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[en] The rat posterodorsal medial amygdala (MePD) links emotionally charged sensory stimuli to social behavior, and is part of the supramedullary control of the cardiovascular system. We studied the effects of microinjections of neuroactive peptides markedly found in the MePD, namely oxytocin (OT, 10 ng and 25 pg; n=6/group), somatostatin (SST, 1 and 0.05 μM; n=8 and 5, respectively), and angiotensin II (Ang II, 50 pmol and 50 fmol; n=7/group), on basal cardiovascular activity and on baroreflex- and chemoreflex-mediated responses in awake adult male rats. Power spectral and symbolic analyses were applied to pulse interval and systolic arterial pressure series to identify centrally mediated sympathetic/parasympathetic components in the heart rate variability (HRV) and arterial pressure variability (APV). No microinjected substance affected basal parameters. On the other hand, compared with the control data (saline, 0.3 µL; n=7), OT (10 ng) decreased mean AP (MAP_5_0) after baroreflex stimulation and increased both the mean AP response after chemoreflex activation and the high-frequency component of the HRV. OT (25 pg) increased overall HRV but did not affect any parameter of the symbolic analysis. SST (1 μM) decreased MAP_5_0, and SST (0.05 μM) enhanced the sympathovagal cardiac index. Both doses of SST increased HRV and its low-frequency component. Ang II (50 pmol) increased HRV and reduced the two unlike variations pattern of the symbolic analysis (P<0.05 in all cases). These results demonstrate neuropeptidergic actions in the MePD for both the increase in the range of the cardiovascular reflex responses and the involvement of the central sympathetic and parasympathetic systems on HRV and APV
Journal
Brazilian Journal of Medical and Biological Research; ISSN 0100-879X; 
; v. 48(2); p. 128-139
; v. 48(2); p. 128-139
[en] The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to over express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently over express hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN(R)) which binds to hSSTR2 and 5 with high affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4 and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a higher high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-depreotide (NEOSPECT(R); NEOTECT (R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study MAURITIUS (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase 2a study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plenitude of preclinical data and clinical studies confirm proof-of-principle for their use in diagnosis as well as therapy of cancer patients. However, an optimal radio peptide formulation does not yet exist for receptor-targeted radionuclide therapy
Journal
[en] Neuroendocrine tumors (NETs) consist of a heterogeneous group of tumors that are uptake neuroamine and/or specific receptors, such as somatostatin receptors, which can play important roles of the localization and treatment of these tumors. When considering therapy with radionuclides, the best radioligand should be carefully investigated. 131I-MIBG and beta-particle emitter labeled somatostatin analogs are well established radionuclide therapy modalities for NETs. 111In, 90Y and 177Lu radiolabelled somatostatin analogues have been used for treatment of NETs. Further, radionuclide therapy modalities, for example, radioimmunotherapy, radiolabeled peptides such as minigastrin are currently under development and in different phases of clinical investigation. For all radionuclides used for therapy, long-tem and survival statistics are not yet available and only partial tumour responses have been obtained using 131I-MIBG and 111In-octreotide. Experimental results using 90Y-DOTA-lanreotide as well as 90Y-DOTA-D -Phe1-Tyr3-octreotide and/or 177Lu-DOTA-Tyr3-octreotate have indicated the possible clinical potential of radionuclides receptor-targeted radiotherapy. It may be hoped that the efficacy of radionuclide therapy will be improved by co-administration of chemotherapeutic drugs whose antitumoral properties may be synergistic with that of irradiation
Journal
Nuclear Medicine and Molecular Imaging; ISSN 1975-129X; ; v. 40(2); p. 90-95
; v. 40(2); p. 90-95
