RSS-Feed abonnieren
DOI: 10.1055/s-0029-1245379
© Georg Thieme Verlag KG Stuttgart · New York
Pharmakologische Vitreolyse
Pharmacological VitreolysisPublikationsverlauf
Eingegangen: 3.3.2010
Angenommen: 30.3.2010
Publikationsdatum:
15. September 2010 (online)

Zusammenfassung
Hintergrund: Der Glaskörper hat entscheidenden Einfluss auf die Entwicklung und den Verlauf der meisten vitreoretinalen Erkrankungen, welche heute mittels Vitrektomie behandelt werden. Da die mechanische Vitrektomie unvollständig ist, sucht man nach pharmakologischen, enzymatischen Alternativen, welche die Intervention sicherer und effektiver machen sollen. Methode: Verschiedene Substanzen (Chondroitinase, Dispase, Hyaluronidase, Plasmin, Microplasmin) wurden präklinisch und im Falle von Hyaluronidase und Microplasmin (ThromboGenics Ltd., Dublin, Leuven) auch klinisch untersucht. Die bislang veröffentlichten präklinischen und klinischen Ergebnisse werden berichtet. Resultate: Microplasmin kann dosisabhängig eine komplette hintere Glaskörperabhebung induzieren. Morphologische, immunzytochemische oder funktionelle Netzhautveränderungen finden sich nicht. Die zwei bislang veröffentlichten Phase-II-Studien bestätigen dieses Wirkprofil bei guter Verträglichkeit. Die übrigen getesteten Substanzen scheinen weniger gut zur pharmakologischen Vitreolyse geeignet zu sein, da sie Netzhautschäden induzieren können (Dispase) oder den Glaskörper nur verflüssigen, ohne ihn primär von der Netzhaut abzulösen (Hyaluronidase). Schlussfolgerung: Microplasmin trennt den Glaskörper von der Netzhaut ohne morphologische oder funktionelle Netzhautveränderungen zu induzieren. Die Ergebnisse der klinischen Prüfung lassen erkennen, dass Microplasmin hilfreich sein kann, die Ablösung des Glaskörpers vor oder bei der Vitrektomie zu erleichtern und die Intervention atraumatischer und sicherer zu machen.
Abstract
Background: The vitreous plays an important role in the development and progression of vitreoretinal diseases. Vitrectomy is the treatment modality of choice in these cases. However, mechanical vitrectomy is incomplete. Therefore, alternative strategies have been pursued including pharmacological means such as enzymes. The goal of pharmacological vitreolysis is to make the surgical intervention easier and less traumatic. Methods: Different substances have been investigated, including chondroitinase, dispase, hyaluronidase, plasmin, and microplasmin. Besides preclinical investigations, hyaluronidase and microplasmin (ThromboGenics Ltd., Dublin, Leuven) have been tested clinically. Results from the literature are reported herein. Results: Plasmin and microplasmin are both capable of inducing posterior vitreous detachment (PVD) in a dose- and time-dependent manner. There are no morphological or functional changes of the retina at therapeutic doses. Two phase II studies published to date demonstrate both efficacy and safety. Phase III studies are ongoing, and results are expected during 2010. Other enzymes tested show limitations in that retinal damage may occur (dispase) or liquefaction (hyaluronidase) occurs without cleavage of the vitreous cortex from the retina. Conclusions: Microplasmin induces PVD. Results from clinical trials show that microplasmin helps to detach the vitreous cortex from the retina. This may be advantageous in terms of complete vitreous removal and less traumatic intervention compared to mechanical techniques, such as vitrectomy and peeling of the internal limiting membrane.
Schlüsselwörter
Glaskörper - Pharmakologie - Retina
Key words
pharmacology - retina - vitreous
Literatur
- 1 Sebag J. The vitreous. Structure, function, pathobiology.. New York: Springer Verlag; 1989
Reference Ris Wihthout Link
- 2
Sebag J.
Vitreous: the resplendent enigma.
Br J Ophthalmol.
2009;
93 (8)
989-991
Reference Ris Wihthout Link
- 3
Sebag J.
Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease.
Graefes Arch Clin Exp Ophthalmol.
2004;
242 (8)
690-698
Reference Ris Wihthout Link
- 4
Sebag J.
