Oral Acetylsalicylic Acid Research Articles

Abstract 5299: Release of Sphingosine-1-Phosphate From Platelets Requires Thromboxane Synthesis and Thromboxane Receptor Activation

The sphingosine-derived lipid signaling molecule sphingosine-1-phosphate (S1P) is an important mediator of vascular homeostasis. S1P signaling has recently been shown to be a downstream signaling component of the receptors for thrombin, the protease-activated receptors (PARs). The present study investigates the requirement of thromboxane formation for the release of S1P induced by the prototypic thrombin receptor PAR1 from human platelets and the consequences for human monocyte and endothelial cell migration. S1P was detected by thin layer chromatography in [3H]sphingosine-labeled platelets and by mass spectrometry. Release of S1P was stimulated about 5 fold (0.3±0.1 vs. 1.6±0.5 nmol/1×106 platelets) by the selective PAR1-activating-peptide (PAR1-AP, 100 μ M). Acetylsalicylic acid (ASA) or the reversible cyclooxygenase inhibitors diclofenac and ibuprofen suppressed S1P release. Oral ASA (500 mg single dose) attenuated S1P release from platelets in healthy volunteers ex vivo which was paralleled by inhibition of TX formation. S1P release was increased by the thromboxane receptor (TXR) agonist U46619, and inhibited by the TXR antagonist ramatroban. In platelets from TXR-deficient mice, thrombin-induced release of S1P was attenuated and not affected by ASA. Supernatants from PAR1-AP-stimulated platelets increased human umbilical vein endothelial cell (HUVECs) migration and the chemotactic capacity of human peripheral blood monocytes (2- and 3-fold, respectively). These effects were inhibited when platelets were pretreated with ASA. S1P receptor-specific antagonists revealed that the chemotactic responses in HUVECs were mediated by the S1P receptor-1 (S1P1) and by S1P1 and S1P3 in monocytes. These data suggest that S1P release from platelets after thrombin receptor activation requires TX synthesis and TXR activation. This novel pathway likely contributes to the regulation of vascular homeostasis during platelet activation and inflammatory processes. Inhibition of S1P may be involved in the anti-inflammatory actions of ASA in vivo, for example by affecting recruitment of endothelial cells and monocytes to sites of vascular injury.

Evaluation of the pharmacokinetic interaction between esomeprazole (40 mg) and acetylsalicylic acid (325 mg) in healthy volunteers

To evaluate the effect of esomeprazole on the pharmacokinetics of low-dose acetylsalicylic acid (ASA) during repeated co-administration. This was an open, randomized, 3-way crossover study in 55 healthy volunteers. Treatment periods comprised 5 days' oral esomeprazole (40 mg) or ASA (325 mg) alone, or in combination, separated by washout of >or= 13 days. The primary pharmacokinetic end points were steady-state area under the concentration-time curve (AUCtau) and observed maximum plasma concentration (Cmax) of ASA +/- esomeprazole. The estimates (90% confidence interval) of the geometric mean ratios for AUCtau and Cmax of ASA +/- esomeprazole were 1.04 (1.00 - 1.09) and 1.12 (1.03 - 1.22), respectively. Corresponding results for esomeprazole +/- ASA were 0.93 (0.89 - 0.98) and 0.96 (0.91 - 1.01), respectively. Administration of esomeprazole and ASA in combination was well tolerated. There was no pharmacokinetic interaction between esomeprazole (40 mg) and ASA (325 mg) during repeated co-administration in healthy volunteers.

Acetylsalicylic Acid Reduces Niacin Extended-Release-Induced Flushing in Patients with Dyslipidemia

