Opioid use for noncancer pain and risk of myocardial infarction amongst adults.

BACKGROUNDS: With increasing use of opioids for chronic noncancer pain comes concern about safety of this class of drugs. Opioid-induced hypogonadism, which could increase the risk for myocardial infarction (MI), has recently come to the attention of clinicians. To evaluate this concern we examined the association between opioid use for noncancer pain and risk of MI amongst adults. METHODS: We conducted a nested case-control study using the UK General Practice Research Database. Amongst 1.7 million opioid users during 1990-2008, we identified 11 693 incident MI cases aged 18-80 years, and randomly selected up to four controls matched by age, gender, index date (date of onset symptoms or diagnosis of first-ever MI) and general practice via risk-set sampling. Cases and controls were required to have no cancer and no major risk factors for MI before the index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from conditional logistic regression. RESULTS: Compared with nonuse, current use of opioids was associated with a 1.28-fold (95% CI 1.19-1.37) risk of MI. Cumulative use of opioids with 11-50 (OR = 1.38, 95% CI: 1.28-1.49) or > 50 (OR = 1.25, 95% CI: 1.11-1.40) prescriptions, was also marginally associated with increased risk of MI. The risk was particularly increased in users of morphine (OR = 1.71, 95% CI: 1.09-2.68), meperidine (OR = 2.15, 95% CI: 1.24-3.74) and polytherapy (OR = 1.46, 95% CI: 1.22-1.76). CONCLUSIONS: Current use of any opioids and cumulative use of 11 or more prescriptions are associated with a small increased risk for MI compared to nonuse and the risk was greater in morphine, meperidine and polytherapy users. Residual confounding, particularly confounding by indication, should be considered in interpreting our results.

Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation.

Numerous studies have shown that protocol biopsies have predictive power. We retrospectively examined the histologic findings and C4d staining in 89 protocol biopsies from 48 ABO-incompatible (ABO-I) transplant recipients, and compared the results with those of 250 controls from 133 ABO-compatible (ABO-C) transplant recipients given equivalent maintenance immunosuppression. Others have shown that subclinical rejection (borderline and grade I) in ABO-C grafts decreased gradually after transplantation. In our study, however, subclinical rejection in the ABO-I grafts was detected in 10%, 14% and 28% at 1, 3 and 6-12 months, respectively. At 6-12 months, mild tubular atrophy was more common in the ABO-C grafts whereas the incidence of transplant glomerulopathy did not differ between the two groups (ABO-C: 7%; ABO-I: 15%; p = 0.57). In the ABO-I transplants, risk factors for transplant glomerulopathy in univariate analysis were positive panel reactivity (relative risk, 45.0; p < 0.01) and a prior history of antibody-mediated rejection (relative risk, 17.9; p = 0.01). Furthermore, C4d deposition in the peritubular capillaries was detected in 94%, with diffuse staining in 66%. This deposition, however, was not linked to antibody-mediated rejection. We conclude that, in the ABO-I kidney transplantation setting, detection of C4d alone in protocol biopsies might not have any diagnostic or therapeutic relevance.

Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease.

OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ACBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 microg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%deltaCBF <300%, n = 8) and "normal" (%deltaCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.

Medical and socioenvironmental predictors of hospital readmission in patients with congestive heart failure.

BACKGROUND: Patients with chronic congestive heart failure (CHF) require frequent rehospitalization because of the exacerbation of CHF. It is of clinical importance to determine predicting factors for readmission to reduce this likelihood. Previous studies have focused primarily on the demographic and medical characteristics in selected subsets of patients. Therefore, within a broad cohort of consecutively hospitalized patients, we sought to identify not only demographic and medical predictors but also socioenvironmental factors associated with readmission. METHODS: We assessed demographic (age, sex), medical (etiology of CHF, New York Heart Association functional class, left ventricular ejection fraction, previous admission for CHF, length of hospital stay, comorbidity, and medications), and socioenvironmental variables (occupation, financial resources, living alone, and follow-up visits) in 230 patients discharged with a diagnosis of CHF and recorded hospital readmission. RESULTS: Within 1 year after discharge, 81 patients (35%) were readmitted. Five variables, including poor follow-up visits (odds ratio [OR] 4.9, 95% CI 2.0-11.8), previous admission for CHF (OR 3.3, 95% CI 1.8-6.1), no occupation (OR 2.6, 95% CI 1.2-5.5), longer hospital stay (OR 3.2, 95% CI 1.2-8.5), and hypertension (OR 2.0, 95% CI 1.1-3.7), were identified as significant independent predictors for readmission by multivariate logistic regression analysis. CONCLUSIONS: Our independent predictors of readmission support the importance of medical and socioenvironmental factors in the deterioration of CHF. Therefore interventions to decrease readmission should also target social management in all hospitalized patients.

