RESUMO
In vivo receptor targeting with radiolabelled peptide-based probes is an attractive approach for the development of novel radiotracers for molecular imaging. This work presents the development and characterization of two novel neuropeptide Y analogues labelled with a positron emitter 68 Ga, for potential use in breast cancer imaging. Both analogues share the same amino acid sequence and were derivatized with NOTA through either a lysine linker (L1) or an acetylated lysine (L2). In both cases, a single product with radiochemical purity higher than 95% was obtained. The two complexes were hydrophilic, showed remarkable in vitro stability, good cellular uptake, binding affinity in the nanomolar range and high cellular internalization rate. Biodistribution studies revealed low blood uptake and elimination through the urinary tract. The addition of an acetyl group in the spacer increased the lipophilicity of C2 and modified the reactivity of the ε-amino group of the lysine which resulted in lower protein binding and lower percentage of injected dose in bladder and urine. The tumour versus muscle ratio was (3.8 ± 0.4) for 68 Ga-L1 and (4.7 ± 0.4) for 68 Ga-L2. These results encourage performing further studies in order to complete the evaluation of both tracers as potential radiopharmaceutical for breast cancer imaging.
Assuntos
Neoplasias da Mama/diagnóstico por imagem , Radioisótopos de Gálio/química , Neuropeptídeo Y/química , Compostos Radiofarmacêuticos/química , Aminas/química , Sequência de Aminoácidos , Animais , Transporte Biológico , Cinerradiografia , Feminino , Humanos , Lisina/química , Camundongos Nus , Neoplasias Experimentais , Neuropeptídeo Y/sangue , Neuropeptídeo Y/farmacocinética , Neuropeptídeo Y/urina , Ligação Proteica , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/urina , Coloração e Rotulagem , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent.
Assuntos
Acetamidas/química , Osso e Ossos/diagnóstico por imagem , Compostos Macrocíclicos/química , Compostos Organofosforados/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Acetamidas/sangue , Acetamidas/farmacocinética , Radioisótopos de Gálio , Humanos , Compostos Macrocíclicos/sangue , Compostos Macrocíclicos/farmacocinética , Estrutura Molecular , Compostos Organofosforados/sangue , Compostos Organofosforados/farmacocinética , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
PURPOSE: To evaluate the effect of hydroalcoholic extract of A. muricata on biodistribution of two radiopharmaceuticals: sodium phytate and dimercaptosuccinic acid (DMSA), both labeled with 99mtechnetium. METHODS: Twenty four Wistar rats were divided into two treated groups and two controls groups. The controls received water and the treated received 25mg/kg/day of A. muricata by gavage for ten days. One hour after the last dose, the first treated group received 99mTc-DMSA and the second sodium 99mTc-phytate (0.66MBq each group), both via orbital plexus. Controls followed the same protocol. Forty min later, all groups were sacrificed and the blood, kidney and bladder were isolated from the first treated group and the blood, spleen and liver isolated from the second treated group. The percentage of radioactivity per gram of tissue (%ATI/g) was calculated using a gamma counter. RESULTS: The statistical analysis showed that there was a statistically significant decrease (p<0.05) in the uptake of %ATI/g in bladder (0.11±0.01and1.60±0.08), kidney (3.52±0.51and11.84±1.57) and blood (0.15±0.01and 0.54±0.05) between the treated group and control group, respectively. CONCLUSION: The A. muricata hydroalcoholic extract negatively influenced the uptake of 99mTc-DMSA in bladder, kidney and blood of rats.
Assuntos
Annona/química , Ácido Fítico/farmacocinética , Extratos Vegetais/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ácido Dimercaptossuccínico Tecnécio Tc 99m/farmacocinética , Animais , Interações Medicamentosas , Rim/efeitos dos fármacos , Masculino , Ácido Fítico/sangue , Extratos Vegetais/sangue , Compostos Radiofarmacêuticos/sangue , Ratos Wistar , Baço/efeitos dos fármacos , Ácido Dimercaptossuccínico Tecnécio Tc 99m/sangue , Distribuição Tecidual , Bexiga Urinária/efeitos dos fármacosRESUMO
The aim of present investigation was to evaluate biodistribution in healthy animals and in tumor models of the radiopharmaceuticals (99m)Tc-EDDA/tricine-HYNIC-Lys3-Bombesin (HYNIC-Lys3-BN) and (99m)Tc-NA/tricine-HYNIC-Lys3-BN. Biodistribution and pharmacokinetics were carried out over 24 hours. To do so, 24 healthy Wistar rats were used and were administered 37.0 ± 0.8 MBq/rat of each radiopharmaceutical. For the tumor model study, 20 CD-1 nude mice were used and prostate tumors (PC3) were implanted in all the mice. Ten days later, tumor volumes were calculated and 40.00 ± 0.04 MBq/mice of each radiopharmaceutical were injected. Both showed high radiochemical purity: 98.08 ± 0.25% for EDDA/tricine product and 95.1 ± 0.3% for the conjugate with NA/tricine. Uptake of the radiopharmaceutical with NA/tricine was significantly higher in organs of the reticulo-endothelial system of healthy Wistar rats during 24h, specifically in the liver and spleen. Both labeled compounds showed no significant differences between their blood elimination half lives. Average of tumor growth was 0.93 ± 0.02 cm(3) and affinity for tumors showed a growing and specific binding of both radiopharmaceuticals, although it was significantly higher for the EDDA/tricine conjugate. This outcome made it possible to corroborate the direct relationship between the density of gastrin releasing peptide and its receptors (GRPr) and the variation of the accumulation of the radiopharmaceuticals in the tumor. Use of EDDA/tricine as coligand is more appropriate than NA/tricine for labeling of HYNIC-Lys3-BN with (99m)Tc.
