October 30, 2014

The effect of the novel phosphodiesterase-4 inhibitor MEM 1414 on the allergen induced responses in mild asthma

Research article

Open Access

Brian R LeakerDave SinghFerhana Y AliPeter J Barnes and Brian O´Connor
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Abstract (provisional)

Background

Inhaled allergen challenge is a standard method to study airway responses to inflammatory provocation and evaluate the therapeutic potential of novel anti-inflammatory compounds in asthma. MEM 1414 is a novel oral PDE4 inhibitor with high affinity and selectivity creating the potential for an improved side effect profile vs non-selective PDE inhibitors. We evaluated the tolerability and effect of MEM 1414 on airway responses in mild asthmatics.

Methods

A randomised double blind placebo controlled cross over study in two centres, in which sixteen steroid naive atopic asthmatics were challenged with inhaled allergen. Subjects were dosed with MEM 1414 (600 mg) or placebo, twice daily orally for 7 days. Allergen challenge was performed on day 6 (2 hours post-dose), and methacholine responsiveness was measured 24 hours post allergen (day 7). Biomarkers of drug effects using ex vivo LPS stimulation of whole blood production of interleukin (IL)-6 and leukotriene (LT)-B4 and fractional exhaled nitric oxide (FeNO) were measured on day 6 (0, 2 and 8 hours post-dose). Plasma pharmacokinetics were measured on days 1, 6 and 7. The primary endpoint was the effect on late asthmatic response to allergen.

Results

Treatment with MEM 1414 abrogated the late phase response with a mean difference in FEV1 (LAR 3-10 hours) of 104 ml (25%) vs placebo (p - 0.005), with no effect on the early response. Biomarker responses were also attenuated with MEM 1414 treatment with reductions in LPS-stimulated whole blood assays for TNFalpha at 8 hours (p - 0.03) and LTB4 at 24 hours (p = 0.0808) with no change in the IL-6 response. The MEM 1414 treatment phase was associated with higher incidence of nausea (6/16 MEM 1414 vs 2/16 placebo) and vomiting (3/16 vs 0/16 placebo).

Conclusions

Oral MEM 1414, a novel PDE4 inhibitor, significantly reduces the late response following inhaled allergen challenge. MEM 1414 also inhibited whole blood assays of cytokine production from inflammatory cells. MEM 1414 was associated with a typical adverse event profile of PDE4 inhibitors, namely nausea and vomiting although these were mild side effects.
Trial registration number: Current controlled trials ISRCTN48047493.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Positive serum specific IgE has a short half-life in patients with penicillin allergy and reversal does not always indicate tolerance

Research

Open Access

Janni HjortlundCharlotte Gotthard MortzTore Bjerregaard StagePer Stahl SkovRonald Dahl and Carsten Bindslev-Jensen
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Expert roundtable on Sublingual Immunotherapy


Journal of Allergy and Clinical Immunology: In PracticeAmerican Academy of Allergy and Asthma and Immunology
Expert Roundtable on 
Sublingual Immunotherapy
FACULTY:
Linda Cox, MD, FAAAAI • Thomas Casale, MD, FAAAAI • Peter Creticos, MD, FAAAAI • Stephen Durham, MA, MD, FRCP
Linda Cox, MD, Clinical Associate Professor, Nova Southeastern UniversityTom Casale, MD, Professor of Medicine, University of South Florida
Peter Creticos, MD, Associate Professor, Johns Hopkins School of MedicineStephen Durham, MD, Professor of Allergy and Respiratory Medicine, Imperial College London
View Web Conference
RELEASE DATE: September 15, 2014 • EXPIRATION DATE: September 15, 2016

Diagnosis and management of food allergies: new and emerging options: a systematic review

Authors Andrew W O'Keefe,1,2 Sarah De Schryver,1 Jennifer Mill,3 Christopher Mill,3 Alizee Dery,1 Moshe Ben-Shoshan1
Published Date October 2014 Volume 2014:7 Pages 141—164
Received 15 July 2014Accepted 19 August 2014, Published 24 October 2014
Approved for publication by Dr Linda Cox

SLIT: indications, follow-up, and management

I Dávila1, A Navarro2, J Domínguez-Ortega3, A Alonso4, D Antolín-Amérigo5, MC Diéguez6, E González-Mancebo7, C Martín8, C Martínez9, B Núñez10, N Prior11, M Reche12, A Rosado13, J Ruiz-Hornillos14, A Sansosti15, M Torrecillas16, MJ Jerez17; QUASAR Group (QUality in the Administration of SLIT in Allergic Rhinitis)

October 28, 2014

Histamine H4 receptor: A Novel Drug Target For Immunoregulation and Inflammation. Open Access Book



Aims and Scope

H4R is the newest member of the histamine receptor family, which was discovered about twelve years ago. It is considered a very promising drug target. The effort to improve the pharmacokinetic properties of the currently available H4R ligands is reflected in a steadily growing number of scientific publications and patent applications. Preclinical data strongly confirms the need for novel potent H4R ligands to explore their therapeutic value in allergy, inflammation, autoimmune disorders, and possibly, cancer.
Readers will be provided with extensive knowledge on histamine metabolism, as well as cellular histamine transport, storage and release, effects of histamine and histamine receptor ligands, with particular attention to the H4R, on inflammatory cells including mast cells, basophils, eosinophils, neutrophils, macrophages, dendritic cells, and T cells. The present knowledge on the regulatory role of histamine and the therapeutic exploitation of histamine receptor ligands in atopic diseases, with emphasis on human and animal models of asthma, allergic dermatitis and pruritus are discussed.

Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies



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