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

Water Network Rehabilitation with a Structured Messy Genetic Algorithm

The importance of water distribution network rehabilitation, replacement and expansion is discussed. The problem of choosing the best possible set of network improvements to make with a limited budget is presented as a large optimisation problem to which conventional optimisation techniques are poorly suited. A multi-objective approach is described, using capital cost and benefit as dual objectives, enabling a range of non-inferior solutions of varying cost to be derived. A Structured Messy Genetic Algorithm is developed, incorporating some of the principles of the Messy Genetic Algorithm, such as strings which increase in length during the evolution of designs. The algorithm is shown to be an effective tool for the current optimisation problem, being particularly suited both to the multi-objective approach and to problems which involve the selection of small sets of variables from large numbers of possibilities. Two examples are included which demonstrate the features of the method an..

Iontophoresis: from the lab to the bed side.

Pioneer work on iontophoresis undertaken by David Maurice during the 1970s and 1980s laid the initial groundwork for its potential implementation as a promising ocular therapeutic modality. A better understanding of tissue interactions within the eye during electric current application, along with better designs of drug delivery devices have enabled us to pursue David Maurice's original ideas and take them from the bench to the bed side. In the present study we demonstrate the potential application of an iontophoresis device (Eyegate, Optis, France) for the treatment of certain human eye diseases. Seventeen patients received a penetrating keratoplasty (PKP) at various intervals before presentation with active graft rejection in our clinic and were treated using this iontophoresis device. Methylprednisolone sodium succinate (MP) 62.5 mg/ml was infused within the Eyegate ocular probe container and an electrical current of 1.5 mA was delivered for 4 min with the negative pole connected to the ocular probe. Patients were treated on an ambulatory basis and received a standard course of three iontophoresis applications given once a day over 3 consecutive days. After treatment, 15 of the 17 treated eyes (88%) demonstrated a complete reversal of the rejection processes. In two eyes, only a partial and temporary improvement was observed. The mean best corrected visual acuity of all 17 patients during the last follow up visit was 0.37 +/- 0.2 compared to 0.06 +/- 0.05 before initiation of the iontophoresis treatment. The mean follow-up time was 13.7 months with a range of 5-29 months for the 17 patients. No significant side-effects associated with the iontophoresis treatment were observed. Thus, for the management of active corneal graft rejection, iontophoresis of MP can be an alternative to very frequent instillations of eye drops, or to pulsed intravenous therapy of corticosteroids

Enhanced oligonucleotide delivery to mouse retinal cells using iontophoresis.

PURPOSE: To study the combination of oligodeoxynucleotides (ODNs) intravitreous injection and saline transpalpebral iontophoresis on the delivery of ODNs to photoreceptors in the newborn rd1/rd1 mice. METHODS: Cathodal or anodal transpalpebral iontophoresis (1.43 mA/cm(2) for 5 min) was applied to eyes of postnatal day 7 (PN7) rd1/rd1 mice immediately before the intravitreous injection of ODNs. The effect of cathodal iontophoresis after ODNs injection was also evaluated. The influence of current intensity (0.5, 1.5, and 2.5 mA) was assayed with cathodal iontophoresis performed prior to ODNs injection. The duration of current-induced facilitation of ODNs delivery to photoreceptors was evaluated for 6 h following iontophoresis. One group of control eyes received cathodal iontophoresis prior to the intravitreous injection of phosphate buffered saline (PBS) or hexachlorofluorescein (Hex). The second control group received ODN or Hex intravitreous injection without iontophoresis. The penetration of fluorescent ODNs in the outer nuclear layer (ONL) was quantified by image analysis of the ONL fluorescence intensity on cryosection microphotographs. Integrity of ODN was assessed using acrylamide gel migration after its extraction from the retina of treated mice. The integrity of retinal structure, 1 and 24 h after iontophoresis, was analyzed using light and electron microscopy. RESULTS: Transpalpebral anodal or cathodal saline iontophoresis enhanced the penetration of ODNs in all retinal layers. Cathodal iontophoresis was more efficient than anodal iontophoresis in enhancing the tissue penetration of the injected ODN. Photoreceptor delivery of ODN was significantly higher when cathodal saline transpalpebral iontophoresis was applied prior than after the injection. The extent of enhanced tissue penetration decreased in parallel to the increased interval between iontophoresis application and the intravitreous injection. Current of 1.5 mA was safe and optimal for the delivery of ODNs to the ONL. One hour after iontophoresis followed by injection, ODN extracted from the retina of treated eyes remained intact. Histology and electron microscopy observations demonstrated that iontophoresis using the optimal parameters did not induce any permanent tissue alterations or structure damage. CONCLUSIONS: Saline transpalpebral iontophoresis facilitates the penetration of injected ODNs in photoreceptors for at least 3 h. This method may be considered for photoreceptor targeted gene therapy

Reabilitação de redes coletivas de sistemas pressurizados de irrigação Rehabilitation of collective networks of pressurized irrigation systems

Apresenta-se, neste trabalho, um método de otimização econômica para a reabilitação de redes ramificadas pressurizadas de distribuição de água para projetos de irrigação que se encontram com deficiência de vazão e pressão nos pontos de consumo. O método poderá ser aplicado a redes malhadas de abastecimento urbano, desde que sejam transformadas em ramificadas, através do método do seccionamento fictício. A metodologia empregada se baseia no método Granados, de otimização econômica de redes pressurizadas; trata-se de um processo iterativo que seleciona, a cada passo, as possibilidades de modificação dos diâmetros das tubulações da rede, de forma a minimizar o custo de investimento da reabilitação do sistema. O método foi testado para uma rede de distribuição que abastece um projeto de irrigação fictício, no qual existe deficiência de pressão em quase todos os pontos de consumo; enfim, o custo para a reabilitação da rede foi de 41% do custo original do sistema.<br>This paper presents a method of economic optimization aiming the rehabilitation of pressurized branched networks of water distribution for irrigation projects, which have flow and pressure deficiency at the consumption points. The method can be applied to looped networks of urban water supply, on condition that they are changed into branched ones, through the fictitious sectioning method. The methodology used is based on the Granados method of economic optimization of pressurized networks, which is an iterative process that selects step by step the possibilities of changes of the network pipe diameters, so as to optimize the investment cost of the rehabilitation system. The method was tested for a distribution network that supplies a fictitious irrigation project, in which there is pressure deficiency in almost all the consumption points. The network rehabilitation cost was 41% of the original cost

Multiobjective evolutionary algorithms applied to the rehabilitation of a water distribution system: a comparative study

Abstract. Recognising the multiobjective nature of the decision process for rehabilitation of water supply distribution systems, this paper presents a comparative study of two multiobjective evolutionary methods, namely, multiobjective genetic algorithm (MOGA) and strength Pareto evolutionary algorithm (SPEA). The analyses were conducted on a simple hypothetical network for cost minimisation and minimum pressure requirement, treated as a two-objective problem. For the application example studied, SPEA outperforms MOGA in terms of the Pareto fronts produced and processing time required.