Concurrent use of intranasal and orally inhaled fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function.

Two double-blind, randomized, placebo-controlled, parallel group safety and efficacy studies included evaluation of the hypothalamic-pituitary-adrenal (HPA)-axis effects of concurrent treatment with intranasal and orally inhaled fluticasone propionate (FP). In the first study, patients with asthma who were > or =12 years of age were assigned randomly to receive twice-daily doses (either 88 or 220 microg) of orally inhaled FP delivered from a metered-dose inhaler (MDI). In the second study, patients were assigned randomly to receive either orally inhaled FP 250 microg or orally inhaled FP 250 microg/salmeterol 50 microg delivered via the Diskus device. In both studies, patients with rhinitis were allowed to continue the use of intranasal FP at their usual dosing. Treatment periods were 26 weeks and 12 weeks for the MDI and Diskus studies, respectively. HPA-axis effects were assessed using response to short cosyntropin stimulation testing. The number and percentage of patients with an abnormal cortisol response, defined as a morning plasma cortisol of <5 microg/dL, a poststimulation peak of <18 microg/dL, or a poststimulation rise of <7 microg/dL, were summarized in two subgroups: patients who used intranasal FP and those who did not. The concurrent administration of intranasal FP and orally inhaled FP via an MDI or Diskus or via Diskus with salmeterol was not associated with HPA-axis effects compared with orally inhaled FP alone. The results of these two studies suggest that concurrent use of intranasal FP with orally inhaled FP administered via MDI or Diskus for treatment of comorbid rhinitis and asthma does not increase the risk of HPA-axis abnormalities.     

Life span differences in digoxin uptake and excretion

Little is known about the underlying mechanisms for the altered susceptibility to digitalis with age. To this end, we investigated the digoxin uptake and excretion in mice and rats of different ages through the life span, including the periods of growth, maturity, and aging. Digoxin uptake by cardiac slices was linear from 0 to 15 min, with steady state occuring at 45 min. The rate in the mature 12-month mouse was significantly less than that of the senescent 30-month mouse. The kinetic parameters revealed a significant decrease in Km with a concomitant increase in Vmax during senescense. On the other hand uptake by renal cortical slices was highest during growth, decreased to a maturation plateau and then declined further during senescence. Renal clearance and the secretory capacity for digoxin increased 30 and 62%, respectively, during growth and progressively decreased from maturity through senescence and were 59 and 77%, respectively, during aging. In summary, there was an increase in digoxin clearance and tubular activity during growth, and in increase in myocardial uptake of digoxin and a decrease in renal excretion during aging. Thus, these results may explain the clinical observations of altered susceptibility to digitalis with age.     

Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases

Chemoattractants and chemokines, such as interleukin 8 (IL-8), are defined by their ability to induce directed cell migration of responsive cells. The signal transduction pathway(s) leading to cell migration remain ill defined. We demonstrate that phosphatidylinositol-3-kinase (PI3K) activity, as determined by inhibition using wortmannin and LY294002, is required for IL-8-induced cell migration of human neutrophils. Recently we reported that IL-8 caused the activation of the Ras/Raf/extracellular signal-regulated kinase (ERK) pathway in human neutrophils and that this activation was dependent on PI3K activity. The regulation of cell migration by IL-8 is independent of ERK kinase and ERK activation since the ERK kinase inhibitor PD098059 had no effect on IL-8-induced cell migration of human neutrophils. Additionally, activation of p38-mitogen-activated protein kinase is insufficient and activation of c-Jun N-terminal kinase is unnecessary to induce cell migration of human neutrophils. Therefore, regulation of neutrophil migration appears to be largely independent of the activation of the mitogen-activated protein kinases. The data argue that PI3K activity plays a central role in multiple signal transduction pathways within the human neutrophil leading to distinct cell functions.     