Assuntos
Bombesina/análogos & derivados , Ácido Edético/análogos & derivados , Glicina/análogos & derivados , Niacina/farmacocinética , Compostos de Organotecnécio/farmacocinética , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Animais , Bombesina/sangue , Bombesina/farmacocinética , Linhagem Celular Tumoral/transplante , Ácido Edético/farmacocinética , Peptídeo Liberador de Gastrina/análise , Trato Gastrointestinal/diagnóstico por imagem , Glicina/farmacocinética , Rim/diagnóstico por imagem , Ligantes , Fígado/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Masculino , Camundongos , Camundongos Nus , Compostos de Organotecnécio/sangue , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Cintilografia , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Receptores da Bombesina/análise , Baço/diagnóstico por imagem , Distribuição TecidualRESUMO
Several dosimetric methods have been proposed for estimating red marrow absorbed dose (RMAD) when radionuclide therapy is planned for differentiated thyroid cancer, although to date, there is no consensus as to whether dose calculation should be based on blood-activity concentration or not. Our purpose was to compare RMADs derived from methods that require collecting patients' blood samples versus those involving OLINDA/EXM software, thereby precluding this invasive procedure. This is a retrospective study that included 34 patients under treatment for metastatic thyroid disease. A deviation of <10 % between RMADs was found, when comparing the doses from the most usual invasive dosimetric methods and those from OLINDA/EXM. No statistical difference between the methods was discovered, whereby the need for invasive procedures when calculating the dose is questioned. The use of OLINDA/EXM in clinical routine could possibly diminish data collection, thus giving rise to a simultaneous reduction in time and clinical costs, besides avoiding any kind of discomfort on the part of the patients involved.
Assuntos
Medula Óssea/metabolismo , Radioisótopos do Iodo/farmacocinética , Dosagem Radioterapêutica , Software , Neoplasias da Glândula Tireoide/radioterapia , Absorção , Adulto , Idoso , Medula Óssea/efeitos da radiação , Feminino , Humanos , Radioisótopos do Iodo/sangue , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/secundárioRESUMO
PURPOSE: People consume vegetables without the knowledge of the side effects of the biological and chemical contents and interactions between radiopharmaceuticals and herbal extract. To this end, current study is focused on the effects of broccoli extract on biodistribution of radiolabeled glucoheptonate (99mTc-GH) and radiolabeling of blood components. METHODS: GH was labeled with 99mTc. Quality control studies were done utilizing TLC method. Biodistribution studies were performed on male rats which were treated via gavage with either broccoli extract or SF as control group for 15 days. Blood samples were withdrawn from rats' heart. Radiolabeling of blood constituents performed incubating with GH, SnCl2 and 99m Tc. RESULTS: Radiochemical yield of 99mTc-GH is 98.46±1.48 percent (n=8). Biodistribution studies have shown that according to the control, the treated group with broccoli has approximately 10 times less uptake in kidney. The percentage of the radioactivity ratios of the blood components is found to be same in both groups. CONCLUSIONS: Although there is no considerable effect on the radiolabeling of blood components, there is an outstanding change on the biodistribution studies especially on kidneys. The knowledge of this change on kidney uptake may contribute to reduce the risk of misdiagnosis and/or repetition of the examinations in Nuclear Medicine.
OBJETIVO: As pessoas consomem verduras sem o conhecimento dos efeitos colaterais dos conteúdos biológicos e químicos e interações entre os medicamentos radiofarmacêuticos e os extratos vegetais. Para este fim, o estudo atual é focado sobre os efeitos do extrato de brócolis na biodistribuição do fármaco glucoheptonato (99mTc-GH) e da marcação de componentes do sangue. MÉTODOS: GH foi marcado com 99mTc. Estudos de controle de qualidade foram feitos utilizando o método do TLC. Os estudos de biodistribuição foram realizados em ratos machos que foram tratados por gavagem com um extrato de brócolis ou SF como grupo controle para 15 dias. Amostras de sangue foram retiradas do coração de ratos. Marcação de constituintes sanguíneos realizados incubação com SnCl2 GH e 99mTc. RESULTADOS: Radioquímica rendimento de 99mTc-GH é 98,46 ± 1,48 por cento (n = 8). Os estudos de biodistribuição mostraram que de acordo com o controle, o grupo tratado com brócolis tem aproximadamente 10 vezes menor absorção no rim. O percentual do ratio de radioatividade dos componentes do sangue é encontrado para ser igual nos dois grupos. CONCLUSÕES: Embora não haja nenhum efeito considerável sobre a marcação dos componentes do sangue há uma mudança notável na biodistribuição especialmente nos rins. O conhecimento desta mudança na captação de rim pode contribuir para reduzir o risco de erro diagnóstico e/ou a repetição dos exames de Medicina Nuclear.
