Evaluation of levocetirizine in beagle dog and cynomolgus monkey telemetry assays: Defining the no QTc effect profile by timepoint and concentration-QTc analysis.

In prior clinical studies, levocetirizine (LEVO) has demonstrated no effect on ventricular repolarization (QTc intervals), therefore it is a relevant negative control to assess in nonclinical assays to define low proarrhythmic risk. LEVO was tested in beagle dog and cynomolgus monkey (nonhuman primate [NHP]) telemetry models to understand the nonclinical-clinical translation of this negative control. One oral dose of vehicle, LEVO (10 mg/kg/species) or moxifloxacin (MOXI; 30 mg/kg/dog; 80 mg/kg/NHP) was administered to instrumented animals (N = 8/species) using a cross-over dosing design; MOXI was the in-study positive control. Corrected QT interval values (QTcI) were calculated using an individual animal correction factor. Blood samples were taken for drug exposure during telemetry and for pharmacokinetic (PK) analysis (same animals; different day) for exposure-response (C-QTc) modeling. Statistical analysis of QTc-by-timepoint data showed that LEVO treatment was consistent with vehicle, thus no effect on ventricular repolarization was observed over 24 h in both species. PK analysis indicated that LEVO-maximum concentration levels in dogs (range: 12,300-20,100 ng/ml) and NHPs (range: 4090-12,700 ng/ml) were ≥4-fold higher than supratherapeutic drug levels in clinical QTc studies. Slope analysis values in dogs (0.00019 ms/ng/ml) and NHPs (0.00016 ms/ng/ml) were similar to the human C-QTc relationship and indicated no relationship between QTc intervals and plasma levels of LEVO. MOXI treatment caused QTc interval prolongation (dog: 18 ms; NHP: 29 ms). The characterization of LEVO in these non-rodent telemetry studies further demonstrates the value and impact of the in vivo QTc assay to define a "no QTc effect" profile and support clinical safety assessment.

Evaluation of moxifloxacin in canine and non-human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration-QTc analysis.

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose-response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration-QTc (C-QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non-human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin-induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C-QTc slope values were 0.7- (dog) and 1.2- (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C-QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

The Need for Accreditation of Office-Based Interventional Vascular Centers.

The rise in office-based interventional vascular laboratories in recent years was prompted in part by expedient ambulatory patient experience and favorable outpatient procedural reimbursement. While studies have shown that clinical safety and treatment efficacy can be achieved in office-based vascular facilities, critics have raised various concerns due to inconsistent patient care standards and lack of organizational oversight to ensure optimal patient outcome. Available literature showed widely varied clinical outcomes which were partly attributable to nonuniform standards in reporting clinical efficacy and adverse events. In this report, various concerns and pitfalls of office-based interventional vascular centers are discussed. Strategies to improve patient care delivery in office-based laboratories including accreditations which serve as external validation of processes to ensure patient care and safety are also mentioned. Finally, the requirements to obtain accreditation in an office-based practice and the differences between these nationally recognized accrediting organizations are discussed herein.

Glycolytic oscillations and limits on robust efficiency.

Both engineering and evolution are constrained by trade-offs between efficiency and robustness, but theory that formalizes this fact is limited. For a simple two-state model of glycolysis, we explicitly derive analytic equations for hard trade-offs between robustness and efficiency with oscillations as an inevitable side effect. The model describes how the trade-offs arise from individual parameters, including the interplay of feedback control with autocatalysis of network products necessary to power and catalyze intermediate reactions. We then use control theory to prove that the essential features of these hard trade-off "laws" are universal and fundamental, in that they depend minimally on the details of this system and generalize to the robust efficiency of any autocatalytic network. The theory also suggests worst-case conditions that are consistent with initial experiments.

Changing pattern of surgical revascularization for critical limb ischemia over 12 years: endovascular vs. open bypass surgery.

