Methylphenidate-risperidone combination in child psychiatry: A retrospective analysis of 44 cases.

INTRODUCTION: Psychotimulant-antipyschotic combinations are frequently used in child psychiatry, but have been rarely described in the literature. METHOD AND PATIENTS: We propose here a retrospective study of 44 children who received the combination methylphenidate (MPH)-risperidone (RIS). The sample is composed of children who received either MPH (n=28) or RIS (n=16) as primary treatment. A vast majority of the children had a comorbid attention deficit hyperactivity disorder (ADHD) diagnosis. RESULTS: For over 60% of patients, regardless of their initial monotherapy, bitherapy decreased the symptoms of ADHD and conduct disorder, sleep disorders and anxiety. Concerning the safety of the bitherapy, a compensation effect on weight gain and appetite was respectively observed in 70% and 50% of patients. Even though iatrogenic tachycardia can be encountered with both drugs, it has never been reported when they are associated and we have reported a total of 3 cases in our study. We have also observed a case of dyskinesia resolved with the discontinuation of the treatment. DISCUSSION/CONCLUSION: MPH-RIS bitherapy appears to be particularly effective in ADHD with conduct disorder symptoms. Although tolerance may limit its use, the benefit/risk ratio seems favourable for a number of children.

Spectroscopic noninvasive measurement of hemoglobin compared with capillary and venous values in neonates.

BACKGROUND: Venepuncture-related blood loss is a common cause of neonatal anemia. Currently, this is the only way to obtain hemoglobin levels. This causes distress for the infant but can also lead to the need for blood transfusions. Recently, a new technique for measuring hemoglobin levels non-invasively has been developed to reduce iatrogenic blood loss and pain. OBJECTIVE: To compare hemoglobin levels obtained using a transcutaneous spectroscopic device (Mediscan 2000, MBR Optical Systems, Wuppertal, Germany) with venous or capillary blood samples in neonates. METHODS: Single-center prospective cohort study of term and preterm infants. The white light spectroscopic device was placed on the forearm for 60 s to measure hemoglobin content within 4 h of venous or capillary blood sampling. Pain reactions of the infants were assessed by using a neonatal pain assessment tool. Results were analyzed by Bland-Altman comparison and Wilcoxon signed-rank test. RESULTS: 80 infants (mean gestational age 29.8 +/- 3.8 weeks, mean birth weight 1,300 +/- 690 g) were enrolled into the study. A total of 313 spectroscopic recordings within 2 h of a clinically indicated blood sample (181 capillary, 142 venous) were taken. The correlation coefficient R(2) was 0.96 for capillary/spectroscopic and 0.99 for venous/spectroscopic pairs. Pain scores were significantly less for the spectroscopic measurements (p < 0.01). CONCLUSION: The results show good correlation between the hemoglobin blood levels and spectroscopic measurements. The slightly lower correlation coefficient for the capillary samples demonstrates a naturally higher variance in these values due to the laboratory method.

Single-dose aprepitant vs ondansetron for the prevention of postoperative nausea and vomiting: a randomized, double-blind phase III trial in patients undergoing open abdominal surgery.

BACKGROUND: The neurokinin(1) antagonist aprepitant is effective for prevention of chemotherapy-induced nausea and vomiting. We compared aprepitant with ondansetron for prevention of postoperative nausea and vomiting. METHODS: Nine hundred and twenty-two patients receiving general anaesthesia for major abdominal surgery were assigned to receive a single preoperative dose of oral aprepitant 40 mg, oral aprepitant 125 mg, or i.v. ondansetron 4 mg in a randomized, double-blind trial. Vomiting episodes, use of rescue therapy, and nausea severity (verbal rating scale) were documented for 48 h after surgery. Primary efficacy endpoints were complete response (no vomiting and no use of rescue therapy) 0-24 h after surgery and no vomiting 0-24 h after surgery. The secondary endpoint was no vomiting 0-48 h after surgery. RESULTS: Aprepitant at both doses was non-inferior to ondansetron for complete response 0-24 h after surgery (64% for aprepitant 40 mg, 63% for aprepitant 125 mg, and 55% for ondansetron, lower bound of 1-sided 95% CI > 0.65), superior to ondansetron for no vomiting 0-24 h after surgery (84% for aprepitant 40 mg, 86% for aprepitant 125 mg, and 71% for ondansetron; P < 0.001), and superior for no vomiting 0-48 h after surgery (82% for aprepitant, 40 mg, 85% for aprepitant, 125 mg, and 66% for ondansetron; P < 0.001). The distribution of peak nausea scores was lower in both aprepitant groups vs ondansetron (P < 0.05). CONCLUSIONS: Aprepitant was non-inferior to ondansetron in achieving complete response for 24 h after surgery. Aprepitant was significantly more effective than ondansetron for preventing vomiting at 24 and 48 h after surgery, and in reducing nausea severity in the first 48 h after surgery. Aprepitant was generally well tolerated.

