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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.

Retrospective study of a prospectively collected database at one center.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.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.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.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 IV.

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

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.

INTRODUCTION: Radiolabeled, low-molecular-weight prostate-specific membrane antigen (PSMA) inhibitors based on the Glu-ureido pharmacophore show promise for the detection and treatment of castration-resistant prostate cancer; however, high renal retention of activity, related in part to overexpression of PSMA in kidneys can be problematic. The goal of the current study was to investigate the use of brush border enzyme-cleavable linkers as a strategy for reducing kidney activity levels from radiolabeled PSMA inhibitors. METHODS: PSMA-769 (6), a derivative of the prototypical PSMA inhibitor (((S)-1-carboxy-5-(4-iodobenzamido)pentyl)carbamoyl)glutamate (12) modified to contain a Gly-Tyr linker, and its protected tin precursor (11) were synthesized starting from the basic pharmacophore molecule Lys-urea-Glu. A radioiodinated analogue of 11 containing d-tyrosine in lieu of l-tyrosine (PSMA-769-d-tyrosine) also was synthesized from its corresponding tin precursor (d-11). Both radioiodinated and (211)At-labeled 6 were synthesized by radiohalogenation of 11 and deprotection in situ. Similarly, radioiodinated d-6 was synthesized from d-11. Paired label biodistribution of [(125)I]12 and [(131)I]6 was performed in normal mice and in SCID mice bearing both PC3 PIP (PSMA+) and PC3 flu (PSMA-) subcutaneous prostate carcinoma xenografts. The biodistribution of [(131)I]6 and [(211)At]6 was also evaluated in this tumor model. Biodistribution of the two radioiodinated diastereomers of 6 was evaluated in normal mice and urine samples were analyzed for the presence of 4-iodohippuric acid. RESULTS: Compounds [(131)I]6 and [(211)At]6 were synthesized from 11 in overall radiochemical yields of 32.5 ± 0.1% (n = 4) and 22% (n = 1), respectively; radiochemical purity was >95%. In normal mice, renal uptake of [(131)I]6 was 1.4-, 2.8- and 161-fold lower than that seen for co-injected [(125)I]12 at 1 h, 4 h and 21 h, respectively. In tumor-bearing mice, kidney uptake of [(131)I]6 was similar to that for [(125)I]12 (P > 0.05) at 1 h and 4 h but was 6- to 7-fold lower at 21 h; however, [(131)I]6 uptake in PC3 PIP tumors was also lower than that seen for [(125)I]12 at 21 h (12.6 ± 3.4 %ID/g vs. 36.8 ± 12.4 %ID/g). Uptake of [(211)At]PSMA-769 in PC3 PIP tumors was slightly higher than that seen for [(131)I]PSMA-769 at 4 h (9.6 ± 1.6 %ID/g versus 7.8 ± 1.6 %ID/g; P = 0.002); its uptake in a number of normal tissues also was higher. In normal mice, kidney uptake of [(125)I]PSMA-769 at 4 h was about 73% of that seen for [(131)I]PSMA-769- d-tyrosine. Activity in the urine of mice receiving [(125)I]PSMA-769 contained mainly 4-[(125)I]iodohippuric acid while unmetabolized intact molecule was present in the case of [(125)I]PSMA-769- d-tyrosine. CONCLUSION: Use of this brush border enzyme-cleavable linker reduced kidney uptake and resulted in improved tumor:kidney uptake ratios. Although further structural improvements are needed, this linker approach might be useful as a component in strategies for reducing renal uptake of radiolabeled PSMA inhibitors.

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.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.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 of0.1 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.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.

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.

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.(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.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 (P0.001). 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.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.

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 600 mg 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 48 h 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-201 600 mg twice daily in patients with non-mCRPC is ongoing. (C) 2015 European Association of Urology. Published by Elsevier B.V.

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.

In an ongoing effort to develop a renal tracer with pharmacokinetic properties comparable to p-aminohippurate and superior to those of both 99mTc-mercaptoacetyltriglycine and 131I-o-iodohippurate (131I-OIH), we evaluated a new renal tricarbonyl radiotracer based on the aspartic-N-monoacetic acid (ASMA) ligand, 99mTc(CO)3(ASMA). The ASMA ligand features 2 carboxyl groups and an amine function for the coordination of the {99mTc(CO)3}+ core as well as a dangling carboxylate to facilitate rapid renal clearance. Methods:rac-ASMA and l-ASMA were labeled with a 99mTc-tricarbonyl precursor, and radiochemical purity of the labeled products was determined by high-performance liquid chromatography. Using 131I-OIH as an internal control, we evaluated biodistribution in normal rats with 99mTc(CO)3(ASMA) isomers and in rats with renal pedicle ligation with 99mTc(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. 99mTc(CO)3(ASMA) metabolites in urine were analyzed by high-performance liquid chromatography. Results: Both 99mTc(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 131I-OIH. The renal clearances of 99mTc(CO)3(rac-ASMA) and 131I-OIH were comparable (P = 0.48). The tracer was excreted unchanged in the urine, proving its in vivo stability. In pedicle-ligated rats, 99mTc(CO)3(rac-ASMA) had less excretion into the bowel (P

