The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

https://dmd.aspetjournals.org/content/dmd/46/11/1670.full.pdf

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route.

Lanosterol is a potential drug for cataracts treatment, which can reverse the aggregation of intracrystalline proteins. The low concentration in lanolin calls for high-performance separation methods. In this study, a counter-current chromatography dual-mode elution method was developed for the first time to separate and purify lanosterol from hexane extract of lanolin after saponification, in which the column was first eluted with the lower phase as mobile phase in head-to-tail mode, followed by the upper phase in the tail-to-head mode. High purity of lanosterol, dihydrolanosterol, and cholesterol can be obtained simultaneously. A solvent system composed of n-heptane/acetonitrile/ethyl acetate (5:5:1, v/v/v) was selected and optimized via partition coefficient determination. Compounds such as 111 mg lanosterol, 84 mg dihydrolanosterol, and 183 mg cholesterol with high purity of 99.77, 95.71, and 91.43%, respectively, analyzed by high-performance liquid chromatography were obtained within 80 min from 700 mg crude extract from 1.78 g lanolin. The method was also used to improve the purity of commercial lanosterol product from 66.97 to above 99%. Counter-current chromatography could serve as a potential and powerful technique for commercial production of highly pure lanosterol.

Separation and purification of lanosterol, dihydrolanosterol, and cholesterol from lanolin by high-performance counter-current chromatography dual-mode elution method.

Purpose of review Age-related cataract occurs when crystallin proteins in the lens partially unfold and subsequently aggregate. Physicians and traditional healers alike have been exploring pharmacologic cataract treatment for hundreds of years. Currently, surgery is the only effective treatment. However, there are an abundance of homeopathic and alternative remedies that have been suggested as treatment for cataract. This article reviews the current understanding of cataract development and discusses several homeopathic remedies purported to treat age-related cataract. Additionally, we will present an overview of evidence regarding the development of pharmacologic cataract reversal therapies. Recent findings Some homeopathic therapies have been shown to prevent cataract development in experimental models. More studies are required to elucidate the potential medicinal and toxic properties of the various alternative therapies. However, in recent years, scientists have begun to investigate substances that address cataract by reversing lens protein aggregation. One such compound, lanosterol, was reported to reverse cataract opacity in vitro and in animal models. Subsequently, 25-hydroxycholesterol and rosmarinic acid were identified as having similar properties. Summary Although challenges and uncertainties remain, further research has the potential to lead to the development of a nonsurgical therapeutic option for age-related cataract.

The quest for homeopathic and nonsurgical cataract treatment.

ABSTRACT Background To evaluate the effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system. Methods Nine elder cynomolgus monkeys were used, consisting of three monkeys without cataract as controls, three monkeys with naturally occurring cortical cataract, and three monkeys with nuclear cataract as intervention groups. Nanoparticulated thermogel with lanosterol and fluorescein was administered by subconjunctival injection in the monkeys with cataract. Fluorescence changes of injected thermogel and cataract progression were observed. Lanosterol concentration in aqueous humor, solubility changes in lens proteins, and oxidative stress levels were analyzed in the lenses of the control and intervention groups. Results Injected thermogel showed decreased fluorescence during follow up. Lanosterol concentration in aqueous humor increased in the first 2 weeks and then gradually decreased, which was in accordance with the changes in cortical lens clarity. However, lenses with nuclear opacification showed little change. In the cortical region of lenses with cortical cataract, solubility of α-crystallin was significantly increased after administration of lanosterol, as well as the reduction of oxidative stress. Conclusions We demonstrated the effect of lanosterol on cataract progression based on in vivo models of primates. Lanosterol showed a short-term and reliable reversal effect on reducing cataract severity in cortical cataract in the early stages, possibly due to the increase in the solubility of lens proteins and changes in the oxidative stress status. Lanosterol administration using subconjunctival drug release system could be a promising nonsurgical approach for future clinical studies of cataract prevention and treatment.

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Inhibitory effect of lanosterol on cataractous lens of cynomolgus monkeys using a subconjunctival drug release system

The in-depth structural and compositional investigation of biodegradable polymeric materials, neat or partly degraded, is crucial for their successful applications. Obviously, an exhaustive structural analysis of all synthetic macromolecules is essential in polymer chemistry to confirm the accomplishment of a preparation procedure, identify degradation products originating from side reactions, and monitor chemical–physical properties. Advanced mass spectrometry (MS) techniques have been increasingly applied in biodegradable polymer studies with a relevant role in their further development, valuation, and extension of application fields. However, single-stage MS is not always sufficient to identify unambiguously the polymer structure. Thus, tandem mass spectrometry (MS/MS) has more recently been employed for detailed structure characterization and in degradation and drug release monitoring of polymeric samples, among which are biodegradable polymers. This review aims to run through the investigations carried out by the soft ionization technique matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and electrospray ionization mass spectrometry (ESI-MS) MS/MS in biodegradable polymers and present the resulting information.

/pdf/matrix-assisted-laser-desorption-and-electrospray-ionization-3d9dznqu.pdf

Matrix-Assisted Laser Desorption and Electrospray Ionization Tandem Mass Spectrometry of Microbial and Synthetic Biodegradable Polymers

Quantitation of lanosterol in the vitreous humor of rabbits after ocular administration of lanosterol/thermogel formulation by ultra high performance liquid chromatography-tandem mass spectrometry with the electrospray ionization mode

Jianguo Sun

Papers

Quantitation of lanosterol in the vitreous humor of rabbits after ocular administration of lanosterol/thermogel formulation by ultra high performance liquid chromatography-tandem mass spectrometry with the electrospray ionization mode