[Thromboxane synthetase inhibitors. I. Synthesis of some imidazolylarylmethanols and their inhibitory activity on platelet aggregation].

Several imidazolylpyridinemethanols and imidazolylbenzenemethanols were prepared and evaluated for an inhibitory activity against arachidonic acid-induced platelet aggregation. The result shows that the arylmethanol moiety is essential for the activity and may correspond to the 15-OH group of prostagrandin H2 (PGH2). Among the compounds tested, 4-[alpha-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid (XV) was found to have a potent inhibitory activity and a long duration of action. Structure-activity relationships are also discussed briefly.

Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors: challenges in comparative effectiveness using Medicare data.

An evidence gap exists in comparing the effectiveness of angiotensin receptor II blockers (ARBs) for hypertension with that of angiotensin-converting enzyme inhibitors (ACEIs). We identified elderly hypertensive patients in whom ACEI/ARB therapy had been initiated after hospitalization for coronary artery disease (CAD), heart failure (HF), or stroke and who were eligible for Medicare and state pharmacy assistance programs. Of 18,801 initiators of ACEIs and 2,641 initiators of ARBs, 2,535 died during the follow-up. We observed substantial differences in characteristics between ARB and ACEI initiators, suggesting that ARB users were more health seeking. The incidence of death and sudden cardiac death (SCD) in ACEI initiators was 77 and 22 per 1,000 person-years, respectively. The relative risk for SCD comparing ARB initiators to ACEI initiators was 0.69 (95% confidence interval (CI) 0.50-0.96); when the analysis was restricted to patients with low ejection fraction (EF), the relative risk was 1.1. The reduced risk of SCD can be explained, at least partly, by (i) residual confounding because ARB users were healthier on unobserved domains and (ii) lack of data on EF.

Temporal trends in adherence to cardiovascular medications in elderly patients after hospitalization for heart failure.

Although the complexity of treatment regimens for patients with heart failure (HF) has increased over time because of the increased availability of efficacious medications, little is known about temporal trends in adherence to treatment regimens in these patients. We assessed trends in adherence to angiotensin-system blockers (ABs), ß-blockers (BBs), and spironolactone (SL) for HF in Medicare beneficiaries enrolled in two statewide pharmacy benefit programs from 1995 to 2004. The proportion of days covered (PDC) (%) was assessed after the first dispensing among users of an AB, BB, or SL. Proportions of full adherence (PDC >80%) did not change over time for ABs (54% in both 1996 and 2003) but increased slightly for BBs (from 47% in 1996 to 57% in 2003) and SL (from 31% in 1996 to 42% in 2003). Black race and dialysis treatment predicted poor adherence to any medications. Adherence to BBs and SL increased modestly over time, but overall nonadherence remained high.

Effectiveness of a law to reduce alcohol-impaired driving in Japan.

OBJECTIVE: To estimate the effect of a new road traffic law against alcohol-impaired driving in Japan. METHODS: Japan passed a new road traffic law in June 2002 intended to reduce alcohol-impaired driving by decreasing the permissible blood alcohol level and by increasing penalties. Using data collected from police reports, the number of traffic fatalities and injuries were analyzed by time series. RESULTS: Simple comparisons of the average of all severe traffic injuries, traffic fatalities, alcohol-impaired traffic injuries, alcohol-impaired severe traffic injuries, and alcohol-impaired traffic fatalities per billion kilometers driven showed reductions after enactment of the new road traffic law in June 2002. The rate of alcohol-related traffic fatalities per billion kilometers driven decreased by 38% in the post-law period. In segmented regression analyses with adjustment for baseline trends, seasonality, and autocorrelation, all traffic injuries, severe traffic injuries, alcohol-impaired traffic injuries, alcohol-impaired severe traffic injuries, and alcohol-impaired traffic fatalities per billion kilometers driven declined significantly from baseline after the new traffic law. CONCLUSION: Large, immediate public health benefits resulted from the new road traffic law in Japan.

