High Loading Dose Research Articles

Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy

BackgroundSome studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated. ObjectiveThe objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE. MethodsA group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected. ResultsOne hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ± 17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100–600 mg), and the weight-adjusted dose was 5 mg/kg (3–6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h.Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found. ConclusionsIn adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.

ONE-YEAR CARDIOVASCULAR OUTCOME IN PATIENTS ON CLOPIDOGREL ANTI-PLATELET THERAPY AFTER ACUTE MYOCARDIAL INFARCTION

The aim of this study was to determine the risk factors in patients on clopidogrel anti-platelet therapy after acute myocardial infarction, for cardiovascular mortality, re-hospitalization and admission to emergency care unit. We followed 175 patients on dual antiplatelet therapy, with clopidogrel and acetylsalicylic acid, for 1 year after acute myocardial infarction, both STEMI and NSTEMI. Beside demographic and clinical characteristics, genetic ABCB1, CYP2C19 and CYP2C9 profile was analyzed using Cox-regression analysis. End-points used were: mortality, re-hospitalization and emergency care visits, all related to cardiovascular system. During the accrual and follow-up period, 8 patients (4.6%) died, mostly as a direct consequence of an acute myocardial infarction. Re-hospitalization was needed in 27 patients (15.4%), in nine patients (33.3%) with the diagnosis of re-infarction. Thirty-two patients (18.3%) were admitted to emergency care unit due to cardiovascular causes, up to 15 times during the follow-up. NSTEMI was an independent predictor of all three events registered (mortality OR=7.4, p<0.05; re-hospitalization OR=2.8, p<0.05); emergency care visit OR=2.4, p<0.05). Other significant predictors were related to kidney function (urea and creatinine level, creatinine clearance), co-morbidities such as arterial hypertension and decreased left ventricular ejection fraction, as well as clopidogrel dosing regimen. As a conclusion, it may be suggested that one of the most significant predictors of cardiovascular events (mortality, re-hospitalization and emergency care visits) is NSTEMI. Besides, clopidogrel administration according to up-to-date guidelines, with high loading doses and initial doubled maintenance doses, improves 1-year prognosis in patients with AMI.

High Loading Dose of Atorvastatin for the Prevention of Serum Creatinine and Cystatin C-Based Contrast-Induced Nephropathy Following Percutaneous Coronary Intervention.

The aim of this study is to assess the efficacy of high-dose atorvastatin on the prevention of contrast-induced nephropathy (CIN) in patients with acute coronary syndrome (ACS) undergoing percutaneous intervention and observe the incidence of cystatin C (CyC)-based CIN. A total of 496 patients with ACS were randomly assigned to either the control group (247 patients receiving conventional dose atorvastatin 10 mg daily from 1 day before to 3 days after contrast administration) or the high-dose atorvastatin group (249 patients receiving atorvastatin 40 mg daily for the same perioperative period). The baseline characteristics of the 2 groups were similar. The primary end point of serum creatinine (SCr)-based CIN occurred in 31 patients in the control group and 16 patients in the high-dose atorvastatin group (12.6% vs 6.4%; P = .02). Cystatin C-based CIN developed in 90 patients in the control group and 46 patients in the high-dose atorvastatin group (36.4% vs 18.5%; P < .001). A multivariable analysis revealed that high-dose atorvastatin was independently associated with a decreased risk of CIN. Our study demonstrated that prophylactic treatment with high-dose atorvastatin reduced the risk of both SCr and CyC-based CIN and suggested that CyC was a more reliable marker for early diagnosis of CIN compared with SCr.

CYP2C19 genotype and adverse cardiovascular outcomes after stent implantation in clopidogrel-treated Asian populations: A systematic review and meta-analysis