Assuntos
Animais , Masculino , Ratos , Células Sanguíneas/metabolismo , Brassica/química , Compostos de Organotecnécio/farmacocinética , Extratos Vegetais/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Açúcares Ácidos/farmacocinética , Especificidade de Órgãos , Compostos de Organotecnécio/sangue , Extratos Vegetais/sangue , Ratos Wistar , Compostos Radiofarmacêuticos/sangue , Açúcares Ácidos/sangue , Fatores de Tempo , Distribuição TecidualRESUMO
PURPOSE: People consume vegetables without the knowledge of the side effects of the biological and chemical contents and interactions between radiopharmaceuticals and herbal extract. To this end, current study is focused on the effects of broccoli extract on biodistribution of radiolabeled glucoheptonate ((99m)Tc-GH) and radiolabeling of blood components. METHODS: GH was labeled with (99m)Tc. Quality control studies were done utilizing TLC method. Biodistribution studies were performed on male rats which were treated via gavage with either broccoli extract or SF as control group for 15 days. Blood samples were withdrawn from rats' heart. Radiolabeling of blood constituents performed incubating with GH, SnCl2 and (99m) Tc. RESULTS: Radiochemical yield of (99m)Tc-GH is 98.46±1.48 % (n=8). Biodistribution studies have shown that according to the control, the treated group with broccoli has approximately 10 times less uptake in kidney. The percentage of the radioactivity ratios of the blood components is found to be same in both groups. CONCLUSIONS: Although there is no considerable effect on the radiolabeling of blood components, there is an outstanding change on the biodistribution studies especially on kidneys. The knowledge of this change on kidney uptake may contribute to reduce the risk of misdiagnosis and/or repetition of the examinations in Nuclear Medicine.
Assuntos
Células Sanguíneas/metabolismo , Brassica/química , Compostos de Organotecnécio/farmacocinética , Extratos Vegetais/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Açúcares Ácidos/farmacocinética , Animais , Masculino , Especificidade de Órgãos , Compostos de Organotecnécio/sangue , Extratos Vegetais/sangue , Compostos Radiofarmacêuticos/sangue , Ratos , Ratos Wistar , Açúcares Ácidos/sangue , Fatores de Tempo , Distribuição TecidualRESUMO
Cassia angustifolia Vahl (senna) is a natural product that contains sennosides, which are active components that affect the intestinal tract and induce diarrhea. Authors have shown that senna produces DNA (deoxyribonucleic acid) lesions in Escherichia coli cultures and can act as an antifungal agent. Natural drugs can alter the labeling of blood constituents with technetium-99m (99mTc) and can affect the biodistribution of radiopharmaceuticals. In this work, we have evaluated the influence of a senna extract on the radiolabeling of blood constituents and on the biodistribution of the radiopharmaceutical sodium pertechnetate (Na99mTcO4)in Wistar rats. Twelve animals were treated with senna extract for 7 days. Blood samples were withdrawn from the animals and the radiolabeling procedure was carried out. The senna extract did not modify the radiolabeling of the blood constituents. A biodistributional assay was performed by administering Na99mTcO4 and determining its activity in different organs and in blood. The senna extract altered the biodistribution of Na99mTcO4 in the thyroid, liver, pancreas, lungs and blood. These results are associated with properties of the chemical substances present in the aqueous senna extract. Although these assays were performed in animals, our findings suggest that caution should be exercised when nuclear medicine examinations using Na99mTcO4 are conducted in patients who are using senna extract.
