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BACKGROUND/OBJECTIVES: This historical control study examined the differences in the incidence of postoperative pneumonia between patients administered liquid and semi-solid nutrients after percutaneous endoscopic gastrostomy (PEG). SUBJECTS/METHODS: The medical records of adult patients who underwent PEG between March 1999 and March 2014 were investigated. The patients were administered either liquid or semi-solid nutrient and examined for gastroesophageal reflux via radiography after PEG. The study period was divided into periods I (liquid nutrient to all patients), II (semi-solid nutrient to patients with reflux and liquid nutrient to those without), and III (semi-solid nutrient to all patients). The patient characteristics and incidence of postoperative pneumonia were stratified by the periods. To assess the relationship between postoperative pneumonia and the periods, a logistic regression analysis was performed. RESULTS: Of 370 patients enrolled, 149 were in period I, 64 in period II, and 157 in period III. Postoperative pneumonia was more frequently observed in period I (20.8%) than in periods II (7.8%) and III (10.2%). The odds ratios were higher in period I (period I vs. II: 3.10 [95% confidence intervals: 1.15-8.38]; period I vs. III: 2.32 [1.21-4.44]). The incidence of gastroesophageal reflux did not greatly differ between periods II (25.0%) and III (35.0%). CONCLUSIONS: The incidence of postoperative pneumonia after PEG was lower in the patients administered semi-solid nutrient than in those administered liquid nutrient, suggesting that semi-solid nutrient administration to patients with PEG tubes is preferable to prevent postoperative pneumonia. Furthermore, it may be favored especially in those with gastroesophageal reflux.
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Nutrición Enteral/efectos adversos , Reflujo Gastroesofágico/epidemiología , Gastrostomía , Neumonía por Aspiración/epidemiología , Adulto , Anciano , Femenino , Reflujo Gastroesofágico/etiología , Humanos , Incidencia , Japón/epidemiología , Masculino , Registros Médicos , Persona de Mediana Edad , Nutrientes/administración & dosificación , Neumonía por Aspiración/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. METHODS: Patients received oxaliplatin (100 mg/m2, day 1), capecitabine (1700 mg/m2 per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m2 for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m2, day 1 and, thereafter, 250 mg/m2 every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). RESULTS: Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m2. Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. CONCLUSIONS: The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m2. The observed response rate was promising and warrants further investigation.
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Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Capecitabina/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , OxaliplatinoRESUMEN
PURPOSE: Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. METHODS: Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1-14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. RESULTS: Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). CONCLUSION: Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neutropenia/inducido químicamente , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/epidemiología , Ácido Oxónico/administración & dosificación , Neoplasias Gástricas/patología , Tasa de Supervivencia , Taxoides/administración & dosificación , Tegafur/administración & dosificación , Resultado del TratamientoRESUMEN
A 51-year-old man was admitted to our hospital complaining of right upper quadrant abdominal and back pain. Severe hepatomegaly (six fingerbreadths) was detected by liver palpation. Blood test results showed cholestatic liver disease. He was diagnosed with amyloidosis by liver biopsy. Bone marrow aspiration revealed 15% of contents to be plasma cells. BJPκ was detected by urine electrophoresis. Therefore, he was diagnosed with the BJPκ type of multiple myeloma with systemic amyloidosis. The patient was treated with bortezomib, dexamethasone and high-dose melphalan with autologous peripheral blood stem cell transplantation. He achieved VGPR (very good partial response) after transplantation. Hepatomegaly improved but swelling persisted, and he was therefore treated with 1.3 mg/m(2)/day of bortezomib and 20 mg/day of dexamethasone on day 1 and day 15 in 28-day cycles. Upon finishing 22 cycles in June 2014, his liver had returned to normal size. Restoration of normal liver size after treatment is rare in cases with severe hepatomegaly due to systemic amyloidosis. We thus report our case with a review of the relevant literature.
