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1.
Ann Oncol ; 28(7): 1547-1553, 2017 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-28368509

RESUMEN

BACKGROUND: Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. PATIENTS AND METHODS: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. RESULTS: A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. CONCLUSIONS: Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Crónica/terapia , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Estudios de Factibilidad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Italia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/mortalidad , Leucemia Mielomonocítica Crónica/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Estudios Prospectivos , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
2.
Diabetologia ; 53(1): 153-9, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19756486

RESUMEN

AIMS/HYPOTHESIS: Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats. METHODS: We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups. RESULTS: Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group. CONCLUSIONS/INTERPRETATION: Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.


Asunto(s)
Hipoglucemiantes/farmacología , Páncreas/metabolismo , Péptidos/farmacología , Ponzoñas/farmacología , Adipoquinas/sangre , Alanina Transaminasa/sangre , Amilasas/sangre , Amilasas/efectos de los fármacos , Animales , Aspartato Aminotransferasas/sangre , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Exenatida , Humanos , Insulina/sangre , Lipasa/sangre , Lipasa/efectos de los fármacos , Masculino , Páncreas/citología , Páncreas/efectos de los fármacos , Páncreas/patología , Pancreatitis/inducido químicamente , Pancreatitis/patología , Ratas , Ratas Sprague-Dawley
3.
J Clin Invest ; 98(3): 671-9, 1996 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-8698858

RESUMEN

Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 microM and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc-dependent endothelial cell-derived 72-and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Captopril/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Animales , Bovinos , Movimiento Celular/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Femenino , Metaloendopeptidasas/antagonistas & inhibidores , Ratas , Ratas Endogámicas F344
4.
Leukemia ; 31(11): 2449-2457, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28321120

RESUMEN

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.


Asunto(s)
Técnicas de Apoyo para la Decisión , Trasplante de Células Madre Hematopoyéticas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Años de Vida Ajustados por Calidad de Vida
5.
Arch Intern Med ; 147(4): 645-9, 1987 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3827451

RESUMEN

Interaction of thiazide diuretics and the serum uric acid and creatinine levels was studied in 3693 stepped care participants in the Hypertension Detection and Follow-up Program not receiving treatment at baseline. Among men grouped into quartiles by their level of uric acid at baseline, the upper quartile (average uric acid, 7.7 mg/dL [458 mumol/L]) had an average serum creatinine level of 1.2 mg/dL (106 mumol/L) and the lowest quartile (uric acid, 4.9 mg/dL [291 mumol/L]) had an average serum creatinine level of 1.1 mg/dL (97 mumol/L). Similar findings were present in women. Therapy with chlorthalidone or other thiazide-type diuretics tended to increase levels of uric acid and creatinine, but the increase in both was less in the upper quartile than in the lower quartile. Among individuals who were prescribed uric acid-lowering drugs, the level of serum creatinine increased just as much as in those whose uric acid level was not pharmacologically lowered. Baseline uric acid level was a weak predictor of mortality in men; the introduction of an interaction term for creatinine suggested that this effect was primarily restricted to those with elevated levels of both uric acid and creatinine at baseline. Change in uric acid level at one year after therapy was inversely correlated with mortality in men. There were few episodes of gout (only 15 recorded in five years among 3693 participants at risk). These results suggest that neither the baseline uric acid level nor the change in uric acid level produced by therapy injures the kidney. These results suggest no reason to lower uric acid levels pharmacologically in the treated hypertensive patient who is not gouty. They leave unanswered whether there is a predictive value to baseline uric acid level not explainable by other correlated cardiovascular risk factors.


Asunto(s)
Benzotiadiazinas , Hipertensión/tratamiento farmacológico , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Ácido Úrico/sangre , Adulto , Anciano , Clortalidona/efectos adversos , Creatinina/sangre , Diuréticos , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/sangre , Hipertensión/mortalidad , Masculino , Persona de Mediana Edad
6.
Rev. argent. dermatol ; 101(1): 31-40, mar. 2020. graf
Artículo en Español | LILACS | ID: biblio-1092407

RESUMEN

RESUMEN Las metástasis cutáneas (MC) constituyen una manifestación infrecuente de neoplasias internas. Su diagnóstico requiere un alto índice de sospecha clínica, pues los hallazgos pueden ser sutiles. Estas ponen de manifiesto la presencia de un tumor maligno diseminado y pueden permitir el diagnóstico de neoplasias internas no conocidas, o indicar la diseminación o recurrencia de otras ya diagnosticadas. La MC del carcinoma de ovario suele aparecer en enfermedad avanzada e indican un mal pronóstico.Su reconocimiento temprano puede llevar a un diagnóstico preciso y rápido, con el consiguiente tratamiento oportuno, aunque en la mayoría de los casos son indicativas de un pronóstico infausto.


SUMMARY Cutaneous metastases are an infrequent manifestation of internal neoplasms. Its diagnosis requires a high index of clinical suspicion, since the findings can be subtle. These reveal the presence of a disseminated malignant tumor and can allow the diagnosis of unknown internal neoplasms, or indicate the dissemination or recurrence of others already diagnosed. MC of ovarian carcinoma usually appears in advanced disease and may indicate a poor prognosis. Early recovery can carry out an accurate and rapid diagnosis, with timely emergency treatment, although in most cases they are indicators of an unfortunate prognosis.


Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Neoplasias Ováricas/complicaciones , Neoplasias Cutáneas/diagnóstico , Metástasis de la Neoplasia/diagnóstico , Adenocarcinoma/complicaciones
7.
J Bone Miner Res ; 5(5): 493-8, 1990 May.
Artículo en Inglés | MEDLINE | ID: mdl-2368630

RESUMEN

Children with monostotic and polyostotic bone dysplasias often exhibit localized bone overgrowth. We investigated the presence of nuclear estrogen and nuclear progesterone receptors by solid-phase radioimmunoassay, immunocytochemistry, and radioligand binding in osteoblast cell cultures derived from the areas of overgrowth of membranous bone, noninvolved membranous bone, and normal membranous bone from children undergoing elective craniotomy. Membranous bone of normal children had demonstrable levels of nuclear estrogen and progesterone receptors identified by radioimmunoassay and immunocytochemical assay. Two- to threefold increased levels of these receptors (p less than 0.001 versus normals) were found in cultures derived from the involved bone of two children with monostotic fibrous dysplasia and in one patient with polyostotic dysplasia (McCune-Albright syndrome). The noninvolved bone in our patients with fibrous dysplasia exhibited nuclear sex steroid hormone receptor levels similar to those in the normal children. Radioligand binding studies demonstrated increased sex steroid hormone receptors in cultures derived from involved osteoblasts. The presence of an increased level of sex steroid hormone receptor was accompanied by increased alkaline phosphatase activity and increased production of osteocalcin in vitro compared to normal or noninvolved bone. The mechanisms by which sex steroid hormone receptor levels are increased in the ostotic dysplasias remain to be established.


Asunto(s)
Displasia Fibrosa Ósea/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Fosfatasa Alcalina/biosíntesis , Núcleo Celular/metabolismo , Células Cultivadas , Niño , Preescolar , Humanos , Osteoblastos/metabolismo , Osteocalcina/biosíntesis
8.
J Clin Endocrinol Metab ; 71(1): 256-9, 1990 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2164528

RESUMEN

Renin, angiotensin-II, and angiotensin-converting enzyme (ACE) have been found in the hypothalamus and pituitary in rats, and renin, angiotensinogen, and ACE have been found in human pituitary lactotrophs. To determine the physiological relevance of the renin-angiotensin system in the pituitary hormone response to stress in humans, we created significant inhibition of ACE by administering a clinically used dose (10 mg) of enalapril (E) 4 h before measuring the stress hormone responses to insulin-induced hypoglycemia. Eight fasting lean healthy males (aged 20-35 yr) were given either placebo (P) or E (10 mg, orally) in two studies separated by at least 5 days in a blinded study design. Glucose, ACTH, cortisol, PRL, and GH levels were measured before E or P and at 20-min intervals beginning 20 min before insulin administration. ACE levels were similar at baseline (E, 21.6 +/- 2.7; P, 22.4 +/- 2.4 mU/mL/min), but were significantly lower at the time of insulin injection with E treatment (E, 2.9 +/- 0.5; P, 20.9 +/- 2.5 mU/mL/min; P less than 0.001). The mean of the total area under the curve of PRL secretion was significantly lower for the E group (E, 3767.2 +/- 710.7; P, 4554.9 +/- 650.1 micrograms/L.min; P less than 0.05). Although the mean peak PRL levels were lower for the E group, this did not reach statistical significance (E, 53.0 +/- 9.7; P, 64.4 +/- 9.4 micrograms/L; 0.05 less than P less than 0.10). These differences in PRL responses appeared to be due primarily to substantial decreases in PRL responses with E in three of the eight subjects. No significant differences were found with ACTH, cortisol, or GH for basal levels, peak levels, or areas under the curve.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Enalapril/farmacología , Hipoglucemia/enzimología , Hipotálamo/enzimología , Insulina/farmacología , Peptidil-Dipeptidasa A/sangre , Hipófisis/enzimología , Hormona Adrenocorticotrópica/sangre , Adulto , Hormona del Crecimiento/sangre , Humanos , Hidrocortisona/sangre , Hipoglucemia/sangre , Hipoglucemia/inducido químicamente , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hipotálamo/fisiología , Masculino , Hipófisis/fisiología , Prolactina/sangre
9.
J Clin Endocrinol Metab ; 42(3): 588-9, 1976 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-176173

RESUMEN

In 11 healthy, normotensive young women taking contraceptive medication (Enovid) for at least one year, plasma levels of angiotensin II were significantly higher than in healthy male and female controls. No significant difference was seen in the serum activity of angiotensin I-converting enzyme measured in vitro. Although serum angiotensin I converting enzyme activity is stimulated in several conditions in which other components of renin-angiotensin-aldosterone system are increased, this is not the case during administration of estrogens.


Asunto(s)
Angiotensina II/sangre , Anticonceptivos Orales/farmacología , Peptidil-Dipeptidasa A/metabolismo , Adulto , Aldosterona/sangre , Presión Sanguínea/efectos de los fármacos , Estrógenos/farmacología , Femenino , Humanos , Masculino , Renina/sangre
10.
FEBS Lett ; 434(1-2): 140-4, 1998 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-9738466

RESUMEN

Lipopolysaccharide (LPS)-induced differentiation of the murine pre-B cell line 70Z/3 is a model for pre-B to B cell differentiation and has been used to show that the transcription factor NF-kappaB is essential to induce the expression of the Ig kappa gene. We have investigated the mechanism involved in late stages of the process when all cells have reached a more mature B phenotype, i.e. beyond 48 up to 96 h of LPS treatment. NF-kappaB binding activity was induced at early times by LPS treatment, but its DNA binding activity disappeared after 84 h of LPS treatment. Accumulation of IkappaB alpha protein in the nucleus correlated with the disappearance of NF-kappaB activity at 72, 84 and 96 h, and treatment of nuclear extracts of 72-96 h LPS-treated cells with Na-deoxycholate restored NF-kappaB binding activity. The data indicate that NF-kappaB, while important to initiate the process of Ig kappa gene transcription in 70Z/3 pre-B cells, is no longer required for its maintenance in differentiated 70Z/3 cells.


Asunto(s)
Linfocitos B/citología , FN-kappa B/fisiología , Animales , Linfocitos B/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Regulación del Desarrollo de la Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/fisiología , Lipopolisacáridos/farmacología , Ratones
11.
Bone ; 24(4): 337-47, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10221546

RESUMEN

Fibroblast growth factors (FGFs) play important roles in the control of skeletal cell growth and differentiation. To identify the mechanisms of regulation of FGF actions during chondrogenesis and osteogenesis, we investigated, by immunohistochemistry, the spatiotemporal expression of the high-affinity FGF receptors (FGFR-1, -2, and -3) and coreceptors (syndecans-1, -2, and -4) in newborn rat condyle and calvaria during chondrogenesis and osteogenesis in vitro. During chondrogenesis at 4 days of culture, condyle chondrocytes showed weak FGFR-1, FGFR-2, and syndecan-1 immunoreactivity; stronger syndecan-2 expression; and marked FGFR-3 and syndecan-4 immunolabeling. At a later stage (i.e., 9 days of culture), FGFR-1, -2, and -3 were coexpressed with syndecan-4 in chondrocytes. Condyle progenitor cells located in the condyle perichondrium initially expressed strong syndecan-2 and -4 and weak syndecan-1 labeling, whereas no FGFR was detectable. When these cells differentiated into osteoblasts, they expressed syndecan-2 and -4 coincidently with FGFR-1, -2, and -3 at 9 days of culture. In newborn rat calvaria, syndecan-1, -2, and -4 were coexpressed mainly with FGFR-1 and -2 in osteoblasts. In the two models, treatment with FGF-2 (100 ng/mL) at 4-9 days of culture increased cell growth and decreased glycosaminoglycan or collagen synthesis, respectively, suggesting interactions of FGF-2 with distinct FGFRs and syndecans during chondrogenesis and osteogenesis. The coincident or distinct spatiotemporal expression pattern of FGFRs and syndecans in chondrocytes, progenitor cells, and osteoblasts represents a dynamic mechanism by which FGF effects on skeletal cells may be controlled in a coordinate manner during cartilage and bone formation in vitro.


Asunto(s)
Cóndilo Mandibular/química , Glicoproteínas de Membrana/análisis , Proteoglicanos/análisis , Receptores de Factores de Crecimiento de Fibroblastos/análisis , Cráneo/química , Animales , Animales Recién Nacidos , Diferenciación Celular/fisiología , Células Cultivadas , Condrogénesis/fisiología , Inmunohistoquímica , Técnicas de Cultivo de Órganos , Osteogénesis/fisiología , Ratas , Ratas Sprague-Dawley , Sindecano-1 , Sindecano-2 , Sindecano-4 , Sindecanos , Células Tumorales Cultivadas
12.
Semin Oncol ; 26(2 Suppl 7): 66-71, 1999 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10348263

RESUMEN

High-dose chemotherapy with autologous stem cell transplantation is an increasingly used procedure in oncohematologic diseases and represents a promising strategy in selected patients with solid tumors. In autologous stem cell transplantation, the risk of reinfusion of clonogenic tumor cells is a remarkable biologic obstacle that can be at least partly overcome by ex vivo graft purging to reduce residual tumor. Mafosfamide and 4-hydroxyperoxycyclophosphamide, active metabolites of cyclophosphamide, are the most widely used pharmacologic agents for ex vivo bone marrow purging. However, in addition to killing tumor cells, they are toxic to normal bone marrow as measured by reduced colony-forming unit granulocyte-macrophage (CFU-GM). Thus, the therapeutic index of these alkylating agents is narrow, and parameters for dose selection must include toxicity to normal bone marrow progenitor cells that can delay bone marrow engraftment and increase risk of infections, bleeding complications, hospitalization, and the need for a costly transplantation procedure. Amifostine (WR-2771, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) selectively protects human CFU-GM progenitor cells from the cytotoxicities of active metabolites of cyclophosphamide without altering its cytotoxic effect on malignant cells. This has been demonstrated both in preclinical and clinical studies in patients with breast cancer, malignant lymphomas, and acute leukemia. Amifostine use during the ex vivo procedure significantly shortened the time to bone marrow engraftment with decreased incidence of infections and need for red blood cell transfusions.


Asunto(s)
Amifostina/uso terapéutico , Trasplante de Médula Ósea , Citoprotección , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas , Sustancias Protectoras/uso terapéutico , Acondicionamiento Pretrasplante , Amifostina/farmacología , Animales , Purgación de la Médula Ósea , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Movilización de Célula Madre Hematopoyética , Humanos , Sustancias Protectoras/farmacología , Trasplante Autólogo
13.
Int J Radiat Oncol Biol Phys ; 15(1): 135-40, 1988 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-3292488

RESUMEN

The ability of the angiotensin converting enzyme (ACE) inhibitor Captopril to modify radiation-induced pulmonary endothelial dysfunction was determined in male rats sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays to the right hemithorax. Half of each dose group consumed feed containing 0.12% w/w Captopril (60 mg/kg/day) continuously after irradiation, and half consumed control feed. Four markers of endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. All data were plotted as dose-response curves, and subjected to linear regression analysis. The Captopril modifying effect was expressed as the ratio of isoeffective doses at a common intermediate response (DRF), or as the ratio of the response curve slopes. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. Captopril exhibited DRF values of 1.4-2.1, and slope ratios of 1.4-5.1 for all four functional markers (p less than 0.05). Thus, the ACE inhibitor Captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months postirradiation. Although the mechanism of Captopril action is not clear at present, these data suggest a novel application for this class of compounds as injury-modifying agents in irradiated lung.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Captopril/uso terapéutico , Pulmón/efectos de la radiación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Animales , Endotelio/efectos de los fármacos , Endotelio/efectos de la radiación , Pulmón/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas
14.
Int J Radiat Oncol Biol Phys ; 13(10): 1505-13, 1987 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-3040646

