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5.
J Bioenerg Biomembr ; 44(5): 571-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22986734

RESUMO

Although the pathogenesis of ischemia reperfusion (IR) injury is based on complex mechanisms, free radicals play a central role. We evaluated membrane fluidity and lipid peroxidation during pancreas transplantation (PT) performed in 12 pigs (six donors and six recipients). Fluidity was measured by fluorescence spectroscopy, and malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA) concentrations were used as an index of lipid oxidation. Pancreatic tissues were collected as follows: (A) donor, immediately before vascular clamping; (B) graft, following perfusion lavage with University of Wisconsin preservation fluid; (C) graft, after 16 h of cold ischemia; and (D) recipient, 30 min vascular postreperfusion. Fluidity and MDA and 4-HDA concentrations were similar in cases A, B, and C. However, there was significant membrane rigidity and increased lipid peroxidation after reperfusion (D). These findings suggest that reperfusion exaggerates oxidative damage and may account for the rigidity in the membranes of allografts during PT.


Assuntos
Peroxidação de Lipídeos , Fluidez de Membrana , Transplante de Pâncreas , Pâncreas/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Feminino , Malondialdeído/metabolismo , Microscopia de Fluorescência/métodos , Pâncreas/patologia , Traumatismo por Reperfusão/patologia , Suínos , Transplante Homólogo
6.
Rev Esp Enferm Dig ; 103(6): 299-303, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21736396

RESUMO

OBJECTIVE: the accuracy of preoperative endorectal ultrasound in the status evaluation of lymph nodes is around 50-70%, with a lack of eco-morphological patterns of clinical use. Since, accurate local staging is of great value in prognosis and decision-making we decided to analyze the referenced eco-morphological parameters in a try to find a proper predictive tool of clinical help that could improve the accuracy of rectal ultrasound. MATERIAL AND METHOD: the resected specimens of 24 patients that were operated on by radical surgery because rectal cancer, without preoperative radiotherapy were suspended in warm water and ultrasound scanned (360º circular probe with a transducer of 10 Mhz). All suspicious nodes were recorded and marked for the definitive histological report. RESULTS: from the 24 specimens, 318 nodes were imaged(210 benign and 100 involved). All ultrasound parameters analysed were significant but only lobulation, echogenicity and hilar reflection were independent values. An score system was design with the addition of all parameters that showed a sensitivity of 98%and specificity of 99,1%. CONCLUSIONS: our study shows that a careful study of ultra-sound lymph node images can get a high level of accuracy and better help in tailoring the treatment of any particular case.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Metástase Linfática/diagnóstico por imagem , Neoplasias Retais/diagnóstico por imagem , Adenocarcinoma/cirurgia , Humanos , Técnicas In Vitro , Excisão de Linfonodo , Valor Preditivo dos Testes , Neoplasias Retais/cirurgia , Sensibilidade e Especificidade , Ultrassonografia
7.
Br J Pharmacol ; 161(5): 1099-110, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20977459

RESUMO

BACKGROUND AND PURPOSE: PM01183 is a new synthetic tetrahydroisoquinoline alkaloid that is currently in phase I clinical development for the treatment of solid tumours. In this study we have characterized the interactions of PM01183 with selected DNA molecules of defined sequence and its in vitro and in vivo cytotoxicity. EXPERIMENTAL APPROACH: DNA binding characteristics of PM01183 were studied using electrophoretic mobility shift assays, fluorescence-based melting kinetic experiments and computational modelling methods. Its mechanism of action was investigated using flow cytometry, Western blot analysis and fluorescent microscopy. In vitro anti-tumour activity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the in vivo activity utilized several human cancer models. KEY RESULTS: Electrophoretic mobility shift assays demonstrated that PM01183 bound to DNA. Fluorescence-based thermal denaturation experiments showed that the most favourable DNA triplets providing a central guanine for covalent adduct formation are AGC, CGG, AGG and TGG. These binding preferences could be rationalized using molecular modelling. PM01183-DNA adducts in living cells give rise to double-strand breaks, triggering S-phase accumulation and apoptosis. The potent cytotoxic activity of PM01183 was ascertained in a 23-cell line panel with a mean GI(50) value of 2.7 nM. In four murine xenograft models of human cancer, PM01183 inhibited tumour growth significantly with no weight loss of treated animals. CONCLUSIONS AND IMPLICATIONS: PM01183 is shown to bind to selected DNA sequences and promoted apoptosis by inducing double-strand breaks at nanomolar concentrations. The potent anti-tumour activity of PM01183 in several murine models of human cancer supports its development as a novel anti-neoplastic agent.


