Optimum Olsen Phosphorus/ZincDTPA ratio for the initial growth of maize in agricultural soils of the Mediterranean region.

BACKGROUND: Zinc (Zn) deficiency in crops is commonly aggravated by high levels of phosphorus (P) in soil. In this work, the initial performance of pot-growing maize in response to the available P and Zn in soils with low available Zn and to the application of P and Zn fertilizers was investigated. RESULTS: The soils (six non-calcareous and 14 calcareous) ranged widely in available P (Olsen P: 5.5-37.9 mg kg-1 ), were poor in available Zn [diethylenetriaminepentaacetic acid-extractable Zn (ZnDTPA ): 0.20-0.84 mg kg-1 ] and had an Olsen P/ZnDTPA ratio of 13 to 111 mg mg-1 . Soil P application generally increased aerial dry matter (ADM) yield; Zn increased ADM yield mostly when applied in combination with P; and the sole application of Zn increased yield only in a soil with a high (28 mg kg-1 ) Olsen P and a low (0.36 mg kg-1 ) ZnDTPA . The increase in ADM yield resulting from optimal application of P and/or Zn to the soil was modest in soils where the Olsen P/ZnDTPA ratio was 30-60 and Olsen P was >14 mg kg-1 . Zinc uptake by the control plants was correlated with the ZnDTPA of the soil. For a certain ZnDTPA value, the level of plant available Zn was higher in non-calcareous than in calcareous soils. CONCLUSION: Soil application of fertilizer P and Zn, in soils with low levels of available Zn, should not only aim at increasing the available P and Zn levels but also balancing them at the appropriate Olsen P/ZnDTPA ratio, which was found to lie in the 30-60 range in the present study. © 2020 Society of Chemical Industry.

Decorporation of Pu/Am Actinides by Chelation Therapy: New Arguments in Favor of an Intracellular Component of DTPA Action.

Diethylenetriaminepentaacetic acid (DTPA) is currently still the only known chelating drug that can be used for decorporation of internalized plutonium (Pu) and americium (Am). It is generally assumed that chelation occurs only in biological fluids, thus preventing Pu/Am deposition in target tissues. We postulate that actinide chelation may also occur inside cells by a mechanism called "intracellular chelation". To test this hypothesis, rats were given DTPA either prior to (termed "prophylactic" treatment) or belatedly after (termed "delayed" treatment) Pu/Am injection. DTPA decorporation efficacy was systematically tested for both plutonium and americium. Both prophylactic and delayed DTPA elicited marked decreases in liver Pu/Am. These results can be explained by chelation within subcellular compartments where DTPA efficacy increased as a function of a favorable intracellular DTPA-to-actinide molar ratio. The efficacy of intracellular chelation of liver actinides decreased with the delay of treatment. This is probably explained by progressive actinide binding to the high-affinity ligand ferritin followed by migration to lysosomes. Intracellular chelation was reduced as the gap between prophylactic treatment and contamination increased. This may be explained by the reduction of the intracellular DTPA pool, which declined exponentially with time. Skeletal Pu/Am was also reduced by prophylactic and delayed DTPA treatments. This decorporation of bone actinides may mainly result from extracellular chelation on bone surfaces. This work provides converging evidence for the involvement of an intracellular component of DTPA action in the decorporation process. These results may help to improve the interpretation of biological data from DTPA-treated contamination cases and could be useful to model DTPA therapy regimens.

Inhibitory potential of three zinc chelating agents against the proteolytic, hemorrhagic, and myotoxic activities of Echis carinatus venom.

