The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients

Background

Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.

Methods

In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.

Results

During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).

Conclusion

High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.     

Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation

Background

Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post-operative renal function in renal transplant recipients.

Methods

120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (−5 to +5 mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE ≤ −15 mEq/L or bicarbonate ≤ 10 mEq/L or PH ≤ 7.15). Minute ventilation was adjusted to keep PaCO₂ within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24 h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days.

Results

In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed.

Conclusion

Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function.     

The prevalence of obesity and its related risk factor in the north of iran in 2006

Background: The main objective of this study was to evaluate the prevalence of the obesity and the related risk factors in the north of Iran. Methods: This was a population-based cross-sectional study that enrolled 2495 subjects (1247 males and 1248 females) using stratified cluster sampling. Interviewers recorded the data using a multidimensional questionnaire including anthropometric indexes. Body mass index equal to or greater than 25 was considered as overweight and that of 30 and 40 as obese and pathologic obese respectively. SPSS 16.0 software was used for statistical data analysis. Results: Mean age of the subjects was 39.2 [95% CI: 38.6, 39.8] yr. Mean body mass index was 25.3 [95% CI: 25.0, 25.6] kg/m(2) for men and 27.5 [95% CI: 27.2, 27.9] kg/m2 for women. The prevalence rates of overweight, obesity and pathologic obesity were 29.9% (745/2495), 22.5% (561/2495) and 1.8% (44/2495) respectively. The prevalence of obesity was higher in urban residents than rural ones, 27.3% versus 18.9% respectively (P<0.001). The prevalence rates of obesity and pathologic obesity were much higher in women than men were, 30.3% versus 15.4% and 3.0% versus 0.6% respectively (P=0.001). The odds ratio estimate was 1.68 [95% CI: 1.40, 2.02] for urban area compared to rural area; 2.60 [95% CI: 2.14, 3.15] for females compared to males; 5.95 [95% CI: 3.54, 9.99] for married people compared to single people; 1.89 [95% CI: 1.44, 2.84] for age group of 55-65 years compared to age group of 15-24 years; 1.76 [95% CI: 1.17, 2.64] for illiterate people compared to those who had academic education; 1.98 [95% CI: 1.13, 2.49] for poor people compared to people with high economic level. Conclusion: The prevalence of obesity and overweight is very high in the north of Iran, hence is a signal of serious health problem, and should be the focus of special attention.     

The Association Between Index of Nutritional Quality (INQ) and Glioma and Evaluation of Nutrient Intakes of These Patients: A Case-Control Study

Introduction: Glioma is the most common adult brain tumors. Dietary factors may play a role in the etiology of glioma. The Index of Nutritional Quality (INQ) provides a general overview for the nutrient content of a food or a diet. This study aimed to investigate the association between INQ and glioma and nutrient intakes. Material and methods: This study was included 128 patients and 256 controls. Dietary intakes of the subjects were evaluated by a food frequency questionnaire (FFQ) and FFQ-derived dietary data were used to calculate INQ scores. Logistic regression was used to calculate the odds ratios and 95% confidence intervals. Results: Cases had higher intake of total fat, saturated fatty acid (SFA), meats, hydrogenated oils and controls had higher intake of monounsaturated fatty acid, polyunsaturated fatty acid, calcium, dairy, fruits, and nuts. Only the INQ of vitamin C, vitamin E, calcium, and fiber are higher in controls. An inverse association was observed between glioma and INQ of calcium, vitamin E, vitamin C, and fiber. Conclusion: The results of this study propose a healthy diet such as high intake of vitamins C and E, calcium, fiber, food groups like fruits and vegetables, and low-fat milk and nuts; and low consumption of total fat, SFA, and red meat may be protective against glioma.     

Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot,Randomized, Double‐Blinded,Placebo‐Controlled Clinical Trial

Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24–48 h before the initiation of cisplatin infusion and continuing to the end of three 21‐day cisplatin‐containing chemotherapy courses on cisplatin‐induced renal electrolytes wasting and kidney function were assessed. Cisplatin‐associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase‐associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin‐induced urine electrolyte wasting or renal function impairment. Copyright © 2015 John Wiley & Sons, Ltd.     

The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors

BACKGROUND

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.

AIMS

To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.

METHODS

Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.

RESULTS

Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).

CONCLUSIONS

Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.     

Thermo- and pH-sensitive dendrosomes as bi-phase drug delivery systems

Fully supramolecular dendrosomes (FSD) as bi-phase drug delivery systems are reported in this work. For preparation of FSD, amphiphilic linear-dendritic supramolecular systems (ALDSS) have been synthesized by host-guest interactions between hyperbranched polyglycerol having β-cyclodextrin core and bi-chain polycaprolactone (BPCL) with a fluorescine focal point. Self-assembly of ALDSS in aqueous solutions led to FSD. They were able to encapsulate paclitaxel with a high loading capacity. The dendrosome-based drug delivery systems were highly sensitive to pH and temperature. They were stable at 20–37 °C and pH7–8, but dissociated and released drug at temperatures lower than 20 °C or higher than 37 °C and pH lower than 7 quickly. Dissociation of FSD building blocks by temperature or pH resulted in inclusion complexes between the released drugs and polyglycerol as the secondary drug delivery system.From the Clinical EditorThis paper reports on the development of a pH- (below 7) and temperature- (below 20 °C or above 37 °C) sensitive delivery system using supramolecular dendrosomes for more specific delivery and release of drugs using paclitaxel as a model.     

4th Global CRO Council for Bioanalysis: coadministered drugs stability, EMA/US FDA guidelines, 483s and carryover

The Global CRO Council for Bioanalysis (GCC) was formed in September 2010. Since then, the representatives of the member companies come together periodically to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry. The 4th GCC Closed Forum brought together experts from bioanalytical CROs to share and discuss recent issues in regulated bioanalysis, such as the impact of coadministered drugs on stability, some differences between European Medicines Agency and US FDA bioanalytical guidance documents and lessons learned following recent Untitled Letters. Recent 483s and agency findings, as well as issues on method carryover, were also part of the topics discussed.     

Adult height and risk of coronary heart disease: Tehran Lipid and Glucose Study

Background

We assessed the relationship between height and coronary heart disease (CHD) in an urban population of Tehran.

Methods

4110 participants of the Tehran Lipid and Glucose Study who were 40 years of age or older (1880 men and 2230 women; mean age, 55.1 and 53.0 years, respectively) and free of CHD at baseline were followed for a mean of 9.1 years. We used Cox proportional hazards regression to evaluate the risk of a first CHD event across height tertiles.

Results

First CHD events occurred in 239 men and 172 women. The estimated crude HR (95% CI) for CHD events associated with an increment of 1 SD in height was 0.96 (0.28–3.33) in men and 0.84 (0.72–0.97) in women. After adjustment for age, the associations were no longer present. Further adjustment for other confounders had little impact on the results: the HR (95% CI) associated with an increase of 1 SD in height was 1.02 (0.87–1.20) in men and 0.82 (0.66–1.02) in women.

Conclusions

After adjustment for age, height was not associated with CHD incidence in men or women.Key words: height, coronary heart disease, cohort study     

Association of educational status with cardiovascular disease: Teheran Lipid and Glucose Study

Objective  

The aim of this study was to evaluate the associations between educational level and cardiovascular disease (CVD) in an older Iranian population.