High-dose Bolus Research Articles

Correlation between lymphocyte counts and response to outpatient intravenous interleukin-2 preceded by famotidine in metastatic melanoma.

8585 Background: Increased numbers of peripheral blood lymphocytes have been seen in patients receiving high-dose continuous and bolus infusion Interleukin-2 (IL-2) regimens. The toxicity of high-dose IL-2 due to a “capillary leak” syndrome requires in-patient administration of such regimens. Daily intravenous doses of IL-2 of 18-21.6 MIU/m2 over 15-30 minutes have been developed to attempt to lessen toxicity of this therapy. Famotidine may increase Interleukin-2 internalization by the IL-2 receptor on lymphocytes (Tsunoda, 1992). Previously, we have shown that patients with metastatic melanoma may be treated safely with outpatient intravenous Interleukin-2 preceded by intravenous famotidine daily for 3-5 days (Quan et al, 2003; Quan et al, 2010). The current study involves 17 patients with metastatic melanoma. Methods: Thirteen patients with stage IV melanoma received IL-2 18 MIU/m2 intravenously (IV) preceded by famotidine 20 mg IV daily for 3 days for six consecutive weeks. Four patients with metastatic melanoma received IL-2 21.6 MIU/m2 IV preceded by famotidine 20 mg IV daily for four days every 3 weeks. Peripheral blood lymphocyte counts were measured on the first day of each week of IL-2 therapy for all patients. Student’s t-test was used to compare the highest lymphocyte counts in responding patients vs. non-responders. Results: Four patients experienced either a complete (2) or partial (2) response. Thirteen patients were non-responders. The median lymphocyte count achieved in the responding patients was 4750/mm3 (range: 3100-5314/mm3) compared to the median of 2400/mm3 (range: 1500-4949/mm3) in the non-responders (p = 0.008). Conclusions: Peripheral blood lymphocyte numbers are significantly higher in patients with metastatic melanoma responding to outpatient intravenous Interleukin-2 preceded by famotidine than in non-responders. Further studies using flow cytometry and lymphocyte cytoxicity assays are currently being done.

Adoptive transfer of short-term cultured tumor-infiltrating lymphocytes (young TIL) in metastatic melanoma patients.

8510 Background: Treatment of metastatic melanoma patients with adoptively transferred Tumor Infiltrating Lymphocytes (TIL) has developed into an effective therapy. The use of unselected, short term cultured (young) TIL simplifies the laboratory production process. Our aim was to explore the effectiveness and toxicity of adoptive young TIL transfer in metastatic melanoma patients (ClinicalTrial.gov NCT00287131). Methods: Patients were eligible if they had progressed on prior IL2 based treatment and had adequate organ function. Amended protocol since 5/10 allowed recruitment of patients with CNS metastasis without major neurologic deficit. Patients received lympho-depleting chemotherapy with CTX and fludarabin before TIL administration followed by high dose bolus IL2 infusion. Results: Sixty five patients were enrolled in the study and Young-TIL cultures were successfully generated for 60 (92%). Ten patients clinically deteriorated during TIL production, resulting in a total drop-out rate of 23% (15/65). 26 of 38 treated and evaluated patients had M1c disease, including two patients with CNS involvement. Overall response rate was 42% (16/38) including 13% CR (n=5) and 29% PR (n=11). Eleven additional patients demonstrated disease stabilization. Median OS was 10 months. There was a significant difference in the median OS of responding and non-responding patients (18 vs. 5 months respectively, p=0.002). Most common grade 3/4 toxicities were neutropenic fever (92%, 35/38) pulmonary congestion (28%), hypotension (9%), diarrhea (9%) and hyperbilirubinemia (9%). All toxicities were transient. Patients were hospitalized on average for 20 days. There was no treatment related mortality. Probability of response was related to short culture duration of TIL (13.9±2.8 vs. 18.4±5.5 days, p=0.005) and higher amount of CD8 cells within the infused TIL population (40.6±17.7 x109 vs. 22.4±17.6 x109 cells, p=0.009). Conclusions: Transfer of Young-TIL can mediate tumor regression in 42% of metastatic melanoma patients with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major impact on cell therapy for melanoma patients.

