CYP2C9, KCNJ11 and ABCC8 polymorphisms and the response to sulphonylurea treatment in type 2 diabetes patients

Purpose

Sulphonylureas (SU) are widely used in the management of type 2 diabetes. We investigated the influence of CYP2C9, KCNJ11 and ABCC8 polymorphisms on the response to SU currently used in everyday clinical practice.

Methods

Patients treated for type 2 diabetes with sulphonylurea in monotherapy (n?=?21) or in combination with metformin (n?=?135) were provided with glucose-monitoring devices and instructed to measure fasting blood glucose levels once per week and additionally at any signs and symptoms suggesting low blood glucose for a period of three months. All patients were genotyped for CYP2C9 rs1799853 and rs1057910 (*2 and *3 allele, respectively), KCNJ11 rs5219 and rs5215, and ABCC8 rs757110.

Results

The average duration of diabetes in the study group was 10.6?±?7.1 years. Most of the patients achieved relatively good blood glucose control (HbA1c 7.0?±?0.9). In total, 76 hypoglycemia events were observed (mean 0.48?±?1.3). No severe hypoglycemia was reported; the lowest blood glucose was 2.1 mmol/l. Although 124 (79.5 %) patients never experienced hypoglycemia, 32 (20.5 %) patients experienced from one to eight events. None of the investigated polymorphisms influenced HbA1c levels or risk for hypoglycemia episodes in the whole group of patients. CYP2C9 genotype significantly influenced the occurrence of hypoglycemia events among the elderly patients (aged 60 years and over; n?=?103). Among them, carriers of two wild-type alleles suffered 0.36?±?0.98 events, while patients with one or two polymorphic alleles had 0.79?±?1.7 or 2.67?±?4.6 events, respectively (p?=?0.014).

Conclusions

Our results indicate that the CYP2C9 genotype may influence the risk for hypoglycemia events in elderly patients, but not in the overall population of type 2 diabetes patients.     

Hyperglycemia in acute aluminum phosphide poisoning as a potential prognostic factor

Aluminum phosphide (AlP) is a solid fumigant widely used in Iran as a grain preservative. When reacted with water or acids, AIP produces phosphine gas, a mitochondrial poison that interferes with oxidative phosphorylation and protein synthesis. Poisoning by AIP is one of the most important causes of fatal chemical toxicity in Iran. There are few studies in the medical literature addressing prognostic factors associated with AlP poisoning. In this prospective study conducted across a 14-month period commencing on 21st March 2006, we enrolled all patients admitted to the ICU of Loghman-Hakim Hospital Poison Center (Tehran, Iran) with AIP poisoning, no history of diabetes mellitus diagnosed before hospitalization, and normal body mass index. We recorded patient-specific demographic information, blood glucose level on presentation (before treatment), arterial blood gas (ABG) analysis, time elapsed between ingestion and presentation, ingested dose, duration of intensive care admission, and outcome data related to each presentation. We enrolled the group of patients who survived the intoxication as a control group and compared their blood glucose levels with those who died because of AlP poisoning. Data were analyzed by Statistical Product and Service Solutions (SPSS) software (Version 12; Chicago, Ilinois, USA) using logistic regression, Pearson correlation coefficient and Student's t-test. P values of 0.05 or less were considered as the statistical significant levels. Forty-five patients (21 women and 24 men) with acute AlP poisoning were included in the study. The mean age was 27.3 +/- 11.5 years (range: 14-62 years). Thirteen patients survived (29%) and 32 expired (71%). AlP poisoning followed deliberate ingestion in all patients. The time elapsed between ingestion and arrival at the hospital was 3.2 +/- 0.4 h. There was no significant difference between survived and non-survived groups according to age, gender, and time to treatment. However, the difference between mean blood glucose levels in survived (143.4 +/- 13.7 mg/dL) and non-survived (222.6 +/- 20 mg/dL) cases was statistically significant (P = 0.021). There was no significant correlation between blood glucose level and time to treatment, age, gender, pH, HCO3 concentration, and ingested dose. Twenty-three (71.9%) of non-survived and four (30.8%) of survived patients had a blood glucose level greater than 140 mg/dL. After adjusting according to age, gender, ingested dose, pH and HCO3 concentration The odds ratio for hyperglycemia as a risk factor for death was 5.7 (CI of 1.4-23.4). In our study, patients who succumbed to AIP poisoning had significantly higher mean blood glucose levels than those who survived. This correlation of hyperglycemic effect and mortality suggests that it may be useful in guiding risk assessment and treatment of AIP poisoning. Management of hyperglycemia may have a useful role in treatment of these patients by allowing increased entrance of glucose into cells and reducing oxygen consumption.     