Vitreoschisis.
Graefes Arch Clin Exp Ophthalmol.
2008;
246 (3)
329-332
Reference Ris Wihthout Link
- 5
Krebs I et al.
Posterior vitreomacular adhesion: a potential risk factor for exudative age-related
macular degeneration?.
Am J Ophthalmol.
2007;
144 (5)
741-746
Reference Ris Wihthout Link
- 6
Bhisitkul R B.
Anticipation for enzymatic vitreolysis.
British Journal of Ophthalmology.
2001;
85
1-2
Reference Ris Wihthout Link
- 7
Sebag J.
Pharmacologic vitreolysis.
Retina.
1998;
18 (1)
1-3
Reference Ris Wihthout Link
- 8
Sebag J.
Pharmacologic vitreolysis--premise and promise of the first decade.
Retina.
2009;
29 (7)
871-874
Reference Ris Wihthout Link
- 9
Nasrallah F P et al.
The role of the vitreous in diabetic macular edema.
Ophthalmology.
1988;
95 (10)
1335-1339
Reference Ris Wihthout Link
- 10
Hikichi T et al.
Association between the short-term natural history of diabetic macular edema and the
vitreomacular relationship in type II diabetes mellitus.
Ophthalmology.
1997;
104 (3)
473-478
Reference Ris Wihthout Link
- 11
Capeans C et al.
Comparative study of incomplete posterior vitreous detachment as a risk factor for
proliferative vitreoretinopathy.
Graefes Arch Clin Exp Ophthalmol.
1998;
236 (7)
481-485
Reference Ris Wihthout Link
- 12
Bonnet M.
The development of severe proliferative vitreoretinopathy after retinal detachment
surgery. Grade B: a determining risk factor.
Graefes Arch Clin Exp Ophthalmol.
1988;
226 (3)
201-205
Reference Ris Wihthout Link
- 13
Tolentino F I, Schepens C L, Freeman H M.
Massive preretinal retraction. A biomicroscopic study.
Arch Ophthalmol.
1967;
78
16-22
Reference Ris Wihthout Link
- 14
Sebag J.
Diabetic vitreopathy.
Ophthalmology.
1996;
103 (2)
205-206
Reference Ris Wihthout Link
- 15
Gandorfer A.
[The need for pharmacology in vitreoretinal surgery SOE Lecture 2007].
Klin Monatsbl Augenheilkd.
2007;
224 (12)
900-904
Reference Ris Wihthout Link
- 16
Gandorfer A.
Objective of Pharmacologic Vitreolysis.
Dev Ophthalmol.
2009;
44
1-6
Reference Ris Wihthout Link
- 17
Faulborn J, Bowald S.
Microproliferations in proliferative diabetic retinopathy and their relationship to
the vitreous: corresponding light and electron microscopic studies.
Graefes Arch Clin Exp Ophthalmol.
1985;
223 (3)
130-138
Reference Ris Wihthout Link
- 18
Schwartz S D et al.
Recognition of vitreoschisis in proliferative diabetic retinopathy. A useful landmark
in vitrectomy for diabetic traction retinal detachment.
Ophthalmology.
1996;
103 (2)
323-328
Reference Ris Wihthout Link
- 19
Johnson M W, Van Newkirk M R, Meyer K A.
Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular
hole formation.
Arch Ophthalmol.
2001;
119 (2)
215-222
Reference Ris Wihthout Link
- 20
Gandorfer A et al.
Pathology of the macular hole rim in flat-mounted internal limiting membrane specimens.
Retina.
2009;
29 (8)
1097-105
Reference Ris Wihthout Link
- 21
Gandorfer A, Rohleder M, Kampik A.
Epiretinal pathology of vitreomacular traction syndrome.
Br J Ophthalmol.
2002;
86 (8)
902-909
Reference Ris Wihthout Link
- 22
Gandorfer A et al.
Resolution of diabetic macular edema after surgical removal of the posterior hyaloid
and the inner limiting membrane.
Retina.
2000;
20 (2)
126-133
Reference Ris Wihthout Link
- 23
Gandorfer A et al.
Epiretinal pathology of diffuse diabetic macular edema associated with vitreomacular
traction.
Am J Ophthalmol.
2005;
139 (4)
638-652
Reference Ris Wihthout Link
- 24
Shimada H et al.
