Lens and eye toxicity research最新文献

Fluorophotometry allows calculation of the permeability coefficient k(a) of the blood-aqueous barrier to fluoresceine after i.v. dye application; aqueous flare can be graded objectively by laser flare measurement and permits in vivo estimation of over-all protein concentration in the aqueous humor. To evaluate a formal relationship between both procedures we performed laser flare measurements on 40 eyes (clinically ranged from healthy to mild uveitis) before and during fluorophotometry. Laser flare count [mec-1] raises exponentially (r = 0.8; p = 0.05) with an increasing permeability coefficient to fluoresceine k(a) [10(-4)min-1]. Laser flare count during the fluorophotometry procedure is not increased (p = 0.05) compared to the prescan. Reproducability was 14% +/- 7.5% for laser flare measurements and 13% +/- 5% for fluorophotometry. Malfunction of the blood aqueous barrier possibly increases the permeability to molecules of high molecular weight not proportional to that of hydrophilic particles of low molecular weight. The exponential regression between the data achieved with both procedures suggests that fluorophotometry is more sensitive in detecting early changes in blood aqueous barrier function whereas laser flare detection could be appropriate in more severe cases of barrier dysfunction.

Silicone oils may induce pathological changes in corneas or retinas by unknown mechanisms but the effects are probably related to certain specific components. Low molecular weight compounds have been implicated in the induction of toxic tissue reactions. Several of these components, that occur as contaminants or by-products in crude silicone oils, were tested for their ability to alter corneal endothelial permeability. In vitro inulin/dextran permeability was measured after one week of in vivo exposure to a non-toxic oil to which various low molecular weight components were added. At least 75% of the anterior chamber volume was replaced with oil +/- additives. A long-chain silanol-terminated polydimethylsiloxane (1000 cps) at 2 mg/ml, tetramethyl-ammonium siloxanolate (a catalyst) at 1 mg/ml and a mixture of a series of linear compounds (MM through MD10M) each at 10 mg/ml all caused a large corneal endothelial permeability increase. A mixture of two short-chain silanol-terminated compounds was less damaging, as was a mixture of a cyclic series. Evidently certain compounds can induce toxic effects on the corneal endothelium whereas other compounds are much less toxic. The linear series and the catalyst, that induce corneal endothelial changes, have been shown to occur in silicone oils.

We examined the effects of intraocular gases on the permeability of the rabbit corneal endothelium to inulin and dextran. Volumes of air (0.16 ml), sulfur hexafluoride (SF6) (0.08 ml), and octafluoropentane (C3F8) (0.04 ml) were infused into the anterior chamber at constant intraocular pressure so that all volumes were equal after expansion. The inulin/dextran permeability was statistically decreased by infusion with Ringer, while air caused an 8.4% increase in dextran permeability but no effect on inulin flux. These small effects were of no biological significance. SF6 caused a 16% and 13% increase in inulin and dextran permeability, respectively, while C3F8 caused an 18% increase in both inulin and dextran permeability. Longevity of gas in the anterior chamber appears important in delineating the deleterious effects. The gases per se do not appear toxic but rather disrupt normal physiologic function through physical process.

Nakano mice (nct/nct) and its congenic strain (Balb/c-nct/nct) develop different types of cataract: the former develop intense nuclear cataract but the latter develop milder opacity at the cortical region of lenses more later in life. The present study was undertaken to compare the elemental compositions at the localized region of these lenses in order to examine the possible role of ions in the opacification of the hereditary cataracts. Eight lenses from Nakano mice (age: 39-40 days) and ten lenses from congenic mice (age: 73 days) were prepared for the X-ray analysis with a high energy ion microprobe at a resolution of 50 microns. The age of mice was two weeks after 50% cataract formation for the respective strain. The maps of the concentrations of S, Cl, K and Ca in the central planes of the frozen-hydrated lenses were obtained. In all of the congenic lenses analyzed, the normal elemental composition, low Cl and Ca, and high K, was retained only in the narrow anterial and equatorial peripheral region and the other region underwent a K loss with a gain of Cl and Ca. In the Nakano lenses, the altered elemental composition was localized in central and in posterial cortical regions. There was no distinct difference in the concentration levels of Cl, K and Ca in the central region of the lenses between the two strains. The level of S was lower in Nakano lenses. High calcium containing spots were detected in low K regions of some of the lenses examined.

The effects of intravitreal expansile gases, sulfur hexafluoride and octafluoropropane, as well as air and needle insertion alone were assessed by iris fluorescein angiography and blood-retinal barrier permeability determination. Iris angiography, at 3 days after injection, indicated no differences between experimental and paired control eyes. Vitreous fluorophotometry on day 1, day 4 and day 7 after gas or sham injection also showed no differences between paired control and experimental eyes regardless of which experimental condition was employed. The results indicate that these gases are non-toxic to the blood-retinal barrier over a 7 day time course.