Effects of exenatide versus sitagliptin on postprandial glucose,insulin and glucagon secretion,gastric emptying,and caloric intake: a randomized,cross-over study

ABSTRACT

Background: This study evaluated the effects of exenatide, a GLP-1 receptor agonist, and sitagliptin, a DPP-4 inhibitor, on 2-h postprandial glucose (PPG), insulin and glucagon secretion, gastric emptying, and caloric intake in T2D patients.

Methods: This double-blind, randomized cross-over, multi-center study was conducted in metformin-treated T2D patients: 54% female; BMI: 33?±?5?kg/m²; HbA_1c: 8.5?±?1.2%; 2-h PPG: 245?±?65?mg/dL. Patients received exenatide (5?µg BID for 1 week, then 10?µg BID for 1 week) or sitagliptin (100?mg QAM) for 2 weeks. After 2 weeks, patients crossed-over to the alternate therapy. Postprandial glycemic measures were assessed via standard meal test; caloric intake assessed by ad libitum dinner (subset of patients). Gastric emptying was assessed by acetaminophen absorption (Clinicaltrials.gov Registry Number: NCT00477581).

Results: After 2 weeks of therapy, 2-h PPG was lower with exenatide versus sitagliptin: 133?±?6?mg/dL versus 208?±?6?mg/dL, p?<?0.0001 (evaluable, N?=?61). Switching from exenatide to sitagliptin increased 2-h PPG by +73?±?11?mg/dL, while switching from sitagliptin to exenatide further reduced 2-h PPG by ?76?±?10?mg/dL. Postprandial glucose parameters (AUC, C_ave, C_max) were lower with exenatide than sitagliptin (p?<?0.0001). Reduction in fasting glucose was similar with exenatide and sitagliptin (?15?±?4?mg/dL vs. ?19?±?4?mg/dL, p?=?0.3234). Compared to sitagliptin, exenatide improved the insulinogenic index of insulin secretion (ratio exenatide to sitagliptin: 1.50?±?0.26, p?=?0.0239), reduced postprandial glucagon (AUC ratio exenatide to sitagliptin: 0.88?±?0.03, p?=?0.0011), reduced postprandial triglycerides (AUC ratio exenatide to sitagliptin: 0.90?±?0.04, p?=?0.0118), and slowed gastric emptying (acetaminophen AUC ratio exenatide to sitagliptin: 0.56?±?0.05, p?<?0.0001). Exenatide reduced total caloric intake compared to sitagliptin (?134?±?97?kcal vs. +130?±?97?kcal, p?=?0.0227, N?=?25). Common adverse events with both treatments were mild to moderate in intensity and gastrointestinal in nature.

Conclusions: Although this study was limited by a 2-week duration of exposure, these data demonstrate that, exenatide had: (i) a greater effect than sitagliptin to lower postprandial glucose and (ii) a more potent effect to increase insulin secretion and reduce postprandial glucagon secretion in T2D patients. In contrast to sitagliptin, exenatide slowed gastric emptying and reduced caloric intake. These key findings differentiate the therapeutic actions of the two incretin-based approaches, and may have meaningful clinical implications.     

Decreased vancomycin clearance in patients with congestive heart failure

Purpose

Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.

Methods

After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.

Results

Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r ²?=?0.649).

Conclusions

Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.     

Higher rate of hyperglycemia than hypoglycemia during Ramadan fasting in patients with uncontrolled type 1 diabetes: Insight from continuous glucose monitoring system

Background

Patients with uncontrolled type 1 diabetes mellitus (T1DM) are at a high risk for Ramadan fasting and are exempt from fasting; however, most still insist on fasting. The aim of this study was to examine glucose level fluctuations in those patients during Ramadan fasting using a real-time continuous glucose monitoring system (RT-CGMS).