Concentration gradient of vascular endothelial growth factor in the vitreous of eyes
with diabetic macular edema.
Invest Ophthalmol Vis Sci.
2009;
50 (6)
2953-2955
Reference Ris Wihthout Link
- 25
Stefansson E.
Physiology of vitreous surgery.
Graefes Arch Clin Exp Ophthalmol.
2009;
247 (2)
147-163
Reference Ris Wihthout Link
- 26
Stefansson E, Landers III M B, Wolbarsht M L.
Vitrectomy, lensectomy, and ocular oxygenation.
Retina.
1982;
2 (3)
159-166
Reference Ris Wihthout Link
- 27
Quiram P A et al.
Microplasmin-induced posterior vitreous detachment affects vitreous oxygen levels.
Retina.
2007;
27 (8)
1090-1096
Reference Ris Wihthout Link
- 28
Goldenberg D T, Trese M T.
Pharmacologic vitreodynamics and molecular flux.
Dev Ophthalmol.
2009;
44
31-36
Reference Ris Wihthout Link
- 29
Gandorfer A et al.
Ultrastructure of the vitreoretinal interface following plasmin assisted vitrectomy.
Br J Ophthalmol.
2001;
85 (1)
6-10
Reference Ris Wihthout Link
- 30
Eckardt C et al.
Removal of the internal limiting membrane in macular holes. Clinical and morphological
findings.
Ophthalmologe.
1997;
94 (8)
545-551
Reference Ris Wihthout Link
- 31
Haritoglou C et al.
Long-term follow-up after macular hole surgery with internal limiting membrane peeling.
Am J Ophthalmol.
2002;
134 (5)
661-666
Reference Ris Wihthout Link
- 32
Hageman G S, Russell S R.
Chondroitinase-mediated disinsertion of the primate vitreous body.
Invest Ophthalmol Vis Sci.
1994;
35
1260
Reference Ris Wihthout Link
- 33
Hikichi T, Kado M, Yoshida A.
Intravitreal injection of hyaluronidase cannot induce posterior vitreous detachment
in the rabbit.
Retina.
2000;
20 (2)
195-198
Reference Ris Wihthout Link
- 34
Sebag J.
Is pharmacologic vitreolysis brewing?.
Retina.
2002;
22 (1)
1-3
Reference Ris Wihthout Link
- 35
Kuppermann B D et al.
Safety results of two phase III trials of an intravitreous injection of highly purified
ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage.
Am J Ophthalmol.
2005;
140 (4)
585-597
Reference Ris Wihthout Link
- 36
Kuppermann B D et al.
Pooled efficacy results from two multinational randomized controlled clinical trials
of a single intravitreous injection of highly purified ovine hyaluronidase (Vitrase)
for the management of vitreous hemorrhage.
Am J Ophthalmol.
2005;
140 (4)
573-584
Reference Ris Wihthout Link
- 37
Stenn K S, Link R, Moelmann G.
Dispase, a neutral protease from Bacillus polymyxa, is a powerful fibronectinase and
type IV collagenase.
J Invest Dermatol.
1989;
93
287-290
Reference Ris Wihthout Link
- 38
Tezel T H, Del P riore LV, Kaplan H J.
Posterior vitreous detachment with dispase.
Retina.
1998;
18 (1)
7-15
Reference Ris Wihthout Link
- 39
Oliveira L B et al.
Dispase facilitates posterior vitreous detachment during vitrectomy in young pigs.
Retina.
2001;
21 (4)
324-331
Reference Ris Wihthout Link
- 40
Jorge R et al.
Intravitreal injection of dispase causes retinal hemorrhages in rabbit and human eyes.
Curr Eye Res.
2003;
26 (2)
107-112
Reference Ris Wihthout Link
- 41
Verstraeten T C et al.
Pharmacologic induction of posterior vitreous detachment in the rabbit.
Arch Ophthalmol.
1993;
111 (6)
849-854
Reference Ris Wihthout Link
- 42
Gandorfer A et al.
Vitreoretinal morphology of plasmin-treated human eyes.
Am J Ophthalmol.
2002;
133 (1)
156-159
Reference Ris Wihthout Link
- 43
Gandorfer A, Ulbig M, Kampik A.
