Inhibition of platelet function with indobufen: Correlation with plasma drug level

Crow, M. J.; Salter, M.C.P.; Donaldson, D.; Rajah, S M

doi:10.1016/0049-3848(85)90159-8

Cited by 17 publications

(8 citation statements)

References 3 publications

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“…21 Whether this applies to clinical conditions characterized by enhanced TXA 2 biosynthesis has not been investigated previously. Our study assessed the dose dependence of the effects of indobufen, a reversible inhibitor of platelet prostaglandin G/H-synthase, 1 on ex vivo and in vivo indexes of TXA 2 biosynthesis and TXA 2 -dependent platelet function. We chose a fourfold range of daily doses (50 to 200 mg BID) to the highest recommended therapeutic dose of the drug.…”

Section: Discussionmentioning

confidence: 99%

“…ndobufen, (±)(1,3-dihydro-l-oxo-2//-isoindol-2-yl)-a-ethylbenzene acetic acid, is a reversible inhibitor of platelet prostaglandin G/H-synthase. 1 The inhibitor effect of the racemic mixture can be largely accounted for by the action of the S-isomer. 2 Indobufen currently is used as an antithrombotic agent at a dosing regimen of 200 mg BID.…”

Section: Inhibition Of Thromboxane Biosynthesis Andmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of thromboxane biosynthesis and platelet function by indobufen in type II diabetes mellitus.

Davı̀

Patrono

Catalano

et al. 1993

Arterioscler Thromb

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Indobufen is a reversible inhibitor of platelet prostaglandin G/H-synthase. To verify the dose dependence of the antiplatelet effect of indobufen on ex vivo and in vivo indexes of thromboxane (TX) biosynthesis and TXAj-dependent platelet function, we studied nine patients with non-insulin-dependent diabetes mellitus (NIDDM). This was a randomized, double-blind, crossover study in which each patient was treated with three different daily regimens (50 rag BID, 100 mg BID, and 200 mg BID) of indobufen for 1 week, with a 7-day washout period between treatments. Urinary 11-dehydro-TXBj excretion averaged 58.2±21.8 ng/h at baseline. TX metabolite excretion was reduced dose dependently by indobufen: by 67% at 50 mg BID, 72% at 100 mg BID, and 81% at 200 mg BID. Platelet cyclooxygenase activity, ATP release, collageninduced platelet aggregation, and bleeding time also were modified dose dependently by indobufen. Biochemical demonstration of suppressed platelet TX A 2 in vivo was accompanied by evidence of inhibited platelet function as assessed ex vivo. Under pathophysiological conditions, such as NIDDM, which are associated with enhanced TX A 2 synthesis, more than 95% suppression of platelet cyclooxygenase activity may be necessary to produce virtually maximal inhibition of platelet TXA 2 biosynthesis in vivo. The inhibitor effect of the racemic mixture can be largely accounted for by the action of the S-isomer. 2Indobufen currently is used as an antithrombotic agent at a dosing regimen of 200 mg BID. At this dose, its antithrombotic effect is comparable to that of aspirin (325 mg TID) plus dipyridamole (75 mg TID) in preventing graft occlusion after coronary artery bypass surgery.3 Dose-ranging studies with indobufen were largely based on capacity-related measurements of platelet function ex vivo. 4 -7 Because the latter do not necessarily reflect the extent of platelet inhibition in vivo, we set out to explore the dose dependence of the antiplatelet effect of indobufen through ex vivo and in vivo measurements of thromboxane (TX) biosynthesis and TX A 2 -dependent platelet function. We performed a double-blind, crossover study in patients with non-insulin-dependent diabetes mellitus (NIDDM) with macrovascular complications because of previous evidence for enhanced TX A 2 biosynthesis in this setting.

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Thromboxane Biosynthesis Andmentioning

confidence: 99%

Inhibition of thromboxane biosynthesis and platelet function by indobufen in type II diabetes mellitus.