Rethinking the toxic methanol level

INTRODUCTION: Treatment thresholds for methanol poisoning are based on case reports and published opinion. Most guidelines recommend treatment for a methanol level > or = 20 mg/dL in a nonacidotic patient. No supportive data have been offered nor has the time of the exposure been addressed. For instance, no distinction has been drawn between a methanol level drawn 1 hr vs. 24 hr from ingestion. We analyzed all published cases of methanol poisoning to determine the applicability of the 20 mg/dL threshold in a nonacidotic patient, specifically those arriving early for care (within 6 hr) with a peak or near-peak blood methanol concentration. METHODS: Using predefined search criteria, a systematic review of the world literature was performed using MEDLINE and EMBASE. In addition, each article's references were hand searched for pre-1966 articles, as were fatality abstracts from all U.S. poison centers. Human cases were included if they reported a known time of a single methanol exposure, acid-base data, blood methanol, and blood ethanol (if not acidotic). RESULTS: Dating to 1879, 372 articles in 18 languages were abstracted using a standard format; 329 articles (2433 patients) involved methanol poisoning, and 70 articles (173 patients) met inclusion criteria. Only 22 of these patients presented for care within 6hr of ingestion with an early methanol level. All but 1 patient was treated with an inhibitor of alcohol dehydrogenase (ADH). A clear acidosis developed only with a methanol level > or = 126 mg/dL. The patient that did not receive an ADH inhibitor was an infant with an elevated early methanol level (46 mg/dL) that was given folate alone and never became acidotic. Intra and inter-rater reliability were 0.95. CONCLUSIONS: Nearly all reports of methanol poisoning involve acidotic patients far removed from ingestion. The small amount of data regarding patients arriving early show that 126 mg/dL is the lowest early blood methanol level ever clearly associated with acidosis. Contrary to conventional teaching, there are case reports of acidosis after only a few hours of ingestion. The data are insufficient to apply 20 mg/dL as a treatment threshold in a nonacidotic patient arriving early for care. Prospective studies are necessary to determine if such patients may be managed without antidotal therapy or dialysis.     

Evaluating the effects of diclofenac sodium and etodolac on renal hemodynamics with contrast-enhanced ultrasonography: a pilot study

Purpose

Contrast-enhanced ultrasonography (CEUS) is a novel approach used for measuring organ perfusion changes. Studies using CEUS to assess the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on renal blood flow (RBF) have not yet been conducted. We aimed to evaluate the effects of NSAIDs on the renal hemodynamics of healthy subjects with CEUS.

Methods

We performed CEUS using the bolus injection method in a total of 10 healthy subjects. Measurements were completed over two study days in a randomized, crossover manner. On each study day, CEUS was performed twice, before and after the administration of NSAIDs. Subjects received an injection of contrast medium and images were recorded. A region-of-interest (ROI) was selected within the renal cortex, signal intensity in the ROI of the kidney was measured and a time-intensity curve (TIC) was automatically generated with attached software.

Results

The mean (±SD) peak intensity decreased significantly after an administration of diclofenac sodium (from 26.0?×?10^?4?±?17.4?×?10^?4 AU to 19.2?×?10^?4?±?12.0?×?10^?4 AU; P?=?0.022), but not significantly with etodolac (from 26.5?×?10^?4?±?9.7?×?10^?4 AU to 25.9?×?10^?4?±?20.8?×?10^?4 AU; P?=?0.474). The mean (±SD) percent reduction in intensity following diclofenac sodium administration was significantly reduced compared with etodolac administration (22.2?±?20.5 % vs. 3.4?±?8.9 %, P?=?0.037).

Conclusions

These finding suggests that diclofenac sodium (P?=?0.022), but not etodolac (P?=?0.474), affects renal hemodynamics even in healthy subjects.     

