acid may improve the condition of the children affected by Alagille's Syndrome, specially when the liver transplantation is required, and indicate a need for long term studies in a larger number of patients.
Asunto(s)
Conductos Biliares Intrahepáticos/anomalías , Colestasis/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéutico , Niño , Enfermedad Crónica , Humanos , Masculino , SíndromeRESUMEN
Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of pain, fever and inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal bleeding. ASA and tNSAIDs inhibit cyclooxygenases (COXs). The COX exists at least in two isoforms, COX-1 and COX-2. Selective inhibitors of COX-2, the coxibs, spares the gastrointestinal tract while exert anti-inflammatory and analgesic effects. However, coxibs increase the risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H2S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. Hybrid molecules generated by coupling a NO or H2S releasing moiety to ASA or tNSAIDs has resulted into new classes of NSAIDs. These agents, the NO-releasing NSAIDs, or CINOD, and the H2S releasing NSAIDs are currently investigated as a potential alternative to tNSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD investigated in clinical trials. These studies have shown a slightly improvement in gastrointestinal tolerability in comparison to naproxen in surrogate endpoints (number of gastric and duodenal ulcers) and a significant reduction in the risk of destabilization of blood pressure control in patients with osteoarthosis taking anti-hypertensive medications in comparison to either naproxen and rofecoxib. The lack of outcome studies, however, has precluded the approval of naproxcinod by the Food and Drug Administration leading to a voluntary withdrawn of an application to the EMEA in May 2011. NSAIDs that releases H2S as a mechanism supporting an intrinsic gastrointestinal and cardiovascular safety are being investigated in preclinical models. Either naproxen and diclofenac hybrids have been reported to cause less gastrointestinal injury than parent NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H2S and/or by exerting anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Hemorragia Gastrointestinal/inducido químicamente , Tracto Gastrointestinal/efectos de los fármacos , Humanos , Sulfuro de Hidrógeno/metabolismo , Inflamación/tratamiento farmacológico , Óxido Nítrico/metabolismo , Dolor/tratamiento farmacológicoRESUMEN
In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptors named the TGR5. With a different rank of potency primary and secondary bile acids activates a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x- receptor (PXR, NR1H2), the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as a braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Inmunidad Innata/fisiología , Animales , Receptor de Androstano Constitutivo , Humanos , Inmunidad Innata/genética , Modelos Biológicos , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
OBJECTIVES: Scleroderma patients frequently present esophageal and gastric emptying abnormalities and small bowel dysfunction. Erythromycin, a macrolide antibiotic, has been found to accelerate gastric and gallbladder emptying in both healthy subjects and diabetic patients. Our objective was to investigate the effects of 4-wk oral erythromycin administration on the gastric and gallbladder emptying, gastrointestinal symptoms (early satiety, abdominal pain, nausea, bloating, vomiting, and constipation), and motilin plasma levels of patients with scleroderma. METHODS: 12 scleroderma patients were investigated before and after 4-wk treatment with 250 mg oral erythromycin three times a day. The effect of a single i.v. dose of 2 mg/kg/h erythromycin on gastric and gallbladder emptying before starting the oral treatment was also evaluated. Gastric and gallbladder emptying after a solid meal were evaluated by sonography. RESULTS: Single i.v. administration of erythromycin before the meal reduced gastric emptying T1/2 from 121.3 +/- 14.0 to 45.5 +/- 7.3 min (p < 0.01) and accelerated gallbladder emptying without affecting the peak. Four-week oral administration of erythromycin reduced gastric emptying T1/2 from 121.3 +/- 14.0 min to 46.5 +/- 8.3 min (p < 0.01). Peak gallbladder emptying was also significantly accelerated, while total emptying remained unchanged (p < 0.01). Furthermore, 4-wk erythromycin administration reduced both motilin plasma levels (from 223.4 +/- 53.8 to 145.4 +/- 67.2 pmol/L, p < 0.01) and symptoms of nausea, vomiting, and abdominal pain (p < 0.01), and increased bowel movements in a subset of scleroderma patients with intestinal pseudo-obstruction. CONCLUSIONS: Erythromycin stimulates gastrointestinal motility in patients with scleroderma. Administered medium-term, it accelerates gastric and gallbladder emptying and alleviates gastrointestinal symptoms.