Plasmin-assisted vitrectomy eliminates cortical vitreous remnants.
Eye.
2002;
16 (1)
95-97
Reference Ris Wihthout Link
- 44
Nagai N et al.
Recombinant human microplasmin: production and potential therapeutic properties.
J Thromb Haemost.
2003;
1 (2)
307-313
Reference Ris Wihthout Link
- 45
Gandorfer A et al.
Posterior vitreous detachment induced by microplasmin.
Invest Ophthalmol Vis Sci.
2004;
45 (2)
641-647
Reference Ris Wihthout Link
- 46
Sakuma T et al.
Safety of in vivo pharmacologic vitreolysis with recombinant microplasmin in rabbit
eyes.
Invest Ophthalmol Vis Sci.
2005;
46 (9)
3295-3299
Reference Ris Wihthout Link
- 47
Sebag J.
Molecular biology of pharmacologic vitreolysis.
Trans Am Ophthalmol Soc.
2005;
103
473-494
Reference Ris Wihthout Link
- 48
Sebag J, Ansari R R, Suh K I.
Pharmacologic vitreolysis with microplasmin increases vitreous diffusion coefficients.
Graefes Arch Clin Exp Ophthalmol.
2007;
245 (4)
576-580
Reference Ris Wihthout Link
- 49
Smet M D et al.
Microplasmin Intravitreal Administration in Patients with Vitreomacular Traction Scheduled
for Vitrectomy The MIVI I Trial.
Ophthalmology.
2009;
116
1349-1355
Reference Ris Wihthout Link
- 50
Benz M S et al.
A Placebo-Controlled Trial of Microplasmin Intravitreous Injection to Facilitate Posterior
Vitreous Detachment before Vitrectomy.
Ophthalmology.
2010;
117
791-797
Reference Ris Wihthout Link
- 51
Uemura de A et al.
Effect of plasmin on laminin and fibronectin during plasmin-assisted vitrectomy.
Arch Ophthalmol.
2005;
123 (2)
209-213
Reference Ris Wihthout Link
- 52
Chen W et al.
Microplasmin degrades fibronectin and laminin at vitreoretinal interface and outer
retina during enzymatic vitrectomy.
Curr Eye Res.
2009;
34 (12)
1057-1064
Reference Ris Wihthout Link
- 53
Kohno T et al.
Immunofluorescent studies of fibronectin and laminin in the human eye.
Invest Ophthalmol Vis Sci.
1987;
28 (3)
506-514
Reference Ris Wihthout Link
- 54
Li X, Shi X, Fan J.
Posterior vitreous detachment with plasmin in the isolated human eye.
Graefes Arch Clin Exp Ophthalmol.
2002;
240 (1)
56-62
Reference Ris Wihthout Link
- 55
Gandorfer A.
Enzymatic vitreous disruption.
Eye.
2008;
22
1273-1277
Reference Ris Wihthout Link
- 56
Yoshida A, Ishiguro S, Tamai M.
Expression of glial fibrillic acidic protein in rabbit müller cells after lensectomy-vitrectomy.
Invest Ophthalmol Vis Sci.
1993;
34
3154-3160
Reference Ris Wihthout Link
- 57
Trese M.
Enzymatic-assisted vitrectomy.
Eye.
2002;
16
365-368
Reference Ris Wihthout Link
- 58
Trese M T, Williams G A, Hartzer M L.
A new approach to stage 3 macular holes.
Ophthalmology.
2000;
107 (8)
1607-1611
Reference Ris Wihthout Link
- 59
Williams J G et al.
Autologous plasmin enzyme in the surgical management of diabetic retinopathy.
Ophthalmology.
2001;
108 (10)
1902-1905
Reference Ris Wihthout Link
- 60
Margherio A R et al.
Plasmin enzyme-assisted vitrectomy in traumatic pediatric macular holes.
Ophthalmology.
1998;
105 (9)
1617-1620
Reference Ris Wihthout Link
Prof. Dr. Arnd Gandorfer
Augenklinik der Ludwig-Maximilians-Universität München
Mathildenstr. 8
80336 München
Telefon: ++ 49/89/51 60 38 56
Fax: ++ 49/89/51 60 47 78
eMail: arnd.gandorfer@med.uni-muenchen.de
