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Biomedical subjects

Garry M Walsh

Publications and source records attributed to Garry M Walsh.

7 recordsLinked to original sources
PubMed2006

Levocetirizine: an update.

Histamine plays a prominent and diverse role in the pathophysiology of allergic disease and therapeutic intervention is therefore typically focused on blocking the effects of this biogenic amine. A new antihistamine, levocetirizine, is the R-enantiomer of cetirizine dihydrochloride and like its parent compound undergoes minimal hepatic metabolism. Levocetirizine has pharmacodynamically and pharmacokinetically favourable characteristics, including high bioavailability, rapid onset of action, limited distribution and a low degree of metabolism. Clinical trials indicate that it is safe and effective for the treatment of allergic rhinitis and chronic urticaria with a minimal number of untoward effects. Furthermore, several recent studies have demonstrated that, in addition to its being a potent antihistamine, levocetirizine has several anti-inflammatory effects that are observed at clinically relevant concentrations that may enhance its therapeutic benefit.

Anti-Inflammatory Agents↗
PubMed2006

Targeting airway inflammation: novel therapies for the treatment of asthma.

It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. Inhaled corticosteroids remain the most important anti-inflammatory treatment for asthma. However, they are rather non-specific in their actions and their use raises concerns over side effects and compliance issues, particularly in children and adolescents. Moreover, a significant sub-group of asthmatic patients responds poorly or not at all to high-dose inhaled or systemic steroid treatment. Therefore, much effort is being made to develop novel more specific and safer therapy for asthma. Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IL-4, IL-5, TNF and IL-13. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include: (1) the use of humanised blocking mAb to their receptors; (2) removal of cytokines or chemokines via binding to soluble receptors or small molecule receptor antagonists; and (3) drugs that block the signal transduction pathways activated following the interaction of cytokines or chemokines with their receptors. Another approach is to use anti-inflammatory cytokines directly or encourage their production thereby suppressing the allergic inflammatory process; these chemokines include IL-10, IL-12 and IFN-gamma. Finally, a further promising area involves targeting the allergic portion of the asthma phenotype using humanised anti-IgE mAb. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.

Anti-Asthmatic Agents↗
PubMed2005

Novel therapies for asthma--advances and problems.

It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. While corticosteroids remain the most important anti-inflammatory treatment for asthma they are rather non-specific in their actions. Their use also raises concerns over side effects and compliance issues, particularly in children and adolescents. There is therefore much effort being made to develop novel more specific and safer therapy for asthma. Efforts are being made to improve existing drugs together with the use of combination therapy with anti-histamines and leukotriene antagonists. An important area for potential advances in glucocorticoid (GC) development include the elucidation of the crystal structure of the GC receptor ligand-binding domain that may provide vital information in dissociating the anti-inflammatory effects of GCs from unwanted side-effects. Other areas include the development of humanised monoclonal antibodies for asthma therapy including those against IgE, IL-4 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for inflammatory cell accumulation in the asthmatic lung. The potential for immunotherapy using T cell peptide epitopes or DNA-based vaccines and the use of anti-inflammatory cytokines such as IL-10 or IFN-gamma are discussed. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. Novel strategies include elucidation of the intracellular pathways controlling granulocyte apoptosis and the receptor mediated events employed by macrophages and bronchial epithelial cells in the recognition and removal of apoptotic cellular corpses. This paper will provide an overview of both the potential and shortcomings of these diverse approaches to drug development for asthma.

Adrenal Cortex Hormones↗
PubMed2004

Membrane receptor-mediated apoptosis and caspase activation in the differentiated EoL-1 eosinophilic cell line.

