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1.
Ann Surg Oncol ; 25(6): 1512-1520, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29511992

RESUMEN

BACKGROUND: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy. METHODS: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node. RESULTS: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment. CONCLUSION: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/terapia , Radioisótopos de Yodo , Escisión del Ganglio Linfático , Ganglios Linfáticos/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Axila , Proteína Axina , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Proteínas de Drosophila , Femenino , Fluorodesoxiglucosa F18 , Humanos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Metástasis Linfática , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Dosificación Radioterapéutica , Adulto Joven
2.
Breast Cancer Res Treat ; 147(3): 557-70, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25168315

RESUMEN

To assess the impact of patient-related factors, including genetic variability in genes involved in the metabolism of chemotherapeutic agents, on breast cancer-specific survival (BCSS) and recurrence-free interval (RFI). We selected early breast cancer patients treated between 2000 and 2010 with 4-6 cycles of (neo-)adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 3 cycles FEC followed by 3 cycles docetaxel. Tumor stage/subtype; febrile neutropenia and patient-related factors such as selected single nucleotide polymorphisms and baseline laboratory parameters were evaluated. Multivariable Cox regression was performed. Of 991 patients with a mean follow-up of 5.2 years, 152 (15.3 %) patients relapsed and 63 (6.4 %) patients died. Advanced stage and more aggressive subtype were associated with poorer BCSS and RFI in multivariable analysis (p < 0.0001). Associations with worse BCSS in multivariable analysis were: homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (hazard ratio [HR] 30.4; 95 % confidence interval [CI] 6.1-151.5; p < 0.001) and higher white blood cell count (WBC) (HR 1.2; 95 % CI 1.0-1.3; p = 0.014). The GT genotype of the ABCB1 variant rs2032582 was associated with better BCSS (HR 0.5; 95 % CI 0.3-0.9, p = 0.021). Following associations with worse RFI were observed: higher WBC (HR 1.1; 95 % CI 1.0-1.2; p = 0.026), homozygous carriers of the rs1057910 variant C-allele in CYP2C9 (HR 10.9; 95 % CI 2.5-47.9; p = 0.002), CT genotype of the CYBA variant rs4673 (HR 1.8; 95 % CI 1.2-2.7; p = 0.006), and G-allele homozygosity for the UGT2B7 variant rs3924194 (HR 3.4; 95 % CI 1.2-9.7, p = 0.023). Patient-related factors including genetic variability and baseline white blood cell count, impacted on outcome in early breast cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Citocromo P-450 CYP2C9/genética , Supervivencia sin Enfermedad , Docetaxel , Epirrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Glucuronosiltransferasa/genética , Humanos , Recuento de Leucocitos , Persona de Mediana Edad , Terapia Neoadyuvante , Polimorfismo de Nucleótido Simple , Taxoides/administración & dosificación , Resultado del Tratamiento
3.
Br J Cancer ; 109(12): 2965-72, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24149178

RESUMEN

BACKGROUND: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. METHODS: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. RESULTS: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. CONCLUSION: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/biosíntesis , Adolescente , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Capecitabina , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel , Doxorrubicina/administración & dosificación , Femenino , Filgrastim , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Persona de Mediana Edad , Terapia Neoadyuvante , Receptores de Estrógenos/biosíntesis , Proteínas Recombinantes/administración & dosificación , Análisis de Supervivencia , Taxoides/administración & dosificación , Adulto Joven
4.
Ann Oncol ; 23(6): 1525-30, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22039087