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 125 I-iothalamate GFR measurements with and without a correction for inaccurate urine collection using 131 I-hippuran. Methods: The last available GFR measurement of adult patients was included. GFR was measured in two subsequent clearance periods with 125 I-iothalamate by the standard method with correction for inaccurate urine collections using 131 I-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, intra-class correlation coefficients (ICC) were calculated and Bland-Altman plots, with accompanying accuracies and precisions, were used. Cohen's K 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 Co-hen's K was 0.81. Conclusion: Agreement was better for GFR measurements corrected for inaccurate urine collections. Therefore, GFR measurements with 125 I-iothalamate should be corrected for inaccurate urine collections using 131 I-hippuran. Without such correction the GFR is easily underestimated which may lead to overtreatment.

Radioisotope renography with 13I-hippuran has been undertaken in 14 kidney donors with normal renal function 26–53 months after unilateral nephrectomy. Immediately after renography simultaneous creatinine, 125iothalamate and 131I-hippuran clearances were determined. Ratios calculated within the first 2.5 min of the renogram could not be correlated to clearance values or to the size of the remaining kidney. There was a statistically significant correlation between clearance values and renal size. The range of the ratios calculated was 5–10%, whereas the range of clearance values was 15–30%. 131I-hippuran reached the bladder after a minimum of 2.0 min. There was a correlation between transit time and time to the renogram's maximum.

The influence of renal function, body size and age on the plasma concentration and urinary excretion of digoxin in 53 hospitalized patients on a maintenance dose of 0.25 mg has been studied. The mean plasma concentration was 1.01 ng/ml (S.D. 0.42); 64% of the patients were underdigitalized (plasma values ≤ 1.00 ng/ml). The plasma level was strongly influenced by kidney function when this was reduced at least 50% (glomerular filtration rate, renal plasma flow), and to a minor degree by age. Studies on the effect of body size on the plasma digoxin level gave equivocal results, but this factor was of minor importance compared to that of kidney function. The urinary excretion of digoxin (on average 35.9% of the administrated dose) was significantly reduced as kidney function decreased. Variations in body size did not affect the excretion, nor was an increased urinary output observed during regular maintenance administration of diuretics (furosemide, thiazides).

131I-hippuran renography combined with recording of an isotope cystogram has been carried out in 23 patients who had received a renal transplant. Altogether 120 renographs were performed. The control series consisted of nine patients with stable renal function 68 to 720 days after transplantation. With acute as well as with chronic rejection an elevation in the third phase of the renogram was seen. An excretion ratio was calculated; this was significantly different from the excretion ratio found in the control series. The renogram became normal pari passu with normalization of renal function in patients with acute rejection. In three patients with obstruction of urinary outflow a reduced excretion ratio was found, accompanied by an increased transit time. The transit time in patients with acute or chronic rejection did not differ from that found in the control patients. It was thus possible in these three cases to differentiate between acute rejection and obstruction by the use of renography combined with isotope cystography.

The glomerular filtration rate (GFR), the effective renal plasma flow (ERPF), and the filtration fraction (FF) have been studied in 38 patients with different renal diseases and varying degrees of renal insufficiency. All diagnoses were verified by percutaneous renal biopsy. Eighteen living kidney donors comprised a control material. In 10 patients in terminal uremia no characteristic functional pattern was found. Twelve patients with interstitial nephritis had a significantly increased FF, 9 with the nephrotic syndrome had a significantly decreased FF, whereas 7 with glomerulonephritis without the nephrotic syndrome did not demonstrate FF values different from those found in normals. A good correlation was found between the size of the FF and the concentration of serum albumin. Creatinine clearance overestimated the true GFR in patients with renal disease. The FF was not significantly increased in hypertensive patients.

Seventeen probenecid congeners were tested as inhibitors of the simultaneous uptake of labelled o-iodohippurate and iodipamide into slices of rabbit renal cortex. Compounds with small substituents on the nitrogen were more inhibitory for o-iodohippurate, while compounds with larger lipophilic substituents were more inhibitory for iodipamide uptake. The results are interpreted in terms of differential inhibition of two transport systems: the classical hippurate or H-system and the liver-like L-system.

Conscious rats were given intracerebral injections by preplaced microsyringes. The injectates were 0.3-0.5 microliters of 125I- and 131I-o-iodohippurate. One hour after injection the isotopes present in the unopened cranial cavity were measured by gamma spectrometry. Some animals received 200 mg/kg probenecid intraperitoneally and this reduced the rate of absorption from injectates into the corpus striatum to 65.7 +/- 12.6% of control; from injectates into the cerebellum to 57.1 +/- 9.8% of control. Dye injections showed that injections into the cerebellum did not remain in the parenchyma, in contrast to injections into the corpus striatum or thalamus. Probenecid was also given as 2.9% solution, pH 7, mixed with the iodohippurate in the microsyringe. It had no effect on injections into the cerebellum, reduced the rate of absorption from the corpus striatum to 80.9 +/- 3.2% of controls and that from the thalamus to 88.3 +/- 2.2%. The results indicate parenchymal probenecid-sensitive transport of iodohippurate from the corpus striatum and thalamus but failed to settle the matter for the cerebellum.

