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Pharmakotherapie des MakulaödemsWirkungsorte
Innere BRS
• NSAIDs• Steroide
Äussere BRS
• NSAIDs• Steroide
• Karbo-anhydraseInhibitoren
Ionen- und FlüssigkeitstransportBlut-Retina-Schranke
o o o o o o o o o o o o o o o
2 K
3 Na
K/Na 2 Cl Na 2 HCO
HCO 3
Cl Na
K Cl
K
Na
H
3
6 mV
HCO
Na
CAI NSAIDsANPCFTR
Kortison
Pharmakologie des zystoiden Makulaödems
Arachidonsäure
5 HPETE
LTA4
LTB4 LTC4
Membranlipide
PGG2
PGE2PGI2
TXA2
TXB2
PGD2
PGF2α
PermeabilitätTc Aggregation Chemotaxis
CyclooxygenaseCOX-1 and COX-2
H2O
Phospholipase A2
NSAIDs
Permeabilität
Medikamentöse Behandlung des Makulaödems
Nicht-steroidale Antiinflammatorika
NSAID: Voltaren Ophta®Acular®Ocuflur®etc.
Akutes CMÖ (21-90 Tage post-op)
Studie Therapie Dauer Visus CMÖ im FA
Heier 2001 Ketoralac 3/12 ↑ ↓
Prednisolon 3/12 ↑ ↓
Ketoralac & 3/12 ↑ ↑ ↓ ↓Prednisolon
Behandlung von CMÖ nach KataraktextraktionNSAIDs vs. 1% Prednisolon
• Topisch: Prednisolon
• Subtenon/retrobulbär: Methylprednisolon
Triamcinolone, 40 mg (1 ml)
• Intravitreal: Triamcinolone, 2-4 mg pars plana
• Implantat: Fluocinolon, Dexamethason
• Systemisch: p.o. oder i.v. 40 - 100 mg/d
Medikamentöse Behandlung des Makulaödems
Table 59-2 Goodman & Gilman 9th Edition*approximated from the literature
Relative Potenz der Kortikosteroide
Corticosteroid Relative Potencies
Cortisone 0.8
Cortisol 1
Prednisone 4
Methylprednisolone 5
Triamcinolone 5Fluorination at 9αposition increases corticosteroid receptor binding
Betamethasone 25
Dexamethasone 25
Fluocinolone acetonide 25*
Corticosteroid Equivalents Over Time
20
15
10
5
1
1000
750
250
0
500
Time (mo)
Cor
ticos
tero
id E
quiv
alen
ce
1 Hr Day 2Day 1
20
15
10
5
1
00 1 2 3 4
Dexamethasone (700 µg)Triamcinolone acetonide (4-mg injection)Fluocinolone
Intravitreal injection dexamethasone (700 µg)
TA free drug levels over time estimated from the dissolution kinetics of the Kenalog® depot in Kim H et al. Retina. 2006;26:523-530. Dexamethasone: Data on file. Irvine, CA: Allergan, Inc.Fluocinolone acetonide: Driot JY et al. J Ocul Pharm Ther. 2004;20:269-275; Beer PM et al. Ophthalmology. 2003;110:681-686.Triamcinolone acetonide: Inoue M et al. Am J Ophthalmol. 2004;138:1046-1048.
Steroide: Subtenon
• Triamcinolon• 40 mg subtenon• Wiederholung bis zu 3 x
1 Monat Abstand• Tropfanästhesie30 G Nadel
Cave: IOD Erhöhung in 36%
•Approximate duration of action: 2.5 years
Retisert prescribing information. http://www.bausch.com/en_US/downloads/ecp/pharma/general/retisert_pkginsert.pdf.
Retisert: Fluocinolon
•Approximate duration of action: At least 2 years
Kane FE, et al. Expert Opin Drug Delivery 2008;5:1039-1046.
Iluvien: Fluocinolon
in vitro Average Daily Wet Release Rates
0.5
0.4
0.3
0.2
0.23 ug/day0.45 ug/day
0.1
0.00 3 6 9 12 15 18 21 24 27 30
Alimera Sciences. Data on file
Time (months)
Fluo
cino
lone
Rel
ease
d (µ
g/da
y)Iluvien
Dexamethason Konzentration im Glaskörper
1. Weitjens O et al. Ophthalmology 2002; 109: 1887–91.2. Weitjens O et al. Am J Ophthalmol 1998; 125: 673–9. 3. Weitjens O et al. Am J Ophthalmol 1997; 123: 358–63.4. Weitjens O et al. Am J Ophthalmol 1999; 128: 192–7. 5. Gan IM et al. Graefes Arch Clin Exp Ophthalmol 2005; 243: 1186–9.