RESUMEN

BACKGROUND: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in locally advanced rectal cancer (LARC). To evaluate in LARC patients, the feasibility and efficacy of a short intense course of induction oxaliplatin before preoperative chemoradiotherapy (CRT). PATIENTS AND METHODS: Patients with T2-T4/N+ rectal adenocarcinoma were randomly assigned to arm A-preoperative CRT with 5-fluorouracil (5-FU) continuous infusion followed by surgery-or arm B-induction oxaliplatin, folinic acid and 5-FU followed by CRT and surgery. The primary end point was the rate of ypT0-1N0 stage achievement. RESULTS: Fifty seven patients were randomly assigned (arm A/B: 29/28) and evaluated for planned interim analysis. On an intention-to-treat basis, the ypT0-1N0 rate for arms A and B were 34.5% (95% CI: 17.2% to 51.8%) and 32.1% (95% CI: 14.8% to 49.4%), respectively, and the study therefore was closed prematurely for futility. There were no statistically significant differences in other end points including pathological complete response, tumor regression and sphincter preservation. Completion of the preoperative CRT sequence was similar in both groups. Grade 3/4 toxicity was significantly higher in arm B. CONCLUSIONS: Short intense induction oxaliplatin is feasible in LARC patients without compromising the preoperative CRT completion, although the current analysis does not indicate increased locoregional impact on standard therapy.


Asunto(s)
Adenocarcinoma/terapia , Antimetabolitos Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fluorouracilo/administración & dosificación , Neoplasias del Recto/terapia , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia Adyuvante , Quimioterapia Adyuvante , Procedimientos Quirúrgicos del Sistema Digestivo , Femenino , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Dosificación Radioterapéutica , Neoplasias del Recto/patología , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/efectos de la radiación , Adulto Joven
5.
Br J Surg ; 97(8): 1226-31, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20602508

RESUMEN

BACKGROUND: An important benefit of neoadjuvant chemotherapy is the increased potential for breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not easily assessed, rendering axilla-conserving treatment difficult. The aim was to assess a new surgical method for evaluating the axillary response to chemotherapy. METHODS: Before neoadjuvant chemotherapy, proven tumour-positive axillary lymph nodes were localized using ultrasound-guided insertion of iodine-125-labelled (I-125) seeds. After neoadjuvant chemotherapy, the marked lymph nodes were removed selectively with the use of a gamma probe. A complete axillary lymph node clearance was carried out to determine whether the pathological response in the marked node was indicative of that in the other lymph nodes. RESULTS: Tumour-positive axillary lymph nodes were localized successfully with I-125 seeds in 15 patients. The marked lymph node was detected and removed selectively after neoadjuvant chemotherapy in all patients. The pathological response to chemotherapy in the marked lymph node was indicative of the overall response in other removed lymph nodes. CONCLUSION: This study showed that marking and selectively removing metastatic lymph nodes after neoadjuvant chemotherapy was feasible. The tumour response in the marked lymph node may be used to tailor further axillary treatment, making axilla-conserving surgery a possibility.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Radioisótopos de Yodo , Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática/diagnóstico por imagen , Radiofármacos , Adulto , Anciano , Axila , Biopsia con Aguja Fina , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Estudios de Factibilidad , Femenino , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Persona de Mediana Edad , Cintigrafía , Ultrasonografía Intervencional
6.
Ann Surg Oncol ; 17(9): 2510-7, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20339948

RESUMEN

BACKGROUND: Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol. MATERIALS AND METHODS: The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol and Pac/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of < or = 10% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min. RESULTS: Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol. Hyperthermia yielded no significant differences in bioavailability data. CONCLUSION: These results showed that both formulations had a similar toxicity profile but differed significantly in bioavailability.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinógenos/farmacología , Hipertermia Inducida , Paclitaxel/farmacología , Peritoneo/efectos de los fármacos , beta-Ciclodextrinas/farmacología , Animales , Antineoplásicos Fitogénicos/química , Disponibilidad Biológica , Carcinógenos/química , Quimioterapia del Cáncer por Perfusión Regional , Dosis Máxima Tolerada , Paclitaxel/química , Ratas , beta-Ciclodextrinas/química
7.
Int J Pharm ; 367(1-2): 148-54, 2009 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-18938234