To develop a (99m)Tc renal tracer with a capacity to measure effective renal plasma flow comparable to that of the clinical gold standard (131)I-o-iodohippurate ((131)I-OIH) and superior to that of (99m)TcO-mercaptoacetyltriglycine, which has a clearance only 50%-60% that of (131)I-OIH, we investigated (99m)Tc-tricarbonyl nitrilotriacetic acid (Na(2)[(99m)Tc(CO)(3)(NTA)]). This radiopharmaceutical, which is based on an aminopolycarboxylate ligand, is formed as a single species and has a dangling carboxylate group favoring tubular transport.Na(2)[(99m)Tc(CO)(3)(NTA)] was prepared by using commercially available NTA and an IsoLink kit and isolated by high-performance liquid chromatography. The stability of Na(2)[(99m)Tc(CO)(3)(NTA)] in isotonic saline was assessed for 24 h and was further evaluated by incubation in 0.1 M cysteine and histidine for 4 h at 37 degrees C. The biodistribution of Na(2)[(99m)Tc(CO)(3)(NTA)], coinjected with (131)I-OIH as an internal control, was evaluated in 5 normal Sprague-Dawley rats at 10 min, 5 normal Sprague-Dawley rats at 60 min (group A), and 6 rats with renal pedicle ligation at 60 min (group B) after injection. Clearance and extraction fraction studies were conducted in 2 normal Sprague-Dawley rats, and urine and plasma from 2 additional normal rats each were analyzed for metabolites by high-performance liquid chromatography.The radiochemical purity of Na(2)[(99m)Tc(CO)(3)(NTA)] was greater than 99%, the complex was stable for 24 h at physiologic pH, and the challenge experiments showed no degradation. In normal rats, the percentage dose in the urine at 10 and 60 min was 108% +/- 9% and 101% +/- 5%, respectively, that of (131)I-OIH; minimal hepatic or gastrointestinal activity was demonstrated. In group B rats, Na(2)[(99m)Tc(CO)(3)(NTA)] was better retained in the blood and had less excretion into the bowel than did (131)I-OIH (P0.01). The plasma clearances of Na(2)[(99m)Tc(CO)(3)(NTA)] and (131)I-OIH were comparable, but the extraction fraction of Na(2)[(99m)Tc(CO)(3)(NTA)] was 93.5% +/- 3.8%, compared with 67.9% +/- 6.1% for (131)I-OIH. Plasma protein binding of Na(2)[(99m)Tc(CO)(3)(NTA)] averaged 67% +/- 7%, and red cell uptake was 7% +/- 2%.Na(2)[(99m)Tc(CO)(3)(NTA)] is stable, exists as a single species, and has pharmacodynamic properties in rats comparable to those of (131)I-OIH.

