RESUMEN
The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Elementos de Facilitación Genéticos/fisiología , Proteínas de Unión al GTP/genética , Proteínas de la Membrana/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiología , Proteínas Proto-Oncogénicas/fisiología , Factores de Transcripción/fisiología , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos C57BL , Familia de Multigenes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína 1 de la Leucemia Linfocítica T Aguda , Pez CebraRESUMEN
RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation-quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.
Asunto(s)
Transformación Celular Neoplásica/genética , Subunidad alfa 3 del Factor de Unión al Sitio Principal/fisiología , Regulación Neoplásica de la Expresión Génica , Linfoma Extranodal de Células NK-T/genética , Neoplasias Nasales/genética , Proteínas Proto-Oncogénicas c-myc/fisiología , Transcripción Genética/genética , Apoptosis , Azepinas/farmacología , Sitios de Unión , División Celular , Línea Celular Tumoral , Subunidad alfa 3 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Elementos de Facilitación Genéticos , Genes Reporteros , Vectores Genéticos , Humanos , Linfoma Extranodal de Células NK-T/etiología , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Terapia Molecular Dirigida , Neoplasias Nasales/etiología , Neoplasias Nasales/metabolismo , Neoplasias Nasales/patología , Mapeo de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-myc/antagonistas & inhibidores , Interferencia de ARN , ARN Interferente Pequeño/genética , Proteínas Recombinantes de Fusión/metabolismo , Triazoles/farmacología , Regulación hacia ArribaRESUMEN
Dual specificity phosphatase 10 (DUSP10), also known as MAP kinase phosphatase 5 (MKP5), negatively regulates the activation of MAP kinases. Genetic polymorphisms and aberrant expression of this gene are associated with colorectal cancer (CRC) in humans. However, the role of DUSP10 in intestinal epithelial tumorigenesis is not clear. Here, we showed that DUSP10 knockout (KO) mice had increased intestinal epithelial cell (IEC) proliferation and migration and developed less severe colitis than wild-type (WT) mice in response to dextran sodium sulphate (DSS) treatment, which is associated with increased ERK1/2 activation and Krüppel-like factor 5 (KLF5) expression in IEC. In line with increased IEC proliferation, DUSP10 KO mice developed more colon tumours with increased severity compared with WT mice in response to administration of DSS and azoxymethane (AOM). Furthermore, survival analysis of CRC patients demonstrated that high DUSP10 expression in tumours was associated with significant improvement in survival probability. Overexpression of DUSP10 in Caco-2 and RCM-1 cells inhibited cell proliferation. Our study showed that DUSP10 negatively regulates IEC growth and acts as a suppressor for CRC. Therefore, it could be targeted for the development of therapies for colitis and CRC.
Asunto(s)
Neoplasias Colorrectales/patología , Fosfatasas de Especificidad Dual/genética , Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Animales , Células CACO-2 , Proliferación Celular/genética , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Sulfato de Dextran/toxicidad , Células Epiteliales/metabolismo , Células Epiteliales/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Genes Supresores de Tumor , Humanos , Intestinos/citología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Tasa de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Resistencia a Medicamentos/genética , Predisposición Genética a la Enfermedad , Factor Estimulante de Colonias de Granulocitos/farmacología , Haploinsuficiencia , Leucemia Mieloide Aguda/genética , Animales , Trastornos de las Plaquetas Sanguíneas/genética , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Citocinas/farmacología , Modelos Animales de Enfermedad , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Genotipo , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/patología , Ratones , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Mutación , Fosforilación , Unión Proteica , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Crohn's disease is a chronic inflammatory bowel disease characterized by transmural inflammation and granuloma formation. Several theories regarding the etiology of Crohn's disease have been proposed, one of which is infection with Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis), which causes a similar disease in animals, and is present in the human food chain. Considerable evidence supports the presence of M. paratuberculosis in the intestinal tissues of many patients with Crohn's disease including culture, detection of homologous mycobacterial DNA, detection of the mycobacterial insertion sequence IS900 by both PCR and in situ hybridization in tissues, and a serologic immune response to recombinant M. paratuberculosis antigens. Despite this evidence, and our personal belief that M. paratuberculosis is a cause of Crohn's disease, widespread acceptance of this hypothesis will require evidence that specific anti-mycobacterial chemotherapy will cure the disease.