RESUMEN

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising strategy in the treatment of peritoneal carcinomatosis. To perform HIPEC, a tensioactive- and solvent-free paclitaxel formulation consisting of water-soluble paclitaxel/randomly methylated-beta-cyclodextrin (Pac/RAMEB) complexes was developed previously. Using MTT and SRB assays the cytotoxic activity of this formulation versus Taxol, was evaluated as well as the cytotoxicity of the different formulation excipients (RAMEB and Cremophor EL. The possible synergistic effect of heat and paclitaxel-based chemotherapy during HIPEC was also evaluated in vitro. The cytotoxicity assays revealed differences in viability between Cremophor EL and RAMEB treated cells of 40 and 50% for the CaCo-2 human and the CC531s rat colon cancer line, respectively, in favour of RAMEB. Despite the higher cytotoxicity of Cremophor EL, Pac/RAMEB complexes and Taxol were equipotent. Using the MTT and SRB assays the average difference in viability between both cell lines was below 10% and IC50 values showed no significant difference. Hyperthermia after drug administration (41 degrees C during 1h) had no effect on cell viability. These results indicated that it was possible to reformulate paclitaxel with a less cytotoxic vehicle while maintaining the cytotoxic activity of the formulation and that there is no synergism between paclitaxel and heat for in vitro cytotoxicity.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Portadores de Fármacos/química , Hipertermia Inducida/métodos , Paclitaxel/farmacología , Neoplasias Peritoneales/terapia , beta-Ciclodextrinas/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Células CACO-2 , Técnicas de Cultivo de Célula , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Portadores de Fármacos/farmacología , Excipientes/química , Excipientes/farmacología , Calor , Humanos , Paclitaxel/administración & dosificación , Paclitaxel/química , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/patología , Ratas , beta-Ciclodextrinas/farmacología
8.
J Pharmacol Toxicol Methods ; 52(1): 168-77, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15935709

RESUMEN

INTRODUCTION: Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization. METHODS: Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05). CONCLUSION: Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification in cardiovascular safety assessment.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Síndrome de QT Prolongado/fisiopatología , Modelos Cardiovasculares , Torsades de Pointes/fisiopatología , Anestesia , Animales , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/clasificación , Perros , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intravenosas , Síndrome de QT Prolongado/inducido químicamente , Contracción Miocárdica , Fenetilaminas/efectos adversos , Bloqueadores de los Canales de Potasio/efectos adversos , Sulfonamidas/efectos adversos , Torsades de Pointes/inducido químicamente
9.
J Infect Dis ; 184(4): 515-8, 2001 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-11471112

RESUMEN

A survey was conducted of exhibitors at a 1999 floral trade show, where a whirlpool spa on display caused a large outbreak of legionnaires disease (LD). In total, 742 exhibitors without LD returned a questionnaire on their whereabouts during the fair and their health afterward and supplied blood samples for the detection of IgM and IgG antibodies against Legionella pneumophila. The exhibitors had higher average antibody levels than did the general population. The closer to the whirlpool that the exhibitors worked, the higher their antibody levels. Both high-normal and high titer levels were found more frequently among workers with more exposure, suggesting that serosurveys among potentially exposed subjects are a valuable tool for outbreak investigation. Some differences in health complaints were observed between the more and less exposed groups, as estimated by the workplace location, but few differences were found between groups with different antibody levels.


Asunto(s)
Anticuerpos Antibacterianos/sangre , Brotes de Enfermedades , Legionella pneumophila/inmunología , Enfermedad de los Legionarios/epidemiología , Enfermedad de los Legionarios/fisiopatología , Exposición Profesional , Adulto , Exposiciones como Asunto , Femenino , Humanos , Hidroterapia , Legionella pneumophila/aislamiento & purificación , Enfermedad de los Legionarios/microbiología , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Ocupaciones , Plantas , Contaminación del Agua
10.
Hepatogastroenterology ; 47(31): 44-8, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10690584

RESUMEN

Inflammatory bowel disease, with Crohn's disease and ulcerative colitis as the two main disorders, is a heterogeneous group of disorders of unknown etiology. Clinical initial presentation is sometimes misleading and causing diagnostic delay which may be important. Identification of subgroups of patients on the basis of genetic, immunologic and clinical markers will be important for exact diagnosis, but also for new drug trials. The current diagnosis depends on clinical, radiographic, endoscopic and laboratory data. The introduction of serological markers such as pANCA and ASCA will allow an increase in the diagnostic accuracy at initial diagnosis of inflammatory bowel disease and may play a role in defining subgroups of the disease.


