EDTMP Research Articles

Empirical molecular modelling of crystal growth modifiers

Molecular modelling has been successfully used to interpret the effect of two molecules on the crystal growth of barium sulfate. The replacement energy was found to correlate with the degree of inhibition as determined from conductivity experiments. It was also able to predict the preferred barium sulfate face for additive adsorption. For EDTP (ethylenediaminetetramethylenephosphonic acid), the energetically favoured adsorption configurations were those where the phosphonate groups occupied vacant sulfate lattice sites, whilst for EDTA (ethylenediaminetetraacetic acid) it was generally not possible for all the carboxylate groups to lie within the surface and so surface barium cation to additive oxygen interactions became important. Whether in the surface or above it, the number of Ba-Omodifier interactions were important in making adsorption of the modifier energetically favourable.

Recommandations pour la pratique clinique : Standards, Options et Recommandations pour la prise en charge par radiothérapie des patients atteints d'ostéosarcome.

The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French regional cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. To update the SOR recommendations for the use of radiation therapy in the management of patients with osteosarcoma. This work was performed in collaboration with the French society against cancers in children and adolescent (SFCE). Data have been identified by literature search using Medline (from January 1992 to October 2003). In addition several Internet sites were searched in October 2003. The 3 mains standards are: 1) local and exclusive curative irradiation is not indicated as primary treatment for osteosarcoma or for local and operable recurrence, except for lesion in inaccessible sites or if the patient refuses surgery; 2) local and prophylactic adjuvant irradiation is not indicated for the treatment of osteosarcoma after chemotherapy (neoadjuvant and/or adjuvant) and complete macro or microscopic surgery, except for non-operable R1 or R2 surgical resection; 3) whole-lung prophylactic irradiation is not indicated in non-metastatic osteosarcoma. Systemic metabolic radiotherapy for pain treatment, using samarium-153 ethylenediaminetetramethylene phosphonic acid (Sm-153-EDTMP) can be offered to patients with painful metastatic osteosarcoma or in case of recurrent bone sites inaccessible to local therapies (surgery, external irradiation).

A statistical analysis of the initial biodistribution of 153Sm-EDTMP in a canine

153Sm ( t 1 / 2 = 46 h ) emits a 103 keV gamma photon and two medium-energy beta particles. Five mCi of Samarium-153 ethylenediaminetetramethylenephosphonic acid ( 153Sm-EDTMP) were administered to a clinically normal dog and whole body scans were obtained at 15 min, 2 h, and 24 h post-injection (PI). Regions of interest (ROIs) were drawn representing abdomen, knee, rib, vertebral bodies, bladder, kidney, and liver, in each image. For each ROI, the mean intensity and standard deviation were computed, and a histogram was created. Clinically significant increased uptakes were found in liver and kidney.

Complexation Properties of Ethylenediaminetetramethylenephosphonic Acid (EDTMP) with AlIII and VIVO

AbstractThe complexation properties (including stoichiometries and stability constants of the complexes formed) of ethylenediaminetetramethylenephosphonic acid with AlIII and VIVO were studied in aqueous solution at an ionic strength of 0.2 M KCl, at 25 °C by means of pH potentiometry. For AlIII both mononuclear (AlLHn) and dinuclear (Al2LHn) species were found in solution, whereas for VIVO only mononuclear complexes were detected. For each metal ion, a solid complex was isolated at acidic pH and was characterized stoichiometrically. 1H and 31P NMR (for AlIII), UV/Vis and EPR (for VIVO) spectra were used to confirm the potentiometric results and to suggest the most probable binding mode of the complexes formed in solution. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

175Yb labeled polyaminophosphonates as potential agents for bone pain palliation

Ytterbium-175 ( T 1/2=4.2 d, E β(max) =480 keV) has radionuclidic properties suitable to be used in palliative therapy of bone metastases. 175Yb can be produced in moderate specific activity and good radionuclidic purity by thermal neutron bombardment of natural Yb target. The analysis of the neutron irradiated sample exhibited the presence of 96.2% 175Yb along with 2.1% 169Yb and 1.7% 177Lu at 6 h post-EOB. Four polyaminomethylene phosphonic acid ligands, ethylenediamine tetramethylene phosphonic acid, propylenediamine tetramethylene phosphonic acid, triethylenetetramine hexamethylene phosphonic acid and diethylenetriamine pentamethylene phosphonic acid were synthesized and radiolabeled with 175Yb. Complexation parameters were optimized to achieve maximum yields (92–99%). All complexes were found to retain their stability at room temperature even after 10 d of preparation. Biodistribution studies of the complexes carried out in Wistar rats showed significant bone uptake (3–4.4%/g in tibia at 3 h post-injection) with rapid clearance from blood and minimum uptake in soft tissues for all the complexes (bone/blood ratio ∼40–150 and bone/muscles ratio ∼40–400 at 3 h post-injection). These studies suggest that 175Yb complexes with the phosphonate ligands have potential for use in palliative treatment of painful bone metastases.

