Anti-Pruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005

Anti-Pruritic Effect of the Topical Phosphodiesterase 4 Inhibitor E6005 Ameliorates Skin Lesions in a Mouse Atopic Dermatitis Model

1. Naoto Ishii1, 
2. Manabu Shirato1,*, 
3. Hisashi Wakita1, 
4. Kazuki Miyazaki2,
5. Yasutaka Takase1, 
6. Osamu Asano2, 
7. Kazutomi Kusano1,
8. Eiichi Yamamoto1, 
9. Chiharu Inoue2, and 
10. Ieharu Hishinuma2

+Author Affiliations

1. ¹ Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan;
2. ² Eisai Co. Ltd., Tokyo, Japan

1. ↵* Corresponding author; email: m-shirato@hhc.eisai.co.jp

Abstract

Phosphodiesterase (PDE) 4 inhibition is a well known anti-inflammatory mechanism, but the development of PDE4 inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005, a novel PDE4 inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC₅₀ of 2.8 nM, and suppressed the production of various cytokines from human lymphocytes and monocytes with IC₅₀ values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate anti-pruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. Based on these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting inhibitory effects comparable to that of tacrolimus. The use of ¹⁴C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with anti-pruritic activity for the treatment of AD.

1. Published online before print May 14, 2013, doi:10.1124/jpet.113.205542
   JPET May 14, 2013jpet.113.205542

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3. Data Supplement

• The American Society for Pharmacology and Experimental Therapeutics

Research article

Investigating highly replicated asthma genes as candidate genes for allergic rhinitis

Anand Kumar Andiappan^1,2*†, Daniel Nilsson^3,4*†, Christer Halldén⁴, Wang De Yun⁵, Torbjörn Säll⁶, Lars Olaf Cardell³ and Chew Fook Tim^1*

• *Corresponding authors: Anand Kumar Andiappan anand_andiappan@immunol.a-star.edu.sg - Daniel NilssonDaniel.Nilsson.2@ki.se - Chew Fook Tim dbscft@nus.edu.sg
• † Equal contributors

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BMC Medical Genetics 2013, 14:51 doi:10.1186/1471-2350-14-51

Published: 10 May 2013

Abstract

Background

Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5–6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR.

Methods

A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens.

Results

A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values - 0.001 with corresponding Q-values - 0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population.

Conclusions

Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously.

Keywords: 

Allergic rhinitis; Association; Asthma; Case–control; Replication

Relieving nasal congestion in children with seasonal and perennial allergic rhinitis

• World Allergy Organ J
• v.6(1); 2013
• PMC3646538

World Allergy Organ J. 2013; 6(1): 5.

Published online 2013 March 4. doi:  10.1186/1939-4551-6-5

PMCID: PMC3646538

Relieving nasal congestion in children with seasonal and perennial allergic rhinitis: efficacy and safety studies of mometasone furoate nasal spray

Eli O Meltzer,1 Carlos E Baena-Cagnani,2 Davis Gates,3 and Ariel Teper3

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Abstract

Background

In surveys of children with allergic rhinitis (AR), nasal congestion has been identified as the most frequently experienced and bothersome symptom. This analysis was conducted to investigate the effect of mometasone furoate nasal spray (MFNS) on congestion in children with AR.

Methods

Two multicenter, double-blind, placebo-controlled studies randomly assigned children to MFNS 100μg or placebo, 1 spray/nostril QD for 4weeks (Study 1: ages 6–11years with seasonal AR [SAR] ≥1year; Study 2: ages 3–11years with perennial AR [PAR] ≥1year). Least square (LS) means were obtained from an ANCOVA model with treatment and study center effects, with baseline score as a covariate. We conducted post hoc evaluation of changes from baseline in AM/PM PRIOR (average of reflective AM and PM scores) nasal congestion (0=none to 3=severe).

Results

Study 1: MFNS (n=134) reduced congestion significantly more than placebo (n=135) on day 2 (P=.004) and on 23/29days (P≤.037). Change from baseline was −0.53 and −0.28 for MFNS and placebo (P<.001) over days 1–15 and −0.64 and −0.38 for MFNS and placebo (P<.001) over days 1–29. Study 2: MFNS (n=185) reduced congestion significantly more than placebo (n=189) on day 3 (P=.015) and on 22/29days (P≤.047). Change from baseline was −0.56 and −0.36 for MFNS and placebo (P<.001) over days 1–15 and −0.64 and −0.45 for MFNS and placebo (P<.001) over days 1–29. MFNS was well tolerated, with no unusual or unexpected adverse events.

