Safety of Same-Day Hospital Discharge Post Patent Foramen Ovale Closure: Findings from a Multicenter Study.

Transcatheter patent foramen ovale (PFO) closure is indicated for patients with cryptogenic stroke. Although procedural safety is well established, there are limited data on the safety of same-day (SD) discharge. We aimed to review the outcomes of PFO closure with SD. Patients who underwent transcatheter PFO closure between January 2011 and May 2022 at 4 large US hospitals were retrospectively analyzed, comparing outcomes of SD versus delayed discharge (DD). The primary end point was a composite of access-site complication, stroke, device embolization, atrial arrhythmia, and bleeding. Secondary analysis comparing imaging modality and outcomes was performed. 554 patients (49.2% female) were analyzed (382 discharged SD). Average age was 54.3 ± 15. Baseline characteristics in both groups were broadly similar. Previous stroke (78.0% SD vs 76.2% DD, p = 0.32) was the commonest indication for PFO closure. In the SD group, there was less general anesthesia use (5.5% vs 16.9%, p <0.001). Intraprocedural intracardiac echocardiography was used more frequently in SD cases (95.0% vs 81.4%, p <0.001). In the DD group, median stay was 1 night, and 34.9% stayed beyond 1 night. At 30 days, there was no difference in the primary composite end point (14.9% vs 11.6%, p = 0.15). There was no inter-group difference in individual adverse events (all p >0.05). When comparing imaging modality and outcomes, there was no difference in composite end points between transesophageal and intracardiac echocardiography (6.5% vs 14.7%, p = 0.063). In conclusion, SD discharge after transcatheter PFO closure appears safe. This efficient approach may be advantageous in optimizing workflow and minimizing hospital occupancy.

Structural Heart Interventions in the Elderly Population.

Aortic stenosis is the most common valvular heart disease in the elderly population. Since the advent of transcatheter aortic valve implantation (TAVI) in 2002, the clinical indications for this alternative to a surgical replacement have continually expanded. While the treatment of octo- and nonagenarians can present significant challenges, here we present a case of TAVI in an elderly patient. Given her suitable anatomy and active lifestyle that had been limited by her disease state, the patient successfully underwent TAVI 3 weeks later and was discharged post-operative day 1. This case is the basis for providing five key points to remember about the work-up for TAVI for severe aortic stenosis in the elderly population.

Outcomes of transcatheter aortic valve replacement in end stage liver and renal disease.

OBJECTIVES: This study evaluates in-hospital, 30-day, and 1-year outcomes post-transcatheter aortic valve replacement (TAVR) in end stage liver disease (ESLD) and/or end stage renal disease (ESRD) compared with patients without these comorbidities. BACKGROUND: TAVR is an alternative to surgical aortic valve replacement in patients with ESLD and ESRD, though current outcomes data are limited. METHODS: We compared 309 patients (N = 29 ESLD and/or ESRD, N = 280 control) age > 18 who underwent transfemoral TAVR from 2014 to 2020 have been compared. RESULTS: Patients with ESLD and ESRD were younger (69.9 ± 11.7 vs. 79.1 ± 9.8, p < .01) with higher STS-PROM scores (8.1 ± 6.7 vs. 4.6 ± 3.9, p < .01). ESRD and ESLD patients had similar rates of in-hospital major vascular complications (3.4% vs. 3.2%, p = .96), major bleeding events (3.4% vs. 3.2%, p = .95), and mortality (0.0% vs. 1.8%, p = .47). Mortality rates were similar at 30-days (3.4% vs. 2.1%, p = .65) with trend to higher mortality at 6-months (6.9% vs. 3.2%, p = .31) and 1-year (15.4% vs. 7.0%, p = .13). Readmission rates were higher in the ESLD and ESRD cohort at 6-months (53.2% vs. 28.6%, p < .01) and 1-year (65.4% vs. 41.0%, p = .02). One patient received dual kidney-liver transplant, 1 patient received a liver transplant, and 7 additional patients were listed for transplant. CONCLUSION: Patients with ESLD and/or ESRD who underwent TAVR had similar mortality at discharge and 30-days compared with patients without these comorbidities with a trend toward increased mortality at 1-year. This study suggests that TAVR is an option for aortic valve disease patients with ESRD and/or ESLD in order to remove cardiac barriers to liver or kidney transplant.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Saccharomyces boulardii in Infants and Children With Acute Diarrhea.

