Uso de radiotrazador de medicina nuclear fluor 18 fluorodexosiglucosa (f18-fdg) en tomografias de emision de positrones (pet) en oncología / Use of nuclear fluor radiotherapy radiodermal 18 fluorodexosiglucose (f18-fdg) in positron emission tomography (PET) in oncology

INTRODUCCIÓN: Antecedentes: l presente informe expone la evaluación del radiotrazador de medicina nuclear Fluor-18-Fluorodexosiglucosa (F-18 FDG) en tomografías de emisión de positrones (PET). Se realiza esta evaluación considerando la necesidad manifestada por el Servicio de Medicina Nuclear del Hospital Nacional Edgardo Rebagliati Martins y del Hospital Nacional Guillermo Almenara Yrigoyen. Aspectos Generales: Las imágenes PET o Tomografías de Emisión de Positrones son técnicas de diagnóstico por imágenes no invasiva de la medicina nuclear, la cual, a través de una substancia emisora de positrones llamada radiotrazador, genera una imagen de su distribución tridimensional en los tejidos. Su evaluación, cuantificación e interpretación es realizada por el médico nuclear. La caracterización bioquímica y biológica de los tejidos, ofrece al médico tratante un tipo de información fundamentalmente diferente que la provista por las imágenes anatómicas. En la actualidad, la mayoría de los tomógrafos PET son equipos que combinan dos tecnologías: PET y TC (Tomografía computarizada) en un único dispositivo con el que se generan simultáneamente imágenes funcionales y anatómicas de los órganos en estudio. Tecnología Sanitaria de Interés: El radiofármaco emisor de positrones F-18 Fluorodexosiglucosa es un análogo de la glucosa y contiene el ingrediente activo 2-deoxy-2-[18F]fluoro-D-glucosa o F-18 FDG). Decae por emisión de positrones y tiene una vida media de 109.7 minutos. METODOLOGÍA: Estrategia de Busqueda: Se realizó una búsqueda de la literatura con respecto a la especificidad, sensibilidad y seguridad de PET-CT usando el F-18 FDG como radiotrazador. Para la búsqueda primaria se revisó la información disponible por entes reguladoras y normativas como la Food and Drug Administration (FDA), y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente se buscaron Guías de Práctica Clínica a través de los metabuscadores: TranslatingResearchintoPractice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y HealthSystemsEvidence. Finalmente, se realizó una búsqueda dentro de la información generada por grupos internacionales que realizan revisiones sistemáticas, evaluación de tecnologías sanitarias y guías de práctica clínica, tales como The Cochrane Library, The National Institute for Health and Care Excellence (NICE), The National Guideline of Clearinghouse, The Canadian Agency for Drugs and Technologies in Health (CADTH),The Scottish Medicines Consortium (SMC), que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov, para identificar estudios primarios en elaboración o que no hayan sido publicados aún. RESULTADOS: Evaluacion de Tecnología: Administración de Medicamentos y Drogas (FDA) del año 1999 (última actualización en el 2010) 3: La evidencia de mejor calidad encontrada fue esta revisión de 18F Fluoro-2-Deoxyglucosa (18-FDG) como agente de diagnóstico de imágenes PET en la evaluación de malignidad de la Administración de Medicamentos y Drogas (FDA por sus siglas en inglés), la cual aprobó su uso como radiofármaco en las áreas de oncología, cardiología y neurología. CONCLUSIONES: s imágenes PET o Tomografías de Emisión de Positrones son técnicas de diagnóstico por imágenes no invasivas de la medicina nuclear, las cuales usan compuestos llamados radiotrazadores para la generación de imágenes. El radiotrazador emisor de positrones F-18 Fluorodexosiglucosa es un análogo de la glucosa, el cual permite identificar tejidos malignos y benignos en el área evaluada, ya que una glicólisis acelerada o menor capacidad de producir energía aeróbicamente son características de células malignas (cancerígenas). La caracterización bioquímica y biológica de los tejidos, ofrece al médico tratante un tipo de información fundamentalmente diferente que la provista por las imágenes anatómicas, por lo que las guías de práctica clínica a nivel \r\ninternacional recomiendan actualmente el uso del radiotrazador tanto para fines se estadiaje como de seguimiento y respuesta al tratamiento oportunas. El uso del radiotrazador de medicina nuclear Fluor 18 Fluorodexosiglucosa (F-18 FDG) en tomografías de emisión de positrones (PET) para el diagnóstico, \r\nestadiaje, y respuesta al tratamiento en enfermedades oncológicas, está recomendado en guías de práctica clínicas internacionales. Sin embargo, es interesante notar que la evidencia científica de sensibilidad y especificidad que respalda dichas recomendaciones es escasa y variable para muchas de las patologías oncológicas. No obstante ello, esta tecnología imagenológica es ampliamente usada en oncología, especialmente para evaluar la respuesta a tratamiento. Cabe resaltar, que la evidencia revisada es consistente respecto a la seguridad del F-18 FDG. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación- IETSI, aprueba el uso de F 18 Fluorodexosiglucosa como radiotrazador para la realización de PET-CT en el manejo oncológico.

