Efficacy of 4% tetrasodium ethylenediaminetetraacetic acid (T-EDTA) catheter lock solution in home parenteral nutrition patients: A quality improvement evaluation.

INTRODUCTION: A functioning and reliable central venous access device is fundamental for home parenteral nutrition patients to administer essential nutrition. Complications of central venous access devices including occlusion, microbial colonization, and biofilm formation are problematic and sometimes life-threatening. A novel lock solution, 4% tetrasodium ethylenediaminetetraacetic acid, has properties that may reduce such complications. PURPOSE: The aim of this study was to determine the safety, efficacy, and cost implications of implementing 4% tetrasodium ethylenediaminetetraacetic acid to prevent catheter-related complications in home parenteral nutrition patients. METHODS: A pre- and post-intervention study was carried over 36 months (12 months pre; 24 months post) by the British Columbia Home Parenteral Nutrition Program in Vancouver, Canada, where 4% tetrasodium ethylenediaminetetraacetic acid was implemented for patients at high risk for central venous access device occlusion and catheter-related infection. Patients were included in the study if they had previous central venous access device complications. The outcomes evaluated were central line-associated bloodstream infection, catheter occlusion requiring thrombolytic treatment, and catheter replacements. RESULTS: In total, 22 out of 105 patients met the inclusion criteria. Two patients were excluded from analyses due to non-adherence and concomitant use of other lock solutions. Post intervention, 20 home parenteral nutrition patients experienced significant reduction in the central line-associated bloodstream infection rate (pre = 1.918/1000 catheter days; post = 0.563/1000 catheter days; p = 0.04) There were no occlusion events reported post intervention. CONCLUSION: For home parenteral nutrition patients, 4% tetrasodium ethylenediaminetetraacetic acid lock solution effectively reduces the risk of central venous access device complications including occlusions and catheter-related infections.

Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects.

10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (Cmax ) and area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-t ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA-10. Adverse events (AEs) were dose-related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA-10 was safe and well-tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA-10 75-300 mg once daily.

Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist.

The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.

Effect of memantine on cough reflex sensitivity: translational studies in guinea pigs and humans.

Cough is the most common complaint for which outpatients in the United States seek medical attention, and yet available therapeutic options for cough lack proven efficacy and are further limited by safety and abuse liabilities. Thus, safe and effective cough suppressants are needed. Recent preclinical studies described the antitussive effects of memantine, an N-methyl-d-aspartate receptor channel blocker used in the treatment of Alzheimer's disease. The goals of the present study were to compare the antitussive effects of memantine, dextromethorphan, and codeine in guinea pigs; to relate the dose-dependent actions of memantine in these studies to peak plasma concentrations achieved following oral administration; and to provide the first ever evaluation of the antitussive effect of memantine in humans. In guinea pigs, memantine and codeine were comparable in efficacy and potency but both were superior to dextromethorphan in the citric acid cough challenge model. The pharmacokinetic analyses suggest that memantine was active in guinea pigs at micromolar plasma concentrations. Subsequently, 14 healthy volunteers as well as 14 otherwise healthy adults with acute viral upper respiratory tract infection (URI) underwent capsaicin cough challenges 6 hours after ingestion of 20 mg memantine and matched placebo in a randomized, double-blind, crossover fashion. In healthy volunteers, memantine significantly inhibited cough reflex sensitivity (P = 0.034). In subjects with URI, responsiveness to capsaicin was markedly increased, and in these patients, the inhibition of cough reflex sensitivity by memantine relative to placebo did not reach statistical significance (P = 0.088). These data support further research to investigate the potential of memantine as a clinically useful antitussive.

Incontinence outcomes in women undergoing primary and repeat midurethral sling procedures.

