Complement component C5a predicts restenosis after superficial femoral artery balloon angioplasty.

PURPOSE: To investigate whether balloon angioplasty of the superficial femoral artery (SFA) increases serum levels of C5a and whether C5a predicts risk of restenosis. METHODS: C5a antigen was measured at baseline and 8 hours after intervention in 131 consecutive patients (76 women; median age 72 years) with intermittent claudication who underwent successful primary SFA balloon angioplasty. Patients were followed for a median 10 months [interquartile range (IQR) 6 to 14] for the occurrence of >50% restenosis by duplex ultrasound. RESULTS: Median C5a levels increased significantly from 39.7 ng/mL (IQR 27.8 to 55.0) at baseline to 53.8 ng/mL (IQR 35.6 to 85.1, p<0.001) 8 hours post intervention. During the follow-up period, 70 (53%) patients developed restenosis. Increasing levels of C5a (quartiles) at baseline were significantly associated with an increased risk for restenosis (p=0.0092). Adjusted hazard ratios (95% confidence intervals) for restenosis with increasing quartiles of baseline serum C5a levels were 1.24 (0.60 to 2.58), 1.93 (0.95 to 3.93), and 2.08 (1.02 to 4.21), respectively, compared to the lowest quartile. This effect was independent of nonspecific inflammation as reflected by plasma levels of C-reactive protein. CONCLUSION: Inflammatory mechanisms play a major role in the development of restenosis after angioplasty. The complement component C5a exerts strong chemotactic and proinflammatory effects. Enhanced complement activation prior to PTA, as measured by higher levels of C5a, was significantly associated with restenosis after SFA balloon angioplasty. Pathways of complement inhibition thus may be worth investigating with respect to improving patency rates.     

Excessive carotid in-stent neointimal formation predicts late cardiovascular events.

PURPOSE: To examine if excessive in-stent neointimal formation causing a subcritical stenosis may indicate enhanced vascular reactivity in response to injury, thus predicting late cardiovascular events. METHODS: One hundred consecutive patients (64 men; median age 71 years) with high-grade internal carotid artery stenoses (68 asymptomatic, 32 symptomatic) underwent carotid artery stenting (CAS). High-sensitivity C-reactive protein (hs-CRP) was measured before CAS. Patients were monitored with duplex ultrasound for excessive in-stent neointimal formation (flow-compromising lumen diameter reduction >/=50%), critical restenosis (>/=70%), or the occurrence of late major adverse cardiovascular events (MACE) defined as myocardial infarction (MI), stroke, and death occurring later than 30 days poststenting. RESULTS: Over a median 23-month follow-up, excessive neointimal formation was observed in 14 (14%) patients, restenosis in 2 (2%), and 30 late MACE in 25 [25%: 4 MIs, 2 ipsilateral strokes (in the patients with restenosis), 8 contralateral strokes, and 16 cardiovascular deaths]. Cumulative MACE-free survival rates at 6, 12, and 24 months were 92%, 84%, and 77%, respectively. Baseline hs-CRP levels were associated both with neointimal hyperplasia (p=0.024) and MACE (p=0.021). Patients with excessive neointimal formation exhibited a significantly increased adjusted risk for MACE (hazard ratio 3.56, p=0.010). CONCLUSIONS: Excessive in-stent neointimal formation after CAS indicates an increased risk for late MACE, potentially reflecting a state of exaggerated vascular reactivity in response to injury. Inflammation, which is associated both with neointimal hyperplasia and MACE, seems a common characteristic of different vascular pathologies.     

