Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6–20 week age range regardless of the biology being studied. The age referred to as ‘adult’ by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans.

1 Salmeterol, a novel, long-acting /J-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of f-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2 Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F2. or electrical stimulation) and human bronchus (contracted by PGF2a) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3 Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by sahueterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the fl-adrenoceptor blocking drug, propranolol (O.1juM). In further studies, on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA2 of 9.0. The slope of the Schild plot was 1.02. 4 Another /i-adrenoceptor blocking drug, sotalol (10pM), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5 In the fJ,-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000-5000 fold less potent, and appeared to be partial agonists. At a concentration of 72#M, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 pM). 6 On the guinea-pig isolated gastric fundus strip, a putative /3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,3-adrenoceptor agonist, BRL 35135.7 In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h. 8 Salmeterol is therefore a potent and selective 12-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inha...

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Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.

Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}-sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)-and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p Ͻ 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 ϫ ED 50 dose (10 g/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED 50 35 and 92 g/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED 50 0.4 g/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED 50 18 g/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease.