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Ferinject®
Carboximaltosade hierro
Carboximaltosa de hierro
ferinject®
La nueva generación de hierro i.v.
Hospital AlemHospital Alemáán / Deutsches Hospitaln / Deutsches Hospital
“¿Son todos los hierros I.V. iguales?”
Jorge E. Jorge E. ToblliToblli..Profesor Regular Titular de Medicina Interna Profesor Regular Titular de Medicina Interna
Universidad de Buenos Aires.Universidad de Buenos Aires.
Profesor de NefrologProfesor de Nefrologíía Universidad Cata Universidad Catóólica Argentina.lica Argentina.
FellowFellow ofof AmericanAmerican SocietySociety ofof NephrologyNephrology
Jefe Laboratorio de Medicina Experimental. Jefe Laboratorio de Medicina Experimental. Hospital AlemHospital Alemáán.n.
Octubre 22, 2008Octubre 22, 2008
Valencia, Valencia, EspaEspaññaa
AnaemiaAnaemia
Iron DeficiencyIron Deficiency is the most prevalent cause of Anaemia
worldwide
AnaemiaAnaemia
Iron Iron DeficiencyDeficiency
IronIron
IronIron
What IV Iron are available in the market today???
????
??
????
??
????
??
IV Iron PreparationsIV Iron Preparations
•• Type I Complex. Type I Complex. (Iron (Iron DextranDextran, , FerrricFerrric CarboximaltoseCarboximaltose))
•• Type II Complex. Type II Complex. (Iron Sucrose Complex)(Iron Sucrose Complex)
•• Type III Complex. Type III Complex. (Iron Gluconate,(Iron Gluconate, Iron ammonium Iron ammonium
citrate, Iron hydroxide sorbitol complexcitrate, Iron hydroxide sorbitol complex))
Are all ““IV Iron CompoundsIV Iron Compounds””the same thing ???
????
??
????
??
????
??
Objectives of the Study
To evaluate toxicity in different IV iron original preparations.
IV Iron TherapyIV Iron Therapy((weeklyweekly) )
Ferric Ferric CarboxymaltoseCarboxymaltose
Ferric Ferric GluconateGluconate
HMW HMW IronIron--DextranDextran
Iron SucroseIron Sucrose
LMW LMW IronIron--Dextran Dextran
Isotonic Saline Isotonic Saline Solution Solution
(Control Group)(Control Group)
IV Iron AdministrationIV Iron Administration
Systolic Blood Pressure
0 3 6 9 12 15 18 21 24 27 30
100102104106108110112114116118120122124126128 Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose*
Isotonic Saline Solution
* **
LMW Iron-Dextran
Ferric Gluconate
*
days
mm
Hg
* p< 0.01 LMW Iron-Dextran versus all groups
Hemoglobin
1 8 29
0
2
4
6
8
10
12
14
16
18
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic SalineSolution
(p= NS)
LMW Iron-Dextran
Ferric Gluconate
days
mg /dL
TSAT after IV Iron
1 8 29
0102030405060708090
100
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solución
LMW Iron-Dextran
Ferric Gluconate
* p< 0.01 versus all groups** p< 0.05 versus all groups
*** p< 0.01 versus all groups
* *
** ** **
*** *** ***
days
%
Serum Iron after IV Iron
1 8 29
0
100
200
300
400
500
600
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
* p< 0.01 versus all groups** p< 0.01 versus all groups
*** p< 0.01 versus all groups
**
** ** **
*** *** ***
days
µg /dL
Proteinuria
0 3 6 9 12 15 18 21 24 27 30
02468
1012141618202224262830
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
*
Isotonic Saline Solution
* p< 0.01 Ferric Gluconate versus all groups
*
LMW Iron-Dextran
Ferric Gluconate
**
*
days
mg/
day
Creatinine Clearance
0 3 6 9 12 15 18 21 24 27 30
0.00.20.40.60.81.01.21.41.61.82.02.22.42.62.83.03.23.4 Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
* p< 0.01 Ferric Gluconate versus all groups
***
days
ml/m
in
More Proteinuria and Lower GFR with Ferric GluconateFerric Gluconate
Aspartate Transferase (AST) after IV Iron
1 8 29
0
50
100
150
200
250
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
**
*†† †† ††††
†
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01†† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
days
UI/L
Alanin Transferase (ALT) after IV Iron
1 8 29
0
25
50
75
100
125
150
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
*
**
†† ††††
†††
days
UI/L
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01†† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
Alkaline Phosphatase after IV Iron
1 8 29
050
100150200250300350400450500550600650700750800
