RESUMEN
BACKGROUND: To date, the safety and tolerability of proton pump inhibitors (PPIs) have been demonstrated in studies of up to 10 years. AIM: To report on the tolerability, safety and efficacy of up to 15 years' continuous treatment with pantoprazole in patients with severe acid-peptic disease. METHODS: Following healing of endoscopically confirmed peptic ulcer or reflux oesophagitis during 4-12 weeks' treatment with pantoprazole (40-80 mg/day), adult patients received open-label maintenance treatment with pantoprazole (40-160 mg/day) for up to 15 years in a single centre combined study (10-year initial study; 5-year extension study). Safety assessments were carried out using endoscopy, clinical examination, clinical laboratory investigations, serum gastrin determination, gastric mucosal histology and mucosal endocrine cell quantification. RESULTS: The safety set comprised 142 patients. At 12 weeks, healing rates were 95.8%. During long-term treatment, mean fasting gastrin levels rose from baseline to moderate levels throughout the study. Mean enterochromaffin-like cell density showed a moderate initial increase during the first 3 years, remaining stable thereafter. These changes were not associated with any clinically relevant changes of the gastric mucosa. Patients with successful Helicobacter pylori eradication showed long-term regression of antral and corpus gastritis during continued pantoprazole treatment. CONCLUSIONS: Daily pantoprazole maintenance therapy for up to 15 years for severe acid-peptic disease is effective and well tolerated, with no identified safety concerns. The longest study to date, these data provide reassuring evidence for the long-term safety of pantoprazole.
Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles/uso terapéutico , Esofagitis Péptica/tratamiento farmacológico , Mucosa Gástrica/efectos de los fármacos , Úlcera Péptica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , 2-Piridinilmetilsulfinilbencimidazoles/efectos adversos , Adulto , Femenino , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/aislamiento & purificación , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pantoprazol , Inhibidores de la Bomba de Protones/efectos adversos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Two major pathways leading to apoptosis have been described. It has been shown that Helicobacter pylori-mediated apoptosis is mainly effected through the mitochondrial pathway (type II). The role of the type I pathway, including the death receptors, has been discussed controversially. Therefore, we investigated the role of Fas ligand (FasL) and TRAIL in H. pylori-mediated apoptosis by overexpressing antiapoptotic proteins in the human gastric epithelial cell line AGS. METHODS: AGS cells overexpressing the antiapoptotic proteins dnFADD, CrmA and Bcl-2 were generated. Apoptosis induced by Fas and H. pylori was monitored by histone ELISA. To investigate the role of TRAIL-mediated apoptosis, AGS cells were transduced with antisense constructs against the proapoptotic TRAIL receptors DR4 and DR5. Protein expression of Fas, TRAIL, DR4, and DR5 was analyzed by Western blot. RESULTS: Fas and H. pylori-mediated apoptosis was significantly inhibited in all generated cell lines, mainly in cells overexpressing CrmA and Bcl-2 with equal effectiveness. In the presence of H. pylori, TRAIL ligand and DR5 receptor were continuously expressed whereas DR4 expression was increasing time dependently. TRAILDR5 antisense significantly reduced H. pylori-mediated apoptosis. CONCLUSIONS: H. pylori-mediated apoptosis is characterized by activation of either type I or type II pathway. Caspase-8 plays an important role since it triggers the Type II pathway. Fas and TRAIL play an important role in the H. pylori-mediated apoptosis.
Asunto(s)
Apoptosis/fisiología , Infecciones por Helicobacter/fisiopatología , Helicobacter pylori/aislamiento & purificación , Glicoproteínas de Membrana/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Proteínas Reguladoras de la Apoptosis , Línea Celular , Proliferación Celular , Células Epiteliales/fisiología , Proteína Ligando Fas , Mucosa Gástrica/fisiopatología , Humanos , Transducción de Señal , Ligando Inductor de Apoptosis Relacionado con TNFRESUMEN
Pheripheral edema was observed in five female patients after taking proton pump inhibitors omeprazole, lansoprazole, or pantoprazole for 7-15 days for peptic acid diseases in recommended standard doses. Edema disappeared two to three days after stopping therapy but reappeared in all five patients after being reexposed to the drugs. In three of the patients drug kinetic investigations were performed and revealed a slow metabolizer status. During dose-finding studies for intravenous proton pump inhibitors omeprazole and pantoprazole, three of six young female volunteers receiving omeprazole and two young female volunteers receiving pantoprazole developed peripheral edema within 8 hr when high doses of the proton pump inhibitors were applied by continuous infusion together with large volumes of fluid. The edema disappeared within 24 hr after stopping the infusion therapy. Serum hormone concentrations in these patients did not change during therapy, neither did the edema factor C1-esterase inhibitor. As a possible mechanism, a competitive inhibition at the receptor site of female hormones involved in water regulation is suspected.