Cyclooxygenase inhibitors and the antiplatelet effects of aspirin.

BACKGROUND: Patients with arthritis and vascular disease may receive both low-dose aspirin and other nonsteroidal antiinflammatory drugs. We therefore investigated potential interactions between aspirin and commonly prescribed arthritis therapies METHODS: We administered the following combinations of drugs for six days: aspirin (81 mg every morning) two hours before ibuprofen (400 mg every morning) and the same medications in the reverse order; aspirin two hours before acetaminophen (1000 mg every morning) and the same medications in the reverse order; aspirin two hours before the cyclooxygenase-2 inhibitor rofecoxib (25 mg every morning) and the same medications in the reverse order; enteric-coated aspirin two hours before ibuprofen (400 mg three times a day); and enteric-coated aspirin two hours before delayed-release diclofenac (75 mg twice daily) RESULTS: Serum thromboxane B(2) levels (an index of cyclooxygenase-1 activity in platelets) and platelet aggregation were maximally inhibited 24 hours after the administration of aspirin on day 6 in the subjects who took aspirin before a single daily dose of any other drug, as well as in those who took rofecoxib or acetaminophen before taking aspirin. In contrast, inhibition of serum thromboxane B(2) formation and platelet aggregation by aspirin was blocked when a single daily dose of ibuprofen was given before aspirin, as well as when multiple daily doses of ibuprofen were given. The concomitant administration of rofecoxib, acetaminophen, or diclofenac did not affect the pharmacodynamics of aspirin CONCLUSIONS: The concomitant administration of ibuprofen but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin. Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin.

Randomised trials of secondary prevention programmes in coronary heart disease: systematic review.

OBJECTIVE: To determine whether multidisciplinary disease management programmes for patients with coronary heart disease improve processes of care and reduce morbidity and mortality. DATA SOURCES: Randomised clinical trials of disease management programmes in patients with coronary heart disease were identified by searching Medline 1966-2000, Embase 1980-99, CINAHL 1982-99, SIGLE 1980-99, the Cochrane controlled trial register, the Cochrane effective practice and organisation of care study register, and bibliographies of published studies. DATA EXTRACTION: Studies were selected and data were extracted independently by two investigators, and summary risk ratios were calculated by using both the random effects model and the fixed effects model. DATA SYNTHESIS: A total of 12 trials (9803 patients with coronary heart disease) were identified. Disease management programmes had positive impacts on processes of care. Patients randomised to these programmes were more likely to be prescribed efficacious drugs (risk ratio 2.14 (95% confidence interval 1.92 to 2.38) for lipid lowering drugs, 1.19 (1.07 to 1.32) for beta blockers, and 1.07 (1.03 to 1.11) for antiplatelet agents). Five out of seven trials evaluating risk factor profiles showed significantly greater improvements with these programmes in comparison with usual care (with effect sizes in the moderate range). Summary risk ratios were 0.91 (0.79 to 1.04) for all cause mortality, 0.94 (0.80 to 1.10) for recurrent myocardial infarction, and 0.84 (0.76 to 0.94) for admission to hospital. Five of the eight trials evaluating quality of life or functional status reported better outcomes in the intervention arms. Only three of these trials reported the costs of the intervention-the interventions were cost saving in two cases. CONCLUSIONS: Disease management programmes improve processes of care, reduce admissions to hospital, and enhance quality of life or functional status in patients with coronary heart disease. The programmes' impact on survival and recurrent infarctions, their cost effectiveness, and the optimal mix of components remain uncertain.