Asunto(s)
Enfermedad de Crohn/etiología , Enfermedad de Crohn/microbiología , Mycobacterium avium/metabolismo , Pared Celular/metabolismo , Colitis Ulcerosa/microbiología , Enfermedad de Crohn/patología , ADN/metabolismo , Elementos Transponibles de ADN/genética , Granuloma/patología , Humanos , Hibridación in Situ , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes/metabolismoRESUMEN
A 59-year-old woman who had an 8-year history of acute myeloblastic leukemia (AML) developed granular lymphocytic leukemia (GLL). She had a small number of granular lymphocytes (GL) in her bone marrow (BM) at the onset of AML. The GL increased during complete remission (CR) of AML, but not at the relapse. During the third CR state of AML, GL increased to 4.0 x 10(9)/l in the peripheral blood (PB). The GL were T-cell receptor (TCR) alpha beta+ T cells and expressed both CD4 and CD8 antigens. Rearrangements of TCR beta and gamma chain genes were detected in the peripheral blood mononuclear cells (PBMNC), confirming that this patient had GLL. The PBMNC from the patient responded weakly to PHA or ConA, yet they responded to her own bone marrow mononuclear cells (BMMNC) or CD4-depleted BMMNC that contained AML cells stronger than her own PBMNC or normal PBMNC. These observations suggest that monoclonal proliferation of GL developed after the reactive proliferation of GL in response to AML cells.
Asunto(s)
Leucemia Linfoide/patología , Leucemia Mieloide Aguda/patología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , División Celular , Gránulos Citoplasmáticos , ADN de Neoplasias/análisis , ADN Viral/análisis , Femenino , Reordenamiento Génico de Linfocito T , Antígenos HLA-DR/análisis , Humanos , Inmunofenotipificación , Persona de Mediana Edad , Neoplasias Primarias Secundarias , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Although the prototype of adult T cell leukemia (ATL) is an aggressive T cell neoplasm, ATL manifests four major clinical subtypes, acute, lymphoma, chronic, and smoldering. We studied the relationship between p53 gene alteration and clinical features in 34 patients with ATL, 14 acute type, 15 chronic type, and five crisis type transformed from chronic type. Using a polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) assay, followed by nucleotide sequencing, we detected mutations of the p53 gene in six of the 14 acute type patients, two of the five crisis type, and one of the 15 chronic type patients. Gene dosage studies, using PCR amplification and Southern blotting, showed loss of heterozygosity (LOH) of the p53 gene in four of the 14 acute type patients, two of the five crisis type, and one of 14 chronic type patients examined. These observations indicated that the frequency of p53 gene alterations in the acute and crisis types of ATL was markedly higher than that in chronic type, suggesting that p53 gene alteration plays a role in the disease progression of ATL.
Asunto(s)
Genes p53 , Leucemia de Células T/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Secuencia de Bases , Cartilla de ADN/química , Mutación del Sistema de Lectura , Heterocigoto , Humanos , Leucemia de Células T/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación Puntual , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
Point mutations of the transcription factor AML1 are associated with leukemogenesis in acute myeloblastic leukemia (AML). Internal tandem duplications (ITDs) in the juxtamembrane domain and mutations in the second tyrosine kinase domain of the Fms-like tyrosine kinase 3 (FLT3) gene represent the most frequent genetic alterations in AML. However, such mutations per se appear to be insufficient for leukemic transformation. To evaluate whether both AML1 and FLT3 mutations contribute to leukemogenesis, we analyzed mutations of these genes in AML M0 subtype in whom AML1 mutations were predominantly observed. Of 51 patients, eight showed a mutation in the Runt domain of the AML1 gene: one heterozygous missense mutation with normal function, five heterozygous frameshift mutations and two biallelic nonsense or frameshift mutations, resulting in haploinsufficiency or complete loss of the AML1 activities. On the other hand, a total of 10 of 49 patients examined had the FLT3 mutation. We detected the FLT3 mutation in five of eight (63%) patients with AML1 mutation, whereas five of 41 (12%) without AML1 mutation showed the FLT3 mutation (P=0.0055). These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0.
