RESUMEN
INTRODUCTION: Systemic amyloidosis is a rare disease caused by the deposition of amyloid fibrils in various organs. Amyloid-targeted radiopharmaceuticals have been developed and applied to diagnose systemic amyloidosis peripherally; however, high-contrast imaging has not been achieved because of the high background signals in normal organs. To overcome this problem, we designed an amyloid-targeted radioiodinated probe 1 with a metabolizable linkage (ester bond) to release of radiolabeled metabolites (m-iodohippuric acid) in normal organs that could be rapidly excreted in the urine. METHODS: Compound 1 was synthesized by conjugating 2-(4-(methylamino)phenyl)benzo[d]thiazol-6-ol, an amyloid-targeting compound, with m-iodohippuric acid. [125I]1 was synthesized via iododestannylation using a tributyltin precursor. Mouse models of amyloid A (AA) amyloidosis, a type of systemic amyloidosis, were prepared by administering amyloid-enhancing factor to mice and used for in vitro autoradiography using organ sections and in vivo evaluation. RESULTS: [125I]1 was obtained with a radiochemical yield of 59% and radiochemical purity of over 95%. An in vitro autoradiographic study demonstrated that [125I]1 specifically binds to amyloid in the splenic tissue. Upon administration to normal mice, [125I]1 was distributed to organs throughout the body, followed by the rapid excretion of radioactivity in the urine as m-[125I]iodohippuric acid. Furthermore, ex vivo autoradiography showed that [125I]1 bound to the amyloid formed around the follicles in the spleens of AA amyloidosis model mice. CONCLUSION: These results suggest that the interposition of a metabolizable linkage between an amyloid-targeting moiety and a radiolabeled hippuric acid would be useful in the design of radiopharmaceuticals for high-contrast imaging of systemic amyloidosis.
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Amiloidosis , Radiofármacos , Ratones , Animales , Radiofármacos/química , Ácido Yodohipúrico , Amiloidosis/diagnóstico por imagen , Amiloide/metabolismoRESUMEN
Graves' disease (GD), the most common cause of hyperthyroidism, is an autoimmune disease directly caused by circulating autoantibodies that bind and activate the TSH receptor, inducing metabolic activation of the thyroid gland; this may be associated with important cardiac (atrial fibrillation) and ocular (ophthalmopathy) complications. Treating GD with real curative intent implies the full elimination of the functioning thyroid parenchyma using surgery or radioactive iodine therapy (RAI). RAI has been used in humans with hyperthyroidism since 1941, thanks to the pioneering work of a physician (Dr. Saul Hertz) and a physicist (Dr. Arthur Roberts). The rationale of RAI is based on the effect of radiation of 131I on target cells leading to DNA damage, both directly, through breakage of molecular bonds, and indirectly through the formation of free radicals. In particular, irradiation causes a broad spectrum of cellular damage due to the production of reactive oxygen species and lipid peroxidation of the plasma membrane. Thus, RAI-related cellular death takes place through both apoptosis and necrosis. The aim of this review was to summarize indications, efficacy, safety profile, and dosimetric aspects of RAI treatment in patients affected by GD.
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Enfermedad de Graves/radioterapia , Radioisótopos de Yodo/química , Apoptosis/efectos de la radiación , Línea Celular , Femenino , Enfermedad de Graves/fisiopatología , Enfermedad de Graves/cirugía , Humanos , Radioisótopos de Yodo/farmacología , Ácido Yodohipúrico/química , Peroxidación de Lípido/efectos de la radiación , Masculino , Especies Reactivas de Oxígeno/metabolismo , Glándula TiroidesRESUMEN
STUDY DESIGN: Retrospective study of a prospectively collected database at one center. OBJECTIVES: Assess the outcomes and complications of adult spinal deformity (ASD) surgery in patients that are 75 years and older compared with patients of 65-75 years of age. With increasing amounts of ASD surgery being performed on elderly patients, it is important to assess how age plays a factor in corrective reconstruction surgery. METHODS: Inclusion criteria for the study were all patients ≥ 65 years of age that underwent thoracolumbar deformity correction involving ≥ four levels at a single institution by two surgeons. Patients were divided based on age into 65-74.9 or ≥ 75 groups. Radiographic parameters were measured preoperatively, postoperatively, and at 2 years. The Numeric Rating Scale (NRS) and Oswestry Disability Index (ODI) were collected preoperatively, at 1 year, and 2 years. Comorbidities included were based around the Charlson Comorbidity Index (CCI) and compared to the incidence of complications and need for further surgery. RESULTS: Both age groups had improvements in their radiographic parameters postoperatively which was maintained at 2 years. Comparing the different age groups with similar comorbidity burden in regard to complications and need for additional surgery yielded no statistically significant difference between groups. Both groups had comparable decreases in NRS and increases in ODI at 2 years. CONCLUSIONS: Analysis of our study population indicates that there is no difference between the outcomes and complications of deformity surgery in patients 75 years and older when compared to a younger elderly population. It also does not appear that a ≥ 3 comorbidity burden has a significant impact on the complications or need for additional surgery in our elderly spinal deformity surgery population. LEVEL OF EVIDENCE: Level IV.
