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Aims To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers.
Methods This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood.
Results Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached Cmax (ng ml−1; mean ± s.d.; 1398 ± 298, 1000 ± 400, respectively) after 2.63 ± 0.79 and 5.9 ± 2.3 h, respectively. For V11294A and V10332, t1/2 were 9.7 ± 3.9 and 9.5 ± 1.7 h, and AUC(0,∞) were 18100 ± 6100 and 18600 ± 8500 ng ml−1 h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 ± 330 and 860 ± 300 ng ml−1, 7 and 3 times their in vitro IC50s for inhibition of TNF release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNF release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNF released (pmol ml−1) in response to a submaximal concentration of LPS (4 ng ml−1) was not significantly altered following placebo treatment (before 681 ± 68 vs 3 h postdose 773 ± 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNF released following treatment with V11294A (before 778 ± 87 vs 3 h postdose 566 ± 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [3H]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A.
Conclusions A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.
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A variety of pharmacological, biochemical and molecular biological studies have revealed the existence of 11 diverse phosphodiesterase (PDE) families which are comprised of at least 15 gene products with further diversity occurring as a consequence of differential splicing and post-translational processing [1, 2]. Of particular interest is the role of PDE4 in regulating the function of a variety of cells thought to participate in the inflammatory process, and there is considerable interest in the development of PDE4 inhibitors for the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD) .
PDE inhibitors are currently being developed for the treatment of asthma although side-effects including nausea and vomiting have halted the development of some examples of this class of drug into the clinic. To date, there are a limited number of clinical studies investigating the efficacy of PDE inhibitors in the treatment of asthma. Inhalation of zardaverine was shown to produce a modest bronchodilator effect in patients with asthma, although unacceptable side-effects of nausea and emesis were reported in a significant number of patients , while oral administration of cilostazol (PDE3 inhibitor) caused bronchodilation and bronchoprotection against methacholine challenge in healthy subjects at the expense of mild to severe headache . AH-2132 (benzafentrine; a mixed PDE3/4 inhibitor) has also been reported to have significant bronchodilator activity in normal volunteers . The PDE4 inhibitor, ibudilast significantly improved baseline airways responsiveness to spasmogens by 2 fold after 6 months treatment  and MKS492 (a PDE3 inhibitor) has been reported to attenuate the early and late asthmatic response in atopic asthmatics .
Recently, the orally active PDE4 selective inhibitors, CDP840  and roflumilast  have been demonstrated to modestly attenuate the development of the late asthmatic response in mild asthmatics whilst having no effect on the acute response, with no significant side-effects being reported in comparison with placebo. The ability of these novel selective PDE4 inhibitors to inhibit the late asthmatic response was not associated with bronchodilation, suggesting actions of this drug other than smooth muscle relaxation. Furthermore, another PDE4 inhibitor RPR73401, has also been shown to have no significant effect on allergen-induced bronchoconstriction in allergic asthmatic subjects , consistent with the suggestion that PDE3 rather than PDE4 may be the important isoenzyme regulating airway smooth muscle tone in asthmatic subjects. However, recent clinical studies with another orally active PDE4 inhibitor, cilomilast have shown that this drug can attenuate bronchoconstriction following exercise in asthmatic subjects , an effect mimicked by 4 weeks of treatment with the selective PDE4 inhibitor rofluminlast . Similarly, cilomilast provided significant clinical improvement in patients with asthma and COPD .
We have previously reported that V11294A is a novel potent orally active PDE4 inhibitor having a wide range of pharmacological activities including the ability to inhibit the release of TNF from human monocytes and proliferation of human mononuclear cells . Furthermore, in phase I clinical trials in human volunteers, V11294A was shown to be without significant emetic effects consistent with studies in the ferret .
In the present study we have assessed the pharmacokinetic and pharmacodynamic profile of a single oral administration of V11294A in healthy volunteers, including the ability of this drug to inhibit TNF release from circulating monocytes as a biomarker.