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1.
J Dairy Sci ; 105(3): 2301-2314, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-34955263

RESUMEN

The objective of this experiment was to evaluate the effects of supplementing a rumen-protected source of Met, N-acetyl-l-methionine (NALM), on lactational performance and nitrogen metabolism in early- to mid-lactation dairy cows. Sixty multiparous Holstein dairy cows in early lactation (27 ± 4.3 d in milk, SD) were assigned to 4 treatments in a randomized complete block design. Cows were blocked by actual milk yield. Treatments were as follows: (1) no NALM (control); (2) 15 g/d of NALM (NALM15); (3) 30 g/d of NALM (NALM30); and (4) 45 g/d of NALM (NALM45). Diets were formulated using a Cornell Net Carbohydrate and Protein System (CNCPS) v.6.5 model software to meet or exceed nutritional requirements of lactating dairy cows producing 42 kg/d of milk and to undersupply metabolizable Met (control) or supply incremental amounts of NALM. The digestible Met (dMet) supply for control, NALM15, NALM30, and NALM45 were 54.7, 59.8, 64.7, and 72.2 g/d, respectively. The supply of dMet was 88, 94, 104, and 115% of dMet requirement for control, NALM15, NALM30, and NALM45, respectively. Milk yield data were collected, dry matter intake (DMI) was measured daily, and milk samples were collected twice per week for 22 wk. Blood, ruminal fluid, urine, and fecal samples were collected during the covariate period and during wk 4, 8, and 16. Data were analyzed using the GLIMMIX procedure of SAS (SAS Institute) using covariates in the model for all variables except body weight. Linear, quadratic, and cubic contrasts were also tested. Treatments did not affect DMI, milk yield, and milk component concentration and yield; however, feed efficiency expressed as milk yield per DMI and 3.5% fat-corrected milk per DMI were quadratically affected, with greater response observed for NALM15 and NALM30 compared with control. Acetate proportion linearly increased, whereas propionate proportion linearly decreased with NALM supplementation. Blood urea nitrogen linearly decreased with NALM supplementation. Total plasma essential AA concentrations were quadratically affected, as greater values were observed for control and NALM45 than other treatments. Plasma Met concentration was quadratically affected as lower levels were observed with NALM15, whereas Met concentrations increased with NALM45 compared with control. Nitrogen utilization efficiency and apparent total-tract nutrient digestibility were not affected by treatment. Supplementation of NALM at 15 or 30 g/head per day resulted in the greatest improvements in feed efficiency without affecting N metabolism of early- to mid-lactation dairy cows.


Asunto(s)
Lactancia , Rumen , Alimentación Animal/análisis , Animales , Bovinos , Dieta/veterinaria , Suplementos Dietéticos , Femenino , Lactancia/fisiología , Metionina , Leche/metabolismo , Rumen/metabolismo
2.
J Dairy Sci ; 104(7): 7671-7681, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33814135

RESUMEN

We previously reported that milk production in dairy cows was increased by adding a specific xylanase-rich exogenous fibrolytic enzyme (XYL) to a total mixed ration (TMR) containing 10% bermudagrass silage (BMD). Two follow-up experiments were conducted to examine whether adding XYL would increase the performance of dairy cows consuming a TMR containing a higher (20%) proportion of BMD (Experiment 1) and to evaluate the effects of XYL on in vitro fermentation and degradability of the corn silage, BMD, and TMR (Experiment 2). In Experiment 1, 40 lactating Holstein cows in early lactation (16 multiparous and 24 primiparous; 21 ± 3 d in milk; 589 ± 73 kg of body weight) were blocked by milk yield and parity and randomly assigned to the Control and XYL treatments. The TMR contained 20% BMD, 25% corn silage, 8% wet brewer's grain, and 47% concentrate mixture in the dry matter (DM). Cows were fed the XYL-treated or untreated experimental TMR twice per day for 10 wk after a 9-d covariate period. In Experiment 2, ruminal fluid was collected from 3 cannulated lactating Holstein cows fed a diet containing 20% bermudagrass haylage, 25% corn silage and 55% concentrate. In Experiment 1, compared with Control, application of XYL did not affect DM intake (24.0 vs. 23.7 kg/d), milk yield (35.1 vs. 36.2 kg/d), fat-corrected milk yield (36.1 vs. 36.9 kg/d), or yields of milk fat (1.29 vs. 1.31 kg/d) or protein (1.07 vs. 1.08 kg/d). However, intake of neutral detergent fiber (4.67 vs. 4.41 kg/d) tended to increase with XYL; consequently, milk protein concentration was increased by XYL (3.02 vs. 2.95%). Feed efficiency tended to be lower in cows fed XYL (1.57 vs. 1.52 kg of fat-corrected milk/kg of DM intake) compared with Control. In Experiment 2, XYL tended to increase the rate of gas production in the TMR, the molar proportion of propionate for corn silage, and that of valerate for the TMR. In addition, XYL increased in vitro DM, neutral detergent fiber, and acid detergent fiber degradability of BMD and corn silage. Application of XYL to a diet with a relatively high proportion of BMD tended to increase digestible neutral detergent fiber intake, increased milk protein concentration, and in vitro degradability of DM, neutral detergent fiber, and acid detergent fiber. However, XYL did not affect milk production and tended to decrease feed efficiency in early lactation cows.


