The impact of R353Q genetic polymorphism in coagulation factor VII on the initial anticoagulant effect exerted by warfarin.

BACKGROUND: The initial rise in INR following warfarin is attributed to rapid decline in coagulation factor VII (F7). The R353Q polymorphism in F7 accounts for approximately 1/3 of the variability in F7 activity (FVIIc). OBJECTIVE: Evaluate the role of R353Q in the initial response to warfarin. METHODS: Twenty-eight healthy, males, carrying CYP2C9*1/*1 (n = 14), CYP2C9*1/*2 (n = 4) or CYP2C9*1/*3 (n = 10) genotypes, received single 20 mg warfarin. S&R-warfarin concentrations, INR, and FVIIc were monitored periodically for 7 days. RESULTS: Baseline and maximal INR were 5.6% and 33.5% higher among carriers of the RQ (n = 12) as compared with those carrying the RR (n = 16) genotype (p = 0.032, p = 0.003, respectively). Baseline and nadir FVIIc were 21.6% and 42.0% lower among subjects carrying the RQ as compared with carriers of the RR genotype (p = 0.001, p = 0.007 respectively). In multiple regression analysis, R353Q predicted 36.6% of the variability in peak INR whereas 20.2%, 9.9%, and 5.9% were attributed to VKORC1 genetic polymorphism, cholesterol concentration, and S Warfarin concentration after 24 h, respectively. CONCLUSIONS: R353Q genetic polymorphism plays a key role in determining the initial response to warfarin. The incorporation of this genetic variant into warfarin loading algorithm should be further investigated.

[Pediatric anesthesia emergence delirium after elective ambulatory surgery: etiology, risk factors and prevalence].

INTRODUCTION: Emergence delirium (ED) is a common problem among children and adults recovering from general anesthesia after surgery. Its symptoms include psychomotor agitation, hallucinations, and aggressive behavior. The phenomenon, which is most probably an adverse effect of general anesthesia agents, harms the recovery process and endangers the physical safety of patients and their health. Ranging between 10% and 80%, the exact prevalence of ED is unknown, and the risk factors of the phenomenon are unclear. GOALS: The aim of the current retrospective study was to determine the prevalence rate of ED in 3947 children recovering from general anesthesia after short elective ambulatory surgery, and to map the influence of various risk factors on this phenomenon. METHOD: Data were collected using electronic medical records. ED severity was assessed using the Pediatric Anesthesia Emergence Delirium Scale. RESULTS AND DISCUSSION: Results showed the prevalence of ED among children. ED was significantly correlated with patients' age, type of surgery and premedication. ED was not correlated with severity of pain, type of anesthesia or with patients' sex.

Results of Membrane-Activated Chelator Stroke Intervention randomized trial of DP-b99 in acute ischemic stroke.

BACKGROUND AND PURPOSE: DP-b99, a lipophilic moderate-affinity chelator of zinc, was postulated to improve recovery after acute ischemic stroke. We evaluated the safety and therapeutic effects of DP-b99 in patients with acute hemispheric ischemic stroke. METHODS: The Membrane-Activated Chelator Stroke Intervention trial was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial of intravenous DP-b99 administered for 4 consecutive days (NCT00893867). Acute ischemic stroke patients within 9 hours of onset, but untreated by alteplase, with a baseline National Institutes of Health Stroke Scale score of 10 to 16, and evidence of language dysfunction, visual field defect, and neglect were eligible. The primary efficacy analysis compared distributions of functional status measured by modified Rankin score in the intent-to-treat population of patients with any post-treatment outcome, adjusted for initial severity. Functional and neurological recovery were secondary measures. Home time was an exploratory end point. RESULTS: Enrollment terminated at n=446 after the planned interim analysis determined futility; follow-up continued. Final modified Rankin score distributions were equal between DP-b99 and placebo-treated groups (P=0.10; P(adj) adjusted for baseline age and National Institutes of Health Stroke Scale=0.21). Fewer patients recovered to modified Rankin score ≤1 in the DP-b99-treated group (45/218; 20.6%) than after placebo (63/219; 28.8%) (P=0.05; P(adj)=0.10). Similarly, fewer patients attained National Institutes of Health Stroke Scale ≤1 after DP-b99 (42/218; 19.3%) than placebo (56/219; 25.6%; P=0.10; P(adj)=0.26). Mortality was similar between DP-b99 and placebo intent-to-treat groups (36/218; 16.5% vs 33/219; 15.1%; P=0.68). Home time was unchanged by treatment (median 36 vs 36.5 days; P=0.25). CONCLUSIONS: Despite encouraging preclinical and phase II trial data, DP-b99 shows no evidence of efficacy in treating human ischemic stroke.