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Vértebras Lumbares/cirugía , Procedimientos Ortopédicos , Procedimientos de Cirugía Plástica , Curvaturas de la Columna Vertebral/cirugía , Vértebras Torácicas/cirugía , Factores de Edad , Anciano , Comorbilidad , Bases de Datos como Asunto , Femenino , Humanos , Incidencia , Ácido Yodohipúrico , Vértebras Lumbares/diagnóstico por imagen , Masculino , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Curvaturas de la Columna Vertebral/diagnóstico por imagen , Curvaturas de la Columna Vertebral/epidemiología , Vértebras Torácicas/diagnóstico por imagen , Factores de Tiempo , Resultado del TratamientoRESUMEN
In our country, the sliding Flexible Intramedullary Nailing is used alone or in combination with Ilizarov frame in children with osteogenesis imperfecta. The study assesses the results of sliding intramedullary nailing in deformity correction in severe types of osteogenesis imperfecta. We retrospectively reviewed 17 consecutive cases (mean age 5.2 y.o.) of types III, IV and VII of osteogenesis imperfecta. In group I (9 patients) the transphyseal FIN was performed using titanium nails. Sliding flexible intramedullary nailing was associated with Ilizarov frame in group II in 8 children. Patients in group I had overall complication rate of 88.9%: proximal nail migration (3), early secondary torsional displacement (4), non-telescoping (12), angular deformity (2), delayed or non-union (2). The reoperation rate was 100%. In group II we observed complications in 6 patients: nail migration (2), bowing of femur (2), non-telescoping (3). The reoperation rate was 87.5%. Flexible intramedullary nailing allows realignment and good functional outcomes. Its major disadvantage is an important complication rate and related reoperation rate. The use of Ilizarov frame provides additional stability and allows early weight-bearing.
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Fémur/cirugía , Fijación Intramedular de Fracturas/métodos , Osteogénesis Imperfecta/cirugía , Adolescente , Clavos Ortopédicos , Niño , Preescolar , Femenino , Fémur/diagnóstico por imagen , Humanos , Lactante , Ácido Yodohipúrico , Masculino , Osteogénesis Imperfecta/diagnóstico por imagen , Reoperación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Para-18F-fluorohippuric acid (18F-PFH) and ortho-124I-iodohippuric acid (124IOIH) were recently identified as potential radiotracers suitable for conducting renography using positron emission tomography (PET). The aim of this work was to estimate preliminary human-equivalent internal radiation dose of 18F-PFH and 124I-OIH using the biodistribution data reported in healthy rats. The results were compared with the absorbed dose data of technetium-99m-mercaptoacetyltriglycine (99mTc- MAG3) as documented in the International Commission on Radiological Protection (ICRP) publication 80. METHODS: The medical internal radiation dose (MIRD) formula was applied to extrapolate data from rats to human and to project the absorbed radiation dose for various organs in humans. S factor was calculated by Monte-Carlo N-particle (MCNP) simulation. RESULTS: Our dose prediction shows that an injection of 18F-PFH or 124I-OIH in humans would result in an estimated effective absorbed dose of 0.09 or 0.17 µSv/MBq respectively for whole body, which is about 135 or 73 times respectively lower than that obtained with an injection of 99mTc-MAG3. All organs except kidneys would receive an estimated effective absorbed dose of <0.1 µSv/MBq for 18F-PFH or 124I-OIH. Kidneys would receive a dose of 0.83 or 0.77 µSv/MBq respectively for 18F-PFH or 124I-OIH. CONCLUSIONS: Our results indicate that 18F-PFH and 124I-OIH would deliver much safer levels and lower radiation doses to the patients compared to 99mTc-MAG3 and warrants a clinical trial to estimate the radiation doses more accurately.
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Hipuratos , Ácido Yodohipúrico , Tomografía de Emisión de Positrones , Dosis de Radiación , Renografía por Radioisótopo/métodos , Animales , Radioisótopos de Flúor , Humanos , Radioisótopos de Yodo , Método de Montecarlo , Ratas , Fármacos Renales , Tecnecio Tc 99m Mertiatida , Distribución TisularRESUMEN
Ortho-[(131)I]iodohippurate [(131)I]OIH (marketed as Hippuran I 131), a gold standard for radionuclide renography, and [(123)I]OIH were in clinical use for decades. Here we radiolabeled OIH with (124)I (a positron emitter) to combine the desirable biological properties of OIH and to enable the use of positron emission tomography (PET) for renography. [(124)I]OIH was synthesized with a slight modification to a previously reported method for the kit preparation of [(123)I]OIH based on the Cu(II) catalyzed isotope-exchange reaction. Our method utilized heating at 120°C under sealed condition in a heating block instead of autoclaving. [(124)I]OIH was obtained with a radiochemical purity of >99.3%, radiochemical yield of 94.5%, and specific activity of ~17 MBq/mg. Biodistribution studies in healthy Sprague Dawley rats revealed results comparable to that of [(131)I]OIH as reported in the literature. The PET-derived [(124)I]OIH renograms revealed an average time-to-peak of 2.8±0.4min and the average time-to-half-maximal activity of 11.4±1.5min, which are also comparable to that of [(131)I]OIH as reported in the literature. Results from this study indicate that the synthesis of [(124)I]OIH without using an autoclave and [(124)I]OIH PET renography are feasible.
