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79162913 the Inventor of Omniscan Steven Quay s 1990 Pubished Admission That It Was Not Safe for Human Use

79162913 the Inventor of Omniscan Steven Quay s 1990 Pubished Admission That It Was Not Safe for Human Use

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Gadolinium Based Contrasting Agents are not safe. This paper implies that Salutar's product which ultimately became GE's product Omniscan knew this was toxic on or around the time it was approved. Also see Robbie Booker vs. GEHC.

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial. Release of Gd3+ from the complex is responsible for the toxicity associated with gadoliium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallatiou in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency.

If you want more information or if you were impacted by gadolinium based contrasting agents go to this support group.

http://health.groups.yahoo.com/group/GASF-NSF/
Gadolinium Based Contrasting Agents are not safe. This paper implies that Salutar's product which ultimately became GE's product Omniscan knew this was toxic on or around the time it was approved. Also see Robbie Booker vs. GEHC.

The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number of factors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complex is minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is substantial. Release of Gd3+ from the complex is responsible for the toxicity associated with gadoliium complexes; this release appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallatiou in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency.

If you want more information or if you were impacted by gadolinium based contrasting agents go to this support group.

http://health.groups.yahoo.com/group/GASF-NSF/

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Published by: gasfgd on Mar 28, 2012
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Magnetic Resonance Imaging, Vol. 8, pp. 467-48 1, I990
Printed n the USA. All rights eserved.0730-725x/90$3.00 + .oaCopyright 1990PergamonPressplc
l
Original Contribution
THE RELATIONSHIP BETWEEN THERMODYNAMICS ANDTHE TOXICITY OF GADOLINIUM COMPLEXES
WILLIAM P. CACHERIS, STEVEN C. QUAY, AND
SCOTT
M.
ROCKLAGESalutar, Inc., Sunnyvale, California 94086, USA
The suitability of gadolinium complexes as magnetic resonance imaging contrast agents depends on a number offactors. A thermodynamic relationship to toxicity exists if one assumes that the chemotoxicity of the intact complexis minimal but that the toxicity of the components of the complex (free metal and uncomplexed ligands) is sub-stantial. Release of Gd3+ from the complex is responsible for the toxicity associated with gadoliium complexes;this release appears to be a consequence of Zn2+, Cu2+, and Ca2+transmetallatiou in vivo. This hypothesis issupported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for fourGd complexes, all become lethally toxic when they release precisely the same quantity of Gd3+, and by subchronicrodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those knownto be caused by Zn2+ deficiency. Finally, this hypothesis predicts that subtle changes in formulation can furtherenhance the intrinsic safety of these complexes.Ke_~words: Thermodynamics; Toxicity; Gadolinium; Contrast.INTRODUCTION
The evaluation of paramagnetic complexes as contrastagents for magnetic resonance imaging has focusedupon the safety and efficacy of these agents.’ Safetyhas been evaluated by acute toxicity (LD,,), sub-chronic toxicity, local tissue tolerance, cardiovascularpharmacology, mutagenic potential, absorption, dis-tribution, metabolism and excretion studies. Thesecomplexes are composed of relatively toxic compo-nents, i.e., metal ion and ligand, bonded together byionic forces and subject to dissociation. An under-standing of the in vivo affinity, i.e., stability, of theseconstituents for each other is important to the futuredevelopment of magnetopharmaceuticals. One mech-anism to explain the toxicity of these complexes is invivo dissociation and/or metabolism to yield toxicmetal ions and free ligands.Many workers have used the in vitro thermodynamicstability constant of the complex as a measure of thein vivo affinity of metal ion and ligand. The relation-ship between thermodynamic stability constant and invivo toxicity, however, does not hold for GdDTPA-BMA, GdDTPA, GdDTPA-BP and GdEDTA. A morecomplete thermodynamic evaluation is needed to as-certain in vivo stability and to explain the observedtoxicity of these complexes.
MATERIALS AND METHODS
Synthesis of GdDTPA-BA4A
A
full description of ligand (DTPA-BMA) andcomplex (GdDTPA-BMA) synthesis is given in Ref. 2.
Synthesis of N,N”-2-Bis(2-pyridylrnethyl)diethylenetriamine
Diethylenetriamine (76 g, 0.74 mol) and pyridine-2-carboxaldehyde (174 g, 1.62 mol) in 2.5 L of abso-lute ethanol were heated for 2 hr at 50°C with stirring.After cooling to room temperature, 25 g of 10% pal-ladium on charcoal was added and the schiff basehydrogenated at slightly greater than 1 atm of hydro-gen, over a 48-hr period. The catalyst was removed byfiltration, the filtrate adjusted to pH 4 with HCl gas
RECEIVED
9/30/89;
ACCEPTED 2/17/90.GdDTPA-BP
and Dilip Worah, Debra Kesler and Dean
Acknowledgments-The
authors thank William Dow and Kessler for performing the animal studies.David Love for synthesizing and formulating GdDTPA- Address all correspondence to Scott M. Rocklage, Salu-BMA, Joan Carvalho for synthesizing and formulating tar, Inc., 428 Oakmead Parkway, Sunnyvale, CA 94086.467
 