Clinical presentation of myocardial infarction contributes to lower use of coronary angiography in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) have high mortality following myocardial infarction (MI), but are less likely to undergo coronary angiography than those without CKD. Whether this phenomenon is explained by differences in the presentation of MI or by bias against performing coronary angiography in patients with CKD is unclear. We examined the clinical presentation of 1876 elderly patients who presented with MI and categorized them by estimated glomerular filtration rate: >60 ml/min (no/mild CKD), 30-60 ml/min (CKD Stage 3) or <30 ml/min (CKD Stage 4/5). Compared with patients with no/mild CKD, patients with CKD Stage 3 or Stage 4/5 had more comorbidity, greater prior nursing home use, and higher frequency of conduction abnormalities or anterior infarction. By contrast, peak creatinine kinase-MB fraction (CK-MB) concentrations were lower and ST-elevation MI was less common in patients with CKD Stage 3 or Stage 4/5. In univariate analyses, patients with CKD Stage 4/5 (odds ratio (OR)=0.34, 95% confidence interval (CI): 0.23-0.50) or Stage 3 (OR=0.57, 95% CI: 0.45-0.73) were markedly less likely to undergo angiography than subjects with no/mild CKD. After multivariable adjustment, the association of CKD Stage 3 with the use of coronary angiography was attenuated (OR=0.78, 95% CI: 0.60-1.03), but CKD Stage 4/5 remained strongly associated with lower use (OR=0.52, 95% CI: 0.34-0.80). Clinical features of MI are different in patients with and without CKD and may partly explain the low use of angiography in patients with CKD Stage 3. However, the clinical features of MI do not account for its underuse in MI patients with CKD Stages 4/5. Whether reduced use of angiography in patients with advanced CKD is justified must be evaluated in formal risk-benefit analyses.

Patterns of cardiovascular risk in rheumatoid arthritis.

BACKGROUND: Although it is known that rheumatoid arthritis is associated with an increased risk of cardiovascular disease (CVD), the pattern of this risk is not clear. This study investigated the relative risk of myocardial infarction, stroke and CVD mortality in adults with rheumatoid arthritis compared with adults without rheumatoid arthritis across age groups, sex and prior CVD event status. METHODS: We conducted a cohort study among all residents aged >or=18 years residing in British Columbia between 1999 and 2003. Residents who had visited the doctor at least thrice for rheumatoid arthritis (International Classification of Disease = 714) were considered to have rheumatoid arthritis. A non-rheumatoid arthritis cohort was matched to the rheumatoid arthritis cohort by age, sex and start of follow-up. The primary composite end point was a hospital admission for myocardial infarction, stroke or CVD mortality. RESULTS: 25 385 adults who had at least three diagnoses for rheumatoid arthritis during the study period were identified. During the 5-year study period, 375 patients with rheumatoid arthritis had a hospital admission for myocardial infarction, 363 had a hospitalisation for stroke, 437 died from cardiovascular causes and 1042 had one of these outcomes. The rate ratio for a CVD event in patients with rheumatoid arthritis was 1.6 (95% confidence interval (CI) 1.5 to 1.7), and the rate difference was 5.7 (95% CI 4.9 to 6.4) per 1000 person-years. The rate ratio decreased with age, from 3.3 in patients aged 18-39 years to 1.6 in those aged >or=75 years. However, the rate difference was 1.2 per 1000 person-years in the youngest age group and increased to 19.7 per 1000 person-years in those aged >or=75 years. Among patients with a prior CVD event, the rate ratios and rate differences were not increased in rheumatoid arthritis. CONCLUSIONS: This study confirms that rheumatoid arthritis is a risk factor for CVD events and shows that the rate ratio for CVD events among subjects with rheumatoid arthritis is highest in young adults and those without known prior CVD events. However, in absolute terms, the difference in event rates is highest in older adults.

