| Reference | [1]. Metabolism. 1979 Apr;28(4 Suppl 1):471-6. doi: 10.1016/0026-0495(79)90059-3.<br />
Aldose reductase inhibition: studies with alrestatin.<br />
Gabbay KH, Spack N, Loo S, Hirsch HJ, Ackil AA.<br />
Studies with the aldose reductase inhibitor alrestatin in animal models have suggested that the sorbitol pathway may be of etiologic significance in the pathogenesis of peripheral neuropathy in diabetes. In normal subjects and in highly selected diabetic patients with severe peripheral neuropathy, alrestatin given either intravenously (50 mg/kg body weight) or orally (1 gm q.i.d.) produced no acute toxicity. The serum half-life of alrestatin was approximately 1 hr, and 99% was recovered in the urine within 24 hr. Two diabetic patients receiving alrestatin intravenously reported subjective improvements in clinical symptoms 2 days following the start of infusions. These improvements lasted approximately 3 wk after infusions were discontinued. However, there were no significant objective changes in peripheral nerve condition velocities, or on neurologic examination. In a 30-day oral trial with alrestatin in 4 diabetics, there were no subjective improvements in clinical symptoms nor were there objective improvements on neurologic examination or in peripheral nerve conduction velocities. In this study, peak serum levels of alrestatin were approximately 3 times lower than those obtained on intravenous administration, and it is possible that a high peak serum level is critical to the attainment of adequate tissue drug concentrations. Furthermore, the patients were suffering from severe clinical peripheral neuropathy, which could represent a stage of permanent irreversible nerve damage. Studies with alrestatin in newly diagnosed diabetics with peripheral nerve conduction velocity deficits but without clinical neuropathy might provide a better test of the sorbitol pathway hypothesis.<br />
DOI: 10.1016/0026-0495(79)90059-3 PMID: 122298<br />
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[2]. Biochemistry. 1997 Dec 23;36(51):16134-40. doi: 10.1021/bi9717136.<br />
The alrestatin double-decker: binding of two inhibitor molecules to human aldose reductase reveals a new specificity determinant.<br />
Harrison DH(1), Bohren KM, Petsko GA, Ringe D, Gabbay KH.<br />
Author information: (1)Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02554, USA.<br />
It is generally expected that only one inhibitor molecule will bind to an enzyme active site. In fact, specific drug design theories depend upon this assumption. Here, we report the binding of two molecules of an inhibitor to the same active site which we observed in the 1.8 A resolution structure of the drug Alrestatin bound to a mutant of human aldose reductase. The two molecules of Alrestatin bind to the active site in a stacked arrangement (a double-decker). This stack positions the carboxylic acid of one drug molecule near the NADP+ cofactor at a previously determined anion binding site and the carboxylic acid of the second drug molecule near the carboxy-terminal tail of the enzyme. We propose that interactions of inhibitors with the carboxy-terminal loop of aldose reductase are critical for the development of inhibitors that are able to discriminate between aldose reductase and other members of the aldo-keto reductase superfamily. This finding suggests a new direction for the introduction of specificity to aldose reductase-targeted drugs.<br />
DOI: 10.1021/bi9717136 PMID: 9405046 [Indexed for MEDLINE]<br />
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[3]. Horm Metab Res. 1978 Jul;10(4):280-2. doi: 10.1055/s-0028-1093414.<br />
Effect of alrestatin on arginine-induced secretion of glucagon and insulin in the rat.<br />
Lippmann W, Kobric M.<br />
Alrestatin, a lens aldose reductase inhibitor, decreased i.v. arginine-induced glucagon levels and augmented arginine-stimulated insulin release in the ether anesthetized rat. Alrestatin may then be useful in the treatment of diabetes mellitus, due to its actions on insulin and glucagon, and its capacity to delay the onset of sugar-induced cataracts in the rat.<br />
DOI: 10.1055/s-0028-1093414 PMID: 98419 [Indexed for MEDLINE]<br />
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[4]. J Neurochem. 1982 Sep;39(3):810-4. doi: 10.1111/j.1471-4159.1982.tb07964.x.<br />
Inhibition of human brain aldose reductase and hexonate dehydrogenase by alrestatin and sorbinil.<br />
O'Brien MM, Schofield PJ, Edwards MR.<br />
Human brain aldose reductase and hexonate dehydrogenase are inhibited by alrestatin (AY 22,284) and sorbinil (CP 45,634). Inhibition by alrestatin is noncompetitive for both enzymes, and slightly stronger for hexonate dehydrogenase (KI values 52-250 microM) than for aldose reductase (KI values 170-320 microM). Sorbinil inhibits hexonate dehydrogenase far more potently than aldose reductase, KI values being 5 5 microM for hexonate dehydrogenase and 150 microM for aldose reductase. The inhibition of hexonate dehydrogenase by sorbinil is noncompetitive with respect to both aldehyde and NADPH substrates, and is thus kinetically similar to the inhibition by alrestatin. However, sorbinil inhibition of aldose reductase is uncompetitive with respect to glyceraldehyde and noncompetitive with NADPH as the varied substrate. Inhibition of human brain aldose reductase by these two inhibitors is much less potent than that reported for the enzyme from other sources.<br />
DOI: 10.1111/j.1471-4159.1982.tb07964.x PMID: 6808090<br />
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[5]. Mol Pharmacol. 1984 May;25(3):425-30.<br />
Human placenta aldose reductase. Forms sensitive and insensitive to inhibition by alrestatin.<br />
Maragoudakis ME, Wasvary J, Hankin H, Gargiulo P.<br />
The inhibition of aldose reductase from a human source by alrestatin was studied. The enzyme from placenta was purified to apparent homogeneity by (NH4)2SO4 precipitation, DEAE-cellulose chromatography, electrofocusing, and affinity chromatography. This enzyme from human or rat placenta at the (NH4)2SO4 state of purification was relatively insensitive to alrestatin (IC50 greater than 50 microM). On purification by electrofocusing, however, human or rat placenta aldose reductase exhibited a marked increase in its sensitivity to alrestatin (IC50 = 1.0 microM). In contrast to human or rat placenta aldose reductase, rat lens aldose reductase was equally sensitive to alrestatin at the corresponding stages of purification (IC50 = 1.0 microM). Experiments in which the sensitive and insensitive forms of placenta aldose reductase were mixed revealed that the difference in susceptibility to alrestatin could not be attributed to nonspecific binding of alrestatin by proteins present in the (NH4)2SO4 fraction. A heat-inactivated (NH4)2SO4 fraction of human placenta aldose reductase added to the sensitive placenta enzyme from human or rats caused a time-dependent conversion to the insensitive form of aldose reductase. This suggested that a heat-stable dissociable factor, associated with placenta aldose reductase at the crude stage, may be responsible for the insensitivity to alrestatin. This insensitivity could be of pharmacological significance if it is relevant in vivo and it exists in tissues where aldose reductase plays a physiological role.<br />
PMID: 6427599
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