Vascular biology of thrombosis: platelet-vessel wall interactions and aspirin effects.

The antithrombotic effect of aspirin has long been recognized, and administration of low doses (80-160 mg/day) for the prevention of ischemic events in patients with coronary artery disease (CAD) is now generally considered to be routine practice. The action of aspirin derives mostly from the selective inhibition of cyclo-oxygenases (Cox). These enzymes (Cox-1 and Cox-2) catalyze the synthesis of eicosanoids, which play an important part in platelet-vessel wall interactions. Cox-1 catalyzes the synthesis of thromboxane A2 (Tx-A2), which causes platelet activation, vasoconstriction, and smooth muscle proliferation. Tx-A2 levels are elevated in conditions associated with platelet activation, including unstable angina and cerebral ischemia. Conversely, Cox-2 controls the synthesis of prostacyclin (PGI2), a local platelet regulator with an effect opposite to that of Tx-A2. PGI2 is produced as a compensatory response to increases in Tx-A2 during ischemic events. Aspirin is a more potent inhibitor of Cox-1 than of Cox-2, unlike other non-steroidal anti-inflammatory drugs (NSAIDs), which have limited selectivity. Aspirin at low doses selectively inhibits the formation of Tx-A2 without inhibiting the basal biosynthesis of cardioprotective PGI2. Furthermore, aspirin causes complete enzyme inhibition, without the recovery of enzyme activity at trough drug levels associated with conventional NSAIDs. The effect of aspirin in the prevention of ischemic events has been well documented in many recent clinical trials involving more than 50,000 patients with CAD. It is clear from these studies that aspirin, alone or in combination with other antithrombotics, significantly reduces the incidence of cardiovascular death, stroke, and myocardial infarction.

Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease.

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies. The first study examined the dose-related effects on indexes of platelet and vascular function induced by the oral inhibitor RPR 109891, when given alone and in combination with aspirin, in patients (n = 100) with stable CAD. The second study (the Antagonism of the FIbrinogen Receptor after Myocardial Events trial) assessed the pharmacodynamics and safety of derived regimens in patients (n = 320) with unstable coronary syndromes. In patients with stable CAD, platelet aggregation was dose dependently inhibited by RPR 109891, and the dose-response relation was shifted to the right by the concomitant administration of aspirin (p = 0.0001). The degree of platelet inhibition induced by 3 doses of RPR 109891 (plus aspirin) was lower in patients with unstable than stable CAD. No drug-related major bleeding occurred in either study. RPR 109891 treatment was associated with acute and delayed thrombocytopenia. In conclusion, chronic treatment with an oral glycoprotein IIb/IIIa antagonist (1) induces antiplatelet effects that are potentiated by concomitant administration of aspirin, (2) may require dose adjustment in syndromes of platelet activation, (3) is associated with a low rate of clinically significant bleeding when doses inducing incomplete inhibition of platelet aggregation are used, and (4) requires frequent monitoring of platelet count unless reliable predictors of delayed thrombocytopenia become available.

Effect of the Pl(A2) alloantigen on the function of beta(3)-integrins in platelets.