Viperbites undeniably cause local manifestations such as hemorrhage and myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and necrosis. The principle toxin responsible is attributed to snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors. In this study, we have evaluated the inhibitory potential of three specific zinc (Zn(2+)) chelating agents; N,N,N',N'-tetrakis (2-pyridylmethyl) ethane-1,2-diamine (TPEN), diethylene triamine pentaacetic acid (DTPA), tetraethyl thiuram disulfide (TTD) on Echis carinatus venom (ECV) induced hemorrhage and myotoxicity. Amongst them, TPEN has high affinity for Zn(2+) and revealed potent inhibition of ECV metalloproteases (ECVMPs) in vitro (IC50: 6.7 µM) compared to DTPA and TTD. The specificity of TPEN towards Zn(2+) was confirmed by spectral and docking studies. Further, TPEN, DTPA, and TTD completely blocked the hemorrhagic and myotoxic activities of ECV in a dose dependent manner upon co-injection; whereas, only TPEN successfully neutralized hemorrhage and myotoxicity following independent injection. Histological examinations revealed that TPEN effectively prevents degradation of dermis and basement membrane surrounding the blood vessels in mouse skin sections. TPEN also prevents muscle necrosis and accumulation of inflammatory cells at the site of ECV injections. In conclusion, a high degree of structural and functional homology between mammalian MMPs and SVMPs suggests that specific Zn(2+) chelators currently in clinical practice could be potent first aid therapeutic agents in snakebite management, particularly for local tissue damage.

A drug-repositioning screening identifies pentetic acid as a potential therapeutic agent for suppressing the elastase-mediated virulence of Pseudomonas aeruginosa.

Pseudomonas aeruginosa, a Gram-negative bacterium of clinical significance, produces elastase as a predominant exoprotease. Here, we screened a library of chemical compounds currently used for human medication and identified diethylene triamine penta-acetic acid (DTPA, pentetic acid) as an agent that suppresses the production of elastase. Elastase activity found in the prototype P. aeruginosa strain PAO1 was significantly decreased when grown with a concentration as low as 20 µM DTPA. Supplementation with Zn(2+) or Mn(2+) ions restored the suppressive effect of DTPA, suggesting that the DTPA-mediated decrease in elastase activity is associated with ion-chelating activity. In DTPA-treated PAO1 cells, transcription of the elastase-encoding lasB gene and levels of the Pseudomonas quinolone signal (PQS), a molecule that mediates P. aeruginosa quorum sensing (QS), were significantly downregulated, reflecting the potential involvement of the PQS QS system in DTPA-mediated elastase suppression. Biofilm formation was also decreased by DTPA treatment. When A549 alveolar type II-like adenocarcinoma cells were infected with PAO1 cells in the presence of DTPA, A549 cell viability was substantially increased. Furthermore, the intranasal delivery of DTPA to PAO1-infected mice alleviated the pathogenic effects of PAO1 cells in the animals. Together, our results revealed a novel function for a known molecule that may help treat P. aeruginosa airway infection.

Decorporation approach following rat lung contamination with a moderately soluble compound of plutonium using local and systemic Ca-DTPA combined chelation.

Decorporation efficacy of prompt pulmonary delivery of DTPA dry powder was assessed following lung contamination with plutonium nitrate and compared to an intravenous injection of DTPA solution and a combined administration of both DTPA compounds. In addition, efficacy of a delayed treatment was assessed. In case of either early or late administration, insufflated DTPA was more efficient than intravenously injected DTPA in reducing the plutonium lung burden due to its high local concentration. Prompt treatment with DTPA powder was also more effective in limiting extrapulmonary deposits by removing the early transportable fraction of plutonium from lungs prior its absorption into blood. Translocation of DTPA from lungs to blood may also contribute to the decrease in extrapulmonary retention, as shown by reduced liver deposit after delayed pulmonary administration of DTPA. Efficacy of DTPA dry powder was further increased by the combined intravenous administration of DTPA solution for reducing extrapulmonary deposits of plutonium and promoting its urinary excretion. According to our results, the most effective treatment protocol for plutonium decorporation was the early pulmonary delivery of DTPA powder supplemented by an intravenous injection of DTPA solution. Following inhalation of plutonium as nitrate chemical form, this combined chelation therapy should provide a more effective method of treatment than conventional intravenous injection alone. At later stages following lung contamination, pulmonary administration of DTPA should also be considered as the treatment of choice for decreasing the lung burden.