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Eritromicina/uso terapéutico , Vaciamiento Vesicular/efectos de los fármacos , Vaciamiento Gástrico/efectos de los fármacos , Enfermedades Gastrointestinales/prevención & control , Esclerodermia Sistémica/fisiopatología , Esquema de Medicación , Eritromicina/administración & dosificación , Femenino , Enfermedades Gastrointestinales/etiología , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Motilina/sangre , Esclerodermia Sistémica/complicaciones , Estimulación Química , Factores de TiempoRESUMEN
BACKGROUND/AIMS: Leukotrienes (LTs) are involved in many inflammatory conditions including gastric damage induced by nonsteroidal anti-inflammatory drugs. Although LTs stimulate acid secretion, the effect they exert on pepsinogen secretion is unknown. The aim of this study was to investigate whether LTs stimulate pepsinogen secretion by isolated chief cells and to identify the intracellular messengers that mediate this action. METHODS: Isolated chief cells were incubated with concentrations of LTB4, LTC4, LTD4, or LTE4 ranging from 0.1 pmol/L to 10 mumol/L, and pepsinogen release, intracellular calcium and inositol(1,4,5)-trisphosphate (IP3) concentrations were measured. Nitric oxide generation was determined by the amount of citrulline generated during incubation. RESULTS: All four LTs caused a concentration-dependent stimulation of pepsinogen secretion with 50% effective concentration of 0.05-0.1 nmol/L and a dose-dependent increase in cytoplasmic free calcium and IP3 concentration. The LTB4 and LTD4 antagonists caused selective, concentration-dependent inhibition of LTB4- and LTD4-induced pepsinogen secretion, calcium mobilization, and IP3 generation. All four LTs increased NO generation, and the effect was inhibited by LTB4 and LTD4 antagonists and an NO synthase inhibitor NG-monomethyl-L-arginine and reversed by L-arginine. NG-monomethyl-L-arginine caused a 50%-60% reduction of LT-induced pepsinogen release. Each of the four LTs caused a fivefold increase in 5'-cyclic guanosine monophosphate. CONCLUSIONS: LTs are powerful stimulators of pepsinogen secretion in isolated chief cells and act via occupancy of specific cell-surface receptors.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Leucotrienos/farmacología , Óxido Nítrico/fisiología , Pepsinógenos/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Calcio/metabolismo , GMP Cíclico/biosíntesis , Mucosa Gástrica/metabolismo , Cobayas , Inositol 1,4,5-Trifosfato/biosíntesis , L-Lactato Deshidrogenasa/metabolismo , Masculino , omega-N-MetilargininaRESUMEN
BACKGROUND & AIMS: The primary mechanism that originates symptoms in response to gastric distention remains undefined. The aim of this study was to determine which factor, whether intragastric volume, pressure, or wall tension, determines perception of gastric distention. METHODS: Healthy subjects underwent increasing gastric distentions (2-minute duration at 5-minute intervals) either at fixed pressure levels using a conventional barostat (n = 10) or at fixed tension levels using a newly developed computerized tensostat (n = 12); perception was scored by a 0-6 scale. Distentions were performed during basal conditions (intravenous saline) and during gastric relaxation by glucagon administration (4.8 microgram/kg intravenous bolus plus 9.6 microgram. kg-1. h-1 infusion). RESULTS: Isobaric distentions with the conventional barostat produced more intense perception during glucagon (95% +/- 40% higher; P < 0.05). However, the factor that determined higher perception could not be ascertained, because at the same pressure levels both intragastric volume and wall tension were greater during glucagon administration (174% +/- 56% and 34% +/- 8% greater, respectively; P < 0.05 vs. saline for both). The tensostat evidenced that perception was selectively related to tension, not to elongation; during glucagon administration, intragastric volumes were significantly larger (80% +/- 28% larger increase; P < 0.05), but perception of isotonic distentions remained the same (27% +/- 22%; nonsignificant change). CONCLUSIONS: Gastric wall tension, but not intragastric volume, determines perception of gastric distention, at least below nociception.