NPH Insulin Versus Insulin Glargine Versus NPH Insulin Plus Insulin Glargine for the Treatment of Dexamethasone-Induced Hyperglycemia in Patients With COVID-19: A Retrospective Cohort Study

Background:Dexamethasone use in patients hospitalized with COVID-19 significantly reduces mortality; however, it commonly results in hyperglycemia. Optimal treatment of dexamethasone-induced hyperglycemia is not well established.Objective:The study purpose was to assess the difference in blood glucose (BG) control between insulin glargine, neutral protamine hagedorn (NPH) insulin, and insulin glargine plus NPH insulin for dexamethasone-induced hyperglycemia in patients with type 2 diabetes (T2DM) and COVID-19 infection.Methods:This retrospective study was conducted in adult inpatients with T2DM and COVID-19 infection who received 6 mg of dexamethasone once daily and insulin during the 5-day study period. The primary outcome was the difference in mean point-of-care (POC) BG levels between study insulins. Secondary outcomes included the incidence of hyperglycemia and hypoglycemia, length of stay, and the percent difference between the mean daily inpatient and home basal insulin doses (for patients who were receiving basal insulin prior to admission in the insulin glargine and insulin glargine and NPH insulin groups only).Results:Ninety-six patients were included in the analysis (67 insulin glargine, 10 NPH insulin, and 19 insulin glargine plus NPH insulin). The difference in mean POC BG level was not different among groups (254 ± 60 mg/dL vs 234 ± 39 mg/dL vs 250 ± 51 mg/dL, respectively; P = 0.548). There were no significant differences in the secondary outcomes.Conclusions:No difference in the mean POC BG level was observed. Dexamethasone-induced hyperglycemia was poorly controlled in patients with T2DM and COVID-19 infection.     

The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects

Purpose

Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated.

Methods

This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n?=?20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period.

Results

Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration–time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P?<?0.05). Moreover, lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P?<?0.05). However, lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration–time curve of metformin.

Conclusions

Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.     

Comparison of intravenous dexketoprofen and dipyrone in acute renal colic

Objective

The aim of this study was to assess the efficacy and safety of a single intravenous (i.v.) bolus of dexketoprofen trometamol compared with an i.v. infusion of dipyrone in patients with moderate to severe pain due to renal colic.

Methods

A total of 308 patients with renal colic and visual analog scale (VAS) score ≥40 mm participated in a multicenter, randomized, double blind, double-dummy, parallel, and active-controlled study and were randomized to dexketoprofen 25 mg (n?=?101), dexketoprofen 50 mg (n?=?104), and dipyrone 2 g (n?=?103).

Results

Mean [± standard deviation (SD)] total pain relief (TOTPAR) scores were similar in the dexketoprofen 50 mg (15.3?±?8.6) and dipyrone (15.5?±?8.6) and slighly higher than in dexketoprofen 25 mg (13.5?±?8.6), although significant differences were not achieved. In the same way, patients in the dexketoprofen 50 mg and dipyrone groups showed higher scores in the sum of pain intensity differences (SPID) and the sum of analogue pain intensity differences (SAPID) than patients in the dexketoprofen 25 mg group, reaching statistical significance in comparison with dexketoprofen 25 mg and dipyrone for SPID and SAPID (p?p?Conclusions Dexketoprofen 50 mg administered as a single i.v. bolus was effective for the relief of moderate to severe pain in patients with renal colic, with a good safety profile and efficacy similar to i.v. dipyrone 2 g. Dexketoprofen produced analgesia that was faster in onset.     