SUMMARY A method is described for measuring csf clearance rates by a single intraventricular injection of I125 Hippuran. The resorption tests showed that in this sample there was a larger between-patient variation in csf production than is usually described in congenital hydrocephalus. It seems that the degree of ventricular enlargement and the possibility of spontaneous arrest are determined by the volume of csf produced. There is reduced production and absorption of csf in post-meningitic hydrocephalus with a resistance to absorption such that spontaneous equilibration is unlikely to occur. State of consciousness and position have no detectable effect on csf production or absorption. Isosorbide appeared to produce both an osmotic removal of csf from the ventricles and a reduced csf production. Acetazolamide had no constant effect on csf production or absorption. No morbidity or mortality ascribable to the test occurred. RESUME Les eflets de la position, du niveau de vigilance et des medications sur l'absorption du LCR mesuree par resorption de l'Hippuran I125 Les auteurs decrivent une methode de mesure de l'elimination du lcr a partir d'une injection unique intra-ventriculaire d'Hippuran I125. Les epreuves de resorption montrent que dans le groupe etudie, la variation de production de lcr entre sujets est plus importante qu'il n'est decrit habituellement dans l'hydrocephalie congenitale. Il semble que le degre d'elargissement ventriculaire et la possibilite d'arret spontane sont provoques par le volume de lcr produit. Il y a diminution de la production et de l'absorption de lcr dans l'hydrociphalie post-meningitique avec une telle resistance a l'absorption qu'un equilibre spontane est impossible. Le niveau de vigilance et la position du sujet n'ont pas d'effet mesurable sur la production ou l'absorption de lcr. L'isosorbide semble provoquer une fuite osmotique du lcr hors des ventricules et une diminution de la production de lcr. L'acetozolamide n'a pas d'effet constant sur la production ou l'absorption de lcr. Il n'a ete observe au cours de l'epreuve ni morbidite, ni mortalite. ZUSAMMENFASSUNG Der Einfluβ von Position, Bewuβtseinslage und Medikamenten auf die Liquorabsorption wird durch die I125Hippuranresorption besfimmt Es wird eine Methode zur Bestimmung von Liquor-Clearance-Werten durch einmalige Injektion von I125 Hippuran in den Ventrikel beschrieben. Die Resorptionstests zeigten, das hierbei eine grosgere Variation der Liquorproduktion unter den Patienten zu beobachten war als gewohnlich fur den congenitalen Hydrocephalus beschrieben wird. Es scheint, das das Mas der Ventrikelvergroserung und die Moglichkeit der spontanen Arrestierung von der produzierten Liquormenge abhangt. Beim postmeningitischen Hydrocephalus gibt es eine reduzierte Produktion und Absorption mit einem physiologischen Widerstand gegen die Absorption, so das ein spontanes Gleichgewicht schwerlich zu erreichen ist. Die Bewustseinslage und Position des Patienten haben keinen nachweisbaren Einflus auf die Liquorproduktion oder-absorption. Isosorbide schienen sowohl einen osmotisch bedingten Abflus des Liquors aus den Ventrikeln als auch eine herabgesetzte Liquorproduktion zu bedingen. Acetozolamide hatten keinen konstanten Einflus auf die Liquorproduktion oder-absorption. Dieser Test hatte keine Morbiditat oder Mortalitat zur Folge. RESUMEN Efectos de la posicion, estado de conciencia y fairmacos sobre la absorcion de liquido cefaloraquideo estimada por la reabsorcion de I125Hippuran Se describe un metodo para la medicion de la velocidad de aclaramiento de lcr por medio de una unica inyeccion intraventricular de I125 Hippuran. Los tests dere absorcion mostraron que en esta muestra habia una variacion en la produccion de lcr entre pacientes mayor de lo que habitualmente se describe en la hidrocefalia congenita. Parece que el grado de agrandamiento ventricular y la posibilidad de una detencion espontanea estan determinadas por el volumen de lcr producido. Existe una produccion y absorcion reducidas de lcr en la hidrocefalia post-meningitica, con una resistencia tal a la absorcion que no es facil que ocurra un equilibrio espontaneo. El estado de la conciencia y la posicion del paciente no tienen efectos detectables sobre la produccion o absorcion del lcr. El isosorbide mostro producir una retirada osmotica de lcr de los ventriculos y una reduccion en la produccion de lcr. La acetazolamida no tuvo un efecto constante sobre la produccion o absorcion del lcr. No ocurrio ninguna morbilidad ni mortalidad como resultado de este test.

A 38-year-old man suffering from chronic glomerulonephritis received a kidney from his HL—A identical sister. The HL—A identity was fully established by tissue typing with well-specified antisera and by mixed lymphocyte culture tests. One year after transplantation kidney function deteriorated, and repeated biopsies of the transplant, I131-Hippuran renography, and arteriography showed that the kidney was undergoing a chronic rejection. It is suggested that incompatibilities with regard to weak histocompatibility systems might have been responsible for the rejection of a human kidney.

An invasive comparative study of some pharmacokinetic aspects of 99mTc-mercaptoacetyltriglycine (MAG3), 131I-orthoiodohippurate (OIH), and 125I-iothalamate (iothalamate) was performed in six pigs 0-150 min after a simultaneous single injection (SI) and during a subsequent 90 min of continuous infusion (CI). The total plasma clearance and the renal clearance of MAG3 were about 75% that of OIH. The renal clearance of MAG3 was about 2 1/2 times the glomerular filtration rate. The distribution volume of MAG3 was 71% that of iothalamate and only 47% that of OIH. There was a significant hepatic plasma clearance of MAG3 of 5.9 ml min-1 and 3.9% of the injected dose was excreted in the bile. HPLC analysis revealed that technetium was excreted in urine and bile mainly labelled to MAG3. The average red blood cell (RBC) binding after single injection/during continuous infusion was 1.0%/2.3% for MAG3, 13.5%/9.0% for OIH, and 3.1%/5.3% for iothalamate. The binding of OIH to RBC in arterial blood increased from 8% at 1 min post-injection to 21% at 150 min post-injection. The RBC binding was higher in the renal vein, indicating incomplete back diffusion from RBC to plasma. The protein binding was 90% for MAG3, 49% for OIH and 16% for iothalamate. The renal plasma extraction of MAG3 was constant but significantly smaller after SI (0.54) than during CI (0.62). Following SI, the renal plasma extraction of OIH decreased continuously from 0.85 to 0.52, 3-150 min post-injection. On the average there was no significant difference in renal plasma extraction after SI and during CI of either OIH (0.72 versus 0.77) or iothalamate (0.26 versus 0.27). It is concluded that MAG3 is preferential to OIH as a tracer for renal function studies using a single injection technique mainly due to the constant renal extraction of MAG3.