AIM: This study was designed to assess the efficacy and safety of Saccharomyces cerevisiae variant boulardii CNCM I-3799 (S. boulardii CNCM I-3799) in the management of acute diarrhea in children. METHODS: A total of 100 infants and children 3-36 months of age with acute diarrhea received medical care according to the World Health Organization guidelines on the management of acute diarrhea in children and were randomly allocated to the probiotic group (S. boulardii CNCM I-3799 at a daily dose of 5 billion CFU twice daily) or to the placebo group. Infants and children were treated for 5 days and an extended follow-up was planned 1 and 2 months after the end of the treatment period. Primary endpoint was the time of recovery from diarrhea defined as the duration of diarrhea. Other parameters, such as frequency and consistency of stools, associated with the severity of diarrhea episodes were defined as secondary endpoints. RESULTS: The administration of S. boulardii CNCM I-3799 was associated with beneficial effects on duration and severity of diarrhea. The time of recovery from diarrhea was significantly shorter in the probiotic group compared with the placebo group (65.8 ± 12 hours vs. 95.3 ± 17.6 hours, P = 0.0001). Faster remission in the probiotic group was also demonstrated by a shorter time before the first episode of semisolid stool [-23.5 hours, diff (95% CI): -7.99 (-31.49 to -15.51), P = 0.0001] and the faster normalization of stool consistency. S. boulardii CNCM I-3799 was well tolerated. CONCLUSION: S. boulardii CNCM I-3799 supplementation in children with acute diarrhea was shown effective in reducing the duration and severity of diarrhea in infants and children.

A Complex Tricuspid Clip: Bridging the Decision.

We present this case of a 22-year-old woman with congenital heart disease as the youngest reported patient, to the best of our knowledge, to successfully undergo treatment of medically refractory torrential tricuspid regurgitation with the MitraClip system as an adjunct to guideline directed therapy. (Level of Difficulty: Advanced.).

An Industry Perspective on Risks and Mitigation Strategies Associated with Post Conduct Phase of Clinical Trial.

OBJECTIVE: To discuss the potential risks and their mitigation strategies in the post-conduct phase of the trial. BACKGROUND: Risk management is very important for the clinical trial (CT) to ensure that the trial delivers its desired outcome(s) in terms of achieving protocol objective and regulatory compliance. METHODOLOGY: Experienced members of the clinical operation team of a pharmaceutical major underwent a series of sessions to identify risks associated with the post-conduct phase of CT and developed mitigation strategies based on own experiences and guidance documents. The risks were categorized into major, minor and critical risks. RESULTS: In the post-conduct phase of a clinical trial, critical risk identified were; failure to communicate to the stakeholder about premature termination of the trial, mismatch of statistical analysis results and protocol objective/ regulatory requirement, clinical study report (CSR) noncompliant with regulatory requirements or delay in CSR preparation. Safety checks suggested to mitigate these risks including the development of related checklist or shell of relevant documents and its review by clinical development, quality assurance (QA) and regulatory affairs (RA) team prior to finalization. Additionally, six major and five minor risk areas were identified and safety checks were suggested. CONCLUSION: Sponsors must act proactively to ensure a systematic approach to conduct various post conduct trial activities and the plans to mitigate the risks that could affect the quality and outcome of the clinical trial. Future Perspective: A close coordination with all stakeholders for timely anticipation of risks and execution of mitigation strategies are required for successful CT outcomes.

Radial Percutaneous Coronary Intervention in Complex Arm and Chest Vasculature: Tips and Tricks.

PURPOSE OF REVIEW: The purpose of this review is to identify the anatomical difficulties an operator may encounter during the transradial approach for cardiac catheterization and to offer tips and tricks to overcome those challenges. RECENT FINDINGS: With increasing implementation of the transradial approach for cardiac catheterization, many new techniques have been utilized to overcome anatomical challenges. This article also discusses the difficulties faced during transradial approach in patients with prior coronary artery bypass grafting (CABG). Numerous large randomized trials have demonstrated the value of the transradial approach over the transfemoral approach during cardiac catheterization. However, this technique is routinely avoided or aborted due to anatomical variations in the upper arm and chest. These obstacles have delayed adoption of transradial access by operators despite the apparent benefits. This article reviews some of the available tips and tricks described in the literature to overcome anatomical obstacles. By implementing some of these tools into practice, an operator may realize improved procedural success, decreased procedure time, and improved patient comfort with the transradial approach.

Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers.

OBJECTIVE: This phase I study of ZYAN1 was conducted to evaluate the safety, tolerability, and pharmacokinetics following oral administration in healthy volunteers. METHODS: The study was a randomized, double-blind, placebo-controlled phase I study carried out in two parts in addition to a third part involving an open-label study to evaluate the food/sex effect. A total of 100 subjects were enrolled into the study as follows: part I-single-dose study with ZYAN1 10, 25, 50, 100, 150, 200, and 300 mg (n = 56); part II-multiple-dose study with every other day dosing of ZYAN1 100, 150, 200, and 300 mg (n = 32); and part III-sex and food effect study with ZYAN1 150 mg (n = 12; open-label). RESULTS: ZYAN1 was well-tolerated after single and multiple oral ascending doses. No drug-related serious adverse events were reported. Following a single ascending dose of ZYAN1, the maximum concentration (C max) ranged from 566.47 ± 163.03 to 17,858.33 ± 2899.19 ng/mL and the median time to C max (t max) was approximately 2.5 h for the studied 30-fold oral doses of ZYAN1. Regardless of single or multiple doses, mean C max and area under the concentration-time curve from time zero to time t (AUC t ) values generally showed a dose-proportional increase. The mean elimination half-life (t ½) of ZYAN1 ranged from 6.9 to 13 h with negligible accumulation. Following a single dose of ZYAN1, the mean serum erythropoietin (EPO) C max values showed dose response (i.e., 6.6 and 79.9 mIU/L for 10 and 300 mg ZYAN1 doses, respectively), while the time to mean maximal serum EPO concentrations ranged from 10 to 72 h. CONCLUSION: Oral single (10-300 mg) and multiple dosing (100-300 mg) of ZYAN1 in healthy subjects was found to be safe and well-tolerated. With increasing ZYAN1 dose, there was almost a proportional increase in mean C max and AUC t . The mean serum EPO concentrations showed a trend of dose response. Based on the t ½, pharmacodynamic activity, and lack of drug accumulation, a once every 2 days dosing regimen of ZYAN1 was appropriate for phase II study. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry trial ID ACTRN12614001240639.

Effect of Food on the Pharmacokinetics of Saroglitazar Magnesium, a Novel Dual PPARαγ Agonist, in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVE: Peroxisome proliferator-activated receptors (PPARs) have recently become a focus of interest for their important roles in glucose and lipid metabolism. In humans, PPARα activation causes a decrease in plasma triglyceride (TG) levels, enhancement of high-density lipoprotein cholesterol (HDL-C) and simultaneous enhancement of very-low-density lipoprotein (VLDL) lipolysis, whereas PPARγ agonists act as insulin sensitizers and improve insulin resistance, which is very useful in patients with type 2 diabetes mellitus (T2DM). Saroglitazar magnesium is a dual PPAR agonist with potent predominant PPARα and moderate PPARγ activity and the first glitazar to be granted marketing authorization in India. This study was conducted to evaluate the oral bioavailability and safety and tolerability of a Lipaglyn™ (saroglitazar magnesium) 4-mg tablet in healthy, adult human subjects under fed relative to fasting conditions. METHODS: This was a single-dose, open-label, randomized, single-treatment, two-period, two-conditions (fed vs. fasting), two-sequence, crossover study planned in 54 healthy subjects. Food effect (high-calorie and high-fat breakfast) was examined by comparing pharmacokinetic data of saroglitazar and its metabolite saroglitazar sulfoxide in plasma samples collected pre-dose and serially up to 72 h post-dose. Pharmacokinetic data were analyzed using the standard non-compartmental approach. RESULTS: A total of 54 subjects were enrolled in the study, out of them 50 subjects had completed the study and were analyzed. The presence of food had a minor impact on the disposition of saroglitazar. While food reduced C max (maximum concentration) of saroglitazar by 30%, the extent of absorption as measured by AUC∞ (area under the concentration time curve from time zero to infinity) was not influenced. This was further supported by the bioequivalence data between fasted and fed conditions for saroglitazar, where 90% CIs (confidence intervals) of the adjusted geometric mean of the fed relative to the fasted condition ranged from 101.37% to 108.07% for AUC∞ and from 63.45% to 74.68% for C max. Other parameters such as T max (time of maximum concentration) and T 1/2 (elimination half-life) were not influenced by the food intake. Saroglitazar was well tolerated in the study, and the reported adverse events were mild in nature. CONCLUSION: For the single-dose study, the absorption rate is affected by food as the 90% CI of C max is outside 80.00-125.00%. However, there is no impact of food on the extent of absorption of saroglitazar. The observed lower C max of saroglitazar with food has no clinical relevance since the therapeutic efficacy of saroglitazar was achieved after multiple-dose administration, suggesting the importance of total exposure.

