A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization

BackgroundRecombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize haematopoietic stem cells. We compared the efficacy and safety of a biosimilar G-CSF (Zarzio^®, Sandoz Biopharmaceuticals) with the originator G-CSF (Neupogen^®, Amgen) in patients with haematological malignancies.MethodsA total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19–69). Patients had multiple myeloma (n = 46), non-Hodgkin's lymphoma (n = 28), Hodgkin's lymphoma (n = 26), or other diagnosis (n = 8). After administration of mobilizing regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomized to a standard daily 10 μg/kg dose of biosimilar G-CSF (n = 54) or originator G-CSF (n = 54).ResultsMedian duration of G-CSF administration was 8 days with both biosimilar G-CSF (range 4–17) and originator G-CSF (range 4–14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean ± SD number of mobilized CD34+ cells/μL in peripheral blood or the number of CD34+ cells/kg body weight. Five patients (9%) in the originator G-CSF group and six patients in the biosimilar G-CSF group (11%) did not mobilize sufficient CD34+ cells. The adverse event profile was similar between groups.ConclusionsA biosimilar G-CSF (Zarzio^®) demonstrated similar efficacy and safety as the reference originator G-CSF (Neupogen^®) in hematopoietic stem cell mobilization in patients with haematological malignancies.     

The role of essential metals in the placental transfer of lead from mother to child

Epidemiological studies have found adverse birth and child health outcomes from prenatal lead exposure, but little is known about factors influencing placental transfer. In this study we describe the placental transfer of lead in a Taiwanese population, and investigate whether three essential metals – zinc, manganese, or selenium – influence transfer. Maternal and cord blood samples (308 pairs) from a birth cohort study were analyzed using multiple linear regression. There was a clear correlation between mother and child lead concentration (r = 0.48, p < 0.001), although lead concentration in cord blood (mean = 1.29, SD = 0.72 μg/dL) was lower than that for mothers (mean = 1.58, SD = 1.11 μg/dL). Cord blood lead was lower where the mother had a higher blood concentration of zinc (p < 0.001) or manganese (p = 0.02). Thus maternal blood zinc and manganese, but not selenium, appeared to decrease the placental transfer of lead. These findings raise the possibility of reducing placental transfer of lead by increasing zinc levels via nutritional supplementation during pregnancy.     

Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein

Intravenous immunoglobulin (IVIG) products are prepared from plasma immunoglobulins from healthy donors. Pilot studies suggest that IVIG may stabilize cognitive functioning in patients with mild-to-moderate Alzheimer's disease. This study measured antibodies to recombinant human tau protein in the IVIG products Gammagard (Baxter), Gamunex (Talecris), and Flebogamma (Grifols). Anti-tau antibodies were measured by ELISA, subtracting IVIG's polyvalent binding from its binding to tau-coated wells to calculate specific anti-tau antibody levels. Because polyvalent binding of IVIG products may interfere with ELISA measurement of their specific antibody levels, the percentage of binding of each IVIG product to tau-coated wells that was specific for tau was also determined. Specific anti-tau antibodies were detected in all three IVIG products, with significant differences between these products (p < 0.001) even when Flebogamma's anti-tau antibodies were doubled to account for its preparation as a 5% solution vs. 10% solutions for Gammagard and Gamunex (means: Gammagard, 3.1 μg/ml; Gamunex, 2.5 μg/ml; Flebogamma, 1.2 μg/ml). The percentages of each IVIG product's specific binding to tau-coated wells also varied between the various products (p < 0.001) and between all pairs of IVIG products (means: Gammagard, 73.1%; Flebogamma, 54.5%; Gamunex, 37.4%; p < 0.01 for all pairwise comparisons). These findings indicate that IVIG products contain specific anti-tau antibodies. The concentrations of these antibodies and the percentages of specific binding of IVIG to tau-coated wells vary between IVIG products. Further studies are indicated to determine if IVIG also contains antibodies to pathologic forms of tau.     