Assuntos
Antineoplásicos/farmacologia , DNA/metabolismo , Neoplasias/tratamento farmacológico , Tetra-Hidroisoquinolinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Sequência de Bases , Linhagem Celular Tumoral , Adutos de DNA/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Ensaio de Desvio de Mobilidade Eletroforética , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Moleculares , Neoplasias/patologia , Tetra-Hidroisoquinolinas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Rev Esp Enferm Dig ; 98(4): 234-40, 2006 Apr.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-16792452

RESUMO

INTRODUCTION: transanal endoscopic microsurgery (TEM) was developed in 1983 by Büess as a minimally invasive technique to manage rectal villous adenomas and early rectal adenocarcinomas. Many studies have been published worldwide about its excellent results in morbidity and recidive rate, but there are few studies addressing functional results. The objective of this study is to analyze the effect of this technique in the anal anatomy and compare with the manometric results. MATERIAL AND METHODS: we devised a prospective study of 40 patients. 39% female, 61% male. All of them filled an incontinence questionnaire (Pescatori scale) and endoanal ultrasonography and manometry was carried out preoperatively, third month postoperative and at sixth month only if incontinence appeared. RESULTS: 32 patients (80%) had villous adenomas and 8 patients (20%) had adenocarcinomas (uT1). Three patients complained of flatus incontinence at 3rd postoperative month that disappeared with normal continence at 6th month. Anorectal manometric values: mean anal resting pressure (ARP) decreased at 3rd month (from 87.2 mmHg to 70.1 mmHg), as it was for maximal squeeze pressure (MSP) from 152.5 mmHg preoperatively to 142.2 mmHg at 3rd month. Ultrasonography demonstrated internal anal sphincter (IAS) rupture in 3 patients, with a full integrity of the external anal sphincter in all patients. CONCLUSIONS: during TEM, a significant anal dilatation occurs, because of rectoscopy (40 mm wide), what can produce a rupture of IAS, with the consequent decreasing in ARP, and a dilatation without rupture of external sphincter what produces a decreasing of MSP. The fall of anal pressures had minima clinical repercussion when sphincter is intact, but when IAS is broken a temporal incontinence develops.


Assuntos
Adenocarcinoma/cirurgia , Adenoma Viloso/cirurgia , Microcirurgia/métodos , Proctoscopia , Neoplasias Retais/cirurgia , Idoso , Canal Anal , Feminino , Humanos , Masculino , Proctoscopia/métodos , Estudos Prospectivos
11.
Rev. esp. enferm. dig ; 98(4): 234-240, abr. 2006. tab
Artigo em Es | IBECS | ID: ibc-048593