OBJECTIVE: This study is a review and evaluation of our 12-year experience of revascularization for critical limb ischemia (CLI) with angioplasty/stenting and bypass surgery to identify specific trends of procedure volume and outcomes in this particular group. METHODS: Endovascular and open bypass procedures done for CLI by a single surgeon between 1993 and 2004 were evaluated retrospectively. Thrombolysis and thrombectomy procedures done as the only revascularization procedure were excluded from analysis. The data were divided into three groups by time periods: the first period, 1993 to 1996; the second period, 1997 to 2000; and the third period, 2001 to 2004. Outcomes were defined according to the reporting standards of the Society for Vascular Surgery/International Society for Cardiovascular Surgery. The study included 416 procedures done in 237 limbs in 192 patients. The mean follow-up was 23 months (range, 1 to 122 months). RESULTS: Primary revascularization procedures for CLI were angioplasty in 153 limbs (65%) and bypass surgery in 84 (35%). Subsequent procedures were angioplasty in 102 limbs (57%) and open surgery (bypass and/or patch angioplasty) in 77 limbs (43%). The rates for technical and clinical success and complications in the entire group were 99%, 95%, and 4%, respectively. One patient died perioperatively (0.5%). Among the three periods, TransAtlantic Inter-Society Consensus lesion types were significantly more severe in patients in the first period (P < .05). Additionally, the complication rate was significantly higher and the mean hospital stay was significantly longer in the first period compared with the second and third periods (P < .05). Furthermore, between the first and third periods, the number of endovascular revascularization procedures done as primary and secondary procedures significantly increased from 15 to 84 (+460%) and from 13 to 57 (+340%), whereas the number of open surgical procedures done as primary and secondary procedures decreased from 39 to 20 (-49%) and from 35 to 18 (-49%), respectively (P < .0001). The assisted primary patency rates in the third period were significantly higher than those in the first and second periods (P = .012); otherwise, the long-term outcomes among the three periods were not statistically different. Multivariate analysis revealed that, while controlling for other factors, the third period showed improvement in the primary patency (P = .032) and assisted primary patency (P = .051), and the bypass group showed improvement in the primary patency (P = .008). CONCLUSIONS: In our experience, open surgical procedures for the treatment of CLI have been largely replaced by angioplasty procedures without compromising outcomes. Angioplasty is a feasible, safe, and effective procedure and can be the procedure of choice for the primary and secondary treatment of CLI. Open surgical procedures can be reserved for lesions technically unsuitable for endovascular procedures and patients who do not demonstrate clinical improvement after angioplasty.

The influence of the ipsilateral superficial femoral artery on iliac angioplasty.

Our objective was to evaluate the impact of the ipsilateral superficial femoral artery (SFA) on percutaneous transluminal angioplasty (PTA) of the iliac arteries. From 1993 to 2005, 183 iliac lesions (179 stenoses, 4 occlusions; 37 common, 35 external, and 111 both iliac arteries) in 127 patients with disabling claudication [94 (52%)], rest pain [43 (23%)], and ulcer/gangrene [46 (25%)] were treated by PTA. TransAtlantic Inter-Society Consensus (TASC) iliac lesion types were A in 48 limbs (26%), B in 92 (50%), C in 38 (21%), and D in 5 (3%). Stents were placed selectively for primary angioplasty failure [residual stenosis (>30%) or pressure gradient (>5 mm Hg)]. Seventy-seven limbs (42%) had patent SFAs (66 intact/<50% stenosis and 11 previously bypassed, pSFA group), 28 (15%) had stenotic SFAs (50-99%, sSFA group), 51 (28%) had occluded SFAs (oSFA group), and 27 (15%) had concomitant SFA angioplasty (aSFA group). The Society for Vascular Surgery and the International Society for Cardiovascular Surgery reporting standards were followed to define outcomes. There were no perioperative deaths. Total complication rate was 1.1% (2/183, groin hematomas). The mean follow-up was 20 months (range 1-115). One hundred twenty-five limbs (68%) had PTA alone for iliac lesions, and 58 (32%) had iliac stenting (a total of 91 stents). TASC iliac lesion types and the status of the ipsilateral profunda femoris artery were not significantly different among the four groups. Seventeen limbs (9%) had subsequent infrainguinal bypass: three in the pSFA, seven in the oSFA, four in the sSFA, and three in the aSFA groups (p = 0.19). The primary patency rate was significantly decreased in the sSFA group (29% at 3 years, Kaplan-Meier log-rank, p < 0.0001) compared with the other three groups; however, there were no significant differences among the pSFA, oSFA, and aSFA groups (67%, 67%, and 86% at 3 years, respectively; p = 0.92). The continued clinical improvement rates were significantly decreased in the sSFA group (36% at 3 years, p = 0.0043) compared with the other three groups; however, there was no significant difference between the pSFA, oSFA, and aSFA groups (81%, 84%, and 75% at 3 years, respectively; p = 0.088). The assisted primary and secondary patency and limb salvage rates were not significantly different among the four groups (p > 0.40). Stratified analysis in patients with TASC type B/type C, critical limb ischemia, or claudicants revealed similar results. The primary patency and continued clinical improvement were significantly decreased in patients with stenotic SFAs, suggesting that concomitant SFA angioplasty might improve iliac patency after iliac PTA for patients with stenotic SFAs. The presence of an occluded SFA did not adversely affect the outcomes of iliac PTA. During iliac PTA, a stenotic SFA should be considered for revascularization via endovascular means but an occluded SFA can be observed.