Adverse drug reactions caused by methotrexate in Saudi population

AimThe aim of this study is to document adverse drug reactions (ARDs) of methotrexate (MTX) in Saudi patients.MethodsCross sectional study of adult patients on MTX, attending rheumatology drug monitoring clinics in a university hospital, over a period of 24 weeks. Adverse drug reactions were sought by patient interview, files review and laboratory abnormalities.ResultsData collected included patients’ demographics, diagnoses, co-morbidities, MTX dose and duration, other medications, laboratory abnormalities and adverse reactions, their severity, preventability, and outcome. Out of a total of 593 patients screened, 186 (31.4%) using MTX were interviewed. Most of the patients were female (88.5%). Adverse drug reactions (ADRs) were detected in 61 patients (32.8%). Patients with ADRs took a mean dose of 12.9 mg (2.5–22.5 mg). Ten ADRs (16.4% of total reactions) were preventable; they ranged between severe, moderate and mild. The most common ADRs were gastrointestinal (GI) (52.5%), followed by anemia (8.2%) and chest tightness (6.6%). The duration of the reaction ranged from few hours to 4 years.ConclusionIn conclusion our patients with adverse reactions were younger, took less medications and had less co-morbidities. Our results were different from those published in the literature relating MTX toxicity.     

The effects of opiate consumption on serum reproductive hormone levels,sperm parameters,seminal plasma antioxidant capacity and sperm DNA integrity

We evaluated the effects of opiate consumption on semen quality, sperm function, seminal plasma antioxidant capacity, and sperm DNA integrity. A total of 142 opiate addict men (group 1) were enrolled in the study and 146 healthy age matched male volunteers (group 2) served as controls. Two semen analyses were performed in all participants. Sperm chromatin structure assay (SCSA) was used to identify sperm DNA integrity. The mean ± SD sperm concentration in opiate users and in control subjects was 22.2 ± 4.4 and 66.3 ± 8.3 million per ml, respectively (P = 0.002). A significant increase in the amount of fragmented DNA was found in opiate consumers compared with that in controls (36.4 ± 3.8% vs. 27.1 ± 2.4%, P = 0.004). Significantly decreased levels of catalase-like and superoxide dismutase-like (SOD) activity were observed in group 1 compared with group 2. Opiate consumption has significant adverse effects on semen quality. In cases of unexplained infertility in men, opium consumption should be considered as a possible factor.     

Reduced Renal Clearance of Cefotaxime in Asians with a Low-Frequency Polymorphism of OAT3 (SLC22A8)

Organic anion transporter 3 (OAT3, SLC22A8), a transporter expressed on the basolateral membrane of the proximal tubule, plays a critical role in the renal excretion of organic anions including many therapeutic drugs. The goal of this study was to evaluate the in vivo effects of the OAT3-Ile305Phe variant (rs11568482), present at 3.5% allele frequency in Asians, on drug disposition with a focus on cefotaxime, a cephalosporin antibiotic. In HEK293- Flp-In cells, the OAT3-Ile305Phe variant had a lower maximum cefotaxime transport activity, V_max, [159 ± 3 nmol*(mg protein)^- 1/min (mean ± SD)] compared with the reference OAT3 [305 ± 28 nmol*(mg protein)^? 1/min, (mean ± SD), p < 0.01], whereas the Michaelis-Menten constant values (K_m) did not differ. In healthy volunteers, we found volunteers that were heterozygous for the Ile305Phe variant and had a significantly lower cefotaxime renal clearance (CL_R; mean ± SD: 84.8 ± 32.1 mL/min, n = 5) compared with volunteers that were homozygous for the reference allele (158 ± 44.1 mL/min, n = 10; p = 0.006). Furthermore, the net secretory component of cefotaxime renal clearance (CL_sec) was reduced in volunteers heterozygous for the variant allele [33.3 ± 31.8 mL/min (mean ± SD)] compared with volunteers homozygous for the OAT3 reference allele [97.0 ± 42.2 mL/min (mean ± SD), p = 0.01]. In summary, our study suggests that a low-frequency reduced-function polymorphism of OAT3 associates with reduced cefotaxime CL_R and CL_sec .©2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3451–3457, 2013     

Excess omega-3 fatty acid consumption by mothers during pregnancy and lactation caused shorter life span and abnormal ABRs in old adult offspring