Asunto(s)
Antiulcerosos/efectos adversos , Bencimidazoles/efectos adversos , Edema/inducido químicamente , Omeprazol/análogos & derivados , Omeprazol/efectos adversos , Úlcera Péptica/tratamiento farmacológico , Inhibidores de la Bomba de Protones , Sulfóxidos/efectos adversos , 2-Piridinilmetilsulfinilbencimidazoles , Adulto , Antiulcerosos/farmacocinética , Femenino , Humanos , Lansoprazol , Persona de Mediana Edad , Omeprazol/farmacocinética , PantoprazolRESUMEN
The ligands interacting with enterochromaffin-like (ECL) and parietal cells and the signaling interactions between these cells were investigated in rabbit gastric glands using confocal microscopy. Intracellular calcium concentration ([Ca(2+)](i)) changes were used to monitor cellular responses. Histamine and carbachol increased [Ca(2+)](i) in parietal cells. Gastrin (1 nM) increased [Ca(2+)](i) in ECL cells and adjacent parietal cells. Only the increase of [Ca(2+)](i) in parietal cells was inhibited by H(2) receptor antagonists (H(2)RA). Gastrin (10 nM) evoked an H(2)RA-insensitive [Ca(2+)](i) increase in parietal cells. Carbachol produced large H(2)RA- and somatostatin-insensitive signals in parietal cells. Pituitary adenylate cyclase-activating peptide (PACAP, 100 nM) elevated [Ca(2+)](i) in ECL cells and adjacent parietal cells. H(2)RAs abolished the PACAP-stimulated [Ca(2+)](i) increase in adjacent parietal cells. Somatostatin did not inhibit the increase of [Ca(2+)](i) in parietal cells stimulated with histamine, high gastrin concentrations, or carbachol but abolished ECL cell calcium responses to gastrin or PACAP. Hence, rabbit parietal cells express histaminergic, muscarinic, and CCK-B receptors coupled to calcium signaling but insensitive to somatostatin, whereas rabbit and rat ECL cells express PACAP and CCK-B calcium coupled receptors sensitive to somatostatin.
Asunto(s)
Señalización del Calcio/fisiología , Mucosa Gástrica/fisiología , Células Parietales Gástricas/metabolismo , Animales , Señalización del Calcio/efectos de los fármacos , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Células Similares a las Enterocromafines/metabolismo , Ácido Gástrico/metabolismo , Mucosa Gástrica/citología , Mucosa Gástrica/metabolismo , Gastrinas/farmacología , Histamina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Hormonas/farmacología , Microscopía Confocal , Mitógenos/farmacología , Neuropéptidos/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Conejos , Ranitidina/farmacología , Somatostatina/farmacología , Organismos Libres de Patógenos EspecíficosRESUMEN
Helicobacter pylori resists gastric acidity by modulating the proton-gated urea channel UreI, allowing for pH(out)-dependent regulation of urea access to intrabacterial urease. We employed pH- and Ca(2+)-sensitive fluorescent dyes and confocal microscopy to determine the location, rate, and magnitude of pH changes in an H. pylori-AGS cell coculture model, comparing wild-type bacteria with nonpolar ureI-deletion strains (ureI-ve). Addition of urea at pH 5.5 to the coculture resulted first in elevation of bacterial periplasmic pH, followed by an increase of medium pH and then pH in AGS cells. No change in periplasmic pH occurred in ureI-deletion mutants, which also induced a slower increase in the pH of the medium. Pretreatment of the mutant bacteria with the detergent C(12)E(8) before adding urea resulted in rapid elevation of bacterial cytoplasmic pH and medium pH. UreI-dependent NH(3) generation by intrabacterial urease buffers the bacterial periplasm, enabling acid resistance at the low urea concentrations found in gastric juice. Perfusion of AGS cells with urea-containing medium from coculture at pH 5.5 did not elevate pH(in) or [Ca(2+)](in), unless the conditioned medium was first neutralized to elevate the NH(3)/NH(4)(+) ratio. Therefore, cellular effects of intrabacterial ammonia generation under acidic conditions are indirect and not through a type IV secretory complex. The pH(in) and [Ca(2+)](in) elevation that causes the NH(3)/NH(4)(+) ratio to increase after neutralization of infected gastric juice may contribute to the gastritis seen with H. pylori infection.