Long-term outcomes and predictors of iliac angioplasty with selective stenting.

OBJECTIVE: To review our 11-year experience of iliac angioplasty with selective stenting and to evaluate the safety, short- and long-term patency, clinical success rates, and predictive risk factors in patients with iliac artery occlusive disease. METHODS: From August 1993 to November 2004, 151 iliac lesions (149 stenoses, 2 occlusions) in 104 patients were treated by percutaneous transluminal angioplasty (PTA). The patients had chronic limb ischemia described as disabling claudication (the Society for Vascular Surgery clinical category 2 or 3) in 76 (50%), rest pain (category 4) in 38 (25%), and ulcer/gangrene (category 5) in 37 (25%). Forty-six limbs (30%) were treated with concomitant infrainguinal endovascular (36, 24%) or open procedures (10, 6%). Thirty-four limbs (23%) had one or more stents placed for primary PTA failure, including residual stenosis (> or =30%), mean pressure gradient (> or =5 mm Hg), or dissection (stent group); whereas, 117 limbs (77%) underwent PTA alone (PTA group). The affected arteries treated were 28 (19%) common iliac, 31 (20%) external iliac, and 92 (61%) both arteries. According to TransAtlantic Inter-Society Consensus (TASC) classification, 39 limbs (26%) were in type A, 71 (47%) in type B, 36 (24%) in type C, and 5 (3%) in type D. Reporting standards of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were followed. RESULTS: There was no perioperative death. Total complication rate was 0.7% (one groin hematoma). The mean follow-up was 21 months (median, 10; range, 1 to 94 months). Only 9 (8%) of 117 of the PTA group had subsequent stent placement for recurrent stenosis. The iliac lesions were more severe and extensive in the stent group than those in the PTA group according to TASC classification (Mann-Whitney U test [M-W], P < .0001) and anatomic location (M-W, P = .0019). The technical success rate was 99%, and the initial clinical success rate was 99%. Overall, the cumulative primary patency rates at 1, 3, and 5 years were 76%, 59%, and 49% (Kaplan-Meier [K-M]). The cumulative assisted primary and secondary patency rates at 7 years were 98% and 99% (K-M). The mean number of subsequent iliac endovascular procedures was 1.4 per limb in patients with primary failure of iliac angioplasty/stenting. The continued clinical improvement rates at 1, 3, and 5 years were 81%, 67%, and 53% (K-M). The limb salvage rates at 7 year were 93% (K-M). Of 15 predictor variables studied in 151 iliac lesions, the significant independent predictors for adverse outcomes were smoking history (P = .0074), TASC type C/type D lesions (P = .0001), and stenotic ipsilateral superficial femoral artery (P = .0002) for the primary patency rates; chronic renal failure with hemodialysis (P = .014), ulcer/gangrene as an indication for PTA (P < .0001), and stenotic ipsilateral superficial femoral artery (P = .034) for the continued clinical improvement (K-M, log-rank test and Cox regression model). CONCLUSIONS: Although the primary patency rates were not high, the assisted primary and secondary patency rates were excellent without primary stenting. Overall, >70% of iliac lesions were treated successfully with PTA alone. The results of this study show that selective stenting offers satisfactory assisted primary and secondary long-term patency after iliac angioplasty. Patients with TASC type C/type D iliac lesions, a stenotic ipsilateral superficial femoral artery, ulcer/gangrene, smoking history, and chronic renal failure with hemodialysis should be followed carefully after endovascular iliac revascularization. These risk factors could be considered indications for primary stenting, although further studies are needed to confirm this.

Thoracic outlet syndrome: pattern of clinical success after operative decompression.