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Ácido Yodohipúrico , Riñón/diagnóstico por imagen , Renografía por Radioisótopo , Animales , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
INTRODUCTION: Little is known about the natural course of renal function and renal hemodynamics in heart failure patients with reduced ejection fraction (HFREF). METHODS AND RESULTS: We prospectively studied effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) in 73 HFREF patients with (125)I-iothalamate/(131)I-hippuran clearances with a mean follow-up of 34.6 ± 4.4 months. Fifteen percent were female, with age 58 ± 12 years and left ventricular ejection fraction (LVEF) 29 ± 10%. Baseline GFR was 81 ± 23 mL/min/1.73 m(2) and declined 0.6 ± 4.7 mL/min/1.73 m(2) per year. Baseline ERPF was 292 ± 83 mL/min/1.73 m(2) and declined 4.3 ± 19 mL/min/1.73 m(2) per year. Of the baseline variables, older age and high urinary kidney injury molecule-1 were the only variables associated with GFR decline (p < 0.05). Following stepwise backward analysis, only age (p < 0.001) remained significant. In addition, we found an association between change in GFR and changes in ERPF, N-terminal pro-brain natriuretic peptide and renovascular resistance. In the multivariable analysis, only the change in ERPF remained significantly associated with a change in GFR (p < 0.001). CONCLUSION: In this cohort of stable chronic HFREF patients, the average decline in GFR over time was small. The decline of GFR was associated with a higher age and a lower baseline GFR, and was strongly related to changes in renal perfusion.
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Insuficiencia Cardíaca/complicaciones , Enfermedades Renales/fisiopatología , Disfunción Ventricular Izquierda/fisiopatología , Factores de Edad , Anciano , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Insuficiencia Cardíaca/fisiopatología , Hemodinámica , Humanos , Ácido Yodohipúrico/farmacocinética , Ácido Yotalámico/farmacocinética , Enfermedades Renales/etiología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. RESULTS AND LIMITATIONS: The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). CONCLUSIONS: The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. PATIENT SUMMARY: The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Administración Oral , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Área Bajo la Curva , Cápsulas , Estudios Cruzados , Progresión de la Enfermedad , Fatiga/inducido químicamente , Humanos , Ácido Yodohipúrico , Masculino , Náusea/inducido químicamente , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Pirazoles/efectos adversos , Pirazoles/sangre , ComprimidosRESUMEN
OBJECTIVES: Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. METHODS: First, we validated RBFMRI measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBFMRI. After validation, we measured RBFMRI in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBFMRI and RBF measured by continuous hippuran infusion. RESULTS: The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBFMRI measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBFMRI compared to RBFHip, whereas in subjects with lower eGFRs, this was significantly less for RBFMRI. CONCLUSIONS: Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. KEY POINTS: Renal blood flow (RBF) can be accurately measured by phase-contrast MRI in ADPKD patients. RBF measured by phase-contrast is associated with ADPKD disease severity. RBF measurement by phase-contrast MRI may be less feasible in patients with an impaired eGFR.
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Imagen por Resonancia Magnética/métodos , Riñón Poliquístico Autosómico Dominante/fisiopatología , Circulación Renal/fisiología , Adulto , Presión Sanguínea/fisiología , Estudios de Cohortes , Medios de Contraste , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Tasa de Filtración Glomerular/fisiología , Hemodinámica/fisiología , Humanos , Radioisótopos de Yodo , Ácido Yodohipúrico , Masculino , Persona de Mediana Edad , Fantasmas de Imagen , Radiofármacos , Arteria Renal/fisiología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: The aim of the study was to assess the hemodynamic and metabolic actions of estrogen plus progestin therapy (EPT) in hypertensive, postmenopausal women treated with perindopril (ACEI) or hydrochlorothiazide (HCTZ). A group of normotensive postmenopausal women was also studied. METHODS: 100 hypertensive and 40 normotensive postmenopausal women were recruited for the study. The hypertensive females were randomly assigned to receive ACEI or HCTZ for 12 months. The patients of the ACEI group and the patients of the HCTZ group, as well as normotensives, were further subdivided into two subgroups each. One subgroup received estrogen plus progestin therapy (EPT+), the other subgroup received no hormone replacement (EPT-). Combined hormone replacement with transdermal patches releasing 17ß-estradiol and norethisterone was used. Office and 24-hour ambulatory blood pressure was measured at baseline and during follow-up. Renal plasma flow (RPF) was measured using the clearance of [125I]-iodohippuran. Pulse wave velocity (PWV) was determined with an automatic device. RESULTS: In normotensive postmenopausal women, transdermal estrogen plus progestin therapy increases RPF and insulin sensitivity, decreases PWV, decreases total and LDL cholesterol, and decreases uric acid serum levels. Perindopril (4 mg/day) and hydrochlorothiazide (25 mg/day) were equally effective in reducing blood pressure in postmenopausal, hypertensive subjects. In these females, perindopril increased RPF and decreased PWV and plasma insulin levels. These effects of the ACEI were not altered by estrogen plus progestin therapy. Hydrochlorothiazide decreased RPF and increased plasma insulin and uric acid concentrations in hypertensive subjects whom were not receiving estrogen plus progestin therapy. CONCLUSIONS: The unfavorable metabolic and hemodynamic actions of the diuretic were counteracted by estrogen plus progestin therapy. Concomitant estrogen plus progestin therapy may be a method to avoid unfavorable hemodynamic and metabolic effects of thiazide diuretics in hypertensive, postmenopausal women.