Asunto(s)
Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiología , Helicobacter pylori/enzimología , Proteínas de Transporte de Membrana , Ureasa/metabolismo , Amoníaco/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Técnicas de Cocultivo , Eliminación de Gen , Genes Bacterianos , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Humanos , Concentración de Iones de Hidrógeno , Mutación , Células Tumorales Cultivadas , Ureasa/genéticaRESUMEN
The development of the lens is dependent on the proliferation of lens epithelial cells and their differentiation into fiber cells near the lens bow/equator. Identification of genes specifically expressed in the lens epithelial cells and their functions may provide insight into molecular events that regulate the processes of lens epithelial cell differentiation. In this study, a novel lens epithelium gene product, LEP503, identified from rat by a subtractive cDNA cloning strategy was investigated in the genome organization, mRNA expression and protein localization. The genomic sequences for LEP503 isolated from rat, mouse and human span 1754 bp, 1694 bp and 1895 bp regions encompassing the 5'-flanking region, two exons, one intron and 3'-flanking region. All exon-intron junction sequences conform to the GT/AG rule. Both mouse and human LEP503 genes show very high identity (93% for mouse and 79% for human) to rat LEP503 gene in the exon 1 that contains an open reading frame coding for a protein of 61 amino acid residues with a leucine-rich domain. The deduced protein sequences also show high identity (91% between mouse and rat and 77% between human and rat). Western blot shows that LEP503 is present as a specific approximately 6.9 kDa band in the water-insoluble-urea-soluble fraction of lens cortex where lens epithelium is included. Immuno-staining shows that LEP503 is localized in the epithelial cells along the entire anterior surface of rat lens. Developmentally, LEP503 is expressed at a low level at newborn, and then the expression level increases by about ten-fold around postnatal day 14 and remains at this high level for about 25 days before it drops back to the low level by postnatal day 84. These data suggest that the LEP503 may be an important lens epithelial cell gene involving the processes of epithelial cell differentiation.
Asunto(s)
Secuencia Conservada/genética , Proteínas del Ojo/genética , Cristalino/metabolismo , Animales , Secuencia de Bases , Western Blotting , Epitelio , Genoma , Humanos , Cristalino/citología , Cristalino/crecimiento & desarrollo , Ratones , Datos de Secuencia Molecular , ARN Mensajero/metabolismo , RatasRESUMEN
We previously reported that PAC1 is expressed on ECL cells resulting in stimulation of [Ca2+]i, histamine and acid secretion. The study reported here characterized the signaling by PAC1 on ECL cells; determined the effects of PACAP on the gastric acid secretion in vivo, and determined the effects of chronic administration of PACAP-27 on ECL cell proliferation. PACAP-27 dose dependently stimulated ECL cell Ca2+ and AC with detectable stimulation at 1 nM and maximal stimulation at 100 nM (six-fold). In rats PACAP-27 administration (10 pmol/kg/h) increased the rate of gastric acid secretion when an antisomatostatin antibody was co-administered. Chronic administration of PACAP (10 pmol/h for seven days) via osmotic pump resulted in a more than twofold increase in BrdU incorporation into ECL cells. PACAP acting at the PAC1 results in dual signaling responses to both [Ca2+]i. AC in ECL cells stimulates gastric acid secretion via the actions of histamine acting at the parietal cell and in whole animals leads to proliferation of ECL cells when administered chronically.
Asunto(s)
Células Similares a las Enterocromafines/fisiología , Ácido Gástrico/metabolismo , Neuropéptidos/farmacología , Receptores de la Hormona Hipofisaria/fisiología , Adenilil Ciclasas/metabolismo , Animales , División Celular/efectos de los fármacos , Células Similares a las Enterocromafines/citología , Células Similares a las Enterocromafines/efectos de los fármacos , Inmunohistoquímica , Técnicas In Vitro , Neuropéptidos/fisiología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratas , Ratas Sprague-Dawley , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria , Receptores del Polipéptido Activador de la Adenilato-Ciclasa HipofisariaRESUMEN
Peptides release histamine from enterochromaffin-like (ECL) cells because of elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) by either receptor-operated or voltage-dependent Ca(2+) channels (VDCC). To determine whether VDCCs contribute to histamine release stimulated by gastrin or pituitary adenylate cyclase-activating polypeptide (PACAP), the presence of VDCCs and their possible modulation by peptides was investigated in a 48-h cultured rat gastric cell population containing 85% ECL cells. Video imaging of fura 2-loaded cells was used to measure [Ca(2+)](i), and histamine was assayed by RIA. Cells were depolarized by increasing extracellular K(+) concentrations or by 20 mM tetraethylammonium (TEA(+)). Cell depolarization increased transient and steady-state [Ca(2+)](i) and resulted in histamine release, dependent on extracellular Ca(2+). These K(+)- or TEA(+)-dependent effects on histamine release from ECL cells were coupled to activation of parietal cells in intact rabbit gastric glands, and L-type channel blockade by 2 microM nifedipine inhibited 50% of [Ca(2+)](i) elevation and histamine release. N-type channel blockade by 1 microM omega-conotoxin GVIA inhibited 25% of [Ca(2+)](i) elevation and 14% of histamine release. Inhibition was additive. The effects of 20 mM TEA(+) were fully inhibited by 2 microM nifedipine. Both classes of Ca(2+) channels were found in ECL cells, but not in parietal cells, by RT-PCR. Nifedipine reduced PACAP-induced (but not gastrin-stimulated) Ca(2+) entry and histamine release by 40%. Somatostatin, peptide YY (PYY), and galanin dose dependently inhibited L-type Ca(2+) channels via a pertussis toxin-sensitive pathway. L-type VDCCs play a role in PACAP but not gastrin stimulation of histamine release from ECL cells, and the channel opening is inhibited by somatostatin, PYY, and galanin by interaction with a G(i) or G(o) protein.