Tandem Breastfeeding and Human Milk Macronutrients: A Prospective Observational Study.

BACKGROUND: Tandem breastfeeding is defined as two or more offspring of different ages who are breastfed by their mother at the same time. Breastfeeding during pregnancy and tandem breastfeeding have not been widely investigated. RESEARCH AIM: To determine the influence of tandem breastfeeding on the macronutrient content of human milk. METHODS: This longitudinal study used a prospective and a retrospective group. Human milk samples from tandem-breastfeeding participants (n = 18) were compared to samples from non-tandem-breastfeeding participants (n = 31). Samples were collected during the last month of pregnancy (pregnancy milk), 72 hr after birth (colostrum) and 14-60 days post-delivery (mature milk). Macronutrients were measured by mid-infrared spectroscopy. RESULTS: Fat content in pregnancy milk was lower than in mature milk (p < .01). Protein content was higher in pregnancy milk than in colostrum and mature milk (p < .01 and p < .001, respectively). Inversely, carbohydrate content in pregnancy milk was lower than in colostrum and mature milk (p = .02 and p < .01, respectively). Fat and energy contents in pregnancy milk of tandem-breastfeeding participants were lower than in mature milk of non-tandem-breastfeeding participants (p < .001 and p < .01, respectively), and protein content was higher than in mature milk (p < .001). Carbohydrate content in colostrum and mature milk of tandem-breastfeeding participants was higher than that of non-tandem-breastfeeding participants (p < .001 for both). CONCLUSION: Human milk produced during pregnancy had different macronutrient content than human milk produced after delivery. Colostrum and mature milk of tandem-breastfeeding participants were similar to human milk produced by non-tandem-breastfeeding participants, with the exception of carbohydrate content.

DP-b99, a membrane-activated metal ion chelator, as neuroprotective therapy in ischemic stroke.

BACKGROUND AND PURPOSE: DP-b99 is a chelator of zinc and calcium ions that acts selectively within cell membranes and has neuroprotective properties in animal models of stroke. We present the results of a multicenter, double-blind, placebo-controlled, randomized trial to assess the safety and potential protective effects of DP-b99 in acute ischemic stroke. METHODS: One hundred and fifty stroke patients with signs of cortical involvement and a National Institutes of Health Stroke Scale (NIHSS) score of 7 to 20 received a 4-day course of intravenous 1 mg/kg per day DP-b99 or placebo within 1 to 9 hours of stroke onset. Treatment with recombinant tissue plasminogen activator was not allowed. RESULTS: No major differences in mortality rate, causes of death, adverse events, safety laboratory tests, and ECG parameters were found between the 2 groups. The baseline NIHSS score of the 72 DP-b99- and 75 placebo-treated patients in the intent-to-treat cohort was (mean+/-SD) 12.2+/-4.0 and 12.6+/-3.3, respectively; the time to needle (mean+/-SD) was 6:36+/-1:47 and 6:28+/-1:33 hours, respectively; and the age (mean+/-SD) was 73.3+/-9.9 and 72.0+/-9.6 years, respectively. The 90-day median change from baseline (the primary end point) was -6.0 and -5.0 NIHSS points in the DP-b99 and placebo groups, respectively (nonsignificant). At 90 days, there was a significantly better outcome in the DP-b99 group compared with the placebo group (modified Rankin scale score of 0, 1, or same as prestroke): 30.6% and 16.0%, respectively (P=0.05). The recovery rate was unaffected by the time to needle. Further analyses indicated that the 90-day median change from baseline in patients with an entry NIHSS score of 10 to 16 was 8.0 and 5.0 points in the DP-b99 and placebo groups, respectively (P=0.03). CONCLUSIONS: In this small-scale study, the primary end point of change in NIHSS score from baseline to 90 days was not met. However, secondary end points demonstrated a significantly improved 90-day recovery rate with treatment with DP-b99 when compared with placebo. In addition, in patients with baseline NIHSS scores of 10 to 16, a significant post hoc change in NIHSS score from baseline to day 90 was observed. No major safety problems were identified. These findings need to be confirmed with a larger prospective study of strokes involving the cortex.