Art der Anwendung Dosis (mg)Verhältnis im Glaskörper
(Dosis [mg]: Cmax im Glaskörper [ng/ml])
Topisch1 0,3 3,7
Oral2 7,5 1,44
Peribulbär3 5,0 2,6
Subkonjunktival4 2,5 29
Intravitreal5 0,4 980
Medikamentöse Behandlung des Makulaödemes
Karboanhydrase-Hemmer:
Oral: Diamox®
Tropfen: Trusopt®, Azopt®
Karboanhydrasehemmer
o o o o o
2 K
3 Na
K/Na 2 ClNa 2 HCO
HCO3
Cl Na
K Cl
K
Na
H
36 mV
HCO
Na
IIIIIIIII
IIIIIIIIIIIII
IIIIIIIIIIIII
IIIIIIIII
Gao et al. Nature Medicine 2007;13:181-188
Extracellular carbonic anhydrase mediates retinal vascular permeability
Karboanhydrasehemmer und Makulaödem
• Leckage beim RPE
RP, Uveitis
• 500 mg Anfangsdosis / Tag
• Langzeit DosisreduktionTitrierung durch den Patienten
• Tachyphylaxie
1980s
Laser photocoagulation
2000
Photodynamic therapy
2005 2006 2007
Pegaptanib Ranibizumab
Bevacizumab off-label
Aflibercept
2011 2012
Pharmacological characteristics ofanti-VEGF therapies
1. Novartis Europharm Ltd. Lucentis SmPC. September 20112. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf3. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 20114. Genentech, Inc. Avastin® prescribing information. September 2011
Ranibizumab Aflibercept Bevacizumab
Company Genentech/Novartis Regeneron/Bayer Genentech/Roche
MOA / class Anti-VEGF-A antibody fragment [targets all VEGF-A isoforms]1
Anti-VEGF-A/PIGF/VEGF-B recombinant fusion protein [targets all VEGF-A isoforms,
VEGF-B and PIGF]3Anti-VEGF-A full-length
antibody [targets all VEGF-A isoforms]4
Molecular weight 48 kDa2 97–115 kDa3 149 kDa4
Structure
2
3
VEGFR1 VEGFR2
Ranibizumab Aflibercept
Company Genentech/Novartis Regeneron/Bayer
MOA / class Anti-VEGF-A antibody fragment [targets all VEGF-A isoforms]1
Anti-VEGF-A/PIGF/VEGF-B recombinant fusion protein [targets all VEGF-A isoforms,
VEGF-B and PIGF]4
Molecular weight 48 kDa2 97–115 kDa4
Half-life in the rabbit eye 2.88 days3 4–6 days
Systemic elimination half-life ~2 hours2 4–5 days5,6
Licensed indications
Wet AMD, visual impairment due to DME, visual impairment due to ME secondary to RVO (BRVO and CRVO)1
Wet AMD in the US4
1. Novartis Europharm Ltd. Lucentis SmPC. September 2011; 2. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000715/WC500043550.pdf; 3. Bakri SJ et al. Ophthalmology 2007;114:2179–82; 4. Regeneron Pharmaceuticals, Inc. EYLEA® prescribing information. November 2011; 5. Dixon JA et al. Expert Opin Investig Drugs 2009;18:1573–80; 6. Tew et al. Clin Cancer Res 2010;16:358–66; 7. Genentech, Inc. Avastin® prescribing information. September 2011
Pharmacological characteristics ofanti-VEGF therapies
Intravitreal aflibercept approved by the FDA for neovascular AMD under the trade name EYLEA®, recently also approved in Australia but it is not yet approved elsewhere
LOCF; Full analysis set; VIEW 1: OCTs mandatory at baseline, weeks 4, 12, 24, 36, and all visits weeks 52-96;VIEW 2: OCTs mandatory at all visits
VIEW Studies: Mean Change inCentral Retinal Thickness to Week 96