The effect of CYP2C19 gene polymorphism on clinical outcomes of patients with coronary artery disease (CAD) treated with clopidogrel remains controversial. Ethnicity has been proposed to influence clopidogrel response following stent implantation in CAD patients with different CYP2C19 genotypes. Furthermore, Asian populations are reported to have a relatively greater prevalence of CYP2C19 loss-of-function (LOF) alleles. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clinical outcomes in Asian populations who underwent percutaneous coronary interventions (PCI) and received clopidogrel therapy. We conducted a comprehensive search in PubMed, EMBASE, and Cochrane Library from their inceptions to January 20, 2017. Studies that reported clopidogrel therapy information, clinically relevant outcomes (adverse cardiovascular events, stent thrombosis and bleeding), and CYP2C19 genotypes among Asian populations were included. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death and myocardial infarction. The safety endpoint was any kind of bleeding. We retrieved 20 studies of 15056 patients reporting 1301 cardiovascular events. The primary analysis showed at least one CYP2C19 LOF allele (*2 and/or *3) carriers were at an increased risk of MACE compared with non-carriers (10.58% vs. 6.07%, OR: 1.99, 95% CI: 1.64 to 2.42, p < .001). Stent thrombosis (ST) was also more frequent in LOF allele carriers (2.22% vs. 0.44%, OR: 4.77, 95% CI: 2.84 to 8.01, p < .001). Inversely, the risk of bleeding was lower in LOF allele carriers (OR: 0.66, 95% CI: 0.46 to 0.96, p < .001). Subgroup analysis was performed to assess differences by high (600 mg) or routine (300 mg) loading dose of clopidogrel and by different nationalities. The risk of MACE in LOF allele carriers remained significantly higher even in high loading dose group (high loading dose: OR 1.72, 95% CI: 1.37 to 2.16, and routine loading dose: OR 2.22, 95% CI: 1.68 to 2.94, p for subgroup heterogeneity = 0.16). Subgroup analysis between three nationalities of China, Korea, and Japan demonstrated that the risk of MACE among Chinese LOF allele carriers was the greatest (OR: 2.28; 95% CI:1.91 to 2.73). In conclusion, among Asian populations with CAD undergoing stent implantation, CYP2C19 LOF allele carriers are at greater risk of adverse cardiovascular events and lower risk of bleeding compared with non-carriers. Genetic testing may be helpful for clinicians to personalize antiplatelet therapy especially in Asian population.

Recent Evolution of the Treatment of Coronary Artery Disease in China: A Conversation With Ya-Ling Han, MD, PhD.

Ya-Ling Han, MD, PhD, was born in Wuhan, Hubei province, in 1953. She graduated from Haebin Medical University in 1978. She received her doctorate in 1994 from Shanghai Second Military Medical University. She was a visiting scholar at the National Heart Center, Singapore. She is currently a professor and the director of the Department of Cardiology, General Hospital of Shenyang Military Region; the director of the Cardiovascular Research Institute; and the director of the Key Laboratory of Acute Severe Cardiovascular Treatment Research of the Chinese People’s Liberation Army. She is the president of the Chinese College of Cardiovascular Physicians and Chairperson-elect of the Chinese Society of Cardiology. Dr Rutherford asks: Could you describe the scope of clinical cardiac care provided in the Department of Cardiology at the General Hospital of Shenyang Military Region? Dr Ya-L ing Han replies : The Department of Cardiology at the General Hospital of Shenyang Military Region, together with the departments of congenital heart disease and cardiovascular surgery, constitute the cardiovascular institute of the People’s Liberation Army, which is among the top 5 centers in China providing comprehensive care for CVD. Our center is located in Northeast China, an area with the highest prevalence of CAD, so the treatment and prevention of CAD is our major focus. We are a busy center: we perform ≈7000 PCIs, 1400 radiofrequency ablations, 550 pacemaker implantations, 900 congenital heart disease interventions, and ≈2500 cardiovascular surgeries annually, with an overall in-hospital mortality rate of <1%. We have pioneered many facets of CVD treatment in China, including PCI for complicated coronary lesions, CTO of coronary arteries, left main coronary disease, treatment of high-risk patients with AMI, novel antithrombotic strategies for coronary patients, and surgical and percutaneous treatment of complicated congenital heart disease. Over the past 2 decades, you and your team have …

Antiplatelet Effect of Different Loading Doses of Ticagrelor in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The APELOT Trial