[en] We successfully achieved complete regression of a pancreatic pseudocyst after Ethibloc embolization of a fistula between the cyst and the pancreatic duct. Previous treatment by percutaneous drainage over 6 weeks had failed. Treatment with a somatostatin analog had not been undertaken
Journal
[en] The technique described is for labeling of another somatostatin analog based on Tyr3-octreotide, using hydrazinonicotinico acid (HYNIC) as a ligand for technetium and EDDA has been successful in preclinical trials and subsequently has developed a formulation for the preparation of kits lyophilized
[es]
La tecnica descrita para la marcacion de otro analogo de somatostatina basado en Tyr3-Octreotide, empleando acido hidrazinonicotinico (HYNIC) como ligando para el tecnecio y EDDA como coligando ha obtenido buenos resultados en ensayos preclinicos y posteriormente fue desarrollada una formulacion para la preparacion de kits liofilizados. DISENO: descripcion de un estudio de investigacion basica de produccion de farmacos. INTER VENCIONES: el peptido de HYNIC-D- Phe3-Tyr3-Octreotide fue sintetizado por el piChem (Graz, Austria), con una pureza quimica > 98%. El pertecnectato 99mTcO4- se ha obtenido del generador ELumatic 99Mo/99mTc de CIS-BIO; los otros reactivos fueron calidad Aldrich-Sigma. El procedimiento se realizo en condiciones asepticas y normas GMP . Se prepararon: EDDA en agua destilada 20mg/ml, el cual se calento por 10 minutos en bano Maria hasta su completa dilucion. Tricina y manitol en agua destilada a una concentracion de 40mg/mL y 100mg/mL respectivamente. Esta solucion se purgo con N2 gaseoso por 15 minutos y se mezclo con la solucion EDDA. Luego se disolvio el HYNIC-TOC en Etanol al 10% a una concentracion final de 0.5?g/?L y SnCl2 en HCl 0.1N (purgado previamente con N2) en una concentracion de 1mg/mL, Esta mezcla se adiciono a la mezcla de EDDA mas tricina y manitol. Mediante un filtro de 0.22 micras y baja union a proteina se dispenso 1 mL de la mezcla anterior en un vial de vidrio para obtener una concentracion final de 20?g de HYNIC-TOC, EDDA 10mg, Tricina 20mg y Manitol 50mg. Se congelo a - 47 grados para posteriormente realizar un ciclo de liofilizacion (liofilizador L YPH-LOCK 18 LABCONCO) durante 24 h. Fueron adicionados, 1.5mL de Na2HPO4 0.2M para reconstitutir el vial de EDDA/HYNIC-TOC y 99mTc de 25-30mCi (0.8-1GBq) en 2 mL de SSN 0.9%; posteriormente se incubo el vial en bano de agua a ebullicion (+/- 92 o C) por 20 min. La disolucion fue rapida, completa y libre de particulas. El pH fue de 6-7 verificado con papel de pH. La pureza radioquimica fue determinada por cromatografia en capa delgada utilizando ITLC-SG y tres solventes: metil-etil-cetona para determinar tecnecio libre (Rf=1), PBS para determinar 99mTc-coligando (Rf=1) y acetonitrilo-agua (1:1) para determinar 99mTc-coloide (Rf=0). Se realizo una prueba de union a proteinas plasmaticas incubando 50uL del peptido marcado (500 uCi y 1 ug del peptido) con 450uL de suero a 37oC durante 15 minutos. Para el control negativo, se mezclaron 50uL del peptido marcado con 450uL de SSN 0.9% y se incubaron bajo las mismas condiciones. Despues de la incubacion, se tomaron 25uL del peptido y se colocaron en una columna de MicrospinR G50 la cual fue centrifugada. Al eluido recogido y a la columna se les midio la actividad en un contador de NaI y se calculo el porcentaje de peptido unido a proteina como el porcentaje del eluido en la columna. Este procedimiento se repitio a los 30 minutos, 1, 2 y 4 horas. Para determinar la estabilidad del plasma se tomaron 25 uL del peptido incubado durante 4 horas y se mezclaron con 25 uL acetonitrilo y se centrifugo a 2000 RPM por 2 min. El eluido se analizo con ITLC en las mismas condiciones descritas para la pureza radioquimica. Las pruebas de esterilidad y apirogenicidad de los kits fueron realizadas por procedimientos farmaceuticos convencionales. CONCLUSIONES: Se han fabricado 3 lotes de 6 viales cada uno; a dos de los 6 viales (de cada lote) se les han realizado los controles de calidad indicados con resultados de calidad optimos. (author)Journal
World Journal of Nuclear Medicine; ISSN 1450-1147; ; v. 7(3); p. 196-197
; v. 7(3); p. 196-197
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