The effect of variable cigarette consumption on the interaction with clozapine and olanzapine

Objective Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting.Methods In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared.Results Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1–6 (n=0), 7–12 (n=13), 13–19 (n=18) and ≥20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01).Conclusion A daily consumption of 7–12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects.     

Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin’s cholesterol lowering capabilities and basal sterol serum levels

We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415–421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis. We analyzed the serum levels of cholesterol, lathosterol, and campesterol in healthy white males which had been grouped on the basis of their SLCO1B1 haplotype: *1a (n=10), *1b (n=10), and *5 (n=8). The subjects received a single oral dose of 40 mg pravastatin. Cholesterol and lathosterol levels were lower in all subjects following pravastatin intake for up to 24. Median levels 6 h post-dosing of lathosterol decreased in each SLCO1B1 haplotype group in the rank order of *1b (−0.11 mg dl^–1; min–max: −0.20 to −0.04; p=0.005) > *1a (−0.09 mg dl^–1; min–max: −0.22 to −0.05; p=0.005) > *5 (−0.07 mg dl^–1; min–max: −0.17 to −0.05; p=0.012). Lathosterol median-change values were significantly greater in haplotype *1b than in haplotype *5 individuals (p=0.041, non-adjusted), which was congruent with the extent of mean changes in lathosterol-to-cholesterol ratios, although the latter did not reach statistical significance. Post-treatment serum levels of campesterol were not affected by SLCO1B1 haplotype. Interestingly, sterol basal serum levels tended to be highest in *1b carriers, followed by those in *1a and *5 individuals, with significant differences in lathosterol concentrations between the *1b and *5 (p=0.041, non-adjusted) haplotype group. Our findings suggest an association of SLCO1B1*1b and *5 haplotypes to pravastatin’s inhibition of the hepatocellular HMG-CoA reductase. Furthermore, SLCO1B1 haplotypes seem to play a role in basal cholesterol homeostasis.     

Does cigarette smoking increase plasma urotensin II concentrations?

Objective Human urotensin II (UII) acts on the urotensin (UT) receptor and is the most potent mammalian vasoconstrictor identified to date. The role of UII in human cardiovascular regulation remains unclear, and the results of plasma measurements have been conflicting, perhaps because different measurement techniques have been used. The effects of cigarette smoking on plasma UII concentrations are unknown. The primary aim of our study was to demonstrate whether cigarette smoking had any effect on plasma UII concentrations in otherwise healthy volunteers. Our secondary aim was to compare the results obtained from assaying simultaneously using both radioimmunoassay (RIA) and immunoluminometric assay (ILMA). Methods Blood was taken from 20 healthy male non-smokers and 20 healthy male cigarette smokers. Plasma was separated and stored at −70°C. Samples were batch analysed simultaneously for UII using RIA and ILMA. Results Median (range) plasma UII concentrations were lower in non-smokers [1.67 (1.0–2.27) pg ml⁻¹] compared to smokers [2.62 (1.87–3.46) pg ml⁻¹] (P = 0.03) measured using RIA. Those who had smoked a cigarette in the 10 min before sampling had greater concentrations of UII [3.10 (1.87–4.60) pg ml⁻¹] compared to controls (P = 0.01). Plasma UII concentrations determined by ILMA were consistently low with no differences between groups. Conclusion The data obtained by RIA show that smoking may increase plasma concentrations of UII with a more pronounced increase when a cigarette has been smoked recently. There was a complete lack of correlation between RIA and ILMA for the whole data set, which suggests that some of the variability in plasma UII reported in the literature may result from differences between assays. Presented in part at the Anaesthetic Research Society meeting, Leicester, UK, 24 November 2005.     