Iron-binding compounds impair Pseudomonas aeruginosa biofilm formation, especially under anaerobic conditions.

The success of Pseudomonas aeruginosa in cystic fibrosis (CF) and other chronic infections is largely attributed to its ability to grow in antibiotic-resistant biofilm communities. This study investigated the effects of limiting iron levels as a strategy for preventing/disrupting P. aeruginosa biofilms. A range of synthetic and naturally occurring iron-chelating agents were examined. Biofilm development by P. aeruginosa strain PAO1 and CF sputum isolates from chronically infected individuals was significantly decreased by iron removal under aerobic atmospheres. CF strains formed poor biofilms under anaerobic conditions. Strain PAO1 was also tested under anaerobic conditions. Biofilm formation by this model strain was almost totally prevented by several of the chelators tested. The ability of synthetic chelators to impair biofilm formation could be reversed by iron addition to cultures, providing evidence that these effective chelating compounds functioned by directly reducing availability of iron to P. aeruginosa. In contrast, the biological chelator lactoferrin demonstrated enhanced anti-biofilm effects as iron supplementation increased. Hence biofilm inhibition by lactoferrin appeared to occur through more complex mechanisms to those of the synthetic chelators. Overall, our results demonstrate the importance of iron availability to biofilms and that iron chelators have potential as adjunct therapies for preventing biofilm development, especially under low oxygen conditions such as encountered in the chronically infected CF lung.

Removal of 65Zn from mouse body by isotopic dilution and by DTPA chelation.

Isotopic dilution with stable zinc and chelation with DTPA are recommended for removal of radioactive zinc from the body; however, it is unclear which method is more effective. In the present study, the efficacies of these methods were compared in order to determine which treatment should be selected in case of internal contamination with radioactive zinc. Intraperitoneal administration of stable zinc dose-dependently removed 65Zn from the mouse body. However, the dose could not be increased above 3 mg/kg due to its toxicity. Oral administration of zinc was less effective than intraperitoneal administration at the same dose. Our results suggest that the recommended dose of stable zinc (2-3 mg/kg, p.o.) has little efficacy. The efficacies of Ca-DTPA and Zn-DTPA were strongly dependent on the elapsed time after 65Zn exposure. Zn-DTPA was more effective than Ca-DTPA, and its recommended dose (30 micromol/kg) significantly removed 65Zn. Therefore, chelation therapy with Zn-DTPA should be started as soon as possible after internal contamination with radiozinc.

Experience with indium-111 and yttrium-90-labeled somatostatin analogs.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide / lanreotide analogs as tumor tracers in nuclear medicine. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or immunologic diseases such as thyroid-associated ophthalmology. The vast majority of human tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-DTPA-DPhe(1)-octreotide (OctreoScan(R)) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (K(d) 10-100 nM) and does not bind to hSSTR1 and hSSTR4, (111)In / (90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d) 200 nM). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to (111)In-DTPA-DPhe(1)-octreotide and (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higherrdquuo; high-affinity binding of (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide to hSSTR2 (K(d) 0.1-1 nM). Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as (99m)Tc-depreotide (NeoSpect(R); NeoTect(R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or nonsmall cell lung cancer ((99m)Tc-depreotide), indicating high diagnostic cabability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. Beneficial results were reported for high-dose treatment with (111)In-DTPA-DPhe(1)-octreotide, based on the emission of Auger electrons. The Phase IIa study "MAURITIUS" (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study) showed in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy / GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the "MAURITIUS" study, cummulative treatment doses up to 200 mCi (90)Y-DOTA-lanreotide were given as short-term infusion. Overall treatment results in 70 patients indicated stable tumor disease in 35% of patients and regressive tumor disease in 10% of tumor patients with different tumor entities expressing hSSTR. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to (90)Y-DOTA-lanreotide treatment, were reported. (90)Y-DOTA-DPhe(1)-Tyr(3)-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore be superior for treatment in patients with neuroendocrine tumors. However, there is only limited excess to long-term and survival data at present. Potential indications for (90Y-DOTA-lanreotide are radioiodine-negative thyroid cancer, hepatocellular cancer and lung cancer. Besides newer approaches and recent developments of 188)Re-labeled radioligands, no clinical results on the treatment response are yet available. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm their potential use in diagnosis as well as "proof-of-principle" for therapy of cancer patients. However, an optimal radiopeptide formulatioents. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy. Ongoing developments may result in peptides more suitable for this kind of receptor-targeted radionuclide therapy.