Success,complications, and restenosis following rotational and transluminal extraction atherectomy of ostial stenoses

Our objectives were to determine procedural success, clinical complications, and follow-up restenosis rates after rotational burr and transluminal extraction atherectomy of coronary artery and saphenous vein graft ostial stenoses. Balloon angioplasty of ostial lesions has been associated with low rates of success and high rates of clinical complications and restenosis compared to nonostial lesions. Atherectomy, due to its ability to excise (extraction atherectomy) or pulverize (rotational atherectomy) atheroma and the internal elastic lamina, may result in improved procedural outcome. We retrospectively studied 101 patients with ostial stenoses treated by rotational burr and transluminal extraction atherectomy over a 3-yr period. Quantitative angiography and clinical follow-up were reviewed to determine success, complication, and restenosis rates. Rotational burr (n = 29) and transluminal extraction (n = 72) atherectomy were associated with high procedural success (93% and 90%, respectively) and a low incidence of complications (6.9% and 4.2%, respectively). Postatherectomy angiographic success was low (52% and 69%, respectively) and required adjunctive balloon angioplasty in 85% of patients overall. This lower success rate likely reflects device undersizing as the overall postatherectomy artery to device ratio was near unity (0.95). The rates of angiographic ostial restenosis remain high (39.1% and 65.9%, respectively, P < 0.05). The high rate of restenosis after transluminal extraction atherectomy was due to the higher rate of restenosis in saphenous vein grafts (80%) compared to TEC treated coronary arteries (59%). When only coronary artery lesions were compared, there was no significant difference between atherectomy device groups with respect to restenosis rates or late loss. Rotational or transluminal extraction atherectomy of ostial stenoses is associated with high procedural success rates and a low incidence of complications; however, the rates of restenosis in these lesions remain high.     

Diagnosis,management, and clinical outcome of cardiac tamponade complicating percutaneous coronary intervention

Cardiac tamponade is an uncommon but life-threatening complication of percutaneous coronary intervention (PCI). The purpose of the present study was to characterize the incidence, management, and clinical outcome associated with this complication. We analyzed a prospective database of 25,697 PCIs performed at William Beaumont Hospital (Royal Oak, Michigan) between October 1993 and December 2000. Cardiac tamponade was observed in 31 of 25,697 PCI procedures (0.12%). Cardiac tamponade was diagnosed in the catheterization laboratory in 17 of 31 patients (55%), and 14 patients (45%) had a delayed presentation (mean time from PCI 4.4 hours). Cardiac tamponade was twice as frequent after use of atheroablative devices compared with percutaneous transluminal coronary angioplasty and stenting (0.26% vs 0.11%, p <0.05). All patients with immediate cardiac tamponade had coronary artery perforation. In 11 of 14 patients with delayed tamponade (79%), no actual site of perforation could be identified. A moderate or large pericardial effusion was observed in 20 patients, and 9 had small effusions without typical echocardiographic features of tamponade. Pericardiocentesis was performed in 30 patients; 19 patients (61%) were treated successfully with aspiration alone, but 12 patients (39%) required further emergency surgical intervention. In-hospital complications included death (42%), emergency surgery (39%), myocardial infarction (29%), and transfusion (65%). Cardiac tamponade is an uncommon but important complication of PCI and is associated with high mortality and morbidity. Most cases are recognized in the catheterization laboratory, but delayed cardiac tamponade may occur and must be considered as a cause of late hypotension after PCI.     

Comparison of outcomes of diabetic and nondiabetic patients undergoing primary angioplasty for acute myocardial infarction

We sought to determine whether diabetes mellitus independently conferred poor prognosis in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI). In 3,742 patients enrolled in the Primary Angioplasty in Myocardial Infarction (PAMI) studies with the intention of undergoing primary PCI, we compared in-hospital mortality, 6-month mortality, and 6-month major adverse cardiovascular events (MACEs), i.e., composite of death, reinfarction, or ischemic target vessel revascularization (TVR), between diabetics (n = 626, 17%) and nondiabetics (n = 3,116, 83%). We evaluated the independent impact of diabetes on outcomes after adjustment for baseline clinical and angiographic differences. Diabetics had worse baseline clinical characteristics, longer pain onset-to-hospital arrival time, and longer door-to-balloon time. They had more multivessel coronary disease and lower left ventricular ejection fractions, but better baseline Thrombolysis In Myocardial Infarction (TIMI) flow. Diabetics underwent primary PCI less often (88% vs 91%, p = 0.01). During the index hospitalization, diabetics were more likely to die (4.6% vs 2.6%, p = 0.005). During 6-month follow-up, diabetics had higher incidences of death (8.1% vs 4.2%, p <0.0001) and MACEs (18% vs 14%, p = 0.036). In multivariate analysis, diabetes was independently associated with 6-month mortality (hazard ratio 1.53, 95% confidence interval 1.03 to 2.26, p = 0.03), but not with in-hospital mortality or 6-month MACEs. We conclude that diabetics with AMI have less favorable baseline characteristics and are less likely to undergo primary PCI than nondiabetics. Despite excellent angiographic results, diabetics had significantly worse 6-month mortality.     