RESUMEN

Male rats were sacrificed 2 or 6 months after a range of single doses of gamma rays (0-30 Gy) to the right hemithorax. Half of each dose group consumed control feed continuously after irradiation, and half consumed feed containing the collagen antagonist D-penicillamine (10 mg/rat/day). Four markers of pulmonary endothelial function were monitored: angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Bronchoalveolar lavage (BAL) fluid also was obtained from the right lung, and was analyzed for macrophage number, and PGI2 and TXA2 concentration. Right lung ACE and PLA activities decreased linearly with increasing dose at both 2 and 6 months postirradiation, and penicillamine had no significant effect on either response. In contrast, PGI2 and TXA2 production by the right lung increased linearly with increasing radiation dose at both autopsy times. Penicillamine significantly ameliorated the increase in PGI2 production at 2 months, and the increase in TXA2 production at both 2 and 6 months postirradiation. Penicillamine dose-reduction factors (DRF) for PGI2 and TXA2 production were 1.3-1.4, and the response curve slope ratios were 1.7-2.5 (p less than 0.05). Penicillamine also ameliorated the dose-dependent increase in TXA2 concentration in the BAL fluid at 2 months. These data indicate that the four "markers" of radiation-induced pulmonary endothelial dysfunction do not respond identically to penicillamine dose-modification. Of the four markers, TXA2 production exhibits the most significant and widespread penicillamine sparing. TXA2 is a potent vasoconstrictor, promoter of platelet aggregation, and mediator of inflammation, and partial prevention of the radiation-induced hyperproduction of this eicosanoid may account in part for penicillamine's therapeutic action in this model.


Asunto(s)
Pulmón/efectos de la radiación , Penicilamina/farmacología , Protectores contra Radiación/farmacología , Animales , Endotelio/efectos de los fármacos , Endotelio/fisiología , Endotelio/efectos de la radiación , Epoprostenol/biosíntesis , Pulmón/efectos de los fármacos , Pulmón/fisiología , Masculino , Peptidil-Dipeptidasa A/metabolismo , Activadores Plasminogénicos/metabolismo , Ratas , Tromboxanos/biosíntesis
15.
Int J Radiat Oncol Biol Phys ; 11(11): 1985-90, 1985 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-2997091

RESUMEN

Male rats were killed 2 months (early fibrosis) or 6 months (peak fibrosis) after a range of single doses of 60Co gamma rays to the right hemithorax. Pulmonary arterial perfusion scans were performed at 2 months on animals scheduled for autopsy at 6 months. Lung angiotensin converting enzyme (ACE) activity was used to monitor endothelial function, and hydroxyproline (HP) concentration served as an index of interstitial collagen accumulation (fibrosis). ACE activity also was measured in right lung bronchoalveolar lavage (BAL) fluid and blood serum, to determine whether information obtained from a minimally invasive procedure might serve as an index or predictor of the severity of lung damage. Linear dose-response curves (r = 0.92-0.99) were obtained for right lung arterial perfusion, ACE activity and HP concentration. At 2 months, perfusion decreased 2.7% per Gy, ACE activity (per lung, per mg wet weight, or per mg protein) decreased 3.0-4.2% per Gy, and HP concentration (per g dry weight) increased 1.7% per Gy. At 6 months, the slopes of the response curves were virtually identical to those at 2 months; the Y intercept of the response curve for ACE activity was unchanged, whereas that for HP concentration was 50% higher at 6 than at 2 months. ACE activity and protein concentration in the BAL increased with increasing dose, but the variation within groups was too large, and the sensitivity was too low to serve as a reliable index of lung status. Serum ACE activity was independent of radiation dose at both autopsy times. Thus in rat lung, arterial perfusion, endothelial dysfunction and interstitial fibrosis exhibit similar but not identical radiosensitivities. The dose-effect curves for these three responses of the lung in situ change less than 5% per Gy over the dose range of 10-30 Gy, a smaller variation than would be predicted from endothelial cell survival data based on clonogenic assays in vitro or in vivo.


