Concurrent Administration Of Aspirin Research Articles

2348Novel direct thrombin inhibitor achieves superior antithrombotic effect with lower bleeding risk than heparin or bivalirudin

Abstract Background We have isolated, variegin, a unique direct thrombin inhibitor (DTI) from tropical bont tick Amblyomma variegatum. Variegin inhibits thrombin active site and exosite-1 with an inhibitory constant of 0.3 nM (9-fold better than bivalirudin). It is also >5 orders of magnitude more selective for thrombin than other blood coagulation serine proteases. Variegin has a plasma half-life of 50 minutes (compared with bivalirudin 25 minutes and heparin ∼ hours). Purpose We aimed to develop variegin into a parenteral anticoagulant for percutaneous coronary intervention (PCI) and tested variegin in several pre-clinical models. Methods In rats, variegin was tested for efficacy (anticoagulation intensity) in a FeCl3-induced carotid artery thrombosis model while safety (bleeding risk) was tested in a tail incision model that recapitulated the time-frame of PCI (∼1 hour) in humans (time-response model). In pigs, an extracorporeal circuit with modified Badimon chambers containing coronary stents was used to assess efficacy, while bleeding risk was evaluated through needle-induced injury on a superficial ear vein, with or without concurrent administration of aspirin and ticagrelor (DAPT). Unfractionated heparin (UFH) and bivalirudin at dosages recommended for PCI were used as references. Ex vivo clotting analyses including thrombin generation test, rotational thromboelastometry, activated partial thromboplastin time and clot waveform analysis were performed in human blood spiked with DAPT and the three anticoagulants. Results In the rat time-response model, a single variegin bolus conferred better antithrombotic effect than a continuous infusion of bivalirudin and more rapid recovery of haemostasis than a single bolus of heparin. In the porcine ex vivo model, without DAPT, UFH, bivalirudin and 1 mg/kg variegin reduced stent thrombus by 35% (P<0.001), 60% (P<0.0001), and 80% (P<0.0001), compared with saline, respectively. In the presence of DAPT, UFH, bivalirudin and only 0.1 mg/kg of variegin (10-fold lowered dose) reduced stent thrombus by 65% (P<0.01), 75% (P<0.001), and 87% (P<0.0001), respectively (Fig. 1A). However, in the presence of DAPT, standard-dose UFH and bivalirudin prolonged bleeding times far longer than low-dose variegin (Fig. 1B). In human platelet rich plasma treated with DAPT, UFH showed a much more precipitous decline in thrombin generation potential than variegin (Fig. 1C). Dose response curves for inhibition of thrombin generation are also steeper in UFH and bivalirudin than in variegin, suggesting larger safety dose margin for variegin (Fig. 1D). These observations potentially account for the better preservation of haemostasis with low-dose variegin in combination with DAPT. Figure 1 Conclusion In the presence of aspirin and ticagrelor, a low dose of variegin, a novel direct thrombin inhibitor, achieved superior antithrombotic effect with significantly lower bleeding risk than heparin or bivalirudin in pre-clinical PCI models.

Enhanced Antithrombotic Effect of Warfarin Associated with Low-Dose Alcohol Consumption

A 58-year-old Caucasian man was receiving long-term anticoagulation with warfarin for the prevention of ischemic stroke; his international normalized ratio (INR) had been stable. His INR increased when he began consistent, low-dose beer consumption for its perceived cardiovascular protection. After he stopped drinking the alcohol, his anticoagulation control improved and returned to previous levels. Information on the effects of alcohol, particularly beer, is limited in nonalcoholic patients who receive warfarin therapy. This case reveals a potential for low-dose beer consumption to elevate INR. We propose that the increased antithrombotic effect of warfarin involved protein-binding interactions and decreased warfarin metabolism through the cytochrome P450 (CYP) enzyme system. Concurrent administration of aspirin and other drugs that are metabolized through or are inhibitors of the CYP system may have enhanced the interaction that occurred in this patient. Caution should be used whenever warfarin and alcohol in any amount are taken together, especially in patients receiving many drugs, and close monitoring of the INR is warranted.

Aspirin augments alcohol in restricting brain growth in the neonatal rat

The purpose of this study was to determine whether the microencephaly in rats resulting from early postnatal alcohol exposure is altered by a concurrent administration of aspirin. Neonatal rats were artificially reared from postnatal day 4 to postnatal day 10, a period of the brain growth spurt in the rat that is similar to the third trimester of human brain development. The alcohol-treated groups received 6.6 g/kg/day of ethanol and either 0.0, 12.5, 25.0 or 50.0 mg/kg/day of aspirin in a milk solution. Control groups received either 0.0 (gastrostomy control), 12.5, 25.0 or 50.0 mg/kg/day of aspirin in a milk solution free of alcohol. Brainstem, cerebellum and total brain weights were measured on postnatal day 10. Alcohol alone significantly reduced the mean total brain weight, cerebellum and brainstem weight by 19.8%, 23.1% and 12.2%, respectively, relative to gastrostomy controls. A significant interaction between ethanol and aspirin was observed for total brain weight. The mean total brain weight of the group receiving both alcohol and 50 mg/kg/day aspirin was significantly lower than all other experimental groups and was reduced 29.5%, relative to gastrostomy controls. The highest dose of aspirin alone significantly reduced cerebellar weight, relative to gastrostomy controls but had no effect on brainstem or total brain weight.