The parameters affecting the absolute radiochemical yield of the isotopic exchange reaction between radioiodine (125I-) and iodohippuric acid isomers on molten ammonium acetate as a medium exchange at 120 degrees C without any carrier added (radioiodine, 125I-) was determined. The isotopic exchange reactions of radioiodine as 125I- for iodine-127 of o- and p-iodohippuric acid isomers occur more rapidly than m-iodohippuric acid isomer. These reactions proceed by nucleophilic second order substitution reaction. The kinetics and thermodynamic parameters of these isotopic exchange reactions were determined. The absolute radiochemical yield and radio pharmaceutical purity were determined by HPLC and TLC techniques.

If it were possible to standardize treatments for various conditions throughout the world, many of the controversies which now occupy much journal space would be eliminated. This is not possible in reality, and so debate continues. However, that it remains inspiring to do so is shown by the many consensus meetings which take place every year. Guidelines and recommendations appear regularly, with the hope that some unification of treatment strategies can be introduced. Standardizing diagnostic methods should be easier, and in this section one of the names most recognisably associated with neurography pleads that comparing the results for methods, both old and new, for treating PUJ obstruction is only possible if the techniques used for investigating the condition are standardized; he produces guidelines which he recommends for this purpose, and which are an update of previous concerns from the Ninth International Symposium of Radionuclides in Nephrourology.

Nonspecific renal radioactivity localization constitutes a problem in targeted imaging and therapy with radiolabeled antibody fragments. Based on the idea that the renal radioactivity levels should be reduced if radiolabeled compounds excreted in the urine are released from antibody fragments by tubular brush border enzymes, 3'-iodohippuryl N epsilon-maleoyl-L-lysine (HML) was designed as a radioiodination reagent for antibody fragments; the glycyl-lysine sequence in HML is a substrate for a brush border enzyme and m-iodohippuric acid is released by cleavage of the linkage. In normal mice, HML-conjugated Fab demonstrated low renal radioactivity levels from early postinjection times. Directly radioiodinated Fab showed migration of radioactivity from the membrane to the lysosomal fraction of the renal cells from 10 to 30 min postinjection. On the other hand, the majority of the radioactivity was detected only in the membrane fraction after injection of HML-conjugated Fab. In tumor-bearing mice, HML-conjugated Fab showed a marked decrease in renal radioactivity localization without impairing the tumor accumulation. These findings indicate that HML is a useful reagent for reducing the renal radioactivity levels of antibody fragments.

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 17β-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.

Renal localization of radiolabeled antibody fragments constitutes a problem in targeted imaging and radiotherapy. Recently, we reported use of a novel radioiodination reagent, 3'-[131I]iodohippuryl N(epsilon)-maleoyl-L-lysine (HML), that liberates m-iodohippuric acid before antibody fragments are incorporated into renal cells. In mice, HML-conjugated Fab demonstrated low renal radioactivity levels from early postinjection times. In this study, renal metabolism of HML-conjugated Fab fragments prepared by different thiolation chemistries and by direct radioiodination were investigated to determine the mechanisms responsible for the low renal radioactivity levels. Fab fragments were thiolated by 2-iminothiolane modification or by reduction of disulfide bonds in the Fab fragments, followed by conjugation with radioiodinated HML to prepare [131I]HML-IT-Fab and [125I]HML-Fab, respectively. In biodistribution studies in mice, both [131I]HML-IT-Fab and [125I]HML-Fab demonstrated significantly lower renal radioactivity levels than those of [125I]Fab. In subcellular distribution studies, [125I]Fab showed migration of radioactivity from the membrane to the lysosomal fraction of the renal cells from 10 to 30 min postinjection. On the other hand, the majority of the radioactivity was detected only in the membrane fraction at the same time points after injection of both [131I]HML-IT-Fab and [125I]HML-Fab. In metabolic studies, while [125I]Fab remained intact at 10 min postinjection, both HML-conjugated Fab fragments generated m-iodohippuric acid as a radiometabolite at the same postinjection time. [131I]HML-IT-Fab registered two radiometabolites (intact [131I]HML-IT-Fab and m-iodohippuric acid), whereas additional radiometabolites were observed with [125I]HML-Fab. This suggested that metabolism of both HML-conjugated Fab fragments would occur in the membrane fractions of the renal cells. The findings of this study reinforced our previous hypothesis that radiochemical design of antibody fragments that liberate radiometabolites that are excreted into the urine by the action of brush border enzymes would constitute a useful strategy to reduce renal radioactivity levels from early postinjection times.

A bolus injection multiple blood sampling method was developed for the simultaneous measurement of blood and plasma clearance of three radiopharmaceuticals in rats. Technetium-99m mercaptoacetyltriglycine ([(99m)Tc]MAG(3)) and iodine-131-orthoiodohippurate ([(131)I]OIH) were used as makers of effective renal blood flow (ERBF), and iodine-125 iothalamate ([(125)I]IOT) was used as a marker of glomerular filtration rate (GFR). These methods can be easily performed in rats without arterial catheterization. Tissue biodistribution was studied in four groups of rats subjected to the following: group A, renal pedicle isolation (sham-operated); group B, ligature of one kidney pedicle; group C, ligature of both renal pedicles; and group D, ligature of both kidney pedicles and the bile duct. Renal clearance of [(99m)Tc]MAG(3) was greater than [(131)I]OIH and both agents were cleared faster than ([(125)I]-IOT). Either of the two markers of ERBF may be used in experimental studies, but it should be borne in mind that these are relative measurements of kidney performance. [(99m)Tc]MAG(3) and [(125)I]-IOT showed bile excretion in healthy rats, so they cannot completely fulfill the requirements for use as markers of ERBF. When renal function was impaired experimentally, [(99m)Tc]MAG(3) and [(125)I]-IOT were excreted in bile and [(131)I]OIH was secreted in the intestine. Thus, while the markers of ERBF and GFR may be reliable under normal physiological conditions, they may give progressively more erroneous values as renal function deteriorates.

