Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Amo, Eva M. del; Urtti, Arto

doi:10.1016/j.exer.2015.05.003

Cited by 191 publications

(163 citation statements)

References 88 publications

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“…We suggest that the damage produced NaCl in mouse involved the larger relative volume used. In human clinical use, the volumes are a tiny fraction of the vitreous volume (Del Amo and Urtti, 2015) and drugs are administered infrequently, so that the injected vehicle volume is not an important issue.…”

Section: Discussionmentioning

confidence: 99%

The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews

Ward

Siegwart

Frost

et al. 2016

Experimental Eye Research

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lntravitreal injection of substances dissolved in a vehicle solution is a common tool used to assess retinal function. We examined the effect of injection procedures (three groups) and vehicle solutions (four groups) on the development of form deprivation myopia (FDM) in juvenile tree shrews, mammals closely related to primates, starting at 24 days of visual experience (about 45 days of age). In seven groups (n = 7 per group), the myopia produced by monocular form deprivation (FD) was measured daily for 12 days during an 11-day treatment period. The FD eye was randomly selected; the contralateral eye served as an untreated control. The refractive state of both eyes was measured daily, starting just before FD began (day 1); axial component dimensions were measured on day 1 and after eleven days of treatment (day 12). Procedure groups: the myopia (treated eye refraction – control eye) in the FD group was the reference. The sham group only underwent brief daily anesthesia and opening of the conjunctiva to expose the sclera. The puncture group, in addition, had a pipette inserted daily into the vitreous. In four vehicle groups, 5 μL of vehicle was injected daily. The NaCl group received 0.85% NaCl. In the NaCl+ascorbic acid group, 1mg/mL of ascorbic acid was added. The water group received sterile water. The water+ascorbic acid group received water with ascorbic acid (1mg/mL). We found that the procedures associated with intravitreal injections (anesthesia, opening of the conjunctiva, and puncture of the sclera) did not significantly affect the development of FDM. However, injecting 5 μL of any of the four vehicle solutions slowed the development of FDM. NaCl had a small effect; myopia development in the last 6 days (−0.15 ± 0.08 D/day) was significantly less than in the FD group (−0.53 ± 0.06 D/day). NaCl+ Ascorbic acid further slowed the development of FDM on several treatment days. H2O (−0.09 ± 0.05 D/day) and H2O+ascorbic acid (−0.08 ± 0.05 D/day) both almost completely blocked myopia development. The treated eye vitreous chamber elongation, compared with the control eye, in all groups was consistent with the amount of myopia. When FD continued (days 12–16) without injections in the water and water+ascorbic acid groups, the rate of myopia development quickly increased. Thus, it appears the vehicles affected retinal signaling rather than causing damage. The effect of H2O and H2O+ascorbic acid may be due to reduced osmolality or ionic concentration near the tip of the injection pipette. The effect of ascorbic acid, compared to NaCl alone, may be due to its reported dopaminergic activity.

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Section: Discussionmentioning

confidence: 99%

The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews

Ward

Siegwart

Frost

et al. 2016

Experimental Eye Research

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“…The half-life obtained in rabbit eyes was scaled down to mice eyes using the following rationale: Small lipophilic compounds are cleared from the vitreous mainly through the RPE43. The CL ivt of small lipophilic compounds in mice is expected to be 30 times smaller than in rabbits.…”

Section: Methodsmentioning

confidence: 99%

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Sahaboglu

Barth

Secer

et al. 2016

Sci Rep

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The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment.

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“…But the relevant anatomical and physiological parameters in rabbit and man show only small differences. The rabbit is the most commonly used animal model for intravitreal pharmacokinetic studies39.…”

Section: Discussionmentioning

confidence: 99%

Intravitreal infusion: A novel approach for intraocular drug delivery

Tian

Liu

et al. 2016

Sci Rep

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Intraocular injection has become an increasingly important intervention in the treatment of posterior segment diseases. However, an acute intraocular pressure (IOP) elevation after intravitreal injection is a common concern. This study aimed to evaluate the efficacy of intravitreal infusion in maintaining stable IOP in a rabbit model. Trypan blue (TB) 0.06% with an external pump was used to evaluate intravitreal infusion in rabbit eyes. Groups A (50 μL), B (100 μL), C (150 μL), and D (200 μL) were slowly infused over 30 minutes with TB. As a control, Group E underwent conventional intravitreal injection of 100 μL of TB. Group F received a bolus infusion of 100 μL of TB within 1 minute. The mean increases in IOP during infusion for each group were: Group A (7.93 ± 3.80 mmHg), B (13.97 ± 3.17 mmHg), C (19.91 ± 6.06 mmHg) and D (29.38 ± 8.97 mmHg). Immediately post-injection in group E the mean increase in IOP amounted to 34.33 ± 6.57 mmHg. The mean increase in IOP of group F after bolus infusion was 49.89 ± 1.71 mmHg. Intravitreal infusion maintains a stable IOP and provides a controlled infusion speed compared with intravitreal injection.

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Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Cited by 191 publications

References 88 publications

The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews

The effect of intravitreal injection of vehicle solutions on form deprivation myopia in tree shrews

Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration

Intravitreal infusion: A novel approach for intraocular drug delivery

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