Niacin extended-release (NER) is safe and effective for treatment of dyslipidemia. However, some patients discontinue NER treatment because of flushing, the most common adverse event associated with niacin therapy. To evaluate the effect of daily oral acetylsalicylic acid (ASA) on NER-induced flushing in patients with dyslipidemia. A randomized, double-blind, placebo-controlled, multicenter, 5-week study was conducted (ClinicalTrials.gov identifier: NCT00626392). Patients (n = 277) were randomly assigned to one of six treatment arms and received a 1-week run-in with ASA 325 mg or placebo followed by 4 weeks of ASA 325 mg or placebo 30 minutes before NER at a starting dose of 500 mg or 1000 mg; all patients were titrated to NER 2000 mg at week 3. The primary endpoint was the maximum severity of flushing events during week 1. In week 1, ASA run-in, ASA pretreatment, and a lower starting dosage of NER (500 mg/day) resulted in reductions in mean maximum severity of flushing; 48% fewer patients who received ASA experienced flushing episodes of moderate or greater intensity relative to placebo (absolute rates 15% vs 29%; p = 0.01). Over 4 weeks, ASA reduced the number of flushing episodes/patient/week by 42% relative to placebo. The discontinuation rate due to flushing was lower in the ASA group compared with placebo (1.8% vs 9.4%; p = 0.007). Overall safety was not different between groups. These data suggest that a clinically meaningful reduction in the severity and incidence of NER-induced flushing may be achieved with ASA use.

Comparison of Oral Aspirin Versus Topical Applied Methyl Salicylate for Platelet Inhibition

Oral acetylsalicylic acid (aspirin) is the primary antiplatelet therapy in the treatment of acute myocardial infarction and acute coronary syndrome. Methyl salicylate (MS; oil of wintergreen) is compounded into many over-the-counter antiinflammatory muscle preparations and has been shown to inhibit platelet aggregation locally and to be absorbed systemically. To assess the ability of topically applied MS to inhibit systemic platelet aggregation for patients who are unable to tolerate oral drug therapy. A randomized, prospective, blinded, crossover study was conducted in 9 healthy men, aged 30-46 years. All subjects ingested 162 mg of aspirin or applied 5 g of 30% MS preparation to their anterior thighs. There was a minimum 2-week washout period between study arms. Blood and urine were collected at baseline and at 6 hours. An aggregometer measured platelet aggregation over time against 5 standard concentrations of epinephrine, and a mean area under the curve (AUC) was calculated. Urinary metabolites of thromboxane B(2) were measured by a standard enzyme immunoassay. Differences in and between groups at baseline and 6 hours were tested by the Wilcoxon signed-rank test. Baseline platelet aggregation did not differ significantly between the 2 arms of the study (median AUC [% aggregation(*)min]; binominal confidence intervals): aspirin 183; 139 to 292 versus MS 197; 118 to 445 (p = 0.51). Both aspirin and MS produced statistically significant platelet inhibition; aspirin decreased the AUC from 183; 139 to 292 to 85; 48 to 128 (p = 0.008) and MS decreased the AUC from 197; 118 to 445 to 112; 88 to 306 (p = 0.011). No significant difference was detected between baseline and 6-hour thromboxane levels for either aspirin (p = 0.779) or MS (p = 0.327). Topical MS and oral aspirin both significantly decrease platelet aggregation in healthy human volunteers.

Acute phase protein response in dogs with experimentally induced gastric mucosal injury

The acute phase response is part of the innate defense system of an animal against trauma, inflammation, and infection. The purpose of this investigation was to evaluate the acute phase response in dogs with acetylsalicylic acid-induced gastric mucosal injuries and to determine its potential diagnostic significance. Ten, healthy, cross-breed dogs (6 females and 4 males) were given oral acetylsalicylic acid in a single oral dose of 200 mg/kg for the experimental model of acute gastric mucosal injury. Heparinized blood samples were collected before (day 0) and on days 1, 4, and 7 after acetylsalicylic acid administration to determine plasma C-reactive protein (CRP), serum amyloid-A (SAA), haptoglobin, fibrinogen, total protein, albumin, and iron concentrations. Total WBC counts were done in whole blood. Endoscopy was done on each of the selected days, and gastric lesions were scored and localized. Hemorrhagic linear erosions were found in all dogs on day 1, concurrent with significant increases in CRP, SAA, haptoglobin, and fibrinogen concentrations, and in WBC counts; however, iron concentration was decreased. Peak haptoglobin and fibrinogen concentrations occurred on day 4, at which time only nonhemorrhagic lesions were observed endoscopically. On day 7, results for all analytes except haptoglobin had returned to baseline levels, along with resolution of most gastric lesions. Results of this study indicate that a rapid acute phase protein response occurs after induced gastric mucosal injury in dogs and may be potentially useful together with gastroscopy in the diagnosis and monitoring of gastric injury.