468 Magnetic Resonance Imaging 0 Volume 8, Number 4, 1990
and then lowered to pH 1 using 12 N HCl. The result-ing precipitate was removed by suction filtration,washed with absolute ethanol until the washings werecolorless, and recrystallized from 95% ethanol. ThisHCl salt was then dissolved in 500 mL of water andneutralized with 5 N NaOH, then raised to pH 12.5,and the free base extracted with methylene chloride(4 x 500 mL). The methylene chloride solution wasdried to give 136 g (65%) of a pale yellow oil. NMR(D,O): 6 2.46 (s, 8H), 3.55 (s, 4H), 7.10 (m, 4H), 7.55(t, J= 12.5 Hz, 2H), 8.25 (d, J= 10 Hz, 2H), 7.50 (t,J = 10 Hz, 2H), 8.40 (d, J = 10 Hz, 2H).
Synthesis of N,N”-2-Bis(2-pyridylmethyl)-N,N,W-Tris(t-Butylcarboxymethyl)Diethylenetriamine
To a solution of N, N”-2-bis(2_pyridyl)diethylenetri-amine (23.6 g, 82.6 mmol) and diisopropylethylamine(53.4 g, 0.4 mol) in 1.2 L of methylene chloride atroom temperature was added dropwise t-butylbromo-acetate (50 g, 0.2 mol) in 300 mL of methylene chloride.After stirring for 24 hr, the solution was evaporatedto dryness and placed under vacuum for 2 hr to re-move excess diisopropylethylamine. The crude solidwas taken up in 1.5 L of methylene chloride, washedwith 0.2 N NaOH, water (2 x 250 mL), brine (200mL) and dried (MgS04). The methylene chloride wasremoved, 200 mL of ethyl acetate added and this so-lution passed through 300 g of silica gel in a buchnerfunnel using EtOAc to elute the product. The purefractions (TLC: MeOH/CH2C12: 3/7) were combinedto give 40.6 g (79.5%) of the ester, NMR (CDC&) 61.26 (s, 9H), x 1.31 (s, 18H), 2.62 (s, 8H), 3.12 (s,2H), 3.17 (s, 4H), 3.78 (s, 4H), 7.02
(t,
J =
10 Hz,2H), 7.35
(d, J = 10
Hz, 2H).
Synthesis of N,N”-2-Bis(2-Pyridylmethyl)Diethylenetriamine-N,W,N”-Triacetic Acid
The tris(t-butylcarboxymethyl)ester (24.8, 0.1 mol)was dissolved in a solution of 600 mL of methylenechloride containing 380 mL of trifluoroacetic acid.The solution was stirred for 48 hr, evaporated underreduced pressure and diluted with 50 mL of water.This solution was applied to 200 mL of AG50-X8, H+form, 100-200 mesh and after washing with water un-til neutral, the product was eluted with 1 N NH40H.After removal of NH40H solution, the product wastaken up in 24 mL of water, adjusted to pH 10 andthe solution applied to AGl-X8, acetate, 100-200mesh. The column was washed with three bed volumesof water and the product eluted with 2 N HOAc togive 12.0 g (69%) of product after several lyophiliza-tions. NMR (D,O) 6 3.02
