Does daily aspirin diminish severity of first-ever stroke?

BACKGROUND: There are still uncertainties about aspirin efficacy in first-ever ischemic stroke prevention. Also it is unknown whether the severity of first ischemic stroke can be modified by aspirin pretreatment. OBJECTIVE: To analyze a series of patients who had their first ischemic stroke while taking aspirin to evaluate the ability of aspirin prophylaxis to diminish the severity of first-ever ischemic stroke. DESIGN: Case-control study. SETTING: Tertiary medical center to which patients were referred. PATIENTS: All consecutive patients admitted to the Tel Aviv Medical Center, Tel Aviv, Israel, from May 1988 through May 1994 because of first-ever ischemic stroke were divided into 2 groups according to aspirin use before stroke: aspirin-treated and non-aspirin-treated groups. MAIN OUTCOME MEASURES: Stroke severity was defined according to activities of daily living within 24 hours after admission: (1) mild stroke, with independence in activities of daily living; (2) moderate stroke, with partial dependency; and (3) severe stroke, with complete dependency. Using chi 2 test, stroke severity was compared between patients taking aspirin before their stroke and non-aspirin-treated patients. RESULTS: Among 2113 consecutive patients with first-ever ischemic stroke, 125 patients had already been taking 100 to 500 mg of aspirin daily. Aspirin-treated and non-aspirin-treated patients did not differ in stroke severity. Mortality was lower in aspirin-treated patients (7.9%) than in non-aspirin-treated patients (12%), but this difference was not statistically significant (P = 17). CONCLUSIONS: We conclude that aspirin as primary prevention treatment has no significant protective effect on severity of first-ever ischemic stroke. The diminution of mortality after first ischemic stroke in patients who had used aspirin should be investigated further.     

Milnacipran. A review of its use in depression

Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.     

Aspirin in essential thrombocythemia: status quo and quo vadis

Aspirin has a well established role in the prevention of arterial thrombosis. Discussion on the efficacy and safety of aspirin in the treatment and prophylaxis of thrombosis in essential thrombocythemia (ET) has become an important issue. The rationale for its use in ET comes from the observation that arterial thrombosis and platelet-mediated microcirculatory disturbances are the major causes of morbidity and mortality in ET. Experimental data have shown persistently elevated levels of thromboxane A2 (TXA2) in ET patients probably reflecting an enhanced in vivo platelet activation. Increased TXA2 biosynthesis and platelet activation in vivo in ET are selectively suppressed by repeated low doses of aspirin. ET-related symptoms such as erythromelalgia, transient neurologic and ocular disturbances are sensitive to aspirin. However, the benefit of low-dose aspirin is still uncertain in the primary prevention of thrombosis in ET. Furthermore, aspirin may unmask a latent bleeding diathesis frequently present in ET which may result in severe hemorrhagic complications. Thus, aspirin is contraindicated in ET patients with a bleeding history or a very high platelet count (> 1500 x 10(9)/L) leading to the acquisition of von Willebrand factor deficiency. If indicated, aspirin is presently used in the widely accepted low-dose regimen of 100 mg daily. However, an optimal effective dose has not yet been established. To further evaluate the efficacy and safety of aspirin in ET, prospective clinical trials are needed.     

Comparison between metoprolol orally osmotic once daily and metoprolol two or three times daily in suppressing exercise-induced and daily myocardial ischemia

Metoprolol is a widely used anti-ischemic drug with a relatively short half-life. To improve patient' compliance and to provide 24-hour coverage, its once daily ORally OSmotic (OROS) formulation was developed. In this multicenter double-blind study, the anti-ischemic effects of metoprolol OROS given once daily at doses of 190 and 285 mg were compared to the regular metoprolol formulation of 100 mg 2 or 3 times daily. Sixty-five patients with stable coronary artery disease, positive exercise tests, and ischemic episodes during daily activity as recorded by ambulatory electrocardiographic monitoring (AEM) were included. In the OROS group, 23 patients completed all 3 treatment periods. In these patients, the number of myocardial ischemic episodes decreased from 239 on placebo to 128 during the 190 mg/day dose (p < 0.0001) and to 86 during the 285 mg/day treatment period (p < 0.0001). In the metoprolol group, there were 204 episodes at baseline and 142 and 140 during the 100 mg 2 or 3 times daily treatment periods (p < 0.0001 for both). During exercise testing, time to 1-mm ST depression increased significantly in the OROS group from 6.3 minutes at baseline to 7.1 and 9.6 minutes during 190- and 285-mg treatment periods. In the metoprolol group, it increased from 5.8 to 7.2 and 8.2 minutes, respectively. Both formulations of metoprolol were well tolerated. The OROS formulation was highly effective in suppressing daily and exercise-induced ischemia and exerted its effect throughout the 24-hour period.     