Circulatory kinetics of intravenously injected 238Pu(IV) citrate and 14C-CaNa3-DTPA in mice: comparison with rat, dog, and reference man.

New ligands for in vivo chelation of Pu(IV) are being synthesized and evaluated in mice for efficacy and toxicity. Biokinetic studies of the new ligands, CaNa3-DTPA, and Pu(IV) are major components of those investigations. Young adult female mice were injected intravenously (iv) with 3H-inulin, 14C-CaNa3-DTPA, or 238Pu(IV) citrate to provide baseline data for plasma clearance, tissue uptake, and excretion rates and to determine the dilution volume (VOD) and renal clearance rate (RC) of filterable substances. Published plasma clearance data for iv-injected 14C-CaNa3-DTPA and Pu(IV) citrate in Reference Man, dog, and rat were collected. Based on combined data for 3H-inulin and 14C-CaNa3-DTPA, VOD = 17% of body weight and RC = 18 mL kg(-1) min(-1) for mice. Retention of 14C-CaNa3-DTPA in the four species is proportional to body weight and inversely proportional to RC: Integrals of the retention of 14C-CaNa3-DTPA from R(t) = 1.0 to R(t) = 0.05 are 108, 43, 28, and 10 DF min, respectively, for Reference Man, dog, rat, and mouse. Clearances of iv-injected Pu(IV) citrate from plasma are in the same order: The plasma curve integrals from injection to 1440 min are 840, 640, 280, and 67 DF min, respectively, for Reference Man, dog, rat, and mouse. In mice, a large fraction of newly injected Pu(IV) is rapidly transferred to the interstitial water of bulk soft tissue (excluding liver and kidneys), from which it is cleared at the same rate as from the plasma. Rapid plasma clearance, escape into interstitial water (22%ID at 20 min), significant early urinary excretion (8%ID in 12 h), and prompt deposition in liver and skeleton (complete in 12 h) are evidence of inefficient binding to plasma protein (mainly transferrin) of newly injected Pu(IV) in mice. Conversely, slow plasma clearance, little early urinary excretion, and delayed deposition in liver and skeleton reflect more efficient binding by transferrin of newly injected Pu(IV) in Reference Man and dog. Pharmacokinetic parameters (effective dosage, effective concentration) of CaNa3-DTPA, alone or combined with plasma Pu(IV) integrals, yielded only qualitative predictions of the relative efficacies of CaNa3-DTPA therapy in four species. The need for improved models of Pu(IV) and ligand biokinetics and the suitability of the three animals for predicting chelation therapy outcomes in humans are discussed.

Gadolinium chelate MR contrast agents.

Several Gadolinium chelates are now available or will shortly become available. They differ in being, variously, ionic or non-ionic and in being of higher or lower osmolality. Although they differ in detail of chemical structure, they are all based on the same general principle and all possess the same extracellular distribution pharmacokinetics (Gd BOPTA excepted), typical for their molecular size. In terms of efficacy there is no convincing evidence that any one is clinically superior to the others. As regards reducing osmolality, it is not self evident that, in the recommended and currently widely used dosage regimens, high osmolality presents any real clinical problems. However, if 'high dosage' regimens or dynamic bolus imaging come to be more widely used, then the newer agents may be perceived to have clinical advantages.

