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Drugs designed to maintain the transparence of the ocular lens
1Laboratoire de Pharmacologie, Faculté de Médecine, Nice, France.
Abstract:
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.
Insights
Researchers explored drugs like aldose reductase inhibitors (ARIs) and acetylsalicylic acid (ASA) for cataract prevention and treatment. While promising in models, clinical efficacy in humans for these cataract drugs is still under investigation.
Area of Science:
- Ophthalmology
- Pharmacology
- Biochemistry
Background:
- Diabetic cataracts stem from lens sugar stress, while senile cataracts result from natural degeneration exacerbated by external factors like radiation and oxidative processes.
- Current research focuses on developing drugs targeting lens metabolism and pathological physiology to combat cataract formation.
Purpose of the Study:
- To review pharmacodynamic, pharmacokinetic, and clinical studies of specific drug candidates for cataract prevention and treatment.
- To evaluate the potential of aldose reductase inhibitors (ARIs) and salicylate-based compounds in managing lens transparency disorders.
Main Methods:
- Review of existing pharmacodynamic, pharmacokinetic, and clinical data for ARIs (sorbinil, AD-5467, CT-112, imirestat), acetylsalicylic acid (ASA), salicylate (SA), and sodium monomethyl trisilanol orthohydroxybenzoate (SMB).
- Assessment of drug efficacy in experimental models of sugar cataract and in vitro studies on lens protein denaturation.
- Analysis of ocular pharmacokinetics and preliminary pharmacodynamic data.
Main Results:
- ARIs demonstrated efficacy in slowing and preventing experimental sugar cataracts, with some showing antioxidant properties and potential to reverse early signs.
- ARIs generally achieve effective lens concentrations, but human clinical efficacy is pending.
- ASA and SA showed potential in preventing lens protein denaturation and inhibiting pigment formation in vitro. Ocular pharmacokinetic data suggest potential efficacy in humans, supported by observations in ASA-treated patients.
Conclusions:
- ARIs show promise in preclinical models for sugar cataracts, but human clinical trials are ongoing.
- Salicylates (ASA, SA, SMB) exhibit mechanisms relevant to preventing lens degeneration and protein denaturation.
- Further clinical evaluation is necessary to confirm the therapeutic benefit of these agents in human cataract management.