Asunto(s)
Proteínas de Unión al ADN/genética , Mutación del Sistema de Lectura , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Factores de Transcripción/genética , Transformación Celular Neoplásica/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Regulación Leucémica de la Expresión Génica , Humanos , Polimorfismo Conformacional Retorcido-Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tirosina Quinasa 3 Similar a fmsRESUMEN
BACKGROUND: Therapy for Helicobacter pylori is generally empiric despite the fact that resistance to metronidazole and clarithromycin compromise therapeutic efficacy. The aim of this study was to aid clinicians in choosing a course of therapy for H pylori infection in the United States. METHODS: The frequency of primary clarithromycin and metronidazole resistance among H pylori isolated from patients enrolled in US-based clinical trials between 1993 and 1999 was reviewed in relation to patient age, sex, region of the United States, and test method (Etest and 2 agar dilution procedures). RESULTS: Clarithromycin and metronidazole resistance rates were based on the results of 3439 pretreatment Etest determinations and 3193 agar dilution determinations. Sex and age were available on 900 and 823 individuals, respectively. Metronidazole resistance was 39% by Etest and 21.6% by agar dilution (P<.001). Clarithromycin resistance was 12% by Etest and 10.6% by agar dilution. Amoxicillin or tetracycline resistance was rare. Metronidazole and clarithromycin resistance was more common in women than men (eg, 34.7% vs 22.6% for metronidazole and 14.1% vs 9.7% for clarithromycin (P =.01 and P =.06, respectively). Antibiotic resistance increased gradually up to age 70 years, then declined significantly (P<.05) regardless of test method. Regional differences in antimicrobial resistance did not occur. CONCLUSIONS: While age and sex had significant effects on resistance rates, regional differences were not present. The high prevalence of resistance to metronidazole and clarithromycin may soon require the performance of antimicrobial susceptibility testing of H pylori isolates prior to initiating treatment.
Asunto(s)
Antibacterianos/uso terapéutico , Antitricomonas/uso terapéutico , Claritromicina/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Metronidazol/uso terapéutico , Adulto , Factores de Edad , Anciano , Farmacorresistencia Microbiana , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Humanos , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores Sexuales , Estados Unidos/epidemiologíaRESUMEN
RUNX1 and CBFB are among the most frequently mutated genes in human leukemias. Genetic alterations such as chromosomal translocations, copy number variations and point mutations have been widely reported to result in the malfunction of RUNX transcription factors. Leukemias arising from such alterations in RUNX family genes are collectively termed core binding factor (CBF) leukemias. Although adult CBF leukemias generally are considered a favorable risk group as compared with other forms of acute myeloid leukemia, the 5-year survival rate remains low. An improved understanding of the molecular mechanism for CBF leukemia is imperative to uncover novel treatment options. Over the years, retroviral transduction-transplantation assays and transgenic, knockin and knockout mouse models alone or in combination with mutagenesis have been used to study the roles of RUNX alterations in leukemogenesis. Although successful in inducing leukemia, the existing assays and models possess many inherent limitations. A CBF leukemia model which induces leukemia with complete penetrance and short latency would be ideal as a platform for drug discovery. Here, we summarize the currently available mouse models which have been utilized to study CBF leukemias, discuss the advantages and limitations of individual experimental systems, and propose suggestions for improvements of mouse models.
Asunto(s)
Factores de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación/genética , Adulto , Animales , Humanos , RatonesRESUMEN
There are multiple test methodologies to determine the antibiogram of an organism. Standardized susceptibility test methods are based upon rapidly growing, aerobic microorganisms in which overnight incubation results in definitive endpoints. In vitro susceptibility testing for fastidious organisms that require complex media for growth, require incubation in atmospheres other than ambient air, or are slow-growing (anaerobes, mycobacteria, filamentous fungi) are problematic and in general are not standardized. H. pylori falls into this category of troublesome organisms. For the microaerobic organism H. pylori, testing is challenging because the organism grows slowly even under optimal culture conditions. Recently the National Committee for Clinical Laboratory Standards (NCCLS) approved the agar dilution method as the test of choice for testing H. pylori. While not entirely reliable in predicting the outcome of treatment for metronidazole resistant organisms, the resistance determined for clarithromycin by this method generally predicts treatment failure. Quality control breakpoints for H. pylori ATCC 43504 were established and breakpoints for clarithromycin were approved by the NCCLS in 1999. Breakpoints are minimum inhibitory concentrations (MIC) of a drug at which an organism is deemed either susceptible or resistant to the antibiotic using standard dosing regimens containing that drug. Significant progress has been made with respect to development of tests to detect antimicrobial resistance, but there still remains no consensus as to the breakpoints for agents used in the treatment of H. pylori infection other than clarithromycin. This article will address the controversies associated with the reporting of antibiotic resistance data and the interpretation of these data.