A comparative study of reactive hyperemia in human forearm skin and muscle

Reactive hyperemia (RH) in forearm muscle or skin microcirculation has been considered as a surrogate endpoint in clinical studies of cardiovascular disease. We evaluated two potential confounders that might limit such use of RH, namely laterality of measurement and intake of non-steroidal anti-inflammatory drugs (NSAIDS). Twenty-three young non-smoking healthy adults were enrolled. In Experiment 1 (n=16), the RH elicited by 3 min of ischemia was recorded in the muscle (strain gauge plethysmography, hand excluded) and skin (laser Doppler imaging) of both forearms. In Experiment 2 (n=7), RH was determined in the dominant forearm only, one hour following oral acetylsalicylic acid (1 g) or placebo. In Experiment 1, peak RH was identical in both forearms, and so were the corresponding durations of responses. RH lasted significantly less in muscle than in skin (p=0.003), a hitherto unrecognized fact. In the skin, acetylsalicylate reduced duration (43 vs. 57.4 s for placebo, p=0.03), without affecting the peak response. In muscle, duration tended to decrease with acetylsalicylate (21.4 vs. 26.0 s with placebo, p=0.06) and the peak increase in blood flow was blunted (27.2 vs. 32.4 ml/min/100 ml tissue with placebo, p=0.003). We conclude that, when using RH as a surrogate endpoint in studies of cardiovascular disease, a confounding by laterality of measurement need not be feared, but NSAIDS may have an influence, although perhaps not on the peak response in the skin.

Safety of Meloxicam in Aspirin-Hypersensitive Patients with Asthma and/or Nasal Polyps

Background: The anti-inflammatory actions of acetylsalicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be due to inhibition of COX-2, whereas the side effects such as gastric damage and aspirin-induced asthma are mediated through inhibition of COX-1. Therefore, a new class of drugs with COX-2 selectivity may be well tolerated by patients with ASA/NSAIDs hypersensitivity. Objective: We investigated whether subjects with asthma and/or nasal polyps (NP) and analgesic intolerance proven by oral ASA provocation test tolerated the selective COX-2 inhibitor, meloxicam. Methods: All subjects were first challenged with ASA using a 2-day, single-blind, placebo-controlled oral provocation test. Thereafter, the subjects showing positive response to ASA provocation underwent a single-blind, placebo-controlled challenge with a cumulative dose of 7.5 mg of meloxicam on 2 separate days. One and three fourths of the divided doses of placebo and the active drug were given at 1-hour intervals. Clinical symptoms, lung function, and blood pressure were monitored during these challenge protocols. Results: Twenty-one patients with asthma and/or NP (10 males and 11 females; mean age: 38.4 ± 2.9 years) who reacted to ASA challenges were enrolled in the study. Response to ASA provocation was rhinitis + bronchospasm in 13, and extrabronchial reactions in 8 (isolated rhinitis in 3) patients. Mean PD₂₀ was 163.4 ± 39.9 mg ASA among patients who reacted with bronchospasm to ASA. Only 1 patient reacted to meloxicam challenge at a cumulative dose of 7.5 mg. Conclusion: This study indicates that 7.5 mg of meloxicam is a safe alternative treatment for ASA-hypersensitive asthma and/or NP patients with proven hypersensitivity via oral ASA challenges.

Iliac Anastomotic Stenting With a Biodegradable Poly-L-Lactide Stent: A Preliminary Study After 1 and 6 Weeks