Asunto(s)
Colágeno/metabolismo , Pulmón/efectos de la radiación , Animales , Supervivencia Celular/efectos de la radiación , Radioisótopos de Cobalto , Relación Dosis-Respuesta en la Radiación , Endotelio/metabolismo , Endotelio/efectos de la radiación , Hidroxiprolina/análisis , Pulmón/metabolismo , Masculino , Peptidil-Dipeptidasa A/análisis , Perfusión , Ratas , Ratas Endogámicas
16.
Int J Radiat Oncol Biol Phys ; 19(6): 1405-9, 1990 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2262365

RESUMEN

The angiotensin converting enzyme inhibitor captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats. The present study determined whether captopril also reduces collagen (hydroxyproline) accumulation in the lungs of rats sacrificed 2 months after a range of single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Captopril was administered in the feed at a regimen of 0, 25, or 50 mg/kg/day continuously after irradiation. Mast cell counts also were obtained from lungs of all animals exposed to 30 Gy. In rats receiving no captopril, there was a radiation dose-dependent increase in right lung hydroxyproline (HP) content and in HP concentration per g wet weight. Captopril produced a drug dose-dependent suppression in this radiation-induced HP accumulation. At a dose of 50 mg/kg/d, captopril reduced the slope of the radiation dose response curve for lung HP content by a factor of 1.7, and completely prevented the increase in HP concentration. At an isoeffect level of 550 micrograms HP per right superior lobe, this dose of captopril exhibited a DRF of 1.7 +/- 0.2. In rats exposed to 30 Gy, moreover, the number of mast cells per mm2 of alveolar cross-sectional surface area decreased from 105 +/- 8 to 100 +/- 7 and 59 +/- 5 in the groups given 0, 25 or 50 mg/kg/d of captopril, respectively, (vs none in sham-irradiated rats). These data are the first to demonstrate that the ACE inhibitor captopril might provide a novel intervention in the pathogenesis of radiation fibrosis.


Asunto(s)
Captopril/farmacología , Colágeno/metabolismo , Pulmón/efectos de la radiación , Mastocitos/efectos de la radiación , Animales , Recuento de Células , Hidroxiprolina/análisis , Pulmón/efectos de los fármacos , Pulmón/ultraestructura , Masculino , Mastocitos/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/efectos de la radiación , Ratas , Ratas Endogámicas
17.
Int J Radiat Oncol Biol Phys ; 22(3): 623-5, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1735701

RESUMEN

The present study determined whether inhibitors of angiotensin converting enzyme (ACE) can ameliorate radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a range of single doses of 60Co gamma rays to the right hemithorax. Four indices of pulmonary endothelial function were monitored: right lung ACE and plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Hydroxyproline (HP) content served as an index of pulmonary fibrosis. Rats consumed either control powdered chow or feed containing one of five modifying agents continuously after irradiation. The modifiers included three ACE inhibitors: Captopril, CL242817, and CGS13945, respectively, a thiol, a thioacetate, and a nonthiol compound. All of the ACE inhibitors are analogues of proline. Two additional modifiers were tested: penicillamine, a thiol with no ACE inhibitory activity; and pentoxifylline, a vasodilator that is neither a thiol nor an ACE inhibitor. Radiation produced a dose-dependent decrease in lung ACE and PLA activity, and an increase in PGI2 and TXA2 production and in HP content. All ACE inhibitors attenuated the radiation-induced suppression in lung ACE and PLA activity. All thiol or thioacetate compounds ameliorated the radiation-induced increase in PGI2, TXA2, and HP. The two agents that were both thiols and ACE inhibitors (Captopril and CL242817) spared all of the radiation reactions, while the compound that was neither a thiol nor an ACE inhibitor (pentoxifylline) spared none of the reactions. These data suggest a novel application for ACE inhibitors in general, and for Captopril in particular, as modifiers of radiation pneumotoxicity.