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Amiloidosis/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Amiloidosis/complicaciones , Proteína de Bence Jones/análisis , Ácidos Borónicos/administración & dosificación , Bortezomib , Dexametasona/administración & dosificación , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Pirazinas/administración & dosificación , Trasplante AutólogoRESUMEN
A 78-year-old woman was diagnosed with multiple myeloma (MM: IgG κ type, stage IIIA, ISS III) at a nearby hospital in August 2010. High-dose dexamethasone therapy was ineffective, and she was treated with 2 courses of bortezomib. She was referred to our hospital with back pain and dyspnea in November. She was diagnosed with interstitial pneumonia (IP) and improved rapidly with steroid pulse therapy. Because the involvement of bortezomib was suspected in IP, lenalidomide therapy was selected for MM. Lenalidomide (15 mg) was administered for 2 courses. The patient achieved a PR and the treatment is still ongoing with a good response. According to the interim report on PMS (post-marketing surveillance), 3 of the 1,177 patients treated with lenalidomide developed IP. The dose level was 25 mg in 2 cases and 10 mg in 1 case. The outcomes of these patients were death in 1 case, not recovered in 1 case, and unknown in 1 case. When lenalidomide is used to treat bortezomib-induced IP, there are no rules or regulations about its dose level. In the present case, the dose of lenalidomide (15 mg) was based on the retreatment dose after bone marrow suppression. Low-dose lenalidomide therapy was effective and safe against MM with a bortezomib-associated lung disorder.
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Antineoplásicos/efectos adversos , Ácidos Borónicos/efectos adversos , Factores Inmunológicos/administración & dosificación , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/complicaciones , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/efectos adversos , Talidomida/análogos & derivados , Anciano , Bortezomib , Femenino , Humanos , Lenalidomida , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Talidomida/administración & dosificación , Resultado del TratamientoRESUMEN
A 64-year-old man had been admitted to a previous hospital because of melena and a diagnosis of ulcerative colitis (UC, pancolitis type) had been made. He had received prednisolone and 5-ASA but steroid-induced hyperamylasemia had developed. Prednisolone had been tapered and halted, but it had resulted in UC relapse and thrombocytopenia. Then, he was referred to our hospital due to severe melena with hypovolemic shock. However, he was also positive for CMV antigen. Thus, we attempted to treat him with ganciclovir for CMV and intravenous cyclosporine (CsA) for UC. According to his clinical course, a reduction of CsA blood concentration induced leukocytopenia. Myelodysplastic syndrome (MDS, RAEB-1) was then revealed after bone marrow biopsy. A high blood CsA concentration may cause the improvement of UC and MDS conditions.
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Colitis Ulcerosa/tratamiento farmacológico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/etiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIM: Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long-Evans cinnamon rats was prevented by feeding an iron-deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once-daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis. METHODS: Human primary hepatocytes undergoing Fas-stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas-stimulation. RESULTS: The apoptosis-inducing activity of anti-Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas-induced production of reactive oxygen species (ROS) and the activation of caspase-3, both of which were also suppressed by antioxidant, N-acetyl-L-cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas-induced fulminant hepatitis. CONCLUSION: These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase-3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.
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Solid cancers are rarely complicated by the occurrence of polyarteritis nodosa (PN), and most cases diagnosed as PN are, in fact, cases of paraneoplastic vasculitis. Paraneoplastic vasculitis is usually resolved after tumor removal. We present a rare case of a 69-year-old man with PN complicated by rectal cancer, without the occurrence of paraneoplastic vasculitis. Microscopic examination of the resected cancer lesion revealed inflammation of some arteries and neutrophil and lymphocyte infiltration, fibrin deposition, stenosis, and vasodilatation of capillaries caused by congestion in the submucosal layer. It was unclear how these findings exerted influence on the rectal cancer. Although the symptoms of PN did not improve after the patient's tumor was removed surgically, the symptoms improved rapidly after oral treatment with prednisolone and cyclophosphamide.
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Alpha-Galactosylceramide (alpha-GalCer) is a potent CD1d ligand that activates natural killer like T-cells (NKT), leading to the production of helper T (Th) 1 and Th2 cytokines that mediate various immunemodulatory and antitumor effects. Here, we determined whether the administration of adenovirus-vector-encoding mouse interleukin-2 (AdmIL-2) can augment the antitumor effect of alpha-GalCer on subcutaneous and metastatic tumors in mice. Mice were intraperitoneally injected with alpha-GalCer on days 7, 10 and 13 after tumor inoculation, with or without intratumoral injection of AdmIL-2 on day 7. alpha-GalCer treatment increased the serum levels of interferon-gamma, while intratumoral injection of AdmIL-2 elevated serum IL-2 levels. A combination of alpha-GalCer and AdmIL-2 (alpha-GalCer/AdmIL-2) inhibited the in vivo tumor growth and improved the survival of tumor-bearing mice, as compared to the use of a single agent. Experiments on spontaneous metastasis models revealed that alpha-GalCer/AdmIL-2 reduced lung metastasis and prolonged survival, as compared to control groups. In addition, the splenic and liver mononuclear cells from mice treated with alpha-GalCer/AdmIL-2 showed enhanced cytolytic activity against NK-sensitive YAC-1 and NK-resistant 3LL tumors. Moreover, alpha-GalCer/AdmIL-2 treatment expanded the absolute numbers of lung and liver NK, NKT and T-cells as well as the TNF-related apoptosis-inducing ligand (TRAIL) expression of these cells. This study shows the efficacy of alpha-GalCer/AdmIL-2 immunomodulatory therapy, and provides a cellular mechanism on how it exerts the antitumor effects.