To assess the technical feasibility, thrombogenicity, and biocompatibility of a new biodegradable poly-L-lactic acid (PLLA) anastomotic stent. A polytetrafluoroethylene bifurcated graft was implanted in 17 pigs through a midline abdominal incision. After transverse graft incision, 17 316L stainless steel stents and 17 PLLA stents were randomly implanted at both iliac anastomotic sites and deployed with a 6-mm balloon under direct vision without angiography. Intended follow-up was 1 week in 6 pigs receiving oral acetylsalicylic acid (ASA) and in 7 pigs receiving ASA/clopidogrel; 4 pigs receiving ASA/clopidogrel were followed for 6 weeks. At the end of the study, the segments containing the stents were surgically explanted and processed for histology to measure the mean luminal diameter, intimal thickness, and the vascular injury and inflammation scores. Initial technical success of stent placement was achieved in all animals without rupture of the suture. Two pigs died (unrelated to the stent) at 3 days after operation (1 in groups A and B). At 1 week, all PLLA stents showed thrombotic occlusion with the use of ASA alone. In contrast, all PLLA stents remained patent with concurrent administration of ASA/clopidogrel. All metal stents were patent regardless of the antiplatelet regimen. The mean luminal diameter of patent PLLA stents (4.13+/-0.17 mm) was comparable to metal stents (4.27+/-0.35 mm, p=0.78) at 1 week, but significantly diminished at 6 weeks (3.21+/-0.44 versus 4.19+/-0.18 mm, p=0.005). Histological analysis showed no signs of excessive recoil. PLLA stents induced a higher inflammation score (1.79+/-0.56) and more intimal hyperplasia (0.34+/-0.11 mm) compared to metal stents [1.27+/-0.44 mm (p<0.001) and 0.18+/-0.04 mm (p=0.006), respectively] at 6 weeks. Vascular injury was comparable between PLLA and metal stents. Biodegradable PLLA stents showed higher thrombogenicity and reduced patency compared to metal stents during early follow-up. Although ASA and clopidogrel prevented thrombotic occlusion, the increased inflammatory response and neointima formation remain major concerns of PLLA stents. A solution to this problem might be the incorporation of anti-inflammatory drugs into the PLLA stent.

Antithrombotic effects of ximelagatran plus acetylsalicylic acid (ASA) and clopidogrel plus ASA in a human ex vivo arterial thrombosis model

It was the objective of this study to compare the antithrombotic effects and bleeding profiles of the oral direct thrombin inhibitor ximelagatran, an anticoagulant, and the antiplatelet agent clopidogrel on top of steady-state acetylsalicylic acid (ASA) in a human arterial thrombosis model. Healthy male volunteers (n=62) received ASA (160 mg once daily), plus either clopidogrel for 6 days (loading dose 300 mg, then 75 mg once daily), or a single dose of ximelagatran (36 or 72 mg) on Day 6. Changes in total thrombus area (TTA) under low shear rate (LSR; 212 s(-1)) and high shear rate (HSR; 1690 s(-1)) conditions were measured, using the ex vivo Badimon perfusion chamber model pre-dose and 2 and 5 hours after dosing on Day 6, and capillary bleeding times (CBT) were determined. Ximelagatran plus ASA significantly reduced TTA under LSR and HSR, compared with ASA alone. Ximelagatran plus ASA reduced TTA more than clopidogrel plus ASA under LSR after 2 hours (36 mg, P=0.0011; 72 mg, P<0.0001) and 5 hours (72 mg, P=0.0057), and under HSR after 2 and 5 hours (72 mg, P<0.05). Compared with ASA alone, CBT was markedly prolonged by clopidogrel plus ASA (ratio 6.4; P<0.0001) but only slightly by ximelagatran plus ASA (72 mg ximelagatran, ratio 1.4; P=0.0010). Both drug combinations were well tolerated. Oral ximelagatran plus ASA has a greater antithrombotic effect in this human ex vivo thrombosis model and a less pronounced prolongation of bleeding time than clopidogrel plus ASA.

Hämostase und Antithrombotika

Considerable progress has been made during the last years with the development of new antiplatelet and antithrombotic agents. The introduction of the ADP-antagonist Clopidogrel some years ago was the first alternative to oral acetylsalicylic acid for long-term treatment. Prasugrel, another ADP-antagonist, is currently in advanced stages of clinical trials. Regarding antithrombotic drugs the interest has been focussed on small molecule direct inhibitors of thrombin and factor Xa. (Xi)Melagatran is one of the recent developments in direct thrombin inhibitors, Dabigatran may follow soon. Several factor Xa inhibitors are currently subject to clinical trials, including Rivaroxaban; others may follow. From a pharmacological point of view these compounds are likely to improve and enlarge the spectrum of available antiplatelet and antithrombotic drugs, respectively.