Aluminium effects on thyroid gland function: iodide uptake, hormone biosynthesis and secretion.

The effects of aluminium (Al) on thyroid function were evaluated in adult Wistar rats intraperitoneally (i.p) injected with 7 mg Al (as lactate)/kg body weight (b.w) per day during a six week period. The time-course kinetics of Na(125)I (3 µCi per 100 g b.w, i.p) was analysed by measuring gamma-radioactivity of thyroid, serum, serum protein precipitate and bile, at times ranging from 2 to 96 h post-dosing. In Al-treated group the (125)I(-) thyroid uptake at 24 h (15,840 ± 570 vs. 18,030 ± 630 dpm/mg, P<0.05) as well as the rate of (125)I(-) release from the gland, calculated as the slope of the plot between 24 and 96 h (84 ± 8 vs. 129 ± 11 dpm/mg/h, P<0.05) were significantly reduced as compared to control. The biliary (125)I(-) excretion was not modified at all studied times. The Al content and lipid peroxidation (69.1 ± 8.5 vs. 53.2 ± 7.0 nmol MDA/g wet weight, P<0.05) of thyroid tissue were increased in Al-treated rats. The serum concentrations of total thyroxine (T4, 3.78 ± 0.14 vs. 4.68 ± 0.12 µg/dL, P<0.05) and total triiodothyronine (T3, 47 ± 4 vs. 66 ± 5 ng/dL, P<0.05) were decreased by effect of Al, but free-T4 (1.05 ± 0.05 vs. 1.04 ± 0.04 ng/dL, NS) and thyrotropin (TSH, 2.7 ± 0.4 vs. 2.6 ± 0.5 ng/ml, NS) remain unchanged. In spite of the Al could indirectly affect thyroid iodide uptake and hormones secretion by a mechanism involving the induction of an oxidative stress state, however, these changes could be managed by the hypothalamus-pituitary-thyroid endocrine axis. We can conclude that in adult rats the Al would not act as a thyroid disruptor.

Inhibitory effect of aluminium on calcium absorption in small intestine of rats with different thyroid hormone status.

To analyse the influence of thyroid status on the effect of aluminium (Al) upon intestinal calcium (Ca) absorption, adult male Wistar rats with experimentally altered thyroid hormones circulating levels, were orally treated (o.g.) with 0 (control), or 50 mg elemental Al (as chloride)/kg body weight (b.w.) per day, for a 14 d period. Hyper- and hypo-thyroid conditions were respectively achieved by means of administration of either sodium levothyroxine (50 microg/kg b.w. per day, o.g.) or methimazole, a thyroxine synthesis inhibitor (1mg/kg b.w. per day, o.g.). In duodenum-jejunum segments, in vitro mucosa-to-serosa (45)Ca flux (JCa(ms)) and kinetics of (45)Ca uptake in isolated enterocytes, were determined. In serum, concentrations of thyroxine (T4) and triiodothyronine (T3) were measured by chemiluminescent enzyme immunoassay. Unlike non-Al-treated rats, JCa(ms) of Al-exposed rats decreased as serum levels of T4 and T3 increased, showing a significant inverse correlation in both cases (T4: r(2)=0.414, P=0.024; T3: r(2)=0.443, P=0.018). Enterocytes isolated from rats treated with Al plus thyroxine showed a reduction of both maximum Ca uptake (4.86+/-0.44 vs. 6.85+/-1.04 nmol Ca/mg protein, P<0.05) and K(m) (0.84+/-0.18 vs. 1.05+/-0.36 mM, P<0.05) when compared to control. The observed variability in the Al effect on Ca transport with thyroid status of rats could be reflecting a negative interaction of Al with thyroid hormone action mechanisms on intestinal Ca absorption, which would take place mainly at Ca entry into enterocyte from lumen.

Effect of aluminium on duodenal calcium transport in pregnant and lactating rats treated with bromocriptine.