Hydroxyethylvaline adduct formation in haemoglobin as a biological monitor of cigarette smoke intake

The ethylene oxide adduct formed on the N-terminal valine in haemoglobin was investigated as a biological monitor of tobacco smoke intake. The modified method developed for the determination of the hydroxyethylvaline adduct (HOEtVal) involved reaction of globin with pentafluorophenyl isothiocyanate, extraction of the HOEtVal thiohydantoin product, derivatization of this by trimethylsilylation and quantitation by capillary gas chromatography with selective ion monitoring mass spectrometry using a tetradeuterated internal standard. The method was applied to globin samples from 26 habitual cigarette smokers and 24 non-smokers. There was a significant correlation between cigarette smoke intake as measured by the average number of cigarettes smoked per day and HOEtVal levels (r=0.537, p<0.01). Background levels were found in non-smokers (mean 49.9 pmol/g Hb, range 22–106 pmol/g Hb). Smoking increased these levels by 71 pmol/g Hb/ 10 cigarettes per day.Cotinine levels in plasma of the smokers were determined by GC-NPD using 2-methyl-4-nitroaniline as internal standard. For non-smokers cotinine was determined by GC-MS selective ion monitoring using d₃-methylcotinine as internal standard. There was no correlation between number of cigarettes smoked per day and cotinine levels (r=0.297, p>0.05) although cotinine was correlated with HOEtVal (r=0.43, p<0.01).The HOEtVal adduct levels thus appear to be a suitable biomonitor for exposure to hydroxyethylating agents in cigarette smoke, reflecting an integrated dose over the erythrocyte lifetime. This is in contrast to plasma cotinine determinations which reflect only the previous day's exposure to nicotine in smoke.     

Genotoxic risk for humans due to work place exposure to ethylene oxide: remarkable individual differences in susceptibility

Single strand breaks of DNA of peripheral mononuclear blood cells from 97 male and female workers occupationally exposed to ethylene oxide were analysed by the alkaline elution method. These individuals were occupied with the sterilization of medical devices in hospitals and in commercial plants. Ethylene oxide in the air of the working areas was detected up to a maximal concentration of 16.5 mg/m³ calculated as 4-h time-weighted average (4h TWA). Mean value was 1.47±0.52 mg/m³ (1 mg/m³ = 0.55 ppm). Compared to the mean elution rate of the DNA from non-smoking workers exposed to air concentrations of ethylene oxide below the detection limit of 0.1 mg/m³ (4h TWA) the non-smokers working in rooms with a concentration of ethylene oxide between 0.5 mg/m³ and 2 mg/m³ showed a statistically significant (P <0.05) 119% higher mean elution rate and even for the non-smokers exposed to 0.1 – 0.5 mg/m³ of ethylene oxide a statistically significant (P <0.05) 53% higher mean elution rate was observed. For smokers a similar tendency was found but the increase in elution rates in response to the external exposure was smaller than in non-smokers and no statistical significance was obtained. According to their sensitivity to ethylene oxide the non-smoking workers could be classified into two subpopulations. In the majority of the non-smokers (67%) approximately 5-fold more DNA strand breaks were induced by ethylene oxide than in the other non-smokers. A lowest detectable effect level could only be specified for non-smokers. For the “higher sensitive” group the lowest detectable effect level in an examination of a single individual was calculated to be 0.6 mg/m³ ethylene oxide in the air (4h TWA). For the “lower sensitive” group a lowest detectable effect level was calculated to be 3.5 mg/m³. Received: 18 October 1993/Accepted: 16 February 1994     

Lower Glial Metabolite Levels in Brains of Young Children with Prenatal Nicotine Exposure

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3–4 years old) children, using proton magnetic resonance spectroscopy (¹H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/¹H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA—p = 0.03) and tCr levels (repeated measures ANOVA–p = 0.003), especially in the basal ganglia of the girls (−19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = −0.67; p < 0.001) and visual motor integration (r = −0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.     

Sister chromatid exchange, (SCE), High-Frequency Cells (HFCs) and SCE distribution patterns in peripheral blood lymphocytes of Spanish adult smokers compared to non-smokers

According to the International Agency for Research on Cancer, smoking tobacco is a major cause of cancer in humans. It causes about half of all male cancer deaths and an ever increasing number of cancer deaths in females. The aim of this study was to establish whether cigarette smoking increases sister chromatid exchanges (SCEs) in peripheral blood lymphocytes in two Spanish population groups; light and heavy smokers. The mean number of High-Frequency Cells (HFCs) was determined and, the SCE distribution pattern among the chromosomes was analysed represented by a ratio described below. A local sample of 101 adult smokers (n = 48) and non-smokers (n = 53), aged from 18 to 49 years, was studied using SCE levels in peripheral lymphocytes. Heavy smoking (⩾10 cigarettes per day) increased significantly the SCE frequency and the HFC parameters. Neither age nor sex significantly influenced the frequencies in the groups studied.     