Syntheses and biological activities of optical isomers of 3-chloro-5-[3-(2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a]pyridine- 3-spiro-4'-piperidino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine (mosapramine) dihydrochloride.

Mosapramine (1) is a new neuroleptic drug with an asymmetric carbon atom (8a) in its imidazopyridine ring. The enantiomers of this agent were synthesized to compare their biological activities, such as antiapomorphine activity, affinity for dopamine D2 receptor and acute toxicity. The key intermediates, (R)-(-)- and (S)-(+)-2-oxo-1,2,3,5,6,7,8,8a-octahydroimidazo[1,2-a]pyridine- 3-spiro-4'-piperidines, were prepared by optical resolution of the corresponding (+/-)-compound and were treated with 3-chloro-5-(3-methanesulfonyloxypropyl)-10,11-dihydro-5H-dibenz[b, f]azepine to afford (R)-(-)-1 and (S)-(+)-1, respectively. There were few differences in the examined biological activities of the two enantiomers as their dihydrochlorides.

Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans.

Rho-kinase plays an important role in modulating Ca(2+) sensitivity of vascular smooth muscle and has been suggested to be involved in the increased systemic vascular resistance in hypertensive animals. However, it remains to be examined whether this is also the case in patients with essential hypertension. Recently, it has been shown that fasudil is a specific Rho-kinase inhibitor. The aim of this study was to examine whether Rho-kinase is involved in the pathogenesis of hypertension in humans by using this Rho-kinase inhibitor. Studies were performed in hypertensive patients (HT group, n=14) and age-matched normotensive subjects (NT group, n=12). Forearm blood flow was measured by a strain-gauge plethysmograph during intra-arterial infusion of graded doses of fasudil (3.2, 6.4, 12.8, and 25.6 microg/min) or sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 microg/min). Resting forearm vascular resistance was significantly higher in the HT group than in the NT group (22+/-4 versus 17+/-5 U, respectively; P<0.05). The extent of the increase in forearm blood flow evoked by fasudil was significantly greater in the HT group than in the NT group (12.3+/-1.4 versus 6.0+/-0.6 mL. min(-1). 100 mL(-1), respectively; P<0.01). The percent decrease in forearm vascular resistance was significantly greater in the HT group than in the NT group (63.6+/-4.7% versus 29.6+/-3.9%, respectively; P<0.01). By contrast, forearm vasodilator response evoked by sodium nitroprusside was comparable between the 2 groups. These results provide the first evidence that Rho-kinase may be involved in the pathogenesis of the increased peripheral vascular resistance in hypertension in humans.

Noise-enhanced heart rate and sympathetic nerve responses to oscillatory lower body negative pressure in humans.

By injecting noise into the carotid sinus baroreceptors, we previously showed that heart rate (HR) responses to weak oscillatory tilt were enhanced via a mechanism known as "stochastic resonance." It remains unclear, however, whether the same responses would be observed when using oscillatory lower body negative pressure (LBNP), which would unload the cardiopulmonary baroreceptors with physically negligible effects on the arterial system. Also, the vasomotor sympathetic activity directly controlling peripheral resistance against hypotensive stimuli was not observed. We therefore investigated the effects of weak (0 to approximately -10 mmHg) oscillatory (0.03 Hz) LBNP on HR and muscle sympathetic nerve activity (MSNA) while adding incremental noise to the carotid sinus baroreceptors via a pneumatic neck chamber. The signal-to-noise ratio of HR, cardiac interbeat interval, and total MSNA were all significantly improved by increasing noise intensity, while there was no significant change in the arterial blood pressure in synchronized with the oscillatory LBNP. We conclude that the stochastic resonance, affecting both HR and MSNA, results from the interaction of noise with the signal in the brain stem, where the neuronal inputs from the arterial and cardiopulmonary baroreceptors first come together in the nucleus tractus solitarius. Also, these results indicate that the noise could induce functional improvement in human blood pressure regulatory system in overcoming given hypotensive stimuli.