(t,
J= 6
Hz, 4H), 3.08
(t,
J = 6
Hz, 4H), 3.14 (s, 4H), 3.41 (s, 2H), 4.08 (s, 4H),
7.52 (m, 4H), 8.05 (t, J=
10 Hz, 4H), 8.40
(d, J=
10 Hz, 2H).
Potentiometric Measurements
Potentiometric titrations, to determine the acid pro-tonation constants as well as the metal ion stabilityconstants of DTPA-BMA and DTPA-BP, were car-ried out with an automatic titrator system.3 The sys-tem was controlled by a BASIC computer programwhich displays the data in tabular form concurrentwith a high resolution plot. Components of the au-totitrating system included a Fisher digital pH meter,Corning glass and AgCl reference combination elec-trode, and a Metrohm digital autoburette. In each ex-periment, temperature was maintained at 25.O”C + 0.1and ionic strength was kept constant at 0.10 M withNaCl. The concentration of metal ions and ligand wasmaintained between 3 x lop3 M and 5
x
10m3M, and0.1000 M HCl was used as the titrant to minimize ionicstrength changes during the course of a titration. Ad-dition of a small amount of NaOH prior to the titra-tions was used to raise the solutions to pH 11.Stability constants for Gd3+, Zn2+, Cu2+, andCa2+ complexes of DTPA-BP and the Zn2+, Cu2+and Ca2+ complexes of DTPA-BMA were determinedby direct titration. For these systems the complexeswere found to be greater than 25% dissociated at pH2, while the data for the GdDTPA-BMA system re-vealed the complex to be dissociated less than 1% atpH 2. Thus GdDTPA-BMA was studied using a li-gand-ligand competition titration. In this experimenta 1: 1: 1 molar ratio of Gd3+, DTPA-BMA, andEDTA was titrated. EDTA forms a complex withGd3+ whose stability constant is accurately known.At high pH, Gd3+ is primarily bound to EDTA. TheGd3+ ion was readily transferred to DTPA-BMA asthe pH was lowered to 2. The rate of metal transferwas sufficiently fast that equilibrium pH measure-ments could be made in a reasonable time period af-ter each addition of acid.
Computations
Proton association constants for DTPA-BMA werecalculated using a BASIC computer program writtenfor polyprotic weak acid equilibrium calculations. Thestability constants of the metal ion complexes werecalculated using a BASIC program designed for metalion, ligand and proton systems containing a variety ofspecies. Both programs employed a modified Newton-Raphson algorithm which solved the simultaneousnonlinear mass balance equations, yielding -log[H+]values. The evaluated equilibrium constants were variedby a combined Simplex/Marquardt nonlinear regres-
 
Thermodynamics and toxicity 0 W.P. CACHERIS ? AL. 469
sion algorithm. The average difference between ob-served and calculated -log [H+] was co.04 throughoutall titrations.Biospeciation calculations were performed with aBASIC program which employed the modifiedNewton-Raphson algorithm. The non-linear equa-tions resulted from the mass balance equations for aneight-component system consisting of Gd3+, Zn’+,Cu2+, Ca2+, ligand, monoaminomonocarboxylateamino acids (which were combined since their stabil-ity constants are very similar), citrate, and human se-rum albumin. The program required equilibriumconstants which were taken from the Iiterature,4-6 at37°C and p = 0.15 M. Values that were not availableat p = 0.15 M were replaced by values at p = 0.10 M.Equilibrium constants that were not known at 37°Cwere calculated from the enthalpy and entropy offormation7 (measured at 25°C). The enthalpy and en-tropy of formation are relatively temperature indepen-dent over small temperature ranges7 and were reliedupon for accurate equilibrium constants at 37°C. Inthe case of GdEDTA it was necessary to take into ac-count ternary complexes of GdEDTA with aminoacids and citrate.8 It can be shown from the relativelysmall value for the equilibrium ML + M = M2L (logK = 4.48 for ZqDTPA) that the binuclear complexesof DTPA are not formed in significant concentrationsin vivo, and these were excluded from the biospecia-tion calculations. A distribution volume of 180 mL/kgwas used to convert dosage to in vivo concentration.The in vivo concentrations of the components usedwere: Ca2+, 2.5 mM: Zn2+, 50 PM: Cu2+, 1 PM:amino acids, 2.76 mM: citrate, 0.11 mM: and albu-min, 0.4 mM.9 The root of the set of equationsyielded the free concentrations of all components.These concentrations were used along with the stabil-ity constants to determine full speciation for each dos-age of the complexes.
Transmetallation Kinetics
A measurement of the rate of Gd3+ release fromGdDTPA-BMA, GdDTPA and GdDTPA-BP wasattempted by a method used by Margerum forGdEDTA and GdCDTA.‘O A solution of 1.288 x10e5 M GdDTPA-BMA (or GdDTPA) was preparedat pH 5.0 with an acetate buffer (0.01 M buffer, p =0.1 M). A lo-fold excess of Cu2+ was added and theformation of the Cu2+ complex was followed by UVabsorption at 268 nm.
Animal Studies
Acute toxicity (LD,,) studies were conductedin Swiss-Webster mice. Five groups of mice, eachcontaining four males and four females, were in-jected intravenously with either GdDTPA-BMA,Na2
[GdDTPA] , GdDTPA-BP ,
Na
[
CaDTPA-BMAI ,
Na[CaDTPA-BP] or formulations containing eitherGdDTPA-BMA + 5 mole %
Na[CaDTPA-BMAI ,
Na2 [GdDTPA]
] +
5 mole % Na3
[CaDTPAl ,
GdDTPA-BP + 5 mole % Na[CaDTPA-BP] orGdDTPA-BMA + 5 mole % Na[CaDTPA-BMA] +123 mole % NaCl. For each LD,, determination,each group of eight mice was given a different dosageof compound. Dose volumes larger than about 40mL/kg body weight were administered as divideddoses, at one-half hour apart. Animals were observed,once daily, for mortality or morbidity for 14 days andthe LDso value was calculated. The calculations weremade using a weighted probit method.” Osmolarityof the various formulations were measured on a Wes-car model 550 vapor pressure osmometer.A subchronic toxicity study was conducted inSprague-Dawley rats. Three groups of rats, each con-sisting of 10 male and 10 female rats, receivedGdDTPA-BMA intravenously three times a week forthree consecutive weeks at dosage levels of 0.1, 2.0,and 5.0 mmol/kg. A fourth group received normal sa-line and served as the negative control. All animalswere observed twice daily for morbidity and mortal-ity. Clinical observations for obvious toxicologic ef-fects were also performed at least once daily. Grossand microscopic evaluations were conducted at studytermination.
RESULTS
Potentiometry
The potentiometric titration curves for DTPA-BMA and ZnDTPA-BMA are shown in Fig. 1. TheDTPA-BMA curve shows a very sharp decrease be-tween pH 9 and 5.5. This is due to the large separationof the pK, values of the two most basic groups of theligand, 9.37 and 4.38 (shown by NMR to be theamines). The third amine of the ligand has a pK, of3.31 and the carboxylates all have pK, values below
2.
The ZnDTPA-BMA curve drops rapidly from theinitial pH of 10 to pH 5, since the only protonation ofthe complex takes place with a pK, of 3.99. At pH 2,the protonated ZnHDTPA-BMA and CuHDTPA-BMA complexes are ca. 35% and 25% dissociated, re-spectively. The CaDTPA-BMA complex undergoes asimilar protonation with a pK, of 4.45, but becomescompletely dissociated at pH 2.7.The results of the potentiometric measurements forDTPA-BMA, DTPA, DTPA-BP and EDTA and theGd3+, Zn2+, Cu2+and Ca2+ thermodynamic stability

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