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Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diuréticos/uso terapéutico , Estradiol/administración & dosificación , Terapia de Reemplazo de Estrógeno , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Noretindrona/administración & dosificación , Perindopril/uso terapéutico , Posmenopausia , Progestinas/administración & dosificación , Administración Cutánea , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial , Diuréticos/efectos adversos , Combinación de Medicamentos , Interacciones Farmacológicas , Estradiol/efectos adversos , Terapia de Reemplazo de Estrógeno/efectos adversos , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Hipertensión/sangre , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Radioisótopos de Yodo , Ácido Yodohipúrico , Noretindrona/efectos adversos , Perindopril/efectos adversos , Polonia , Polifarmacia , Posmenopausia/sangre , Progestinas/efectos adversos , Análisis de la Onda del Pulso , Flujo Plasmático Renal/efectos de los fármacos , Factores de Tiempo , Parche Transdérmico , Resultado del Tratamiento , Rigidez Vascular/efectos de los fármacosRESUMEN
The aim of this study was to monitor nonsurgical and surgical root canal treatment (RCT) of teeth with primary and secondary infections and apical periodontitis (AP). This prospective clinical study comprised the treatment of 80 patients with primary and persistent secondary infections and AP. Of this initial sample, forty patients did not return. Periapical index using cone beam computed tomography scans (CBCTPAI) was used to aid diagnosis, planning and to determine the better therapeutic strategy. Twenty patients (26 teeth) diagnosed with primary infection and AP received conventional RCT and were followed up for 10 to 36 months. Twenty patients (31 teeth) diagnosed with persistent secondary infection were submitted to periapical surgical and followed up for 6 to 30 months. The results showed RCT successful in 19/26 cases with complete AP healing (5/26 with partial repair) in 10-36 months of follow up. For the surgically managed cases, effectiveness of surgical therapy was detected in 10/31 cases with complete healing (10/31 cases with partial repair) within 6-30 months follow up. The return of patients for clinical and radiographic follow-up, and obedience to the proposed time period was very short from ideal. The levels of success in both therapeutic protocols were high. RCT failures were detected even with rigorous standard clinical protocols.
O objetivo do estudo foi monitorar tratamentos de canais radiculares (TCR) convencionais e com auxílio de cirurgia periapical. Este estudo prospectivo constituiu de 80 pacientes portadores de infecções primárias e secundárias persistentes e periodontite apical (PA). O índice periapical utilizando tomografia computadorizada de feixe cônico (CBCTPAI) foi utilizado como auxiliar no diagnóstico, planejamento e para determinar a melhor estratégia terapêutica. Apenas 40 pacientes retornaram para o TCR. Em 20 pacientes (26 dentes) com diagnósticos de infecções primárias e PA foram feitos TCR convencionais e monitoramentos por 10 a 36 meses. Em 20 pacientes (31 dentes) com diagnósticos de infecções secundárias persistentes foram submetidos a procedimentos cirúrgicos e acompanhamentos durante 6 a 30 meses. Os resultados mostraram TCR bem sucedidos em 19 de 26 casos, com curas completas das PA (5 de 26 com reparação parcial) em controles de 10 a 36 meses. Para os casos de tratamentos cirúrgicos foram detectadas eficácias das terapêuticas cirúrgicas em 10 de 31 casos com curas completas (10 de 31 casos com reparação parcial) em controles de 6 a 30 meses. O retorno dos pacientes para controle clínico e radiográfico e a obediência ao período de tempo proposto está muito aquém do ideal. Os níveis de sucesso em ambos os protocolos terapêuticos se mostraram elevados. Fracassos no TCR foram detectados mesmo utilizando protocolo clínico com rigoroso padrão.
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Animales , Masculino , Ratones , Benzoatos/farmacocinética , Radioisótopos de Yodo/farmacocinética , Ácido Yodohipúrico/farmacocinética , Fenilacetatos/farmacocinética , Isomerismo , Ratones EndogámicosRESUMEN
This work presents a novel approach for labeling hippuric acid with I-131 using microwaves. It utilizes copper(II) acetate as a catalyst of the labeling. The process involves the use of this catalytic copper(II) acetate at low dilutions that were nevertheless sufficient to produce labeled hippuric acid with high radiochemical purity in a short time. Therefore, the novel technique overcomes the limitations of previously reported conventional methods that involve heating.