Associations of Prolonged QTc in Sickle Cell Disease.

Sudden death is a leading cause of mortality in sickle cell disease, implicating ventricular tachyarrhythmias. Prolonged QTc on an electrocardiogram (ECG), commonly seen with myocardial ischemia, is a known risk for polymorphic ventricular tachycardia (VT). We hypothesized that prolonged QTc is associated with mortality in sickle cell disease. ECG were analyzed from a cohort of 224 sickle patients (University of Illinois at Chicago, UIC) along with available laboratory, and echocardiographic findings, and from another cohort of 38 patients (University of Chicago, UC) for which cardiac MRI and free heme values were also measured. In the UIC cohort, QTc was potentially related to mortality with a hazard ratio (HR) of 1.22 per 10ms, (P = 0.015), and a HR = 3.19 (P = 0.045) for a QTc>480ms. In multivariate analyses, QTc remained significantly associated with survival after adjusting for inpatient ECG status (HR 1.26 per 10ms interval, P = 0.010) and genotype status [HR 1.21 per 10ms interval, P = 0.037). QTc trended toward association with mortality after adjusting for both LDH and hydroxyurea use (HR 1.21 per 10ms interval, P = 0.062) but was not significant after adjusting for TRV. In univariate analyses, QTc was related to markers of hemolysis including AST (P = 0.031), hemoglobin (P = 0.014), TR velocity (P = 0.036), higher in inpatients (P<0.001) and those with an SS compared to SC genotype (P<0.001) in the UIC cohort as well as to free heme in the UC cohort (P = 0.002). These findings support a relationship of prolonged QTc with hemolysis and potentially mortality in sickle cell disease.

Safety and efficacy of rescue angioplasty for ST-elevation myocardial infarction with high utilization rates of glycoprotein IIb/IIIa inhibitors.

BACKGROUND: Fibrinolytic therapies remain widely used for ST-elevation myocardial infarction, and for "failed reperfusion," rescue percutaneous coronary intervention (PCI) is guideline recommended to improve outcomes. However, these recommendations are based on data from an earlier era of pharmacotherapy and procedural techniques. METHODS AND RESULTS: To determine factors affecting prognosis after rescue PCI, we studied 241 consecutive patients (median age 55 years, interquartile range [IQR] 48-65) undergoing procedures between 2001 and 2009 (53% anterior ST-elevation myocardial infarction and 78% transferred). The median treatment-related times were 1.2 hours (IQR 0.8-2.2) from symptom onset to door, 2 hours (IQR 1.3-3.2) from symptom onset to fibrinolysis (93% tenecteplase), and 3.9 hours (IQR 3.1-5.2) from fibrinolysis to balloon. Procedural characteristics were stent deployment in 95% (11.6% drug eluting) and 78% glycoprotein IIb/IIIa inhibitor use, and Thrombolysis In Myocardial Infarction (TIMI) 3 flow rates pre-PCI and post-PCI were 41% and 91%, respectively (P < .001). At 30 days, TIMI major bleeding occurred in 16 (6.6%) patients, and 23 (9.5%) patients received transfusions; nonfatal stroke occurred in 4 (1.7%) patients (2 hemorrhagic). Predictors of TIMI major bleeding were female gender (odds ratio 3.194, 95% CI 1.063-9.597; P = .039) and pre-PCI shock (odds ratio 3.619, 95% CI,1.073-12.207; P = .038). Mortality at 30 days was 6.2%, and 3.2% in patients without pre-PCI shock. One-year mortality was 8.2% (5.3% in patients without pre-PCI cardiogenic shock), 5.2% had reinfarction, and the target vessel revascularization rate was 6.4% (2.6% in arteries ≥ 3.5 mm in diameter). Pre-PCI shock, female gender, and post-PCI TIMI flow grades ≤ 2 were significant predictors of 1-year mortality on multivariable regression modeling, but TIMI major bleeding was not. CONCLUSIONS: Rescue PCI with contemporary treatments can achieve mortality rates similar to rates for contemporary primary PCI in patients without pre-PCI shock. Whether rates of bleeding can be reduced by different pharmacotherapies and interventional techniques needs clarification in future studies.