RESUMO

Introducción: la microcirugía transanal endoscópica (TEM)fue desarrollada en 1983 por Büess como técnica mínimamenteinvasiva para el tratamiento de adenomas y adenocarcinomas enestadio precoz de recto. Son múltiples los estudios realizados entodo el mundo sobre sus resultados de morbimortalidad y tasa derecidiva, pero sin embargo son muy pocos los estudios publicadossobre los resultados funcionales. El objetivo de este estudio fueanalizar el efecto que esta cirugía provoca en la anatomía del canalanal y compararlo con los resultados funcionales.Material y métodos: realizamos un estudio descriptivo prospectivode 40 pacientes: 39% mujeres, 61% hombres. En todosellos se cumplimentó una encuesta de función esfinteriana (test dePescatori) y ecografía endoanal y manometría preoperatoria, al 3ermes postoperatorio, y al 6º sólo si apareció incontinenciaResultados: Treinta y dos pacientes (80%) fueron operados deadenomas y 8 pacientes (20%) de adenocarcinomas uT1. Tres pacientespresentaron incontinencia a gases al 3er mes postoperatorioque se normalizó al 6º mes. Valores de la manometría anorrectal: lapresión media en reposo (PMR) había disminuido a los 3 meses conrespecto al valor preoperatorio de 87,2 a 70,1 mmHg, al igual quela presión máxima de contracción (PMC) de 152,5 mmHg de formapreoperatoria a 142,2 mmHg. Ecográficamente se pudo demostrarrotura del esfínter anal interno en 3 pacientes, estando en todos lospacientes íntegro el esfínter externo.Conclusiones: durante el tiempo quirúrgico de la TEM y debidoal diámetro del rectoscopio (40 mm), existe una dilataciónmantenida del canal anal. Esto unido al hecho de que es frecuenteque haya que modificar la posición del mismo, se traduce, en algunoscasos, en un riesgo de rotura del EAI, con la consiguientecaída en la PMR. En definitiva la caída que se objetiva en las presionesendoanales tiene una mínima repercusión en la clínica amenos que exista una lesión esfinteriana lo que conlleva incontinencia,en cualquier caso siempre temporal


Introduction: transanal endoscopic microsurgey (TEM) wasdeveloped in 1983 by Büess as a minimally invasive technique tomanage rectal villous adenomas and early rectal adenocarcinomas.Many studies have been published worldwide about its excellentresults in morbidity and recidive rate, but there are few studiesaddressing functional results. The objective of this study is to analyzethe effect of this technique in the anal anatomy and comparewith the manometric results.Material and methods: we devised a prospective study of40 patients. 39% female, 61% male. All of them filled an incontinencequestionnaire (Pescatori scale) and endoanal ultrasonographyand manometry was carried out preoperatively, third monthpostoperative and at sixth month only if incontinence appeared.Results: 32 patients (80%) had villous adenomas and 8 patients(20%) had adenocarcinomas (uT1). Three patients complainedof flatus incontinence at 3rd postoperative month that disappearedwith normal continence at 6th month. Anorectalmanometric values: mean anal resting pressure (ARP) decreasedat 3rd month (from 87.2 mmHg to 70.1 mmHg), as it was formaximal squeeze pressure (MSP) from 152.5 mmHg preoperativelyto 142.2 mmHg at 3rd month. Ultrasonography demonstratedinternal anal sphincter (IAS) rupture in 3 patients, with a full integrityof the external anal sphincter in all patients.Conclusions: during TEM, a significant anal dilatation occurs,because of rectoscopy (40 mm wide), what can produce a ruptureof IAS, with the consequent decreasing in ARP, and a dilatationwithout rupture of external sphincter what produces a decreasingof MSP. The fall of anal pressures had minima clinical repercussionwhen sphincter is intact, but when IAS is broken a temporalincontinence develops


Assuntos
Masculino , Feminino , Idoso , Humanos , Microcirurgia/métodos , Adenocarcinoma/cirurgia , Adenoma Viloso/cirurgia , Proctoscopia , Neoplasias Retais/cirurgia , Estudos Prospectivos , Canal Anal
13.
Rev Esp Enferm Dig ; 97(7): 491-6, 2005 Jul.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-16262528