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Radioisótopos de Yodo/química , Ácido Yodohipúrico/química , Microondas , Compuestos Organometálicos/química , Radiofármacos/síntesis química , Catálisis , Marcaje Isotópico/métodosRESUMEN
UNLABELLED: The pharmacokinetics of the tricarbonyl core radiopharmaceutical (99m)Tc(CO)3-nitrilotriacetic acid ((99m)Tc(CO)3(NTA)) in rats and subjects with normal renal function are comparable to those of (131)I-o-iodohippuran ((131)I-OIH), the radiopharmaceutical gold standard for the measurement of effective renal plasma flow. Our objective was to compare the pharmacokinetics of these 2 tracers in subjects with renal failure. METHODS: (99m)Tc(CO)3(NTA) was prepared with commercially available NTA and a commercially available labeling kit and isolated by reversed-phase high-performance liquid chromatography. Approximately 74 MBq (2.0 mCi) of (99m)Tc(CO)3(NTA) were coinjected with approximately 11.1 MBq (300 µCi) of (131)I-OIH in 8 subjects with stage 3-4 renal failure; simultaneous images were obtained for 24 min, followed by an anterior image over the gallbladder and abdomen. Plasma clearances were determined from 10 blood samples obtained 3-180 min after injection using the single-injection, 2-compartment model. Plasma protein binding, red cell uptake, and percentage injected dose in the urine at 30 and 180 min were determined. RESULTS: There was no difference in the plasma clearances of (99m)Tc(CO)3(NTA) and (131)I-OIH (177 ± 63 vs. 171 ± 66 mL/min/1.73 m(2), respectively) (P = 0.41). The plasma protein binding and red cell uptake of (99m)Tc(CO)3(NTA) were 35% ± 7% and 6% ± 3%, respectively; both values were significantly lower than the plasma protein binding (71% ± 5%) and red cell uptake (16% ± 2%) of (131)I-OIH (P < 0.001). There was no significant difference in the percentage injected dose in the urine at 30 min (P = 0.24) and at 3 h (P = 0.82); for comparison, the percentage dose in the urine at 3 h was 77% ± 9% for (99m)Tc(CO)3(NTA) and 78% ± 11% for (131)I-OIH. Image quality with (99m)Tc(CO)3(NTA) was excellent and no activity was identified in the gallbladder or intestine. CONCLUSION: Results in patients with renal failure show the clearance and rate of urine excretion of (99m)Tc(CO)3(NTA) to be equivalent to that of (131)I-OIH.
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Ácido Yodohipúrico/farmacocinética , Compuestos de Organotecnecio/sangre , Compuestos de Organotecnecio/farmacocinética , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/metabolismo , Proteínas Sanguíneas/metabolismo , Femenino , Tasa de Filtración Glomerular , Humanos , Radioisótopos de Yodo , Ácido Yodohipúrico/metabolismo , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Compuestos de Organotecnecio/metabolismo , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
We previously demonstrated that Fab fragments labeled with 3'-[(131)I]iodohippuryl N(ε)-maleoyl-l-lysine ([(131)I]HML) showed low renal radioactivity from early postinjection time, due to a liberation of m-[(131)I]iodohippuric acid by the action of renal brush border enzymes. Since there are lots of enzymes on renal brush border membrane, peptide linkages other than the glycyl-l-lysine were evaluated as the cleavable linkages to explore the chemical design. In this study, we evaluated four peptide linkages with a general formula of m-iodobenzoyl-glycyl-X (X: l-tyosine O-methyl, l-asparagine, l-glutamine, and N(ε)-Boc-l-lysine). In vitro studies using renal brush border membrane vesicles (BBMVs) demonstrated that 3'-[(125)I]iodohippuryl O-methyl-l-tyrosine (2c) liberated the highest amount of m-[(125)I]iodohippuric acid among the four substrates and the change in the linkage structure altered enzyme species responsible for the hydrolysis reaction. To further assess the applicability of the linkage, a radioiodination reagent containing a glycyl-tyrosine linkage, 3'-[(125)I]iodohippuryl O-((2-maleimidoethyl)carbamoyl)methyl-l-tyrosine (HMT, 12c), was designed, synthesized, and subsequently conjugated to an Fab fragment. [(125)I]HMT-Fab exhibited renal radioactivity levels similar to and significantly lower than [(125)I]HML-Fab and directly radioiodinated Fab, while the blood clearance rates of the three were similar. The analyses of urine for 24 h postinjection of [(125)I]HMT-Fab showed that m-[(125)I]iodohippuric acid was excreted as the major radiometabolite. The findings indicated that glycyl-tyrosine linkage is also available to reduce renal radioactivity levels of radioiodinated Fab fragments, due to liberation of m-iodohippuric acid by the action of enzymes present on renal brush border membrane. These findings suggest that an appropriate selection of peptide linkages would allow the liberation of a designed radiolabeled compound from covalently conjugated polypeptides to prepare radiolabeled polypeptides of low renal radioactivity levels. For the selection of the most appropriate peptide linkage, the in vitro system using BBMVs would be useful to narrow the candidates to just a few.