The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs

Connexin 43 is located in the cardiomyocyte sarcolemma and in the mitochondrial membrane. Sarcolemmal connexin 43 contributes to the spread of myocardial ischemia/reperfusion injury, whereas mitochondrial connexin 43 contributes to cardioprotection. We have now investigated the antiarrhythmic dipeptide ZP1609 (danegaptide), which is an analog of the connexin 43 targeting antiarrhythmic peptide rotigaptide (ZP123), in an established and clinically relevant experimental model of ischemia/reperfusion in pigs. Pigs were subjected to 60 min coronary occlusion and 3 h reperfusion. ZP1609 (n?=?10) was given 10 min prior to reperfusion (75 μg/kg b.w. bolus i.v. + 57 μg/kg/min i.v. infusion for 3 h). Immediate full reperfusion (IFR, n?=?9) served as control. Ischemic postconditioning (PoCo, n?=?9; 1 min LAD reocclusion after 1 min reperfusion; four repetitions) was used as a positive control of cardioprotection. Infarct size (TTC) was determined as the end point of cardioprotection. Systemic hemodynamics and regional myocardial blood flow during ischemia were not different between groups. PoCo and ZP1609 reduced infarct size vs. IFR (IFR, 46?±?4 % of area at risk; mean?±?SEM; PoCo, 31?±?4 %; ZP1609, 25?±?5 %; both p?<?0.05 vs. IFR; ANOVA). There were only few arrhythmias during reperfusion such that no antiarrhythmic action of ZP1609 was observed. ZP1609 when given before reperfusion reduces infarct size to a similar extent as ischemic postconditioning. Further studies are necessary to define the mechanism/action of ZP1609 on connexin 43 in cardiomyocytes.     

Effect of CYP2C9 and SLCO1B1 polymorphisms on the pharmacokinetics and pharmacodynamics of nateglinide in healthy Chinese male volunteers

Purpose

Nateglinide is commonly used in the treatment of patients with type 2 diabetes mellitus. Our objective was to assess the association between CYP2C9 and SLCO1B1 polymorphisms and the metabolism of nateglinide in healthy Chinese male volunteers.

Methods

A total of 35 healthy Chinese male volunteers with different CYP2C9 and SLCO1B1 genotypes were given a single oral dose of 120 mg nateglinide. Plasma concentrations of nateglinide and blood glucose level were measured up to 8 h.

Results

In subjects with the CYP2C9*1/*3 & 521TT, CYP2C9*1/*1 & 521TC/CC and CYP2C9*1/*3 & 521TC genotype, AUC_0-∞ of nateglinide was 56 %, 34 % and 56 % higher (P?=?0.002, P?=?0.041 and P?=?0.013, respectively), and the CL/F of nateglinide was 35 %, 11 % and 36 % lower (P?=?0.000, P?=?0.003 and P?=?0.002, respectively) than that in the reference group. When only considering 521 T>C polymorphism, it had no significant association with the pharmacokinetics of nateglinide. CYP2C9*3 and 521 T>C polymorphisms were the significant predictors of the AUC_0-∞ and CL/F of nateglinide (adjusted multiple R ² ?=?34 % and 43 %, respectively) according to multiple linear regression analyses, but they have no significant association with changes in the blood glucose-lowering effect of nateglinide.

Conclusions

Both SLCO1B1 521 T>C and the CYP2C9*3 polymorphisms can significantly affect the pharmacokinetics of nateglinide, but they could only partially explain the interindividual variability of plasma concentration of nateglinide. Moreover, 521 T>C and the CYP2C9*3 polymorphisms have no effect on pharmacodynamics of nateglinide in healthy Chinese male subjects.     

Effect of pramlintide as an adjunct to basal insulin on markers of cardiovascular risk in patients with type 2 diabetes

ABSTRACT

Objective: Intensification of insulin therapy in patients with type 2 diabetes, while improving glycemic control, often leads to an increase in body weight and other markers of cardiovascular risk. The effects of pramlintide as an adjunct to basal insulin titration (without mealtime insulin) on glycemia and cardiovascular risk markers were examined.

Research design and methods: This was a post hoc analysis of a 16-week, double-blind, placebo-controlled study in patients with type 2 diabetes (N?=?211) using insulin glargine (without mealtime insulin)?±?oral agents. Patients were randomized to treatment with placebo or pramlintide (60 or 120?µg with major meals), and insulin glargine was titrated to target a fasting plasma glucose concentration of ≥70 to <100?mg/dL.

Main outcome measures: Endpoints included the change from baseline to Week 16 in body weight, high sensitivity C-reactive protein (hsCRP), triglycerides, HDL, LDL, and blood pressure.