RESUMO

INTRODUCTION: Proctalgia fugax (PF) is a benign, self-limiting disease characterized by episodes of intense anorectal pain at frequent intervals in the absence of organic proctological disease. Even though PF was described more than a century ago, its etiology remains unclear. Currently there is no information available. Few papers quoting many ways of management have been published. The aim of this study was to investigate patients complaining of this condition and to treat them with sequential therapy. PATIENTS AND METHODS: We devised a descriptive, prospective study of patients complaining of acute perianal pain--duration less than 30 minutes--without organic disease or previous perianal surgery since 1996 to 2002 in our Department. We treated these patients using a three-step treatment (1: information, hip bath, benzodiazepines; 2: sublingual nifedipine 10 mg, or topic 0.1% nitroglycerin on demand; 3: internal anal sphincterotomy if hypertrophy of the internal anal sphincter was demonstrated by anal ultrasonography and no improvement was confirmed with the previous steps of treatment). We defined remarkable improvement as a decrease in the number of episodes by half or in pain intensity by 50%. RESULTS: Fifteen patients with an average follow-up of 4 years. Anal endosonography confirmed a grossly thickened internal anal sphincter (IAS) in 5 cases. After the first step of treatment 7 patients improved and 1 patient was cured; after the second step of treatment 3 patients improved and 1 was cured; the third step was applied to 3 patients with a thickened IAS; 1 patient improved and 1 patient was cured. CONCLUSION: A total resolution of PF is not always possible, but we may improve symptoms and their frequency. Almost 50% of patients in our series improved with the first step of treatment; 30% of our patients had IAS hypertrophy. Anal endosonography can help in the diagnosis of organic diseases or IAS hypertrophy, for which we can perform an internal anal sphincter myectomy.


Assuntos
Canal Anal , Doenças do Ânus/terapia , Doença Aguda , Adulto , Canal Anal/diagnóstico por imagem , Canal Anal/patologia , Canal Anal/cirurgia , Ansiolíticos/administração & dosagem , Ansiolíticos/uso terapêutico , Doenças do Ânus/diagnóstico por imagem , Doenças do Ânus/tratamento farmacológico , Doenças do Ânus/patologia , Doenças do Ânus/cirurgia , Banhos , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Endossonografia , Feminino , Seguimentos , Humanos , Hipertrofia , Masculino , Pessoa de Meia-Idade , Nifedipino/administração & dosagem , Nifedipino/uso terapêutico , Nitroglicerina/administração & dosagem , Nitroglicerina/uso terapêutico , Dor/tratamento farmacológico , Dor/etiologia , Manejo da Dor , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/uso terapêutico
14.
Rev. esp. enferm. dig ; 97(7): 491-496, jul. 2005. tab
Artigo em Es | IBECS | ID: ibc-041835

RESUMO

Introducción: la proctalgia fugaz (PF) es una patología benigna,autolimitada, caracterizada por dolor anorrectal intenso, a intervalosfrecuentes, sin causa orgánica aparente. Su etiología noestá clara, a pesar de ser conocida desde hace un siglo y existenpocos artículos publicados sobre esta patología, con escaso númerode pacientes, aplicando tratamientos variados con mayor o menorfortuna. El propósito de este trabajo ha sido estudiar a una seriede pacientes aquejados de esta patología y aplicar a todos ellosun tratamiento de manera secuencial en dependencia de su respuestaal mismo.Material y métodos: realizamos un estudio descriptivo prospectivode pacientes aquejados de dolor perianal brusco, < 30min de duración, sin lesión orgánica concomitante ni intervenciónprevia perianal desde 1996-2002 en nuestro Servicio, sometiéndolesa un tratamiento de manera secuencial, basado en 3 escalonesterapéuticos (1. información, baños de asiento, tranquilizantes;2. nifedipino 10 mg sublingual, o nitroglicerina tópica 0,1%en el momento de la crisis; y 3. esfinterotomía lateral interna si hipertrofiadel esfínter anal interno y no mejoría con los otros escalones).Definimos mejoría significativa cuando se producía un importantedistanciamiento de los episodios (disminución nº crisis ala mitad) y/o disminución del dolor en un 50%.Resultados: quince pacientes con un seguimiento medio de 4años. Mediante ecografía endoanal se pudo demostrar la existenciade hipertrofia del esfínter anal interno (EAI) en 5 casos. Tras laaplicación del escalón 1 mejoraron 7 pacientes y curó 1 paciente;con el escalón 2 mejoraron 3 pacientes y 1 curó, y se aplicó el escalón3 a 3 pacientes que presentaban hipertrofia del EAI mejorando1 y curando otro paciente.Conclusión: la curación de la PF no siempre es factible, perosí es posible aliviar los síntomas, así como su frecuencia. Casi el50% de los pacientes de nuestra serie mejoró con el escalón 1 deltratamiento. Un tercio de nuestros pacientes presentaban hipertrofiadel EAI. La ecografía endoanal ayudará tanto a descartar lesionesorgánicas concomitantes como a diagnosticar una hipertrofiadel EAI, que se beneficiaría de una esfinterotomía lateral interna