Ischemia-driven target vessel revascularization after-primary percutaneous coronary intervention: patients at risk and their outcomes

Clinical and angiographic correlates of ischemia-driven target vessel revascularization (ITVR) in patients undergoing primary percutaneous coronary interventions (PCI) are currently less well known. Accordingly, we examined 2,981 patients enrolled in different Primary Angioplasty in Myocardial Infarction trials, who underwent primary PCI to evaluate risk factors and outcomes of individuals requiring subsequent ITVR. At 6 months, ITVR was required in 321 patients (11%). Compared to the cohort without ITVR, patients requiring ITVR were younger (P=0.036), females (P=0.018), and more likely to have systolic blood pressure >100 mmHg on presentation (P=0.022), family history of premature coronary artery disease (P=0.035), and postprocedure dissection (P=0.001). In contrast, Killip Class >I on presentation (P=0.05), left circumflex as infarct-related artery (P=0.022), and the use of ticlopidine (P=0.044) and stents (p=0.057) were less frequent among ITVR patients. Multivariate analysis identified younger age (for each 10-year decrease, odds ratio [OR], 1.18; 95% confidence interval [CI], 1.06-1.32), female gender (OR: 1.41, 95% CI: 1.05-1.89), and final dissection (OR: 1.69, 95% CI: 1.23-2.33) as independent risk factors for ITVR. In-hospital reinfarction (P < 0.001) was increased and at 6 months remained higher in ITVR patients; in-hospital and 6-month mortality did not differ between the two groups. Our study identifies the incidence, risk factors, and outcomes of patients requiring ITVR after primary PCI. Importantly, our data suggest that no increase in mortality occur, if ITVR is promptly performed to treat recurrent ischemia after primary PCI.     

Usefulness of the presence of peripheral vascular disease in predicting mortality in acute myocardial infarction patients treated with primary angioplasty (from the Primary Angioplasty in Myocardial Infarction Database)

Patients with acute myocardial infarction (AMI) often have multiple co-morbidities that influence outcome. We sought to evaluate the impact of peripheral vascular disease (PVD) on the outcome of patients with AMI treated with primary angioplasty. We evaluated 3,716 patients with AMI who underwent emergency catheterization with planned primary angioplasty in the Primary Angioplasty in Myocardial Infarction trials. Patients with a history of PVD (claudication, stroke, or transient ischemic attack) were compared with patients without PVD. Of the 3,716 patients, 394 (10.6%) had PVD and were older, more often women, and more frequently had a history of diabetes mellitus, hypertension, smoking, congestive heart failure, angina, myocardial infarction, and coronary revascularization. They presented more often with a heart rate >100 beats/min, Killip class >1, lower ejection fraction, and multivessel disease. No difference was found in stent use, final percentage of stenosis, or Thrombolysis In Myocardial Infarction 3 flow. Patients with PVD had a twofold increased in-hospital mortality (5.3% vs 2.6%, p = 0.0021). The difference remained significant at 1 month, 6 months, and 1 year (12.6% vs 6%, p < 0.0001). In multivariate logistic regression analysis, a history of PVD was an independent predictor of in-hospital mortality and death at 1 year (odds ratio 1.64, 95% confidence interval 1.04 to 2.57, p = 0.032). In conclusion, patients with AMI with PVD have increased co-morbidities and higher mortality despite treatment with primary angioplasty. The presence of PVD is an independent predictor of in-hospital mortality and death at 1 year.