Asunto(s)
Helicobacter pylori/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Análisis Costo-Beneficio , Farmacorresistencia Microbiana , Humanos , Insuficiencia del TratamientoRESUMEN
Topical treatment of severe ocular infections may require the use of antibiotics fortified in concentration beyond commercially available preparations. The authors studied tear pharmacokinetics, tissue bioavailability, epithelial toxicity, and comparative antibacterial efficacy of topical tobramycin concentrations ranging from 0.3-5.0%. Tear pharmacodynamics demonstrate bioassay-measurable levels with each preparation up to 6 hr after a single 50-microliter drop challenge. Comparing various fortified concentration levels yields progressive parallel-biphasic decay curves in antibiotic tear-film concentrations. Both tear and corneal data demonstrate increases in measured antibiotic levels largely proportional to the increases in drug concentration instilled. Tobramycin was undetectable in corneas treated with 0.3% tobramycin, yet measurable with higher drug levels. A rabbit epithelial wound-healing model demonstrated progressive toxicity ranging from no effect of 0.3% tobramycin on healing rates compared with paired controls, to a significant decrease in re-epithelialization rates with 1.1% (P = 0.03) and 4.0% (P = 0.02) tobramycin. Finally, a Pseudomonas aeruginosa keratitis model in the rat demonstrates the antibiotic efficacy of topical tobramycin treatment over untreated controls (P less than 0.00001), and a progressively enhanced efficacy with increasing tobramycin concentrations is suggested. Concentration enhancement of topical ocular medication is useful in the treatment of severe ocular infection.
Asunto(s)
Tobramicina/administración & dosificación , Animales , Infecciones Bacterianas/tratamiento farmacológico , Disponibilidad Biológica , Modelos Animales de Enfermedad , Oftalmopatías/tratamiento farmacológico , Queratitis/tratamiento farmacológico , Cinética , Masculino , Soluciones Oftálmicas , Infecciones por Pseudomonas/tratamiento farmacológico , Conejos , Ratas , Ratas Endogámicas , Lágrimas/metabolismo , Tobramicina/metabolismo , Tobramicina/farmacologíaRESUMEN
PURPOSE: Medical therapy of Mycobacterium chelonae keratitis is difficult because there are so few effective antimicrobial agents and single agent therapy frequently fails clinically. To identify more effective medical treatment regimens, the in vitro antimicrobial efficacy of amikacin, the most frequently used single agent, was investigated in combination with four antibiotics previously reported to have activity against M. chelonae: erythromycin, imipenem, ciprofloxacin, and vancomycin. METHODS: The drug combinations were tested by the checkerboard method against seven corneal isolates of M. chelonae. RESULTS: The combination of amikacin with erythromycin or vancomycin consistently led to synergistic or additive effect, however the minimum inhibitory concentrations for vancomycin were very high. The combination of amikacin with imipenem or ciprofloxacin led to results ranging from antagonism to additive effects. CONCLUSIONS: Of the antibiotics tested, erythromycin showed the most activity against M. chelonae in combination with amikacin. In vitro combination drug testing of M. chelonae by the checkerboard method should be further evaluated for clinical relevance in microbial keratitis.
Asunto(s)
Amicacina/farmacología , Quimioterapia Combinada/farmacología , Mycobacterium chelonae/efectos de los fármacos , Úlcera de la Córnea/tratamiento farmacológico , Úlcera de la Córnea/microbiología , Sinergismo Farmacológico , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium chelonae/aislamiento & purificaciónRESUMEN
BACKGROUND: In a previous study, the use of a citric acid test meal produced a rapid dose-dependent increase in urease activity that was significantly greater than that resulting from a pudding meal, ascorbic acid or sodium citrate. The mechanism was hypothesized to be related to the ability of citric acid to delay gastric emptying and possibly to enhance intragastric distribution of the urea. OBJECTIVE: To compare the effects of sodium citrate, two doses of citric acid and a pudding meal on gastric motor function. METHOD: Eleven normal healthy volunteers were investigated using non-invasive techniques to measure gastric emptying and gastric motility. We evaluated gastric emptying using the Meretek 13Ceebiscuit solid phase gastric emptying breath test, which employs a 340-calorie biscuit containing 200 mg of the edible 13C-blue-green alga Spirulina platensis, after the administration of test meals of pudding, 2 g and 4 g of citric acid and 2 g of sodium citrate. Electrogastrograms (Digitrapper EGG) were also recorded for 30 min before and 180 min after the test meal. RESULTS: Gastric emptying, as assessed by the half-time (T1/2), was delayed similarly with the pudding (136.8 +/- 9 min) and with 4 g of citric acid (144.5 +/- 7 min) (P > 0.7). Sodium citrate (108.7 +/- 6 min) and 2 g of citric acid (110.1 +/- 6 min) had similar effects on gastric emptying (P=0.986), and were significantly less effective in delaying gastric emptying (P < 0.01) compared to pudding or 4 g of citric acid. The electrogastrograms remained normal and there were no differences among meals and no relation with the gastric emptying results. CONCLUSIONS: The increased intragastric urea hydrolysis associated with citric acid test meals cannot be attributed to delayed gastric emptying. Changes in the intragastric distribution of urea or a direct effect of citric acid on the bacteria (e.g. via the cytoplasmic protein, UreI) are more likely to be responsible.