Assuntos
Células Sanguíneas/efeitos dos fármacos , Compostos Radiofarmacêuticos/farmacocinética , Extrato de Senna/farmacologia , Senna/química , Pertecnetato Tc 99m de Sódio/farmacocinética , Animais , Células Sanguíneas/metabolismo , Masculino , Modelos Animais , Compostos Radiofarmacêuticos/sangue , Ratos , Ratos Wistar , Pertecnetato Tc 99m de Sódio/sangue , Fatores de TempoRESUMO
The present work describes the preparation, labeling, physicochemical characterization, and in vitro cytotoxic evaluation of long circulating pH-sensitive liposomes containing (159)Gd-DTPA-BMA. These liposomes were successfully obtained and submitted to neutron irradiation for gadolinium labeling. Their size, distribution, and homogeneity were determined by photon correlation spectroscopy, while their zeta potential was determined by laser Doppler anemometry. The morphology and structural organization were evaluated by atomic force microscopy. The stability and release profiles of Gd-DTPA-BMA in the liposomes were determined in vitro in Dubelco's Modified Eagle's Medium and rat serum at 70%. The results showed that liposomes remained physically stable after 8 h of irradiation and presented a low release profile of its content in two different biological mediums. The formulation of liposomes containing (159)Gd and its respective controls were evaluated by in vitro cytotoxicity against tumor cells RT2. The results showed increased cytotoxic activity of approximately 1170 fold in relation to free Gd-DTPA-BMA.
Assuntos
Gadolínio DTPA/química , Compostos Radiofarmacêuticos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Físico-Química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Estabilidade de Medicamentos , Gadolínio DTPA/administração & dosagem , Gadolínio DTPA/sangue , Gadolínio DTPA/farmacologia , Técnicas In Vitro , Lipossomos , Camundongos , Microscopia de Força Atômica , Estrutura Molecular , Tamanho da Partícula , Fótons , Radioisótopos , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacologia , Ratos , Solubilidade , Propriedades de SuperfícieRESUMO
Cassia angustifolia Vahl (senna) is a natural product that contains sennosides, which are active components that affect the intestinal tract and induce diarrhea. Authors have shown that senna produces DNA (deoxyribonucleic acid) lesions in Escherichia coli cultures and can act as an antifungal agent. Natural drugs can alter the labeling of blood constituents with technetium-99m (99mTc) and can affect the biodistribution of radiopharmaceuticals. In this work, we have evaluated the influence of a senna extract on the radiolabeling of blood constituents and on the biodistribution of the radiopharmaceutical sodium pertechnetate (Na99mTcO4)in Wistar rats. Twelve animals were treated with senna extract for 7 days. Blood samples were withdrawn from the animals and the radiolabeling procedure was carried out. The senna extract did not modify the radiolabeling of the blood constituents. A biodistributional assay was performed by administering Na99mTcO4 and determining its activity in different organs and in blood. The senna extract altered the biodistribution of Na99mTcO4 in the thyroid, liver, pancreas, lungs and blood. These results are associated with properties of the chemical substances present in the aqueous senna extract. Although these assays were performed in animals, our findings suggest that caution should be exercised when nuclear medicine examinations using Na99mTcO4 are conducted in patients who are using senna extract.
Assuntos
Animais , Masculino , Ratos , Células Sanguíneas/efeitos dos fármacos , Compostos Radiofarmacêuticos/farmacocinética , Extrato de Senna/farmacologia , Senna/química , /farmacocinética , Células Sanguíneas/metabolismo , Modelos Animais , Ratos Wistar , Compostos Radiofarmacêuticos/sangue , /sangue , Fatores de TempoRESUMO
A computer program based on a Bayesian statistical model has been developed for calculating tracer clearance from any number of plasma samples drawn at arbitrary time intervals. Bayesian prior parameters were calculated from clinical data for Tc99m-MAG3, Tc99m-EC, I131-OIH, Tc99m-DTPA, and Yb169-DTPA and then used to calculate clearance from prospective data. Clearance estimates using only one or two plasma samples were found to closely approximate the results of using multiple samples. When only one or a few samples are available, the program supplements the observed data by a Bayesian prior probability distribution (based on prior clinical measurements) to achieve agreement with multisample clearance. When many points are available, the observed data overwhelm the prior probability, and results approach those of conventional curve fitting but with less sensitivity to bad data points and less risk of fitting failure.
Assuntos
Humanos , Compostos Radiofarmacêuticos/farmacocinética , Rim/fisiologia , Simulação por Computador , Teorema de Bayes , Glomérulos Renais/fisiologia , Itérbio/farmacocinética , Modelos Estatísticos , Probabilidade , Testes de Função Renal , Compostos Radiofarmacêuticos/sangue , Radioisótopos do Iodo/farmacocinética , Taxa de Depuração Metabólica , Tecnécio/farmacocinética , Túbulos Renais/fisiologiaRESUMO
PURPOSE: The labeling of red blood cells (C) with 99mTc is employed in clinical nuclear medicine for a variety of diagnostic procedures. Drugs can alter this labeling method and modify the disposition of the radiopharmaceuticals. In this paper, the influence of glucantime on the labeling of blood constituents with 9mTc was reported. METHODS: Blood was withdrawn from rats and incubated with glucantime. Stannous chloride and 99mTc were added. After centrifugation, plasma (P) and (C) were isolated. Samples of P and C were precipitated with TCA 5%, centrifuged and insoluble (IF) and soluble fractions (SF) separated. The percentages of total activity injected (%ATI) in C, IF-P and IF-C were calculated (p < 0.05). RESULTS: The %ATI on C decreased from control to following concentrations of glucantime (6.25%; 12.5%; 25%; 50%; 100%), respectively: 94.06 +/- 1.29 (control) to 77.15 +/- 2.79; to 76.68 +/- 1.88; to 75.15 +/- 2.79; to 72.64 +/- 4.40 and to 63.05 +/- 3.84. On IF-C the %ATI decreased from control to all the concentrations of glucantime (3.125%;6.25%; 12.5%; 25%; 50%; 100%), respectively: 93.34 +/- 1.18 (control) to 78.81 +/- 2.76; to 74.76 +/- 4.82; to 74.02 +/- 5.32; to 64.35 +/- 4.82; to 62.81 +/- 1.97 and to 54.55 +/- 3.58. CONCLUSIONS: This effect was probably due to products present in this drug that may complex with ions (Sn(+2) and 99mTcO4) or have a direct or indirect effect on intracellular stannous ion concentration.