Results: Pramlintide-treated patients lost weight and placebo-treated patients gained weight during 16 weeks of treatment (?1.6?±?0.3?kg vs. +0.7?±?0.3?kg, p?<?0.001; mean?±?SE). hsCRP was reduced in pramlintide-treated versus placebo-treated patients (?0.8?±?0.2?mg/L vs. 0.1?±?0.2?mg/L, p?<?0.01; mean?±?SE). Patients with baseline hsCRP?>?3?mg/L (high cardiovascular risk) demonstrated greater hsCRP reductions with pramlintide versus placebo treatment at Week 16 (p?<?0.05). Patients with baseline triglycerides ≥150?mg/dL or ≥200?mg/dL (high cardiovascular risk) showed significant reductions from baseline in triglyceride concentrations with pramlintide (?43?±?14?mg/dL or ?59?±?19?mg/dL; p?<?0.05; mean?±?SE) but not with placebo (1?±?29?mg/dLor ?3?±?54?mg/dL; mean?±?SE). No significant differences between pramlintide and placebo were observed for changes in HDL, LDL, or blood pressure. Pramlintide treatment was generally well tolerated. The most frequent adverse event related to pramlintide was mild-to-moderate nausea (31% pramlintide vs. 10% placebo). Pramlintide added to basal insulin did not increase the incidence of hypoglycemia. A limitation of the study was its relatively short duration.

Conclusions: Pramlintide, as an adjunct to basal insulin, was associated with improvements in several cardiovascular risk markers, warranting long-term clinical studies to determine its potential effects on cardiovascular risk.     

Naphthalene Biomarkers and Relationship with Hemoglobin and Hematocrit in White, Black, and Hispanic Adults: Results from the 2003–2004 National Health and Nutrition Examination Survey

Naphthalene is an important contaminant in indoor and outdoor air. Acute overexposure can have toxic effects, resulting in hemolysis. There have been no studies evaluating the impact of environmental exposure on red blood cell indices. We examined 1- and 2-hydroxynaphthalene urinary metabolites (NAP1 and NAP2) in non-Hispanic White, non-Hispanic Black, and Mexican-American adults in the USA and their relationship with hemoglobin (Hb) and hematocrit (HCT). Using the 2003–2004 National Health and Nutrition Examination Survey data, weighted generalized linear regression analyses were used to examine the association between Hb (in grams per deciliter) and HCT (in percent) with NAP1 and NAP2 (per 100,000 ng/L). Beta coefficients ± SE are reported. NAP1 and NAP2 were highest in non-Hispanic Blacks, followed by non-Hispanic Whites, and lowest in Mexican-American adults. There was a positive association between NAP1 and Hb (0.39?±?0.11, p?=?0.0034) and HCT (1.14?±?0.28, p?=?0.0009) after adjusting for age, gender, race, education, and smoking. Stratified analysis by smoking showed similar results with the association being stronger for smokers (Hb 0.63?±?0.23, p?=?0.02; HCT 1.43?±?0.79, p?=?0.09) than nonsmokers (Hb 0.34?±?0.14, p?=?0.03; HCT 1.08?±?0.42, p?=?0.02). The association was also stronger for non-Hispanic blacks (Hb 0.54?±?0.20, p?=?0.02; HCT 1.43?±?0.55, p?=?0.02) than for non-Hispanic whites (Hb 0.37?±?0.18, p?=?0.06; HCT 1.20?±?0.51, p?=?0.03) and was not significant for Mexican-Americans (Hb 0.30?±?1.7, p?=?0.10; HCT 0.99?±?0.52, p?=?0.08). NAP2 was not significantly associated with Hb or HCT. The observed disparity in NAP1 and NAP2 levels by race/ethnicity is consistent with published literature. The origin of these differences in exposure is unclear but may reflect differences in environmental exposure as well as genetic susceptibility. The positive association between NAP1 with HCT and Hb is an unexpected finding. Further research is needed to understand the possible biological mechanisms or other explanations for this association.     