BackgroundWe hypothesized that a high ticagrelor loading dose (LD) may improve platelet inhibition in patients with non–ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). MethodsThis interventional multicentre open-label trial randomized 278 patients with NSTE-ACS to a high (360 mg) or conventional (180 mg) ticagrelor LD. The primary outcome was the platelet reactivity index (PRI) 1 hour after administration of the LD. Secondary outcomes included PRI at 0.5 hour, 1 hour, 8 hours, and 24 hours; periprocedural myocardial infarction (PMI); major cardiac adverse events; and bleeding events. ResultsTwo hundred sixty-two patients completed the major end points. PRI was lower in the high-LD group than in the conventional-LD group at any time point (all, P < 0.05), including at 1 hour (12.2% vs 16.7%; P = 0.023). At 0.5 hour, the high-LD group showed a lower high-platelet reactivity rate (49.6% vs 60.2%; P = 0.013) and a higher low-platelet reactivity rate (24.8% vs 12.8%; P = 0.017) than did the conventional LD group. No significant differences in the bleeding rates were found between the 2 groups (14% vs 14.3%). Four cases of PMI and 1 death in each group, as well as 1 acute myocardial infarction in the conventional LD group, occurred. There was no stroke, target lesion revascularization, or target vessel revascularization. ConclusionsDoubling the ticagrelor LD achieved faster onset and greater platelet inhibition without an increase in adverse events in patients with NSTE-ACS undergoing PCI.

Efficacy and Safety of High Loading Dose of Colistin in Multidrug-Resistant Acinetobacter baumannii: A Prospective Cohort Study.

We aimed to assess the efficacy and safety of a high loading dose of colistin and no loading dose of colistin to treat multidrug-resistant (MDR) Acinetobacter baumannii infections. We conducted a prospective cohort study of patients with MDR A baumannii infections at a university-affiliated hospital from December 2014 to January 2016. In the high loading dose group, the patients received a high loading dose of 300 mg colistin base activity (CBA) followed by a maintenance dose of 150 mg CBA twice daily, and patients in the no loading dose group received only the maintenance dose. The primary outcome was clinical response. The secondary outcomes were 28-day mortality and microbiological response. A total of 255 cases were identified. The high loading dose of colistin strategy provided no significant difference in good clinical response when compared to the no loading dose group (65.5% vs 70.4%; P = .442), without a significant difference in the development of renal dysfunction (52.3% vs 49.4%; P = .664). However, microbiological eradication was significantly higher among patients who received the high loading dose of colistin when compared to those who received the no loading dose (87.9% vs 70.4%; P = .0006). The high loading dose of colistin strategy was effective and safe for treating patients with MDR A baumannii.

Enhanced protection against experimental Junin virus infection through the use of a modified favipiravir loading dose strategy

A collection of Old and New World arenaviruses are etiologic agents of viral hemorrhagic fever, a syndrome that features hematologic abnormalities, vascular leak, hypovolemia, and multi-organ failure. Treatment is limited to ribavirin for Lassa fever and immune plasma for Argentine hemorrhagic fever. Improved therapeutic options that are safe, more effective and widely available are needed. Here, we show that modification of favipiravir treatment to include a high-dose loading period achieves complete protection in a guinea pig model of Argentine hemorrhagic fever when treatment was initiated two days following challenge with Junin virus (JUNV). This loading dose strategy also protected 50% of animals from lethal disease when treatment was delayed until 5 days post-infection and extended the survival time in those that succumbed. Consistent with the survival data, dramatic reductions in serum and tissue virus loads were observed in animals treated with favipiravir. This is the first report demonstrating complete protection against uniformly lethal JUNV infection in guinea pigs by administration of a small molecule antiviral drug.

High-Loading Dose of Microencapsulated Gliclazide Formulation Exerted a Hypoglycaemic Effect on Type 1 Diabetic Rats and Incorporation of a Primary Deconjugated Bile Acid, Diminished the Hypoglycaemic Antidiabetic Effect.

Gliclazide is a drug commonly used in type 2 diabetesmellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10h post-dose and analysed for blood glucose and gliclazide serum concentrations. Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.

Vitamin D3 Loading Is Superior to Conventional Supplementation After Weight Loss Surgery in Vitamin D-Deficient Morbidly Obese Patients: a Double-Blind Randomized Placebo-Controlled Trial