Ischaemic stroke in progressive systemic sclerosis

Progressive systemic sclerosis (PSS) or scleroderma is a multisystem disease affecting the skin, lungs, myocardium, kidneys and gastrointestinal tract. Primary involvement of cerebral arteries in PSS has been reported but is very rare. A 61-year-old woman suffering from scleroderma for six years was hospitalised for two subsequent episodes of transient acute dysarthria and left hemiparesis. After five hours from the first onset of symptoms, she was submitted to brain magnetic resonance (MR) protocol that showed a right subinsular ischaemic lesion and whole right middle cerebral artery (MCA) territory hypoperfusion. Intracranial and epiaortic MR angiography reported a focal stenosis in the M2 portion of MCA. She was immediately treated with i.v. high dose steroids and oral acetylsalicylic acid. At one-month follow up, MR findings were confirmed. We have documented a cerebral infarct in a PSS patient. In our opinion, the ischaemic stroke was caused by a localised autoimmune angiopathy.

Assessment of a platelet function analyser in horses: Reference range and influence of a platelet aggregation inhibitor

The objective of this study was to assess whether a new human platelet function analyser (the PFA-100) could be used to evaluate platelet function in horses and detect acetylsalicylic acid (ASA)-induced platelet dysfunctions. Citrated blood samples from 40 healthy horses were processed to obtain reference values for closure time (CT) using cartridges with collagen–ADP (CT–ADP) and collagen–epinephrine (CT–EPI) as platelet agonists. In addition, CT–ADP and CT–EPI were also measured before and 24 h after oral ASA administration in another 12 healthy horses. The sensitivity and specificity of the test were also determined. In normal horses, means ± SD value for CT–ADP was 85.1 ± 13.1 s (median, 82 s), and CT–EPI ranged from 158 to >300 s (median 291 s). Calculated reference ranges were 60.5–115.9 s and 158.5–>300 s for CT–ADP and CT–EPI, respectively. Administration of ASA significantly ( P < 0.001) prolonged CT–ADP values from 91.0 ± 13 to 113.5 ± 14.4 s, and CT–EPI values were also significantly ( P < 0.008) prolonged after ASA administration. Sensitivity and specificity results for ADP cartridges showed that a prolonged CT value would be highly suggestive of a platelet aggregation inhibition. In conclusion, ADP cartridges can be used in horses to assess primary haemostasis and may be a valuable test for the detection of platelet aggregation inhibition.

Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats.

Angiotensin II (Ang II)-induced oxidative stress has been suspected to play an important part in the pathogenesis of many cardiovascular diseases. Our previous study demonstrated that acetylsalicylic acid (ASA) possesses potent antioxidative properties. To evaluate the pathogenetic role of oxidative stress in Ang II-induced hypertension and cardiovascular hypertrophy. Chronic infusion of Ang II (200 ng/kg per min for 12 days) increased the aortic and cardiac tissue production of superoxide anion (O2) (lucigenin-enhanced chemiluminescence method) by 77 and 35%, respectively. These effects were associated with progressive increases in systolic blood pressure (from 135 to 194 mmHg) and heart/body weight ratio (from 2.25 to 2.69). Chronic treatment with oral ASA alone (100 mg/kg per day for 12 days) significantly reduced aortic and cardiac production of O2 (by 31 and 33%, respectively), without alteration in blood pressure and heart/body weight ratio in control normotensive animals. However, concurrent treatment with ASA in Ang II-infused rats completely prevented the Ang II-induced production of O2, in addition to hypertension and cardiac hypertrophy. Similar protective effects were observed in cultured aortic smooth muscle cells, in which increases in O2 production and [H]leucine incorporation (221 and 38%, respectively) induced by Ang II (10 mol/l) were totally prevented by concurrent incubation with ASA (10 mol/l). Losartan, but not PD 123319, also blocked the Ang II-induced oxidative and hypertrophic effects in those cells. Other anti-inflammatory drugs, such as salicylic acid, indomethacin and ibuprofen, did not show similar anti-Ang II and antioxidative effects in vivo. Oxidative stress plays a major part in chronic Ang II-induced hypertension and cardiovascular hypertrophy. Chronic concurrent treatment with ASA was found to prevent those Ang II-induced effects on the cardiovascular system, presumably through its antioxidative properties.

Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double‐blind, randomised, three‐attack study.

Eur Neurol. 2002;47(2):88‐98This multicentre, randomised, double‐blind study compared oral zolmitriptan 2.5 mg with a combination of oral acetylsalicylic acid 900 mg and metoclopramide 10 mg as acute anti‐migraine therapy for 3 migraine attacks. In total, 666 patients took at least one dose of study medication (326 took zolmitriptan and 340 took acetylsalicylic acid plus metoclopramide). The percentage of patients with a 2‐hour headache response after the first dose for all 3 attacks (the primary end point) was 33.4% with zolmitriptan and 32.9% with acetylsalicylic acid plus metoclopramide [odds ratio 1.06, 95% confidence interval (CI) 0.77‐1.47; p = 0.7228]. For the majority of secondary end points, the two treatments demonstrated comparable efficacy. However, post hoc analysis showed that significantly more patients receiving zolmitriptan were free of pain 2 h after the first dose in all 3 attacks compared with patients receiving acetylsalicylic acid plus metoclopramide (10.7 vs. 5.3%; odds ratio 2.19, 95% CI 1.23‐4.03; p = 0.0095). In addition, post hoc analysis showed that the overall 2‐hour pain‐free response rate was consistently higher with zolmitriptan (34.6%) than with acetylsalicylic acid plus metoclopramide (27.9%) (odds ratio 1.40, 95% CI 1.09‐1.78; p = 0.007). Both treatments reduced migraine‐associated nausea, vomiting, phonophobia and photophobia. There were no important inter‐group differences with respect to the onset of meaningful migraine relief, the frequency of headache recurrence, the usage or efficacy of a second dose of medication or the use of escape medication. However, at the last attack, the proportion of patients who expressed overall satisfaction with the treatment was significantly higher in the zolmitriptan group, i.e. 83.7%, versus 75.0% with acetylsalicylic acid plus metoclopramide (p = 0.0346). Both agents were well tolerated. Adverse events were reported by 40.8% (133/326) of zolmitriptan‐treated patients and 29.1% (99/340) of those treated with acetylsalicylic acid plus metoclopramide. The incidence of withdrawals due to adverse events was very low with both zolmitriptan (0.9%) and the combination regimen (1.5%); the latter percentage included 1 patient who withdrew from the study due to phlebitis, which was classified as a serious adverse event. This study showed that zolmitriptan is effective and well tolerated for the acute treatment of moderate to severe migraine. Zolmitriptan was at least as effective as acetylsalicylic acid plus metoclopramide in achieving a 2‐hour headache response, but significantly more effective than the combination therapy for other end points, including the 2‐hour pain‐free response. Comment: As the global project physician for zolmitriptan (1976‐1978), I was personally involved in designing this study, which surprisingly did not show greater efficacy for zolmitriptan when compared to high‐dose aspirin‐metoclopramide. However, as pointed out by Stew Tepper above, this pattern has been described with the other triptans and only when compared against pain‐free and sustained pain‐free responses do the triptans deliver the goods. This study also raises symmetry issues in the comparison groups regarding previous baseline treatments. In this study, the majority of patients had previously successfully used the aspirin‐metoclopramide product, whereas triptan users were in the minority, due to the lack of availability of triptans for the treatment of migraine in France at this time. DSM

Zolmitriptan versus a Combination of Acetylsalicylic Acid and Metoclopramide in the Acute Oral Treatment of Migraine: A Double-Blind, Randomised, Three-Attack Study