Complexation of 188Re-phosphonates: in vitro and in vivo studies

Summary MDP (methylenediphosphonate) and HEDP (hydroxyethylidene diphosphonate), both diphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid), a tetraphosphonate ligand, have been previously labeled with 188Re for use in metastatic bone-pain palliation. The aim of this study was a comparison between the three complexes 188Re-MDP, 188Re-HEDP and 188Re-EDTMP concerning the complexation conditions, in order to achieve maximum yield, stability and bone uptake. Methods: MDP was dissolved in water and HEDP and EDTMP were dissolved in NaOH 1N followed by reduction of pH with HCl 1N. To all mixtures stannous chloride and 188Re4 - were added in a nitrogen atmosphere. The preparations were heated in boiling water bath for 15min. Yield as well as radiochemical stability was estimated by ITLC. Different concentrations of phosphonates and stannous chloride were evaluated. Biodistribution studies in Swiss mice were done for the three 188Re-phosphonates that presented the best radiochemical yield. The optimal ligand concentration for maximum complexation was 85.2mM for MDP, 72.8mM for HEDP and 45.8mM for EDTMP. The best amount of SnCl2·2H2O} was 1.5mg/mL for 188Re-HEDP and 1mg/mL for both 188Re-MDP and 188Re-EDTMP. In these conditons the three complexes showed a complexation rate above 95. Reasonable radiochemical stability for 24 hours was achieved by 188Re-EDTMP when employing ascorbic acid. All products showed a great uptake by the kidneys. 188Re-EDTMP had the greatest uptake by femur (3.1±0.2 ID/g) followed by 188Re-MDP (1.2±0.1 ID/g) and 188Re-HEDP (1.0±0.1 ID/g), 4 hours post injection. 188Re-EDTMP displayed a femur bone/muscle ratio of 28.5, 188Re-MDP 4.9 and 188Re-HEDP 4.9. In conclusion 188Re-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further dosimetric studies and clinical trials.

Evaluation of a freeze-dried kit for EDTMP-based bone-seeking radiopharmaceuticals

A freeze-dried kit developed for formulation of ethylenediamine-tetramethylenephosphonic acid (EDTMP) chelates with “pain-palliation” radiolanthanides (e.g., 153Sm and 177Lu) or “diagnostic” 99mTc has been evaluated, meeting quality and safety criteria required for medicinal use. The EDTMP kit enables an instant one-step preparation of a radiopharmaceutical of high radiochemical purity (>99%) and has a sufficiently long shelf life. Comparative biodistribution studies of 177Lu-EDTMP and 99mTc-EDTMP prepared from the kit revealed similar tissue uptake and clearance to those obtained for pre-formulated 153Sm-EDTMP. The most significant difference was observed for 99mTc-EDTMP, which shows a high retention in kidney, reaching ca. 2% ID after 90 min p.i.v. Although preliminary clinical evaluations suggest that 99mTc-EDTMP possesses limited value for bone scintigraphy, application of the radiopharmaceutical for specific diagnostic purposes may still be considered, e.g., investigation of bone metastases or ossification processes in inflammatory spondyloarthropathy.

Interaction of immunoglobulin G with N,N,N′,N′-ethylenediaminetetramethylenephosphonic acid-modified zirconia

Zirconia beads (25–38 μm in diameter) were modified with N,N,N′,N′-ethylenediaminetetramethylenephosphonic acid to generate a pseudo-biospecific support, r_PEZ. To better understand the force of interaction between the IgG and the r_PEZ, the equilibrium dissociation constant ( K d) was determined by static binding isotherms, as a function of temperature and by frontal analysis at different linear velocities. Temperature had no significant impact on the maximum static binding capacity ( Q max) and the equilibrium-binding constant ( K d), whereas pH and the salt concentration had a noticeable impact on both Q max and K d values. Q max was found to be in the range of 55–65 mg IgG per ml of beads and unaffected by temperature. The maximum dynamic binding capacity ( Q x) was found to be in the range of 20–12 mg IgG per ml of beads. The adsorption rate constant ( k a) was determined by a split-peak approach to be between 982 and 3242 l mol −1 s −1 depending on the linear velocity. Adsorption rate of IgG on r_PEZ was studied as a function of both feed concentration and linear velocity. The standard enthalpy and entropy values were estimated for the interaction of IgG with this novel support. The binding constants were also determined by modeling the batch protein-uptake data.