Target biomacromolecular assay systems utilize as endpoints quantifiable alterations in key macromolecules elicited by various chemicals and formulations. The EYTEX Assay System, an example of a target biomacromolecular test method, has been used to predict the in vivo ocular irritancy potential of chemicals and formulations. The biomacromolecular reagent is a standardized matrix which can be produced routinely. One hundred test chemicals, representing diverse chemical classes with a wide range of toxic responses in vivo, were evaluated in the EYTEX system. In vitro results were compared to maximum 24-hour Draize scores and Draize classifications. The concordance of the in vitro and in vivo results demonstrated the relevance of the alteration of the EYTEX macromolecular matrix to the prediction of in vivo ocular irritation. The relevance of the in vitro endpoint of turbidity of the EYTEX matrix to in vivo ocular irritation has thus been demonstrated for a large number of test agents in other evaluation studies (1, 2, 3, 4, 5, 6, 7, 8). Integration of macromolecular-based test methods with in vitro cytotoxicity or cellular response methods may provide complementary information about mechanisms of target-induced toxicity. The target biomacromolecular assay systems which provide standardized, reproducible reagents are valuable components of test batteries.

The effect of an intravitreal injection of norfloxacin on the retina was evaluated by in-vivo electroretinogram (ERG) and histological examination in pigmented rabbits. The intraocular pharmacokinetics after an intravitreal injection of norfloxacin were also investigated. An intravitreal injection of 50 micrograms norfloxacin produced no significant change in the ERG. An injection of 500 micrograms norfloxacin decreased the amplitude of the oscillatory potentials, and delayed their peak latencies 3 hours after the injection, but these changes recovered within 7 days. A marked suppression of the c-wave was noted in one pigmented rabbit. Neither 50 micrograms nor 500 micrograms norfloxacin caused any apparent changes in the visual evoked potential and in the retinal histology 7 days after the injection. The intraocular pharmacokinetic study showed that the concentration of norfloxacin in the choroid-retina was almost the same level as that in the vitreous body 3 hours after the injection. However, the former was higher than the latter 7 days after the injection, suggesting the persistency of norfloxacin in the choroid-retina. An intravitreal injection of 50 micrograms norfloxacin could be used without retinal toxicity. A high dose-intravitreal use of norfloxacin needs careful attention with respects to its persistency in the pigmented ocular tissues.

The recent interest in treating acne with one of the retinoid drugs has been accompanied by a wide variety of ocular side effects involving the eyelids, cornea, lens, optic nerve and retina. In one group of patients being evaluated for possible efficacy of a retinoic acid analogue in treating psoriasis, several patients complained of difficulty driving at night due to decreased dark adaptation which we were able to document. Fortunately, most of the above side effects tend to disappear within months after the drug is discontinued. However, we have recently seen two cases of dry eye syndrome associated with Accutane therapy that have persisted for more than two years. In addition, scattered reports have appeared regarding cataracts in young patients (teens to early 40's) which developed during, and/or after Accutane treatment. We have examined lens matter derived from two such patients who had extracapsular cataract extractions. Their lens proteins showed an elevation in UV absorptivity (between 330-390 nm) compared with matched control material (derived from Eye Bank specimens) and HPLC analyses demonstrated an abnormal peak in their profiles which was similar to one present in control samples incubated with retinoic acid and was not present in lens protein samples derived from cataracts not associated with Accutance therapy. These observations demonstrate that some of the Accutane induced ocular side affects are not reversible when the drug is stopped, and patients on such therapy should be carefully monitored.

The cornea, in addition to its refractive function for the eye, and by way of its very dense sensory innervation, serves a very important protective function for the visual organ. The cornea receives mainly sensory innervation from the first division of the trigeminal ganglion and a sparse amount of sympathetic fibers. The sensory nerves carry out their protective function by responding to various types of stimuli in a way so that they are all perceived psychologically as painful. Neurophysiological data indicates that, despite the morphological similarity of free-nerve endings in the cornea, they are differentiated functionally. A concentration series, (0.005 to 10% solution in saline), of various potential irritants (phosphate detergent, baby shampoo, liquid chlorine bleach, herbal shampoo, onion juice, SDS, and sodium chloride) was applied directly to the cornea of the anesthetized rabbit. Neural activity was assessed from extra-cellular records of long ciliary nerve over a ten second application period, and for ten seconds following stimulus removal. Baby shampoo was non-stimulatory over the applied concentration range. Sodium chloride, on the other hand, exhibited linear response dynamics over the range of 0.01 to 5% (p < 0.001). SDS was highly stimulatory, but showed no predictable concentration or response relationship. All of the other irritants tested responded in a logarithmic fashion. This suggests that the application of neurophysiological techniques to assess the pain and potential inflammatory aspects of a substance for human use can be monitored in this fashion. Moreover, response profiles for various classes of compounds and homologous series, as well as pH and osmolality, can be established.