This multicentre, randomised, double-blind study compared oral zolmitriptan 2.5 mg with a combination of oral acetylsalicylic acid 900 mg and metoclopramide 10 mg as acute anti-migraine therapy for 3 migraine attacks. In total, 666 patients took at least one dose of study medication (326 took zolmitriptan and 340 took acetylsalicylic acid plus metoclopramide). The percentage of patients with a 2-hour headache response after the first dose for all 3 attacks (the primary end point) was 33.4% with zolmitriptan and 32.9% with acetylsalicylic acid plus metoclopramide [odds ratio 1.06, 95% confidence interval (CI) 0.77–1.47; p = 0.7228]. For the majority of secondary end points, the two treatments demonstrated comparable efficacy. However, post hoc analysis showed that significantly more patients receiving zolmitriptan were free of pain 2 h after the first dose in all 3 attacks compared with patients receiving acetylsalicylic acid plus metoclopramide (10.7 vs. 5.3%; odds ratio 2.19, 95% CI 1.23–4.03; p = 0.0095). In addition, post hoc analysis showed that the overall 2-hour pain-free response rate was consistently higher with zolmitriptan (34.6%) than with acetylsalicylic acid plus metoclopramide (27.9%) (odds ratio 1.40, 95% CI 1.09–1.78; p = 0.007). Both treatments reduced migraine-associated nausea, vomiting, phonophobia and photophobia. There were no important inter-group differences with respect to the onset of meaningful migraine relief, the frequency of headache recurrence, the usage or efficacy of a second dose of medication or the use of escape medication. However, at the last attack, the proportion of patients who expressed overall satisfaction with the treatment was significantly higher in the zolmitriptan group, i.e. 83.7%, versus 75.0% with acetylsalicylic acid plus metoclopramide (p = 0.0346). Both agents were well tolerated. Adverse events were reported by 40.8% (133/326) of zolmitriptan-treated patients and 29.1% (99/340) of those treated with acetylsalicylic acid plus metoclopramide. The incidence of withdrawals due to adverse events was very low with both zolmitriptan (0.9%) and the combination regimen (1.5%); the latter percentage included 1 patient who withdrew from the study due to phlebitis, which was classified as a serious adverse event. This study showed that zolmitriptan is effective and well tolerated for the acute treatment of moderate to severe migraine. Zolmitriptan was at least as effective as acetylsalicylic acid plus metoclopramide in achieving a 2-hour headache response, but significantly more effective than the combination therapy for other end points, including the 2-hour pain-free response.

Incomplete Thromboxane Inhibition with 100 mg of Intravenous Acetylsalicylic Acid in Patients with Acute ST Elevation Myocardial Infarction: A Placebo-Controlled Pilot Trial

Background: Acetylsalicylic acid (ASA) is now a standard treatment of acute myocardial infarction (AMI). ASA inhibits thromboxane A 2 (TXA 2) production by blocking the constitutive cyclooxygenase (COX)-1 enzyme, but only to a small degree the inducible COX-2. COX-2 is induced by increased concentrations of cytokines, which is related to an enhanced inflammatory response. Previously, we have found a complete inhibition of TXA 2 synthesis in healthy volunteers after intravenous administration of 50 mg of ASA. We measured in a randomized, placebo-controlled pilot trial the effect of 100 mg of ASA injected intravenously on TXA 2 synthesis in AMI patients treated with streptokinase. Methods and results: Nineteen patients with AMI treated with streptokinase were randomized to 100 mg of ASA or placebo injected intravenously. Se-TXB 2 and bleeding time were measured before and after drug administration. One hundred and eighty minutes after intravenous ASA administration, treatment with oral ASA was initiated. We found a significant decrease in serum concentrations of TXB 2 after 30, 60 and 180 min following ASA injection compared to placebo, but in none of the patients was complete inhibition of TXA 2 production achieved. No significant change in bleeding time could be demonstrated. Conclusion: Intravenous ASA in a dosage of 100 mg did not completely prevent TXA 2 production in AMI patients treated with streptokinase. This may be due to synthesis of TXA 2 by the inducible COX-2 enzyme and/or to a transcellular metabolism in platelets of prostanoids generated by endothelial cells.

Gastro-intestinal permeability is increased in patients with limited systemic sclerosis

Objective: to evaluate gastro-intestinal (GI) permeability in patients with limited systemic sclerosis (LSS) at baseline and after oral acetylsalicylic acid (ASA). Methods: 13 patients with LSS and 10 controls were studied. Baseline GI permeability was assessed with orally administered sucrose, mannitol, and lactulose. Gastric lesions and Helicobacter status were investigated by endoscopy. In 5 patients and 6 controls (with normal baseline permeability) the GI permeability response was assessed after oral ASA. Results: compared with controls, gastric (p<0.05) and intestinal (p<0.02) permeability was higher in LSS patients, at baseline. After oral ASA gastric permeability (sucrose) increased in both groups (controls: 186%, LSS: 265%), whereas the lactulose/mannitol ratio raised significantly only in LSS (+ 31% and + 148%; p<0.05 vs controls). Conclusions: baseline permeability is altered in LSS; the exaggerated response of the small intestine to ASA may represent a genetically determined or a disease-related dysfunction of the mucosal barrier.