Asunto(s)
Lactancia , Ensilaje , Animales , Bovinos , Cynodon , Dieta/veterinaria , Fibras de la Dieta , Digestión , Femenino , Embarazo , Rumen , Ensilaje/análisis , Zea mays
3.
J Dairy Sci ; 102(9): 8059-8073, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31326164

RESUMEN

Four experiments were conducted to examine the effects of a recombinant bacterial expansin-like protein (BsEXLX1) from Bacillus subtilis and a commercial exogenous fibrolytic enzyme (EFE) preparation for ruminants on hydrolysis of pure substrates (cellulose and xylan) and in vitro digestibility of bermudagrass haylage (BMH). Recombinant Escherichia coli BL21 strain was used to express BsEXLX1; the protein was purified using an affinity column. In experiment 1, carboxymethylcellulose, Whatman #1 filter paper (General Electric, Boston, MA) and oat-spelt xylan substrates were subjected to 4 treatments (1) sodium citrate buffer (control), (2) BsEXLX1 (162 µg/g of substrate), (3) EFE (2.3 mg/g of substrate), and (4) EFE + BsELX1 in 3 independent runs. Samples were incubated at optimal conditions for both additives (pH 5 and 50°C) or at ruminal (pH 6 and 39°C) or ambient (pH 6 and 25°C) conditions for 24 h and sugar release was measured. In experiment 2, digestibility in vitro of BMH was examined after treatment with the following: (1) control (buffer only), (2) BsEXLX1 (162 µg/g of dry matter), (3) EFE (2.2 mg/g of dry matter), and (4) EFE + BsEXLX1 in 3 independent runs at 39°C for 24 h. Experiment 3 examined effects of EFE and BsEXLX1 on simulated preingestive hydrolysis and profile of released sugars from BMH after samples were suspended in deionized water with sodium azide at 25°C for 24 h in 2 independent runs. In experiment 4, the sequence of the BsEXLX1 purified protein was compared with 447 ruminal bacterial genomes to identify similar proteins from the rumen. In experiment 1, compared with EFE alone, EFE and BsEXLX1 synergistically increased sugar release from carboxymethylcellulose and Whatman #1 filter paper under all simulated conditions; however, hydrolysis of xylan was not improved. In experiment 2, compared with EFE alone, treatment with EFE and BsEXLX1 increased neutral detergent fiber and acid detergent fiber digestibility of bermudagrass haylage (by 5.5 and 15%, respectively) and total volatile fatty acid concentrations, and decreased acetate-propionate ratio. In experiment 3, compared with EFE alone. The EFE and BsEXLX1 synergistically reduced concentrations of neutral detergent fiber and acid detergent fiber and increased release of sugars by 9.3%, particularly cellobiose (72.5%). In experiment 4, a similar sequence to that of BsEXLX1 was identified in Bacillus licheniformis, and similar hypothetical protein sequences were identified in Ruminococcus flavefaciens strains along with different protein structures in E. xylanophilum and Lachnospiraceae. This study showed that an expansin-like protein synergistically increased the hydrolysis of pure cellulose substrates and the hydrolysis and digestibility in vitro of BMH.