High on treatment platelet reactivity and stent thrombosis.

BACKGROUND: Stent thrombosis (ST) remains a major adverse outcome of percutaneous coronary intervention (PCI). We examined potential associations between high on treatment platelet reactivity and the risk of ST and assessed the effects of increased antiplatelet dosage on platelet inhibition. METHODS: Differences in clinical characteristics and the effect of aspirin and clopidogrel on platelet reactivity were determined after angiographically proven ST in 16 patients and in 40 patients without ST. Platelet reactivity was determined using the VerifyNow assays (Accumetrics Inc., San Diego, CA). Patients found with high on treatment platelet reactivity (P2Y12 Reaction Units ≥ 235 and/or Aspirin Reaction Units ≥ 550) returned following two weeks of double dose antiplatelet therapy for further analyses. RESULTS: High post aspirin and/or clopidogrel platelet reactivity was significantly more common in patients with ST versus controls (75% vs. 2.5%, p = < 0.001). Overall, ST patients were younger (52.8 ± 10.5 vs. 59 ± 9.6 years; p = 0.039), had more pre-existing coronary artery disease (75% vs. 42%; p = 0.028) and smaller reference vessel diameters (2.9 ± 0.36 vs. 3.2 ± 0.54 mm; p = 0.047) when compared to controls. After double dose therapy, antiplatelet reactivity improved significantly in ten out of 12 subjects on clopidogrel (83.3%) and the two patients on aspirin who initially had high on treatment platelet reactivity. CONCLUSION: This study demonstrates that high on treatment platelet reactivity with aspirin and/or clopidogrel is common amongst patients who develop stent thrombosis. Additionally this resistance can be improved with doubling the prior dose of antiplatelet therapy.

Abciximab as an adjunctive therapy for patients undergoing percutaneous coronary interventions.

INTRODUCTION: Platelets play a central role in the pathophysiology of acute coronary syndromes (ACS) and activation of platelet glycoprotein (GP) IIb/IIIa receptor is critical to platelet aggregation. Abciximab, a human murine chimeric antibody to the GPIIb/IIIa receptor, is an important biological therapy in the management of patients presenting with ACS. AREAS COVERED: The objective of this review is to define the role of abciximab in the management of ACS by interpreting the available data from randomized clinical trials using abciximab in various clinical scenarios, particularly in percutaneous coronary intervention (PCI). We also review different modes of delivery and describe the adverse effects of abciximab including thrombocytopenia. Where possible, we attempt to compare abciximab to the other available GPIIb/IIIa inhibitors. We hope the reader will gain a better understanding of the benefits and risks of abciximab and the important role it has in the management of cardiology patients. EXPERT OPINION: Abciximab was a breakthrough drug in the management of high risk ACS patients undergoing PCI. However, with newer available therapies and improvement in PCI technology, dose and delivery of this drug have evolved as we try to extract maximum benefit while minimizing the adverse effects associated with it.

Ultrasound-mediated delivery of echogenic immunoliposomes to porcine vascular smooth muscle cells in vivo.

Vascular smooth muscle cells (VSMCs) are important targets in the treatment of atherosclerosis. However, the arterial media, where the majority of VSMCs reside, have proven to be a difficult target for drug/gene delivery. We have demonstrated that ultrasound enhances drug/gene delivery to VSMCs in vitro by using echogenic immunoliposomes (ELIPs) as the vector. This study aimed to evaluate whether ultrasound can similarly enhance the delivery of an agent to VSMCs, particularly within the arterial media, in vivo, using ELIP. Anti-smooth-muscle cell actin-conjugated calcein-loaded ELIP were injected into the peripheral arteries of Yucatan miniswine (n = 8 arterial pairs). The right-sided porcine arteries were treated with 1-MHz continuous-wave ultrasound at a peak-to-peak pressure amplitude of 0.23 +/- 0.05 MPa for 2 minutes. The contralateral arteries served as controls. Arteries were harvested after 30 minutes and imaged with fluorescence microscopy. Image data were converted to grayscale and analyzed by using computer-assisted videodensitometry. There was significant improvement in calcein uptake in all three arterial layers in the arteries exposed to ultrasound (> 300%). This enhanced uptake was site specific and appeared limited to the ultrasound-treated arterial segment. We have demonstrated enhanced delivery of a small molecule to VSMCs in all arterial wall layers, particularly the arterial media, using ultrasound and targeted ELIP. The combined effect of ultrasound exposure and ELIP as a contrast agent and a drug/gene-bearing vector has the potential for site-specific therapy directed at VSMC function.