Prognostic factors in methylprednisolone pulse therapy for alopecia areata

Many treatments induce remission in patients with alopecia areata. Systemic steroids, for example, are effective in the treatment of severe alopecia areata but have many side-effects. To avoid these side-effects, high-dose bolus infusions of methylprednisolone have been used to treat severe alopecia areata. The purpose of this study was to evaluate the prognostic factors associated with pulse therapy and to establish proper indications for methylprednisolone pulse therapy. Seventy patients with severe alopecia areata were treated i.v. with methylprednisolone on 3 consecutive days. All of the patients had rapid and extensive hair loss with the bald area exceeding 50% of the scalp. Seventy percent of the patients showed terminal hair growth and 41.4% showed complete responses with acceptable cosmetic outcomes. The prognostic factors that influenced successful outcome were the disease duration before treatment and the type of alopecia areata. Based on these two factors, a good response was obtained for all types of alopecia areata with a duration of 3months or less before treatment and for the plurifocal type of alopecia areata with a duration of 4-6months. Methylprednisolone pulse therapy is indicated for those alopecia areata patients who fall within our good response group.

Pulse Interleukin-2 with Famotidine Induces CD56+ Lymphocytes in the Peripheral Blood of Patients with Metastatic Melanoma or Kidney Cancer

Increased lymphokine-activated killer (LAK) cell numbers and cytotoxicity against tumor cell lines have been seen in patients receiving high-dose continuous and bolus infusion interleukin-2 (IL-2) regimens. LAK are CD56 positive on flow cytometry. Daily intravenous doses of IL-2 of 18-21.6 MIU/m(2) over 15-30 minutes ("pulses") have been developed to attempt to lessen the toxicity of this therapy. It has been previously shown that the patients with metastatic melanoma or kidney cancer may be treated safely with pulse IL-2 daily for 5 days preceded by intravenous famotidine. Cycles were repeated every 21 days. Because LAK numbers have not been previously described with this regimen, the present study has examined CD56 numbers via peripheral blood flow cytometry in 11 patients with samples scheduled at baseline, after two cycles, and after four cycles. Eight (8) patients had melanoma and 3 had kidney cancer. Median CD56 counts after two cycles was significantly higher than baseline (p = 0.001). Similarly, CD56 counts at 2 months later were also greater than baseline (p = 0.009). There was no difference between median values after two cycles versus after four cycles. Patients who were clinical responders had a median CD56 count of 650 after two cycles when compared with nonresponders who had a median CD56 count of 290 (p = 0.005). CD56 counts are significantly elevated in patients treated with pulse IL-2 with famotidine and clinical responders have significantly higher CD56 than nonresponders.

A randomized two‐by‐two comparison of high‐dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: The tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial

In the absence of high-dose thienopyridines, placebo-controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head-to-head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high-dose bolus (25 μg/kg) plus 12-hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30-day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. With limited assessment, this direct comparison of high-dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations.

Persistent Coronary No Flow After Wire Insertion Is an Early and Readily Available Mortality Risk Factor Despite Successful Mechanical Intervention in Acute Myocardial Infarction: A Pooled Analysis From the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent

These studies sought to investigate the impact on mortality of coronary flow after passage of the wire through the culprit vessel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical reperfusion. Reduced spontaneous coronary flow before percutaneous coronary intervention influences mortality in patients with STEMI. Response to vessel wiring in patients with an occluded coronary artery before intervention might further discriminate outcomes irrespective of pre- and post-intervention coronary flow. Data from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials were pooled: of 919 index procedures, 902 films (98%) were technically adequate for core laboratory TIMI (Thrombolysis In Myocardial Infarction) flow determination. TIMI flow grade 0 was present before percutaneous coronary intervention in 59% of infarct vessels, TIMI flow grade 1 to 2 was found in 21%, whereas the remainder of infarct arteries presented with TIMI flow grade 3. In 49% of patients who showed persistent TIMI flow grade 0 after wire insertion (AWI), mortality was higher at 30 days (5.3%) and 1 year (9.4%) compared with patients in whom TIMI flow grade before percutaneous coronary intervention was either >0 (0.8%; p < 0.003 and 3.6%, p < 0.008) or improved from 0 AWI (1.5%, p < 0.04 and 3.6%, p < 0.02). After correcting for multiple imbalances, including baseline and final flow, persistent TIMI flow grade 0 AWI remained associated at 30 days to 2-fold (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 1.08 to 5.00; p = 0.038) and at 1 year to almost 3-fold increases of mortality (RR: 2.7, 95% CI: 1.3 to 5.6; p = 0.008). STEMI patients displaying persistent no-flow AWI have a lower survival rate despite an apparently successful mechanical intervention. As an early marker for high residual mortality risk, persistent no-flow AWI may qualify STEMI patients for dedicated pharmacomechanical treatment strategies.