Asunto(s)
Alimentación Animal , Proteínas Bacterianas/administración & dosificación , Bovinos/metabolismo , Cynodon , Proteínas en la Dieta/administración & dosificación , Digestión , Xilosidasas/administración & dosificación , Animales , Bacillus subtilis , Cynodon/química , Fibras de la Dieta/metabolismo , Fermentación , Hidrólisis , Distribución Aleatoria , Proteínas Recombinantes/administración & dosificación , Rumen/metabolismo
4.
J Dairy Sci ; 101(4): 3008-3020, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29428756

RESUMEN

The study was conducted to examine the effect of supplementing bentonite clay with or without a Saccharomyces cerevisiae fermentation product (SCFP; 19 g of NutriTek + 16 g of MetaShield, both from Diamond V, Cedar Rapids, IA) on the performance and health of dairy cows challenged with aflatoxin B1 (AFB1). Twenty-four lactating Holstein cows (64 ± 11 d in milk) were stratified by parity and milk production and randomly assigned to 1 of 4 treatment sequences. The experiment had a balanced 4 × 4 Latin square design with 6 replicate squares, four 33-d periods, and a 5-d washout interval between periods. Cows were fed a total mixed ration containing 36.1% corn silage, 8.3% alfalfa hay, and 55.6% concentrate (dry matter basis). Treatments were (1) control (no additives), (2) toxin (T; 1,725 µg of AFB1/head per day), (3) T + clay (CL; 200 g/head per day; top-dressed), and (4) CL+SCFP (CL+SCFP; 35 g/head per day; top-dressed). Cows were adapted to diets from d 1 to 25 (predosing period) and then orally dosed with AFB1 from d 26 to 30 (dosing period), and AFB1 was withdrawn from d 31 to 33 (withdrawal period). Milk samples were collected twice daily from d 21 to 33, and plasma was sampled on d 25 and 30 before the morning feeding. Transfer of ingested AFB1 into milk aflatoxin M1 (AFM1) was greater in T than in CL or CL+SCFP (1.65 vs. 1.01 and 0.94%, respectively) from d 26 to 30. The CL and CL+SCFP treatments reduced milk AFM1 concentration compared with T (0.45 and 0.40 vs. 0.75 µg/kg, respectively), and, unlike T, both CL and CL+SCFP lowered AFM1 concentrations below the US Food and Drug Administration action level (0.5 µg/kg). Milk yield tended to be greater during the dosing period in cows fed CL+SCFP compared with T (39.7 vs. 37.7 kg/d). Compared with that for T, plasma glutamic oxaloacetic transaminase concentration, indicative of aflatoxicosis and liver damage, was reduced by CL (85.9 vs. 95.2 U/L) and numerically reduced by CL+SCFP (87.9 vs. 95.2 U/L). Dietary CL and CL+SCFP reduced transfer of dietary AFB1 to milk and milk AFM1 concentration. Only CL prevented the increase in glutamic oxaloacetic transaminase concentration, and only CL+SCFP prevented the decrease in milk yield caused by AFB1 ingestion.


Asunto(s)
Aflatoxina B1/farmacología , Silicatos de Aluminio/metabolismo , Bentonita/metabolismo , Bovinos/metabolismo , Leche/química , Saccharomyces cerevisiae/química , Silicatos de Aluminio/administración & dosificación , Alimentación Animal/análisis , Animales , Bentonita/administración & dosificación , Bovinos/inmunología , Arcilla , Dieta/veterinaria , Suplementos Dietéticos/análisis , Femenino , Fermentación , Estado de Salud , Lactancia , Distribución Aleatoria
5.
Ann Oncol ; 24(12): 3123-8, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24146218

RESUMEN

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Capecitabina , Cetuximab , Quimioradioterapia , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Modelos de Riesgos Proporcionales , Neoplasias del Recto/mortalidad , Estudios Retrospectivos , Método Simple Ciego , Resultado del Tratamiento
7.
Clin Transl Oncol ; 8(2): 98-102, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16632423

RESUMEN

The choice of the most suitable chemotherapy schedule for the adjuvant treatment of colon cancer has been reviewed by the TTD group, as well as the principles of risk assessment for patients with stage II disease. In the light of data now available, oxaliplatin- based schedules (FOLFOX4 or FLOX) are recommended. Alternatives in special situations are monotherapy with capecitabine, UFT/LV, or 5- FU/LV in infusion. In patients with stage II disease, the indication of chemotherapy must be individualized and based on the patient's risk of recurrence (perforation, obstruction, peritumoral lymphovascular involvement, poorly differentiated histology, number of lymph nodes examined < or = 11, pre-surgical CEA), and comorbidities that can compromise the safety of treatment or survival of the patient.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Algoritmos , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Esquema de Medicación , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Metástasis Linfática , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Tegafur/administración & dosificación , Uracilo/administración & dosificación
8.
J Neurochem ; 93(4): 963-73, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15857399