OBJECTIVE: To evaluate the pattern of clinical results in patients with neurogenic thoracic outlet syndrome (N-TOS) after operative decompression and longitudinal follow-up. METHODS: From May 1994 to December 2002, 254 operative sides in 185 patients with N-TOS were treated by the same operative protocol: (1) transaxillary first rib resection and the lower part of scalenectomy for the primary procedure with or without (2) the subsequent upper part of scalenectomy with supraclavicular approach for patients with persistent or recurrent symptoms. This retrospective cohort study included 38 men and 147 women with an age range of 19 to 80 years (mean, 40 years). Evaluated were primary success, defined as uninterrupted success with no procedure performed, and secondary success, defined as success maintained by the secondary operation after the primary failure. Success was defined as > or =50% symptomatic improvement judged by the patient using a 10-point scale, returning to preoperational work status, or both. RESULTS: Follow-up was 2 to 76 months (mean, 25 months). Eighty sides underwent a secondary operation for the primary clinical failure. No technical failures and no deaths occurred < o =30 days after the operations. The complication rate was 4% (13/334) and consisted of 7 pneumothoraxes, 3 subclavian vein injuries, 1 nerve injury, 1 internal mammary artery injury, and 1 suture granuloma. Of 254 operative sides, the primary and secondary success was 46% (118/254) and 64% (163/254). Most the primary failures (90%, 122/136) and the secondary failures (66%, 23/35) occurred < or =18 months after the respective operation. CONCLUSIONS: The long-term results of operations for TOS in this study were much worse than those initially achieved, and most of the primary and secondary failures occurred < or =12 months of the respective operations. A minimum of 18-month follow-up on patients and standardized definition of the outcomes are necessary to determine the true effectiveness and outcome of operative treatment of N-TOS.

The effectiveness of percutaneous transluminal angioplasty for the treatment of critical limb ischemia: a 10-year experience.

OBJECTIVE: To determine the efficacy, safety, and long-term results, including continued clinical improvement and limb salvage, of percutaneous transluminal angioplasty (PTA) in patients with critical limb ischemia (CLI). METHODS: From August 1993 to March 2004, 138 limbs in 111 patients with CLI (rest pain in 62 [45%] and ulcer/gangrene in 76 [55%]) were treated by PTA. In iliac lesions, stents were placed selectively for primary PTA failure: residual stenosis (>30%) or pressure gradient (>5 mm Hg). Stent placement was limited in infrainguinal lesions. The most distal affected arteries treated with angioplasty were the iliac artery in 45 limbs (33%; iliac group), the femoropopliteal artery in 41 limbs (30%; FP group), and tibial arteries in 52 limbs (37%; BK group). All analysis was performed according to an intent-to-treat basis. Reporting standards of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were followed to evaluate initial success, and late follow-up status was evaluated with the Kaplan-Meier method. Patency was evaluated by using ultrasound scanning and ankle-brachial pressure index measurement. RESULTS: There was one (0.9%) perioperative death. Twenty stents were placed selectively in 14 iliac arteries. Mean follow-up was 14.7 months (range, 1-75 months). Overall, initial technical and clinical success rates were 96.4% and 92.8%, respectively. The cumulative primary, assisted primary, and secondary patency; continued clinical improvement; and limb salvage rates +/- SE at 5 years were 31.4% +/- 10.4%, 75.5% +/- 5.7%, 79.6% +/- 5.5%, 36.1% +/- 10.0%, and 89.1% +/- 4.0%, respectively. In each subgroup, the primary, assisted primary, and secondary patency; continued clinical improvement; and limb salvage rates at 3 years were 51.6%, 94.7%, 97.8%, 65.1%, and 95.0%, respectively, in the iliac group; 49.4%, 72.2%, 76.4%, 57.4%, and 92.7%, respectively, in the FP group; and 23.5%, 41.8%, 46.1%, 51.1%, and 77.3%, respectively, in the BK group. Of the 12 predictable variables, hypertension, multiple segment lesions, more distal lesions, and TransAtlantic Inter-Society Consensus classification type D were significant independent risk factors for the outcomes ( P < .05; univariate log-rank test and Cox regression multivariate analysis). CONCLUSIONS: PTA is a feasible, safe, and effective procedure for the treatment of CLI. The high limb salvage rate is attributed to the high assisted primary and secondary patency rates despite the low primary patency rate. Angioplasty can be the primary choice for the treatment of CLI due to iliac and infrainguinal arterial occlusive disease.