Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294

Gale, Donna D; Höfer, Peter; Spina, Domenico; Seeds, Esther A.M.; Banner, Katharine H.; Harrison, S; Douglas, Garry J.; Matsumoto, Tatsui; Page, Clive; Wong, Richard H.; Jordan, Stephan; Smith, Forrest L.; Banik, Nandini; Halushka, Perry V.; Cavalla, David; Rotshteyn, Yakov; Kyle, Donald J.; Burch, Ronald M.; Chasin, Mark

doi:10.1016/s1094-5539(02)00175-x

Cited by 18 publications

(17 citation statements)

References 21 publications

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“…V11294A is a potent PDE4 inhibitor which has been demonstrated to inhibit a number of inflammatory cell functions including mononuclear cell proliferation, TNF release from monocytes, tracheal smooth muscle relaxation and recruitment of eosinophils to the airways following antigen challenge in immunized guinea‐pigs and rabbits [15]. The effect of V11294A on cellular function is similar to that previously reported for other PDE4 inhibitors [16].…”

Section: Resultssupporting

confidence: 58%

“…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 [15]. Furthermore, in phase I clinical trials in human volunteers, V11294A was shown to be without significant emetic effects consistent with studies in the ferret [15].…”

Section: Introductionmentioning

confidence: 52%

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Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

Gale¹,

Landells

Spina

et al. 2002

Brit J Clinical Pharma

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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 C max (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, t 1 / 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 I C 50 s 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 [ 3 H]-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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Section: Resultssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 52%

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

Gale¹,

Landells

Spina

et al. 2002

Brit J Clinical Pharma

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“…After stimulation by 780 lM AA for 5 min, the action was terminated by adding 10 mM EDTA and boiling for 3 min followed cooling to 4°C. After centrifugation of washed platelets at 4,000 rmp for 10 min, the supernatant was used to determine the cAMP level through cAMP ELISA kit following the procedure as described by the manufacturer [16].…”

Section: Camp Assaymentioning

confidence: 99%

Antiplatelet activity of 3-butyl-6-bromo-1(3H)-isobenzofuranone on rat platelet aggregation

Gao

Qiao

et al. 2011

J Thromb Thrombolysis

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This study aimed to explore the impact of 3-butyl-6-bromo-1(3H)-isobenzofuranone (Br-NBP) on rat platelet aggregation induced by arachidonic acid (AA). Anti-platelet activities in vitro and ex vivo in rat platelets and the possible mechanism were also investigated. The 50% inhibitory concentration (IC(50)) of Br-NBP was 84 μM in washed platelet added AA (final concentration, 780 μM) in vitro, meanwhile intravenous injection of Br-NBP also potently inhibited platelet aggregation ex vivo. Br-NBP significantly restrained thromboxane B(2) formation and Ca(2+) mobilization caused by AA, but failed to regulate 6-keto-prostaglandin F(1α) production and malonaldehyde content. Treatment of Br-NBP improved cAMP, cGMP levels and NO synthesis but prevented serotonin secretion and PF(4) release. Results suggested that Br-NBP inhibited rat platelet aggregation and that the anti-platelet activity was related to both arachidonic acid cascade and cGMP-NO signal path.

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“…One group from each strain was used to determine baseline parameters in the normoxic state; the other groups were exposed to 7 days hypoxia (8% oxygen). One group from each strain was left untreated during hypoxia, while another hypoxic SAD mouse group was treated with the PDE-4 inhibitor rolipram, at the dosage of 30 mg/kg once a day by gavage (43)(44)(45)(46). Treatment was started 48 h before hypoxia and maintained during hypoxia.…”

Section: Hypoxia Studiesmentioning

confidence: 99%

Protective effects of phosphodiesterase‐4 (PDE‐4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice

Franceschi¹,

Platt

Malpeli³

et al. 2008

FASEB j.

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Pulmonary arterial hypertension (PAH) is one of the leading causes of morbidity and mortality in adult patients with sickle cell disease (SCD). Here, we developed a model to study the early stage of PAH in SCD. We exposed wild-type and transgenic sickle cell SAD (Hbb(s)/Hbb(s)) mice to hypoxia (8% O(2)) for 7 days. Prolonged hypoxia in SAD mice only induced 1) increased neutrophil count in both bronchoalveolar lavage (BAL) and peripheral circulation; 2) increased BAL IL1beta, IL10, IL6, and TNF-alpha; and 3) up-regulation of the genes endothelin-1, cyclo-oxygenase-2, angiotensin-converting-enzyme, and IL-1beta, suggesting that amplified inflammatory response and activation of the endothelin-1 system may contribute to the early phase of PAH in SCD. Since phosphodiesterases (PDEs) are involved in pulmonary vascular tone regulation, we evaluated gene expression of phosphodiesterase-4 (PDE-4) isoforms and of PDE-1, -2, -3, -7, -8, which are the main cyclic-adenosine-monophosphate hydrolyzing enzymes. In SAD mouse lungs, prolonged hypoxia significantly increased PDE-4 and -1 gene expressions. The PDE-4 inhibitor, rolipram, prevented the hypoxia-induced PDE-4 and -1 gene up-regulation and interfered with the development of PAH, most likely through modulation of both vascular tone and inflammatory factors. This finding supports a possible therapeutic use of PDEs inhibitors in the earlier phases of PAH in SCD.

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Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294

Cited by 18 publications

References 21 publications

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V11294A in healthy volunteers

Antiplatelet activity of 3-butyl-6-bromo-1(3H)-isobenzofuranone on rat platelet aggregation

Protective effects of phosphodiesterase‐4 (PDE‐4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice

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