Prediction of 1-Year Clinical Outcomes Using the SYNTAX Score in Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Substudy of the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent

This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined. SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SXLOW ≤9 (n = 311), 9 < SXMID ≤16 (n = 234), SXHIGH >16 (n = 262). At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all-cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1-year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively. SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2×2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515)

A general dual-bolus approach for quantitative DCE-MRI

Purpose To present a dual-bolus technique for quantitative dynamic contrast-enhanced MRI (DCE-MRI) and show that it can give an arterial input function (AIF) measurement equivalent to that from a single-bolus protocol. Methods Five rabbits were imaged using a dual-bolus technique applicable for high-resolution DCE-MRI, incorporating a time resolved imaging of contrast kinetics (TRICKS) sequence for rapid temporal sampling. AIFs were measured from both the low-dose prebolus and the high-dose main bolus in the abdominal aorta. In one animal, TRICKS and fast spoiled gradient echo (FSPGR) acquisitions were compared. Results The scaled prebolus AIF was shown to match the main bolus AIF, with 95% confidence intervals overlapping for fits of gamma-variate functions to the first pass and linear fits to the washout phase, with the exception of one case. The AIFs measured using TRICKS and FSPGR were shown to be equivalent in one animal. Conclusion The proposed technique can capture even the rapid circulation kinetics in the rabbit aorta, and the scaled prebolus AIF is equivalent to the AIF from a high-dose injection. This allows separate measurements of the AIF and tissue uptake curves, meaning that each curve can then be acquired using a protocol tailored to its specific requirements.

The Impact of Dose Rate on Ethylene Glycol Developmental Toxicity and Pharmacokinetics in Pregnant CD Rats

High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low-level exposures that do not saturate GA metabolism have a low potential for developmental effects. Toward the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an sc implantable pump. In the sc bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, whereas increases in 2 malformations and 2 variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure versus sc infusion of EG. Although dose rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.

E0522 Dual antiplatelet plus tirofiban therapy have a beneficial effect on acute coronary syndrome in diabetic patients undergoing percutaneous coronary intervention

BackgroundDiabetes is strongly associated with clopidogrel resistance, thrombosis and the development of coronary artery disease (CAD). Some trials suggest that inhibition of glycoprotein IIb/IIIa can improve the outcome of clopidogrel...

Effects of Kangpa bolus on behaviors and dopamine concentration of striatum in Parkinson's disease model animals

Objective To investigate the effects of Kangpa bolus on behaviors, dopamine and its metabolites of striatum in animals with Parkinson' s disease (PD). Methods The mice models of muscle tremor and rigor were established to observe the antagonism of Kangpa bolus. Step-down and step-through tests were used to evaluate the effects of Kangpa bolus on learning and memory function in mice. The rat model of PD was established to observe the effects of Kangpa bolus on rotation behaviors. The contents of DA and homovanillic acid( HVA) in the injured side of striatum were detected by ELISA. Results Compared with model group(723. 1 ±79.3) s,the duration of tremor in mice shortened significantly (P < 0. 01) in Kangpa bolus high dose and middle dose group ((548.0±27.0)s,(590.9 ±28.7)s). Compared with model group(3194.5 ±251.7)s,the duration of rigor in mice shortened significantly(P<0.01) in Kangpa bolus all dose group((2300.1 ±352.5)s,(2478.2 ±276.6)s, (2559.3 ±207.6) s). In step-down test, compared with model group (3. 10 ±0.74), the number of errors decreased significantly(P<0.01) in Kangpa bolus high dose and middle dose group (1.60 ±0. 97,1. 80 ±0.63). In step-through test, compared with model group( 2.30 ± 0. 68), the number of errors decreased significantly (P < 0.01) in Kangpa bolus high dose and middle dose group(0.80 ±0.79,1.10 ±0.74). Compared with model group (340.6 ±18.8) , the number of rotations of PD rats in thirty minutes reduced significantly (P< 0.01) in Kangpa bolus high dose and middle dose group(286.5 ± 12.1,296.6 ± 12.7) after three weeks treatment. Compared with model group(9.43 ±1.79,0. 87 ±0.12) nmol/L,the contents of DA and HVA in the injured side of striatum increased significantly(P<0. 01 ) in Kangpa bolus high dose( 18. 9 ±4. 01,1. 50 ± 1. 39) nmol/L and middle dose group (17.3±3.01,1.39±0.53)nmol/L Conclusion Kangpa bolus has some therapeutic effects on the animals of PD. Key words: Parkinson disease; Kangpa bolus; Step-down test; Step-through test; Rotation test