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Carcinoma Pulmonar de Lewis/terapia , Galactosilceramidas/uso terapéutico , Interleucina-2/fisiología , Células Asesinas Naturales/metabolismo , Células T Asesinas Naturales/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Adenoviridae/genética , Animales , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Línea Celular Tumoral , Proliferación Celular , Pruebas Inmunológicas de Citotoxicidad , Citotoxicidad Inmunológica/inmunología , Femenino , Citometría de Flujo , Galactosilceramidas/administración & dosificación , Técnicas de Transferencia de Gen , Inyecciones Intraperitoneales , Interferón gamma/sangre , Interleucina-2/sangre , Interleucina-2/genética , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Células T Asesinas Naturales/inmunología , Metástasis de la Neoplasia , Análisis de Supervivencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Carga TumoralRESUMEN
BACKGROUND: Although the etiology of inflammatory bowel disease has not been fully clarified, reactive oxygen species is speculated to be involved. Extracellular superoxide dismutase (EC-SOD), an isozyme of SODs, is known to function mainly in body fluids. We investigated the efficacy of an ex vivo EC-SOD gene transfer into dextran sulfate sodium (DSS)-induced colitis mice. MATERIALS AND METHODS: Experimental colitis was induced by providing Balb/c mice with DSS in sterile distilled water provided as desired. The syngenic fibroblasts were obtained from Balb/c mice embryos and retrovirally transduced with the hEC-SOD gene. These engineered cells were confirmed to secrete EC-SOD in culture medium by enzyme-linked immunosorbent assay and were inoculated subcutaneously in the backs of DSS-treated mice. Mucosal injury of the colon was evaluated by the disease activity index (DAI: body weight, rectal bleeding, and stool consistency), grading of histologic disease severity, and levels of cytokine (tumor necrosis factor-alpha, interleukin-1beta) production. 8-Hydroxydeoxyguanosine (8-OHdG) levels in the mucosal tissue were assessed by immunohistochemical staining. Malondialdehyde (MDA) was measured using a colorimetric assay. RESULTS: A significant improvement was observed in DAI score and histologic severity as well as in mucosal tissue levels of inflammatory cytokines, 8-OHdG, and MDA of mice treated with the EC-SOD gene as compared with those without gene therapy, not only in a mild colitis model but also in a severe colitis model. Survival of treated mice in these models was significantly prolonged. CONCLUSIONS: Ex vivo transfer of the EC-SOD gene was feasible for treatment of DSS-induced colitis.
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Colitis/inducido químicamente , Colitis/terapia , Sulfato de Dextran/farmacología , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Superóxido Dismutasa/metabolismo , Animales , Anticoagulantes/farmacología , Medios de Cultivo/metabolismo , Citocinas/metabolismo , Femenino , Fibroblastos/metabolismo , Inmunohistoquímica , Inflamación , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos BALB C , Especies Reactivas de OxígenoRESUMEN
PURPOSE: To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile. METHODS: Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m2 administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m2 in level 1, 50 mg/m2 in level 2, or 60 mg/m2 in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy). RESULTS: Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months. CONCLUSIONS: The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/terapia , Radioterapia Adyuvante/métodos , Anciano , Anemia/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Esofagitis/inducido químicamente , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neutropenia/inducido químicamente , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Radioterapia Adyuvante/efectos adversos , Inducción de Remisión , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.
