Determination of picotamide in human plasma and urine by high-performance liquid chromatography

Fossati, Tiziano; Parisi, Simona; Abbiati, G.; Castiglioni, Carlo Andrea

doi:10.1016/0378-4347(92)80264-q

Cited by 6 publications

(2 citation statements)

References 3 publications

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“…Our data indicate that picotamide is more potent in inhibiting vascular contractions induced by 5-HT than those induced by U46619 or phenylephrine. Although picotamide inhibits vascular conffactions induced by the latter agonists at relatively high doses, the concentrations of the drug necessary to inhibit 5-HTinduced contractions are similar to those reached in vivo (36). After oral administration to human volunteers, plasma levels of picotamide are approximately 1Q-0-2 x 10-s M, similar to the order of magnitude of the pA, against 5-HT found in our experiments.…”

Section: Discussionsupporting

confidence: 84%

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

et al. 1997

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SummaryPicotamide is a dual thromboxane (Tx) A2 receptor antagonist/Tx synthase inhibitor although some observations suggest an anti-vasoconstrictor effect independent of TxA2 inhibition/antagonism. The aim of our study was to assess whether picotamide antagonises vascular contractions induced by different vasoactive substances in vitro. Picotamide inhibited competitively the contraction of rabbit aortic rings induced by the TxA2 mimetic U46619 (pA2 = 3.59) but also the contractions induced by phenylephrine (pA2 = 3.93) and serotonin (5-HT) (pA2 = 5.81) although in a not competitive way. Picotamide did not inhibit potassium-induced contractions, thus excluding aspecific effects on vascular smooth muscle. Picotamide inhibited 5-HT-induced platelet aggregation in vitro with an IC50 (212 μM) similar to that found when other aggregating stimuli are used, but it did not affect shape change (IC50> 1 mM) suggesting that the effects of picotamide can not be ascribed to 5-HT2-receptor antagonism; in the same experimental conditions neither a Tx-receptor antagonist (BM13.177) nor a dual Tx-receptor antagonist/synthase inhibitor (ridogrel) affected 5-HT-induced platelet responses.Our studies demonstrate that picotamide exerts antivasoconstrictor and platelet inhibitory effects unrelated to TxA2 antagonism. This activity may contribute to the anti-thrombotic/anti-ischaemic effects of the drug in vivo.

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Section: Discussionsupporting

confidence: 84%

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

et al. 1997

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“…Both 2NTX-99 and 2NTX-101 appeared to be pure, and only trace amounts of 2NTX-101 were present in 2NTX-99. Extraction from rat plasma was carried out after alkalinization on C18 Bond Elut cartridges, followed by elution with ethyl acetate, evaporation, and reconstitution in 300 l of 0.6 M HCl and 600 l of ethyl acetate (Fossati et al, 1992). The lower acidic aqueous phase was taken to dryness and redissolved in 40 l of solvent A before injection into the HPLC system.…”

Section: Thromboxane Receptor Studiesmentioning

confidence: 99%

Pharmacological Characterization of 2NTX-99 [4-Methoxy-N¹-(4-trans-nitrooxycyclohexyl)-N³-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations

Buccellati¹,

Sala²,

Rossoni³

et al. 2006

J Pharmacol Exp Ther

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Thromboxane (TX) A 2 , prostacyclin (PGI 2 ), and nitric oxide (NO) regulate platelet function and interaction with the vessel wall. Inhibition of TXA 2 , implemented synthesis of PGI 2 , and supply of exogenous NO may afford therapeutic benefit. 2NTX-99 [4-methoxy-N 1 -(4-trans-nitrooxycyclohexyl)-N 3 -(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a new chemical entity related to picotamide, showed antithromboxane activity and NO donor properties. 2NTX-99 relaxed rabbit aortic rings precontracted with norepinephrine or U46619 (9,11-dideoxy-9␣,11␣-methanoepoxy-prosta-5Z,13E-dien-1-oic acid; EC 50 , 7.9 and 17.1 M, respectively), an effect abolished by 10 M 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). 2NTX-99 inhibited arachidonic acid (AA)-induced washed platelet aggregation (EC 50 , 9.8 M) and TXB 2 formation (Ϫ71% at 10 M), and its potency increased in the presence of aortic rings (EC 50 , 1.4 M). In whole rabbit aorta incubated with homologous platelets, AA caused contraction and TXA 2 formation, reduced by 2NTX-99 (10 -40 M): contraction, Ϫ28 and Ϫ47%, TXA 2 formation, Ϫ37 and Ϫ75.4%, respectively, with concomitant increase in PGI 2 . 2NTX-99 (20 -40 M) inhibited U46619-induced aggregation in rabbit platelet-rich plasma (PRP) (Ϫ74 Ϯ 6.7 and Ϫ96 Ϯ 2.4%, respectively) and inhibited collagen-induced aggregation in human PRP (Ϫ48.2 Ϯ 10 and Ϫ79.2 Ϯ 6%), whereas ozagrel was ineffective. In human embryonic kidney 293 cells transfected with the TXA 2 receptor isophorm ␣ receptor, 2NTX-99 did not compete with the ligand,,1]-hept-2-yl]-5-heptanoic acid), or prevent inositol phosphate accumulation. After oral administration (50 -250 mg/kg), 2NTX-99 inhibited TXA 2 production in rat clotting blood (Ϫ71 and Ϫ91%); at 250 mg/kg, an area under the curve, 0 to 16 h, of 149.5 h/g/ml and a t 1/2 of 6 h were calculated, with a C max value of 31.8 Ϯ 8.2 g/ml. An excellent correlation between plasma concentrations and TXA 2 inhibition occurs. 2NTX-99 controls platelet function and vessel wall interaction by multifactorial mechanisms and possesses therapeutic potential.

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P

Bruchhausen

Ebel

Hackenthal³

et al. 1999

Hagers Handbuch Der Pharmazeutischen Praxis

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Determination of picotamide in human plasma and urine by high-performance liquid chromatography

Cited by 6 publications

References 3 publications

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Pharmacological Characterization of 2NTX-99 [4-Methoxy-N¹-(4-trans-nitrooxycyclohexyl)-N³-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations

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Determination of picotamide in human plasma and urine by high-performance liquid chromatography

Cited by 6 publications

References 3 publications

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Antivasoconstrictor and Antiaggregatory Activities of Picotamide Unrelated to Thromboxane A2 Antagonism

Pharmacological Characterization of 2NTX-99 [4-Methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations

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Pharmacological Characterization of 2NTX-99 [4-Methoxy-N¹-(4-trans-nitrooxycyclohexyl)-N³-(3-pyridinylmethyl)-1,3-benzenedicarboxamide], a Potential Antiatherothrombotic Agent with Antithromboxane and Nitric Oxide Donor Activity in Platelet and Vascular Preparations