ABSTRACT
V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4. In contrast, rolipram induced severe retching and vomiting at 10 mg/kg, p.o. In conclusion, V11294 is an orally active PDE4 inhibitor that exhibits antiinflammatory activity in vitro, and in vivo at doses that are not emetogenic.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Purines/pharmacology , 3',5'-Cyclic-AMP Phosphodiesterases/isolation & purification , Animals , Cyclic Nucleotide Phosphodiesterases, Type 3 , Cyclic Nucleotide Phosphodiesterases, Type 4 , Humans , Phosphodiesterase Inhibitors/adverse effects , Phosphodiesterase Inhibitors/blood , Phosphodiesterase Inhibitors/metabolism , Purines/blood , Purines/metabolism , Rolipram/adverse effects , Rolipram/blood , Rolipram/metabolismABSTRACT
The effect of electroacupuncture (EA) on cyclophosphamide-induced emesis in ferrets was studied at acupuncture point Neiguan (P6) with various electrical stimulation parameters (5-100 Hz, 1.5-3 V, 5-20 min, n=6/group). The combination therapy of EA (100 Hz, 1.5 V and 10 min) with the lower doses of ondansetron (0.04 mg/kg), droperidol (0.25 mg/kg) and metoclopramide (2.24 mg/kg) significantly reduced the total number of emetic episodes by 52%, 36% and 73%, respectively, as well as the number of emetic episodes in the first phase as compared to the sham acupuncture control (P<.01). These EA/drug combinations also showed a significant effect in preventing emesis as compared to either EA or drug alone (P<.05). The present study suggests that acupuncture may be useful as an adjunctive therapy in the treatment of chemotherapy-induced emesis.