Lack of effect of a bisphosphonate (pamidronate disodium) infusion on subsequent skeletal uptake of Sm-153 EDTMP.

Patients who are candidates for samarium-153 ethylenediaminetetramethylenephosphonic acid (Sm-153 EDTMP) therapy often receive monthly infusions of pamidronate disodium or other bisphosphonates. Because both drugs are related compounds that concentrate in bone, it was advisable to determine whether previous bisphosphonate administration has blocked subsequent uptake of Sm-153 EDTMP. The authors compared skeletal uptake of Sm-153 EDTMP before and 1 to 4 days after pamidronate infusion in three patients with breast cancer metastatic to bone. In two of the patients, they continued to compare Sm-153 EDTMP uptake at approximately 1, 2, 3, and 4 weeks after pamidronate infusion. There was no difference in skeletal uptake of Sm-153 EDTMP before or at any time after pamidronate infusion. Pamidronate infusion did not interfere with skeletal uptake of Sm-153 EDTMP.

Use of a modified zirconia support in the separation of immunoproteins

Zirconia beads (25–38 μm in diameter) were modified with N, N, N′, N′-ethylenediaminetetramethylenephosphonic acid to generate a zirconia based pseudoaffinity support, further referred to as r_PEZ. The influence of pH, salt concentration and temperature on the binding of human immunoglobulin G (hIgG) to r_PEZ was studied. Temperature had no significant impact on the maximum binding capacity ( Q max), and the equilibrium-binding constant ( K d), whereas pH and the salt concentration had a noticeable impact on both Q max and K d. The Q max value of 55 mg hIgG/ml of bead was obtained at a pH of 5.5 and found to decrease with an increase of pH. The modified zirconia support allowed the separation of immunoglobulins (IgG, IgA and IgM) from untreated human serum. Elution was possible under mild conditions with a step salt gradient. Overall protein recoveries in the range of 109–125% were obtained with human serum. Human IgG, human IgA, and human IgM yields of 29.50±6.3, 3.22±0.7, and 6.84±0.7%, respectively, were obtained at a linear velocity of 4.32 cm/min. Purity of products, obtained from a single chromatographic step was estimated to be greater than 89.0±2.6%. The utility of r_PEZ in the selective removal of immunoglobulins, as in immunoadsorption was discussed.

Finger doses received during 153Sm injections.

This study was undertaken to determine the dose received by the skin of the fingers of clinical and laboratory staff during injections of 153Sm. The use of 153Sm, chelated with ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP), is coming into more frequent use in radionuclide therapy since its approval by the U.S. Food and Drug Administration in March 1997. 153Sm emits a range of medium-energy therapeutically useful beta particles that have been found beneficial in the palliation of metastatic bone cancer pain. It also emits a range of gamma rays. Calculations have been undertaken to provide the beta-particle and gamma-ray dose rates, at a depth within the skin corresponding roughly to the basal cell layer, when the finger is placed in direct contact with the external surface of a syringe containing 153Sm. The beta-particle dose rates were modeled using an empirically based Monte Carlo approach previously described by Beddoe and Kelly. The gamma-ray dose rates were modeled using a distributed point source approach previously reported by Pattison et al. In the calculations it is assumed that a typical administered activity is 2.6 GBq, with a finger-syringe contact time of 30 s. The skin dose, due to both beta particles and gamma rays when the finger is centrally placed over an active volume of 0.3 mL in a 1-mL syringe, is calculated to be 77 mGy per injection. Similarly, for an active volume of 1.0 mL in a 2.5-mL syringe, the dose is calculated to be 10 mGy per injection. In view of the ICRP recommended weekly skin dose limit of 10 mGy, both of the above two doses are excessive. If, however, the fingers are placed at the rear end of the syringe barrel, where they are only exposed to the gamma rays, the above two doses are reduced to 0.069 and 0.139 mGy per injection, respectively. Both of these two doses are well within the recommended weekly dose limits for the skin. It is found that the weekly dose limit for the skin is readily exceeded if the fingers are in direct contact with the external surface of the syringe and located over the active volume. However, if handled at the rear end of the syringe barrel, a typical weekly workload can be managed without exceeding the recommended dose limits.