Benzonatate Ingestion Reported to the National Poison Center Database System (NPDS)

Little has been published on benzonatate ingestion, with the few case reports suggesting significant risk of seizures after poisoning. A 7-year retrospective review of all single substance ingestion of benzonatate reported to the National Poison Center Database System (NPDS) from 2000 to 2006. In this review, there were 2,172 patients, of which 1,280 (58%) were female. Mean age was 20 years, with 676 (30%) <6 years. Serious outcomes occurred in 116 (moderate, n?=?81, 4%; major, n?=?31, 1%; and death, n?=?4, 0.2%). Mean age of those with serious outcome was 21 years, with 41 (35%) in children less than 6 years old. Forty-nine percent (1,084) patients were treated in a healthcare facility (HCF) of which 148 (7%) were admitted for medical care. Clinically significant effects that were documented included tachycardia (n?=?31, 1%), agitation (n?=?30, 1%), seizure (n?=?23, 1%), coma (n?=?14, 0.6%), ventricular dysrhythmia (n?=?9, 0.4%), cardiac arrest (n?=?8, 0.3%), hypotension (n?=?7, 0.3%), and asystole (n?=?6, 0.2%). Of patients with seizures reported, eight patients (0.4%) had multiple/discrete seizures and two had status epilepticus documented. Dysrhythmias but not seizures occurred in all fatalities in this review. Significant CNS and cardiac effects occurred in a small subset of this study (<1%), while half the patients received direct medical care in an HCF. No correlation between age and severity of medical outcome was detected by statistical analysis. A prospective study to better evaluate potential HCF triage criteria such as dosage, age, or preexisting conditions may be warranted. The fatalities from this study were due to dysrhythmias rather than seizures as previously reported in previous case reports. There were no clinical correlations between severity of outcomes and dose ingested. A median dose of 200 mg or greater suggests a potential for producing serious outcomes in a benzonatate exposure.     

The Acoustic Features of Inhalation can be Used to Quantify Aerosol Delivery from a Diskus™ Dry Powder Inhaler

Purpose

Some patients are unable to generate the peak inspiratory flow rate (PIFR) necessary to de-agglomerate drug particles from dry powder inhalers (DPIs). In this study we tested the hypothesis that the acoustic parameters of an inhalation are related to the PIFR and hence reflect drug delivery.

Methods

A sensitivity analysis of the relationship of the acoustics of inhalation to simultaneously recorded airflow, in a cohort of volunteers (n?=?92) was performed. The Next Generation Impactor (NGI) was used to assess in vitro drug delivery from salmeterol/fluticasone and salbutamol Diskus? DPIs. Fine particle fraction, FPF, (<5 μm) was measured at 30–90 l/min for 2–6 s and correlated with acoustically determined flow rate (IFRc). In pharmacokinetic studies using a salbutamol (200 μg) Diskus?, volunteers inhaled either at maximal or minimal effort on separate days.

Results

PIFRc was correlated with spirometrically determined values (R ²?=?0.88). In in vitro studies, FPF increased as both flow rate and inhalation duration increased for the salmeterol/fluticasone Diskus? (Adjusted R ²?=?0.95) and was proportional to flow rate only for the salbutamol Diskus? (Adjusted R ²?=?0.71). In pharmacokinetic studies, blood salbutamol levels measured at 20 min were significantly lower when PIFRc was less than 60 l/min, p?Conclusion Acoustically-determined PIFR is a suitable method for estimating drug delivery and for monitoring inhalation technique over time.     

Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis

Objectives

To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs).

Methods

A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥?6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 <?3.2; and (2) patients without a response to DMARDs, with persistent DAS28?≥?3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression.

Results

Serum P-gp levels were significantly higher in RA patients (n?=?151) than in the controls (n?=?30) (158.70?±?182.71 ng/mL vs. 14.12?±?8.97 ng/mL, p?<?0.001). The P-gp level was correlated with the DAS28 score (r?=?0.39, p?<?0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206?±?21.47 ng/mL vs 120.60?±?15.70 ng/mL; p?=?0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54–7.27, p?=?0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29–5.40, p?=?0.01).

Conclusion

Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.

     

Lurasidone in the treatment of schizophrenia: a 6-week, placebo-controlled study

Rationale

There is an unmet need in the treatment of schizophrenia for effective medications with fewer adverse effects.