Effect of High-Dose Once-Yearly Bolus of Oral Vitamin D on Falls and Fractures in Older Women

The reported effects of vitamin D supplements on falls and fractures in randomized controlled trials (RCTs) are inconsistent [1]. However, in meta-analyses, vitamin D supplements have been shown to reduce the risk of falls and fractures, which depended on the dose of vitamin D supplements and the achieved serum levels of 25(OH)D3 [2, 3]. Vitamin D can be given in daily doses or as a bolus. Many studies have shown that adherence to treatment is low. Therefore, a high-dose bolus could be of interest to increase adherence, even more so in the elderly. Aims

Prehospital high-dose tirofiban in patients undergoing primary percutaneous intervention. The AGIR-2 study

Compared with administration in the catheterization laboratory, early treatment with glycoprotein IIb/IIIa inhibitors provides benefits to patients with ST-segment elevation myocardial infarction who undergo primary percutaneous intervention. Whether this benefit is maintained on top of a 600 mg loading dose of clopidogrel is unknown. In a multicentre, controlled, randomized study, 320 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention received a high-dose bolus of tirofiban given either in the ambulance (prehospital group) or in the catheterization laboratory. The primary endpoint was a TIMI flow grade 2-3 of the infarct-related vessel at initial angiography. Secondary endpoints included ST-segment resolution 1h after percutaneous coronary intervention and peak serum troponin I concentration. Tirofiban was administered 48 (95% confidence interval 21.4-75.0) min earlier in the prehospital group. At initial angiography, the combined incidence of TIMI 2-3 flow was 39.7% in the catheterization-laboratory group and 44.2% in the prehospital group (p=0.45). No difference was found on postpercutaneous intervention angiography or peak troponin concentration. Complete ST-segment resolution 60 min after the start of intervention was 55.4% in the catheterization-laboratory group and 52.6% in the prehospital group (p=0.32). Prehospital initiation of high-dose bolus tirofiban did not improve significantly initial TIMI 2 or 3 flow of the infarct-related artery or complete ST-segment resolution after coronary intervention compared with initiation of tirofiban in the catheterization laboratory (NCT00538317).

Continuous positive airway pressure for cardiogenic pulmonary edema: a randomized study

Study Objective The purpose of this randomized controlled trial was to determine the immediate and delayed effects of noninvasive ventilation for patients in acute cardiogenic pulmonary edema (ACPE) in addition to aggressive usual care in a medical prehospital setting. Methods Out-of-hospital patients in severe ACPE were eligible for the study. Patients were randomized to receive either usual care, including conventional optimal treatment with furosemide, oxygen, and high-dose boluses of isosorbide dinitrate plus oxygen, or conventional medications plus out-of-hospital continuous positive airway pressure (CPAP). The primary outcome was the treatment success defined as all of respiratory rate less than 25 breaths per minute and oxygen saturation of greater than 90% at the end of 1-hour study. Secondary end points included death during 30 days after inclusion. Lengths of intensive care unit and hospital stays were also recorded. Results In total, 124 patients were enrolled into the study. The 2 groups had similar baseline characteristics. For the primary outcome analysis, 22 (35.5%) of 62 patients were considered as experiencing a treatment success in the usual care group vs 19 (31.7%) of 60 in the CPAP group ( P = .65). Seven patients died within 30 days in the usual care group vs 6 in the CPAP group ( P = .52). There were no statistically significant differences between the treatment groups for length of stay either in hospital or in the intensive care unit. Conclusion In the prehospital setting, in spite of its potential advantages for patients in ACPE, CPAP may not be preferred to a strict optimal intravenous treatment.