RESUMEN

Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1alpha has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1alpha (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 microm) but not by the metabotropic glutamate receptor antagonist MCPG (500 microm), indicating a direct action of SDF-1alpha on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1alpha induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPgammaS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a G(i/o) protein. This study extends the functions of SDF-1alpha to a direct modulation of voltage-dependent membrane currents of neuronal cells.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Quimiocinas CXC/farmacología , Glicina/análogos & derivados , Neuronas/efectos de los fármacos , Porinas/metabolismo , Animales , Bencilaminas , Cloruro de Cadmio/farmacología , Células Cultivadas , Quimiocina CXCL12 , Ciclamas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Regulación de la Expresión Génica/efectos de los fármacos , Glicina/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Compuestos Heterocíclicos/farmacología , Humanos , Hipotálamo/citología , Inmunohistoquímica/métodos , Ratones , Neuroblastoma , Neuronas/metabolismo , Técnicas de Placa-Clamp/métodos , Porinas/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , ARN Mensajero/biosíntesis , Receptores CXCR4/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Bloqueadores de los Canales de Sodio/farmacología , Tetraetilamonio/farmacología , Tetrodotoxina/farmacología , Canales Aniónicos Dependientes del Voltaje
9.
Ann Oncol ; 15(4): 559-67, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15033659

RESUMEN

BACKGROUND: We conducted a phase I/II study of weekly irinotecan [30 min intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m(2) weekly 48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: The maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of gastrointestinal solid tumors (in phase I), and the antitumor activity and toxicity of the recommended phase I dose (in phase II) were determined. RESULTS: Diarrhea was the DLT, and irinotecan 80 mg/m(2) plus 5-FU 3 g/m(2) was the recommended phase I dose. In phase II, the confirmed response rate was 44% [95% confidence interval (CI) 29% to 59%] and the median overall survival was 23.8 months. However, grade 3/4 diarrhea affected 59% of patients and led to withdrawal of three patients. A second cohort of patients studied using the same schedule but with a reduced 5-FU starting dose of 2.25 g/m(2) showed improved tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2 months. CONCLUSIONS: We found weekly irinotecan 80 mg/m(2) plus TTD regimen (5-FU 2.25 g/m(2) given as 48-h i.v. infusion) to be a feasible and active combined chemotherapy for the first-line treatment of advanced colorectal cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
10.
Methods Find Exp Clin Pharmacol ; 25(8): 639-43, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14671682

RESUMEN

The efficacy and toxicity of irinotecan (CPT-11) 350 mg/m(2) i.v. once every 3 weeks was assessed in 60 patients with advanced colorectal cancer (CRC) showing failure to 5-fluorouracil (5-FU) treatment. The overall objective response rate was 13.6% (1 complete response and 4 partial responses) and 25 patients (42.4%) showed stable disease; the median time to disease progression was 4.4 months and the median survival was 10.5 months. The main non-hematological toxicities were alopecia (80.3% of patients), diarrhea (75.0%), and nausea/vomiting (71.7%); neutropenia was the main hematological toxicity. Grade 3 or 4 diarrhea appeared in 21 of 131 cycles (16.1%), whereas grade 3 or 4 neutropenia appeared in 78 cycles (25.0%). In conclusion, the present phase II study confirms that CPT-11 350 mg/m(2) every 3 weeks is active and well tolerated as second-line chemotherapy for CRC in 5-FU resistant patients.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Fluorouracilo/uso terapéutico , Adolescente , Adulto , Anciano , Alopecia/inducido químicamente , Camptotecina/efectos adversos , Camptotecina/farmacología , Quimioterapia Adyuvante , Diarrea/inducido químicamente , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Irinotecán , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neutropenia/inducido químicamente , España , Resultado del Tratamiento , Vómitos/inducido químicamente
11.
Colorectal Dis ; 5 Suppl 3: 10-9, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23573556