Comparative effects of staphylokinase and alteplase in rabbit bleeding time models

BACKGROUND: The pathogenesis of bleeding associated with thrombolytic therapy remains largely unknown, although spontaneous bleeding appears to correlate with bleeding time prolongation. Here, the comparative effects on cuticle bleeding times (CBT) and ear puncture bleeding times (EBT) of recombinant staphylokinase (Sak) and alteplase (recombinant tissue-type plasminogen activator, rt-PA) at equivalent doses, alone and in combination with aspirin and heparin, were studied in rabbits. METHODS AND RESULTS: Groups of 4 to 9 rabbits were allocated to one of the 8 following intravenous infusions: saline; aspirin 15 mg/kg and heparin - 100 IU/kg bolus and 10 IU/kg infusion over one hour; 1.5 mg/kg rt-PA; 1.5 mg/kg rt-PA plus aspirin and heparin; 4.5 mg/kg rt-PA; 0.5 mg/kg Sak; 0.5 mg/kg Sak plus aspirin and heparin and 1.5 mg/kg Sak. Bleeding times were determined 30 and 15 min before and 5, 15, 30 and 60 min after the administration over one min of saline, rt-PA or Sak, by simultaneously severing a nail cuticle (CBT) and by puncturing the ear (EBT). Bleeding times were unaffected by saline and by both doses of Sak in monotherapy. Heparin-aspirin and low dose rt-PA significantly lengthened EBT but not CBT. Both CBT and EBT were significantly prolonged (to a mean of > 4 times pretreatment at 5 min) after high-dose rt-PA and after the combined administration of heparin and aspirin with either Sak or tr-PA. rt-PA provoked significantly longer bleeding than Sak in the CBT (p = 0.001; mean estimated difference = 23 min), but not in the EBT. rt-PA but not Sak degraded plasma fibrinogen dose-dependently. CBT correlated inversely with fibrinogen (r= -0.66, p=0.001) but EBT did not. CONCLUSION: At equivalent doses Sak displays a significantly higher fibrin specificity and prolongs bleeding time less than rt-PA, particularly in the nail cuticle bleeding time model in which larger vessels are injured that require fibrinogen for hemostasis.     

Ameliorative influence of a nootropic drug on motor activity of rats after bilateral carotid artery occlusion

The effects of the peptidergic nootropic drug Cerebrolysin on spatial memory and motor activity were examined in intact and ischemic rats. Ischemic-hypoxic damage was induced by injection of Na-cyanide followed by bilateral occlusion of common carotid arteries. Immediately afterwards Cerebrolysin or saline was administered, either by continuous intraventricular (i.v.) infusion or by daily intraperitoneal (i.p.) injection. Rats were tested for spatial memory and motor activity in the Morris water maze on days 3 and 4 post-surgery. The best dose of the substance for i.p. administration was known from previous studies. Therefore we had to investigate the dose-response-relationship and tolerability of the drug after i.v. administration in intact rats. Infusion (i.v.) of a high dose of Cerebrolysin (0.57 mg/day) decreased motor activity and spatial memory of intact rats (p < 0.01 and p < 0.05, respectively) but low dose of Cerebrolysin was well tolerated in the intact animals. Ischemia led to deterioration of motor activity in control rats (p < 0.01). Cerebrolysin significantly counteracted deleterious motor changes due to ischemia up to the level of intact controls after both i.v. infusion (0.0057 mg/day) and daily i.p. drug administration (100 mg/kg bw and day) indicating an accelerating recovery after ischemia.     