OBJECTIVE: To assess stress urinary incontinence (SUI) and other lower urinary tract symptom outcomes in women undergoing repeat midurethral sling procedures compared with those undergoing primary midurethral sling procedures. METHODS: Cure was defined as responses of "not at all" or "somewhat" to both questions of the SUI subscale of the Urogenital Distress Inventory-6; symptom effect was assessed using the Incontinence Impact Questionnaire-7. Multivariable models were created controlling for baseline Medical Epidemiologic and Social Aspects of Aging questionnaire urge score and Urogenital Distress Inventory-6 stress subscale score. RESULTS: One thousand three hundred sixteen patients had charts available for review: 135 of 1,316 (10.2%) had undergone prior midurethral sling procedures; 799 of 1,316 (61%) questionnaires were returned, with 92 from those having undergone prior midurethral sling procedures. Median follow-up time was 36.4 months with a range of 11.4-71.5 months. Cure rates were 71% (95% confidence interval [CI] 67.7-74.3%) in the primary midurethral sling group and 54% (95% CI 43.8-64.2%) in the repeat midurethral sling group (P<.001). Women undergoing repeat midurethral sling procedures experienced significantly greater improvement in symptom-specific quality of life (QOL) compared with those undergoing primary midurethral sling procedures (-28.87±37.6 compared with -18.42±32.73, P=.01). Multivariable analyses revealed that women in the repeat midurethral sling group had increased risk of SUI failure (odds ratio 1.7, 95% CI 1.1-2.8). CONCLUSION: Women undergoing repeat midurethral sling procedures had almost two times the odds of SUI treatment failure but greater improvement in symptom effect on QOL than did those undergoing a primary midurethral sling procedure. This information can help counsel patients regarding their expectations of repeat midurethral sling surgery for recurrent SUI . LEVEL OF EVIDENCE: II.

Treatment of presumed hypotension in very low birthweight neonates: effects on regional cerebral oxygenation.

CONTEXT: Previous studies have correlated poor neurological outcomes with hypotension. Treatment of hypotension in very low birthweight (VLBW) infants is common, and most often is based solely on the blood pressure measurement. Whether treatment improves cerebral oxygenation is unclear. OBJECTIVE: To determine if treatment of hypotension in VLBW neonates results in an increase in cerebral oxygenation. PATIENTS AND METHODS: In this single centre observational study, neonates <30 weeks and <1500 grams, blood pressure and regional cerebral oximetry (rCSO2) with near infrared spectroscopy were continuously monitored and digitally recorded. If patients were treated for hypotension during the first 3 days of life, effects of treatment on blood pressure and regional cerebral saturation were determined. RESULTS: Twenty-eight of 50 patients were treated by the medical team for hypotension, of which 22 had accurate data recorded for analysis. Both normal saline 10 ml/kg, and dopamine 2.5-5 mcg/kg per min significantly increased blood pressure, (saline 26.8±3.5 to 28.8±4.2 mm Hg, p<0.005; dopamine 27.6±1.9 to 29.5±3.2 mm Hg, p<0.02). Pre-treatment values of rCSO2 were similar to published normative values and treatment with either normal saline or dopamine had no effect on rCSO2. CONCLUSION: These results suggest that treating hypotension in VLBW neonates based solely on a blood pressure measurement of less than 30 mm Hg, while increasing blood pressure, may not increase cerebral oxygenation, possibly because many of these patients are in the autoregulatory zone for cerebral blood flow.

Surgical staples compared with subcuticular suture for skin closure after cesarean delivery: a randomized controlled trial.

OBJECTIVE: To compare the risk of cesarean wound disruption or infection after closure with surgical staples compared with subcuticular suture. METHODS: Women with viable pregnancies at 24 weeks of gestation or greater undergoing scheduled or unscheduled cesarean delivery were randomized to wound closure with surgical staples or absorbable suture. Staples were removed at postoperative days 3-4 for low transverse incisions and days 7-10 for vertical incisions. Standardized wound evaluations were performed at discharge (days 3-4) and 4-6 weeks postoperatively. The primary outcome was a composite of wound disruption or infection within 4-6 weeks. Secondary outcomes included operative time, highest pain score on analog scale, cosmesis score, and patient scar satisfaction score. Analyses were by intent to treat. RESULTS: Of 398 patients, 198 were randomized to staples and 200 to suture (but four received staples). Baseline characteristics including body mass index, prior cesarean delivery, labor, and type of skin incision were similar by group. The primary outcome incidence at hospital discharge was 7.1% for staples and 0.5% for suture (P<.001, relative risk 14.1, 95% confidence interval [CI] 1.9-106). Of 350 (87.9%) with follow-up at 4-6 weeks, the cumulative risk of the primary outcome at 4-6 weeks was 14.5% for staples and 5.9% for suture (P=.008, relative risk 2.5, 95% CI 1.2-5.0). Operative time was longer with suture closure (median time of 58 versus 48 minutes; P<.001). Pain scores at 72-96 hours and at 6 weeks, cosmesis score, and patient satisfaction score did not differ by group. CONCLUSION: Staples closure compared with suture is associated with significantly increased composite wound morbidity after cesarean delivery. CLINICAL TRIAL REGISTRATION: : ClinicalTrials.gov, www.clinicaltrials.gov, NCT01008449. LEVEL OF EVIDENCE: : I.