Effect of pectinolytic enzymes on the theophylline release from pellets coated with water insoluble polymers containing pectin HM or calcium pectinate

Theophylline pellets were coated with cellulosic (Aquacoat ECD 30, Surelease clear) or acrylic (Eudragit NE30D, RS30D) polymer aqueous dispersions, containing 10% (related to the insoluble polymer content) of pectin HM or calcium pectinate, using a Uni-Glatt fluidized-bed coating apparatus. When commercial pectinolytic enzymes were added to the dissolution media (0.05 M acetate - phosphate buffer, pH 6.0), the release of theophylline from the coated pellets was generally slower than that observed in the media without enzymes. The enzymatic slowing down of the drug release, depending on the type of the aqueous polymer dispersion used, is more important with mixed Eudragit NE/calcium pectinate coated pellets. The results obtained have been examined with regard to the validity of the approach based on the combination of pectins and the insoluble polymer aqueous dispersions intended for specific-delivery of drugs to the colon. The mechanism of the hydrophilic drug release from pellets coated with insoluble polymer aqueous dispersions containing an aqueous gel-forming polymer has been also discussed.     

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with ^99mTc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h.Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC_0-360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate.The two formulations showed interesting pharmacokinetic profiles (T_max of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.     

Outcome of conservative therapy of patients with severe intermittent claudication.

BACKGROUND: Intermittent claudication due to peripheral artery disease (PAD) can be treated conservatively, or by revascularization. OBJECTIVES: To assess the short-term outcome of conservatively-treated claudicants, and determine predictors for clinical improvement. Design. A retrospective cohort study. METHODS: We evaluated Fontaine stage, walking distance and ankle brachial index (ABI) at baseline and after median 9 months (interquartile range (IQR) 6-24) in 181 patients with severe claudication. RESULTS: We found clinical improvement by at least one Fontaine stage in 38 patients (21%) with an increased walking distance from baseline median 100 m (IQR 50-150) to follow-up median 650 m (IQR 300 to unlimited; p<0.001), but without changes in ABI (median 0.57, IQR 0.48-0.73 vs. median 0.54, IQR 0.45-0.81; p=0.10). One hundred and thirty-eight patients (76%) remained clinically and hemodynamically stable. A worsening of the clinical stage but without amputation was recorded in five patients (3%). Female gender (hazard ratio (HR) 0.51, p=0.052), diabetes (HR 0.35, p=0.020), and baseline ABI below 0.44 (HR 0.31, p=0.019) were associated with a reduced probability of clinical improvement. CONCLUSION: Certain patients with intermittent claudication show substantial clinical improvement with conservative medical therapy, despite any lack of hemodynamic improvement. Given the low number of patients with clinical deterioration in the short term, primarily conservative therapy should be the preferred initial option for most claudicants.     

Haem oxygenase-1 genotype and cardiovascular adverse events in patients with peripheral artery disease

BACKGROUND: A functional GT dinucleotide length polymorphism in the haem oxygenase-1 (HO-1) gene promoter is thought to be involved in the pathogenesis of cardiovascular disease. Short (< 25) (GT)n repeats are suggested to facilitate enhanced HO-1 up-regulation in response to injury and confer potent anti-inflammatory and antioxidative effects. MATERIALS AND METHODS: We investigated the association between the HO-1 GT-polymorphism and cardiovascular outcome in 472 patients with advanced peripheral artery disease. Cardiovascular risk profile and DNA samples for determination of the HO-1 genotype (carrier vs. noncarrier of a short (GT)n repeat allele) were obtained at baseline, and patients were followed for median 21 months for the occurrence of coronary events (myocardial infarction, percutaneous coronary interventions and coronary artery bypass graft), cerebrovascular events (stroke or carotid revascularization) and all-cause mortality. RESULTS: Coronary events occurred in 48 patients (9%), cerebrovascular events in 40 patients (9%) and 59 patients (13%) died. In total, 173 major adverse cardiovascular events (MACE) occurred in 133 patients (28%). Carriers of the short (GT)n repeat allele had a 0.46-fold reduced adjusted hazard ratio for coronary events (P = 0.016) as compared to noncarriers. No significant difference was found for cerebrovascular events, mortality and overall MACE. CONCLUSION: Apparently, the HO-1 genotype exerts potentially protective effects against coronary adverse events in patients with peripheral artery disease. Homozygous and heterozygous carriers of < 25 (GT)n repeats had lower rates of myocardial infarction, percutaneous coronary interventions and coronary bypass operations compared to patients with longer (GT)n repeats.