Effect of impulsivity on craving and behavioral reactivity to smoking cues

Introduction Nearly 25% of American adults remain regular smokers. Current smokers may be especially likely to possess characteristics that impair their ability to quit, such as impulsivity. Impulsive individuals may be overly prone to smoke because they are particularly drawn to rewarding stimuli and related cues. The aim of this study was to test the hypothesis that more impulsive smokers are more responsive to cigarette cues than other smokers. Materials and methods In a repeated measures design, 60 euthymic, adult smokers (50% female) were exposed to a smoking cue and a neutral cue in two experimental sessions. Cue reactivity was operationalized as changes in cigarette craving and preference for immediate vs delayed smoking after cue exposure. Results Impulsivity predicted a heightened craving response to both cues but particularly the smoking cue (t [161] = 3.21, p = 0.002). Smokers with high levels of impulsivity exhibited a greater preference for immediate rewards over larger, delayed rewards in terms of both hypothetical (t [58] = 5.99, p = 0.001) and actual (z = 3.02, p = 0.003) rewards. Conclusion These data suggest that increased reactivity to environmental smoking cues contributes to the link between impulsivity and smoking.     

A PET study on regional coexpression of 5-HT<Subscript>1A</Subscript> receptors and 5-HTT in the human brain

Rationale Several lines of evidence suggest inter-dependency between the serotonin transporter (5-HTT) and the 5HT_1A receptor, two recognised targets for the treatment of anxiety and depression. Objectives to examine the correlation of regional expression levels for these two serotonergic markers in the human brain in vivo. Methods Twelve male control subjects were examined with PET twice on the same day, using the radioligands [¹¹C]WAY 100635 and [¹¹C]MADAM for quantification of the 5-HT_1A receptor and the 5-HTT, respectively. The binding potential (BP) was calculated for raphe nuclei, hippocampus and frontal cortex. Results In all regions, the BP for both [¹¹C]WAY 100635 (raphe nuclei 1.85–4.71, hippocampus 2.52–6.17, frontal cortex 2.03–3.79) and [¹¹C]MADAM (2.70–7.65, 0.47–1.76, 0.18–0.51) varied several fold between subjects. In the raphe nuclei, where the two markers are situated on the same neurons, the ratio of [¹¹C]WAY 100635 binding to [¹¹C]MADAM BP binding varied considerably (0.43–1.05). There was a positive correlation between the two markers in the raphe nuclei (r _xy = 0.68, p < 0.05) and in the hippocampus (r _xy = 0.97, p < 0.001) but not in the frontal cortex (r _xy = −0.25, p = 0.44). Conclusions The results support a correlation between density levels of the 5-HT_1A-receptor and the 5-HTT in the raphe nuclei and hippocampus but not in the frontal cortex. A suggested clinical implication is that the inter-individual variability in 5-HT_1A-receptor and 5-HTT densities, as well as the ratio of these, is of particular interest in relation to individual responses to selective serotonin reuptake inhibitor treatment.     

Exposure to epichlorohydrin and dimethylformamide, glutathione S-transferases and sister chromatid exchange frequencies in peripheral lymphocytes

Workers in epoxy resin, synthetic leather, and printed circuit board manufacturing plants are exposed to epichlorohydrin (ECH), or dimethylformamide (DMF), or both. ECH, an alkylating agent, has been shown to cause malignancy in animals, but its genotoxicity in humans is unclear. DMF is a well-known hepatotoxic chemical, although evidence of its genotoxicity in humans is also limited. In this study, we examined the effects of exposure to ECH and DMF on sister chromatid exchange (SCE) in plant workers, in order to examine the genotoxicity of these two agents. Because the genotoxicity of certain agents can be modulated by metabolic traits, we also investigated influence of the glutathione S-transferase (GST) μ (GST M1) and GST θ (GST T1) genes on the genotoxicity of ECH and DMF. A total of 85 male plant workers were included in this study. The subjects were divided into five exposure groups, based on their job titles and the airborne ECH and DMF concentrations in their areas of work. A questionnaire was administered to obtain detailed occupational, smoking, alcohol consumption, and medication histories. Standardized cytogenetic methods were used to determine the frequency of sister chromatid exchange (SCE) in peripheral blood lymphocytes. GST M1 and GST T1 genotypes were identified using polymerase chain reaction (PCR). In analysis, smoking was significantly associated with increased SCE frequency (P < 0.01). Workers with high ECH exposure also had significantly higher SCE frequencies than those with low or no ECH exposure (P < 0.05). However, DMF exposure was not associated with SCE frequency. The GST M1 null genotype was also found to be associated with an increased SCE frequency (P = 0.06). We conclude that ECH exposure may be associated with genetic toxicity and that DMF does not appear to be genotoxic. Received: 24 November 1998 / Accepted: 9 March 1999     