Asunto(s)
Contracción Muscular/fisiología , Percepción/fisiología , Estómago/fisiología , Adulto , Dilatación , Femenino , Balón Gástrico , Glucagón/farmacología , Humanos , Masculino , Percepción/efectos de los fármacos , Presión , Umbral Sensorial/efectos de los fármacos , Estómago/efectos de los fármacos , Transductores de PresiónRESUMEN
There is recent evidence that nitric oxide, a soluble gas produced from L-arginine, is released by the smooth muscle cells and neurons of the gastrointestinal tract where it exerts a myorelaxive action. However, little is known about the effects nitric oxide has on gastric and gallbladder motility during the inter- and postprandial phases in man. We therefore investigated the effects 200 mg/kg/hr L-arginine exerts on the gastric and gallbladder motility induced by 2 mg/kg erythromycin or a liquid meal in 21 subjects in a double-blind, placebo-controlled study. Gastric and gallbladder emptying were evaluated by sonography. Fasting antral motility was expressed as antral motility index (MI). In fasting subjects, L-arginine administration determined a threefold increase in plasma nitrite concentrations. Administration of erythromycin caused a significant rise in the antral MI, which was inhibited by L-arginine (P < 0.05). Ingestion of a liquid meal also significantly increased antral MI, but it returned to basal values 90 min after the end of the meal. Although L-arginine administration caused a significant reduction in the antral MI (P < 0.05), it did not inhibit gastric emptying. L-Arginine provoked an approximately 40% increase in basal gallbladder volume, completely blocked erythromycin-induced emptying, and partially, but significantly, prevented the emptying induced by a liquid meal (P < 0.01). Our study suggests that nitric oxide may be implicated in the physiological modulation of gastric and gallbladder motility during the inter- and postprandial phases in man.
Asunto(s)
Arginina/farmacología , Eritromicina/farmacología , Conducta Alimentaria/efectos de los fármacos , Vaciamiento Vesicular/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Óxido Nítrico/fisiología , Adulto , Análisis de Varianza , Método Doble Ciego , Interacciones Farmacológicas , Ayuno/fisiología , Conducta Alimentaria/fisiología , Femenino , Vaciamiento Vesicular/fisiología , Motilidad Gastrointestinal/fisiología , Humanos , Masculino , Nitritos/sangreRESUMEN
BACKGROUND: Gastrointestinal involvement is frequent in patients with scleroderma. Erythromycin, a macrolide antibiotic, has been shown to accelerate gastric emptying in normal subjects and diabetic patients. The present study investigated the effects of acute erythromycin administration on gastric and gallbladder motility in patients with scleroderma and gastrointestinal involvement. METHODS: Twelve scleroderma patients and 14 healthy subjects were investigated. Each subject was investigated on 4 different days. Gastric and gallbladder emptying and gastric motility were determined by sonography and manometry, and the effect of 2 mg/kg/h erythromycin in fasted patients or after semisolid meal evaluated. RESULTS: The half-time of gastric emptying in response to semisolid meal was 121.3 +/- 14.0 min (SE) in scleroderma patients and 45.7 +/- 10.4 min in healthy subjects (P < 0.01). The peak of gallbladder emptying occurred later in scleroderma patients (95.0 +/- 5.0 min) than in healthy subjects (45.0 +/- 8.0 min) (P < 0.01). Erythromycin stimulated gastric and gallbladder motility in fasted subjects, as shown by manometry and sonography, and accelerated gastric and gallbladder emptying when administered immediately before the meal (P < 0.01). CONCLUSIONS: Erythromycin accelerates gastric and gallbladder emptying in scleroderma patients and might be helpful in the treatment of gastrointestinal motor abnormalities in these patients.
Asunto(s)
Eritromicina/análogos & derivados , Vaciamiento Vesicular/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Esclerodermia Sistémica/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Ingestión de Alimentos , Eritromicina/farmacología , Eritromicina/uso terapéutico , Ayuno , Femenino , Humanos , Masculino , Manometría , Persona de Mediana Edad , Esclerodermia Sistémica/diagnóstico por imagen , UltrasonografíaRESUMEN
OBJECTIVES: Duodenogastric reflux is a physiological phenomenon in both fasting and postprandial state. Because this suggests that bile acids may reflux into the esophagus together with the acid in patients with reflux esophagitis, we investigated the circadian variations of acid and pepsin secretion and intragastric bile acid concentrations in 25 patients with reflux esophagitis and in 15 healthy controls. METHODS: Between-meal, nocturnal gastric and meal-stimulated acid and pepsin secretion and bile acid concentrations were measured by continuous gastric aspiration and intragastric titration. RESULTS: Bile acids were found in 85 and 59% of gastric samples (p < 0.05). Intragastric bile acid concentrations were 6-8-fold higher in esophagitis patients than controls during the day. Approximately 10% of gastric samples from reflux esophagitis patients had a pH greater than 7, and all contained more than 500 mumol/L bile acids. Bile acids and pepsin were simultaneously revealed in 98% of the gastric samples from patients with reflux esophagitis with pH less than 4. Mean daily acid output (meal excluded) averaged 3.5 +/- 0.1 in healthy subjects and 2.7 +/- 0.2 mmol/30 minutes in esophagitis patients (p < 0.05); meal-induced acid secretions were similar. Total (24-h) acid secretion averaged 192.3 +/- 12.4 and 162.4 +/- 10.5 mmol/24 h (p < 0.05). There were no differences in the daily pepsin output. CONCLUSIONS: Our data indicate that almost all "acid" gastroesophageal refluxes should be considered as "mixed" refluxes. Because bile acids are found in the stomach irrespective of whether the environment was acid or alkaline, pH-metry provides no useful information on the pattern of duodenogastric reflux into the esophagus. Variability in the composition of the gastro-esophageal refluxate may explain why the severity of esophageal lesions differs in patients with similar pattern of acid refluxes.