Objective—To determine the effect of number of blood samples and sampling times on plasma clearance of technetium Tc 99m pentetate (Tc99mP) and orthoiodohippurate sodium I 131(OIH). Animals—20 dogs and 14 cats. Procedure—Plasma clearances of OIH and Tc99mP were calculated by use of a 2-compartment model, on the basis of a 12-point curve as a reference method. Plasma clearance was calculated by use of all possible combinations of 4 to 11 samples. Time schedule yielding the smallest difference from the reference method was considered to be optimal. Regression analysis was performed between the 12-point model and models using a reduced number of samples. Results—SD of the difference between the 12-point clearance and the models with reduced numbers of samples increased when the number of samples decreased. The SD of the difference between 12-point clearance and 4-point clearance was 4.17 ml/min for OIH and 0.94 ml/min for Tc99mP in dogs and 0.45 ml/min for OIH and 0.11 ml/min for Tc99mP in cats. Optimal schedules were distributed logarithmically and included an early sample at 5 or 10 minutes, a late sample at 2.5, 3, 4, or 5 hours for OIH, and a late sample at 4 or 5 hours for Tc99mP. Conclusions and Clinical Relevance—Plasma clearances of OIH and Tc99mP can be accurately calculated in dogs and cats by use of a single-injection 2-compartment pharmacologic model with a reduced number of blood samples, resulting in an acceptable margin of error. (Am J Vet Res 2000;61:280–285)

Recent advances have increased the value of radionuclide renography in evaluating the patient with suspected disease of the genitourinary tract. The use of the consensus process to help standardize procedures and recommend interpretative criteria provides guidance for the nuclear medicine practitioner, serves as a basis to improve the standard of practice, and facilitates pooling of data from different centers. This review draws on the consensus criteria to present a personal approach to radionuclide renography with a particular emphasis on diuresis renography and the detection of renovascular hypertension. Patients are encouraged to come well hydrated and void immediately prior to the study. Our standard radiopharmaceutical is 99m Tc mercaptoacetyltriglycine (MAG 3 ). Routine quantitative indices include a MAG 3 clearance, whole kidney and cortical (parenchymal) regions of interest, measurements of relative uptake, time to peak height (T max ), 20 min/max count ratio, residual urine volume and a T 1/2 in patients undergoing diuresis renography. A 1-minute image of the injection site is obtained at the conclusion of the study to check for infiltration because infiltration can invalidate a plasma sample clearance and alter the renogram curve. A postvoid image of the kidneys and bladder is obtained to calculate residual urine volume and to better evaluate drainage from the collecting system. In patients undergoing diuresis renography, the T 1/2 is calculated using a region of interest around the activity in the dilated collecting system. A prolonged T 1/2 , however, should never be the sole criterion for diagnosing the presence of obstruction; the T 1/2 must be interpreted in the context of the sequential images, total and individual kidney function, other quantitative indices and available diagnostic studies. The goal of ACE inhibitor renography is to detect renovascular hypertension, not renal artery stenosis. Patients with a positive study have a high probability of cure or amelioration of the hypertension following revascularization. In patients with azotemia or in patients with a small, poorly functioning kidney, the test result is often indeterminate (intermediate probability) with an abnormal baseline study that does not change following ACE inhibition. In patients with normal renal function, the test is highly accurate. To avoid unrealistic expectations on the part of the referring physician, it is often helpful to explain the likely differences in test results in these two-patient populations prior to the study.

Purpose The surgical treatment of choice for significant hydronephrosis is dismembered pyeloplasty. While in open surgery, extensive resection of the dilated pelvis is common practice, laparoscopically usually only a sparing resection is performed. We compared the treatment results of both techniques to investigate whether extensive resection is necessary or not in dismembered pyeloplasty procedures. Methods To obtain comparable renal units, matched pairs according to age and relative kidney uptake as shown by (123)J-orthoiodohippurate renography were selected out of a total of 76 patients who underwent dismembered pyeloplasty between 2000 and 2007. Twenty-four patients complied with the criteria for inclusion in the study. Changes in urinary drainage preoperatively and at three months postoperatively were compared between both groups. Results The mean age in the sparing resection group was 3.8 years (range 0.3 to 14 years); in the extensive resection group it was 3.4 years (range 0.5 to 10 years). Mean urinary drainage improved significantly in both groups from 35.1 +/- 10.7 % to 75.2 +/- 13.2 % (sparing resection) vs. 45.1 +/- 23.7 % to 70.2 +/- 22 % (extensive resection). There were no differences between the groups (p > 0.05). Conclusions We conclude that extensive resection of the renal pelvis is not necessary in dismembered pyeloplasty procedures since there were no differences in the renographic outcome of comparable patients treated by the different surgical methods.