Effects of acipimox on haemorheology and plasma lipoproteins in patients with mixed hyperlipoproteinaemia

Dolasetron mesilate is a selective 5-HT3 receptor antagonist that prevents chemotherapy-induced and postoperative nausea and vomiting. For the majority of patients in intravenous dolasetron trials for chemotherapy-induced nausea and vomiting, dosing has been based on body weight (mg/kg). The approved weight-based dose is 1.8 mg/kg based on results of controlled clinical trials. However, trials of dolasetron evaluating oral doses for prevention of chemotherapy-induced emesis, and intravenous doses for prevention and treatment of postoperative emesis have used a fixed milligram dose. To identify an appropriate intravenous fixed milligram dose for the prevention of chemotherapy-induced nausea and vomiting, this analysis was performed to derive efficacy results for fixed milligram doses from pooled results obtained with dosing based on body weight. Intravenous dolasetron doses for 1,598 patients treated on a mg/kg basis (0.3, 0.6, 1.2, 1.8, 2.4, 3.0 and 5.0 mg/kg) in 14 clinical trials were converted to fixed milligram doses based on weight. Fixed-dose groups were established at doses of 50, 75, 100, 125, 150, and 200 mg. Doses less than or equal to the midpoint between two dose groups were included in the lower dose group. Pooled results showed that the 100 mg intravenous dolasetron dose group (who received actual doses of 88-112 mg) produced the highest rate (53%) of complete response (0 emetic episodes and no rescue medication in the 24-h period following initiation of chemotherapy).     

A case-control study of risk factors of acute cerebrovascular disease

BACKGROUND: Stroke is the cardiovascular disease which causes the greatest number of deaths in Galicia, mortality, particularly in women, being higher than in the rest of Spain. The aim of this study was to investigate the risk factors of stroke and its importance in Galicia. METHODS: A hospitalary study of cases and controls was performed including 76 patients with stroke and 76 controls individually paired for age, sex, population habitat and date of admission with anamnesis, weight, height and blood pressure, analysis and electrocardiogram being carried out in all. RESULTS: An association was found between the disease and family history of stroke (odds ratio = 3.6, confidence interval 95% = 1.2-13.3), personal history of stroke (17.9; 4.0-79.1), personal history of atrial fibrillation (15.0; 3.3-68.3), high blood pressure (4.5; 1.9-11.6) and ingestion of alcohol greater than or equal to 80 g/day in comparison with abstemious patients adjusted for the effect of high blood pressure (2.5; 1.1-5.7). An association was also observed with serum cholesterol levels greater than or equal to 250 mg/dl (6.46 mmol/l) (3.3; 1.2-8.8, in comparison with cholesterol less than 200 mg/dl). No association was found with the cigarette smoking (1.2; 0.7-2.3). CONCLUSIONS: The results observed for high blood pressure and the ingestion of alcohol regardless of the same are of importance in primary prevention due to being modifiable risk factors. The association with family history of stroke and auricular fibrillation reinforce the needs for primary prevention measures in these subpopulations while having had a stroke or a transitory ischemic attack is the characteristic with the most risk reinforcing the need for secondary prevention measures which have found to be effective. The controls presented abnormally low cholesterol levels that do not reflect those of the population from which they originate, thus existing the possibility that the association observed is spurious.     

Experience with once daily dosing of gentamicin: considerations regarding dosing and monitoring

Plasma concentrations of gentamicin following a fixed dose of 240 mg once daily to patients with normal renal function were measured. The purpose was to establish guidelines to achieve a sufficiently high peak concentration with an appropriately low risk of accumulation. In 40 patients, 1-hour concentrations of plasma gentamicin had a median of 9.3 mg/l (range: 4.5-19.0 mg/l) and 9.7 mg/l (range: 3.6-14.6 mg/l) on days 1 and 3 of gentamicin treatment, respectively. Thirty-nine patients had 1-hour concentrations > 5 mg/l. The 1-hour concentrations varied considerably intra- and interindividually but showed a significant inverse correlation with body weight, surface area and the estimated endogenous creatinine clearance. The plasma gentamicin elimination half-life correlated significantly with age and inversely with body weight and creatinine clearance. There was no increase in the mean plasma creatinine from day 0 to day 4. No patients showed signs of nephrotoxicity, although 2 patients, both elderly and with low body weight, showed signs of beginning gentamicin accumulation. In conclusion, gentamicin treatment with the dose of 240 mg once daily in 3 days to adults with normal kidney function generally does not require adjustment or monitoring. However, the dose should be increased in young patients with an excessive body weight, and decreased doses are needed for old and underweight patients. Monitoring of trough plasma gentamicin concentration is not necessary with treatment duration of 3 days or less.     

Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose

BACKGROUND: A variety of studies have supported the finding that regular intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory agents can affect colorectal cancer carcinogenesis. These agents inhibit the synthesis of prostaglandins. High levels of prostaglandins are observed in colon cancer tissues. PURPOSE: Experiments were planned to determine the lowest dose of aspirin that can markedly suppress the levels of mucosal prostaglandins E2 and F(2alpha) in colorectal mucosa and to determine whether a relationship exists between these levels and plasma levels of both acetylsalicylic acid and its metabolite, salicylic acid. METHODS: Healthy men and women aged 18 years or older participated in the study. The participants took a single, daily dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours after the first dose of aspirin, and 24-30 hours and 72-78 hours after the last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E2 and F(2alpha) by use of a competitive enzyme immunoassay. Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography. All P values are two-sided. RESULTS: A total of 65 subjects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162, or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induced toxic effects and did not complete the protocol; other subjects reported acceptable side effects. The lowest dose to significantly suppress colorectal mucosal prostaglandin E2 concentrations from baseline at 24 hours after the first dose (by 22.6%; P = .002) and at 24-30 hours after the last dose (by 14.2%; P = .021) was 162 mg. At 72-78 hours after the last dose, there was significant suppression for subjects receiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F(2alpha) concentrations from baseline at 24 hours after the first dose (by 18.3%; P = .032) was 324 mg. The lowest dose causing a marked reduction in the level of prostaglandin F(2alpha) at 24-30 hours (by 15.1%; P = .003) and 72-78 hours (by 23.0%; P = .0002) after the last dose was 40.5 mg. No detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of the biopsy time points. CONCLUSIONS: The lowest doses of aspirin taken daily for 14 days to significantly suppress concentrations of colorectal mucosal prostaglandins E2 and F(2alpha) were 81 and 40.5 mg, respectively. The suppression occurred without detectable amounts of aspirin or salicylic acid in the plasma at the time points studied. On the basis of these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a chemopreventive agent for colorectal cancer.     

Comparative activity of cefepime, ceftazidime and imipenem in a mouse infection caused by Klebsiella pneumoniae producing a broad spectrum beta-lactamase

Mice experimentally infected with extended-spectrum beta-lactamase-producing Klebsiella pneumoniae strains were injected twice daily for three days with ceftazidime, cefepime, or imipenem (25, 50, or 100 mg/kg/injection). Treatment efficacy was based on five-day survival and on the spleen viable bacteria count 16 hours after the last treatment dose. Under these experimental conditions, ceftazidime showed some activity on strains with low levels of resistance to ceftazidime. Cefepime used in a dose of 50 or 100 mg per injection demonstrated good activity but was slightly less effective than imipenem.     

Genotoxicity of hydrazino-phtalazine antihypertensive drugs assessed by an in vitro micronucleus assay

Oral anticoagulant therapy is effective antithrombotic treatment for several indications. The results of prothrombin time monitoring should be reported as the International Normalized Ratio (INR). An INR of 2 to 3 is the recommended therapeutic range for all indications except for the prevention of systemic embolism in patients with mechanical heart valves and for the long-term treatment of patients with myocardial infarction, for whom an INR range of 2.5 to 3.5 is recommended. Oral anticoagulant therapy with warfarin sodium is the preferred approach for preventing stroke in most patients with atrial fibrillation. The available data suggest that warfarin is more effective than aspirin. Aspirin, 325 mg/d, is indicated for patients in whom warfarin is contraindicated or in patients less than 75 years of age who are at low risk for stroke because risk factors are absent. In patients 75 years of age or more, close monitoring of warfarin treatment is prudent to avoid major bleeding due to poor anticoagulant control. In selected patients, patient-self-monitoring and adjustment of warfarin treatment using a portable prothrombin time monitor may be effective and safe.     