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Pulmón/efectos de la radiación , Fibrosis Pulmonar/tratamiento farmacológico , Animales , Captopril/uso terapéutico , Radioisótopos de Cobalto , Indoles/uso terapéutico , Masculino , Prolina/análogos & derivados , Prolina/uso terapéutico , Fibrosis Pulmonar/etiología , Ratas , Ratas Endogámicas , Relación Estructura-Actividad
18.
Thromb Haemost ; 79(3): 571-3, 1998 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9531043

RESUMEN

Plasma F 1+2 levels, the activation peptide originating from the factor Xa-mediated activation of prothrombin, increase in many clinical conditions associated with hypercoagulability and decrease in patients on oral anticoagulant treatment (OAT). However. the usefulness of F 1+2 measurement to monitor OAT has not yet been investigated in clinical studies. Before those studies are attempted, the plausibility of its implementation in the laboratory control of OAT should be evaluated. In this respect, a thorough investigation of the pattern of changes of F 1+2 as a function of increased intensity of anticoagulation expressed as International Normalized Ratio is essential. One hundred and thirty-two patients on long-term warfarin treatment were recruited to cover 8 ranges of anticoagulation from < 1.5 to 9.0 INR. F 1+2 was measured in batch on frozen plasma and INR was determined on fresh plasma. The relationship of F 1+2 vs. INR showed a hyperbolic pattern with F 1+2 levels decreasing progressively and significantly as a function of increasing INR up to 3.0. A further decrease in F 1+2 levels observed at INR up to 4.0 was not statistically significant. At INR greater than 4.0, F 1+2 reached a plateau, with mean levels not significantly different for patients at increasing INR up to 9.0. Since the risk of bleeding increases at INR greater than 4.5, our results suggest that F 1+2 is of little value to assess the hemorrhagic risk in patients on OAT.


Asunto(s)
Anticoagulantes/administración & dosificación , Monitoreo de Drogas , Fragmentos de Péptidos/análisis , Protrombina/análisis , Warfarina/administración & dosificación , Administración Oral , Factores de Edad , Anciano , Humanos , Persona de Mediana Edad
19.
Am J Cardiol ; 56(13): 896-904, 1985 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-3904388

RESUMEN

The effects of the digitalis glycosides on systemic vascular resistance (SVR) in patients with congestive heart failure (CHF) are controversial. Most investigators report a reduction in total SVR, an action that has been attributed primarily to withdrawal of elevated sympathetic tone. Direct proof of this hypothesis is lacking, however, and the roles played by the renin-angiotensin-aldosterone and vasopressin systems have not been fully explored. Moreover, in several studies of patients with CHF, SVR did not decrease after the administration of digitalis. To clarify these issues, the hemodynamic and hormonal effects of digoxin were correlated in 11 normotensive men in sinus rhythm with CHF due to dilated cardiomyopathy. Patients were evaluated at rest and during submaximal exercise before and 6 hours after the intravenous infusion of 1.0 mg of digoxin (mean serum concentration 1.7 ng/ml). With digoxin therapy, heart rate, pulmonary wedge pressure and right atrial pressure declined and cardiac output increased. Although vasopressin was unchanged, both plasma norepinephrine concentrations and plasma renin activity decreased, the reduction in norepinephrine correlating with the increase in cardiac output. Despite these hemodynamic and hormonal effects, there was no change in total SVR at rest or during exercise. It is concluded that the improvement in cardiac function with digoxin in this patient group was a result of the inotropic properties of the drug, without an associated reduction in impedance. The failure of total SVR to decrease despite decreases in plasma norepinephrine levels and plasma renin activity might be explained by concomitant digitalis-induced vasoconstriction, impaired ability of arterioles to dilate in CHF, or offsetting alterations in other vasoactive hormone systems.


Asunto(s)
Cardiomiopatía Dilatada/complicaciones , Digoxina/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Resistencia Vascular/efectos de los fármacos , Cardiomiopatía Alcohólica/complicaciones , Digoxina/sangre , Epinefrina/sangre , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Renina/sangre
20.
Biochem Pharmacol ; 38(15): 2411-9, 1989 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-2547380

RESUMEN

Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.


Asunto(s)
Cardiomegalia/tratamiento farmacológico , Clorobenzoatos/farmacología , Enfermedades Pulmonares/tratamiento farmacológico , Elastasa Pancreática/antagonistas & inhibidores , Alcaloides de Pirrolicidina/antagonistas & inhibidores , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/patología , Epoprostenol/biosíntesis , Hidroxiprolina/metabolismo , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Masculino , Monocrotalina , Tamaño de los Órganos/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , Alcaloides de Pirrolicidina/toxicidad , Ratas , Ratas Endogámicas , Tromboxano A2/biosíntesis , Activador de Tejido Plasminógeno/metabolismo
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