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

Texture and rheological characterization of kappa and iota carrageenan in the presence of counter ions

The effect of cation concentration and ion valency (0-0.2% (w/v) of KCl or CaCl2·2H2O) on the mechanical, micro-structural and rheological properties of aqueous kappa (?) and iota (?) carrageenan dispersions were investigated using a texture analyzer, cryo-SEM and an oscillatory rheometer, respectively. The probe penetration method demonstrated a decrease in "hardness" of carrageenan systems with increasing cation concentration, after exhibiting an initial maximum. The Young's modulus (E) of ?-carrageenan gels was determined using the uniaxial compression method. E was approximately 3 times the shear modulus recorded under the same experimental conditions; indicating the elimination of slip by the use of roughened parallel plates. The storage modulus of ?-carrageenan gels with Ca2+ demonstrated a similar trend to mechanical properties. However the syneresis observed in ?-carrageenan systems with storage, may have reduced the sensitivity of probe penetration method. Cryo-SEM observation of gels revealed a microstructure consistent with the observed mechanical propertie

Environment-sensitive polymers for ophthalmic drug delivery

Ophthalmic drug delivery is a challenging endeavor for pharmaceutical scientists, owing to many physiological barriers of the eye. Ocular drugs are often formulated as solutions, but the precorneal drainage, lymphatic clearance, tearing and corneal barrier restrict the bioavailability of the administered drug. Consequently, in situ forming gels have been investigated by many to improve the ocular bioavailability of the administered drug. In situ gelling systems are formulated with stimuli-sensitive polymers. These polymeric systems are liquid at room temperature, but undergo sol-gel transition on the ocular surface. This phenomenon enhances the ocular retention of the administered drug and also provides sustained release of the incorporated drug - both of which reduce the frequency of drug administration required for effective management of ocular diseases. This review article summarizes the various polymers that undergo sol-gel transition owing to physical (temperature, light) or chemical (ions, pH) stimuli on the eye

The nerve growth factor signaling and its potential as therapeutic target for glaucoma

Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC's survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma

IGF-1 signaling via the PI3K/Akt pathway confers neuroprotection in human retinal pigment epithelial cells exposed to sodium nitroprusside insult

The pathological increase in the levels of the second messenger nitric oxide (NO) in the vitreous cavity and retina leads to injury and cell death of the retinal pigment epithelium (RPE) cells and eventually may contribute to the occurrence and development of diabetic retinopathy. In this study, we developed a cellular model of retinopathy using D407 cells (a human RPE cell line) exposed to sodium nitroprusside (SNP) and investigated the protective effect of the insulin-like growth factor-1 (IGF-1) towards this insult. Cell death and apoptosis were examined by the methyl thiazolyl tetrazolium assay and Hoechst staining, respectively. Specific inhibitors were used and phosphorylation of relevant signaling proteins was determined by Western blotting. SNP, in a concentration-dependent fashion, increased the production of reactive oxygen species (ROS) and lipid peroxidation process causing cell death by apoptosis of D407 cells. IGF-1, in a time- and dose-dependent manner, conferred protection towards SNP-mediated insult. Both phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) were activated by IGF-1 in relation to the protective effect. Blockade of the PI3K/Akt pathway abolished the protective effect of IGF-1 whereas inhibition of the MAPK pathway was ineffective. SNP decreased the phosphorylation of Akt in the cells while IGF-1 reversed this inhibitory effect. These results indicate that the protective effect of IGF-1 on D407 exposed to SNP insult is mediated by the PI3K/Akt pathway. This proposal may be exploited in the clinic to improve the viability of insulted retinal cells for maintaining physiological vision