New rapid test for evaluation of scale inhibitors

A new method of evaluation of scale inhibitors efficiency has been developed and tested. This method is based upon solution conductivity measurement. It consists of determining a supersaturation level of any scale forming compound in a given water, at defined conditions, in the presence of a specified amount of scale inhibitor and also without inhibitor. This method allows the stabilizing features of compounds under investigation to be differentiated. With this method the efficiency of preventing CaCO3 precipitation from aqueous solutions was determined for three phosphonate compounds which are effective as corrosion inhibitors of mild steel in neutral water: 2-phosphonobutane-1,2,4-tricarboxylic acid (TBTC), ethylenediaminetetramethylenephosphonic acid (EDTMP) and phosphono-N-methylenephosphonic derivative of polycaproamide (PMPP). It was ascertained that the above compounds are effective in preventing CaCO3 crystallization from water. EDTMP showed the best stabilizing properties and PBTC what poorer ones.

177Lu-EDTMP

Lutetium-177 (177Lu) has both beta particle emissions for a therapeutic effect and gamma emissions for imaging. This study was undertaken to synthesize and evaluate 177Lu-EDTMP (ethylenediaminetetramethylene phosphonic acid) as a therapeutic radiopharmaceutical for the palliation of pain from bone metastases. Chelation of 177Lu to EDTMP was obtained by heating for 30 min in boiling water at pH 8.8, resulting in a radiochemical yield of over 99%. The compound was stable for 20 days without any appreciable dissociation. Biodistribution studies in normal rats indicated selective bone accumulation, showing faster blood clearance, higher bone uptake and higher bone-to-soft tissue ratios than 99Tcm-MDP. In conclusion, 177Lu-EDTMP has favourable biological and physical characteristics for the palliative treatment of painful bone metastases.

The behavior of phosphonates in wastewater treatment plants of Switzerland

The behavior of three phosphonates in seven Swiss wastewater treatment plants was investigated. The phosphonates ATMP (aminotrismethylene-phosphonic acid) and EDTMP (ethylenediaminetetramethylenephosphonic acid) were found in the influents of wastewater treatment plants at concentrations between <0.05 μmol l −1 (detection limit) and 0.8 μmol l −1, DTPMP (diethylenetriaminepentamethylenephosphonic acid) from <0.05 to 2 μmol l −1. The highest concentration was found in the influent of a wastewater treatment plant with significant input from the textile industry. The effluent of this wastewater treatment plant contained an average DTPMP concentration of 0.12 μmol l −1, which reflects a 85% decrease from the influent concentration. The phosphonate concentrations in all other effluents were below detectable levels. As phosphonates are not biodegradable, the elimination must be due to sorption processes. The phosphonates are almost quantitatively transferred to the anaerobic digester. The investigation of the anaerobic degradation showed no evidence for mineralization. Compared to EDTA (ethylenediaminetetraacetic acid) which is not eliminated during wastewater treatment, phosphonates have less impact on the metal speciation in natural waters.

Formation of Glyphosate and AMPA During Ozonation of Waters Containing Ethylenediaminetetra(methylenephosphonic acid)

Ozonation of the complexing agent ethylenediaminetetra(methylenephosphonic acid) (EDTMP) was studied with bench-scale experiments. As it turned out that EDTMP is totally oxidized within a few seconds, a mechanism for the reaction of EDTMP with ozone is presented which predicts the formation of the herbicide N-phosphonomethylglycine (glyphosate) and its major metabolite aminomethylphosphonic acid (AMPA). The experimental results confirm the predicted mechanism as well as the formation of glyphosate and AMPA during ozonation of waters containing EDTMP.