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
***
†† †† †††† †
days
UI/L
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01†† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
More reaction in Liver enzymes in HMW IronHMW Iron--DextranDextran, LMW IronLMW Iron--DextranDextran
and Ferric GluconateFerric Gluconate
Oxidative StressOxidative Stress
• Homogenates preparation
1- Lipoperoxidation by thiobarbituric reactive species (TBARS)
2- Glutathione ratio (GSH/GSSG)
3- Catalase activity
4- CuZn Superoxide Dismutase (CuZnSOD)
5- Glutathione Peroxidase (GPx)
Oxidative Stress Evaluation Oxidative Stress Evaluation (After the last IV iron administration on the fourth week)(After the last IV iron administration on the fourth week)
TBARs at 4 weeks after a weekly IV Iron administration
Liver Heart Kidney
0
20
40
60
80
100
120
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
* p< 0.01 versus all groups
* **
HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose
nnm
ol M
DA
Eq/
g p
rote
in
More Lipoperoxidation in ““Ferric GluconateFerric Gluconate””
Catalase at 4 weeks after a weekly IV Iron administration
Liver Heart Kidney
0
100
200
300
400
500
Ferric Carboxymaltose
HMW Iron-Dextran
Iron Sucrose
Isotonic Saline Solution
LMW Iron-Dextran
Ferric Gluconate
* p< 0.01 versus all groups
*
*
*
µm
ol H
2O2/m
in/ m
g p
rote
in
More Peroxidation in ““Ferric GluconateFerric Gluconate””
CuZnSOD at 4 weeks after a weekly IV Iron administration
Liver Heart Kidney
0
5
10
15
20
25
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
**
*
HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose
† †
† †
† †
U/m
g pr
otei
n
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
Less Production of Superoxide in Ferric CarboxymaltoseFerric Carboxymaltose and Iron SucroseIron Sucrose
GSH / GSSG after a weekly IV Iron administration
Liver Heart Kidney
0123456789
10
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
**
*
HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose†
††
††
††
††
ratio
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01†† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
GPx at 4 weeks after a weekly IV Iron administration
Liver Heart Kidney
050
100150200250300350400450500550600650700750800
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
*
*
*
HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose† †
† †† †U/
mg
prot
ein
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
Less consumption of Anti-Oxidative stress Defenses in Ferric CarboxymaltoseFerric Carboxymaltose and Iron SucroseIron Sucrose
Final Remarks
Less Oxidative Stress in Ferric CarboxymaltoseFerric Carboxymaltose & Iron SucroseIron Sucrose
Prussian Blue at 4 weeksafter a weekly IV Iron administration
Liver Heart Kidney
0
5
10
15
Isotonic Saline Solution
*
*
*
Ferric Carboxymaltose
††
† †† †
Ferric Gluconate
HMW Iron-Dextran
LMW Iron-Dextran
Iron Sucrose** *
Stai
ning
(%) /
are
a
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
PrussianPrussian Blue in Blue in LiverLiver atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
PrussianPrussian Blue in Heart 4 Blue in Heart 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
PrussianPrussian Blue in Kidney Blue in Kidney atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
Immunostaining for Ferritin at 4 weeksafter a weekly IV Iron administration
Liver Heart Kidney
0
5
10
15
20
Isotonic Saline Solution
*
*
*
Ferric Carboxymaltose
† †
† †
† †
Ferric Gluconate
HMW Iron-Dextran
LMW Iron-Dextran
Iron Sucrose** *
Stai
ning
(%) /
are
a
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
Ferritin in Ferritin in LiverLiver atat 4 4 weeksweeks(x100)(x100)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
Ferritin in Heart Ferritin in Heart atat 4 4 weeksweeks(x1000)(x1000)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
Ferritin in kidney Ferritin in kidney atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran
ISSIron Gluconate Iron Sucrose
LMW Iron Dextran
Let's go now to the inflammatory markers!!!Let's go now to the inflammatory markers!!!
