COMPARATIVE STUDY OF THE EFFECTS OF TWO ANTI-GLAUCOMATOUS DRUGS ON THE CORNEAL THICKNESS IN RABBITS WITH CORNEAL AUTOGRAFTS
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ARCH SOC ESP OFTALMOL 2008; 83: 257-262 ORIGINAL ARTICLE
COMPARATIVE STUDY OF THE EFFECTS OF TWO ANTI-
GLAUCOMATOUS DRUGS ON THE CORNEAL
THICKNESS IN RABBITS WITH CORNEAL AUTOGRAFTS
ESTUDIO COMPARATIVO DE LOS EFECTOS DE DOS DROGAS
ANTIGLAUCOMATOSAS SOBRE EL ESPESOR CORNEAL EN
CONEJOS CON AUTOINJERTO DE CÓRNEA
CHIARADIA PA1, CASIRAGHI JF2, FISCHBARG J3, LAVENA PI4
ABSTRACT RESUMEN
Purpose: To determine the central corneal thick- Objetivo: Determinar las variaciones del espesor
ness after administration of the anti-glaucomatous centrocorneal tras la administración de dos drogas
medications latanoprost 0.005% or dorzolamide antiglaucomatosas: latanoprost 0,005% o dorzola-
2%, as assessed in rabbits which have had total cor- mida 2% en conejos con auto injerto de cornea de
neal thickness autografts. espesor total.
Methods: A bilateral total corneal thickness auto- Métodos: Diez conejos recibieron un autoinjerto de
graft was performed in ten rabbits. One rabbit was córnea de espesor total bilateralmente. Un animal
excluded from the subsequent study in which the fue excluido del estudio. En los nueve restantes, a
antiglaucomatous medication was started two los dos meses de la intervención se instauró trata-
months post-operatively. Latanoprost 0.005% was miento con un fármaco antiglaucomatoso tópico. El
instilled once per day into the right eye, whereas the ojo derecho recibió latanoprost al 0,005%, una vez
left eyes were treated with dorzolamide 2% twice a al día, y el ojo izquierdo recibió dorzolamida al 2%
day. The eyes were examined by biomicroscopy cada 12 horas. Los ojos fueron examinados 0, 4, 10,
and ultrasound pachymetry immediately prior to 17 y 27 semanas después del inicio del tratamiento
commencement, and 4, 10, 17 and 27 weeks after con fármacos mediante biomicroscopia y paquime-
starting the anti-glaucomatous treatment. In each tría ultrasónica. En cada tiempo examinado, se rea-
instance three assessments of the central corneal lizaron 3 medidas del espesor central corneal en
thickness in each eye were made. At the end of the cada ojo.
study, the influence of time and treatment on the Al final del estudio se analizó la influencia del tiem-
corneal thickness was analyzed using a generalized po y del tratamiento sobre el espesor corneal utili-
Received: Dec. 12, 2005. Accepted: March 6, 2008.
Clinics Hospital San Martín. Buenos Aires University. Buenos Aires, Argentina.
1 Ph.D. in Medicine. Chief of Cornea Section. Ophthalmology Service.
2 Ph.D. in Medicine. Chief of Glaucoma Section. Ophthalmology Service.
3 Ph.D. in Medicine. Professor of Columbia University. Columbia University Medical Center, College of Physicians and Surgeons, New York,
USA.
4 Ph.D. in Medicine. Plant Medic.
This paper was partially funded with NIH Grant EY061178 (JF).
Correspondence:
Pablo Chiaradia
Arenales, 1733 - PB «A»
1061 Buenos Aires
Argentina
E-mail: pchiaradia@fibertel.com.arCHIARADIA PA, et al.
linear model for repeated measurements. All pene- zando un modelo lineal generalizado de medidas
trating keratoplasties were performed by the same repetidas. Todas las queratoplastias penetrantes fue-
surgeon (C.H.P). ron efectuadas por el mismo cirujano (CHP).
Results: Treatment with dorzolamide resulted in Resultados: El tratamiento con dorzolamida produ-
corneal edema and a significant increase in central jo edema corneal y un aumento significativo del
corneal thickness, whereas the treatment with lata- espesor corneal central mientras que el tratamiento
noprost resulted in neither corneal edema nor cor- con latanoprost no produjo edema corneal ni modi-
neal thickness changes. ficó el espesor corneal.
Conclusions: Dorzolamide, when instilled into the Conclusión: La dorzolamida, aplicada sobre ojos
eyes of rabbits with corneal autografts, could have de conejo con autoinjerto de córnea tiene un efecto
a negative effect on the graft, impairing the endot- negativo sobre el injerto, posiblemente empeorando
helial function through inhibition of the ionic la función del endotelio corneal mediante la inhibi-
pump. This effect could cause graft failure, which ción de la bomba iónica. Este efecto puede evaluar-
may be able to be defined with ultrasound pachi- se mediante paquimetría ultrasónica y podría pro-
metry (Arch Soc Esp Oftalmol 2008; 83: 257-262). vocar un fallo del injerto.
