Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

The therapeutic potential of galectin-3 inhibition in fibrotic disease.

Galectin-3 is a beta-galactoside-binding mammalian lectin and part of the 15 member galectin family that are evolutionarily highly conserved. It is the only chimeric protein with a C-terminal carbohydrate recognition domain (CRD) linked to a proline, glycine, and tyrosine rich additional N-terminal domain. Galectin-3 binds several cell surface glycoproteins via its CRD domain as well as undergoing oligomerization, via binding at the N-terminal or the CRD, resulting in the formation of a galectin-3 lattice on the cell surface. The galectin-3 lattice has been regarded as being a crucial mechanism whereby extracellular galectin-3 modulates cellular signalling by prolonging retention time or retarding lateral movement of cell surface receptors in the plasma membrane. As such galectin-3 can regulate various cellular functions such as diffusion, compartmentalization and endocytosis of plasma membrane glycoproteins and glycolipids and the functionality of membrane receptors. In multiple models of organ fibrosis, it has been demonstrated that galectin-3 is potently pro-fibrotic and modulates the activity of fibroblasts and macrophages in chronically inflamed organs. Increased galectin-3 expression also activates myofibroblasts resulting in scar formation and may therefore impact common fibrotic pathways leading to fibrosis in multiple organs. Over the last decade there has been a marked increase in the scientific literature investigating galectin-3 in a range of fibrotic diseases as well as the clinical development of new galectin-3 inhibitors. In this review we will examine the role of galectin-3 in fibrosis, the therapeutic strategies for inhibiting galectin-3 in fibrotic disease and the clinical landscape to date.

Development of operational models of receptor activation including constitutive receptor activity and their use to determine the efficacy of the chemokine CCL17 at the CC chemokine receptor CCR4.

BACKGROUND AND PURPOSE The operational model provides a key conceptual framework for the analysis of pharmacological data. However, this model does not include constitutive receptor activity, a frequent phenomenon in modern pharmacology, particularly in recombinant systems. Here, we developed extensions of the operational model which include constitutive activity and applied them to effects of agonists at the chemokine receptor CCR4. EXPERIMENTAL APPROACH The effects of agonists of CCR4 on [(35) S]GTPγS binding to recombinant cell membranes and on the filamentous (F-) actin content of human CD4(+) CCR4(+) T cells were determined. The basal [(35) S]GTPγS binding was changed by varying the GDP concentration whilst the basal F-actin contents of the higher expressing T cell populations were elevated, suggesting constitutive activity of CCR4. Both sets of data were analysed using the mathematical models. RESULTS The affinity of CCL17 (also known as TARC) derived from analysis of the T cell data (pK(a) = 9.61 ± 0.17) was consistent with radioligand binding experiments (9.50 ± 0.11) while that from the [(35) S]GTPγS binding experiments was lower (8.27 ± 0.09). Its intrinsic efficacy differed between the two systems (110 in T cells vs. 11). CONCLUSIONS AND IMPLICATIONS The presence of constitutive receptor activity allows the absolute intrinsic efficacy of agonists to be determined without a contribution from the signal transduction system. Intrinsic efficacy estimated in this way is consistent with Furchgott's definition of this property. CCL17 may have a higher intrinsic efficacy at CCR4 in human T cells than that expressed recombinantly in CHO cells.

Pharmacological characterization of GSK1004723, a novel, long-acting antagonist at histamine H(1) and H(3) receptors.

BACKGROUND AND PURPOSE: Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist. EXPERIMENTAL APPROACH: GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography. KEY RESULTS: In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h. CONCLUSIONS AND IMPLICATIONS: GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.

Priority water research questions as determined by UK practitioners and policy makers.

Several recent studies have emphasised the need for a more integrated process in which researchers, policy makers and practitioners interact to identify research priorities. This paper discusses such a process with respect to the UK water sector, detailing how questions were developed through inter-disciplinary collaboration using online questionnaires and a stakeholder workshop. The paper details the 94 key questions arising, and provides commentary on their scale and scope. Prioritization voting divided the nine research themes into three categories: (1) extreme events (primarily flooding), valuing freshwater services, and water supply, treatment and distribution [each >150/1109 votes]; (2) freshwater pollution and integrated catchment management [100-150 votes] and; (3) freshwater biodiversity, water industry governance, understanding and managing demand and communicating water research [50-100 votes]. The biggest demand was for research to improve understanding of intervention impacts in the water environment, while a need for improved understanding of basic processes was also clearly expressed, particularly with respect to impacts of pollution and aquatic ecosystems. Questions that addressed aspects of appraisal, particularly incorporation of ecological service values into decision making, were also strongly represented. The findings revealed that sustainability has entered the lexicon of the UK water sector, but much remains to be done to embed the concept operationally, with key sustainability issues such as resilience and interaction with related key sectors, such as energy and agriculture, relatively poorly addressed. However, the exercise also revealed that a necessary condition for sustainable development, effective communication between scientists, practitioners and policy makers, already appears to be relatively well established in the UK water sector.

The management of household hazardous waste in the United Kingdom.

Waste legislation in the United Kingdom (UK) implements European Union (EU) Directives and Regulations. However, the term used to refer to hazardous waste generated in household or municipal situations, household hazardous waste (HHW), does not occur in UK, or EU, legislation. The EU's Hazardous Waste Directive and European Waste Catalogue are the principal legislation influencing HHW, although the waste categories described are difficult to interpret. Other legislation also have impacts on HHW definition and disposal, some of which will alter current HHW disposal practices, leading to a variety of potential consequences. This paper discusses the issues affecting the management of HHW in the UK, including the apparent absence of a HHW-specific regulatory structure. Policy and regulatory measures that influence HHW management before disposal and after disposal are considered, with particular emphasis placed on disposal to landfill.

Household hazardous waste in municipal landfills: contaminants in leachate.

Household hazardous waste (HHW) includes waste from a number of household products such as paint, garden pesticides, pharmaceuticals, photographic chemicals, certain detergents, personal care products, fluorescent tubes, waste oil, heavy metal-containing batteries, wood treated with dangerous substances, waste electronic and electrical equipment and discarded CFC-containing equipment. Data on the amounts of HHW discarded are very limited and are hampered by insufficient definitions of what constitutes HHW. Consequently, the risks associated with the disposal of HHW to landfill have not been fully elucidated. This work has focused on the assessment of data concerning the presence of hazardous chemicals in leachates as evidence of the disposal of HHW in municipal landfills. Evidence is sought from a number of sources on the occurrence in landfill leachates of hazardous components (heavy metals and xenobiotic organic compounds [XOC]) from household products and the possible disposal-to-emissions pathways occurring within landfills. This review demonstrates that a broad range of xenobiotic compounds occurring in leachate can be linked to HHW but further work is required to assess whether such compounds pose a risk to the environment and human health as a result of leakage/seepage or through treatment and discharge.