Consuming omega-3 fatty acids (ω-3 FA) during pregnancy and lactation is beneficial to fetal and infant development and might reduce the incidence and severity of preterm births by prolonging pregnancy. Consequently, supplementing maternal diets with large amounts of ω-3 FA is gaining acceptance. However, both over- and under-supplementation with ω-3 FA can harm offspring development. Adverse fetal and neonatal conditions in general can enhance age-related neural degeneration, shorten life span and cause other adult-onset disorders. We hypothesized that maternal over- and under-nutrition with ω-3 FA would shorten the offspring's life span and enhance neural degeneration in old adulthood. To test these hypotheses, female Wistar rats were randomly assigned to one of the three diet conditions starting from day 1 of pregnancy through the entire period of pregnancy and lactation. The three diets were Control ω-3 FA (ω-3/ω-6 ratio ~ 0.14), Excess ω-3 FA (ω-3/ω-6 ratio ~ 14.5) and Deficient ω-3 FA (ω-3/ω-6 ratio ~ 0% ratio). When possible, one male and female offspring from each litter were assessed for life span and sensory/neural degeneration (n = 15 litters/group). The Excess offspring had shorter life spans compared to their Control and Deficient cohorts (mean ± SEM = 506 ± 24, 601 ± 14 and 585 ± 21 days, p ≤ 0.004) when the study terminated on postnatal day 640. The Excess offspring had a higher incidence of presbycusis than the Control and Deficient groups (33.3, 4.3 and 4.5%, p = 0.011) and a persistence of other sensory/neurological abnormalities and lower body weights in old adulthood. In conclusion, ω-3 FA over-nutrition or imbalance during pregnancy and lactation had adverse effects on life span and sensory/neurological function in old adulthood. The adverse outcomes in the Excess offspring were likely due to a “nutritional toxicity” during fetal and/or neonatal development that programmed them for life-long health disorders. The health implication is that consuming or administering large amounts of ω-3 FA during pregnancy and lactation seems inadvisable because of adverse effects on the offspring.     

Colistin-based treatment for extensively drug-resistant Acinetobacter baumannii pneumonia

Data for treatment and outcomes of extensively drug-resistant Acinetobacter baumannii (XDR-AB) pneumonia are limited. A retrospective cohort study of 236 adult patients with XDR-AB pneumonia was conducted between January 2009 and December 2012. The median age of subjects was 70 years (range 17–95 years), 53% were male, 55% had ventilator-associated pneumonia and 42% had been admitted to the intensive care unit. All XDR-AB isolates were susceptible only to tigecycline and colistin; 52 (22%) of the 236 subjects did not receive an agent active against XDR-AB, with an associated 28-day survival of 0%. Colistin-based two-drug combination treatment was prescribed to 166 subjects (70%); regimens included (i) colistin and high-dose sulbactam (n = 93); (ii) colistin and tigecycline (n = 43); and (iii) colistin and high-dose prolonged infusion of a carbapenem (n = 30). The 28-day survival rate and mean length of hospital stay were not statistically different between these three regimens (65%, 53% and 60% and 39, 39 and 38 days, respectively). Predictors of mortality included Acute Physiology and Chronic Health Evaluation (APACHE) II score [adjusted odds ratio (aOR) = 1.11; P < 0.001 for each point increase], duration from infection onset to receipt of active regimen (aOR = 1.01; P = 0.002 for each hour delay), underlying malignancy (aOR = 3.46; P = 0.01) and chronic kidney disease (aOR = 2.85; P = 0.03). These findings suggest that the three colistin-based two-drug combination regimens may be treatment options for XDR-AB pneumonia.     

E-cigarette advertisements,and associations with the use of e-cigarettes and disapproval or quitting of smoking: Findings from the International Tobacco Control (ITC) Netherlands Survey

BackgroundMuch attention has been directed towards the possible effects of e-cigarette advertisements on adolescent never smokers. However, e-cigarette advertising may also influence perceptions and behaviours of adult smokers. The aim of our study was to examine whether noticing e-cigarette advertisements is associated with current use of e-cigarettes, disapproval of smoking, quit smoking attempts, and quit smoking success.MethodsWe used longitudinal data from two survey waves of the ITC Netherlands Survey among smokers aged 16 years and older (n = 1198). Respondents were asked whether they noticed e-cigarettes being advertised on television, on the radio, and in newspapers or magazines in the previous 6 months.ResultsThere was a significant increase in noticing e-cigarette advertisements between 2013 (13.3%) and 2014 (36.0%), across all media. The largest increase was for television advertisements. There was also a substantial increase in current use of e-cigarettes (from 3.1% to 13.3%), but this was not related to noticing advertisements in traditional media (OR = 0.99, p = 0.937). Noticing advertisements was bivariately associated with more disapproval of smoking (Beta = 0.05, p = 0.019) and with a higher likelihood of attempting to quit smoking (OR = 1.37, p = 0.038), but these associations did not reach significance in multivariate analyses. There was no significant association between noticing advertisements and quit smoking success in either the bivariate or multivariate regression analysis (OR = 0.92, p = 0.807).ConclusionNoticing e-cigarette advertisements increased sharply in the Netherlands between 2013 and 2014 along with increased e-cigarette use, but the two appear unrelated. The advertisements did not seem to have adverse effects on disapproval of smoking and smoking cessation.     

Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: A randomized controlled trial

There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol^®, a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3 mg, 5 mg, or 6.5 mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5 mg than with 3 mg (p=0.048), 5 mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the C_max fell within the sampling period (over 2 h), C_max was 1.42–4.57 ng/mL and T_max was 67–92 min. The AUC_0–2 h (n=11) was 1.67–3.51 ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC.     

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients

ObjectiveTo describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score.Patients and methodsBy December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (< 20 mg/day), high dose GCS (> 20 mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]).ResultsThere were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses > 20 mg/day in 255—23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34–0.95). We classified 16 (7%) of the 255 patients treated with > 20 mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity.ConclusionThe management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.     

Police confrontations among street-involved youth in a Canadian setting

BackgroundStreet-level policing has been recognized as a driver of health-related harms among people who inject drugs (IDU). However, the extent of interaction between police and street-involved youth has not been well characterized. We examined the incidence and risk factors for police confrontations among street-involved youth in a Canadian setting.MethodsUsing data derived from participants enrolled in the At-Risk Youth Study (ARYS) between 2005 and 2011, we assessed factors associated with being stopped, searched, or detained by police without arrest in the previous six months using generalized estimating equations (GEE) with logit link for binary outcomes.ResultsAmong 991 participants followed during the study period, 440 (44.4%) reported being stopped, searched, or detained by police for an incidence density of 49.20 (95% confidence interval [CI]: 36.42–65.01) per 100 person years. In multivariate GEE analyses, factors associated with police confrontations included: male gender (adjusted odds ratio [AOR] = 1.35), homelessness (AOR = 2.05), recent incarceration (AOR = 1.78), daily cannabis use (AOR = 1.31), daily heroin injecting (AOR = 1.36), crack pipe/syringe sharing (AOR = 1.61), injection drug use (AOR = 1.37), public drug use (AOR = 2.19), sex work involvement (AOR = 1.67), and drug dealing (AOR = 1.49) (all p < 0.05). In total, 19.0% of participants reported that police confiscated their drug paraphernalia without arresting them. Additionally, 16.9% of individuals reported experiencing violence at the hands of police.ConclusionWe found that various factors, such as homelessness and markers of more severe addiction, increased the likelihood of being confronted by police, and police confrontations were associated with markers of health-related harm among street youth. These findings highlight the need for social and structural interventions that best enable police to fulfil public safety and public order objectives without negatively influencing health behaviours of street youth.     

Vitamin D Binding Protein rs7041 polymorphism and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor

BackgroundVitamin D deficiency represents a major health problem in general population, especially for its association with cardiovascular disorders and thrombotic risk, even in patients on dual antiplatelet therapy (DAPT). Vitamin D Binding Protein (VDBP) is the main transporter of vitamin D in the bloodstream and genetic polymorphisms of this protein have been shown to account for a significant variability of vitamin D levels and its systemic effects. Contrasting data have linked the rs7041 T → G substitution with cardiovascular disease. However, no study has so far addressed the role of rs7041 polymorphism on platelet reactivity in patients on DAPT, that was the aim of the present study.MethodsPatients treated with DAPT (ASA and clopidogrel or ticagrelor) for an ACS or elective PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by Multiplate® (Roche Diagnostics AG), and VDBP genetic status by polymerase chain reaction and restriction fragment length polymorphism technique. Fasting samples were obtained for main chemistry parameters and vitamin D levels assessment.ResultsWe included 400 patients, 187 (46.8%) receiving clopidogrel and 213 (53.2%) ticagrelor. The genetic polymorphism rs7041 (T → G) was observed in 318 patients, (79.5%), in 38.7% of them in homozygosis. Main clinical and chemistry features did not significantly differ according to genetic status, but for a higher rate of ACE-inhibitors and beta-blockers use among the carriers of the G allele (p = 0.04 and p = 0.01, respectively).VDBP genetic status did not affect the rate of HRPR with ADP-antagonists (25.6% vs 24.6% vs 28.5%, p = 0.59; adjusted OR[95%CI] = 0.94[0.52–1.7], p = 0.83 for T/G patients; adjusted OR[95%CI] = 1.14[0.6–2.2], p = 0.67 for G homozygotes).However, the rate of HRPR with ADP-antagonists was influenced by severe hypovitaminosis D (< 10 ng/ml) only in patients carrying the G allele, especially in homozygosis (T/T: 25.9% vs 26.1%, p = 0.99; G carriers: 22.1% vs 35.3%, p = 0.02, p_interaction = 0.019; adjusted OR[95%CI] = 1.93[1.11–3.34], p = 0.02 for G carriers).ConclusionThe present study shows that rs7041 polymorphism of Vitamin D Binding Protein does not affect platelet reactivity or the rate of HRPR among patients receiving DAPT. However the carriage of the G allele could condition the impact of hypovitaminosis D on the response to antiplatelet agents, increasing the occurrence of HRPR especially in homozygotes, thus suggesting a more significant role of vitamin D deficiency among these patients.     