Some Effects of Prophylactic Aspirins and Heparins on Concurrent Arterial and Venous Thrombosis in the Same Animal

The antithrombotic effect of unfractionated heparin (UFH), a low-molecular weight heparin (LMWH), oral acetylsalicylic acid (ASA), intravenous lysine-aspirin (L-ASA) and oral soluble aspirin (S-ASA) was measured on platinum wire simultaneously in artery and vein, in groups of 12–20 rats with concurrent untreated controls. Subcutaneous LMWH and intravenous lysine-aspirin reduced mean thrombus weight by 33% and 19%, respectively, in the artery only. Venous thrombosis was reduced 56% by oral ASA and 26% by oral soluble aspirin. Other reductions did not reach statistical significance. While thrombus deposition was induced by both 2 cm (upper site) and 1cm (lower site) wires, the results obtained on the 2 cm wires in the upper vein and artery were more reliable.

Percutaneous Absorption of Salicylic Acid after Repeated (14-day) In Vivo Administration to Normal, Acnegenic or Aged Human Skin

The objective of the present work was to determine the relative bioavailability of salicylic acid (SA) after repeated (14-day) topical application to subjects who presented normal, acnegenic, or photodamaged facial skin. To emulate exposure characteristics likely to be encountered by subjects in these two subpopulations, individuals presenting facial acne were treated with 2% SA in a hydroalcoholic vehicle, and volunteers with aged or photodamaged skin received a comparable topical dose of SA in a cream (moisturizer-like) vehicle. Plasma concentration-time profiles and cumulative urinary excretion of SA were measured after the last dose in subjects who had received 15 consecutive daily topical applications of 27mg of SA or oral doses of 81mg of acetylsalicylic acid (ASA). The rate and extent of percutaneous absorption of SA were not affected by facial skin condition. Faster rates of absorption (Cmax) were obtained with a hydroalcoholic compared with a cream vehicle. Systemic SA exposures were at least five-fold higher with oral ASA than topical SA. Based on systemic salicylate concentrations resulting from ingestion of 81mg of ASA, these results support that patients without gross skin disorders are at minimal risk of adverse systemic effects from routine use of topical products containing 2% SA.

Oral acetylsalicylic acid induces biliary cholesterol secretion in the rat.

Several agents can alter biliary cholesterol secretion, critical for cholesterol excretion and gallstone formation. Although salicylate effects on bile formation and gallstones have been studied, biliary lipid secretion has not been measured during oral aspirin treatment. We examined whether oral acetylsalicylic acid affects bile lipid secretion. Three groups of young rats were fed chow for 3 wk. Two of the groups then received aspirin at either 1.67 or 3.33 g/kg diet for 4 d. Serum, hepatic, and bile lipids were measured, as were enzymes of cholesterol synthesis and esterification. With oral aspirin, bile cholesterol secretion increased by 42% and hepatic cholesteryl ester content decreased by 40%. Serum cholesterol and hepatic free cholesterol did not change. To evaluate mechanisms of the cholesterol hypersecretion, hypothyroid animals fed low-fat or fish oil diets and repleted with triiodothyronine were also studied. Aspirin stimulated cholesterol secretion to a degree similar to triiodothyronine. An additive response was seen in fish oil-fed rats. Aspirin did not appear to have a primary action on 3-hydroxy-3-methylglutaryl-CoA reductase or acyl CoA:cholesterol acyltransferase activities, and had no direct effect on esterification of cholesterol by isolated hepatocytes. Aspirin may directly increase cholesterol transport into bile or have cell membrane effects which alter cholesterol transport. It remains to be determined whether the observed alterations in bile cholesterol secretion are specific to the rat or also apply to humans.