Asunto(s)
Citratos/farmacología , Ácido Cítrico/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Infecciones por Helicobacter/patología , Helicobacter pylori/enzimología , Urea/metabolismo , Adolescente , Adulto , Anciano , Pruebas Respiratorias , Citratos/administración & dosificación , Ácido Cítrico/administración & dosificación , Productos Lácteos , Femenino , Helicobacter pylori/patogenicidad , Humanos , Hidrólisis , Masculino , Persona de Mediana Edad , Citrato de SodioRESUMEN
BACKGROUND: Antisecretory therapy may exacerbate Helicobacter pylori corpus gastritis. The rate and mechanism(s) remain unknown. AIM: To investigate the early events in proton pump inhibitor therapy on antral and corpus H. pylori gastritis. METHODS: Nine H. pylori-infected volunteers underwent gastric biopsy with jumbo forceps for culture and histology. Histology was scored in the range 0-5 using a visual analogue scale. The depth of inflammation in gastric pits was scored in the range 1-3 (superficial or less than one-third, one-third to two-thirds and greater than two-thirds of the gastric pit, respectively). Tissue interleukin-1 beta and interleukin-8 levels were measured by enzyme-linked immunoabsorbent assay. Omeprazole, 20 mg b.d., was given for 6.5 days and biopsies were repeated on day 7. RESULTS: Proton pump inhibitor therapy resulted in a fall in H. pylori density in the antrum and corpus. Inflammation and tissue levels of interleukin-8 and interleukin-1 beta decreased in the antrum and increased in the corpus mucosa. There was a significant increase in the depth of inflammation to include the proliferative zone in the corpus. CONCLUSIONS: Within 1 week of starting proton pump inhibitor therapy, there was a marked extension of corpus inflammation into the gastric pit and an increase in corpus mucosal interleukin-1 beta and interleukin-8 levels. H. pylori eradication should be considered for all patients receiving long-term antisecretory therapy.
Asunto(s)
Antiulcerosos/efectos adversos , Gastritis/inducido químicamente , Infecciones por Helicobacter , Helicobacter pylori , Omeprazol/efectos adversos , Inhibidores de la Bomba de Protones , Adulto , Femenino , Gastritis/microbiología , Humanos , MasculinoRESUMEN
BACKGROUND: Quadruple therapy (bismuth, metronidazole and tetracycline (BMT) + proton pump inhibitor) is touted as being > 95% effective, regardless of metronidazole resistance. We tested a 10-day b.d. quadruple therapy for treatment of H. pylori infection. METHODS: Anti-H. pylori therapy consisted of lansoprazole 15 mg b.d. plus tetracycline 500 mg b.d., metronidazole 500 mg b.d., and swallowable Pepto-Bismol caplets (2 b.d.) for 10 days. H. pylori status was evaluated by culture and histology before and 4 or more weeks after therapy. RESULTS: The cure rate for intention-to-treat was 70%. Treatment success was calculated overall and separately in relation to antimicrobial resistance patterns. The cure rate among the metronidazole-sensitive isolates was 89.7% (26 of 29) vs. 41.2% (7 of 17) of the metronidazole-resistant isolates (P < 0.005). Moderate (n = 1) or severe (n = 3) side-effects were experienced in four patients with only one withdrawing because of side-effects. CONCLUSION: Twice a day quadruple therapy is effective for metronidazole-sensitive strains but its usefulness is markedly reduced by the presence of pre-treatment metronidazole resistance. Twice a day quadruple therapy can be recommended in locations where background metronidazole resistance is uncommon. Possibly, 14-day therapy or a higher dosage of metronidazole provide better results with metronidazole-resistant H. pylori.