The effect of circulating antigen and radiolabel stability on the biodistribution of an indium labelled antibody.

This study has investigated two of the main problems with radiolabelled antibody imaging, the formation of circulating immune complexes (I.C.) and the non specific binding of radiolabel to the antibody molecule. Patients undergoing immunoscintigraphy with 111In labelled monoclonal antibody ICR2 were divided into three groups who received either the radiolabelled antibody alone (control, n = 12), the radiolabelled antibody which was incubated with the chelating agent diethylene triamine pentacetic acid (DTPA) prior to size exclusion chromatography (n = 6) or whose injectate was treated with DTPA and cold MAb administered intravenously prior to radiolabelled MAb administration (n = 6). Radiolabelled antibody uptake in abdominal organs was measured by region of interest analysis using a gamma camera with online computer and that in tumour and normal tissues by gamma well counting of biopsies. Circulating antigen and immune complex was measured by high pressure liquid chromatography (HPLC). The sensitivity of tumour imaging and the tumour uptake of radiolabelled antibody was not significantly different between the groups. Patients with high circulating antigen levels developed high levels of circulating immune complex but also had high tumour uptakes of radiolabelled antibody. Administration of cold MAb increased the splenic, but did not effect the tumour uptake of radiolabelled antibody and only minimally reduced levels of circulating immune complex. Chelate administration reduced the urinary excretion of radioactivity but increased the liver uptake of radioactivity. These results have shown that successful antibody imaging can be carried out despite high levels of circulating antigen, that large doses of unlabelled antibody are required to prevent immune complex formation and that removal of non specifically bound 111In does not reduce the liver uptake of radioactivity.

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

Model studies of the iron-catalysed Haber-Weiss cycle and the ascorbate-driven Fenton reaction.

Complementary hydroxylation assays and stopped-flow e.s.r. techniques have been employed in the investigation of the effect of various iron chelators (of chemical, biological and clinical importance) on hydroxyl-radical generation via the Haber-Weiss cycle and the ascorbate-driven Fenton reaction. Chelators have been identified which selectively promote or inhibit various reactions involved in hydroxyl-radical generation (for example, NTA and EDTA promote all the reactions of both the Haber-Weiss cycle and the ascorbate-driven Fenton reaction, whereas DTPA and phytate inhibit the recycling of iron in these reactions). The biological chelators succinate and citrate are shown to be relatively poor catalysts of the Haber-Weiss cycle, whereas they are found to be effective catalysts of .OH generation in the ascorbate-driven Fenton reaction. It is also suggested that continuous redox-cycling reactions between iron, oxygen and ascorbate may represent an important mechanism of cell death in biological systems.

Effects of common therapeutic concentrations of oxygen on lung clearance of 99mTc DTPA and bronchoalveolar lavage albumin concentration.

We studied the effects of oxygen concentrations (21 to 50%) considered clinically "safe" on clearance of inhaled technetium-labeled diethylene triamine pentaacetate (99mTc DTPA) and the concentration of albumin in bronchoalveolar lavage (BAL) fluid of normal subjects. We also measured several markers of cell injury and inflammation in the BAL fluid including total and differential cell counts, lactate dehydrogenase, alkaline phosphatase, extracellular potassium, and several eicosanoids. Subjects inhaled oxygen (50, 40, 30, or 21%) for a mean of 45 h; there were no symptoms or bronchoscopic signs of oxygen toxicity. The concentration of albumin in BAL fluid was increased compared with baseline measurements in a dose-dependent manner in subjects exposed to 30% oxygen and above. Clearance of 99mTc DTPA was increased only in subjects who inhaled 50% oxygen. There were no significant changes in BAL fluid volume or total and differential cell counts after oxygen exposure. A trend towards an increased percentage of polymorphonuclear leukocytes was noted in the 50% oxygen group. We found no evidence of cell injury or inflammation in the BAL fluid. Supplemental humidity did not appear to influence the findings in the 50% oxygen group. Thus, oxygen in concentrations considered clinically "safe" increases clearance of 99mTc DTPA and BAL albumin concentration in normal subjects after a relatively short time of exposure.