Safety and efficacy of fibrate–statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: A meta-analysis

BackgroundDyslipidemia is a major risk factor for the development of cardiovascular disease. Treatment with fibrate, statins, or other lipid-lowering drugs prevents primary or recurrent cardiovascular events. However, all lipid-lowering drugs have side effects, which may become more severe if combination therapy is prescribed.MethodsWe performed a meta-analysis of published data to compare the safety and efficacy of fibrates alone, compared to fibrate–statin combinations, in patients with dyslipidemia. Six articles were assessed in terms of the efficacy of therapy and nine from the viewpoint of therapeutic safety.ResultsIn terms of efficacy, fibrate–statin combinations afforded significantly greater reductions in the levels of total cholesterol (SE = −2.248; 95% CI 1.986–2.510), LDL cholesterol (SE = −2.274; 95% CI 2.015–2.533), and triglycerides (SE = −0.465; 95% CI 0.272–0.658) compared to fibrate alone. In terms of safety, treatment with fibrate alone was associated with a significant decrease in the number of kidney-related adverse events (RR = −0.547; 95% CI 0.368–0.812), compared to treatment with fibrate–statin combinations.ConclusionWe suggest that treatment with a fibrate–statin combination affords clinical benefits that are superior to treatment with fibrate alone, but increases the risk of side effects (particularly renal). Therapy should thus be carefully monitored.     

Psychosocial and metabolic function by smoking status in individuals with binge eating disorder and obesity

Individuals with binge eating disorder (BED) report smoking to control appetite and weight. Smoking in BED is associated with increased risk for comorbid psychiatric disorders, but its impact on psychosocial functioning and metabolic function has not been evaluated. Participants were 429 treatment-seeking adults (72.4% women; mean age 46.2 ± 11.0 years old) with BED comorbid with obesity. Participants were categorized into current smokers (n = 66), former smokers (n = 145), and never smokers (n = 218). Smoking status was unrelated to most historical eating/weight variables and to current eating disorder psychopathology. Smoking status was associated with psychiatric, psychosocial, and metabolic functioning. Compared with never smokers, current smokers were more likely to meet lifetime diagnostic criteria for alcohol (OR = 5.51 [95% CI = 2.46–12.33]) and substance use disorders (OR = 7.05 [95% CI = 3.37–14.72]), poorer current physical quality of life, and increased risk for metabolic syndrome (OR = 1.80 [95% CI = 0.97–3.35]) and related metabolic risks (reduced HDL, elevated total cholesterol). On the other hand, the odds of meeting criteria for lifetime psychiatric comorbidity or metabolic abnormalities were not significantly greater in former smokers, relative to never smokers. Our findings suggest the importance of promoting smoking cessation in treatment-seeking patients with BED and obesity for its potential long-term implications for psychiatric and metabolic functioning.     