Intracoronary Compared to Intravenous Abciximab and High-Dose Bolus Compared to Standard Dose in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Transradial Primary Percutaneous Coronary Intervention: a Two-by-Two Factorial Placebo-Controlled Randomized Study

Platelet aggregation inhibition (PAI) of > or =95% has been associated with improved outcomes after percutaneous coronary intervention (PCI) and glycoprotein IIb/IIIa inhibitor treatment. A greater thrombotic burden in acute ST-segment elevation myocardial infarction (STEMI) might require higher doses and/or intracoronary delivery of glycoprotein IIb/IIIa inhibitors to achieve optimal PAI. Using a 2 x 2 factorial placebo-controlled design, 105 patients with STEMI who had been referred for primary PCI within 6 hours of symptom onset were randomized to intracoronary (IC) or intravenous (IV) delivery of an abciximab bolus at a standard dose (0.25 mg/kg) or high dose (> or =0.30 mg/kg) of abciximab. The primary end point was PAI measured at 10 minutes after the bolus of abciximab. Secondary end points included the acute and 6-month outcomes using angiographic parameters, cardiac biomarkers, cardiovascular magnetic resonance imaging, and clinical end points. At 10 minutes after the bolus, the proportion of patients with > or =95% PAI was not different between the IC and IV groups (53% vs 54%, p = 1.00) nor between the high-dose and standard-dose bolus groups (56% vs 51%, p = 0.70). Acutely, the angiographic myocardial blush grades, peak release of cardiac biomarkers, necrosis size, myocardial perfusion, and no reflow as assessed by magnetic resonance imaging, and clinical end points were similar between the groups and did not suggest a benefit for IC compared to IV or high-dose versus standard-dose bolus of abciximab. No increase occurred in bleeding complications with the high-dose bolus or IC delivery. The clinical, angiographic and cardiac magnetic resonance imaging outcomes at 6 and 12 months were similar between the 4 groups. In conclusion, in patients with STEMI presenting with symptom onset <6 hours and undergoing transradial primary PCI, PAI remained suboptimal, despite a higher dose bolus of abciximab. A higher dose bolus or IC delivery of abciximab bolus was not associated with improved acute or late results compared to the standard IV dosing and administration.

Safety of downstream high-dose tirofiban bolus among 1578 patients undergoing percutaneous coronary intervention: the Sant'ANna TIrofiban Safety study

The Sant'ANna TIrofiban Safety study (SANTISS) is an open-label investigator-initiated single-centre registry launched to assess the combination of bleeding and access site in-hospital complications (primary end-point) in patients undergoing percutaneous coronary intervention (PCI) by femoral approach only. We compared patients who were on oral single antiaggregating drug (AAD) and received, just prior to PCI, high-dose tirofiban and a second oral antiplatelet agent (triple AAD: group 1, n = 970) with those who were already on an oral double AAD regimen and did not receive tirofiban (double AAD: group 2, n = 608). Group 2 patients were slightly older, presented less frequently with unstable angina and had chronic renal failure more frequently. They were more than twice as frequently on rescue PCI, being more than three-fold less frequently on primary PCI (all: 0.01>P < 0.001). Overall, there were 87 in-hospital (average 4.7 days of stay) complications: 51 (5.3%) in group 1 and 36 (5.9%) in group 2 (not significant). Haemotransfusions were needed in 34 patients: 21 (2.2%) in group 1 and 13 (2.1%) in group 2 (not significant). Of the 16 hospital deaths, eight (0.8%) were seen in group 1 and eight (1.3%) in group 2 (not significant). Multivariate prediction showed a high predictive accuracy (areas under the curve >0.700) of female sex, rescue PCI and chronic renal failure to index complications, with highly significant odds ratios. The presence of high-dose tirofiban did not increase complication risk. In the real world, high-dose tirofiban is well tolerated by patients on elective, primary or rescue PCI, and the in-hospital complication rate, including major bleeding, is low. This may have pharmacoeconomic consequences.