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Adenocarcinoma/tratamiento farmacológico , Anafilaxia/inducido químicamente , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Compuestos Organoplatinos/efectos adversos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Compuestos Organoplatinos/administración & dosificación , OxaliplatinoRESUMEN
OBJECTIVES: To establish a novel strategy of fungal infection control. METHODS: We examined the influences of antimicrobial peptides including a synthesized short lactoferrin peptide (FKCRRWQWRM, Peptide 2; Pep2) on the synthesis of Candida cell wall polysaccharides, ergosterol synthesis, membrane permeability and the efflux of ATP. RESULTS: Colony formation of Candida albicans was synergistically suppressed by a combination of low concentrations of each drug and peptide. All peptides and amphotericin B, but not itraconazole, revealed weak inhibitory activities against ergosterol synthesis and the peptides weakly suppressed the synthesis of Candida cell wall components, glucan, mannan and chitin. Cell membrane permeability was not only increased by these peptides but also clearly increased by both amphotericin B and itraconazole. ATP efflux was however up-regulated by low concentrations of the peptides, especially by Pep2 and Hst5, although both antifungal drugs did not exert any influence on ATP efflux. The expression of the Candida drug resistance genes 1 and 2 (CDR1 and CDR2) was increased by both drugs, but this increase was suppressed by each peptide. In addition, larger amounts of amphotericin B and itraconazole remained in Candida cells in the presence of Pep2 or Hst5 due to the lower excretion. The effects of both peptides on ATP efflux and increase of intercellular amphotericin B and itraconazole were blocked by anion channel inhibitors 4,4'-diisothiocyanatestilbene-2, 2'-disulphonic acid and 5-nitro-2-(3-phenylpropylamino) benzoic acid. CONCLUSIONS: The examined peptides, especially Pep2 and Hst5, enhance the candidacidal activity of antifungal drugs by promoting anion channel-associated ATP efflux from Candida cells and decreasing efflux of the drugs, which could be useful clinical applications.
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Adenosina Trifosfato/metabolismo , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Lactoferrina/farmacología , Fragmentos de Péptidos/farmacología , Transportadoras de Casetes de Unión a ATP/genética , Candida albicans/genética , Candida albicans/crecimiento & desarrollo , Candida albicans/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Farmacorresistencia Fúngica/efectos de los fármacos , Farmacorresistencia Fúngica/genética , Sinergismo Farmacológico , Ergosterol/metabolismo , Proteínas Fúngicas/genética , Expresión Génica/efectos de los fármacos , Lactoferrina/química , Proteínas de Transporte de Membrana/genética , Pruebas de Sensibilidad Microbiana , Fragmentos de Péptidos/química , Polisacáridos Bacterianos/metabolismoRESUMEN
A 77-year-old man was diagnosed as having essential thrombocythemia in 1992. Treatment with hydroxyurea was started in 1997, which stabilized the platelet count. The patient then suffered from pharyngalgia and rhinitis with a high fever, immediately after which he developed tarry stools and anemia and was admitted to our hospital. The physical examination revealed splenomegaly, oral aphthous ulcers, genital ulcers and skin lesions on the lower limbs. His hematological and biochemical tests revealed anemia and increased level of C-reactive protein. He also had an HLA-B51 phenotype. The findings of gastro-intestinal and colon fiberoscopy showed a duodenal ulcer and multiple ulcers on ascending colon. He was thus diagnosed as having intestinal tract-type Behçet disease. After withdrawal of the hydroxyurea administration, the intestinal ulcers, oral aphthous ulcers and genital ulcers improved.