BackgroundBariatric patients often suffer from vitamin D deficiency (VDD), and both, morbid obesity and VDD, are related to non-alcoholic fatty liver disease. However, limited data are available regarding best strategies for treating VDD, particularly, in bariatric patients undergoing omega-loop gastric bypass (OLGB). Therefore, we examined the efficacy and safety of a forced vitamin D dosing regimen and intervention effects in liver fibrotic patients.MethodsIn this double-blind, randomized, placebo-controlled trial, 50 vitamin D-deficient patients undergoing OLGB were randomly assigned to receive, in the first month postoperatively, oral vitamin D3 (≤3 doses of 100,000 IU; intervention group) or placebo as loading dose (control group) with subsequent maintenance dose (3420 IU/day) in both groups until 6-month visit.ResultsCompared with control group, higher increase of 25(OH)D (67.9 (21.1) vs. 55.7 nmol/L (21.1); p = 0.049) with lower prevalence of secondary hyperparathyroidism (10 vs. 24 %; p = 0.045) was observed in intervention group. No (serious) adverse events related to study medication were found. The loading dose regimen was more effective in increasing 25(OH)D in patients with significant liver fibrosis while this was not the case for conventional supplementation (placebo with maintenance dose) (71.5 (20.5) vs. 22.5 nmol/L (13.8); p = 0.022; n = 14).ConclusionsOur findings indicate that a high vitamin D3 loading dose, in the first month postoperatively, with subsequent maintenance dose is effective and safe in achieving higher vitamin D concentrations in OLGB patients. Unexpectedly, it is more effective in patients with significant liver fibrosis which is of potentially high clinical relevance and requires further investigation.

Impact of a high loading dose of amikacin in patients with severe sepsis or septic shock.

BackgroundThe therapeutic effect of aminoglycosides is highest and optimal when the peak plasma concentration (C max)/minimal inhibitory concentration (MIC) ratio is between 8 and 10. The French guidelines recommend to use high doses of aminoglycosides for empiric antibiotic therapy in patients suffering from severe sepsis or septic shock. In clinical practice, the recommended target is an amikacin C max between 60 and 80 mg/L, which corresponds to approximately 8 times the MIC breakpoint, as defined by the European Committee on Antimicrobial Susceptibility Testing. The aim of this study was to assess the incidence and impact on mortality of an amikacin concentration between 60 and 80 mg/L in patients suffering from severe sepsis or septic shock.MethodsThis was a prospective observational cohort study conducted in two intensive care units (ICU). Patients receiving amikacin at a loading dose of 30 mg/kg for severe sepsis or septic shock were enrolled in the cohort. The target C max for amikacin was between 60 and 80 mg/L, as recommended by French guidelines (i.e. C max/MIC breakpoint = 8–10).ResultsOver the study period, the amikacin C max was <60 mg/L, between 60 and 80 mg/L, and >80 mg/L in 20 (18.2%), 46 (41.8%) and 44 (40%) of the 110 selected patients, respectively. Mortality rate was 40, 28.3 and 56.8% in the groups of patients with C max < 60 mg/L, 60 mg/L < C max < 80 mg/L and C max > 80 mg/L, respectively. Following multivariate analysis, mortality rate was significantly lower in the group of patients with amikacin C max between 60 and 80 mg/L than in the group of patients with amikacin C max > 80 mg/L (P = 0.004). The multivariate analysis also revealed that the factors independently associated with a higher in-ICU mortality rate were age (P = 0.02) and norepinephrine dose (P = 0.0001).Conclusions With a loading dose of 30 mg/kg of amikacin, concentration was potentially suboptimal (C max < 60 mg/L) in only 18.2% of patients. The pharmacodynamic target (60 mg/L < C max < 80 mg/L) recommended by French guidelines was reached in 41.8% of patients and was associated with reduced in-ICU mortality. But amikacin overexposure (i.e. C max > 80 mg/L) was frequent and potentially associated with increased mortality.

Investigations on porous PLA composite scaffolds with amphiphilic block PLA‐b‐PEG to enhance the carrying property for hydrophilic drugs of excess dose

ABSTRACTTo address concern of the dispersion property of hydrophilic drugs of excess dose loaded in a hydrophobic poly(lactic acid) (PLA) matrix, this work developed a PLA and PLA‐b‐polyethylene glycol (PEG) composite scaffold ( ) and studied its carrier properties for aspirin as a model hydrophilic drug. The porous functional scaffolds were prepared from PLA and PLA‐b‐PEG solutions with the dose of 5, 10, and 15 wt % aspirin preloaded. The products and control samples of pure PLA with the same loading amount for comparison were characterized by scanning electron microscopy and X‐ray diffraction to examine the miscibility and porous structure. Rapid degradations in a strongly basic solution were performed to determine the actual loading amount and the encapsulation ratio. The in vitro release in phosphate buffer saline (PBS) at 37.5 °C indicated that the addition of amphiphilic block polymer may efficiently enhance the dispersion property and stabilize the release of hydrophilic drugs, especially with a high loading dose. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 44489.