Conclusion

MFNS effectively relieved nasal congestion and was well tolerated in children with SAR or PAR.

Keywords: Mometasone furoate nasal spray, Placebo, Pediatric, Nasal congestion, Allergic rhinitis, Efficacy, Safety, Controlled clinical trial

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Association between Polymorphisms of the IL-23R Gene and Allergic Rhinitis

PLoS One. 2013; 8(5): e63858.

Published online 2013 May 16. doi:  10.1371/journal.pone.0063858

PMCID: PMC3655942

Association between Polymorphisms of the IL-23R Gene and Allergic Rhinitis in a Chinese Han Population

Di Hu, Guohua Hu, Jing Zhu, Yang Shen, Houyong Kang, and Suling Hong*

Sunil K. Ahuja, Editor

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Abstract

Objective

Polymorphism of the interleukin-23 receptor gene corresponds with susceptibility to several immune-related diseases. For the terminal differentiation of IL-17-producing effector T-helper cells in vivo, the interleukin-23 receptor gene is of vital importance. As shown recently, Th17 cells probably have a great influence on the pathogenesis of allergic airway diseases. Our intention was to establish an association between polymorphisms in the IL-23R gene and allergic rhinitis (AR) in the Chinese Han population.

Methods

We included 358 AR patients and 407 control Chinese subjects in a case-control comparison. The study involved obtaining blood samples for DNA extraction genotyping and determination of 4 selected single-nucleotide polymorphisms in IL-23R by performing PCR restriction fragment length polymorphism analysis (PCR-RFLP).

Results

A substantially growing prevalence of the homozygous rs7517847 GG genotype and G allele appeared in the AR patients unlike that observed in the control individuals (P<0 .001="" addition="" against="" agtg="" and="" ar="" control="" frequencies="" ggca="" ggcg="" haplotype="" haplotypes="" high="" in="" individuals="" may="" observed="" of="" p="" patients="" protection="" provide="" results="" substantially="" suggest="" that="" the="" unlike="" were="">

Conclusions

To the best of our knowledge, this is the first study to demonstrate an important association between polymorphisms in IL-23R and AR in the Chinese Han population. A strong association between rs7517847 in a SNP of IL-23R, and AR was identified.

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Paraplegia due to Spinal Epidermoid Cyst Rupture at Asthma Attack

Ann Rehabil Med 2013 Apr; 37(2): 274-279

Paraplegia due to Spinal Epidermoid Cyst Rupture at Asthma Attack

Kweon Young Kim, MD, Jung Hun Kang, MD, Dae Woo Choi, MD, Min Hong Lee, MD, Jae Hyouk Jang, MD

Department of Rehabilitation Medicine, Chosun University Hospital, Gwangju, Korea

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Spinal epidermoid cyst is less than 1% of the entire spinal cord tumor and a rare tumor. It is a slowly proliferating benign tumor and can be a result of either congenital or acquired factors. In particular, reports of acute paraplegia due to spinal epidermoid cyst rupture are very rare. Since authors experienced paraplegia resulting from congenital spinal epidermoid cyst rupture during an asthma attack, it is reported with a review of literature.