And why not thrombolysis in the ambulance (at least for some)?

The fear that alteplase may aggravate primary intracerebral hemorrhages has led to the mandatory prerequisite for prealteplase imaging in all acute stroke patients in order to exclude such hemorrhages. Consequently, in a situation in which "time is brain," administration of alteplase is delayed until the patients are transferred to a hospital where such imaging is available, at the cost of additional ischemic damage to the brain parenchyma. Yet, theoretical considerations and empirical data suggest that alteplase's effects on primary intracerebral hemorrhages may not be that detrimental. Moreover, at least some of the patients who are at a high risk of having primary cerebral bleeds, or at a high risk of developing symptomatic secondary bleeds, can be excluded from alteplase therapy on clinical grounds, and using nonimaging point-of-care devices, before their hospital arrival. We propose that clinical research should be initiated to define a population of stroke patients in whom alteplase may be administered preimaging, resulting in a greater benefit than harm and in improved functional outcome compared to deferred, postimaging, alteplase treatment.

The Membrane-Activated Chelator Stroke Intervention (MACSI) Trial of DP-b99 in acute ischemic stroke: a randomized, double-blind, placebo-controlled, multinational pivotal phase III study.

RATIONALE: Zinc is both a direct neurotoxin and a signaling mediator in multiple early and late detrimental processes following ischemia. DP-b99, a lipophilic moderate-affinity chelator of zinc, is a first-in-class multitargeted neuroprotective agent for ischemic stroke. DP-b99 has completed several Phase I studies and two double-blind placebo-controlled Phase II trials, which supported the safety of DP-b99 and were consistent with a beneficial effect on poststroke recuperation. AIM: Membrane-Activated Chelator Stroke Intervention is a Phase III study. The primary objective is to evaluate the safety and therapeutic effects of intravenous 1.0 mg/kg/day DP-b99, initiated within nine-hours of stroke onset in patients with moderately severe hemispheric acute ischemic stroke, through the analysis across the whole distribution of scores of the primary efficacy endpoint of the modified Rankin Scale, 90 days after the stroke. METHODS: The Membrane-Activated Chelator Stroke Intervention study is a randomized, double-blind, placebo-controlled, multicenter, multinational, parallel-arm trial comparing a placebo group to a group treated with intravenous DP-b99 for four consecutive days. Non-rtPA-treated acute ischemic stroke patients--with a baseline NIHSS score of 10-16 and a clinical syndrome that includes language dysfunction, visual field defect and/or neglect--will be stratified on a 1:1 basis to one of the two treatments. Half will be randomized within 0-4.5 h of stroke onset. Follow-up after the four treatment days will occur on days 12, 30 and 90. An interim futility analysis will be performed after primary endpoint data have been collected for 50% of 770 subjects planned to be enrolled. A data and safety monitoring board will assess safety data and will oversee the interim analysis. CONCLUSION: This Phase III Membrane-Activated Chelator Stroke Intervention trial is based on promising data derived from previous Phase I and II DP-b99 trials and capitalizes on lessons learned from failures of past stroke studies in relation to neuroprotection, patient selection and data analysis.

