Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Naphthalene feeding can result in cataract formation in rats and rabbits due to specific metabolites of naphthalene. The concomitant administration of the aldose reductase inhibitor Al1576 to naphthalene-fed rats was proven to prevent cataract formation. To determine whether this effect was directly linked to the ability of Al1576 to inhibit enzyme aldose reductase, a variety of structurally diverse aldose reductase inhibitors, including the carboxylic acids tolrestat, Ponalrestat, and FK366, and the spirohydantoins, sorbinil and Al1576, were investigated for their ability to inhibit naphthalene-induced cataracts. Brown Norway rats, administered naphthalene by gavage, were fed normal rat chow containing these aldose reductase inhibitors at levels known to inhibit sugar cataract formation. The lens changes in these rats were monitored over a 90-day period by portable slit-lamp microscopy and histologic study. Al1576 showed a dose-dependent reduction in naphthalene-induced cataract formation, with no naphthalene-associated deposits seen in toluidine blue-stained lens sections. Sorbinil also reduced lens changes, whereas tolrestat, Ponalrestat, and FK366 had no effect. These results suggest that inhibition of naphthalene-induced cataract formation by structurally diverse aldose reductase inhibitors was not linked to the inhibition of aldose reductase.
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PMID:Effect of aldose reductase inhibitors on naphthalene cataract formation in the rat. 190 36

It has been suggested that sugar cataracts associated with diabetes mellitus result from the accumulation of excess sorbitol within lens fibrils. Swelling of lens fibrils occurs when water moves in to maintain osmotic balance; the excess water causes disruption of fibrils and cataract formation. Other studies have indicated that more than sorbitol-induced osmotic stress is involved. Our study used lenses collected from rats after 21 or 44 d of streptozotocin diabetes. Cataracts formed in untreated 44-d streptozotocin diabetic rats, but were not apparent in the 21-d untreated diabetic animals. Lens sorbitol increased in the diabetic animals both before and after cataract formation. Lens taurine varied inversely with the sorbitol content in a fashion that resulted in no net change in total lens osmoles. Lens water did not increase in the diabetic animals with or without cataracts. The aldose reductase inhibitor Sorbinil prevented the increase in lens sorbitol in both the 21- and 44-d streptozotocin diabetic rats; cataract formation was prevented in the 44-d diabetic animals. The lens water in untreated diabetic animals with cataracts did not differ from lens water in the Sorbinil-treated diabetic animals that did not develop cataracts. Sorbinil treatment of diabetic animals was associated with normalization of both lens sorbitol and taurine levels. Taurine has been shown to serve both as an osmoregulator and as an antioxidant. The apparent increase in lens osmolality attributed to sorbitol was counterbalanced by an equimolar reduction in taurine concentration. The reciprocal relationship between taurine and sorbitol reduces the likelihood of an osmotic mechanism for sugar cataractogenesis; the reduced lens taurine, however, may increase the risk of lens protein oxidation and subsequent cataract formation. Thus in vivo sugar cataract formation may be an oxidative process rather than an osmotic phenomenon.
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PMID:Nonosmotic diabetic cataracts. 213 28

Our recent investigations have shown that the Eisai compound, E-0722, (2R-4S-6-fluoro-1-2-methylspirochroman 4,4'-imidazolidine 2,5'-dione) is a more potent aldose reductase inhibitor than Sorbinil (D-6-fluorospirochroman 4,4'-imidazolidine 2,5'-dione). In the previous studies these aldose reductase inhibitors were added to the 50% galactose diet fed to rats to determine their effect on galactose-induced alterations in the lens and the development of cataract. In this report we present our results on the effect of prefeeding the aldose reductase inhibitor, E-0722, on the alterations in rat lens following subsequent feeding of galactose. For this study, young Sprague Dawley rats were prefed either rat chow or rat chow plus 50% galactose containing 1mg/day/Kg body weight of E-0722 for 1 or 2 weeks. After this dietary regimen, the animals were transferred to diets containing 50% galactose for different periods. For controls, rats were fed either rat chow or 50% galactose without the prefeeding of E-0722. Our results obtained through gross observation of the lenses, light microscopic studies of lens sections and assay of Na+-K+-ATPase (NPPase) activity show that the prefeeding of E-0722 prior to galactose feeding delays galactose-induced alterations and the development of mature cataract.
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PMID:Prefeeding of aldose reductase inhibitor and galactose cataractogenesis. 255 45