IL6 immunostaining at 4 weeksafter a weekly IV Iron administration
Liver Heart Kidney
0123456789
10
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
*
*
*
HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose
† † † † † †
* * *
Perc
enta
ge o
f Flu
ores
cenc
e / c
ross
-sec
tiona
are
a
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
IL6 in IL6 in LiverLiver atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
IL6 in Heart IL6 in Heart atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
IL6 in kidney IL6 in kidney atat 4 4 weeksweeks(x400)(x400)
ISS
FerricCarboxymaltose
Iron Gluconate
HMW Iron Dextran
Iron Sucrose
LMW Iron Dextran
TNFα immunostaining at 4 weeksafter a weekly IV Iron administration
Liver Heart Kidney
0123456789
10
Iron Sucrose
Isotonic Saline Solution
Ferric Gluconate
**
*HMW Iron-Dextran
LMW Iron-Dextran
Ferric Carboxymaltose
† †
† †
† †
** *
Perc
enta
ge o
f Flu
ores
cenc
e / c
ross
-sec
tiona
are
a
* versus all groups p< 0.01† versus Ferric Carboxymaltose, Iron Sucrose and Isotonic Saline Solution p< 0.01
TNFTNFαα in in LiverLiver atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
TNFTNFαα in Heart in Heart atat 4 4 weeksweeks(x400)(x400)
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
ISSIron Gluconate Iron Sucrose
TNFTNFαα in Kidney in Kidney atat 4 4 weeksweeks
(x400)(x400)
ISSIron Gluconate Iron Sucrose
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
BoneBone MarrowMarrow atat 4 4 weeksweeks((GiemsaGiemsa, x400), x400)
ISSIron Gluconate Iron Sucrose
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
Bone Marrow Myeloid:Erythroid ratio aftera weekly IV Iron administration
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
(p=NS)
Ferric CarboxymaltoseHMW Iron-Dextran
LMW Iron-Dextran
Ferric Gluconate
Iron SucroseIsotonic Saline Soluciónra
tio
Bone Marrow Cellularity aftera weekly IV Iron administration
0102030405060708090
100Ferric Carboxymaltose
HMW Iron-Dextran
LMW Iron-Dextran
Ferric GluconateIron Sucrose
Isotonic Saline Solución
(p=NS)
Perc
etag
e / c
ross
sec
tion
PrussianPrussian Blue in Blue in BoneBone MarrowMarrowatat 4 4 weeksweeks (x400)(x400)
ISSIron Gluconate Iron Sucrose
FerricCarboxymaltose
HMW Iron Dextran LMW Iron Dextran
Are all ““IV Iron CompoundsIV Iron Compounds””the same thing ???
????
??
????
??
????
??
NO !!!!! All ““IV Iron CompoundsIV Iron Compounds”” are
not the same thing
Now, you probably Now, you probably have the answer!!!have the answer!!!
Ferric Ferric CarboxymaltoseCarboxymaltose&
Iron SucroseIron Sucrose
IronIron SucroseSucroseComplexComplex
FerricFerricCarboximaltoseCarboximaltose
Which is the best ?Which is the best ?
Development objectives of FCM
The disadvantages of iron dextran and iron sucrose led tothe aim to develop an iron compound WITH:
• A better safety and tolerance profile than existing products
• Neutral pH and low osmolarity and WITHOUT:
• Dextran-induced hypersensitivity reactions (DIAR)
• Low dosage limits like iron sucrose
• Long application duration like iron sucrose and dextran
Low reactivity with molecules in blood and living cells
Structure similar to ferritin
Low toxicity
Deposition within the physiological iron stores (RES(reticuloendothelial system) in the liver) after application
No induction of oxidative stress
MW of about 150 kDa
Dosis Total de hierro Dosis Total de hierro SEGURIDAD SEGURIDAD
ISCISC
++ ++
FCMFCM
FerricFerric CarboximaltoseCarboximaltose
Margarita AngerosaMargarita Angerosa
Ana UcedaAna Uceda
Mariana FeldmanMariana Feldman
Julieta BoladoJulieta Bolado
Gabriel CaoGabriel Cao
Patricia PaganoPatricia Pagano
Pablo PiornoPablo Piorno
Marta CostaMarta Costa
Hospital AlemHospital Alemáán / Deutsches Hospitaln / Deutsches Hospital
Muchas gracias por vuestra atenciMuchas gracias por vuestra atencióón!!!n!!!
Jorge E. Jorge E. ToblliToblli..Profesor Regular Titular de Medicina Interna Profesor Regular Titular de Medicina Interna
Universidad de Buenos Aires.Universidad de Buenos Aires.
Profesor de NefrologProfesor de Nefrologíía Universidad Cata Universidad Catóólica Argentina.lica Argentina.
FellowFellow ofof AmericanAmerican SocietySociety ofof NephrologyNephrology
Jefe Laboratorio de Medicina Experimental. Jefe Laboratorio de Medicina Experimental. Hospital AlemHospital Alemáán.n.
Octubre 22, 2008Octubre 22, 2008
Valencia, Valencia, EspaEspaññaa
Ferinject®
Carboximaltosade hierro
Carboximaltosa de hierro
ferinject®
La nueva generación de hierro i.v.
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