The aim of present work was to study the effect of oral aluminium (Al) overload on intestinal calcium (Ca) absorption in the critical stages of pregnancy and lactation of rats and to find out possible relationships with prolactin (PRL) and 17beta-estradiol (E2) circulating levels. Adult female Wistar rats were orally treated from day 1 of pregnancy with 0 (control), or 50 mg elemental Al (as chloride)/kg body weight per day. Ca transport was determined by everted duodenal sacs technique using 2 microCi of (45)CaCl(2) as flux marker (JCa(ms)). Al treatment reduced JCa(ms) either in late pregnancy (day 19) or in middle lactation (day 9 postpartum). Oral administration of bromocriptine (BrC), an inhibitor of PRL secretion, at dose of 10 mg/kg body weight given 18 h before JCa(ms) measurements were done, produced a significant decrease in the inhibitory effect of Al on JCa(ms), expressed as percent of control, at day 9 of nursing (vehicle: 51+/-7%, BrC: 28+/-4%, P <0.05). A positive correlation between Al effects on JCa(ms) and the physiological variations of E2 serum levels along pregnancy and lactation in BrC-treated rats was also found (r(2)=0.277, P =0.001). We conclude Al could reduce transcellular Ca absorption in the duodenum by interfering with physiological mechanisms of Ca transport partially mediated by serum level increments of E2 and PRL, observed in late pregnancy and mainly during middle lactation of rats.

Aluminium-induced impairment of transcellular calcium absorption in the small intestine: calcium uptake and glutathione influence.

Aluminium (Al) has been recognised as a cause of bone tissue disorders. The aims of this work were to investigate: (i) whether Al affects calcium (Ca) entry into enterocyte, and (ii) the possibility that the Al effect upon calbindin-D-related Ca transport would be influenced by intestinal glutathione (GSH) levels. In isolated chicken duodenal enterocytes, 100 microM Al lactate produced a decrease in both, the maximum uptake rate and the affinity constant of 45Ca uptake (CaUPT). This effect of Al on CaUPT was concentration-dependent in the micromolar range, showing an inhibitory saturation type phenomenon which appeared to be higher at pH 6.5 than at pH 7.4, and was not modified by the Ca channel activators A23187 and capsaicin. The simultaneous administration of Al (50 mg elemental Al/kg body weight, as AlCl3) and GSH (10 mmol/kg body weight) to rats during 7 days, prevented the inhibitory effects of Al on Ca transport. The protective effect of GSH was accompanied by an increased duodenal calbindin-D9k expression. Experimental depletion of intestinal GSH by means of D,L-buthionin-[S,R] sulfoximine, a gamma-glutamylcystein-synthase inhibitor, given as a single i.p. dose of 2 mmol/kg body weight, enhanced the degree of reduction of Ca absorption ascribed to Al. Our results suggest that Al might interfere Ca uptake by enterocytes through a general effect on cell membrane, and that an oxidative stress state induced by Al would reduce intestine GSH level affecting calbindin-D function and/or synthesis, thus leading to a reduced transcellular Ca absorption in the small intestine.

Short-term oral exposure to aluminium decreases glutathione intestinal levels and changes enzyme activities involved in its metabolism.

To study the effects of aluminium (Al) on glutathione (GSH) metabolism in the small intestine, adult male Wistar rats were orally treated with AlCl3.6H2O at doses of 30, 60, 120 and 200 mg/kg body weight (b.w.) per day, during seven days. Controls received deionized water. At doses above 120 mg/kg b.w., Al produced both a significant reduction of GSH content and an increase of oxidized/reduced glutathione ratio (P < 0.05). The index of oxidative stress of the intestine mucosa in terms of lipid peroxidation evaluated by thiobarbituric acid reactive substances was significantly increased (52%) at higher Al dose used. The duodenal expression of the multidrug resistance-associated protein 2 in brush border membranes, determined by Western blot technique, was increased 2.7-fold in rats treated with 200mg AlCl3/kg b.w (P < 0.01). Intestine activities of both GSH-synthase (from 60 mg/kg b.w.) and GSSG-reductase (from 120 mg/kg b.w.) were significantly reduced (26% and 31%, respectively) while glutathione-S-transferase showed to be slightly modified in the Al-treated groups. Conversely, gamma-glutamyltranspeptidase activity was significantly increased (P < 0.05) due to the Al treatment. Al reduced in vitro mucosa-to-lumen GSH efflux (P < 0.05). A positive linear correlation between the intestine GSH depletion and reduction of in situ 45Ca intestinal absorption, both produced by Al, was found (r = 0.923, P = 0.038). Taking as a whole, these results show that Al would alter GSH metabolism in small intestine by decreasing its turnover, leading to an unbalance of redox state in the epithelial cells, thus contributing to deteriorate GSH-dependent absorptive functions.