RESUMEN

The introduction of oxaliplatin into the chemotherapy of advanced colorectal cancer has substantially increased the frequency and magnitude of clinical response compared with that achieved using 5-FU/leucovorin, and has extended progression-free and overall survival. Research is now in progress on several fronts to determine how oxaliplatin-based therapy can be optimized. A phase III multicentre trial recently compared the efficacy and safety of the FUFOX regimen, based on high dose infusional 5-FU/leucovorin and 50 mg/m2 oxaliplatin given weekly for 4 weeks in a 5-week cycle (n = 123) with the Mayo clinic 5-FU/leucovorin regimen (n = 129) in the first-line therapy of metastatic disease. The response rate with the FUFOX regimen was 48.3%, more than twice that in the Mayo regimen (22.6%; P < 0.0001) and median survival was 20.4 months, despite the fact that the FUFOX regimen had lower toxicity. The value of high dose oxaliplatin and 5-FU/leucovorin has also been demonstrated in the FOLFOX series of studies, where patients who received more than 85 mg/m2 oxaliplatin per 2-week cycle had double the response rate of patients receiving less than 85 mg/m2. In the FOLFOX7 regimen based on a simplified high dose bolus/infusional regimen of 5-FU/leucovorin (sLV5FU2) plus 130 mg/m2 oxaliplatin, a response rate of over 40% has been achieved in second line therapy. Studies have also compared first-line therapy based on oxaliplatin with irinotecan-based first-line therapy. A large trial coordinated by the North Central Cancer Treatment Group (NCCTG) recently compared the IFL regimen, which is currently the standard irinotecan-based first-line treatment for advanced colorectal cancer in the United States, with oxaliplatin-based treatment using the FOLFOX4 regimen. Compared with irinotecan-based chemotherapy, oxaliplatin was associated with a 30% increase in overall survival (19.5 months vs. 15.0 months; P = 0.0001), a higher response rate (45% vs. 31%, P = 0.002) and lower toxicity. Further studies are investigating how therapy can be optimized over multiple lines. In a phase III two-line study comparing first-line therapy with FOLFOX6 and second line therapy with irinotecan-based therapy (FOLFIRI) (n = 109) with the reverse sequence (n = 111), progression-free and overall survival were comparable whichever regimen was used first, although patient numbers were smaller than in the NCCTG study and less able to detect treatment differences. FOLFOX6 was also more effective than FOLFIRI in second-line therapy. Currently, studies based on FOLFOX7, novel FOLFIRI regimens and sLV5FU2 are in progress to determine how disease control can be sustained in the long-term, and the development of drug resistance delayed, in multiline therapeutic management. In parallel with these studies, two large phase III trials are now investigating the role of oxaliplatin in the adjuvant treatment of nonmetastatic colorectal cancer. The first of these studies, MOSAIC, has already shown a very encouraging 23% decrease in the risk of relapse at 3 years (P = 0.002) with FOLFOX4 compared to LV5FU2.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Tasa de Supervivencia
12.
Ann Oncol ; 9(7): 727-31, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9739438

RESUMEN

PURPOSE: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Adulto , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Esquema de Medicación , Femenino , Fluorouracilo/uso terapéutico , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Análisis de Supervivencia
13.
Ann Oncol ; 7(6): 581-5, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8879371

RESUMEN

BACKGROUND: In a previous phase I-II trial we showed that the maximum tolerable dose (MTD) of 5-fluorouracil (5-FU) in a weekly 48-hour continuous infusion (CI) was 3.5 g/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained, and a median survival of 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. On this basis we attempted to modulate high-dose 5-FU (3 g/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. PATIENTS AND METHODS: From July 1992 to June 1994, 110 previously untreated patients with advanced, measurable colorectal cancer were included in a multicenter study. The patients received, on an outpatient basis, 5-FU 2 g/m2 by continuous infusion for 48 hours once a week until progression or the appearance of toxic effects. Oral leucovorin (60 mg every six hours) was also given during the 5-FU infusion. RESULTS: Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. The overall response rate was 37.5% (95% CI, 28% to 46.8%), the median time to progression 7.4 months and median survival 14.5 months. W.H.O. grade 3 diarrhea occurred in 27 patients (24.5%); grade 3 mucositis was observed in 9 (8.1%) patients and grade 4 in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients, while grade 3 hand-foot syndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurred in one patient and grade 3-4 thrombocytopenia in two. CONCLUSIONS: Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as the main limiting toxic effects. Its antitumor activity does not seem superior to that obtained with a weekly 48-hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia
14.
J Infus Chemother ; 6(3): 118-22, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-9229321