Lipid contribution to the affinity of antigen association with specific antibodies conjugated to liposomes.

Immunoliposomes, directed to clinically relevant cell-surface molecules with antibodies, antibody fragments or peptides, are used for site-specific diagnostic evaluation or delivery of therapeutic agents. We have developed intrinsically echogenic liposomes (ELIP) covalently linked to fibrin(ogen)-specific antibodies and Fab fragments for ultrasonic imaging of atherosclerotic plaques. In order to determine the effect of liposomal conjugation on the molecular dynamics of fibrinogen binding, we studied the thermodynamic characteristics of unconjugated and ELIP-conjugated antibody molecules. Utilizing radioimmunoassay and enzyme-linked immunosorbent assay protocols, binding affinities were derived from data obtained at three temperatures. The thermodynamic functions DeltaH(o) , DeltaG(o) and DeltaS(o) were determined from van't Hoff plots and equations of state. The resultant functions indicated that both specific and nonspecific associations of antibody molecules with fibrinogen occurred through a variety of molecular interactions, including hydrophophic, ionic and hydrogen bonding mechanisms. ELIP conjugation of antibodies and Fab fragments introduced a characteristic change in both DeltaH(o) and DeltaS(o) of association, which corresponded to a variable contribution to binding by phospholipid gel-liquid crystal phase transitions. These observations suggest that a reciprocal energy transduction, affecting the strength of antibody-antigen binding, may be a singular characteristic of immunoliposomes, having utility for optimization and further development of the technology.

Fibrin targeting of tissue plasminogen activator-loaded echogenic liposomes.

We recently reported entrapment of tissue-plasminogen activator (tPA) into echogenic liposomes (ELIP) with retention of echogenicity and thrombolytic effect. Integral to the potential of this agent for ultrasound-detectable local drug delivery is the specific binding of tPA-ELIP to clots. tPA contains fibrin-binding sites; we hypothesized that tPA when associated with ELIP, will maintain fibrin binding properties, rendering further manipulation for targeting of the tPA-ELIP unnecessary. We demonstrated strong fibrin binding of the ELIP-associated tPA. Fibrin binding for ELIP-associated tPA was twice that of free tPA. This strong affinity for fibrin was confirmed using echogenicity analysis of porcine clots in vitro. Both objective (mean gray scale analysis) and subjective (visual estimation by two experienced echocardiographers) evaluation of the clots showed enhanced highlighting of clots treated with tPA-ELIP when compared to control. The findings in this study represent new approaches for fibrin-targeted, ultrasound-directed and enhanced local delivery of a thrombolytic agent.

Increased systemic catecholamines in complex regional pain syndrome and relationship to psychological factors: a pilot study.

We have demonstrated that subjects with complex regional pain syndrome (CRPS) have asymmetric venous pool plasma concentrations of norepinephrine (NE) when affected and unaffected limbs are compared, with most demonstrating decreased NE levels in the affected limb. This pilot study explored whether systemic venous plasma catecholamine levels in CRPS subjects with sympathetically maintained pain (SMP) differ from those found in healthy volunteers. We also explored whether catecholamine levels were correlated with scores on psychometric measures of depression, anxiety, and personality. Venous blood samples from 33 CRPS/SMP patients (from unaffected limbs) and 30 healthy control subjects were assayed for plasma NE and epinephrine (E) concentrations. Plasma NE levels were significantly higher in the CRPS group (P < 0.001). Statistical comparisons of E levels across groups did not achieve significance (P < 0.06), although 52% of CRPS/SMP patients had E levels exceeding the 95% confidence interval based on control data. Significant positive correlations were found between E levels and scores on the Beck Depression Inventory and Scales 1, 3, and 6 on the Minnesota Multiphasic Personality Inventory-2 (all P < 0.05). This preliminary work suggests that increased NE and E levels in CRPS/SMP patients may result from the pain of CRPS, consequent affective distress, or both. Alternatively, our findings could reflect premorbid adrenergic hyperactivity caused by affective, endocrine, or other pathology, which might predispose these individuals to develop the syndrome. Definitive studies are needed to examine these hypotheses in detail.