KEYWORD

Epidermoid cyst, Asthma, Paraplegia

Ann Rehabil Med 2013 Apr; 37(2): 274-279

Exercise and Airway Injury in Athletes

Home > Vol 26, No 1 (2013) > Couto

Exercise and Airway Injury in Athletes

Mariana Couto, Diana Silva, Luis Delgado, André Moreira

Abstract

Olympic level athletes present an increased risk for asthma and allergy, especially those who take part in endurance sports, such as swimming or running, and in winter sports. Classical postulated mechanisms behind EIA include the osmotic, or airway-drying, hypothesis. Hyperventilation leads to evaporation of water and the airway surface liquid becomes hyperosmolar, providing a stimulus for water to move from any cell nearby, which results in the shrinkage of cells and the consequent release of inflammatory mediators that cause airway smooth muscle contraction. But the exercise-induced asthma/bronchoconstriction explanatory model in athletes probably comprises the interaction between environmental training factors, including allergens and ambient conditions such as temperature, humidity and air quality; and athlete’s personal risk factors, such as genetic and neuroimmuneendocrine determinants. After the stress of training and competitions athletes experience higher rate of upper respiratory tract infections (URTI), compared with lesser active individuals. Increasing physical activity in non-athletes is associated with a decreased risk of URTI. Heavy exercise induces marked immunodepression which is multifactorial in origin. Prolonged, high intensity exercise temporarily impairs the immune competence while moderate activity may enhance immune function. The relationship between URTI and exercise is affected by poorly known individual determinants such genetic susceptibility, neurogenic mediated immune inflammation and epithelial barrier dysfunction. Further studies should better define the aetiologic factors and mechanisms involved in the development of asthma in athletes, and propose relevant preventive and therapeutic measures.

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The safety of codeine in patients with non-steroidal anti-inflammatory drug hypersensitivity

The safety of codeine in patients with non-steroidal anti-inflammatory drug hypersensitivity: A preliminary study

Celebioglu, E.; Karakaya, G.; Kalyoncu, A.F.

Published in Allergol Immunopathol (Madr). 2013;41:163-8. - vol.41 núm 03

• English: [ Abstract | Full text | PDF ]

Abstract

Background

Drug provocation testing should be performed before safely prescribing an analgesic for patients that are hypersensitive to non-steroidal anti-inflammatory drugs (NSAIDs). Whether or not the direct histamine releasing effect of codeine renders it useful in NSAID-hypersensitive patients is unknown. This study aimed to determine if codeine could be recommended as a safe treatment option for NSAID-hypersensitive patients without the need for oral drug provocation testing.

Methods

The study included NSAID-hypersensitive patients with and without concurrent asthma, rhinitis, and chronic urticaria that presented to the allergy clinic between 1 January 1991 and 31 December 2010. Patient data were collected from the allergy clinic computer database. Patients challenged with codeine were included in the codeine group. The non-codeine group included those patients that were tested with analgesics other than codeine.

Results

In total, data for 1071 patients, of whom 301 were in the codeine group, were analysed. The reaction rate to codeine was 7.3% and when compared in pairs, the rate was significantly lower than to meloxicam and nimesulide (odds ratios=0.26–0.31, respectively). The reaction rate to codeine did not differ from that to benzydamine, rofecoxib, and paracetamol. Symptomatic dermographism was associated (p=0.009) with test positivity to any drug.

Conclusions

Although, codeine was among the safest alternative drugs and none of the patients had an anaphylactic reaction to it, thus a challenge with codeine may be considered especially in patients with dermographism. The results of this preliminary study should be confirmed in a prospective study including a control group.

Obesity and asthma: An association modified by age

Gonzalez-Barcala, F.J.; Pertega, S.; Perez-Castro, T.; Sampedro, M.; Sanchez-Lastres, J.; San-Jose-Gonzalez, M.A.; Bamonde, L.; Garnelo, L.; Valdés-Cuadrado, L.; Moure, J.D.; Carreira, J.M.; Lopez-Silvarrey, A.

Published in Allergol Immunopathol (Madr). 2013;41:176-80. - vol.41 núm 03

• English: [ Abstract | Full text | PDF ]

Abstract

Background

Some studies indicate some causal relationship between obesity and asthma, while others show inconsistent results. Our objective was to evaluate the prevalence of asthma according to obesity in children.

Methods

A cross-sectional study, following the ISAAC study methodology, was conducted on two randomly selected groups consisting of 6–7 year-old children (n=7485) and 13–14 year-old adolescents (n=8496).

The asthma symptoms and potential risk factors were determined from the questionnaire. Overweight and obesity were defined based on the body mass index.

Multiple logistic regression was used to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals.

Results

Obesity was associated with an increase in wheezing ever (OR: 1.35) and exercise-induced asthma (OR: 1.62) in the 6–7 year-old group. No significant relationship was observed in the adolescent population.

Conclusion

Obesity was associated with a higher prevalence of asthma in young children, but not in adolescents.

Key words: Paediatric asthma. Obesity. Risk factor. Age.