Asunto(s)
Ácidos y Sales Biliares/metabolismo , Ritmo Circadiano/fisiología , Esofagitis Péptica/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Pepsina A/metabolismo , Adulto , Anciano , Esofagitis Péptica/enzimología , Esófago/fisiopatología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Persona de Mediana Edad , Estómago/enzimologíaRESUMEN
The cerebrohepatorenal syndrome of Zellweger is a congenital syndrome of multiple manifestations, including hepatomegaly and liver dysfunction. Treatment is generally of a supportive nature, aimed at improving nutrition and growth, controlling the central nervous system symptoms and limiting progression of liver disease. Because the liver disease in Zellweger syndrome may be attributed to an overproduction and accumulation of cholestanoic acids, exacerbated by diminished primary bile acid synthesis, we hypothesized that primary bile acid administration would be beneficial in improving liver function by a mechanism involving down-regulation in the synthesis of these atypical bile acids. We report here the clinical and biochemical responses to primary bile acid administration in a 2-mo-old boy who was seen with the typical signs of Zellweger syndrome. Liver disease was evident from hepatomegaly and elevated serum liver enzymes and bilirubin. The diagnosis was supported by markedly elevated serum very long chain fatty acids and the bile acids dihydroxycholestanoic acid and trihydroxycholestanoic acid. Confirmation of the lack of peroxisomes was established by electron microscopy. When the patient was 6 mo old, the primary bile acids cholic acid and chenodeoxycholic acid, (100 mg each/day) were administered orally. A significant improvement in biochemical indices of liver function occurred with a normalization of the serum bilirubin and liver enzymes and a histological improvement in the extent of inflammation and bile duct proliferation and disappearance of cannalicular plugs. Serum and urinary cholestanoic acids showed a significant decrease within a few days. A striking and sustained increase in growth was observed after therapy, and an improvement in neurological symptoms was noted. In conclusion, this study indicates that primary bile acid therapy improves liver function and growth in the patient with peroxisomal dysfunction and should be considered in the supportive therapies for this condition.
Asunto(s)
Ácidos y Sales Biliares/uso terapéutico , Síndrome de Zellweger/tratamiento farmacológico , Administración Oral , Ácidos y Sales Biliares/orina , Biopsia , Ácidos Grasos/sangre , Cromatografía de Gases y Espectrometría de Masas , Crecimiento , Humanos , Lactante , Fenómenos Fisiológicos Nutricionales del Lactante , Hígado/patología , Hígado/fisiopatología , Pruebas de Función Hepática , Masculino , Enfermedades del Sistema Nervioso/etiología , Ácidos Pipecólicos/sangre , Espectrometría de Masa Bombardeada por Átomos Veloces , Síndrome de Zellweger/genética , Síndrome de Zellweger/fisiopatologíaRESUMEN
3 alpha,7 beta-Dihydroxy-23-methyl-5 beta-cholan-24-oic acid (MUDCA) and its two diastereoisomers, alpha- and beta-MUDCA, were infused intraduodenally in biliary fistula hamsters in order to evaluate the effect on bile flow and their hepatic biotransformation processes compared with the natural analog ursodeoxycholic acid (UDCA). In addition, the corresponding glycine conjugates were compared. The bile acids were administered at different doses (0.7-6 mumol/min/kg) over periods of 90 min. The results indicate that the racemic mixture exhibits a potent choleretic effect at both low and high doses, while the two individual diastereoisomers show this effect only at high doses. The presence of a C-23 methyl group in the side chain prevents hepatic amidation and alternative conjugations occur, such as glucuronidation, in order to facilitate their biliary secretion. Biotransformation of the methyl derivatives of UDCA occurred mainly by conversion to more polar glucuronide conjugates. There was little alteration to the molecule and, unlike UDCA, very little amidation occurred. These data indicate that the presence of a C-23 methyl group prevents the usual side-chain amidation common to the most naturally occurring bile acids and that glucuronidation is a requisite for efficient biliary excretion.