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Inmunoconjugados/química , Inmunoconjugados/farmacocinética , Fragmentos Fab de Inmunoglobulinas/análisis , Radioisótopos de Yodo/química , Radioisótopos de Yodo/farmacocinética , Riñón/enzimología , Microvellosidades/enzimología , Animales , Dipéptidos/química , Inmunoconjugados/metabolismo , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/metabolismo , Radioisótopos de Yodo/metabolismo , Ácido Yodohipúrico/metabolismo , Masculino , RatonesRESUMEN
UNLABELLED: In an ongoing effort to develop a renal tracer with pharmacokinetic properties comparable to p-aminohippurate and superior to those of both (99m)Tc-mercaptoacetyltriglycine and (131)I-o-iodohippurate ((131)I-OIH), we evaluated a new renal tricarbonyl radiotracer based on the aspartic-N-monoacetic acid (ASMA) ligand, (99m)Tc(CO)(3)(ASMA). The ASMA ligand features 2 carboxyl groups and an amine function for the coordination of the {(99m)Tc(CO)(3)}(+) core as well as a dangling carboxylate to facilitate rapid renal clearance. METHODS: rac-ASMA and l-ASMA were labeled with a (99m)Tc-tricarbonyl precursor, and radiochemical purity of the labeled products was determined by high-performance liquid chromatography. Using (131)I-OIH as an internal control, we evaluated biodistribution in normal rats with (99m)Tc(CO)(3)(ASMA) isomers and in rats with renal pedicle ligation with (99m)Tc(CO)(3)(rac-ASMA). Clearance studies were conducted in 4 additional rats. In vitro radiotracer stability was determined in phosphate-buffered saline, pH 7.4, and in challenge studies with cysteine and histidine. (99m)Tc(CO)(3)(ASMA) metabolites in urine were analyzed by high-performance liquid chromatography. RESULTS: Both (99m)Tc(CO)(3)(ASMA) preparations had greater than 99% radiochemical purity and were stable in phosphate-buffered saline, pH 7.4, for 24 h. Challenge studies on both revealed no significant displacement of the ligand. In normal rats, the percentage injected dose in urine at 10 and 60 min for both preparations averaged, respectively, 103% and 106% that of (131)I-OIH. The renal clearances of (99m)Tc(CO)(3)(rac-ASMA) and (131)I-OIH were comparable (P = 0.48). The tracer was excreted unchanged in the urine, proving its in vivo stability. In pedicle-ligated rats, (99m)Tc(CO)(3)(rac-ASMA) had less excretion into the bowel (P < 0.05) than did (131)I-OIH and was better retained in the blood (P < 0.05). CONCLUSION: Both (99m)Tc(CO)(3)(ASMA) complexes have pharmacokinetic properties in rats comparable to or superior to those of (131)I-OIH, and human studies are warranted for their further evaluation.
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Ácido Yodohipúrico/farmacocinética , Riñón/metabolismo , Compuestos de Organotecnecio/farmacocinética , Animales , Radioisótopos de Yodo , Isomerismo , Marcaje Isotópico , Riñón/diagnóstico por imagen , Ligandos , Masculino , Compuestos de Organotecnecio/química , Trazadores Radiactivos , Cintigrafía , Ratas , Ratas Sprague-DawleyRESUMEN
Technetium-99m-diethylene triamine pentaacetic acid ((99m)Tc-DTPA) has been widely used after (131)I-ortho-hippurate ((131)I-OIH) for renography and to test renal function. Only a few reports refer to normal values range of (99m)Tc-DTPA renography half maximum time (HMT). We have measured the normal value range of (99m)Tc-DTPA renography HMT in our department, of 433 healthy kidney donors from 2007 to 2010, and compared these results with those of (131)I-OIH renography. There were 326 men and 107 women, 18y-69y (median age 29y), subjects were measured before the donation of their kidneys operation and their biochemical, ultrasound and renal function tests were normal. All subjects drunk at least 1 litre of tap water before renography. The (99m)Tc-DTPA dynamic scintigraphy was performed in the posterior view by injecting intravenously as a bolus 185-296MBq. Dynamic imaging was performed immediately after the injection, using a high-resolution low-energy general purpose collimator and a large field of view dual-detector gamma-camera (Hawkeye; General Electric Medical Systems, USA). Matrix was 64Χ64, the phase acquisition time of blood perfusion was 1s/frame and 30 frames were collected. Dynamic acquisition was 30s/frame and 39 frames were collected. Total acquisition time was 20min. We defined as background two regions of interest around the kidneys and the aorta, for radioactive decay correction. We also compared (99m)Tc-DTPA renography HMT values with the HMT values of (131)I-OIH, between the two kidneys, and between men and women. The findings were evaluated by using frequency distribution analysis, paired Sample Student's t-test and one sample t test, with a level of significance P<0.05. We used the SPSS 10.0 statistical software. Since values beyond a high boundary were regarded as unusual, we used the P(95), i.e. " 95% of HMT reference ranges value" to determine the medical reference range of values, as the HMT normal limit. This reference value is used especially when the data shows a skewed distribution. For the HMT (P(95) value), the normal reference values found between mean values of the left and the right kidney were: 10.76±4.14min and 10.89±4.55min, respectively and P=0.416, two tailed. For the left kidney HMT, there was no significant difference between men: 10.90±4.31min and women: 10.33±3.57min, (t=1.235, v=432, P=0.2186, two tailed), and similar findings were found between men's right kidney HMT: 11.02±4.89min and women's right kidney HMT: 10.49±3.32min, (t=1.253, v=266.59, P=0.211, two tailed). By comparing the mean value of (99m)Tc-DTPA renography HMT measured (10.76min, 10.89min) with the mean value of (131)I renography HMT that we found in the literature as referring to both left and right kidneys (4min). We found a significant difference (P=0.000, two tailed). Renography may be used to diagnose urinary tract obstruction, estimate the split renal function and is useful.