The polymorphism responsible for the Pl(A2) alloantigen on the beta(3)-component of beta(3)-containing integrins is reported to be a risk factor for coronary thrombosis. This study examined the effect of Pl(A2) on the function of beta(3)-integrins using platelets from subjects homozygous and heterozygous for Pl(A1) and Pl(A2). There was overlap in the distribution of the dissociation constant (K(d)) and maximum fibrinogen binding (B(max)) values for fibrinogen binding to alpha(IIb)beta(3) on platelets from Pl(A1) and Pl(A2) homozygotes and Pl(A1)/Pl(A2) heterozygotes. However, whereas there was no statistical difference in these values for the Pl(A1) homozygotes and Pl(A2) heterozygotes, the K(d) for the Pl(A2) homozygotes was significantly lower than that for the Pl(A1)/Pl(A2) heterozygotes, but was not statistically different from that for the Pl(A1) homozygotes. No differences were detected in ADP sensitivity between platelets from Pl(A1) homozygotes and Pl(A1)/Pl(A2) heterozygotes, in the IC(50) for RGDS inhibition of fibrinogen binding to alpha(IIb)beta(3), in the alpha(v)beta(3)-mediated adhesion of platelets to osteopontin and vitronectin, and in the phorbol ester-stimulated adhesion to fibrinogen of B lymphocytes expressing alpha(IIb)beta(3) containing either the Pl(A1) or the Pl(A2) polymorphism. Finally, no differential effects of Pl(A2) on turbidometric platelet aggregation, platelet secretion, or platelet thrombus formation were found as measured in the PFA-100. Because no differences were detected in the ability of beta(3)-integrins to interact with ligands based on the presence or absence of the Pl(A2) polymorphism, the results suggest that factors unrelated to beta(3)-integrin function may account for the reported association of the Pl(A2) allele with coronary thrombosis.

A systematic review of randomized trials of disease management programs in heart failure.

PURPOSE: Disease management programs are often advocated for the care of patients with chronic disease. This systematic review was conducted to determine whether these programs improve outcomes for patients with heart failure. METHODS: Randomized clinical trials of disease management programs in patients with heart failure were identified by searching Medline 1966 to 1999, Embase 1980 to 1998, Cinahl 1982 to 1999, Sigle 1980 to 1998, the Cochrane Controlled Trial Registry, the Cochrane Effective Practice and Organization of Care Study Registry, and the bibliographies of published studies. We also contacted experts in the field. Studies were selected and data extracted independently by two investigators, and summary risk ratios (RR) and 95% confidence intervals (CI) were calculated using both the random and fixed effects models. RESULTS: A total of 11 trials (involving 2,067 patients with heart failure) were identified. Disease management programs were cost saving in 7 of the 8 trials that reported cost data and also appeared to have beneficial effects on prescribing practices. Hospitalizations (RR = 0.87, 95% CI: 0.79 to 0.96) but not all-cause mortality (RR = 0.94, 95% CI: 0.75 to 1.19) were reduced by the programs. However, there were considerable differences in the effects of various interventions on hospitalization rates; specialized follow-up by a multidisciplinary team led to a substantial reduction in the risk of hospitalization (RR = 0.77, 95% CI 0.68 to 0.86, n = 1366), whereas trials employing telephone contact with improved coordination of primary care services failed to find any benefit (RR = 1.15, 95% CI 0.96 to 1.37, n = 646). CONCLUSION: Disease management programs for the care of patients with heart failure that involve specialized follow-up by a multidisciplinary team reduce hospitalizations and appear to be cost saving. Data on mortality are inconclusive. Further studies are needed to establish the incremental benefits of the different elements of these programs.

Cyclooxygenase inhibition and thrombogenicity.

Cyclooxygenase (COX)-1 and COX-2 catalyze the formation of prothrombotic and antithrombotic eicosanoids, respectively. Aspirin, conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and COX-2-specific inhibitors exhibit different patterns of inhibition of COX-1-mediated thromboxane biosynthesis and COX-2-mediated prostacyclin biosynthesis. The relationship between the pharmacologic inhibition of these vasoactive eicosanoids and the thromboprophylaxis or thrombogenicity exhibited by different therapeutic agents is currently unclear. Future studies are needed to assess the antithrombotic properties of commonly used NSAIDs, the hypothetical thrombogenicity of COX-2-specific inhibitors in high-risk patients, the need for concomitant aspirin with selective versus nonselective COX inhibitors, and the antiplatelet and gastric toxicity of the aspirin/COX-2-specific inhibitor combination in comparison with the aspirin/conventional NSAID combination.

Standing orders for influenza vaccination increased vaccination rates in inpatient settings compared with community rates.