Caspases are key molecules in the control of apoptosis, but relatively little is known about their contribution to eosinophil apoptosis. We examined caspase-3, -8, and -9 activities in receptor ligation-dependent apoptosis induction in the differentiated human eosinophilic cell line EoL-1. Differentiated EoL-1 exhibited bi-lobed nuclei, eosinophil-associated membrane receptors, and basic granule proteins. Annexin-V fluorescein isothiocyanate binding to EoL-1 revealed significant (P<0.01) apoptosis induction in cells cultured for 20 h with monoclonal antibodies (mAb) specific for CD45 (71%+/-4.3), CD45RA (58%+/-2.3), CD45RB (68%+/-2.4), CD95 (47%+/-2.6), and CD69 (52%+/-2.1) compared with control (23%+/-1.6) or CD45RO mAb (27%+/-3.9). The pan-caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (fmk) and inhibitors of caspase-8 (Z-Ile-Glu-Thr-Asp-fmk) and caspase-9 (Z-Leu-Glu-His-Asp-fmk) significantly inhibited mAb-induced apoptosis of EoL-1 but had no effect on constitutive (baseline) apoptosis at 16 and 20 h. Caspase activity was analyzed using the novel CaspaTag trade mark technique and flow cytometry. EoL-1 treated with pan-CD45, CD45RA, CD45RB, and CD95 mAb exhibited caspase-3 and -9 activation at 12 h post-treatment, which increased at 16 and 20 h. Activated caspase-8 was detected 12 and 16 h after ligation with CD45, CD45RA, CD45RB, and CD95 mAb followed by a trend toward basal levels at 20 h. CD69 ligation resulted in caspase-3 activation, a modest but significant activation of caspase-8, and a loss in mitochondrial transmembrane potential but had no significant effect on activation of caspase-9. Thus, the intrinsic and extrinsic caspase pathways are involved in controlling receptor ligation-mediated apoptosis induction in human eosinophils, findings that may aid the development of a more targeted, anti-inflammatory therapy for asthma.

Annexin A5↗
PubMed2002

Second-generation antihistamines in asthma therapy: is there a protective effect?

Second-generation histamine H(1) receptor antagonists are recognized as being highly effective treatments for allergic-based disease and are among the most frequently prescribed drugs in the world. The newer antihistamines represent a heterogeneous group of compounds with markedly different chemical structures, a spectrum of antihistaminic properties, adverse effects, half-life, tissue distribution, metabolism and varying degrees of anti-inflammatory effects. Histamine is an important mast cell- and basophil-derived mediator that has been implicated in the pathogenesis of asthma, resulting in smooth muscle contraction, mucus hypersecretion, and increased vascular permeability leading to mucosal edema. Antihistamines should never be used as monotherapy for asthma but there is evidence that these drugs give a measure of protection in histamine-induced bronchoconstriction. Furthermore, several studies have demonstrated that the use of second-generation antihistamines, as adjunct therapy, may benefit those patients whose allergic asthma co-exists with allergic rhinitis. Indeed, many patients present with both allergic rhinitis and asthma. The link between the upper and lower respiratory airways is now well established and there is increasing evidence that allergic rhinitis is a risk factor for the development of asthma. More recently, a number of novel antihistamines have been developed which are either metabolites of active drugs or enantiomers and there is emerging evidence that at least one of these drugs, desloratadine, may give significant symptomatic benefit in some types of asthma. It is of interest to note that cetirizine provides a primary pharmacological intervention strategy to prevent the development of asthma in specifically-sensitized high risk groups of infants. Moreover, the documented anti-inflammatory activities of antihistamines may provide a novel mechanism of action for the therapeutic control of virus-induced asthma exacerbations by inhibiting the expression of intercellular adhesion molecule-1 (ICAM-1) by airway epithelial cells. Finally, several well-conducted studies suggest that combination therapy with antihistamines and antileukotrienes may be as effective as corticosteroid use in patients with allergic asthma and seasonal allergic rhinitis.

Asthma↗
PubMed2002

Emerging safety issues regarding long-term usage of H(1)receptor antagonists.

The second generation histamine H(1)-receptor antagonists are important therapeutic tools in the treatment of atopic disease and may also have a place as an adjunct therapy for those patients whose allergic asthma coexists with allergic rhinitis. They are amongst the most widely prescribed and safest drugs in the world. However, as second generation H(1)-receptor antagonists are used to treat non-life threatening conditions, the risk of adverse effects is of vital importance. For many, the potential for sedation by some of the newer antihistamines still remains an issue, while there have recently been widespread concerns regarding the potential for cardiotoxicity and the impact of drug-drug interactions associated with some second generation H(1)-receptor antagonists. Consequently, progress with this class of drugs should involve not only increased efficacy but also improvements in their safety and specificity. Moreover, there is a trend towards using second generation H(1)-receptor antagonists as long-term therapy rather than confining their use to treating the short-term manifestations of allergic disease. To this end, a number of novel, potent and safe antihistamines have been developed which are either metabolites of active drugs or enantiomers. This review will examine some of the safety issues associated with established and newer second generation drugs particularly in relation to their long-term usage in adults and children.

Adult↗