Clinical pharmacology of DP-b99 in healthy volunteers: first administration to humans.

AIMS: To investigate the safety, tolerability and pharmacokinetics of DP-b99 in healthy volunteers. DP-b99 is a newly developed lipophilic, cell permeable derivative of BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid), which selectively modulates the distribution of metal ions in hydrophobic milieu, and is in clinical development as a neuroprotectant for cerebral ischaemic stroke. To our knowledge no BAPTA derivative has ever been administered to man. Here we report the first human administration of DP-b99 in a phase I, two-part, double-blind, randomized placebo controlled study, with single IV doses of 0.003-1.0 mg kg(-1) day(-1) DP-b99 (part 1) or multiple ascending doses of 0.03-1.0 mg kg(-1) day(-1) DP-b99 over 4 days (part 2). METHODS: A double-blind, dose escalating tolerability study of DP-b99 in normal (young - aged between 18 and 40 years and elderly - aged between 65 and 85 years) healthy adult male volunteers was conducted. Part 1 of the study investigated single administration of ascending intravenous doses, and part 2 examined the effects of ascending doses given repeatedly over 4 days. Twenty-four young volunteers in part 1 received single dose administrations and 26 young volunteers in part 2 received repeated ascending dose administrations of either intravenous DP-b99 or placebo. Subsequently, 10 elderly volunteers received repeated intravenous DP-b99 (1 mg kg(-1)) or placebo in part 2 over 4 days. Adverse events were identified by either subject self reporting or based upon laboratory parameters (blood chemistry, complete blood cell count, prothrombin time (PT), activated partial thromboplastin (PTT), physical examination, vital signs (blood pressure, pulse rate, respiratory rate, body temperature) and urinalysis. A comprehensive set of cardiovascular parameters was assessed as well (blood pressure, 12 lead-ECG recordings and continuous bedside cardiac monitoring for 6 h on day 1). RESULTS: The administration of DP-b99 up to the highest dose of 1.0 mg kg(-1) was well tolerated and had an acceptable safety profile up to the highest dose of 1.0 mg kg(-1) tested in both study parts. No serious or severe adverse events were encountered. Eight mild to moderate adverse events were observed in six of the seven young subjects treated with four repeated doses of 1.0 mg kg(-1), with reversible phlebitis being the most frequently reported adverse event. The drug was tolerated better at the injection site by the elderly group compared with the younger subjects. No adverse effects were observed in cardiovascular parameters sensitive to trans-membranous calcium concentrations. The pharmacokinetic parameters were derived by noncompartmental analysis. On day 1 following administration of 1 mg kg(-1) the mean half-life of DP-b99 in young volunteers was 3.47 +/- 0.90 h and in the elderly was 2.11 +/- 0.09 h. On day 4 following the same administration of DP-b99 the mean half-life was 4.36 +/- 1.49 and 2.10 +/- 1.14 h in the young and elderly, respectively. There was higher systemic exposure in the elderly, for example C(max), had a mean 1.6-fold higher exposure on day 1 (95% CI Lower 0.90, Upper 2.74) and 2.5-fold on day 4 (95%CI 1.70, 3.68). This increase is in line with the presumed central role of hepatic blood flow in the elimination of DP-b99. No accumulation was observed after repeated dosing with 1 mg kg(-1) (mean accumulation calculated by AUC(0, 24 h) (day 4) : AUC(0, 24 h) (day 1) and was observed to be between 0.9 and 1.3 (young, elderly). CONCLUSIONS: This study suggests that DP-b99 is well tolerated in healthy young and elderly volunteers within the dose range evaluated. Studies to investigate further the efficacy of the compound are in progress.