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Síndrome de Behçet/inducido químicamente , Hidroxiurea/efectos adversos , Trombocitemia Esencial/tratamiento farmacológico , Anciano , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Biomarcadores/sangre , Antígenos HLA-B/sangre , Antígeno HLA-B51 , Humanos , MasculinoRESUMEN
To establish a novel strategy for the control of fungal infection, we examined the antifungal and neutrophil-activating activities of antimicrobial peptides. The duration of survival of 50% of mice injected with a lethal dose of Candida albicans (5 x 10(8) cells) or Aspergillus fumigatus (1 x 10(8) cells) was prolonged 3 to 5 days by the injection of 10 microg of peptide 2 (a lactoferrin peptide) and 10 microg of alpha-defensin 1 for five consecutive days and was prolonged 5 to 13 days by the injection of 0.1 microg of granulocyte-monocyte colony-stimulating factor (GM-CSF) and 0.5 microg of amphotericin B. When mice received a combined injection of peptide 2 (10 microg/day) with amphotericin B (0.5 microg/day) for 5 days after the lethal fungal inoculation, their survival was greatly prolonged and some mice continued to live for more than 5 weeks, although the effective doses of peptide 2 for 50 and 100% suppression of Candida or Aspergillus colony formation were about one-third and one-half those of amphotericin B, respectively. In vitro, peptide 2 as well as GM-CSF increased the Candida and Aspergillus killing activities of neutrophils, but peptides such as alpha-defensin 1, beta-defensin 2, and histatin 5 did not upregulate the killing activity. GM-CSF together with peptide 2 but not other peptides enhanced the production of superoxide (O2-) by neutrophils. The upregulation by peptide 2 was confirmed by the activation of the O2- -generating pathway, i.e., activation of large-molecule guanine binding protein, phosphatidyl-inositol 3-kinase, protein kinase C, and p47phox as well as p67phox. In conclusion, different from natural antimicrobial peptides, peptide 2 has a potent neutrophil-activating effect which could be advantageous for its clinical use in combination with antifungal drugs.
Asunto(s)
Anfotericina B/administración & dosificación , Antifúngicos/administración & dosificación , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus , Candida albicans , Lactoferrina/administración & dosificación , Péptidos/administración & dosificación , Animales , Aspergilosis/metabolismo , Aspergilosis/patología , Candidiasis/patología , Células Cultivadas , Femenino , Ratones , Activación Neutrófila/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , alfa-Defensinas/administración & dosificaciónRESUMEN
BACKGROUND & AIMS: Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer. METHODS: Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity. RESULTS: Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months. CONCLUSIONS: Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.
Asunto(s)
Adenoma/tratamiento farmacológico , Apoptosis/fisiología , Neoplasias del Colon/tratamiento farmacológico , Ácido Desoxicólico/toxicidad , Detergentes/toxicidad , Glutatión Transferasa/metabolismo , Glutatión/análogos & derivados , Sulindac/análogos & derivados , Adenoma/patología , Adenoma/prevención & control , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/patología , Neoplasias del Colon/prevención & control , Ciclooxigenasa 2 , Ácido Desoxicólico/metabolismo , Detergentes/metabolismo , Inhibidores Enzimáticos/farmacología , Fibroblastos/citología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glutatión/farmacología , Glutatión Transferasa/antagonistas & inhibidores , Glutatión Transferasa/genética , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Isoenzimas/genética , Pulmón/citología , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/genética , ARN Mensajero/análisis , Sulindac/administración & dosificación , TransfecciónAsunto(s)
Alprostadil/uso terapéutico , Colitis Isquémica/complicaciones , Colitis Isquémica/tratamiento farmacológico , Colon/patología , Vasodilatadores/uso terapéutico , Alprostadil/administración & dosificación , Colon/irrigación sanguínea , Colonoscopía , Colorantes , Constricción Patológica , Femenino , Humanos , Verde de Indocianina , Infusiones Intravenosas , Mucosa Intestinal/irrigación sanguínea , Persona de Mediana Edad , Flujo Sanguíneo Regional , Vasodilatadores/administración & dosificaciónRESUMEN
Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-L-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.
Asunto(s)
Apoptosis , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno , Receptor fas/fisiología , Factor Apoptótico 1 Activador de Proteasas , Caspasa 3 , Caspasa 9 , Caspasas/metabolismo , Citocromos c/metabolismo , Humanos , Peróxido de Hidrógeno/farmacología , Células Jurkat , Permeabilidad , Proteínas/metabolismoRESUMEN
Although T-prolymphocytic leukemia (T-PLL) is characterized by organ infiltration, small-intestinal involvement is rare. We performed an unrelated allogeneic bone marrow transplantation in a patient with T-PLL who had multiple lymphomatous polyposis of the small intestine refractory to combination chemotherapy (cyclophosphamide, vincristine, and prednisolone [COP] and fludarabine plus cyclophosphamide). The patient developed no graft-versus-host disease (GVHD) and remains in complete remission 16 months after the transplantation. T-PLL is usually refractory to chemotherapy and is a T-cell malignancy with poor prognosis. There have been several reports on allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for T-PLL, but none on allo-HSCT for T-PLL patients with intestinal involvement. It is suggested that allo-HSCT may improve the prognosis in patients with T-PLL involving the small intestine.