High dose urography in patients with renal failure. A double blind investigation of iohexol and metrizoate.

The new non-ionic contrast medium iohexol 350 mg I/ml was compared with the ionic contrast medium metrizoate 350 mg I/ml in a double blind, two-group urographic study performed on 20 patients with stable, impaired renal function. A dose of contrast medium of 500 mg I/kg body weight was given to each patient. Iohexol resulted in significantly fewer subjective adverse reactions than metrizoate. A similar image quality was obtained with the two contrast media. No clinically significant difference existed between the two contrast media with respect to influence on blood pressure, pulse or clinical chemical parameters. A tendency to deterioration of renal function after urography was found in both groups, but no difference of statistical significance existed between the two contrast media with respect to possible nephrotoxicity. Inadequate hydration may have been partly responsible for the nephrotoxic effect of the urographic procedure.

Paramagnetic contrast agents in magnetic resonance imaging: research at Vanderbilt University.

Experimental studies in animals have demonstrated the application of particulate and chelated paramagnetic oral contrast agents in magnetic resonance imaging (at 0.5 tesla). The ability of a soluble paramagnetic species, ferrous gluconate, to improve imaging studies of the pancreas presently is being evaluated in clinical trials. Two paramagnetic metal ion chelates, Cr EDTA and Gd DTPA, have been evaluated extensively as potential intravascular contrast agents. Renal function, tissue vascularity, abnormalities of the blood-brain barrier, and infarction of myocardial tissue may all be assessed with IV contrast enhanced magnetic resonance imaging. The contrast materials tested all represent first generation compounds. Improved relaxation characteristics, toxicity, distribution, and flexibility will result from development of second generation agents, primarily within the particulate and chelate classes.

Chemical and biological studies of Tc-99m N,N'-bis(mercaptoacetamido)-ethylenediamine: a potential replacement for I-131 iodohippurate.

The tetradentate chelating agent N,N'-bis(benzoylmercaptoacetamido)ethylenediamine was synthesized for evaluation as a potential technetium-99m renal-function radiopharmaceutical. Complexes were prepared using different reducing agents and analyzed by high-performance liquid chromatography. Biological studies were performed in mice, rats, and rabbits and indicated that the new agent is cleared by the kidneys significantly faster than Tc-99m DTPA (p less than 0.01) and slightly slower than I-131 o-iodohippuric acid (p greater than 0.05). There was no evidence of significant renal retention. Renal excretion in all species studied was 70--75% of the injected dose in 30 min; biliary excretion in rats was 7% in animals with normal renal function and 18% in 90 min in the absence of renal function. We conclude that limited clinical trials are warranted.

Ruthenium-97 DTPA: a new radiopharmaceutical for cisternography.

Ruthenium-97 DTPA (diethylenetriamine penta-acetic acid) was evaluated for its possible use as a cerebrospinal fluid imaging agent. Ru-97 has favorable physical properties that are highly suitable for imaging: decay by electron capture; gamma energy = 216 keV, 85%; T 1/2 = 2.9 days. Dogs were injected with 0.4 mCi Ru-97 DTPA or In-111 DTPA into the cisterna magna. The movement of the agents was monitored with a camera interfaced to a computer, or with a dual-probe system placed over the head and urinary bladder. In addition, blood and urine samples were collected at fixed intervals for 6 hr. High-quality images were obtained up to 48 hr after injection. The results show that the kinetics and excretion of Ru-97 DTPA are similar to those of In-111 DTPA. Radiation dose for identical activities is twice as high for In-111, in part because of greater abundance of the low-energy electron emission of In-111.