BACKGROUND: Hospitalization of older adults during the period of influenza vaccination in the fall of each year presents a barrier to immunization against influenza. This study evaluates a program using standing orders for influenza vaccination to increase vaccination rates among hospitalized older adults and to determine the effect of vaccination on readmission rates for influenza-like illness. METHODS: An influenza vaccination program using a standing order policy was implemented to vaccinate all consenting persons 65 years and older prior to hospital discharge. This was a prospective, single center, cohort study in a tertiary care university teaching hospital during an 8-week vaccination period in the fall of 1994 and follow-up during the subsequent influenza season. The vaccination status of each patient was recorded as no vaccination, vaccination received in hospital, or vaccination in the community prior to or after the hospitalization. Hospital vaccination rates were compared with the rate of vaccination of older adults in the community. During the subsequent influenza season, the number of subjects reporting symptoms of influenza-like illness (ILI) or who were readmitted to hospital with influenza-related illness was compared in an analysis of vaccinated versus unvaccinated subjects. RESULTS: Seven hundred and sixty-one patients were interviewed, and 332 of these individuals had been vaccinated in the community prior to their hospital admission. Of the remaining 429 unvaccinated patients who were eligible for vaccination in the study, 171 were vaccinated in our immunization program, eight were vaccinated in the community after discharge, and 244 were not vaccinated. We were able to increase the absolute vaccination rate by 22%, when compared with community rates, with our immunization program. The number of subjects with ILI symptoms or readmission to hospital was too small to compare the vaccinated to the unvaccinated group in the study. CONCLUSIONS: An inpatient influenza immunization program using a standing order policy was able to target a particularly high-risk subset of persons 65 years and over who might otherwise have not received influenza vaccination.

Thrombosis in patients with connective tissue diseases treated with specific cyclooxygenase 2 inhibitors. A report of four cases.

Specific inhibitors of cyclooxygenase 2 (COX-2) have been approved for the treatment of osteoarthritis and rheumatoid arthritis. Unlike nonsteroidal anti-inflammatory drugs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. As a result, theoretical concerns have been raised that specific COX-2 inhibitors could shift the hemostatic balance toward a prothrombotic state. Patients with connective tissue diseases (CTD), who may be predisposed to vasculopathy and thrombosis, often have arthritis or pain syndromes requiring treatment with antiinflammatory agents. Herein we describe 4 patients with CTD who developed ischemic complications after receiving celecoxib. All patients had a history of Raynaud's phenomenon, as well as elevated anticardiolipin antibodies, lupus anticoagulant, or a history compatible with antiphospholipid syndrome. It was possible to measure a urinary metabolite of thromboxane A2 in 2 of the patients as an indicator of in vivo platelet activation, and this was markedly elevated in both. In addition, the patients had evidence of ongoing inflammation as indicated by elevated erythrocyte sedimentation rate, hypocomplementemia, and/or elevated levels of anti-DNA antibodies. The findings in these 4 patients suggest that COX-2 inhibitor-treated patients with diseases that predispose to thrombosis should be monitored carefully for this complication.

A cross-national survey of tube-feeding decisions in cognitively impaired older persons.

OBJECTIVES: Many factors affect the decision to institute long-term tube-feeding in older persons. The objectives of this cross-national survey are to examine the tube-feeding decision-making process for cognitively impaired older persons from the perspective of the substitute decision-makers (SDM) and to contrast this process in US and Canadian healthcare settings. DESIGN: Survey. SETTING: Chronic care facilities in Ottawa and nursing homes in Boston. PARTICIPANTS: Patients more than age 65 who were tube-fed for at least 2 months and who were unable to make their own healthcare decisions at the time of tube placement were identified at both sites. The SDMs of 46 patients in Ottawa and 48 patients in Boston were surveyed. MEASUREMENTS: The survey asked questions relating to the following categories: health status of the patient, advance directives, communication with the healthcare team, perceived goals of tube-feeding, decision satisfaction, and sociodemographic data. RESULTS: Tube-fed patients in Boston were more likely to have a diagnosis of dementia than those in Ottawa (60.4% vs 10.9%, P < .001) and were less likely to have had an acute neurological event (35.4% vs 71.7%, P < .001). There was a greater likelihood in Boston than in Ottawa (68.7% vs 6.5%, P < .001) for tube-feeding decisions to be made in a nursing home (vs an acute hospital). In the combined cohort, 19.1% of patients had a living will, and only 47.9% of SDMs felt confident that the patients would want to have a feeding tube. The majority of SDMs at both sites felt they understood the benefits (83.0%), but not the risks (48.9%), of tube-feeding. The most commonly perceived reasons for tube-feeding were to "prolong life" (84.0%) and to "prevent aspiration" (67.0%). Approximately half of all SDMs felt they had received adequate support from the healthcare team. A minority of SDMs (38.3%) at both sites stated that they would want a feeding tube for themselves, and only 40% of SDMs felt the feeding tube had improved the patients' quality of life. CONCLUSIONS: A greater proportion of patients have feedings tubes inserted because of a degenerative dementia in Boston compared with an acute neurological event in Ottawa. Despite the difference in diagnostic indication for tube-feeding, the substitute decision-making process was seriously limited at both sites by poor implementation of the principle of substituted judgement, a need for broader advance directives, and improved transfer of knowledge between clinicians and decision-makers.