Davı̀

Patrono

Catalano

et al. 1993

Arterioscler Thromb

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“…The inhibition of cyclooxygenase is transient and reversible, compared to the irreversible acylation of the enzyme caused by acetylsalicylic acid. [1][2][3][4][5][6] The butyric acid side chain of INDB contains an asymmetric ␣-carbon so that INDB exists as (+)-S-and (−)-R-enantiomers. Although the cyclooxygenase-inhibiting activity resides principally in the (+)-S-enantiomer, [2][3][4] INDB has been used up to now in therapy as the racemate.…”

mentioning

confidence: 99%

Protein binding of indobufen enantiomers: Pharmacokinetics of free fraction—studies after single or multiple doses of rac‐indobufen

Główka

Caldwell

2002

Chirality

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The binding of the enantiomers of indobufen (INDB) to human serum proteins was investigated using the racemic mixture or the pure (+)-S-enantiomer in a concentration range of 2.5-100.0 mg/L. In addition, the pharmacokinetics of free (unbound) and total INDB enantiomers were studied 1) following administration of a single 200 mg rac-INDB tablet to healthy volunteers, and 2) in obliterative atherosclerosis patients at steady state. The free fraction of INDB was obtained by ultrafiltration. Using the racemic mixture, the binding parameters of the two enantiomers were different, showing enantioselectivity in protein binding. The (-)-R-enantiomer was bound more strongly to human serum albumin, with association constant K = 11.95 +/- 0.98 x 10(5) M(-1) and n = 0.72 +/- 0.02 binding sites. The comparable data for the (+)-S-enantiomer were K = 4.65 +/- 0.02 x 10(5) M(-1), n = 0.92 +/- 0.01. When the binding of (+)-S-enantiomer was studied alone, the association constant K (2.10 +/- 0.18 x 10(5) M(-1)) was lower and the number of binding sites was increased, to n = 1.87 +/- 0.17. Competition occurred between the enantiomers, with the (-)-R-enantiomer displacing its antipode. The fraction of both enantiomers bound to serum proteins was 99.0%, which increased with decreasing initial concentration of the enantiomers. In healthy volunteers the (+)-S-enantiomer was eliminated faster than its (-)-R antipode, resulting in a lower AUC for the (+)-S-enantiomer. Significant differences were observed in the total INDB enantiomer concentrations. The mean unbound fraction of (-)-R- and (+)-S-INDB was 0.45% and 0.43%, respectively. Levels of the free (+)-S-enantiomer were higher than its (-)-R-antipode at steady state in patients with obliterative atherosclerosis who also took other drugs. The free enantiomer fraction increased to around 1% upon repeated administration. We conclude that the more rapid elimination of the (+)-S enantiomer is associated with its weaker binding to serum proteins.

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“…1) is an inhibitor of platelet aggregation acting through cyclooxygenase and resulting in the inhibition of thromboxane synthesis. [1][2][3][4][5] The inhibition of cyclooxygenase is transient and reversible compared with the irreversible inhibition caused by acetylsalicylic acid. The butyric acid INDB possesses an asymmetric ␣-carbon and, therefore, occurs as the (+)-S-and (−)-Renantiomers.…”

mentioning

confidence: 99%

Stereoselective pharmacokinetics of indobufen from tablets and intramuscular injections in man

Główka

2000

Chirality

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Inhibition of platelet function with indobufen: Correlation with plasma drug level

Cited by 17 publications

References 3 publications

Inhibition of thromboxane biosynthesis and platelet function by indobufen in type II diabetes mellitus.

Inhibition of thromboxane biosynthesis and platelet function by indobufen in type II diabetes mellitus.

Protein binding of indobufen enantiomers: Pharmacokinetics of free fraction—studies after single or multiple doses of rac‐indobufen

Stereoselective pharmacokinetics of indobufen from tablets and intramuscular injections in man

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