The Antigastrolesive Activity of Rioprostil, a 16-Methyl Prostaglandin-E! Analogue in Healthy Volunteers

The antigastrolesive activity of rioprostil, an orally effective synthetic 16-methyl analogue of prostaglandin-E1, with potent antisecretory and antigastrolesive properties in animals, is evaluated in a series of studies involving 166 healthy male volunteers. Three double-blind, randomized, parallel, placebo-controlled studies are conducted independently at three study centres. In two studies the protective effect of rioprostil against endoscopically-demonstrated mucosal changes caused by concurrent administration of aspirin is examined. The third study evaluates the inhibitory effect of rioprostil on faecal blood loss produced by co-administration of aspirin. Oral doses of rioprostil give significant dose-dependent protection against aspirin-induced mucosal changes. The total mucosal scores at day 3 and day 11 are significantly lower in each of the rioprostil + aspirin groups compared with the aspirin treated group. The total mucosal scores generally decrease with increasing rioprostil dose. Daily faecal blood loss is significantly lower in each of the groups of subjects treated with rioprostil + aspirin, compared with those treated with aspirin + placebo. This study shows that rioprostil provides significant protection against mucosal damage caused by high doses of concomitantly administered aspirin.

Effective antiplatelet drug concentrations in experimental arterial thromboembolism

Although drugs that modify platelet function have been widely studied as antithrombotic agents in experimental and clinical studies, there is limited information regarding the relationship between in vivo drug blood concentrations and antithrombotic efficacy. This study compared the pharmaco kinetics of three antiplatelet agents with their antithrombotic effects in an experimental model of arterial thromboembolism in baboons. Thrombus formation was measured as steady-state platelet utilization induced by thrombogenic arteriovenous cannulae. The drugs studied were aspirin, dipyridamole and sulfinpyrazone. Aspirin was administered in daily doses of 20 mg/kg, dipyridamole in daily doses of 2.5 and 10 mg/kg, and sulfinpyrazone in daily doses of 20 and 100 mg/kg; each drug was given in two equal doses per day. Multiple blood samples were collected for drug analysis after steady-state had been reached. The average concentrations of dipyridamole at steady-state were 26 + 15 and 79 ± 69 ng/ml after 2.5 and 10 mg/kg/day. These concentrations were associated with 28 and 87% inhibition of cannula platelet consumption, respectively. The average steady-state concentrations of acetylsalicylic and salicylic acids were 0.67 ± 0.80 and 3.76 ± 2.60 μg/ml, respectively, after 20 mg/kg/day. Aspirin had no effect on platelet consumption. Average concentrations of sulfinpyrazone were 1.05 ± 0.45 and 12.25 ± 5.73 gg/ml after 20 and 100 mg/kg/day, with significant concentrations of the sulfide metabolite. These concentrations were associated with 23 and 85% inhibition of platelet consumption, respectively. No significant pharmacokinetic interactions were observed after concurrent administration of aspirin and dipyridamole or sulfinpyrazone. As the experimental model used involves thrombus formation on an artificial surface, it is likely that these results are most relevant to patients with arterial prosthetic devices.

Interaction of sudoxicam and aspirin in animals and man.

In rats, both the plasma concentrations and the anti-inflammatory activity of sudoxicam are depressed by concurrent administration of aspirin, being similar to that reported for other nonsteroidal agents, whereas, in man and monkey, plasma concentrations of sudoxicam are not affected by concurrent administration of aspirin. In this respect sudoxicam differs from such other nonsteroidal anti-inflammatory agents as indomethacin and naproxen.

Intermittent high dose oral methotrexate therapy in psoriasis.

SUMMARY.— Eighteen patients with intractable or severe psoriasis have been treated for up to 28 months with intermittent large oral doses of methotrexate. The disease was completely controlled in 9 and partially controlled in 5 patients. Severe clinical side-effects were seen in 5 patients, in 4 of whom therapy had to he abandoned. These effects were severe abdominal pain and vomiting in 2; reactivation of colitis, serious ataxia, and epidermal necrolysis in 1 patient each. Concurrent administration of aspirin probably contributed to toxicity by potentiating the action of methotrexate in 2 of these cases. No serious haematological or biochemical abnormalities developed but mild transient leucopenia occurred in 2, thrombocytopenia in 1, and raised serum transaminases in 7.