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Renografía por Radioisótopo , Pentetato de Tecnecio Tc 99m , Humanos , Ácido Yodohipúrico , Riñón/diagnóstico por imagen , Pruebas de Función RenalRESUMEN
OBJECTIVE: We recently identified p-[(18)F]fluorohippurate ([(18)F]PFH) as a potential positron emission tomography (PET) renal agent. The objective of this study was to compare renogram parameters of [(18)F]PFH with o-[(125)I]iodohippurate ([(125)I]OIH) as a surrogate for the renal imaging gold standard (131)I-OIH and with a clinically used agent [(99m)Tc]MAG3. METHODS: Normal Sprague-Dawley rats (n=4) were sequentially imaged on days 1, 2, and 3 using [(99m)Tc]MAG3 (18.1-19.1 MBq, dynamic planar), [(18)F]PFH (2.6-4.1 MBq, dynamic PET), and [(125)I]OIH (7.7-13.5 MBq, dynamic planar), respectively. The PET data were binned into frames of 30 s each, whereas the planar images were acquired as 30 s per frame. Regions of interest were drawn on both kidneys, and decay-corrected renograms were generated for each imaging modality. RESULTS: The PET-derived [(18)F]PFH renograms revealed an average time-to-peak (T(max)) of 4.8±2.4 min, which was comparable to the T(max) of 3.6±1.7 min and 4.3±1.7 min for [(125)I]OIH and [(99m)Tc]MAG3 renograms, respectively. The average time-to-half-maximal activity was found to be 16.6±6.6 min, 8.3±2.4 min, and more than 20 min with [(18)F]PFH, [(125)I]OIH, and [(99m)Tc]MAG3, respectively. CONCLUSIONS: Compared with [(99m)Tc]MAG3, the renogram parameters of [(18)F]PFH seem to be closer to those obtained from [(125)I]OIH. The quality of the renogram and the images obtained with the dynamic [(18)F]PFH PET study were remarkably better than those obtained with the [(99m)Tc]MAG3 dynamic planar imaging study.
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Radioisótopos de Flúor , Hipuratos , Ácido Yodohipúrico , Renografía por Radioisótopo/métodos , Tecnecio Tc 99m Mertiatida , Animales , Radioisótopos de Yodo , Túbulos Renales/diagnóstico por imagen , Túbulos Renales/fisiología , Renografía por Radioisótopo/normas , Ratas , Estándares de ReferenciaRESUMEN
BACKGROUND AND OBJECTIVES: Experimental studies suggest a detrimental role for vasopressin in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, it is unknown whether endogenous vasopressin concentration is associated with disease severity in patients with ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma copeptin concentration (a marker of endogenous vasopressin levels) was measured in 102 ADPKD patients (diagnosis based on Ravine criteria) by an immunoassay. Plasma and urinary osmolarity were also measured. To assess disease severity, GFR and effective renal blood flow were measured by continuous infusion of 125I-iothalamate and 131I-hippuran, total renal volume by magnetic resonance imaging, and 24-hour urinary albumin excretion by nephelometry. RESULTS: In these ADPKD patients, copeptin was associated with the various markers of disease severity in ADPKD (positively with total renal volume [R=0.47] and albuminuria [R=0.39] and negatively with GFR [R=-0.58] and effective renal blood flow [R=-0.52], all P<0.001). These associations were independent of age, gender, and use of diuretics. Copeptin was furthermore associated with plasma osmolarity (P<0.001) but not with 24-hour urinary volume, 24-hour urinary osmolarity or fractional urea excretion (P=0.7, 0.9, and 0.3, respectively). CONCLUSIONS: On cross-sectional analysis, copeptin is associated with disease severity in ADPKD patients, supporting the results of experimental studies that suggest that vasopressin antagonists have a renoprotective effect in ADPKD and offering a good prospect for clinical studies with these agents.