Dietary therapy with Lactobacillus GG, bovine colostrum or bovine immune colostrum in patients with juvenile chronic arthritis: Evaluation of effect on gut defence mechanisms

The effect of dietary therapy with a human Lactobacillus strain GG (ATCC 53103), bovine colostrum, or bovine immune colostrum with specific antibodies against anaerobic intestinal bacteria on gut defence mechanisms were studied in juvenile chronic arthritis. Thirty patients with juvenile chronic arthritis were randomly allocated to receive a freeze-dried powder of Lactobacillus GG, or bovine colostrum, or bovine immune colostrum, for a two-week period. Immunologic and non-immunologic gut defence mechanisms were indirectly investigated in blood and faecal samples. In patients receiving Lactobacillus GG, the median (interquartile range) frequency of immunoglobulin-secreting cells, determined by enzyme-linked immunospot assay, increased in the IgA class from 1840 (690–2530) to 3480 (1030–13 170)/10⁶ cells; p=0.02. Likewise the median (interquartile range) frequency of specific antibody-secreting cells against dietary antigens increased during the Lactobacillus GG therapy in the IgM class from 3.8 (1.4–5.0) to 11.2 (5.0–30.0)/10⁶ cells; p=0.02. In addition, Lactobacillus GG therapy decreased the median (interquartile range) activity of faecal urease, which has been associated with mucosal tissue damage, from 40.3 (21.7–54.3) to 28.6 (24.5–49.4) nmol. min⁻¹ (mg protein)⁻¹; p=0.10, while, in patients receiving bovine colostrum, faecal urease activity increased (from 42.2 to 80.6; p=0.04). All findings were transient. We suggest that gut defence mechanisms are disturbed in juvenile chronic arthritis and we further suggest that orally administered Lactobacillus GG has a potential to reinforce the mucosal barrier mechanisms in juvenile chronic arthritis.     

Environmental tobacco smoke exposure among smokers and non-smokers receiving outpatient substance abuse treatment

Introduction

Environmental Tobacco Smoke (ETS) has been linked to numerous health problems. While research has demonstrated high prevalence of tobacco use among individuals receiving treatment for substance use disorders (SUDs), no studies have examined ETS among individuals receiving treatment for SUDs, paying specific attention to non-smokers who may be at risk for high exposure to ETS.

Methods

Participants (N = 261) enrolled in outpatient substance abuse treatment completed a survey, in which 14 items were used to quantify ETS exposure and smoking policies across several environments.

Results

Among smokers, 85% reported that their significant others also smoked as compared to 15% among non-smokers (χ² = 6.624, p < .05). A logistic regression examined the characteristics that predicted smoking in the home. The overall model was significant, (χ² = 36.046, p < .0005) with variables that independently predicted smoking in the home included having less than a high school diploma, being female, and living with a smoker. Income, age, and living with children were not found to be significant. Overall, 42% white collar workers 26% of service workers and 30% of blue collar workers reported no exposure to ETS. Sixty-seven percent of smokers strongly agreed or agreed that the hazards of secondhand smoke have been clearly demonstrated versus 58% of non-smokers.

Conclusions

Smokers and non-smokers enrolled in outpatient substance abuse treatment are frequently exposed to ETS at home, work, and in social settings. The dangers of ETS should be addressed among this population through education, smoke-free policies, and cessation resources, with help from their treatment facility.     