Platelet reactivity in patients with impaired renal function receiving dual antiplatelet therapy with clopidogrel or ticagrelor

BackgroundSuboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCI). Chronic kidney disease (CKD) is a common comorbidity of patients with coronary artery disease, and may potentially influence platelet reactivity. So far only few studies have assessed the role of CKD on response to dual antiplatelet therapy (DAPT) with conflicting results. Therefore, the aim of our study was to evaluate the impact of CKD on platelet function in patients treated with DAPT after a recent acute coronary syndrome (ACS) or PCI.MethodsPatients treated with DAPT, acetylsalicylic acid (ASA) + adenosine diphosphate antagonist (ADP-antagonist) such as clopidogrel or ticagrelor, for ACS or elective patients undergoing PCI were scheduled for platelet function assessment at 30–90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®- Roche Diagnostics AG), high residual platelet reactivity (HRPR) was considered for ASPI test > 862 AU*min (for ASA) and ADP test values ≥ 417 AU*min (for ADP-antagonists). Chronic renal failure was defined as an estimated glomerular filtration rate of 60 mol/min/1.73m² or less, calculated by applying MDRD (Modification of Diet in renal Disease) formula.ResultsOur population included a total of 537 patients of which 308 (57.3%) received ASA and clopidogrel and 229 (42.6%) received ASA and ticagrelor. Patients with renal failure at baseline (101 out of 537, 18.8%) were older, with higher prevalence of hypertension, previous myocardial infarction and coronary artery bypass graft surgery. Moreover, they had a lower ejection fraction at baseline and were more often in therapy with diuretics, but less often with statins at admission. They had lower haemoglobin and higher glycated haemoglobin. HRPR was observed in 1.5% of patients treated with ASA with no difference according to renal function (p = 0.18). HRPR for ADP-antagonists was observed in 23.7% of patients, with no difference according to renal function (p = 0.50). This result was confirmed either with clopidogrel (31.9% versus 38%, p = 0.41) and ticagrelor (13.1% versus 10.8%, p = 0.99), also after correction for all baseline confounders (clopidogrel: adjusted OR[95%CI] = 1.26 [0.60–2.63], p = 0.54) (ticagrelor: adjusted OR[95%CI] = 0.95 [0.54–1.65], p = 0.84). The absence of association between renal function and platelet reactivity was confirmed at linear regression analysis both with clopidogrel (r = − 0.04, p = 0.52) and ticagrelor (r = 0.006, p = 0.92).ConclusionIn patients receiving DAPT, chronic renal failure did not influence ADP-mediated platelet reactivity, with both ticagrelor or clopidogrel. No influence of chronic renal failure was found on the effectiveness of ASA.     

Patterns of antimicrobial therapy in severe nosocomial infections: empiric choices,proportion of appropriate therapy,and adaptation rates—a multicentre,observational survey in critically ill patients

This prospective, observational multicentre (n = 24) study investigated relationships between antimicrobial choices and rates of empiric appropriate or adequate therapy, and subsequent adaptation of therapy in 171 ICU patients with severe nosocomial infections. Appropriate antibiotic therapy was defined as in vitro susceptibility of the causative pathogen and clinical response to the agent administered. In non-microbiologically documented infections, therapy was considered adequate in the case of favourable clinical response <5 days. Patients had pneumonia (n = 127; 66 ventilator-associated), intra-abdominal infection (n = 23), and bloodstream infection (n = 21). Predominant pathogens were Pseudomonas aeruginosa (n = 29) Escherichia coli (n = 26), Staphylococcus aureus (n = 22), and Enterobacter aerogenes (n = 21). In 49.6% of infections multidrug-resistant (MDR) bacteria were involved, mostly extended-spectrum β-lactamase (EBSL)-producing Enterobacteriaceae and MDR non-fermenting Gram-negative bacteria. Prior antibiotic exposure and hospitalisation in a general ward prior to ICU admission were risk factors for MDR. Empiric therapy was appropriate/adequate in 63.7% of cases. Empiric schemes were classified according to coverage of (i) ESBL-producing Enterobacteriaceae and non-fermenting Gram-negative bacteria (“meropenem-based”), (ii) non-fermenting Gram-negative bacteria (schemes with an antipseudomonal agent), and (iii) first-line agents not covering ESBL-Enterobacteriaceae nor non-fermenting Gram-negative bacteria. Meropenem-based schemes allowed for significantly higher rates of appropriate/adequate therapy (p < 0.001). This benefit remained when only patients without risk factors for MDR were considered (p = 0.021). In 106 patients (61%) empiric therapy was modified: in 60 cases following initial inappropriate/inadequate therapy, in 46 patients in order to refine empiric therapy. In this study reflecting real-life practice, first-line use of meropenem provided significantly higher rates of the appropriate/adequate therapy, irrespective of presence of risk factors for MDR.