Steady-state pharmacokinetic simulation of intermittent vs. continuous infusion valproic acid therapy in non-critically ill and critically ill patients

Objectives: Valproic acid (VPA) is a broad-spectrum antiepileptic drug used for a variety of neurologic disorders. The relatively short half-life seen with intermittent intravenous bolus doing may lead to serum concentration variability. Continuous infusion VPA therapy is an approach to mitigate these effects. The objective of this study is to characterize the pharmacokinetics of continuous infusion of VPA in acutely ill patients and to determine dosing regimens that most frequently obtain goal steady-state serum concentrations.Methods: This is a retrospective pharmacokinetics study in adult patients receiving continuous infusion VPA per institutional protocol for seizure or status migrainosus. Pharmacokinetic parameters were reviewed for 234 patients (25 critically ill) and compared between the two groups (non-critically ill vs. critically ill). Intermittent and continuous infusion dosing strategies were modeled utilizing Monte Carlo simulations for both cohorts. Frequencies of serum concentration attainment were reported.Results: The percent target attainment for the non-critically ill group and critically ill group were 69.4 and 58.3% (p = 0.282) post-loading dose and 69.7 and 37.5% (p = 0.004) steady state, respectively. The volume of distribution was significantly different between the two groups (0.35 vs. 0.68 L/kg, p = < 0.0001). Highest frequency of target attainment (50–100 mcg/ml) occurred in the continuous infusion 2 mg/kg/h simulation for both critically ill (45.19%) and acutely ill (48.16%) groups.Discussion: Critically ill patients have an increased volume of distribution. Increasing the volume of distribution requires higher loading doses of VPA to obtain desired therapeutic concentrations. Continuous infusion VPA provides more consistent serum steady-state concentrations while mitigating pharmacokinetic variability.

Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy.

The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 sampling intervals were analyzed. A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean ± standard deviation parameter estimates were 25.2 ± 17.3 liters for the central volume, 0.89 ± 1.17 h(-1) for the rate constant for the drug distribution from the central to the peripheral compartment, 2.38 ± 6.60 h(-1) for the rate constant for the drug distribution from the peripheral to the central compartment, 4.45 ± 2.35 liters/h for hemodiafiltration clearance, and 4.69 ± 2.42 liters/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK/pharmacodynamic (PD) targets of a maximum concentration in plasma (Cmax)/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.).

Evidence for the changing regimens of acetylcysteine.

Paracetamol overdose prior to the introduction of acetylcysteine was associated with significant morbidity. Acetylcysteine is now the mainstay of treatment for paracetamol poisoning and has effectively reduced rates of hepatotoxicity and death. The current three-bag intravenous regimen with an initial high loading dose was empirically derived four decades ago and has not changed since. This regimen is associated with a high rate of adverse effects due mainly to the high initial peak acetylcysteine concentration. Furthermore, there are concerns that the acetylcysteine concentration is not adequate for 'massive' overdoses and that the dose and duration may need to be altered. Various novel regimens have been proposed, looking to address these issues. Many of these modified regimens aim to decrease the rate of adverse reactions by slowing the loading dose and thereby decrease the peak concentration. We used a published population pharmacokinetic model of acetylcysteine to simulate these modified regimens. We determined mean peak and 20h acetylcysteine concentrations and area under the under the plasma concentration-time curve to compare these regimens. Those regimens that resulted in a lower peak acetylcysteine concentration have been shown in studies to have a lower rate of adverse events. However, these studies were too small to show whether they are as effective as the traditional regimen. Further research is still needed to determine the optimum dose and duration of acetylcysteine that results in the fewest side-effects and treatment failures. Indeed, a more patient-tailored approach might be required, whereby the dose and duration are altered depending on the paracetamol dose ingested or paracetamol concentrations.

Effects of different doses of dexmedetomidine on heart rate and blood pressure in intensive care unit patients.