Objective

This study aims to evaluate the efficacy and safety of lurasidone, an atypical antipsychotic, for the treatment of schizophrenia.

Methods

Patients with an acute exacerbation of schizophrenia were randomized to 6 weeks of double-blind treatment with once-daily, fixed-dose lurasidone 40 mg (N?=?50), lurasidone 120 mg (N?=?49), or placebo (N?=?50). The primary efficacy measure was mean change from baseline to day 42 (last observation carried forward) in the Brief Psychiatric Rating Scale derived (BPRSd) from the Positive and Negative Syndrome Scale (PANSS).

Results

Mean change in BPRSd was significantly greater in patients receiving lurasidone 40 and 120 mg/day versus placebo (?9.4 and ?11.0 versus ?3.8; p?=?0.018 and 0.004, respectively). Treatment with lurasidone 120 mg/day was superior to placebo across all secondary measures, including PANSS total (p?=?0.009), PANSS positive (p?=?0.005), PANSS negative (p?=?0.011), and PANSS general psychopathology (p?=?0.023) subscales and Clinical Global Impression of Severity (CGI-S; p?=?0.001). Treatment with lurasidone 40 mg/day was superior to placebo on the PANSS positive subscale (p?=?0.018) and CGI-S (p?=?0.002). The most common adverse events for patients receiving lurasidone were nausea (16.2 versus 4.0 % for placebo) and sedation (16.2 versus 10.0 % for placebo). Minimal changes in weight, cholesterol, triglyceride, and glucose levels were observed.

Conclusions

In this study, which was limited by a relatively high discontinuation rate, lurasidone provided effective treatment for patients with acute exacerbation of chronic schizophrenia and had minimal effects on weight and metabolic parameters.     

What are the adverse effects of ethanol used as an antidote in the treatment of suspected methanol poisoning in children?

BACKGROUND: Ethanol used as an antidote is said to have various adverse effects, particularly in children. The rate of these adverse effects is not known. METHODS: Twenty-one-year retrospective chart review (1980-2000) from suspected methanol poisoning patients treated with ethanol in two large pediatric tertiary care centers. RESULTS: A total of 60 children (median age of 24 months) received ethanol for suspected methanol poisoning: 39 orally and 21 intravenously. Median initial methanol level was 4.16 mmol/L (13.3 mg/dL) (range 0 to 87.5 mmol/L or 0 to 280 mg/dL). Median duration of ethanol treatment was 16 hours (range 1.5 to 72 hours). None [0% (95% CI 0-5%)] of the 60 patients developed symptomatic hypoglycemia. Of the 50 patients that had a glucose level measured, none [(0% [95% CI 0-6%)] had a serum glucose concentration < 2.78 mmol/L (< 50 mg/dL). Eight patients [16% (95% CI 8-30%)] had at least one serum glucose concentration between 2.78-3.61 mmol/L (50-65 mg/dL), but none of those had symptoms compatible with hypoglycemia. A total of 42 patients [84% (95% CI 70-92%)] had all their serum glucose concentrations > 3.61mmol/L (> 65 mg/dL). There was no identifiable difference in the glucose intake between the serum glucose concentration groups. Six out of the 60 patients [10% (95% CI 4-21%)] were described as more drowsy after ethanol but none was comatose or needed intubation. No child showed signs of hypothermia [0/40 (95% CI 0-8%)] (rectal temperature < 35 degrees C), hepatotoxicity (0/12) (AST or ALT > 100 U/L) or even thrombophlebitis (0/21). None of the 22 patients with toxic levels of methanol (> or = 26.2 mmol/L- > or = 20 mg/dL) died or had ethanol-induced morbidity despite wide variation in ethanol levels. CONCLUSION: The rate of clinically important adverse effects related to ethanol used as an antidote to treat methanol poisoning in children was either absent or low in a tertiary care pediatric hospital setting. There was no morbidity or mortality associated with ethanol when it was used despite wide variation in ethanol levels. These results suggest that with appropriate monitoring and intravenous glucose intake in a controlled environment such as a pediatric intensive care unit, ethanol therapy does not carry as many risks as currently believed.