RESUMEN

Background In a previous phase I to II trial, we have shown that the maximum tolerable dose (MTD) of 5-Fluorouracil (5-FU) in 48-hour continuous infusion (CI) weekly was 3.5 gr/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained and the median survival reached was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with Leucovorin. On this basis we tried to modulate high-dose 5-FU (3 gr/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. Overall response rate was 37.5% (95% CI, 28% to 46.8%). Median time to progression has been 7.4 months, and median survival 14.4 months. WHO grade 3 diarrhea was seen in 27 patients (24.5%). Grade 3 mucositis was also seen in 9 (8.1%) patients, and grade 4 was observed in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients. Grade 3 hand-foot syndrome was detected in only 5 (4.5%) patients. Grade 4 leukopenia was observed in 1 case and grade 3 to 4 thrombocytopenia was observed in two cases, respectively. Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as main limiting toxicities. Its antitumor activity does not seem superior to that obtained with a weekly 48 hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Administración Oral , Adulto , Anciano , Anemia/inducido químicamente , Anemia/complicaciones , Antídotos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Diarrea/inducido químicamente , Diarrea/complicaciones , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Leucopenia/inducido químicamente , Leucopenia/complicaciones , Masculino , Persona de Mediana Edad , España , Resultado del Tratamiento , Vómitos/inducido químicamente , Vómitos/complicaciones
15.
J Dairy Sci ; 79(1): 105-13, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8675772

RESUMEN

Thirty-two cows, averaging 112 DIM, were assigned to four dietary treatments: 1) control, 2) Ca salts of fatty acids, 3) nicotinamide, and 4) Ca salts of fatty acids blended with nicotinamide during manufacture. Preliminary studies showed that nicotinamide survives blending with Ca salts of fatty acids during manufacture and that a blended mixture of nicotinamide and Ca salts of fatty acids gave results similar to those from nicotinamide plus Ca salts of fatty acids supplemented separately. Calcium salts of fatty acids increased milk fat percentage, decreased milk protein percentage, but had no effect on production of milk, FCM, fat, or protein. Nicotinamide increased production of milk and protein, decreased fat percentage, but had no effect on either production of FCM and protein or percentage of protein. Calcium salts of fatty acids increased NEFA in blood, and dietary nicotinamide increased concentrations of nicotinamide in blood, but glucose and BHBA in blood were unaffected by either dietary ingredient. Therefore, in these midlactation cows, the decreased milk protein percentage caused by supplemental dietary fat was prevented by nicotinamide. Supplementation with only nicotinamide increased total production of milk protein.


Asunto(s)
Bovinos/fisiología , Dieta , Grasas de la Dieta/administración & dosificación , Lactancia/efectos de los fármacos , Leche/metabolismo , Niacinamida/farmacología , Ácido 3-Hidroxibutírico , Animales , Glucemia/metabolismo , Metabolismo Energético , Ácidos Grasos/administración & dosificación , Ácidos Grasos no Esterificados/sangre , Femenino , Hidroxibutiratos/sangre , Proteínas de la Leche/metabolismo , Niacinamida/administración & dosificación , Niacinamida/sangre , Paridad
16.
Cancer ; 76(4): 559-63, 1995 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-8625147

RESUMEN

BACKGROUND: In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m2 for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. METHODS: From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m2 by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. RESULTS: Patients received a median dose intensity of 5-FU of 2.2 g/m2/week (range, 0.76-3 g/m2/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16-45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand-foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. CONCLUSIONS: Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m2 of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m2.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Leucovorina/administración & dosificación , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Análisis de Supervivencia
18.
Ginecol Obstet Mex ; 45(267): 11-23, 1979 Jan.
Artículo en Español | MEDLINE | ID: mdl-540751

RESUMEN

PIP: Seven courses of theoretical and practical training in family planning were offered in 1974-75 in Mexico City, and directed to general practitioners. There were 110 participants. Activities included, among others, insertions and extractions of IUDs, prescription of OC (oral contraception), control of patients, and complete pelvic examinations. At the beginning of the course it was obvious that there were serious deficiencies in the theoretical areas, as well as in specific clinical skills as applied to family planning. There was a strong improvement in attitudes toward family planning from a purely social point of view, especially concerning unmarried women, or women with high parity. While before the course the participants tended to suggest salpingochlasia as the only form of permanent contraception, they would most consider vasectomy at the end of the course. Reasons against induced abortion, when present, were of a religious or ethical nature. Results obtained with these courses showed the importance of training in family planning for general practitioners, were it only to emphasize their duties toward the community, and to improve their medical skills in such field.^ieng


Asunto(s)
Servicios de Planificación Familiar , Medicina Familiar y Comunitaria , Femenino , Humanos , Masculino , México , Programas Nacionales de Salud , Relaciones Médico-Paciente , Proyectos Piloto , Embarazo
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