The aim of the present study was to observe and compare the sedative effect of different doses of DEX on heart rate (HR) and blood pressure (BP) in critically ill patients admitted to intensive care units (ICUs). The study included patients that were retained in ICUs and required sedation between January and March 2014. Patients were excluded if they had a BP of >200 mmHg, a HR of <60 bpm or were in a state of shock. The included patients were randomized into three groups: Group A, 1.0 µg/kg/10 min DEX; group B, 0.5 µg/kg/10 min DEX; and group C, 0.4 µg/kg/h DEX. After receiving these initial designated doses of DEX via an intravenous (IV) infusion pump for 10 min, the patients were maintained continuously at an identical dose of 0.4 µg/kg/h DEX. Ramsay score, HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), breathing rate (BR) and peripheral capillary oxygen saturation (SpO2) were recorded prior to the IV pump infusion and at 2, 4, 6, 8, 10, 60, 120, 180 and 240 min following infusion. Patients in groups A and B achieved sedation more rapidly compared with those in group C (P<0.05). HR decreased more significantly at 8 and 60 min after the initial IV pump infusion with DEX in groups A and B compared with group C (P<0.05). SBP decreased significantly at 10 min after IV pump infusion in group A compared with groups B and C (P<0.05). No significant difference existed in the SBP reduction trend between the three groups during the maintenance period. Therefore, the routine dose of DEX (0.4 µg/kg/h) provides an ideal sedative effect in ICU patients. The recommended loading dose for a more rapid sedation is 0.5 µg/kg/h. High loading doses of DEX via IV pump infusion should be avoided in elderly individuals, patients with acute exacerbation of chronic obstructive pulmonary disease and anemic patients, in whom combination medication, such as midazolam or propofol, may be considered when necessary.

Biological and mechanical characterization of chitosan-alginate scaffolds for growth factor delivery and chondrogenesis.

Chitosan-alginate (Ch-Al) natural polysaccharide blends have been used for wound healing, tissue engineering, and drug delivery due to their ability to form pH-dependent ionic chain-chain interactions. Yet, the biomechanical properties and growth factor (GF) release kinetics of Ch-Al, which are important in controlling the microenvironment during tissue regeneration, have not been fully explored. This study examines the compressive elastic modulus of many Ch-Al scaffold formulations and crosslinking conditions, and also the strain recovery after compressive deformation of Ch-Al scaffolds, both of which make Ch-Al an attractive composite for reproducing articular cartilage's resistance to and resiliency under compression. Cell viability, proliferation, and in vitro cartilaginous matrix production (collagen type II, glycosaminoglycans, aggrecan) without supplemental GFs are also investigated, demonstrating the polymer blend's inherent chondrogenic properties. Additionally, this study explores the ability of Ch-Al chain functional groups to control and extend GF delivery and minimize GF burst release, using model proteins BSA and histone at high loading dose and chondrogenic protein TGF-β1 at low loading dose in complete media. Expedited cartilaginous matrix synthesis on Ch-Al with low dose TGF-β1 release is evaluated, with Ch-Al supporting homogeneous matrix deposition and lacunae formation as early as 3 weeks due to Ch-Al's maintenance of GF bioactivity and sustained GF delivery. These results illustrate the potential to focus the formulational range of Ch-Al to provide enhanced mechanical performance and controlled, bioactive GF release to cooperatively promote cartilage regeneration. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 272-282, 2017.

Epidemiology and Treatment of MDR Enterobacteriaceae

The major progress in the history of medicine represented by the discovery of antibiotics is nowadays compromised by the universal spread of antibiotic resistance. World Health Organization (WHO) lists third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae and carbapenem-resistant K. pneumoniae in a group of seven bacteria of international concern, responsible for both healthcare-associated and community-acquired infections. Patients infected by these pathogens have limited therapeutic options, worse clinical outcomes, increased mortality rates, and a higher healthcare resources consumption. In infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, appropriate monotherapy is effective and carbapenems are the drugs of choice; however, β-lactams/β-lactamase inhibitors (BLBLIs) are regarded as an alternative mainly in patients without severe infections, with E. coli bacteremia with urinary source or with low minimum inhibitory concentrations (MICs). For infections caused by carbapenem-resistant Enterobacteriaceae (CRE), where the predicted mortality rate of patients is high, a combination antimicrobial treatment should be preferred. Many important variables in the treatment such as the role of high dosages and loading doses, the variable degrees of dosage reduction for impaired renal function, and the inclusion of carbapenems or tigecycline are a matter of debate. Despite the obscure vision provided by a notable number of meta-analyses, tigecycline is an effective and safe option for the treatment of MDR Enterobacteriaceae, as part of a combination regimen in case of infections caused by CRE, where a higher dosage (200 mg/daily) should be preferred. Colistin is the most active in vitro agent against CRE. Despite clinical data about the efficacy of fosfomycin against MDR Enterobacteriaceae are limited, this molecule represents an interesting option for the treatment of lower urinary tract and even systemic infections caused by difficult-to-treat Gram-negative pathogens. Based on in vitro studies, ceftolozane–tazobactam and ceftazidime–avibactam will represent very interesting new drugs for the treatment of ESBL-producing and CRE infections, respectively.