Prevention of post-surgical adhesion formation using aspirin in a rodent model: a preliminary report

Pelvic adhesions are one of the major factors which significantly and adversely affect surgery outcome due to intra- and postoperative morbidity and reduce future female fertility. Using a rodent model, we evaluated the efficacy of aspirin, a non-steroidal anti-inflammatory drug, in the prevention of adhesion formation. A total of 72 female Wistar rats received a standardized primary traumatic lesion to the right uterine horn. They were randomly divided into eight groups: group I (control) had no treatment and group II received a single pre-operative 0.70 mg aspirin. All the succeeding groups (III-VIII) received aspirin in doses of 0.35, 0.70, or 1.40 mg every 6 h for either 48 or 96 h in addition to the pre-operative aspirin (0.70 mg). All animals were killed 4 weeks later and adhesions were assessed using a modified adhesion scoring scale. The lowest adhesion score was found in the group treated with 0.35 mg of aspirin for 96 h, and the highest was found among the groups treated with either 0.70 or 1.40 mg for 48-96 h respectively (P < 0.05). These results are in line with the hypothesis that administration of a low dose of aspirin selectively inhibits the production of thromboxane A2, whereas basal prostacyclin biosynthesis is preserved. This phenomenon might contribute to reducing postoperative adhesion formation in a rat model. Thus, future studies into the prevention of adhesion formation may require the additional use of a non-steroidal anti-inflammatory drug, for which aspirin deserves further attention, before extrapolation into human therapy.     

Impairment of memory following discrete thalamic infarction

Thirteen healthy men (age range 24-59 years) received three single doses (30, 75, and 150 mg/day) of aspirin for seven days, followed by a wash-out period of three weeks, in a randomized order. The arachidonic acid metabolite 12-L-5,8,10-heptadecatrienoic acid (12-HHT) was taken as a measure of platelet cyclooxygenase activity. There was a large inter-individual variation in 12-HHT production prior to and during aspirin treatment. After one week of treatment the mean reduction was 69, 72 and 83% for the doses 30, 75 and 150 mg/day respectively. When the degree of cyclooxygenase inhibition was expressed per microgram aspirin administered per kg bw, a positive correlation was established to the activity before medication. It was found that doses exceeding 1500 micrograms per kg bw is required to achieve a predictable reduction in cyclooxygenase activity. Thus, by determining the pre-treatment cyclooxygenase activity in an individual it should be possible to adjust the enzyme activity to any desired level below 40% of its initial value. 150 mg aspirin/day for one week had a stimulating effect on the platelet basal production of 12-HHT when measured three weeks after the cessation of treatment. This rebound phenomenon was also observed up to six weeks after a single dose of 600 or 1200 mg of aspirin.     

Effects of very low dose and enteric-coated acetylsalicylic acid on prostacyclin and thromboxane formation and on bleeding time in healthy subjects