Asunto(s)
Enfermedades Inflamatorias del Intestino/diagnóstico , Sulfato de Bario , Biomarcadores/análisis , Biopsia , Colonoscopía , Medios de Contraste , Diagnóstico Diferencial , Enema , Gastroscopía , Humanos , Enfermedades Inflamatorias del Intestino/clasificación
11.
Hepatogastroenterology ; 46(26): 709-16, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10370599

RESUMEN

Colorectal cancer is one of the most frequent malignancies and one of the greatest causes of cancer death in the Western world. The prognosis is determined by the stage at diagnosis. Patients with metastatic colon cancer have a bad prognosis. Chemotherapeutic treatment with 5-Fluorouracil (5-FU) and folinic acid is actually considered as the standard treatment in patients with metastatic disease. Although the survival benefit is relatively small, many patients can benefit from this treatment in terms of tumor regression or symptom improvement. Several new drugs are actually in development and create hope for improved tumor or symptom control and longer survival. Thymidylate synthase inhibitors (raltitrexed), topoisomerase I inhibitors (irinotecan), the oral 5-FU prodrugs (capecitabine, UFT), ethynyluracil, and oxaliplatin are promising new drugs. The challenge will be to determine the best combination of these new drugs and the exact sequence in which these drugs will be used. Adjuvant post-operative chemotherapy in colon cancer is one of the most important advances in oncology that has been introduced into the clinic during the last years. For rectal cancer, an adjuvant treatment should consist of a combined chemo-radiotherapy. The search for better prognostic factors for recurrence should help to focus on a better adjuvant treatment for patients with the highest risk for recurrence.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Tasa de Supervivencia
12.
JPEN J Parenter Enteral Nutr ; 23(1): 7-11, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-9888411

RESUMEN

BACKGROUND: Glutamine is a major fuel and an important nitrogen source for the small intestinal cell. It plays a key role in maintaining mucosal cell integrity and gut barrier function. Increased permeability may be a factor in the pathogenesis of Crohn's disease and may be an interesting parameter in the follow-up of the disease. Therefore, the aim of this study was to examine whether oral glutamine supplements are able to restore an increased intestinal permeability in patients with Crohn's disease. METHODS: The inclusion criteria for the study were Crohn's disease and a disturbed small intestinal permeability for 51Cr-EDTA. Of 38 patients screened, 18 had an increased permeability (6 hours urinary excretion >1.1% of label recovered in urine). Fourteen patients were included in the study and were randomized to receive either oral glutamine (7 g three times per day; n = 7) or placebo (7 g glycine three times per day; n = 7) in addition to their normal treatment during a 4-week period. The study was performed in a double-blind manner. RESULTS: Baseline permeability (mean +/- SD) was 2.32%+/-0.77% dose in the glutamine group and 2.29%+/-0.67% dose in the placebo group. Permeability did not change significantly after glutamine (3.26%+/-2.15% dose) or after placebo (2.27%+/-1.32% dose). There was no significant effect on plasma glutamine, plasma glutamate, plasma ammonium, Crohn's disease activity index, C-reactive protein, or nutritional status. CONCLUSIONS: Oral glutamine supplements, in the dose administered, do not seem to restore impaired permeability in patients with Crohn's disease.


Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Glutamina/uso terapéutico , Intestino Delgado/efectos de los fármacos , Administración Oral , Adulto , Antropometría , Enfermedad de Crohn/metabolismo , Método Doble Ciego , Femenino , Glutamina/sangre , Glutamina/farmacología , Humanos , Intestino Delgado/metabolismo , Masculino , Permeabilidad/efectos de los fármacos
13.
Appl Microbiol Biotechnol ; 53(1): 108-14, 1999 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-10645630

RESUMEN

This paper introduces a new type of system to simulate conditions in the large intestine. This system combines removal of metabolites and water with peristaltic mixing to obtain and handle physiological concentrations of microorganisms, dry matter and microbial metabolites. The system has been designed to be complementary to the dynamic multi-compartmental system that simulates conditions in the stomach and small intestine described by Minekus et al. [Minekus M, Marteau P, Havenaar R, Huis in't Veld JHJ (1995) ATLA 23:197-209]. High densities of microorganisms, comparable to those found in the colon in vivo, were achieved by absorption of water and dialysis of metabolites through hollow-fibre membranes inside the reactor compartments. The dense chyme was mixed and transported by peristaltic movements. The potential of the system as a tool to study fermentation was demonstrated in experiments with pectin, fructo-oligosaccharide, lactulose and lactitol as substrates. Parameters such as total acid production and short-chain fatty acid (SCFA) patterns were determined with time to characterize the fermentation. The stability of the microflora in the system was tested after inoculation with fresh fecal samples and after inoculation with a microflora that was maintained in a fermenter. Both approaches resulted in total anaerobic bacterial counts higher than 10(10) colony-forming units/ml with physiological levels of Bifidobacterium, Lactobacillus, Enterobacteriaceae and Clostridium. The dry matter content was approximately 10%, while the total SCFA concentration was maintained at physiological concentrations with similar molar ratios for acetic acid, propionic acid and butyric acid as measured in vivo.


Asunto(s)
Bacterias/metabolismo , Colon/metabolismo , Fermentación , Peristaltismo , Absorción , Computadores , Ácidos Grasos/metabolismo , Heces/microbiología , Humanos , Agua
14.
Gastroenterology ; 115(3): 584-90, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9721155

RESUMEN

BACKGROUND & AIMS: Impaired short-chain fatty acid metabolism by the colonocyte has been suggested as a pathogenic factor in ulcerative colitis (UC). The aim of this study was to measure in vivo butyrate metabolism in UC and to correlate butyrate oxidation with colonic permeability. METHODS: Butyrate oxidation was measured by means of a 14CO2-breath test after rectal instillation of 14C-butyrate. 51Cr-ethylenediaminetetraacetic acid (EDTA) was added to the enema, and the urinary % dose excretion of 51Cr-EDTA after 6 hours was a measure for permeability. RESULTS: Patients with active extensive UC showed a significantly lower butyrate oxidation and increased colonic permeability in comparison to healthy controls. Butyrate oxidation correlated significantly negative with clinical activity. Oxidation of butyrate was not decreased in most patients with inactive extensive UC. In 3 patients with inactive disease and decreased oxidation, a relapse occurred within a few weeks after the test, whereas all patients with normal oxidation maintained their remission for at least 3 months. A significantly negative correlation existed between butyrate oxidation and colonic permeability. CONCLUSIONS: Patients with active extensive UC have a decreased colonic butyrate oxidation. However, the fact that remission is associated with normal oxidation suggests that UC mucosa is not intrinsically altered in butyrate oxidation, making this unlikely to be a primary defect in UC.


Asunto(s)
Butiratos/metabolismo , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/fisiopatología , Colon/fisiopatología , Pruebas Respiratorias , Butiratos/administración & dosificación , Butiratos/farmacocinética , Dióxido de Carbono/análisis , Radioisótopos de Carbono , Radioisótopos de Cromo , Colon/fisiología , Ácido Edético , Enema , Humanos , Absorción Intestinal , Oxidación-Reducción , Permeabilidad , Valores de Referencia
15.
Br J Haematol ; 89(3): 678-80, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7734380

RESUMEN

Patients with Down syndrome have been found to have characteristic in vivo and in vitro methotrexate toxicity. The in vitro methotrexate toxicity characteristic of Down syndrome can be diminished by the in vivo administration of supplemental high doses of folic acid. A possible explanation for the increased sensitivity to methotrexate which has been documented in patients with Down syndrome may be due to imbalances in nucleotide pools which result from a gene dosage effect and to greater methylation demands. Supplemental folic acid may be beneficial by virtue of a down-regulation of excess gene activity and may also provide needed monocarbons.