Assessment of tumor blood flow in breast tumors with T1‐dynamic contrast‐enhanced MR Imaging: Impact of dose reduction and the use of a prebolus technique on diagnostic efficacy

To prospectively evaluate whether dose reduction and the application of a prebolus technique can effectively alleviate signal saturation effects in T1 dynamic contrast enhanced (T1-DCE) magnetic resonance imaging (MRI) data in breast tumors and lead to increased diagnostic efficacy of the regional tumor blood flow (TBF) values obtained with deconvolution of T1-DCE MRI data. After obtaining informed consent, 23 women (32-80 years) with histologically proven breast tumors underwent MR mammography that included a whole-breast T1 DCE sequence. In the slice where the tumor enhanced maximally, a prebolus protocol was applied. One mL of Gd-DTPA solution at 2 mL/s was injected at the beginning of a dynamic axial single slice inversion-prepared turbo field echo acquisition. At the 400th dynamic, a high dose of either 20 mL (15 patients) or 10 mL (8 patients) of contrast agent was injected at 2 mL/s and a further 400 dynamics were acquired. From the aortic prebolus curve an arterial input function (AIF) was reconstructed by time-shifting and adding the prebolus data. The relative enhancement time course from the tumor region of interest was deconvolved with the reconstructed AIF to generate the impulse response function, the maximum of which yielded the TBF. The institutional ethical committee approved the study. Reducing the contrast dose by a factor of 2 led to an increase in diagnostic contrast for the TBF values of malignant and benign tumors by a factor of slightly more than 2. Addition of the prebolus technique improved this further by 45%. receiver operating characteristic analysis showed a significant increase of diagnostic yield related to the combined use of a prebolus and minimal dose. Using a prebolus approach provides an estimate of the unsaturated AIF, while reduction of the high-dose bolus minimizes possible saturation effects in the tumor time course.

Cytokine Working Group Study of Lymphodepleting Chemotherapy, Interleukin-2, and Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Metastatic Melanoma: Clinical Outcomes and Peripheral-Blood Cell Recovery

Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

Effect of High-Dose Intracoronary Adenosine Administration During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: A Randomized Controlled Trial

Effect of High-Dose Intracoronary Adenosine Administration During Primary Percutaneous Coronary Intervention in Acute Myocardial Infarction: A Randomized Controlled Trial

Differences in sensitivity to the convulsant pilocarpine in substrains and sublines of C57BL/6 mice

In rodents, the cholinomimetic convulsant pilocarpine is widely used to induce status epilepticus (SE), followed by hippocampal damage and spontaneous recurrent seizures, resembling temporal lobe epilepsy. This model has initially been described in rats, but is increasingly used in mice, including the C57BL/6 (B6) inbred strain. In the present study, we compared the effects of pilocarpine in three B6 substrains (B6JOla, B6NHsd and B6NCrl) that were previously reported to differ in several behavioral and genetic aspects. In B6JOla and B6NHsd, only a small percentage of mice developed SE independently of whether pilocarpine was administered at high bolus doses or with a ramping up dosing protocol, but mortality was high. The reverse was true in B6NCrl, in which a high percentage of mice developed SE, but mortality was much lower compared to the other substrains. However, in subsequent experiments with B6NCrl mice, striking differences in SE induction and mortality were found in sublines of this substrain coming from different barrier rooms of the same vendor. In B6NCrl from Barrier #8, administration of pilocarpine resulted in a high percentage of mice developing SE, but mortality was low, whereas the opposite was found in B6NCrl mice from four other barriers of the same vendor. The analysis of F1 mice from a cross of female Barrier 8 pilocarpine-susceptible mice with resistant male mice from another barrier (#9) revealed that F1 male mice were significantly more sensitive to pilocarpine than the resistant parental male mice whereas female F1 mice were not significantly different from resistant Barrier 9 females. These observations strongly indicate X-chromosome linked genetic variation as the cause of the observed phenotypic alterations. To our knowledge, this is the first report which demonstrates that not only the specific B6 substrain but also sublines derived from the same substrain may markedly differ in their response to convulsants such as pilocarpine. As the described differences have a genetic basis, they offer a unique opportunity to identify the genes and pathways involved and contribute to a better understanding of the underlying molecular mechanisms of seizure susceptibility.