Closure times measured by the platelet function analyzer PFA-100 are longer in neonatal blood compared to cord blood samples.

BACKGROUND: Although neonatal platelets have been shown to be hyporesponsive to most agonists in vitro, several groups have reported shorter closure times (CT) in term cord blood samples than in children and adults. It is unknown whether this is also true for preterm neonates, or for neonates of any gestational age (GA) during the 1st week of life, since limited studies have evaluated neonatal blood samples. OBJECTIVES: We designed this study to determine the effects of GA and postconceptional age on platelet function using the platelet function analyzer PFA-100. METHODS: We measured CTs in cord blood samples and in neonatal blood samples of varying GAs on days of life 1-2, and > or = 7. RESULTS: CTs were determined in 51 cord blood samples, 34 neonatal blood samples obtained on day of life 1-2, 16 neonatal blood samples from preterm neonates > or = 7 days old, and 10 adults. We found a significant inverse relationship between ADP CTs and GA in both cord blood and neonatal blood day of life 1-2 samples (p = 0.02 and p = 0.01, respectively). When cord blood samples were compared with neonatal and adult blood, epinephrine and ADP CTs were significantly longer in adult blood as well as in neonatal samples obtained at either of the two time points (p < or = 0.01 for all). CONCLUSIONS: Platelet function in response to ADP appears to improve with advancing GA. The differences between cord blood and neonatal blood CTs indicate that substantial changes in primary hemostasis occur shortly after birth. The reasons underlying these changes are unknown.

Long-term disease control of refractory anaplastic large cell lymphoma with vinblastine.

Anaplastic large cell lymphoma (ALCL) is a unique clinical and pathologic subtype of lymphoma characterized by the proliferation of large, highly pleomorphic CD30-positive cells. Overall 70% to 80% of children with ALCL are cured with modern chemotherapy regimens, but the disease is often resistant to multiple therapies after relapse. Single agent vinblastine therapy has been effective in some cases of refractory ALCL. We report a case of ALCL originally diagnosed in an 8-year-old girl. After relapse, the disease was refractory to multiagent chemotherapy, but has showed remarkable response to, and dependence on, single agent vinblastine treatment for almost 7 years.

Sites and kinetics of donor thrombopoiesis following transplantation of whole bone marrow and progenitor subsets.

INTRODUCTION: Little is known about the sites and kinetics of thrombopoiesis following bone marrow transplant. The spleen is a site of hematopoiesis in a healthy mouse, and hematopoietic activity increases in response to stress. We hypothesized that the spleen is a major site of early post-transplant thrombopoiesis. METHODS: We transplanted whole bone marrow (WBM) or lineage depleted progenitor subsets fractionated based on expression of c-kit and Sca-1 from transgenic mice expressing green fluorescent protein into lethally irradiated C57BL/6 recipients. We also transplanted whole bone marrow cells into healthy and splenectomized mice. Post-transplant megakaryopoiesis was assessed by measuring circulating platelet number, percent donor-derived platelets, bone marrow cellularity, splenic weight, megakaryocyte size, and megakaryocyte concentration from hour 3 to day 28 post transplant. RESULTS: Following transplant, circulating donor-derived platelets were derived only from c-kit expressing subsets. Donor-derived platelets first appeared on post-transplant day five. Splenectomy reduced the number of these earliest circulating platelets. Splenic megakaryopoiesis increased dramatically from day 7-14 post-transplant. However, splenectomy accelerated platelet engraftment during this time frame. CONCLUSION: Overall, these results demonstrate that the first platelets are produced by c-kit expressing megakaryocyte progenitors in the bone marrow and spleen. After post-transplant day 5, the net effect of the spleen on thrombopoiesis is to slow engraftment due to immune effects or hypersplenism.