disease characterized by episodes of intense anorectal pain at frequentintervals in the absence of organic proctological disease.Even though PF was described more than a century ago, its etiologyremains unclear. Currently there is no information available.Few papers quoting many ways of management have been published.The aim of this study was to investigate patients complainingof this condition and to treat them with sequential therapy.Patients and methods: we devised a descriptive, prospectivestudy of patients complaining of acute perianal pain –durationless than 30 minutes– without organic disease or previous perianalsurgery since 1996 to 2002 in our Department. We treatedthese patients using a three-step treatment (1: information, hipbath, benzodiazepines; 2: sublingual nifedipine 10 mg, or topic0.1% nitroglycerin on demand; 3: internal anal sphincterotomy ifhypertrophy of the internal anal sphincter was demonstrated byanal ultrasonography and no improvement was confirmed withthe previous steps of treatment). We defined remarkable improvementas a decrease in the number of episodes by half or in painintensity by 50%.Results: Fifteen patients with an average follow-up of 4 years.Anal endosonography confirmed a grossly thickened internal analsphincter (IAS) in 5 cases. After the first step of treatment 7 patientsimproved and 1 patient was cured; after the second step oftreatment 3 patients improved and 1 was cured; the third stepwas applied to 3 patients with a thickened IAS; 1 patient improvedand 1 patient was cured.Conclusion: a total resolution of PF is not always possible,but we may improve symptoms and their frequency. Almost 50%of patients in our series improved with the first step of treatment;30% of our patients had IAS hypertrophy. Anal endosonographycan help in the diagnosis of organic diseases or IAS hypertrophy,for which we can perform an internal anal sphyncter myectomy


Assuntos
Adulto , Pessoa de Meia-Idade , Humanos , Doenças do Ânus/tratamento farmacológico , Doenças do Ânus/terapia , Canal Anal/patologia , Canal Anal/cirurgia , Canal Anal , Ansiolíticos/administração & dosagem , Ansiolíticos/uso terapêutico , Doenças do Ânus/cirurgia , Benzodiazepinas/administração & dosagem , Benzodiazepinas/uso terapêutico , Endossonografia , Nitroglicerina/uso terapêutico , Vasodilatadores/administração & dosagem
16.
An Med Interna ; 20(8): 403-9, 2003 Aug.
Artigo em Espanhol | MEDLINE | ID: mdl-14516260

RESUMO

BACKGROUND: Sometimes Graves disease (GD) can appear in association with thyroid nodules, which seems to increase the risk of carcinoma. In this article, we try to establish clinical characteristics, diagnostic means and appropriate treatment for Graves patients with co-existent nodules. METHOD: A retrospective study was made of 153 consecutive patients who underwent operation for GD between 1967 and 2000. Each patient was subject to a regular protocol including physical examination, diagnostic test, total or subtotal thyroidectomy and follow-up in the long term with the purpose of making a valuation of the postsurgical morbidity, evolution and relapses. Data were processed through computing in order to get the statistical information. RESULTS: 28.1% of GD had thyroid nodules and carcinoma was diagnosed in four patients (9.3%), all of them belonging to papillary variety. Surgery consisted of 57 subtotal thyroidectomies (37.3%) and 94 total thyroidectomies. Parathyroid and recurrent morbidity was established in 4.6 and 3.9%, respectively, a year later since the operation, though it had a strong tendency to decrease from 1980. 96% of cases showed no relapse. CONCLUSIONS: Nodular GD is very common in our setting, especially in Graves patients with late beginning who wait for ages until they are undergone surgery. Initial treatment should be by means of braking therapy with antithyroid drugs and clinical, cytologic and ultrasonographic control. Surgery would be advised, from the outset or during the follow-up, in view of either any suspicion about cancer or presence of local growth. The procedure of choice is total thyroidectomy performed with low morbidity.