Asunto(s)
Antibacterianos/uso terapéutico , Bismuto/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Metronidazol/uso terapéutico , Omeprazol/análogos & derivados , Compuestos Organometálicos/uso terapéutico , Inhibidores de la Bomba de Protones , Salicilatos/uso terapéutico , Tetraciclina/uso terapéutico , Tetraciclinas/uso terapéutico , 2-Piridinilmetilsulfinilbencimidazoles , Quimioterapia Combinada , Femenino , Humanos , Lansoprazol , Masculino , Persona de Mediana Edad , Omeprazol/uso terapéutico , FumarRESUMEN
BACKGROUND: Emergence of antibiotic resistant Helicobacter pylori has necessitated the identification of alternate therapies for the treatment of this infection. AIM: To assess the in vitro efficacy of two investigational agents: DMG-MINO CL 344 (a N,N-dimethylglycylamido derivative of minocycline), and davercin, a cyclic carbonate of erythromycin A as compared to older antibiotics (clarithromcyin, azithromycin, minocycline, tetracycline, ofloxacin, ciprofloxacin, cefixime) against clinical isolates of H. pylori. METHODS: Testing was performed using the agar dilution method approved by the NCCLS subcommittee on antimicrobial susceptibility testing, Helicobacter pylori working group. Under these guidelines, Mueller-Hinton agar containing 5% aged sheep blood was used. All incubations were done under CampyPak Plus conditions for 72 h at 37 degrees C. The drug concentrations in the agar ranged from 0.016 to 16 microg/mL. Twenty-one clarithromycin-resistant and 16 clarithromycin-susceptible clinical isolates of H. pylori obtained from patients with duodenal ulcer were used. H. pylori ATCC 43504 was used as the control in all determinations. RESULTS: Against clarithromycin susceptible isolates, all antimicrobial agents except the fluoroquinolones were highly effective. Against clarithromycin-resistant H. pylori, the MIC50/MIC90 values showed that the tetracyclines and cefixime were the most efficacious agents. The fluoroquinolones and macrolides were ineffective. Macrolide cross-resistance was detected. CONCLUSION: Macrolide cross-resistance prevents the use of this entire class of antimicrobials when clarithromycin resistance is present. Tetracyclines and cefixime are possible alternative agents for the treatment of H. pylori infection in these patients.
Asunto(s)
Antibacterianos/farmacología , Eritromicina/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori/efectos de los fármacos , Minociclina/análogos & derivados , Minociclina/farmacología , Farmacorresistencia Microbiana , Eritromicina/análogos & derivados , Helicobacter pylori/fisiología , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
BACKGROUND: Antibiotic resistance has increasingly been recognized as the major cause of treatment failure for Helicobacter pylori infection. New therapies for patients with metronidazole- or clarithromycin-resistant H. pylori are needed. AIM: To investigate the role of nitrofurantoin quadruple therapy for the treatment of H. pylori. METHODS: Patients with confirmed H. pylori infection received nitrofurantoin (100 mg t.d.s.), omeprazole (20 mg b.d.), Pepto-Bismol (two tablets t.d.s.), and tetracycline (500 mg t.d.s.) for 14 days. Four or more weeks after the end of therapy, outcome was assessed by repeat endoscopy with histology and culture or urea breath testing. RESULTS: Thirty patients were entered, including 25 men and five women; the mean age was 54.9 years. The most common diagnoses were duodenal ulcer (23%) and GERD (18%). The intention-to-treat cure rate was 70% (95% CI: 50.6-85%). Nitrofurantoin quadruple therapy was more effective with metronidazole-sensitive strains (88%; 15 out of 17) than with metronidazole-resistant strains (33%; three out of nine; P=0.008). Two of the treatment failures had pre-treatment isolates susceptible to metronidazole, which were resistant after therapy. CONCLUSIONS: Because nitrofurantoin quadruple therapy performed inadequately in the presence of metronidazole resistance, we conclude that nitrofurantoin is unlikely to find clinical utility for the eradication of H. pylori.
