Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Antiviral drugs for cytomegalovirus diseases

Cytomegalovirus infections are associated with severe morbidity and mortality is patients at risk for disease because of immune system disabilities; in particular, recipients of stem cell (HSCT) or solid organ (SOT) transplants. There are three systemic drugs approved for CMV treatment: ganciclovir, or its prodrug valganciclovir, foscarnet, and cidofovir. An anti-sense therapeutic, ISIS 2922, is also approved specifically as in intravitreal treatment for CMV retinitis. Ganciclovir, and more recently, valganciclovir, have been useful in proactive approaches of CMV disease management; in both prophylactic and preemptive regimens in HSCT and SOT populations. The major anti-herpes agent valacyclovir has also been approved for prophylaxis of renal transplant recipients, or SOTs outside of the US. These drugs have provided major advances in CMV disease management, although they are limited by intolerable toxicities, oral bioavailability and efficacy, and risk of drug resistance with extended use. Several drugs are in early clinical development which may address these limitations; this review will provide an overview of our current arsenal of available drugs, and of those in the early clinical development pipeline.     

Beneficial drugs for liver diseases

Liver diseases are a major problem of worldwide proportions. However, the number of drugs actually used successfully in humans is very small. In this review some of the most promising/studied drugs utilized for liver diseases were chosen and analysed critically from the basic to the clinical point of view. Antiviral agents are not discussed because excellent reviews have appeared on this topic. The compounds/preparations described herein are, alphabetically: colchicine, corticosteroids, curcumin, glycyrrhizin, interferons (for their antifibrotic properties), Liv 52, nitric oxide, resveratrol, silymarin, sulfoadenosylmethionine, and thalidomide. Colchicine and corticosteroids have been studied extensively in animals and humans; most clinical studies suggest that these compounds are not useful in the treatment of liver diseases. Glycyrrhizin is an herbal medicine with several components that has interesting hepatoprotective properties in patients with subacute liver failure but deserves more prospective controlled trials. Interferon has shown interesting antifibrotic properties in animals and humans; prospective studies on their antifibrotic/fibrolytic activity are required. Curcumin, resveratrol and thalidomide are very attractive newly discovered protective and curative compounds on experimental hepatic diseases. Their mechanism of action is associated with the ability to down-regulate NF-kappaB and to decrease pronecrotic and profibrotic cytokines. Unfortunately, clinical studies are lacking. Sulfoadenosylmethionine and silymarin are also promising drugs utilized mainly in cholestasis but the benefits can be expanded if more controlled trials are performed. The future is to carry out controlled prospective double-blind multicenter studies with the newly discovered drugs with proven beneficial effects on animals. Fundamental hepatobiology should also be encouraged.     

Emerging drugs for lysosomal storage diseases

Importance of the field: Because orphan drug regulations encouraged development of drugs for rare disorders by granting marketing exclusivity for many years and other commercial benefits, treatment has become achievable for a few lysosomal storage disorders also. The presently available therapies, however, are not able to address all aspects of these multisystemic disorders and do not cure the patient. Therefore, there is a need for producing new drugs that are based on known pathophysiological mechanisms, such as enzyme replacement or inhibition of substrate synthesis, or which use new approaches to prevent the build-up of storage material.

Areas covered in this review: New compounds that are being designed by different pharmaceutical companies can be divided in two groups, enzyme targeted and substrate targeted drugs. Enzyme targeted drugs include substances that modify the enzyme to make it more accessible to organs such as the bone or the brain, enhance enzyme activity (chaperones) or activate enzyme synthesis by small molecules that induce read-through of premature stop codons of genes that bear a nonsense mutation. To the group of substrate targeted drugs belong substances that inhibit the synthesis or modify the structure of the substrate (substrate deprivation or substrate optimization, respectively). For this review, a literature research has been undertaken that covers the years 1968 – 2010.

What the reader will gain: The reader of this paper will get an overview of drugs for lysosomal storage disorders that are on the market or are under development. This will help in the understanding of the pathophysiological mechanisms that underlie these rare metabolic diseases. In addition, the reader should realize that the increasing number of these very expensive drugs may lead to significant consequences for the health economic system.

Take home message: In the last years, the interest of scientists and pharmaceutical companies in lysosomal storage disorders has increased dramatically, leading to the production of a rising number of different drugs. These drugs act at several stages of the pathophysiological cascade, for example, at the level of the substrate (substrate deprivation) or of the enzyme (enzyme enhancement). The presently available treatments are not able to address all clinical manifestations of these disorders, and it will still take a long time until new drugs are developed that are capable of curing the patients.     

Predictive genetic testing in minors for adult-onset genetic diseases

This article analyses the ethical discussion of predictive genetic testing in minors for genetic conditions for which there is no phenotypic evidence for disease at the considered time of testing and for which there is currently no treatment available to prevent or forestall the development of the condition. After a presentation of the position of various professional guidelines, we discuss the position and arguments that have been advanced in a recent article that defends a position that is opposed to the professional recommendations. In the article, we discuss the position of voluntary choices and autonomous and informed decision-making in a context of open communication. Thereafter, we analyze the nonmedical benefits and harm related to this type of testing. Finally, we critically analyze 4 arguments: the potential provision of good news if a test is performed, the unbearability of knowing, identity and adjustment, and parental anxiety and uncertainty.     