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Glicopéptidos/sangre , Riñón Poliquístico Autosómico Dominante/diagnóstico , Vasopresinas/sangre , Adulto , Albuminuria/sangre , Albuminuria/diagnóstico , Albuminuria/fisiopatología , Albuminuria/orina , Biomarcadores/sangre , Estudios Transversales , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunoensayo , Radioisótopos de Yodo , Ácido Yodohipúrico , Ácido Yotalámico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nefelometría y Turbidimetría , Países Bajos , Concentración Osmolar , Riñón Poliquístico Autosómico Dominante/sangre , Riñón Poliquístico Autosómico Dominante/fisiopatología , Riñón Poliquístico Autosómico Dominante/orina , Valor Predictivo de las Pruebas , Análisis de Regresión , Flujo Sanguíneo Renal Efectivo , Índice de Severidad de la Enfermedad , UrodinámicaRESUMEN
UNLABELLED: Studies in rats showed that the pharmacokinetics of the tricarbonyl core radiopharmaceutical (99m)Tc(CO)(3)-nitrilotriacetic acid, (99m)Tc(CO)(3)(NTA), were essentially identical to those of (131)I ortho-iodohippuran ((131)I-OIH), the clinical gold standard for the measurement of effective renal plasma flow. Our objective was to compare the pharmacokinetics of these 2 tracers in healthy volunteers. METHODS: (99m)Tc(CO)(3)(NTA) was prepared with commercially available NTA and a commercially available kit and isolated by reversed-phase high-performance liquid chromatography. Approximately 74 MBq (2 mCi) of (99m)Tc(CO)(3)(NTA) were coinjected with 9.25 MBq (250 microCi) of (131)I-OIH in 9 volunteers, and simultaneous imaging of each tracer was performed for 24 min. Plasma clearances were determined from 8 blood samples obtained 3-90 min after injection using the single-injection, 2-compartment model. Plasma protein binding, red cell uptake, and percentage injected dose in the urine at 30 and 180 min were determined. RESULTS: There was no difference in the plasma clearances of (99m)Tc(CO)(3)(NTA) and (131)I-OIH, 475 +/- 105 mL/min versus 472 +/- 108 mL/min, respectively. The plasma protein binding and red cell uptake of (99m)Tc(CO)(3)(NTA) were 43% +/- 5% and 9% +/- 6%, respectively; both values were significantly lower (P < 0.001) than the plasma protein binding (75% +/- 3%) and red cell uptake (17% +/- 5%) of (131)I-OIH. There was no significant difference in the percentage injected dose recovered in the urine at 30 min and at 3 h; for comparison, the percentage dose in the urine at 3 h was 91% +/- 4% for (99m)Tc(CO)(3)(NTA) and 91% +/- 6% for (131)I-OIH (P = 0.96). Image quality with (99m)Tc(CO)(3)(NTA) was excellent, and the renogram parameters were similar to those of (131)I-OIH. CONCLUSION: Preliminary results in healthy volunteers suggest that the pharmacokinetic behavior of (99m)Tc(CO)(3)(NTA) is comparable to that of (131)I-OIH.
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Salud , Ácido Yodohipúrico/farmacocinética , Riñón/metabolismo , Compuestos de Organotecnecio/farmacocinética , Adulto , Femenino , Humanos , Radioisótopos de Yodo/química , Ácido Yodohipúrico/química , Riñón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Compuestos de Organotecnecio/sangre , Compuestos de Organotecnecio/orina , Trazadores Radiactivos , Renografía por Radioisótopo , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Measuring GFR using exogenous markers without a bladder catheter, errors can be easily made due to incomplete urine collection. The aim was to quantify agreement for 125I-iothalamate GFR measurements with and without a correction for inaccurate urine collection using 131I-hippuran. METHODS: The last available GFR measurement of adult patients was included. GFR was measured in two subsequent clearance periods with 125I-iothalamate by the standard method with correction for inaccurate urine collections using 131I-hippuran. The uncorrected and corrected GFR measurements were compared within and between the time periods for each individual patient. To study the agreement between both methods, intraclass correlation coefficients (ICC) were calculated and Bland-Altman plots, with accompanying accuracies and precisions, were used. Cohen's kappa was calculated to analyze the agreement of both methods for classifying patients according to the stages of chronic kidney disease (CKD). RESULTS: For the 332 stable included patients, the mean GFR of the uncorrected measurements was 77.8 ml/min (34.7) and the mean GFR of the corrected measurements was 81.0 ml/min (34.9). The ICC was 0.80 for the uncorrected measurements with an accuracy of 7.3 ml/min and a precision of 21.7 ml/min. For the corrected GFR measurements the ICC was 0.98, with an accuracy of 2.1 ml/min and a precision of 6.5 ml/min. Comparison between the methods showed an ICC of 0.95, an accuracy of 3.2 and a precision of 11.0. In total, 86% of the patients were classified similarly into CKD stages with both methods, overall Cohen's kappa was 0.81. CONCLUSION: Agreement was better for GFR measurements corrected for inaccurate urine collections. Therefore, GFR measurements with 125I-iothalamate should be corrected for inaccurate urine collections using 131I-hippuran. Without such correction the GFR is easily underestimated which may lead to overtreatment.