Platelet reactivity following high loading doses of clopidogrel in patients undergoing primary percutaneous coronary angioplasty: A pilot study: The CArdiovascular Percutaneous Intervention TriAL Group (CAPITAL) LOAD Study

BackgroundRapid inhibition of platelet function is critical in patients referred for primary percutaneous coronary intervention (PCI) to prevent stent thrombosis. We sought to determine the antiplatelet effects of two clopidogrel high loading dose (LD) strategies on platelet reactivity in patients presenting with ST-elevation myocardial infarction (STEMI). MethodsPatients referred for primary PCI were randomly assigned to one of two clopidogrel LDs initiated before catheterization: 600mg vs. 600/600mg (second dose 3h after first LD). Platelet function testing was performed at baseline, and at 1, 2, 4, 6, 24, and 48h after the initial LD using the VerifyNow device. The primary endpoint was the proportion of patients with high platelet reactivity (HPR) at 24h defined as a P2Y12 reaction unit (PRU) measurement >208. ResultsFifty-four patients were assigned to clopidogrel as a single 600mg LD (n=27) or as a 600/600mg double LD (n=27). The proportion of patients with HPR at 24h was recorded in 44.0% assigned to the 600mg LD and 24.0% of patients assigned to 600/600mg LD, p=0.23. The mean PRU at 24h was 191±102 in the 600mg group and 152±94 in the 600/600mg group, p=0.16. There was no difference at all time points in HPR, and in mean PRUs between the LD regimens. ConclusionsHigh platelet reactivity persisted at 24h in a significant proportion of patients referred for primary PCI regardless of two clopidogrel high LD strategies. These results may have implications regarding the risk of early stent thrombosis in STEMI patients treated with clopidogrel.

Effect of perioperative Atorvastatin treatment on lipoprotein-associated phospholipase A2 level and heart function in elderly patients with acute ST-segment elevation myocardial infarction and type 2 diabetes

Objective To investigate the effects of perioperative high loading dose of Atorvastatin treatment on lipoprotein-associated phospholipase A2 (Lp-PLA2) and heart function in patients with acute ST-segment elevation myocardial infarction and type 2 diabetes who underwent emergency percutaneous coronary intervention (PCI). Methods Totally 83 cases with acute ST-segment elevation myocardial infarction and type 2 diabetes who underwent emergency PCI from September 2012 and August 2014 were randomly divided into two groups. In control group (n=42) patients took Atorvastatin 20 mg daily before and after emergency PCI, and in intensive group (n=41) patients took atorvastatin 40 mg daily before and after emergency PCI. Each group was given the same basic treatment according to the guideline. Blood samples were obtained from all the patients before PCI and at 3, 7 days after PCI, and levels of Lp-PLA2 and brain natriuretic peptide (BNP) were detected. And the left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured at 1 day and 1 month after PCI. Results The levels of Lp-PLA2 and BNP at 3 days after PCI were obviously increased in the two groups versus baseline〔(297.8±53.4) mg/L vs. (194.7±39.1) mg/L, (270.3±47.0) mg/L vs. (205.6±27.5) mg/L, both P<0.05〕, and decreased in intensive versus control group〔(270.3±47.0) mg/L vs. (297.8±53.4 ) mg/L and (353.8±76.3) mg/L vs. (375.4±57.0) mg/L, P<0.05〕. And levels of Lp-PLA2 and BNP at 7 days after PCI were improved more in intensive than in control group〔(227.2±33.3)mg/L vs. (249.3±42.3) mg/L, (206.0±48.2)mg/L vs. (267.6±50.8) mg/L, P<0.05〕. There were no significant differences in LVEDD and LVEF between the two groups 1 day after PCI. Meanwhile, the LVEDD was decreased and the LVEF was increased in the two groups 1 month after PCI as compared with 1 day after PCI (both P<0.05). Conclusions Perioperative high loading dose of Atorvastatin treatment may stabilize the plaques and improve heart function in acute stage in patients with acute ST-segment elevated myocardial infarction and type 2 diabetes after emergency PCI. Key words: Atorvastatin; Myocardial infarction; Angioplasty, transluminal, percutaneous coronary; Phospholipases A2