Developing antiangiogenic peptide drugs for angiogenesis-related diseases

Angiogenesis is regulated by stimulators and inhibitors and involve multiple biological processes including endothelial cell proliferation, migration, cell-cell and cell-matrix adhesion, assembly into tube structures as well as apoptosis. Designing and developing peptides for therapeutic application to inhibit angiogenesis is an important area in antiangiogenic drug development. Small peptides have advantages over proteins for therapeutic application, due to their stability, solubility, increased bio-availability and lack of immune response in the host cell. Endogenous protein angiogenesis stimulators and inhibitors hold vital information for designing antiangiogenic peptides for drug development. These proteins function through their interaction with extracellular matrix molecules, cell surface receptors, proteases, as well as growth factors and cytokines. Conserved domains such as thrombospondin type 1 repeats (TSRs), kringle domains as well as critical amino acid residues present in these domains are involved in their functions. By exploiting these properties, several small peptides have been designed, synthetically made and being tested for therapeutic efficacy. Peptides derived from type 1 repeat of thrombospondin, alpha 4 and beta 1 chains of laminin, arginine rich N terminus of endostatin, leucine rich repeat 5 of decorin, pigment epithelium derived factor and N terminal of parathyroid hormone are examples of small antiangiogenic peptides derived from endogenous proteins. Such bioactive peptides are further modified physico-chemically to increase their potency and stability. In addition, phage-display library screening and combinatorial approach are also in use to identify novel antiangiogenic peptides targeting tumour and various proteins. This review will provide a comprehensive summary of the current status of the antiangiogenic peptides and their relevance for drug designing and development. Several critical issues that need to be resolved in translating this concept into clinical practice are also discussed.     

Serotonergic modulating drugs for functional gastrointestinal diseases

After many years of basic research we have now begun to learn how to manipulate the serotonergic mechanisms within the gut. This has lead to a number of significant advances including 5HT3 antagonists for the treatment of functional diarrhoea, 5HT4 agonists for the treatment of constipation and 5HT1 agonists for the treatment of impaired fundal relaxation. Initial enthusiasm has been somewhat dented by the withdrawal of alosetron because of ischaemic colitis, but it remains to be seen whether this adverse event will be seen with other 5HT3 antagonists. Finally it should be recognized that, in a substantial proportion of patients attending clinics complaining of functional symptoms, anxiety is a major component. The drugs so far described are by and large devoid of CNS effects. It remains possible therefore that a drug which combines both peripheral and central effects would likely to be beneficial.     

Human genetic risk assessment for chemical substances

A very practical concern in the evaluation of the mutagenic potential of any substance is what impact that substance will have on human ill health as a result of inducing additional genetic-based disease in future generations. Currently employed short-term tests cannot address this issue in a quantitative sense and are probably qualitatively inadequate in some instances. It is recognized that occasions arise where some level of human exposure to mutagenic substances has to be tolerated, and in order to make a sound risk/benefit analysis, strong quantitative data are required. Present whole-animal tests appear to be insufficient for generating these data for various reasons. Consequently, active research programs are required to provide better methods for obtaining the necessary data base for making the analyses.     

维甲酸类药物在皮肤科疾病治疗中的应用

维甲酸类药物（retinoic acids,RAs）是一组与维生素A结构相似的化合物,包括维生素A的各种天然及人工合成衍生物,是维持生长和发育必不可少的物质。1960年,德国皮肤病学家Stuttgen成功地将维甲酸类药物外用于各种角化不良及角化过度性皮肤病治疗。     

Repurposing drugs targeting metabolic diseases for cancer therapeutics

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Finding new tricks for old drugs: an efficient route for public-sector drug discovery

With the annotation of the human genome approaching completion, public-sector researchers - spurred in part by various National Institutes of Health Roadmap Initiatives - have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of 'drug-like' compounds can be readily screened to yield chemically novel scaffolds, transforming these 'chemical probes' into drugs is a daunting endeavour. A more efficient approach involves screening libraries of approved and off-patent medications; both phenotypic- and molecular target-based screening of 'old drugs' can readily yield compounds that could be immediately used in clinical trials. Using case studies, we describe how this approach has rapidly identified candidate medications suitable for clinical trials in disorders such as progressive multifocal leukoencephalopathy and amyotrophic lateral sclerosis. This approach has also led to the discovery of the molecular targets responsible for serious drug side effects, thereby allowing efficient 'counter-screening' to avoid these side effects.     

治疗心血管病常用药物与性功能障碍

治疗心血管病常用药物在医治躯体疾病的同时,可能影响病人的性生活质量,其中用于冠心病二级预防的药物尤为明显。本文综述了近年来治疗心血管病常用药物对性功能的影响、作用机制及防治方法。     

注册分类3化学药品研发思路探讨

本文根据化学药品注册分类3品种的研发特点以及当前的技术审评要求,探讨了注册分类3药品的基本研发思路,即首先要加强立题合理性的论证,其次要明晰原研产品的质量特性,再者要以原研产品的质量特性为主线构建完善的质量控制体系。