Aldose reductase is implicated in the pathogenesis of sugar cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for the restoration of lens physiology despite the persistence of diabetes or galactosemia. In the present study, the effect of aldose reductase inhibition subsequent to stage-I cataract formation was investigated in the galactose-maintained rat. Our results indicated that despite continuation of galactose feeding the aldose reductase inhibitor, Sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process involved: decrease in lens dulcitol, gradual recovery of fiber thickness and partial restoration of lens myo-inositol content. At this stage of cataractogenesis, despite continuance of galactose feeding, the effects of Sorbinil treatment were comparable to the reparative process achieved by restoration of a normal diet.
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PMID:Reversal of stage-I sugar cataract by Sorbinil, an aldose reductase inhibitor. 392 28

Sorbinil, an aldose reductase inhibitor, in combination with diet normalization, arrested stage-II galactose cataract and restored lens transparency. During the reversal process, determination of lens dry weight, dulcitol and myo-inositol content as well as individual fiber cell ultrastructure offered a comprehensive index of lens integrity. In this study, young rats received a 50% galactose diet for 10 days to produce a stage-II sugar cataract. Then they were placed on one of the following diets: 50% galactose and Sorbinil (20 mg/kg); 50% galactose; normal diet, normal diet and Sorbinil (20 mg/kg). From each group, equal numbers were sacrificed at 5, 10 and 20 days. Although differences were obtained after 5 and 10 days, the 20-day reversal period provided the most significant findings. Only the combination of Sorbinil and normal diet restored lens transparency, normalized lens myo-inositol content and dry weight and partially restored fiber cell integrity as evidenced by diminished granulation and increased fiber synthesis. Neither Sorbinil treatment during galactose administration nor normal diet alone were sufficient to protect against further cataractogenesis, thus indicating a synergistic effect of Sorbinil in combination with normal diet.
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PMID:Synergism of sorbinil and normal diet on reversal of stage-II sugar cataract. 393 Nov 5

Medical treatment of cataract depends on understanding the mechanism of cataract formation. This is established in sugar cataract, in which sugar is metabolised to sugar alcohol. Sugar alcohol accumulates and the resultant osmotic stress is considered to cause lens fibre damage. The conversion of sugar to alcohol is effected by the enzyme aldose reductase and interest now centres around the use of aldose reductase inhibitors. A controlled clinical trial into the effect of the spirohydantoin Sorbinil in adult diabetic cataract has started at Oxford. Aldose reductase inhibitors may also act on non-diabetic cataract, which is supported by some clinical evidence. The biochemical basis of this and other possible treatments for cataract are outlined.
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PMID:Medical therapy in the prevention of cataract. 393 85

We have demonstrated an increase in activity of arylsulfatase A and B during galactose induced cataract development in rats. Our recent investigation shows that acid phosphatase activity, which increases substantially during galactose cataract development in rats, could be contained to near normal level if Sorbinil, an aldose reductase inhibitor, was fed along with galactose to the rat. We have observed that the activity of other lysosomal enzymes, arylsulfatase A and/or B, also increases during galactose cataractogenesis. In the present report, we provide information with regards to the effect of Sorbinil on the activity of these enzymes during cataractogenesis. A modified Hopsu-Havu and Helminen method (1974) with p-nitrocatecholsulfate as substrate was used for localization of both arylsulfatase A and B; and the method of Hara et al. (1979) was utilized to obtain quantitative data on the level of arylsulfatase A and B activity. Ultrastructural cytochemistry shows that arylsulfatase activity in all lenses was primarily localized in epithelial cells in lysosomes with very little or no activity in cortical fibers. The number of arylsulfatase positive lysosomes and the activity level of these enzymes increased with the progression of cataract development. Galactose induced damage to lens morphology and increase in activity of arylsulfatase A and B was inhibited by inclusion of 50mg/Kg (diet) Sorbinil in the galactose containing cataractogenic diet. However, Sorbinil had no significant effect on the enzyme activity following the establishment of mature cataracts.
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PMID:Ultrastructural cytochemistry: effect of Sorbinil on arylsulfatases in cataractous lenses. 402 88