Asunto(s)
Antibacterianos/farmacología , Antiinfecciosos Urinarios/farmacología , Antiulcerosos/farmacología , Bismuto/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Metronidazol/farmacología , Nitrofurantoína/farmacología , Omeprazol/farmacología , Compuestos Organometálicos/farmacología , Salicilatos/farmacología , Tetraciclina/farmacología , Administración Oral , Adulto , Anciano , Antibacterianos/administración & dosificación , Antiinfecciosos Urinarios/administración & dosificación , Antiulcerosos/administración & dosificación , Bismuto/administración & dosificación , Pruebas Respiratorias , Farmacorresistencia Microbiana , Quimioterapia Combinada , Femenino , Infecciones por Helicobacter/patología , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Nitrofurantoína/administración & dosificación , Omeprazol/administración & dosificación , Compuestos Organometálicos/administración & dosificación , Salicilatos/administración & dosificación , Tetraciclina/administración & dosificación , Resultado del Tratamiento , Urea/análisisRESUMEN
AIM: Effective anti-Helicobacter pylori therapies with few side-effects are needed. We studied the effectiveness of a low-dose combination of metronidazole, amoxycillin and omeprazole for treatment of ulcer patients in Seoul, Korea. METHODS: Patients with gastric or duodenal ulcer received metronidazole (125 mg b.d.), amoxycillin (500 mg b.d.) and omeprazole (20 mg at bedtime) for 2 weeks. Endoscopic examinations were performed before treatment and at least 6 weeks after completion of antimicrobial therapy. H. pylori status was confirmed by histological examination of two gastric biopsies using the Genta stain. RESULTS: Seventy-nine patients (64 men, 15 women, mean age 46 years) with peptic ulcer were enrolled. H. pylori infection was cured in 56 (71%) 95% CI: 60-81%). The cure rate in non-smokers was significantly higher than in smokers (88% vs. 65%, P = 0.035). Twelve pre-treatment isolates were available and metronidazole resistance was noted in all; H. pylori infection was cured in 10. Thirty-six patients cured of H. pylori have been followed for 1 year (mean of 361 days) and 2 cases became reinfected (5.5%, 95% CI: 1-18%). CONCLUSIONS: The low-dose combination of metronidazole, amoxycillin and omeprazole was effective even the in face of metronidazole resistance. Recurrence of H. pylori infection is infrequent even in countries with a high prevalence of H. pylori infection.
Asunto(s)
Amoxicilina/uso terapéutico , Antiulcerosos/uso terapéutico , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Metronidazol/uso terapéutico , Omeprazol/uso terapéutico , Penicilinas/uso terapéutico , Adulto , Anciano , Farmacorresistencia Microbiana , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: To compare H2-receptor antagonists and proton pump inhibitors as adjuvants to triple therapy for Helicobacter pylori eradication. METHODS: H. pylori-infected patients with peptic ulcer were randomized to receive either 300 mg nizatidine or 30 mg lansoprazole plus 1 g amoxicillin and 500 mg clarithromycin taken b.d. for 7 days. H. pylori eradication was assessed 4 weeks after therapy. Using meta-analytical techniques, we combined the results of this study with other randomized controlled comparisons of H2-receptor antagonists and proton pump inhibitors as adjuvants to triple therapy. RESULTS: One hundred and one patients were randomized. H. pylori eradication was 94% (47/50) [95% confidence interval (CI), 83-99%] (intention-to-treat) in the H2-receptor antagonist group vs. 86% (44/51) (95% CI, 74-94%) in the proton pump inhibitor group (P = 0.3). There has been a total of 12 similar studies (1415 patients). The overall efficacy was similar in intention-to-treat analysis: 78% (549/701) with H2-receptor antagonists vs. 81% (575/714) with proton pump inhibitors (odds ratio, 0.86; 95% CI, 0.66-1.12). A non-significant trend favouring H2-receptor antagonist (79% vs. 69%; odds ratio, 1.14; 95% CI, 0.76-1.71; P = 0.5) was seen in the comparison of clarithromycin-containing regimens. In contrast, in non-clarithromycin-containing trials, there was a slight, but significant, advantage with proton pump inhibitors (85% vs. 78%; odds ratio, 0.64; 95% CI, 0.45-0.92; P = 0.02). CONCLUSION: Overall, proton pump inhibitor and H2-receptor antagonist antisecretory agents appear to be similarly effective as adjuvants for H. pylori triple therapy. It is unlikely that the direct anti-H. pylori effect of proton pump inhibitors is responsible for their ability to enhance anti-H. pylori therapy.