Ocular alternatives

Needs for the Future. One significant need in the area of ocular alternatives is for the validation of current in vitro assays. The key point is that users of the assay(s) need to have confidence in their ability to interpret and reliably use the data generated. This confidence level can only be achieved by parallel testing in one s own laboratory with compounds similar to those likely to be evaluated as unknowns. The validation process will be a long, somewhat tedious project, but will be necessary before in vitro alternatives can be used responsibly... 

The ocular hypotensive lipids in typical ophthalmology practice are considered first-line alternatives to topical P-blockers because of their superior efficacy and safety profiles. Many clinicians may choose to use the ocular hypotensive lipids as first-line agents, especially in patients that have an initial requirement to lower IOP by more than 25%, or in patients that have relative or absolute contraindications to topical P-blockers. However, latanoprost is currently the only ocular hypotensive lipid drug that has a Food and Drug Administration (FDA) indication for first-line therapy. Bimatoprost and travoprost are indicated by the FDA for patients who are intolerant of other IOP-lowering therapy or insufficiently responsive to another IOP-lowering medication.10,38... 

As a part of the Federal Hazardous Substances Act (FHSA), a modified Draize test was adopted [63-65] as the official method for evaluation of acute ocular irritancy [66]. It is a pass/fail determination that remains in effect today. Two refinements have been accepted as alternatives (a) the test which uses a small volume more consistent with the capacity of the inferior con-... 

Booman, K.A., DeProspo, J., Demetrulias, J., Diedger, A., Griffith, J.F., Grochosky, G., Kong, B., McCormick, W.C., North-Root, H., Rozen, M.G., and Sedlak, R. I. (1989). The SDA alternatives program Comparison of in vitro data with Draize test data. J. Toxicol.—Cut. Ocular Toxicol. 8 35 19. 

Finally, as previously stated, if in vitro models are to be fully effective, the underlying mechanisms of ocular irritation need to be identified. Many of the in vitro assays proposed as alternatives to in vivo testing are based on correlations rather than mechanisms of irritation. The scoring or ranking of substances utilizing the in vitro endpoint may correlate with the severity of the in vivo response, but the reason for the agreement may be unclear and strictly fortuitous for the compounds evaluated. The ideal assay would monitor several biochemical or biological events specifically... 

Borenfreund, E. and Borrero, O. (1984). In vitro cytotoxicity assays potential alternatives to the Draize ocular irritancy test. Cell Biol. Toxicol. 1 33-39. 

Bruner, L.FI. and Parker, R.D. (1990). Evaluation of six in vitro alternatives for ocular irritancy testing. Toxicologist 10 258. 

Flower, C. (1987). Some problems in validating cytotoxicity as a correlate of ocular irritancy. In Alternative Methods in Toxicology, Vol. 5. (Goldberg, A.M., Ed.). Mary Ann Liebert, New York, pp. 269-274. 

Engelke M, Patzke J, Tykhonova S, Zorn-Kruppa M. Assessment of ocular irritation by image processed quantification of cell injury in human corneal cell cultures and in corneal constructs. Altern Lab Anim 32 345-353 (2004). 

ICCVAM has evaluated alternative test methods for acute oral toxicity, genetic toxicity, biologies, immunotoxicity, dermal corrosion and irritation, ocular toxicity, developmental toxicity, pyrogeni-city, and endocrine disrupter effects (ICCVAM 2007). As examples, alternative test systems for dermal corrosion and irritation are described in the following text. 

Developments to improve ocular endotamponades were focused initially on lower-density FCLs as alternatives to the PFCLs [23-25]. 

Ocular chemical injuries are a significant problem. Existing published data on the epidemiology of such injuries are incomplete. Currently recommended decontamination with water or other commonly available solutions such as normal saline cannot always prevent serious eye injuries. Alternative active eye decontamination solutions should continue to be investigated. 

Maurer, J.K., Parker, R.D., Jester, J.V. Extent of initial comeal injury as the mechanistic basis for ocular irritation key findings and recommendations for the development of alternative assays. Regul Xoxicol Pharmacol 36(1), 106-117 (2002)... 

The ocular hypertensive response in this case could have been due to systemic absorption of glucocorticoid through the skin of the eyelid, especially when there was a surgical wound. Alternatively, a sufficient amount of ointment could have seeped over the eyelid margins, causing the rise in intraocular... 

Ocular damaging and irritant agents can be identified and evaluated by the Draize rabbit test [114]. However, more recently this test has been criticized on the basis of ethical considerations and unreliable prognosis of human response. Alternative methods such as the evaluation of toxicity on ocular cell cultures have been recommended and are being indicated as promising prognostic tools [115-120]. Direct confocal microscopic analysis [121], hydration level of isolated corneas [122], and various other tests on isolated corneas or animal eyes have also been proposed for evaluation of ocular toxic effects. 

Despite its widespread use and study during the first 60 years of the twentieth century, iontophoresis was never fully adopted as standard procedure. The lack of carefully controlled trials and the paucity of toxicity data were among the reasons that precluded its acceptance as an alternative for drug delivery. However, the last decade years have witnessed the development and optimization of the technology of ocular iontophoresis for fast and safe delivery of high drug concentrations in a specific ocular site [13]. 

Transscleral iontophoresis of steroids (dexamethasone and methylprednisolone) can be an alternative treatment for many ocular inflammations. Lam et al. [36] demonstrated high... 

Head, K.A., Natural therapies for ocular disorder, part two cataracts and glaucoma, Alternative Medicine Review A Journal of Clinical Therapeutic, 6, 141-166, 2001. 

In addition to the work presented here, several alternative viral-vectored approaches have been reported recently. An adeno-associated viral vector (AAV) encoding the soluble VEGF receptor 1, sFlt-1, shows promise for long-term inhibition of two types of ocular neovascularization (Lai et al., 2002). This vector, when injected into the anterior chamber, resulted in expression in both the corneal endothelium and iris pigment epithelium and reduced corneal NV by 36%. Subretinal injection of the same vector reduced choroidal NV subsequent to laser lesions around the optic nerve. These results suggest that a secretable factor expressed in one or more transduced cell populations can be elfective in the control of ocular NV occurring in a disparate cell population. 

An alternative approach utilizes temperature-sensitive systems. Poloxamer FI27 undergoes phase transition induced by changes in temperature. At room temperature the poloxamer remains a solution. When the solution is instilled onto the eye surface (34 °C) the elevated temperature causes the solution to become a gel, thereby prolonging its contact with the ocular surface. One of the disadvantages of such a system is that it is characterized by a high polymer concentration (25% poloxamer), and the surfactant properties of poloxamer may be detrimental to ocular tolerability. 

Abraham MH, Hassanisadi M, Jalali-Heravi M et al. (2003) Draize rabbit eye test compatibility with eye irritation thresholds in humans a quantitative structure-activity relationship analysis. Toxicol Sci 76 384-391 Curren RD, Harbell JW (1998) In vitro alternatives for ocular irritation. Environ Health Perspect 106, Suppl 2 485M92 Draize JH, Woodard G, Calvery HO (1944) Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther 82 377-390... 

PURPOSE AND RATIONALE This test uses an ex vivo model of corneal organ culture, preferentially porcine, to obtain information of the possible ocular toxicity of various chemicals. This test is used as an alternative to the Draize Test to minimize or replace the use of live animal testing of ocular irritancy (Symposium, Proceeding 1996). The test allows for determination of reversibility of corneal injury following exposure to chemicals, drugs or cosmetics (Xu etal. 2004). 

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