Assuntos
Doença de Graves/diagnóstico , Doença de Graves/cirurgia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/cirurgia , Adulto , Feminino , Doença de Graves/complicações , Humanos , Masculino , Estudos Retrospectivos , Nódulo da Glândula Tireoide/complicações , Tireoidectomia/métodos , Resultado do Tratamento
17.
An. med. interna (Madr., 1983) ; 20(8): 403-409, ago. 2003.
Artigo em Es | IBECS | ID: ibc-23857

RESUMO

Fundamento: La enfermedad de Graves-Basedow (EGB) puede presentarse en ocasiones asociada a nódulos tiorideos, lo que parece aumentar la posibilidad de padecer un carcinoma. En el presente artículo, intentamos establecer las particularidades clínicas, los medios diagnósticos y el tratamiento adecuado para los pacientes en los que coexisten ambas patologías. Método: Se estudiaron 153 EGB intervenidas consecutivamente entre los años 1967 y 2000. Todas ellas fueron sometidas a un protocolo uniforme que incluyó exploración, pruebas complementarias, tiroidectomía subtotal o total y seguimiento a largo plazo con el fin de valorar la evolución de la morbilidad postquirúrgica y las recidivas. Los datos obtenidos fueron registrados informáticamente para su posterior análisis estadístico. Resultados: Un 28.1 por ciento de las EGB se asociaban a nódulos y se diagnosticaron cuatro carcinomas (9,3 por ciento) todos ellos pertenecientes a la variedad papilar. Se practicaron 57 tiroidectomías subtotales (37,3 por ciento) y 94 totales. La morbilidad paratiroidea y recurrencial al año de la intervención se estableció en un 4,6 y 3,9 por ciento, respectivamente, aunque con una marcada tendencia a disminuir desde 1980. Un 96 por ciento de los casos no presentó ninguna recidiva. Conclusiones: El Graves-Basedow nodular es muy frecuente en nuestro medio, sobre todo en pacientes con EGB de inicio tardío y que esperan años hasta intervenirse. El tratamiento inicial debe ser mediante una terapia frenadora con antitiroideos de síntesis y control clínico, citológico y ultrasonográfico. La cirugía será indicada, de inicio o durante el seguimiento, ante cualquier sospecha de cáncer o la presencia de síntomas compresivos. La técnica idónea es una tiroidectomía total practicada con baja morbilidad (AU)


Assuntos
Adulto , Masculino , Feminino , Humanos , Tireoidectomia , Nódulo da Glândula Tireoide , Resultado do Tratamento , Estudos Retrospectivos , Doença de Graves
18.
Artigo em Espanhol | IBECS | ID: ibc-115344

RESUMO

We present the clinical case of a 36 year old woman who had a previous kidney transplant with a spontaneous twin pregnancy and bilateral reflux. The pregnancy progressed without complications until the appearance of a severe foetal growth retardation which required ending the pregnancy. We present this case and make a review of renal transplant and gestation (AU)


Assuntos
Humanos , Feminino , Adulto , Insuficiência Renal Crônica/complicações , Transplante de Rim , Complicações na Gravidez/cirurgia , Gravidez de Gêmeos , Resultado da Gravidez
19.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 29(6): 233-237, jun. 2002. tab
Artigo em Espanhol | IBECS | ID: ibc-115326