Asunto(s)
Bilis/efectos de los fármacos , Ácido Ursodesoxicólico/análogos & derivados , Enfermedad Aguda , Animales , Bicarbonatos/metabolismo , Bilis/química , Bilis/metabolismo , Fístula Biliar/metabolismo , Biotransformación , Cricetinae , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Duodeno , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Mesocricetus , Estereoisomerismo , Relación Estructura-Actividad , Ácido Ursodesoxicólico/administración & dosificación , Ácido Ursodesoxicólico/análisis , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacologíaRESUMEN
The activation of a self-amplifying cascade of caspases, of which caspase-8 is the apical protease, mediates Fas-, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-, and TNF-alpha-induced apoptosis in colon cell lines. Nitric oxide (NO) protects from apoptosis induced by Fas and TNF-alpha. We examined whether NCX-456, an NO-releasing derivative of mesalamine, protects colon epithelial cells from cytokine-induced apoptosis. Caco-2 and HT-29 cell lines express death factor receptors and are driven to apoptosis in response to incubation with Fas-agonistic antibody, TNF-alpha/interferon-gamma, and TRAIL. The two novel observations reported here are that 1) cotreatment of cells with NCX-456, but not mesalamine, resulted in concentration-dependent protection against death factor-induced apoptosis and inhibition of caspase activity, and 2) exposure to dithiothreitol, an agent that effectively removes NO from thiol groups, resulted in a 70% recovery of caspase activity, which is consistent with S-nitrosation as a major mechanism for caspase inactivation. These data suggest that caspase S-nitrosation represents a mechanism for protection of colonic mucosal epithelial cells from death factor-induced death.
Asunto(s)
Apoptosis/efectos de los fármacos , Colon/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Células Epiteliales/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Ácidos Aminosalicílicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales/farmacología , Células CACO-2 , Caspasa 8 , Caspasa 9 , Inhibidores de Caspasas , Caspasas/biosíntesis , Caspasas/genética , Colon/citología , Colon/metabolismo , Citocinas/toxicidad , Citoprotección , Inhibidores Enzimáticos/farmacología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Proteínas Ligadas a GPI , Células HT29 , Humanos , Interferón gamma/farmacología , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Mesalamina/farmacología , Óxido Nítrico/metabolismo , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/biosíntesis , Receptores del Factor de Necrosis Tumoral/genética , Miembro 10c de Receptores del Factor de Necrosis Tumoral , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores Señuelo del Factor de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/farmacología , Receptor fas/genética , Receptor fas/metabolismoRESUMEN
The proteinase-activated receptor 2 (PAR-2) is a member of a family of G protein-coupled receptors for proteases. Proteases cleave PARs within the extracellular N-terminal domains to expose tethered ligands that bind to and activate the cleaved receptors. PAR-2 is highly expressed in colon in epithelial and neuronal elements. In this study we show that PAR-2 activation prevents the development and induces healing of T helper cell type 1-mediated experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. A role for PAR-2 in the protection against colon inflammation was explored by the use of SLIGRL-NH(2), a synthetic peptide that corresponds to the mouse tethered ligand exposed after PAR-2 cleavage. TNBS-induced colitis was dose-dependently reduced by the administration of SLIGRL-NH(2), whereas the scramble control peptide, LSIGRL-NH(2), was uneffective. This beneficial effect was reflected by increased survival rates, improvement of macroscopic and histologic scores, decrease in mucosal content of T helper cell type 1 cytokines, protein, and mRNA, and a diminished myeloperoxidase activity. SLIGRL-NH(2), but not the scramble peptide, directly inhibited IFN-gamma secretion and CD44 expression on lamina propria T lymphocytes. Protection exerted by PAR-2 in TNBS-treated mice was reverted by injecting mice with a truncated form of calcitonin gene-related peptide and by sensory neurons ablation with the neurotoxin capsaicin. Collectively, these studies show that PAR-2 is an anti-inflammatory receptor in the colon and suggest that PAR-2 ligands might be effective in the treatment of inflammatory bowel diseases.