Key words: Corneal thickness, latanoprost 0.005%, Palabras claves: Espesor corneal, latanoprost
dorzolamide 2%, pachymetry. 0,005%, dorzolamida 2%, paquimetría.
INTRODUCTION tions in rabbit eyes after penetrating keratoplasty
and the administration of two antiglaucomatous
Intra-ocular pressure increase is a frequent com- drugs: dorzolamide 2% and latanoprost 0.005% and
plication after penetrating keratoplasty, on many the characteristics of the evolution of its effects.
occasions difficult to control.
The pharmakinetic parameters and safety ranges
of anti-glaucomatous drugs in normal corneae are SUBJECTS, MATERIAL AND
well known and have proved to be safe and effective. METHODS
The negative effect of topically administered car-
bonic anhydrase inhibitors (CAI) on the corneal Ten albino New Zealand rabbits aged 12-15
endothelial pump has been the object of study, months were utilized, weighing between 1.5 and 1.7
demonstrating the safety of the drug on healthy cor- kg, obtained at the farm of Gilardoni S.A., General
neae in what concerns translucency, thickness and Rodríguez, province of Buenos Aires, Argentina.
endothelial cellularity (1-5). All the experimental manipulations of the animals
CAI are capable of reducing the formation of cell were carried out following the animal experimenta-
bicarbonate ions, thus reducing the associated tion standards issued by the National Drug, Food
transport of sodium and water and giving rise to and Medical Technology Administration (ANMAT),
possible corneal edema in eyes with deficient the National Health and Agricultural Food Quality
endothelial function. Service (SENASA) and the Exact and Natural
The function of corneal endothelium vis-à-vis the Sciences College of Buenos Aires University. The
corneal thickness can be indirectly assessed in vivo. animals were anesthetized with xylocine clorhydra-
Accordingly, ultrasound pachymetry is a useful te 2%, Rompun® (Bayer), 5 mg/kg subcutaneous
method for observing patients subjected to penetra- and Ketamine, Ketalar® (Parke Davis), 30 mg/kg
ting keratoplasty (6). There is a linear relationship intramuscular, after which a bilateral cornea self-
between hydration and corneal thickness, as the graft was made with a penetrating thickness of 7 mm
central thickness of a graft is a clinically relevant diameter. The trephination was made by hand with
measure for evaluating a transplant. manual trephinators (Trephine handle) manufactu-
Considering that corneal thickness variations are red by Storz Instrument Company, model F3096, 7
an indirect measure of endothelial insufficiency, mm (St. Louis, Missouri, USA). The grafts were
this study has analyzed the corneal thickness varia- sutured with 10-0 nylon (Alcon Inc., USA).
258 ARCH SOC ESP OFTALMOL 2008; 83: 257-262Antiglaucomatous drugs in cornea self-graft
Two months after the intervention, treatment was
established with a topical antiglaucomatous drug in
both eyes. The right eye was given latanoprost at
0.0005%, Xalatan® (Pharmacia, Belgium) once a
day, while the left eye was given dorzolamide 2%
Trusopt® (Merck Sharp & Dohme-Chibert, Cler-
mont – Ferrand, France), every 12 hours. The eyes
were assessed at 0, 4, 10, 17 and 27 weeks after
beginning the treatment by means of biomicroscopy
and ultrasound pachymetry (BVI Pachymeter, Poc-
ket Model– BV International - Clermont – Ferrand,
France). The corneal thickness measures were
included in an Excel® spreadsheet, Office XP ver-
sion, Microsoft Corp. and analyzed with the SPSS
statistical program, version 11.5. (SPSS Inc, Illi- Fig. 1: Rabbit eye 27 weeks after applying latanoprost
0.005% once a day.
nois, USA).
At the end of the study we analyzed the influen-
ce of time and treatment over the corneal thickness For the statistical analysis of the corneal thick-
utilizing a generalized linear model of repeated ness evolution (tables II and III) we considered the
measures. influence of time and of treatment and a third effect
of repeated measures for considering all three para-
RESULTS
One animal was excluded due to endophthalmitis
in the left eye, developed 8 weeks after the inter-
vention.
In the nine remaining animals, the biomicrosco-
pic assessment was made in week 0, 4, 10, 17 and
27 and showed corneal edema which progressively
increased in the eyes treated with dorzolamide 2%
(figs. 1 and 2).
Ultrasonic pachymetry was utilized to confirm
said corneal thickening (table I, fig. 3).