The medical review article revisited: has the science improved?

BACKGROUND: The validity of a review depends on its methodologic quality. OBJECTIVE: To determine the methodologic quality of recently published review articles. DESIGN: Critical appraisal. SETTING: All reviews of clinical topics published in six general medical journals in 1996. MEASUREMENTS: Explicit criteria that have been published and validated were used. RESULTS: Of 158 review articles, only 2 satisfied all 10 methodologic criteria (median number of criteria satisfied, 1). Less than a quarter of the articles described how evidence was identified, evaluated, or integrated; 34% addressed a focused clinical question; and 39% identified gaps in existing knowledge. Of the 111 reviews that made treatment recommendations, 48% provided an estimate of the magnitude of potential benefits (and 34%, the potential adverse effects) of the treatment options, 45% cited randomized clinical trials to support their recommendations, and only 6% made any reference to costs. CONCLUSIONS: The methodologic quality of clinical review articles is highly variable, and many of these articles do not specify systematic methods.

Decision-making for long-term tube-feeding in cognitively impaired elderly people.

BACKGROUND: The decision to start long-term tube-feeding in elderly people is complex. The process by which such decisions are made is not well understood. The authors examined the factors involved in the decision to start long-term tube-feeding in cognitively impaired older people from the perspective of the substitute decision-maker. METHODS: A telephone survey was administered to the substitute decision-makers of tube-fed patients over 65 years old in chronic care facilities in Ottawa. Subjects were recruited from September 1997 to March 1998. Patients were incapable of making their own decisions about tube-feeding. Data were collected on sociodemographic factors, patients' health status, advance directives, communication between the substitute decision-maker and the health care team, and the decision-maker's perceived goals of tube-feeding and satisfaction with the decision regarding tube-feeding. RESULTS: Among the 57 cases in which the patient was eligible for inclusion in the study, 46 substitute decision-makers agreed to participate. Most of the patients had not given advance directives, and only 26 substitute decision-makers (56.5%) were confident that the patient would want to be tube-fed. A physician spoke with the substitute decision-maker about tube-feeding for 15 minutes or less in 17 cases (37.0%) and not at all in 13 cases (28.3%). Most of the substitute decision-makers (39 [84.8%]) felt that they understood the benefits of tube-feeding, but less than half (21 [45.7%]) felt that they understood the risks. The prevention of aspiration and the prolongation of life were the medical benefits most often cited as reasons for tube-feeding. Just over half (24 [52.2%]) of the substitute decision-makers felt that they had received adequate support from the health care team in making the decision. Substitute decision-makers of patients less than 75 years old were more likely than those of older patients to feel supported (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0-17.9). Compared with the physician's making the decision independently, substitute decision-makers felt more supported if they primarily made the decision (OR 16.5, 95% CI 2.7-101.4) or if they made the decision together with the physician (OR 5.3, 95% CI 1.0-27.9). Most (20 [43.5%]) of the substitute decision-makers did not feel that tube-feeding improved the patient's quality of life, and less than half (21 [45.7%]) indicated that they would choose the intervention for themselves. INTERPRETATION: The substitute decision-making process for tube-feeding in cognitively impaired elderly people is limited by a need for advance directives, lack of confidence in substituted judgement and poor communication of information to the substitute decision-maker by the health care team.

Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids.

Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1alpha was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.

Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2.

Prostaglandins (PG) are synthesized by two isoforms of the enzyme PG G/H synthase [cyclooxygenase (COX)]. To examine selectivity of tolerated doses of an inhibitor of the inducible COX-2 in humans, we examined the effects of celecoxib on indices of COX-1-dependent platelet thromboxane (Tx) A2 and on systemic biosynthesis of prostacyclin in vivo. Volunteers received doses of 100, 400, or 800 mg of celecoxib or 800 mg of a nonselective inhibitor, ibuprofen. Ibuprofen, but not celecoxib, significantly inhibited TxA2-dependent aggregation, induced ex vivo by arachidonic acid (83 +/- 11% vs. 11. 9 +/- 2.2%; P < 0.005) and by collagen. Neither agent altered aggregation induced by thromboxane mimetic, U46619. Ibuprofen reduced serum TxB2 (-95 +/- 2% vs. -6.9 +/- 4.2%; P < 0.001) and urinary excretion of the major Tx metabolite, 11-dehydro TxB2 (-70 +/- 9.9% vs. -20.3 +/- 5.3%; P < 0.05) when compared with placebo. Despite a failure to suppress TxA2-dependant platelet aggregation, celecoxib had a modest but significant inhibitory effect on serum TxB2 4 hr after dosing. By contrast, both ibuprofen and celecoxib suppressed a biochemical index of COX-2 activity (endotoxin induced PGE2 in whole blood ex vivo) to a comparable degree (-93.3 +/- 2% vs. -83 +/- 6.1%). There was no significant difference between the doses of celecoxib on COX-2 inhibition. Celecoxib and ibuprofen suppressed urinary excretion of the prostacyclin metabolite 2,3 dinor 6-keto PGF1alpha. These data suggest that (i) platelet COX-1-dependent aggregation is not inhibited by up to 800 mg of celecoxib; (ii) comparable COX-2 inhibition is attained by celecoxib (100-800 mg) and ibuprofen (800 mg) after acute dosing; and (iii) COX-2 is a major source of systemic prostacyclin biosynthesis in healthy humans.

A randomized, placebo-controlled, crossover study of E5510 and aspirin in healthy volunteers.

Platelet inhibition significantly reduces the risk of cardiovascular mortality and morbidity. However, current antiplatelet therapies have limitations, and more efficacious agents are needed. E5510 is a novel compound that has multiple platelet inhibitory effects in in vitro studies. We compared the in vivo, pharmacodynamic effects of maximal antiplatelet doses of E5510 (20 mg) with 300 mg aspirin in a placebo-controlled, triple crossover trial in nine healthy volunteers. Collagen-induced platelet aggregation and serum thromboxane B2 (TxB2) were similarly inhibited by both compounds in the first 12 h but showed recovery at 24 h in the E5510 group only (p < 0.05). Thrombin and U46619-induced platelet aggregation, as well as basal and prostaglandin E2 (PGE2)-stimulated platelet cyclic adenosine monophosphate (cAMP) levels were unchanged after ingestion of either agent. E5510 and aspirin reduced systemic thromboxane formation without affecting prostacyclin biosynthesis. Neither E5510 nor aspirin inhibited the excretion of 8-epi PGF2alpha and 5,6-DHET, two indices of cyclooxygenase-independent arachidonate metabolism. In conclusion, (a) E55 10 in vivo most likely induces a reversible inhibition of cyclooxygenase, without affecting thromboxane synthetase, phosphodiesterase, thrombin, or thromboxane receptor-mediated signaling; (b) single doses of aspirin or E5510 affect thromboxane/prostacyclin profiles favorably, supporting their use in acute coronary syndromes. This study outlines a comprehensive and minimally invasive approach for the assessment of the in vivo mechanism of action of novel antiplatelet agents.