Sorbinil, a potent aldose reductase inhibitor, can effectively block the progression of a galactose cataract even though the cataractous process is well underway. The prevention of dulcitol accumulation by Sorbinil is just as effective in reversing the cataract as the removal of galactose from the diet. The progression and reversal of the cataract were followed by ophthalmoscopy and histology. The results also further support the concept that in galactosemia the cataract is not caused by the toxic effects of galactose per se but by the consequence of the aldose reductase reaction.
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PMID:Reversal of galactose cataract with Sorbinil in rats. 684 Oct 13

Research into the biological basis of lens transparency has demonstrated the implication of lens sugar stress in the diabetic cataract whereas senile cataract is the result of natural degeneration which is enhanced by various external factors such as cosmic and ionizing rays, or oxidative processes. Drugs have been developed which are aimed at being effective on lens pathological physiology and metabolism, concurrently. Such molecules: aldose reductase inhibitors (ARIs: sorbinil, AD-5467, CT-112 and imirestat), acetyl salicylic acid (ASA), salicylate (SA) and sodium monomethyl trisilanol orthohydroxybenzoate (SMB, a prodrug for salicylate) have undergone pharmacodynamic, pharmacokinetic and/or clinical studies which are presented here. ARIs have shown efficacy in slowing down and preventing the progression of experimental sugar cataracts; sorbinil can partially reverse the very early morphological signs of sugar cataract. Sorbinil and imirestat have also demonstrated anti-oxidant properties. ARIs administration (per os or by topical instillation) generally results in lens levels compatible with concentrations that are efficient on biochemical mechanisms of cataract formation. However, at the present time, clinical evaluations are in progress and as yet, there is no confirmation of their efficacy in man. ASA and SA can prevent various mechanisms of lens protein denaturation; they inhibit AR and prevent, in vitro, the formation of some pigments found in the aged cataractous lens. Extrapolation of the ASA ocular pharmacokinetics results in animal to man, suggest that ASA administration per os could result in efficacious levels in the lens. This is also sustained by the observation of a reduced frequency of cataracts in ASA treated diabetic rheumatoid arthritis patients. SMB pharmacokinetic studies have shown small but persistent levels of the active principle in the lens. They suggest that the capsule slows down SA diffusion into the lens and that, on the contrary, lens epithelium facilitates its penetration. Preliminary results of pharmacodynamic studies are given.
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PMID:Drugs designed to maintain the transparence of the ocular lens. 785 38

We reported that in utero galactose-induced cataracts could be inhibited if aldose reductase inhibitors (ARIs) were included in the galactose diet of pregnant rats. These studies involved morphological and cytochemical approaches. We undertook this investigation to evaluate the effects of ARIs in preventing the formation, accumulation and depletion of dulcitol in lenses of in utero galactose exposed neonates and in mothers during and following pregnancy. Sprague Dawley rats were fed Purina Rat Chow with 50% galactose either with or without 15mg Sorbinil or 1mg Eisai compound E-0722/day/Kg body weight during and following pregnancy. The lenses of neonates and mothers were processed to determine dulcitol concentrations. At parturition there was a significant amount of dulcitol in the lenses of pups and their mothers, which reduced rapidly in the lenses of pups regardless of the diet fed to the nursing mother. While galactose had a cross-placental but not a milk-mediated effect, the ARIs had both cross-placental and milk-mediated effects on dulcitol accumulation and depletion, respectively. The galactose feeding of mothers post-parturition maintained the high lenticular dulcitol concentration and the absence of galactose led to a reduction in lenticular dulcitol. The correlation between dulcitol accumulation and cataract development is discussed.
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PMID:Aldose reductase inhibitors and galactose toxicity in neonatal and maternal rat lenses. 810 40


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