Increased bodyweight and inadequate response to aspirin in individuals with coronary artery disease.

Recent reports have suggested that aspirin effect might be influenced by bodyweight, with decreased efficacy in heavier individuals. We investigated the influence of bodyweight on aspirin pharmacodynamics in two independent datasets of patients taking non-enteric coated aspirin 100 mg QD for coronary artery disease (CAD). In the first dataset, 368 patients had their platelet aggregation assessed using VerifyNow Aspirin and measured in Aspirin Reaction Units (ARU). In the second dataset, 70 patients had serum thromboxane B2 (TXB2) dosage assessed by an ELISA assay and measured in pg/mL. Platelet aggregation was independently associated with bodyweight, with 8.41 (95% CI 1.86-14.97; adjusted p-value = 0.012) increase in ARU for every 10 kg. Furthermore, the rate of non-response to aspirin (defined as ARU ≥ 550) was significantly associated with increased bodyweight (adjusted p-value = 0.007), with OR = 1.23 (95% CI 1.06-1.42) for every 10 kg. Similar results were found considering body mass index (in kg/m2), with 15.5 (95% CI 5.0 to 25.9; adjusted p-value = 0.004) increase in ARU for every 10 kg and non-response OR = 1.43 (95% CI 1.13 to 1.81, adjusted p-value = 0.003) for every 5 kg/m2. Moreover, serum TXB2 was higher in patients weighting more than 70 kg (222.6 ± 62.9 versus 194.9 ± 61.9 pg/mL; adjusted p-value = 0.018). In two different datasets of patients with CAD on non-enteric coated aspirin 100 mg QD, increased bodyweight was independently associated with impaired response to aspirin.

Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine.

Because of the discrepancy between the capacity of platelets to synthesize thromboxane B2 ex vivo and the actual synthetic rate in vivo, measurement of thromboxane B2 in plasma is highly influenced by sampling-related artifacts. We have developed and validated a radioimmunoassay for a major enzymatic derivative of thromboxane B2 with an extended plasma half-life, i.e., 11-dehydrothromboxane B2. The binding of the tracer is displaced by as low as 1 pg/ml of the homologous ligand, with a high degree of specificity for the open ring structure as well as for the omega side-chain. This method can detect changes in the plasma concentration and urinary excretion of 11-dehydrothromboxane B2 associated with stimulated short-term increases of thromboxane B2 secretion in the human circulation.

Local effect of thromboxane B2 on the contractility of the human non pregnant uterus.

The effect of intra-uterine instillation of 100 micrograms thromboxane B2 [TXB2] on the contractility of the non-pregnant uterus was studied in 30 subjects during the different phases of the menstrual cycle [menstrual, proliferative, periovulatory and secretory]. Twenty control cases received a similar volume of diluted ethanol. The TXB2 proved to be a powerful uterine stimulant at all phases and the response [maximum elevation in tonus and duration] appeared to be most pronounced in the secretory phase. The implication of these findings in the control of uterine activity is discussed.

Urinary excretion of arterial blood prostaglandins and thromboxanes in man.

To determine the fraction of the arterial prostaglandin E2 (PGE2), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) that is excreted unmetabolized into human urine, the 3H-labeled compounds were separately infused into the renal artery or brachial vein of 23 subjects. Urine extracts were subjected to sequential chromatography on thin-layer plates, Sephadex LH-20, and reverse-phase high-pressure liquid chromatography to isolate the unmetabolized fraction. Dual isotope ratio techniques were used to identify peak fractions, to assess purity, and to calculate recovery. Following renal artery infusions, 32.2% of 6-keto-PGF1 alpha, 13.5% of TXB2, and 3.9% of PGE2 were excreted unmetabolized. Calculated fractional excretion of these compounds on a single transit through the kidney are approximately 30, 13, and 3.9%, respectively. Following brachial vein infusion of [3H]prostaglandin I2, 2.7% of the infusate was excreted as 6-keto-PGF1 alpha, suggesting that circulating prostaglandin I2 may contribute to urinary 6-keto-PGF1 alpha. When combined with published measurements of urinary PGE2, 6-keto-PGF1 alpha, and TXB2, these data can be used to calculate the maximum arterial blood concentration of these substances. The results indicate that arterial blood concentration of PGE2, TXB2, and 6-keto-PGF1 alpha in man are only a few picograms per milliliter or less.

Cardiovascular and pulmonary effects of thromboxane B2 in the dog.

The hemodynamic properties of thromboxane B2 (TxB2), a product of prostaglandin endoperoxide metabolism, have not been thoroughly described. TxB2 is a bronchoconstrictor, but its effects on the systemic circulation and circulating platelets are unknown. Its precursor, thromboxane A2(TxA2), is a potent vasoconstrictor as well as a platelet-aggregating agent. Using intact anesthetized dogs, we investigated the effects of TxB2 on pulmonary artery pressure (PAP), airway pressure (AP), systemic arterial pressure (SAP), and myocardial contractility (MC). Vascular responses were evaluated in relation to changes in platelet population and aggregability. Intravenous TxB2 (25 and 50 micrograms/kg) increased AP (mean 62% and 69%) and PAP (50% and 86%), respectively, whereas SAP and MC responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP (36%). Intraventricular administration of TxB2 produced a consistent elevation of SAP (10%) with a concomitant fall in MC (11%). These vascular responses were not consistent with alterations in platelet number or aggregability. A tachyphylactic response to TxB2 developed in AP and PAP at both dose levels and with both routes of administration. Intravenous and intraventricular TxB2 (25 micrograms/kg) produced a parallel decreasing response in PAP, suggesting the possible saturation of TxB2 binding sites or the depletion of a catabolic enzyme in the lung.