Glutathione S-transferase (GST) M1 and GST T1 genotypes and hematopoietic effects of benzene exposure

This study investigated whether or not the genotypes glutathione S-transferase θ (GST T1) and μ (GST M1) correlated with low white blood cell (WBC) count found in benzene exposed workers. We found that individuals with genotypes positive for both GST T1 and GST M1 showed the highest prevalence of low WBC [odds ratio (OR) = 4.67, P = 0.046, 95% confidence interval (CI) = 1.02–24.15] when the benzene exposure was high. Multiple logistic regression showed that benzene exposure (OR = 2.81, P = 0.062, 95% CI = 0.96–8.30) was associated with increased OR on low WBC and interactions between the benzene exposure and the genotype of GST T1 were also observed. These observations suggest that GST T1 and GST M1 may play important roles in the biotransformation of benzene, the effect which leads to its hematotoxicity. Received: 17 September 1998 / Accepted: 11 January 1999     

Effects of acute tyrosine/phenylalanine depletion on the selective processing of smoking-related cues and the relative value of cigarettes in smokers

Rationale Acute tyrosine/phenylalanine depletion (ATPD) is a validated neurobiological challenge that results in reduced dopaminergic neurotransmission, allowing examination of the effects of a hypodopaminergic state on craving-related processes. Objectives We studied 16 nonabstaining smokers (>10 cigarettes/day; 9 males; age 20–33 years) to whom was administered a tyrosine/phenylalanine-free mixture (TYR/PHE-free) and a balanced amino acid mixture (BAL) in a double-blind, counterbalanced, crossover design. Methods Subjective cigarette craving, attentional bias to smoking-related word cues, relative value of cigarettes, negative mood, and expired carbon monoxide (CO) levels were measured at various timepoints through 300 min. Participants smoked at hourly intervals to prevent acute nicotine withdrawal during testing. Results The TYR/PHE-free mixture, as compared to the BAL mixture, was associated with a greater increase in CO levels from baseline (p = 0.01). Adjusting for the potential confounding influence of between-condition differences in CO levels across time, TYR/PHE-free mixture was associated with increased demand for cigarettes (p = 0.01) and decreased attentional bias toward smoking-related words (p = 0.003). There were no significant differences between conditions in either subjective craving or depressed or anxious mood (p values > 0.05). Conclusion Among nonabstaining daily smokers, acute dopaminergic depletion via ATPD may influence smoking behavior and indices of smoking-related motivation, such as attentional bias to smoking cues and relative cigarette value, which are not readily captured by subjective craving.     

The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin

Objective Vildagliptin is a potent and selective dipeptidyl peptidase-IV (DPP-4) inhibitor that improves glycemic control in patients with type 2 diabetes mellitus by increasing α- and β-cell responsiveness to glucose. This study investigated the pharmacokinetics of vildagliptin in patients with hepatic impairment compared with healthy subjects. Methods This was an open-label, parallel-group study in patients with mild (n = 6), moderate (n = 6) or severe (n = 4) hepatic impairment and healthy subjects (n = 6). All subjects received a single 100-mg oral dose of vildagliptin, and plasma concentrations of vildagliptin and its main pharmacologically inactive metabolite LAY151 were measured up to 36 h post-dose. Results Exposure to vildagliptin (AUC_0–∞ and C_max) decreased non-significantly by 20 and 30%, respectively, in patients with mild hepatic impairment [geometric mean ratio (90% CI): AUC_0–∞, 0.80 (0.60, 1.06), p = 0.192; C_max, 0.70 (0.46, 1.05), p = 0.149]. Exposure to vildagliptin was also decreased non-significantly in patients with moderate hepatic impairment [−8% for AUC_0–∞, geometric mean ratio (90% CI): 0.92 (0.69, 1.23), p = 0.630; −23% for C_max, geometric mean ratio (90% CI): 0.77 (0.51, 1.17), p = 0.293]. In patients with severe hepatic impairment, C_max was 6% lower than that in healthy subjects [geometric mean ratio (90% CI): 0.94 (0.59, 1.49), p = 0.285], whereas AUC_0–∞ was increased by 22% [geometric mean ratio (90% CI): 1.22 (0.89, 1.68), p = 0.816). Across the hepatic impairment groups, LAY151 AUC_0–∞ and C_max were increased by 29–84% and 24–63%, respectively, compared with healthy subjects. The single 100-mg oral dose of vildagliptin was well tolerated by patients with hepatic impairment. Conclusions There was no significant difference in exposure to vildagliptin in patients with mild, moderate or severe hepatic impairment; therefore, no dose adjustment of vildagliptin is necessary in patients with hepatic impairment.     