OBJECTIVE: Low dose acetylsalicylic acid (ASA) is widely used as an anti-aggregatory agent in the primary and secondary prevention of cardiovascular diseases. In an effort to spare prostacyclin formation and to reduce gastrointestinal side-effects, both very low doses and enteric-coated formulations of ASA have been introduced. However, it still remains unclear whether these different formulations and dosages are equally effective with respect to inhibition of platelet aggregation and thromboxane A2 (TXA2) formation. METHODS: In a randomized study, we therefore investigated the effects of 100 mg ASA plain (p), 100 mg ASA enteric-coated (ec) and 40 mg ASA (p) to 36 healthy male subjects given for 7 days on platelet aggregation and endogenous prostanoid formation rates. Platelet aggregation and platelet TXB2 release in platelet rich plasma (PRP) and serum TXB2 and 6-keto-PGF1alpha levels were determined at baseline and after 7 days of each medication. The urinary metabolites of TXA2 (2,3-dinor-TXB2) and prostacyclin (2,3-dinor-6-keto-PGF1alpha) were measured by gas chromatography/tandem mass spectrometry in 24-h-urines at baseline and on day 7 of each medication. RESULTS: Collagen-induced platelet aggregation was 73.1+/-1.6% of maximal aggregation at baseline. It was inhibited by 68.9%, 58.6% and 24.0% by ASA 100 mg plain, 100 mg enteric-coated, and 40 mg plain on day 7, respectively. Platelet TXB2 release was 11592.0+/-367.5 pg x ml(-1) PRP. It was inhibited by 90.1%, 86.5%, and 55.2% by ASA 100 mg plain, 100 mg enteric-coated, and 40 mg plain, respectively. Serum TXB2 was almost completely reduced on day 7 by 100 mg ASA, but not by 40 mg ASA; serum 6-keto-PGF1alpha was slightly, but significantly reduced in all three groups. Urinary 2,3-dinor-TXB, excretion was 196.0+/-41.5 pg x mg(-1) creatinine at baseline. It was reduced by 80.3% and 79.1% by ASA 100 mg plain and enteric-coated, respectively (each P < 0.05 versus baseline), but only by 55.4% by ASA 40 mg plain (P < 0.05 versus both formulations of ASA 100 mg). CONCLUSIONS: Our present data show that the plain and enteric-coated formulations of 100 mg ASA are equally effective in inhibiting platelet aggregation, platelet thromboxane production, and urinary 2,3-dinor-TXB2 excretion rates. In contrast, a very low dose of 40 mg ASA was significantly less effective in inhibiting these indices of platelet activation in healthy human subjects. ASA enteric-coated 100 mg may be a useful alternative to 100 mg ASA (p) in patients with gastrointestinal side-effects, whereas 40 mg ASA (p) may be too low to inhibit sufficiently platelet activity in patients with cardiovascular diseases in whom platelet activity is increased.     

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study

BACKGROUND: Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. METHODS: The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. RESULTS: We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. CONCLUSIONS: Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.     

Lineage commitment of HLA-DR/CD38-defined progenitor cell subpopulations in bone marrow and mobilized peripheral blood assessed by four-color immunofluorescence

ONO-9302 [epristeride; (-)-17beta-(tert-butylcarbamoyl)androsta-3,5-diene-3-carboxy lic acid] is a novel inhibitor of steroid 5alpha-reductase. We studied in vitro and in vivo effects of ONO-9302 on the rat prostatic tissue in comparison with those of the anti-androgen allylestrenol. ONO-9302 inhibited the rat prostatic enzyme with an IC50 value of 11 nM, whereas allylestrenol was about 80,000-fold less potent. The growth of ventral prostate, which was induced by the subcutaneous injection of testosterone propionate in the castrated rats, was significantly reduced by ONO-9302 at oral doses of 1-100 mg/kg/day. Allylestrenol showed a significant effect only at a dose of 100 mg/kg/day. In mature male rats, ONO-9302 significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day and decreased prostatic 5alpha-dihydrotestosterone (DHT) content associated with a rise in testosterone (T) content at doses of 0.1-100 mg/kg/day. Plasma hormone levels (i.e., T, DHT, luteinizing hormone (LH) and follicle stimulating hormone (FSH)) were not altered significantly. Allylestrenol significantly reduced the ventral prostate weight at doses of 10-100 mg/kg/day. However, unlike ONO-9302, allylestrenol reduced both the prostatic DHT and T contents and also lowered plasma T, DHT, LH and FSH levels at a dose of 30 mg/kg/day. These results suggest that ONO-9302 reduces the prostatic growth by inhibiting the conversion of T to DHT in the prostate without lowering blood T level unlike anti-androgen drugs.     

The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines

The English-language literature was systematically reviewed to clarify the role of combination antithrombotic therapy with warfarin and acetylsalicylic acid (ASA) versus monotherapy with either agent, including data from several recently published trials. Sixteen published studies with evaluable efficacy and/or safety data were identified. For patients with prosthetic heart valves at high risk of thromboembolism, combined warfarin and ASA therapy may be beneficial compared with warfarin alone. Combination therapy may also be used for primary prevention in patients at high risk for ischemic heart disease, although the expected benefits are small. Evidence does not support the use of combined antithrombotic therapy in patients with established ischemic heart disease, ischemic stroke, coronary artery bypass grafts or atrial fibrillation. Combination therapy is associated with an increased risk of minor and major bleeding. The highest dose of ASA that can be recommended in combination with warfarin is 100 mg daily.