RESUMO

La listeriosis es una infección infrecuente. Se contagia a través de los alimentos infectados por la Listeria monocytogenes, que típicamente tiene predilección por mujeres gestantes, inmunodeprimidos, ancianos y niños. Teniendo gran variedad de manifestaciones clínicas, cuyas complicaciones para la madre y el feto son graves, pudiendo complicar un embarazo con abortos, muerte fetal anteparto, parto pretérmino y con listeriosis neonatal. En este artículo describimos un caso de listeriosis neonatal y una revisión de la bibliografía actual (AU)


Assuntos
Humanos , Feminino , Gravidez , Listeriose/complicações , Complicações Infecciosas na Gravidez/diagnóstico , Listeria monocytogenes/patogenicidade , Cesárea
20.
J Drug Target ; 9(3): 185-200, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11697204

RESUMO

BACKGROUND/AIMS: Several members of a novel family of bile acid derivatives with cytostatic and virostatic activity have been synthesized and characterized. The aim of this work was to investigate the liver organotropism and biotransformation of two novel compounds with enhanced DNA-reactivity: Bamet-D3, in which a glycine-polyamine tandem was used as a spacer to separate the glycocholic acid moiety from the platinum(II) atom, and Bamet-UD2, in which cisplatin was directly bound to the carboxylate group of two ursodeoxycholic acid moieties. METHODS: Drug uptake and "in vitro" toxicity were investigated using rat hepatocytes in primary culture. Following i.v. administration of 0.5 mumol cisplatin, Bamet-D3 or Bamet-UD2, bile output, urinary and fecal excretion, organ distribution and pharmacokinetic parameters were determined in short-term (3 h) and long-term (14 days) experiments carried out on anaesthetized and conscious rats, respectively. Liver biotransformation was investigated by HPLC analysis of bile samples. Total platinum was measured by flameless atomic absorption spectroscopy. Using Nude mice, antitumour activity was investigated in subcutaneously implanted Hepa 1-6 mouse hepatoma cells. RESULTS: Uptake by rat hepatocytes was Bamet-UD2 (11.3 nmol/mg protein) > Bamet-D3 (5.6 nmol/mg protein) > cisplatin (2.1 pmol/mg protein). Bamet-UD2 induced "in vitro" cell toxicity, which was not observed for Bamet-D3 or cisplatin. On the contrary, no toxicity "in vivo" for Bamet-UD2 was found which was observed for cisplatin and Bamet-D3. This may be related with the fact that bile output of Bamet-UD2, which occurs with no major biotransformation, was > 10 fold higher than that of cisplatin and 3-fold higher than that of Bamet-D3, which was previously transformed into at least three different metabolites. Fecal excretion was Bamet-UD2 > Bamet-D3 > cisplatin, whereas urinary output was Bamet-D3 > cisplatin > Bamet-UD2. Accordingly, a marked liver- and a reduced kidney-vectoriality for Bamet-UD2, but not for Bamet-D3, was observed. Bamet-UD2 and cisplatin, but not Bamet-D3, were efficient in inhibiting tumour growth whereas, only Bamet-UD2 significantly prolonged survival time. CONCLUSIONS: There results indicate that Bamet-UD2 is a cisplatin-ursodeoxycholate derivative with strong antitumour activity, marked hepatobiliary organotropism, and reduced toxic side-effects as compared to the parent drug cisplatin.


Assuntos
Antineoplásicos/farmacocinética , Fígado/metabolismo , Compostos Organoplatínicos/farmacocinética , Ácido Ursodesoxicólico/farmacocinética , Animais , Antineoplásicos/metabolismo , Área Sob a Curva , Bile/efeitos dos fármacos , Bile/metabolismo , Biotransformação , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Meia-Vida , Masculino , Camundongos , Camundongos Nus , Compostos Organoplatínicos/metabolismo , Ratos , Ratos Wistar , Distribuição Tecidual , Ácido Ursodesoxicólico/metabolismo
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