Likewise, no statistically significant variations
were observed in the corneal thickness of rabbits Fig. 2: Eyes with keratoplasty to which Dorzolamide
treated with latanoprost 0.0005%. 2% was administered and evolved to corneal edema.
Tabla I. Descriptive measure and evolution through time
Eyes Time Mean Typical error Confidence Interval 95%
Upper limit Lower limit
Right (n=9) Base 564.963 46.764 457.126 672.800
4 weeks 554.481 43.836 453.395 655.568
10 weeks 556.593 43.776 455.646 657.539
17 weeks 555.593 40.763 461.593 649.592
27 weeks 556.815 39.538 465.640 647.989
Left (n=9) Base 573.667 47.287 464.623 682.711
4 weeks 636.296 36.976 551.029 721.563
10 weeks 646.481 32.346 571.890 721.073
17 weeks 712.000 48.792 599.484 824.516
27 weeks 714.370 45.140 610.277 818.463
ARCH SOC ESP OFTALMOL 2008; 83: 257-262 259CHIARADIA PA, et al.
well as the interaction between both (fig. 3 and
tables I, II and III).
DISCUSSION
In the long term, topical carbonic anhydrase inhi-
bitors alter the endothelial function as evidenced in
the literature in corneas with keratopathies or ocu-
lar surgery.
It is known that the endothelial pump is effective
after the administration of topical CAIs in healthy
Fig. 3: Evolution through time of each eye. The coordi- or slightly damaged corneas, but it becomes ineffi-
nates show the corneal thickness factor and the x-axis cient in the presence of an important endothelial
show the time factor. Differences are observed after
administering two drugs (dorzolamide 2% and latano-
compromise. According to a study by Gordon et al
prost 0.005%). (1), dorzolamide causes irreversible corneal edema
in patients with glaucoma and surgery history and
previous endothelial compromise.
meters in each instance. The proposed and tested Some communications (7) point out that the
model includes the effect of time and eye factor as endothelial function of the corneas with pathology
Table II. Evaluation of statistical significance. Multivariate contrasts (c)
Effect Tests used Value F Gl of hypothesis Gl of error Significance
TIME Pillai trace 0.822 5.785(b) 4.000 5.000 0.041*
Wilks Lambda 0.178 5.785(b) 4.000 5.000 0.041*
Hotelling Trace 4.628 5.785(b) 4.000 5.000 0.041*
Roy’s square root 4.628 5.785(b) 4.000 5.000 0.041*
EYES Pillai trace 0.606 12.285(b) 1.000 8.000 0.008**
Wilks Lambda 0.394 12.285(b) 1.000 8.000 0.008**
Hotelling Trace 1.536 12.285(b) 1.000 8.000 0.008**
Roy’s square root 1.536 12.285(b) 1.000 8.000 0.008**
TIME * EYES Pillai trace 0.884 9.543(b) 4.000 5.000 0.015*
Wilks Lambda 0.116 9.543(b) 4.000 5.000 0.015*
Hotelling Trace 7.634 9.543(b) 4.000 5.000 0.015*
Roy’s square root 7.634 9.543(b) 4.000 5.000 0.015*
* Significant at 5%; ** Significant at 1%.
Table III. Tests of intra-subject effects
Source Tests used Sum of Type 3 square G1 Squared mean F Significance
TIME Assumed sphericity 168498.015 4 42124.504 5.147 0.003**
Greenhouse-Geisser 168498.015 1.237 136176.832 5.147 0.041*
Huynh-Feldt 168498.015 1.351 124723.957 5.147 0.037*
Lower Limit 168498.015 1.000 168498.015 5.147 0.053
EYES Assumed sphericity 659885.570 1 659885.570 12.285 0.008**
Greenhouse-Geisser 659885.570 1.000 659885.570 12.285 0.008**
Huynh-Feldt 659885.570 1.000 659885.570 12.285 0.008**
Lower Limit 659885.570 1.000 659885.570 12.285 0.008**
TIME * EYES Assumed sphericity 205956.652 4 51489.163 8.778 0.000**
Greenhouse-Geisser 205956.652 1.404 146724.500 8.778 0.008**
Huynh-Feldt 205956.652 1.612 127764.358 8.778 0.006**
Lower Limit 205956.652 1.000 205956.652 8.778 0.018*
* Significant at 5%; ** Significant at 1%.
260 ARCH SOC ESP OFTALMOL 2008; 83: 257-262Antiglaucomatous drugs in cornea self-graft
or previous surgery is compromised because the increase in corneal thickness against the group tre-
drug kinetics are altered and the endothelium recei- ated with latanoprost 0.005%. Ultrasound pachy-
ved larger concentrations than otherwise. The cor- metry allowed for the identification and follow-up
neal involvement due to the action of a drug can be of said changes.
evaluated in vitro measuring the variations of tran-
sendothelial electrical potentials (8).
Our study expresses the progression of corneal
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