Assuntos
Eritrócitos/diagnóstico por imagem , Meglumina/farmacologia , Compostos Organometálicos/farmacologia , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Animais , Proteínas Sanguíneas/metabolismo , Eritrócitos/efeitos dos fármacos , Marcação por Isótopo , Masculino , Meglumina/sangue , Antimoniato de Meglumina , Compostos Organometálicos/sangue , Cintilografia , Compostos Radiofarmacêuticos/sangue , Ratos , Estatísticas não Paramétricas , Tecnécio/sangue , Compostos de Estanho/sangue , Distribuição Tecidual/efeitos da radiaçãoRESUMO
OBJETIVO: A marcação de hemácias sangüíneas (C) com 99mTc é muito utilizada nos procedimentos diagnósticos na medicina nuclear. Drogas podem alterar este método de marcação e modificar a biodisponibilidade de radiofármacos. Neste trabalho, foi avaliada a influência de glucantime na marcação de elementos sangüíneos com 99mTc. MÉTODOS: Sangue foi retirado de ratos e incubado com glucantime. Adicionou-se cloreto estanoso e 99mTc. Após centrifugação, plasma (P) e (C) foram isolados. Amostras de P e C foram precipitadas com TCA 5 por cento, centrifugadas e separadas em frações solúveis (FS) e insolúveis (FI). Os percentuais de atividade total injetada (por cento ATI) em C, FI-P e FI-C foram calculados (p<0,05). RESULTADOS: O %ATI em C diminuiu, em relação ao controle, nas seguintes concentrações de glucantime (6,25 por cento;12,5 por cento; 25 por cento; 50 por cento; 100por cento), respectivamente: 94,06±1,29 (controle) para 77,15±2,79; para 76,68±1,88; para 75,15±2,79; para 72,64±4,40 e para 63,05±3,84. Em FI-C, o %ATI diminuiu, em relação ao controle, em todas as concentrações de glucantime (3,125 por cento; 6,25 por cento; 12, 5 por cento; 25 por cento; 50 por cento; 100 por cento), respectivamente: 93,34±1,18 (controle) para 78,81±2,76; para 74,76±4,82; para 74,02±5,32; para 64,35±4,82; para 62,81±1,97 e para 54,55±3,58. CONCLUSÕES: Este efeito provavelmente foi devido a produtos presentes nesta droga que podem se complexar com íons (Sn+2 e 99mTcO-4) ou ter um efeito direto ou indireto na concentração intracelular do íon estanoso.
Assuntos
Animais , Masculino , Ratos , Eritrócitos , Meglumina/farmacologia , Compostos Organometálicos/farmacologia , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Proteínas Sanguíneas/metabolismo , Eritrócitos/efeitos dos fármacos , Marcação por Isótopo , Meglumina/sangue , Compostos Organometálicos/sangue , Compostos Radiofarmacêuticos/sangue , Estatísticas não Paramétricas , Tecnécio/sangue , Compostos de Estanho/sangue , Compostos de Estanho , Distribuição Tecidual/efeitos da radiaçãoRESUMO
99mTc-UBI 29-41 is an antimicrobial peptide fragment that directly radiolabeled with 99mTc shows high in vitro and in vivo stability, rapid background clearance, minimal accumulation in non-target tissues and rapid detection of infection sites. Molecular mechanics (MM) calculation has been an essential tool in explaining experimental results associated with molecular recognition and stability. This work is an attempt to explain the 99mTc-UBI 29-41 specificity for bacteria and to understand from a structural point of view, the experimental results indicative of a molecular recognition and stability not well favored for two other cationic peptides (99mTc-Tat-1-Scr and 99mTc-Tat-2-Scr ) used as control. Structures of 99mTc-UBI, 99mTc-Tat-1-Scr, 99mTc-Tat-2-Scr and of the corresponding free cationic peptides were built and the optimized structures, in the best stable configurations, were calculated by a MM procedure. In order to correlate the calculated and experimental results, in vitro stability tests with cysteine challenge and stability to dilution in human serum and in saline solution, were performed for the three labeled cationic peptides. The three complexes can be represented by the general formula [Tc(V)(O)(H2O)2(Lysn=1,2-Argn=0,1-peptide)]10+,11+. The potential energies were 104.5, 95.6 and 90.8 kcal/mol for 99mTc-Tat-1-Scr, 99mTc-Tat-2-Scr and 99mTc-UBI 29-41, respectively. Experimental and calculated results were in good agreement. It is thus possible to predict and explain that in similar solution media 99mTc-Tat-2-Scr would be more stable than 99mTc-Tat-1-Scr and why 99mTc-UBI shows the highest stability. In conclusion, the in vitro specific binding to bacteria and the accumulation at infection sites in humans of 99mTc-labeled UBI could be the result of its high thermodynamic stability, selectivity and stereospecificity.