The influence of EDTMP-concentration on the biodistribution of radio-lanthanides and 225-Ac in tumor-bearing mice

High-resolution gamma spectroscopy was applied to measure simultaneously the biodistribution of carrier-free radionuclides of several lanthanides ( 141Ce, 145Sm, 149Gd, 167Tm) and 225Ac in tumor-bearing nude mice. Mixtures of the radiotracers were injected in solutions containing different concentrations of EDTMP (ethylenediaminetetramethylenephosphonic acid). The strong dependence of liver uptake on the ionic radius of the radio-lanthanides was confirmed for all tracers used. The ratios of radioactivity concentrated in tumor to that concentrated in liver are strongly influenced by the EDTMP concentration, reaching values close to 10 for Tm, 3 for Sm, and 1 for Ac. The optimal EDTMP concentrations, giving highest tumor-to-liver ratios of enrichment, were between 1 and 10 mM for 100 μL injected volume for the animal model used in this experiment. In radionuclide therapy using EDTMP as ligands, close control of ligand concentration will be necessary.

The Influence of EDTMP-Concentration on the Biodistribution of Radio-Lanthanides and 225-Ac in Tumor-Bearing Mice

High-resolution gamma spectroscopy was applied to measure simultaneously the biodistribution of carrier-free radionuclides of several lanthanides (141Ce, 145Sm, 149Gd, 167Tm) and 225Ac in tumor-bearing nude mice. Mixtures of the radiotracers were injected in solutions containing different concentrations of EDTMP (ethylenediaminetetramethylenephosphonic acid). The strong dependence of liver uptake on the ionic radius of the radio-lanthanides was confirmed for all tracers used. The ratios of radioactivity concentrated in tumour that concentrated in liver are strongly influenced by the EDTMP concentration, reaching values close to 10 for Tm, 3 for Sm, and 1 for Ac. The optimal EDTMP concentrations, giving highest tumor-to-liver ratios of enrichment, were between 1 and 10 mM for 100 microL injected volume for the animal model used in this experiment. In radionuclide therapy using EDTMP as ligands, close control of ligand concentration will be necessary.

The kinetics of the crystallization of barium chromate in presence of polyphosphate and phosphonates

The inhibiting effect of polyphosphate and phosphonates on the crystallization of barium chromate for both seeded and unseeded systems has been investigated using the changes in ionic conductivity of the lattice ions in supersaturated solutions containing stoichiometric concentrations of barium and chromate at 298 K. The inhibitors studied are sodium tripolyphosphate (STP), ethylenediaminetetramethylenephosphonic acid (ENTMP), and 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP). The effect of these inhibitors on the growth of crystals has been studied at several inhibitor concentrations. The influence of these additives on barium chromate crystallization could be interpreted in terms of aLangmuir type adsorption isotherm. The crystallization retarding effect due to inhibitors is in the orderHEDP>STP>ENTMP. The inhibitors studied can be used as effective compounds for scale formation control.

EFFECT OF ADDITIVES ON THE CRYSTALLIZATION OF BARIUM SULPHATE

Abstract The kinetics of crystallization of barium sulphate for both seeded and unseeded systems in presence of additives have been studied by following the changes in ionic conductivity in supersaturation solutions containing stoichiometric concentrations of the lattice ions at 298 K. The additives investigated include: 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP), hexa methylenediaminetetramethylenephosphonic acid (HMNTMP), ethylenediaminetetramethylenephosphonic acid (ENTMP) and nitrilotrimethylenephosphonic acid (NTMP). The effect of these additives on the growth kinetics has been studied at several inhibitor concentrations. The retarding effect of these inhibitors is interpreted in terms of adsorption of inhibitor ions at the active crystal growth sites following the Langmuir isotherm. The order, in terms of decreasing the inhibitory effect on the rate of growth of barium sulphate of the studied additives is HEDP > HMNTMP > ENTMP > NTMP. This order holds for both seeded and unseeded systems.

Effectiveness of Cr III , Mn II , Co II and Ni II paramagnetic complexes in promoting the ortho- into para-positronium conversion reactions

The conversion reactions of ortho- into para-positronium, Ps, atoms promoted by CrII complexes with water, urea and ethylenediaminetetraacetic acid, by the complexes of CrIII, CoII and NiII ions with ethylenediaminetetramethylene-phosphonic acid, nitrilotrismethylene-phosphonic acid, urea and by the complexes of MnII ions with urea, glycine and iminodiacetic acid have been investigated in order to ascertain the role of the metal ion in the reactions. All the complexes considered are octahedral and of high spin type. The reaction rate constants of the complexes are correlated to the corresponding electron delocalization caused by the ligands as described by the ratio B/B0=β between the inter-electronic repulsion parameters in complexed and free gaseous metal ions. The rate constant per fully delocalized unpaired electron of the metal ion was deduced and found to be (3.7 ± 0.6) dm3 mol–1n s–1 electron–1.