Asunto(s)
Síndrome de Down/sangre , Ácido Fólico/farmacología , Linfocitos/efectos de los fármacos , Metotrexato/antagonistas & inhibidores , Adolescente , Adulto , Células Cultivadas , Humanos , Discapacidad Intelectual/sangre , Linfocitos/patología , Metotrexato/toxicidad , Índice Mitótico/efectos de los fármacos
16.
J Intellect Disabil Res ; 37 ( Pt 6): 491-505, 1993 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8123996

RESUMEN

Three enzymes intervening in de novo purine synthesis, as well as cystathionine B-synthetase, have been mapped to chromosome 21. In order to gain a better understanding of purine synthesis anomalies in Down's syndrome, the present authors studied the variations in mitotic index of lymphocyte cultures to which various inhibitors or metabolites of purine synthesis had been added. In spite of common gene dosage effects, unexpected and highly significant differences were noted between Down's syndrome patients without complications and those presenting with additional psychotic features. In Down's syndrome patients without complications, a highly significant decrease in mitotic index was noted in the presence of exogenous inosine. A significant decrease in the presence of adenosine and guanosine was also noted. These findings are in keeping with the expected metabolic repercussions of genes mapped to chromosome 21. In Down's syndrome patients with psychotic complications, the in vitro reactions were quite different. A paradoxal increase in mitotic index was noted in the presence of inosine and of adenosine, but the response to guanosine did not differ from that observed in normal controls. These findings were unexpected and seem to indicate that, in spite of the gene dosage effect, psychotic Down's syndrome patients are unable to compensate abnormal purine synthesis and resulting imbalances. Furthermore, a marked difference in purine metabolic reactions was noted between Down's syndrome patients receiving supplemental folic/folinic acid and those on no therapy. This suggests that some modulation of the gene dosage effect may be possible.


Asunto(s)
Síndrome de Down/metabolismo , Purinas/metabolismo , Adenosina/deficiencia , Adenosina/farmacología , Adolescente , Niño , Cromosomas Humanos Par 21 , Síndrome de Down/genética , Síndrome de Down/psicología , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/farmacología , Guanosina/deficiencia , Guanosina/farmacología , Humanos , Inosina/farmacología , Masculino , Índice Mitótico/efectos de los fármacos , Fenotipo
17.
Genitourin Med ; 62(3): 163-5, 1986 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3089906

RESUMEN

The in vitro activity of seven metallic compounds was tested against penicillinase (beta lactamase) producing strains of Neisseria gonorrhoeae (PPNG) and non-PPNG strains. On a weight basis, the mercurials showed the greatest in vitro activity. Phenylmercuric borate, thiomersal, and mercuric chloride inhibited 90% of all strains at concentrations of 5 mg/l, 5 mg/l, and 20 mg/l respectively. Silver nitrate inhibited 90% of the strains at 80 mg/l and the MIC90 for mild silver protein was 200 mg/l. Copper and selenium salts had lower in vitro activities, inhibiting 90% of all the strains at 320 mg/l and 640 mg/l respectively. Silver nitrate and the six other compounds tested showed equal activities against PPNG and non-PPNG strains. This finding supports the recommendation for prophylaxis of gonococcal conjunctivitis of the newborn with 1% silver nitrate eye drops.


Asunto(s)
Metales/farmacología , Neisseria gonorrhoeae/efectos de los fármacos , Cobre/farmacología , Sulfato de Cobre , Cloruro de Mercurio/farmacología , Pruebas de Sensibilidad Microbiana , Compuestos de Fenilmercurio/farmacología , Proteínas/farmacología , Ácido Selenioso , Selenio/farmacología , Plata/farmacología , Nitrato de Plata/farmacología , Timerosal/farmacología
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