Asunto(s)
Canales de Calcio Tipo L/genética , Células Similares a las Enterocromafines/química , Células Similares a las Enterocromafines/metabolismo , Liberación de Histamina/fisiología , Ácido 3-piridinacarboxílico, 1,4-dihidro-2,6-dimetil-5-nitro-4-(2-(trifluorometil)fenil)-, Éster Metílico/farmacología , Toxina de Adenilato Ciclasa , Animales , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/metabolismo , Cartilla de ADN , Dihidropiridinas/farmacología , Células Similares a las Enterocromafines/efectos de los fármacos , Proteínas de Unión al GTP/metabolismo , Galanina/farmacología , Ácido Gástrico/metabolismo , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Gastrinas/farmacología , Expresión Génica/fisiología , Histamina/metabolismo , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Neuropéptidos/farmacología , Neurotransmisores/farmacología , Péptido YY/farmacología , Toxina del Pertussis , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Potasio/farmacología , Conejos , Ratas , Receptores Histamínicos H2/fisiología , Somatostatina/farmacología , Estómago/citología , Tetraetilamonio/farmacología , Factores de Virulencia de Bordetella/farmacología , omega-Conotoxina GVIA/farmacologíaRESUMEN
Pituitary adenylate cyclase activating polypeptide (PACAP) is present in gastric nerves, and PACAP receptors (PAC1) are found on gastric enterochromaffin-like (ECL) cells. Expression of PAC1 splice variants in purified ECL cells was determined by RT-PCR. PACAP effects on ECL cells were analyzed by video imaging of [Ca(2+)](i) and histamine release; its effects on gastric glands were examined by confocal microscopy of [Ca(2+)](i) in ECL and parietal cells. PACAP action on D cells was measured by [Ca(2+)](i) and radioimmunoassay. PACAP effects on acid secretion were determined in fistula rats with or without neutralizing anti-somatostatin antibodies. All splice variants of PAC1 were found, but vasoactive intestinal polypeptide (VIP) receptor (VPAC) products were absent. PACAP-27 and -38 dose-dependently raise [Ca(2+)](i) in ECL cells, and stimulated histamine release. VIP had a much lower affinity, which demonstrates the presence of PAC1 but not VPAC. PACAP elevated [Ca(2+)](i) in ECL and parietal cells of superfused gastric glands, but only the parietal cell signal was inhibited by ranitidine, showing the absence of PAC1 on parietal cells, and demonstrating functional coupling between the cell types. PACAP and VIP stimulated calcium signaling and somatostatin release from D cells with almost equal efficacy. Acid secretion was stimulated after intravenous injection of PACAP into rats treated with somatostatin antibody. PACAP is a candidate as a mediator of neural regulation of acid secretion.
Asunto(s)
Empalme Alternativo , Células Similares a las Enterocromafines/fisiología , Ácido Gástrico/metabolismo , Mucosa Gástrica/fisiología , Variación Genética , Receptores de la Hormona Hipofisaria/genética , Animales , Calcio/metabolismo , Células Cultivadas , Células Similares a las Enterocromafines/citología , Células Similares a las Enterocromafines/efectos de los fármacos , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Liberación de Histamina/efectos de los fármacos , Microscopía por Video , Neuropéptidos/farmacología , Neurotransmisores/farmacología , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Ratas , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria , Receptores de la Hormona Hipofisaria/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
This report contains the observations of 9 women who received omeprazole for severe reflux disease during different stages of pregnancy. Four patients took omeprazole at the time of conception, and 3 of these patients continued omeprazole therapy without interruption until delivery. One patient discontinued therapy in the 8th week of pregnancy but had to take the drug again from the 28th week to delivery. The other 5 patients started therapy in weeks 24, 30, 33, 34 and 36 of pregnancy because of bleeding in 2 patients and unbearable H2 receptor refractory reflux symptoms in the other 3 patients. All patients were carefully monitored. In all cases omeprazole was well tolerated. No severe side effects were observed in any of the mothers or their newborns. No malfunctions or malformations were observed in the newborns. Follow-up of the children between 2 and 12 years showed normal development in all children. These data together with the data on 8 such pregnancies published by other authors suggest that omeprazole is safe when given during pregnancy at whatever phase.