Radionuclide renal diagnostic studies play an important role in assessing renal allograft function especially in the early post transplant period. In the last two decades various quantitative parameters have been derived from the radionuclide renogram to facilitate and confirm the changes in perfusion and/or function of the kidney allograft. In this review article we discuss the quantitative parameters that have been used to assess graft condition with emphasis on the early post-operative period. These quantitative methods were divided into parameters used for assessing renal graft perfusion and parameters used for evaluating parenchymal function. The blood flow in renal transplants can be quantified by measuring (a) the rate of activity appearance in the kidney graft; (b) the ratio of the integral activity under the transplanted kidney and arterial curves e.g. Hilson's perfusion index and Kircher's kidney/aortic ratio; (c) calculating the renal vascular transit time by deconvolution analysis. The literature overview on these parameters showed us that they have some practical disadvantages of requiring high quality bolus injection and numerical variations related to changes in the site and size of regions of interest. In addition, the perfusion parameter values suffer from significant overlap when various graft pathologies coexist. Quantitative evaluation of the graft parenchymal extraction and excretion was assessed by parameters derived from 123I/131I-OIH, 99mTc-DTPA or 99mTc-MAG3 renograms. We review in this article a number of parenchymal parameters which include (1) plasma clearance methods like glomerular filtration rate (GFR) and effective renal plasma flow (ERPF); (2) renal transit times such as parenchymal mean transit time, Tmax, T1/2; (3) parenchymal uptake and excretion indices as the accumulation index, graft uptake capacity at 2 and 10 min, excretion index and elimination index. These indices, however, are non-specific and far from defining a specific cause for graft parenchymal dysfunction. In conclusion, despite that the literature is replete with mathematical strategies for quantitating perfusion and parenchymal functions, none of these have enough diagnostic power for specific diagnosis of graft dysfunction. In addition, no universal agreement on the use of certain quantitation parameters in transplant patients has been reached.

The aim of this study was to evaluate the reproducibility of 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) clearance and to compare it with that of 131I-orthoiodohippurate (131I-OIH), which is widely used in clinical practice. Twelve young healthy volunteers with a mean age of 23.4 years (range 19-28) were enrolled in the study. The investigations were repeated at an interval of 1 month under similar physiological conditions. Each volunteer received a simultaneous injection of 99Tcm-MAG3 and 131I-OIH that was commercially available in an already labelled form. Blood samples were obtained at 44 and 104 min post-injection. Clearance values were calculated using the two-sample method. The mean (+/- S.D.) change from the first to the second measurement was -7.1 +/- 11.1% for 99Tcm-MAG3 and 1.7 +/- 13.6% for 131I-OIH. There were no significant differences between the first and the second measurements of 99Tcm-MAG3 and 131I-OIH clearance, respectively. 99Tcm-MAG3 clearance was shown to be very similar to that of 131I-OIH in healthy volunteers.

Interposition of a metabolizable linkage has been performed to reduce the hepatic radioactivity levels of radiolabeled antibodies. To estimate the validity of this strategy, a radioiodination reagent (HML) that provides a stable attachment for m-iodohippuric acid with proteins in plasma while facilitating rapid and selective release of the compound after lysosomal proteolysis in the liver was conjugated with a monoclonal antibody (mAb) against osteogenic sarcoma (OST7, IgG1). Radiolabeled OST7 conjugates with a plasma-labile ester bond for releasing m-iodohippuric acid (MIH), plasma-stable amide bonds for releasing radiometabolites of hepatobiliary excretion (MPH), or slow elimination rates from hepatocytes ([111In]EMCS-Bz-EDTA) were prepared with similar conjugation chemistry. The four radiolabeled OST7 conjugates were characterized both in vitro and in vivo. All the radiolabeled OST7 conjugates had similar radiochromatograms on size-exclusion HPLC and similar antigen binding affinities. While MIH-OST7 indicated accelerated clearance of radioactivity from the blood due to the release of m-iodohippurate, the rest of the three radiolabeled OST7 conjugates remained stable in serum incubation studies and had similar radioactivity elimination from the blood in vivo. When injected into normal mice, HML-OST7 demonstrated tissue-to-blood ratios of radioactivity similar to those of MIH-OST7 and significantly lower than those of the other two radiolabeled OST7 conjugates. In biodistribution studies in nude mice, both HML-OST7 and MIH-OST7 exhibited tumor-to-liver or tumor-to-intestine ratios of radioactivity higher than those of [111In]EMCS-Bz-EDTA-OST7 or MPH-OST7, respectively. HML-OST7, MPH-OST7, and [111In]EMCS-Bz-EDTA-OST7 indicated there were no changes in the radioactivity levels in the tumor between 24 and 48 h postinjection, whereas MIH-OST7 significantly decreased the radioactivity levels in the tumor at these time points. HML reduced the radioactivity levels in nontarget tissues without impairing the tumor radioactivity levels delivered by OST7. These findings indicated that the design of a radiolabeled mAb that is stable in plasma and liberates the radiometabolite of rapid urinary excretion constitutes an effective strategy for achieving target-selective radioactivity delivery.

Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptides after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L-HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteolysis in hepatic cells were investigated after conjugation of [131I]-L-HML with galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I]-L-HML-NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murine liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.

A method for accurate measurement of GFR in conscious, spontaneously voiding rats. Renal function measurement by clearance methods relies on accurately timed urine collection. In small experimental animals, renal function measurement is usually performed under anesthesia and/or with the application of bladder catheters to ensure accurate urine collection. To avoid both anesthesia and the need for bladder catheters we developed a method to measure glomerular filtration rate (GFR) in spontaneously voiding conscious rats. GFR was measured as the urinary clearance of constantly infused 125I-iothalamate. To correct for incomplete bladder emptying, urinary clearance of 125I-iothalamate was multiplied by the ratio of plasma and urinary clearance of simultaneously infused 131I-hippuran, a correction method that has been previously validated in humans. Reproducibility of the technique was evaluated by analysis of the results of four consecutive clearance periods during the day (intra-assay variation) in a group of 17 rats and of two consecutive clearance periods on two or three separate days in a group of 20 rats (inter-assay variation), all with normal renal function. Application of the correction method reduced the intra-assay coefficient of variation (mean ± SD) from 37.4 ± 14.3 to 5.4 ± 2.3% (P < 0.05). The mean inter-assay coefficient of variation fell slightly from 23.4 ± 10.3 to 11.0 ± 7.2% (P < 0.10). In rats with moderately impaired renal function (N = 8) the intra-assay variation fell from 27.9 ± 20.7 to 2.7 ± 1.6% (P < 0.05). Our data show that this correction method is a useful technique to assess renal function in conscious, spontaneously voiding rats.

Iodine-131 labelled meta-iodobenzylguanidine ([131I]MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [131I]MIBG (3.1-7.5 GBq) to 17 patients (n=32 courses), aged 2-73 years, 56%+/-10%, 73%+/-11%, 80%+/-10% and 83%+/-10% of the dose was cumulatively excreted as total radioactivity in urine at t=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%-18% of [131I]meta-iodohippuric acid ([131I]MIHA), the cumulatively excreted radioactivity consisted of >85% [131I]MIBG, with 6% of the dose excreted as free [131I]iodide, 4% as [131I]MIHA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [131I]MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [131I]meta-iodobenzoic acid in two patients, a possible metabolic pathway for [131I]MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity.

Radioiodinated meta -iodobenzylguanidine ([ 123 I/ 131 I]MIBG) is used for diagnostic scintigraphy of neural crest tumours (such as neuroblastoma and malignant phaeochromocytoma) and for scintigraphic assessment of cardiac neuronal integrity. Moreover, [ 131 I]MIBG is also used for radionuclide therapy of neural crest tumours. Part I of this paper presents a simple solid phase extraction procedure for the separate quantification of [ 123 I/ 131 I]MIBG and its radiolysis product [ 123 I/ 131 I]iodide in biological matrices. The method has been validated for whole blood, plasma, urine and saliva. After intravenous administration of [ 123 I]MIBG, containing only 2% free [ 123 I]iodide, to a patient, the [ 123 I]iodide level—expressed as percentage of total radioactivity in each matrix sample—amounted to: 3% (urine), 5% (blood cells), 20% (whole blood), 32% (plasma) and 100% (saliva). Part II describes a sensitive HPLC procedure, including sample pretreatment, for the determination of [ 131 I]iodide, [ 131 I]MIBG and three metabolites, including [ 131 I] meta -iodohippuric acid ([ 131 I]MIHA) and [ 131 I] meta -iodobenzoic acid, in urine of patients treated with therapeutic amounts of [ 131 I]MIBG. The parent drug and its metabolites could be detected in urine for at least 5 days after administration. The procedure was highly reproducible for the quantification of [ 131 I]MIBG and [ 131 I]MIHA, yielding relative standard deviations of

We previously demonstrated that Fab fragments labeled with 3'-[(131)I]iodohippuryl N(e)-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(e)-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.

This is a review of investigations on iodo-benzoic acid, iodohippuric acid, and iodophenol derivatives by NQR, NMR, and emission Mössbauer spectroscopy. The influence of intermolecular, intramolecular, and bifurcated O-H…I and O-H…O bonds on the properties of iodine-carbon bonds is demonstrated. Ionized and non-ionized forms of tyrosine differ by the probability of H-bond formation. The simultaneous use of 127I NQR and emission Mössbauer 125I spectroscopy open the possibility to determine the types of tellurium-organic substances formed in the process of K-decay of 125I.