Assuntos
Modelos Moleculares , Compostos de Organotecnécio/sangue , Compostos de Organotecnécio/química , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/química , Infecções Bacterianas/diagnóstico por imagem , Simulação por Computador , Estabilidade de Medicamentos , Humanos , Ligação Proteica , Conformação Proteica , Cintilografia , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/química , Relação Estrutura-AtividadeRESUMO
Monoclonal Antibody (mAb) ior C5 is a murine IgG(1) that recognizes the tumor associated antigen (TAA) ior C2, a cell surface O-linked glycoprotein carbohydrate chain not present in most normal tissues and homogeneously expressed in the cytoplasm of normal colon epithelium and heterogeneously expressed in more than 83% of primary colorectal carcinomas. This study was designed to investigate the pharmacokinetics, biodistribution and the absorbed radiation doses of (99m)Tc-labeled mAb ior C5 antibody in colorectal tumor patients. Ten patients were administered 3 mg of anti-O-linked glycoprotein carbohydrate chain TAA ior C2 murine monoclonal antibody ior C5 radiolabeled with (99m)Tc activity of 1435.0 +/- 123 MBq by intravenous (i.v.) bolus infusion. Blood and urine samples were collected from 4 out of 10 patients at timed intervals from 10 min and up to 24 h after injection of the (99m)Tc-labeled mAb ior C5 for pharmacokinetic studies. Whole body images were taken in 5 out of 10 patients for quantitative normal organ biodistribution and dosimetry studies and planar anterior and posterior and SPECT images were taken in 5 out of 10 patients for tumor localization. Mean absorbed doses were estimated using the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The effective dose equivalent (EDE) and effective dose (ED) were calculated as prescribed in International Commission on Radiological Protection (ICRP) publications 30 and 60. Plasma disappearance curves of (99m)Tc-labeled murine antibody ior C5 were best fit by a two-compartment model in all patients with (t(1/2alpha)) of 4.32 +/- 2.18 h and (t(1/2beta) of 32.6 +/- 3.82 h. Among the main target organs, accumulation of the radiolabeled antibody was found in liver (9.38 +/- 0.80%), heart (8.92 +/- 0.94%) and spleen (1.37 +/- 0.30%) at 5 min post-administration. These values were reduced at 24 h to (5.91 +/- 0.73%) and (0.62 +/- 0.22%), respectively, for the heart and spleen and increased to (9.78 +/- 1.99%) for liver. Estimates of radiation absorbed dose to normal organs in rad/mCi administered were: whole body, 0.0181 +/- 0.0017; heart wall, 0.0768 +/- 0.0090; kidneys, 0.0530 +/- 0.0260; liver, 0.0565 +/- 0.0109 and spleen, 0.0540 +/- 0.0128. The effective dose equivalent and effective dose estimates for adults were 0.0314 +/- 0.0031 and 0.0249 +/- 0.0027 rem/mCi administered. This feasibility study indicates that the O-linked glycoprotein carbohydrate chain TAA ior C2 is expressed in primary and metastatic colorectal carcinomas and shows very limited expression in normal adult tissues. The very good pattern of biodistribution of (99m)Tc-labeled mAb ior C5 in patients will allow imaging of colorectal carcinoma lesions.
