Indobufen activity on intraplatelet arachidonic acid metabolism

144

THROMBOSIS RESEARCH

1986

Suppl. VI,

285 INCKXWEN ACTIVITYON INTRAPLATELET ARACHICDJIC ACIDMETAEUI9l AbbateR.,FavillaS., PanettaA., Pinto S., GensiniG.F. and Neri SerneriG.G. ClinicaMica

I, Universityof Florence,Florence,Italy.

The effects of 8 concentrations (fron5 ng/ml to 20 ug/ml) of indcbufen on intraplatelet arachidonic acid (AA)metabolismwere investigated in vitro.The experimentswere carriedout on washed platelets, fran 9 healthyyoung subjects.The platelet llets~t-e incubatedwith indobufenor dilutionfluid for 5 min. at 37" C, labeledwith 1-l$ C AA (1~4) and stinulated with thrarbin(5 NIH U/ml). The AA metaboliteswere separatedand identifiedby HPLC. Five ng/ml concentration induceda 7.5t3.2%inhibitionof TxE$ production, the I.C.50 was 0.250 pg/ml and an inhibitoryeffectof-k% was found alreadyat 2.5yg/ml. The ccnpleteinhibition of cyclooxygenase(CO) was obtained at 10 bg /ml concentrationof indcbufen. The relationshipbe-n TxB2 inhibitionand log drug concentrationwas linear (r-=0.97,pc 0.001). The metabolizaticn of AA throughlipoxygenase (LO1 increased after incubationwith indcbufen, with an increaseof 50 % at 250 pg/ml and of 83 % at 2@g/ml concentration. The % of the increasewas linearlyrelatedwith the log drug concentration(r= 0.56, p C 0.01). These findingsshm that even at very 1~ concentrations indcbufeninducesa decreaseof COP activity with a parallelincreaseof LOP. At drug concentrations of the same order of magnitudeof those reportedafterdrug acininistration in vivo, a ccnpleteinhibitionof TxA2 prod&ion occurred.

286 PCR

4099.

A

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days

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1985, 1000

900,

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inhibition

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at 15

ascending biological

Haemostas.

all

observed

prolonged over

at

0.70,

is

mg

35

of

hours

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not 300

with to

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activity

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days

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TOLERANCE

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doses

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rising

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pharmacological

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