carboximaltosa de hierrofer ferinject inject carboximaltosa …...de hierro carboximaltosa de...

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 ???

????

??

????

??

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??

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


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


HMW Iron-Dextran

Iron Sucrose


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


HMW Iron-Dextran

Iron Sucrose

*


* 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


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


HMW Iron-Dextran

Iron Sucrose


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


HMW Iron-Dextran

Iron Sucrose


LMW Iron-Dextran

Ferric Gluconate

*

**

†† ††††

†††

days

UI/L


Alkaline Phosphatase after IV Iron

1 8 29

050

100150200250300350400450500550600650700750800


HMW Iron-Dextran

Iron Sucrose


LMW Iron-Dextran

Ferric Gluconate

***

†† †† †††† †

days

UI/L


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


Ferric Gluconate

* p< 0.01 versus all groups

* **

HMW Iron-Dextran

LMW Iron-Dextran


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


HMW Iron-Dextran

Iron Sucrose


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


Ferric Gluconate

**

*

HMW Iron-Dextran

LMW Iron-Dextran


† †

† †

† †

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


Ferric Gluconate

**

*

HMW Iron-Dextran

LMW Iron-Dextran

Ferric Carboxymaltose†

††

††

††

††

ratio


GPx at 4 weeks after a weekly IV Iron administration

Liver Heart Kidney

050

100150200250300350400450500550600650700750800

Iron Sucrose


Ferric Gluconate

*

*

*

HMW Iron-Dextran

LMW Iron-Dextran

Ferric Carboxymaltose† †

† †† †U/

mg

prot

ein


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


*

*

*


††

† †† †

Ferric Gluconate

HMW Iron-Dextran

LMW Iron-Dextran

Iron Sucrose** *

Stai

ning

(%) /

are

a


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)




PrussianPrussian Blue in Kidney Blue in Kidney atat 4 4 weeksweeks(x400)(x400)




Immunostaining for Ferritin at 4 weeksafter a weekly IV Iron administration

Liver Heart Kidney

0

5

10

15

20


*

*

*


† †

† †

† †

Ferric Gluconate

HMW Iron-Dextran

LMW Iron-Dextran

Iron Sucrose** *

Stai

ning

(%) /

are

a


Ferritin in Ferritin in LiverLiver atat 4 4 weeksweeks(x100)(x100)




Ferritin in Heart Ferritin in Heart atat 4 4 weeksweeks(x1000)(x1000)




Ferritin in kidney Ferritin in kidney atat 4 4 weeksweeks(x400)(x400)


HMW Iron Dextran


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


Ferric Gluconate

*

*

*

HMW Iron-Dextran

LMW Iron-Dextran


† † † † † †

* * *

Perc

enta

ge o

f Flu

ores

cenc

e / c

ross

-sec

tiona

are

a


IL6 in IL6 in LiverLiver atat 4 4 weeksweeks(x400)(x400)




IL6 in Heart IL6 in Heart atat 4 4 weeksweeks(x400)(x400)




IL6 in kidney IL6 in kidney atat 4 4 weeksweeks(x400)(x400)

ISS


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


Ferric Gluconate

**

*HMW Iron-Dextran

LMW Iron-Dextran


† †

† †

† †

** *

Perc

enta

ge o

f Flu

ores

cenc

e / c

ross

-sec

tiona

are

a


TNFTNFαα in in LiverLiver atat 4 4 weeksweeks(x400)(x400)




TNFTNFαα in Heart in Heart atat 4 4 weeksweeks(x400)(x400)




TNFTNFαα in Kidney in Kidney atat 4 4 weeksweeks

(x400)(x400)




BoneBone MarrowMarrow atat 4 4 weeksweeks((GiemsaGiemsa, x400), x400)




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)




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.

carboximaltosa de hierrofer ferinject inject carboximaltosa …...de hierro carboximaltosa de...

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