Pharmacokinetic aspects of retinal drug delivery

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.Peer reviewe

Drug discovery in ophthalmology: past success, present challenges, and future opportunities

BACKGROUND: Drug discovery has undergone major transformations in the last century, progressing from the recognition and refinement of natural products with therapeutic benefit, to the systematic screening of molecular libraries on whole organisms or cell lines and more recently to a more target-based approach driven by greater knowledge of the physiological and pathological pathways involved. Despite this evolution increasing challenges within the drug discovery industry are causing escalating rates of failure of development pipelines. DISCUSSION: We review the challenges facing the drug discovery industry, and discuss what attempts are being made to increase the productivity of drug development, including a refocusing on the study of the basic biology of the disease, and an embracing of the concept of ‘translational research’. We consider what ophthalmic drug discovery can learn from the sector in general and discuss strategies to overcome the present limitations. This includes advances in the understanding of the pathogenesis of disease; improvements in animal models of human disease; improvements in ophthalmic drug delivery and attempts at patient stratification within clinical trials. SUMMARY: As we look to the future, we argue that investment in ophthalmic drug development must continue to cover the whole translational spectrum (from ‘bench to bedside and back again’) with recognition that both biological discovery and clinical understanding will drive drug discovery, providing safe and effective therapies for ocular disease

Ruthenium(III) catalyzed oxidation of indigo carmine by manganese(III) in sulfuric acid medium: a kinetic and mechanistic study

Aims: Reactions of manganese(III)-porphyrins have been reported as possible models for closely related and biologically significant systems. Method: In this study, a stock solution of manganese(III) sulfate was prepared using a standard method of anodic oxidation of manganese(II) in H2SO4. The Indigo carmine (IC)-Mn(III) reaction catalyzed by Ru(III), under pseudo-first-order conditions, has been spectrophotometrically monitored at the IC λmax IC (610 nm) at constant temperature. The experimental rate law for the reaction is: rate = k' [IC][H+]x[Ru(III)]y, where x and y are fractional orders. Objective: The reaction rate shows a zero-order dependence on the concentration of the oxidant, Mn(III), indicating its involvement in fast steps following the slow step. Additionally, the effect on the rate of adding the reduction product, Mn(II), has been found to be negligible. Variations of the ionic strength and the dielectric constant of the reaction medium have negligible effect on the rate. Result: Based on the effect of temperature, activation parameters have been evaluated using Arrhenius and Erying plots. A suitable mechanism has been presented. The rate law derived is consistent with experimental data