Assuntos
Anticorpos Monoclonais/farmacocinética , Neoplasias Colorretais/diagnóstico , Complemento C5/farmacocinética , Dosagem Radioterapêutica , Tecnécio/farmacocinética , Distribuição Tecidual , Idoso , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos Glicosídicos Associados a Tumores/química , Antígenos Glicosídicos Associados a Tumores/genética , Complemento C5/administração & dosagem , Cuba , Estudos de Viabilidade , Feminino , Meia-Vida , Corpo Humano , Humanos , Injeções Intravenosas , Masculino , Camundongos , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/urina , Tecnécio/administração & dosagemRESUMO
The aim of this work was to synthesize [166Dy]Dy/166Ho-DTPA-Biotin to evaluate its potential as a new radiopharmaceutical for targeted radiotherapy. Dysprosium-166 (166Dy) was obtained by neutron irradiation of enriched 164Dy(2)O(3) in a Triga Mark III reactor. The labeling was carried out in aqueous media at pH 8.0 by addition of [166Dy]DyCl(3) to diethylenetriaminepentaacetic-alpha,omega-bis(biocytinamide) (DTPA-Biotin). Radiochemical purity was determined by high-performance liquid chromatography (HPLC) and TLC. The biological integrity of labeled biotin was studied evaluating its avidity for avidin in an agarose column and by size-exclusion HPLC analysis of the radiolabeled DTPA-Biotin with and without the addition of avidin. Stability studies against dilution were carried out by diluting the radiocomplex solution with saline solution and with human serum at 37 degrees C for 24 h. The [166Dy]Dy/166Ho-labeled biotin was obtained with a 99.1+/-0.6% radiochemical purity. In vitro studies demonstrated that [166Dy]Dy/166Ho-DTPA-Biotin is stable after dilution in saline and in human serum and no translocation of the daughter nucleus occurs subsequent to beta(-) decay of 166Dy that could produce release of 166Ho(3+). Avidity of labeled biotin for avidin was not affected by the labeling procedure. Biodistribution studies in normal mice showed that the [166Dy]Dy/166Ho-DTPA-Biotin has a high renal clearance. In conclusion, the radiolabeled biotin prepared in this investigation has adequate properties to work as a stable in vivo generator system for targeted radiotherapy.
Assuntos
Biotina/análogos & derivados , Biotina/química , Disprósio/química , Hólmio/química , Ácido Pentético/análogos & derivados , Ácido Pentético/química , Compostos Radiofarmacêuticos/química , Animais , Biotina/sangue , Biotina/farmacocinética , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Estabilidade de Medicamentos , Feminino , Injeções Intravenosas , Marcação por Isótopo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Pentético/sangue , Ácido Pentético/farmacocinética , Radioisótopos/química , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
Sechium edule (chayotte) is used as food or as medication in popular medicine. The labeling of blood elements with technetium-99m (99mTc) has been altered by drugs (synthetic and natural). Some authors have reported biological effects concerning the chayotte. We have evaluated the influence of chayotte extracts (macerated and infusion) on the labeling of blood elements with 99mTc. In vitro study, blood was incubated with the extracts, (6.25, 12.5, 25, 50 and 100% v/v). In in vivo study, the animals were treated with the extracts (100% v/v), as drinking water (15 and 60 days) and samples of blood were withdrawn. The blood samples were incubated with stannous chloride and with 99mTc. Plasma (P) and blood cells (BC) were isolated, also precipitated with trichloroacetic acid and soluble (SF) and insoluble fractions (IF) separated. There was a (p < 0.05) decrease in the radioactivity in BC, IF-BC and IF-P with the infusion (100%) and a slight decrease in the uptake of 99mTc by BC and a strong decrease in the fixation in IF-P with the macerated when the extracts were administrated in vivo (15 days). In 60 days, there was a decrease in BC (98.77 to 53.53%), in IF-BC (90.36 to 21.20%) and in IF-P (77.20 to 11.01%). In vitro study no alterations on the labeling of blood elements were found, however, we have found alterations on the fixation of 99mTc in the in vivo study, probably, due to the metabolization of chayotte capable to induce the generation of active metabolites.
Assuntos
Proteínas Sanguíneas/metabolismo , Cucurbitaceae/química , Eritrócitos/efeitos dos fármacos , Eritrócitos/diagnóstico por imagem , Tecnécio/sangue , Animais , Eritrócitos/metabolismo , Técnicas In Vitro , Extratos Vegetais/farmacologia , Cintilografia , Compostos Radiofarmacêuticos/sangue , Ratos , Ratos Wistar , SolubilidadeRESUMO
The use of eggplant has been suggested to treat different diseases. We studied the effect of eggplant extract on the labeling of red blood cells (RBC) and plasma proteins with technetium-99m (Tc-99m) and on biodistribution of sodium pertechnetate (Tc-99m) in rats. Blood was incubated with an eggplant extract (final concentrations 3.12 to 250.00 mg/ml) for 60 min. Then, stannous chloride (SnCl2) (0.06 or 1.2 microg/ml) and Tc-99m, as sodium pertechnetate, were added. Samples of RBC and plasma (P) were separated and also precipitated and soluble (SF) and insoluble (IF) fractions were isolated. The percent of radioactivity (%ATI) in the fractions was calculated. In the biodistribution study, Wistar rats were treated with eggplant extract (300 mg/ml) for 4 weeks, in drinking water. Tc-99m was administered in the rats, after 90 min they were sacrificed and organs and blood were isolated. When 0.06 microg/ml SnCl2 was used, eggplant extract: i/ inhibited the label of RBC (97.14 +/- 2.01 to 52.21 +/- 3.97%ATI), ii/ decreased the labeling in IF-P from 38.79 +/- 11.73 to 5.49 +/- 2.65%ATI, and iii/ diminished the labeling in IF-RBC from 90.04 +/- 2.65 to 46.17 +/- 9.49%ATI. This inhibitory effect was not observed with SnCl2 1.2 microg/ml. In the biodistribution study, the %ATI: i/ increased in the liver from 2.15 +/- 0.54 to 3.11 +/- 1.29 and ii/ in the other organs the Tc-99m uptake was not modified. The uptake of Tc-99m in red blood cells protein (IF-RBC) decreased from 66.62 +/- 19.67 to 31.66 +/- 8.84%. It is possible to suggest that some components of the eggplant extract present an oxidation power able to alter the fixation of the Tc-99m on the blood elements. Moreover, as eggplant is metabolized in the liver, this fact could justify the alteration of the uptake in this organ.
Assuntos
Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Pertecnetato Tc 99m de Sódio/sangue , Pertecnetato Tc 99m de Sódio/farmacocinética , Solanum melongena/química , Animais , Proteínas Sanguíneas/metabolismo , Eritrócitos/diagnóstico por imagem , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Técnicas In Vitro , Extratos Vegetais/farmacologia , Cintilografia , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
It is estimated that about 2.5 million people only in the United States are affected by epilepsy. Labelled red blood cells (RBC) and plasma proteins (PP) are used for several evaluations in nuclear medicine and drugs affecting those labelings have previously been described. The aim of this study was to evaluate whether the most popular antiseizure drugs interfere with the 99mTc labeling process of RBC and PP. Heparinized blood withdrawn from Wistar rats was incubated with phenobarbital (0.2, 2, 20, 200, 2,000 microg/ml), phenytoin (0.15, 1.5, 15, 150, 1,500 microg/ml), carbamazepine (0.7, 7, 70 microg/ml), clonazepam (0.5, 5, 50, 500 microg/ml) or valproic acid (0.5, 5, 50, 500 microg/ml) for I hr. Stannous chloride (SnCl2), in two different concentrations (0.012 or 1.2 microg/ml) and 99mTc were added. Plasma and cellular fractions were isolated by centrifugation, soluble and insoluble fractions were separated by trichloroacetic acid precipitation. The percentage of radioactivity was calculated for each fraction. Statistical analysis was performed with ANOVA and Dunnet tests. The analysis of the results has shown that phenobarbital (2,000 microg/ml) and clonazepam (50 microg/ml) significantly have reduced the RBC labeling efficiency when it was used the optimal SnCl2 concentration (1.2 microg/ml) and clonazepam (5, 50 microg/ml) has significantly decreased the PP labeling efficiency with 99mTc. Phenytoin (1,500 microg/ml) has decreased the RBC labeling efficiency when the experiments were carried out with a small SnCl2 concentration (0.012 microg/ml). We can suggest that with this in vitro assay, at the therapeutic level of phenytoin, phenobarbital, carbamazepine and valproic acid will not interfere on the 99mTc labeling process of RBC. Interference is displayed at higher phenobarbital concentrations (2,000 microg/ml). However, humans do not tolerate this concentration. On the other hand, a decreased RBC and PP labeling efficiency with 99mTc may be expected for clonazepam at therapeutic levels.
Assuntos
Anticonvulsivantes/efeitos adversos , Proteínas Sanguíneas/efeitos dos fármacos , Proteínas Sanguíneas/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/diagnóstico por imagem , Tecnécio/sangue , Animais , Clonazepam/efeitos adversos , Eritrócitos/metabolismo , Humanos , Técnicas In Vitro , Cintilografia , Compostos Radiofarmacêuticos/sangue , Ratos , Ratos WistarRESUMO
UNLABELLED: Glomerular filtration rate (GFR) is an important index of renal function. The aim of this study was to compare the GFR with 99m Tc. DTPA without urine collection estimated with three, two and single-sample methods. We studied 148 patients (54 women and 94 men, 3-84 years old) with diverse renal diseases. After intravenous administration of Tc99m DTPA three (90-120-180 min. Method 1; n = 44) or two (120 and 180 min or 180 and 240 min Method 2, n = 104) blood samples were taken. The GFR (ml/min) were calculated using monoexponential analysis, or with only the sample of the 180 or 240 min with the methods of Jacobsson, Russel, Groth-Aasted, Dakubu and Constable. RESULTS: 1) In 37/148 (25%) the GFR by Method 1-2 was less than 30 ml/min. All the single-sample methods did not perform well. 2) in 107/148 (75%) the GFR using method 1 and 2 was superior to 30 ml/min. The single sample methods showed clinically acceptable absolute error differences with method 1 and 2. However, we cannot suggest a preferable one single sample method that covers all the range of GFR that we analyzed. In conclusion, the 2 sample technique provides an estimate of GFR and we also suggest ultrafiltering the plasma before measuring radioactivity to give better accuracy in calculating GFR.