Comparison of acute and subacute effects of deflazacort and prednisone on glucose metabolism in man

Summary Corticosteroid treatment produces glucose intolerance with insulin resistance. Recent reports have indicated that deflazacort (DF) is significantly less diabetogenic than prednisone (PN). A euglycaemic hyperinsulinaemic (100 µU/ml) glucose clamp (EHGC) and ³H-glucose infusion for 240 min were performed in 6 healthy volunteers (HV) after administration of 15 mg PN or 18 mg DF, 12 h and 2 h before test. The glucose metabolic clearance rate (MCR) was significantly (p=0.02) higher after DF (4.75±0.58 ml/min·kg) than after PN (3.31±0.27 ml/min·kg). Basal hepatic glucose production (HGP) was significantly (p=0.003) lower after DF (3.58±0.33 mg/kg·min) than after PN (4.44±0.23 mg/kg·min). A similar pattern was obtained for glucose volume (GV) and glucose pool (GP). The kinetic parameters of insulin were not significantly different after the two drugs. After 7 day of PN 30 mg/day or DF 36 mg/day, EHGC and ³H-glucose infusion for 240 min were performed in 10 HV. Glucose MCR values were significantly (p=0.03) higher after DF (5.03±0.91 ml/min·kg) than after PN (2.80±0.26 ml/min·kg). HGP values did not different significantly after the two drugs. GV (p=0.001) and GP (p=0.002) were significantly lower after DF than after PN. Insulin kinetics were not significantly different after the two drugs. It is concluded that on acute and 7-day administration to healthy subjects DF, in an anti-inflammatory dose equivalent to PN, shows significantly less influence on glucose metabolism.     

Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin

Objective The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe.Methods A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition.Results The S-warfarin between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin during baseline (p=0.45) or inhibition (p=0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42±29% and 26±18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (C_{at 1 h}) or (−) 3S,5R-fluvastatin AUC_{0–12 h} and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between C_{at 1 h} and extent of warfarin inhibition.Conclusions Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.     

Possible role of MDR1 two-locus genotypes for young-age onset ulcerative colitis but not Crohn’s disease

Background The role of the single nucleotide polymorphisms (SNPs) on positions 2677G>T/A and 3435C>T of the multi-drug-resistance gene 1 (MDR1) in inflammatory bowel disease (IBD) remains unclear. Aims To further elucidate the potential impact of MDR1 two-locus genotypes on susceptibility to IBD and disease behaviour. Patients and methods Three hundred eighty-eight German IBD patients [244 with Crohn’s disease (CD), 144 with ulcerative colitis (UC)] and 1,005 German healthy controls were genotyped for the two MDR1 SNPs on positions 2677G>T/A and 3435C>T. Genotype–phenotype analysis was performed with respect to disease susceptibility stratified by age at diagnosis as well as disease localisation and behaviour. Results Genotype distribution did not differ between all UC or CD patients and controls. Between UC and CD patients, however, we observed a trend of different distribution of the combined genotypes derived from SNPs 2677 and 3435 (χ² = 15.997, df = 8, p = 0.054). In subgroup analysis, genotype frequencies between UC patients with early onset of disease and controls showed significant difference for combined positions 2677 and 3435 (χ² = 16.054, df = 8, p = 0.034 for age at diagnosis ≥25, lower quartile). Herein the rare genotype 2677GG/3435TT was more frequently observed (odds ratio = 7.0, 95% confidence interval 2.5 – 19.7). In this group severe course of disease behaviour depended on the combined MDR1 SNPs (χ² = 16.101, df = 6, p = 0.017 for age at diagnosis ≥25). No association of MDR1 genotypes with disease subgroups in CD was observed. Conclusions While overall genotype distribution did not differ, combined MDR1 genotypes derived from positions 2677 and 3435 are possibly associated with young age onset of UC and severe course of disease in this patient group.     

Mercury exposure and neurochemical impacts in bald eagles across several Great Lakes states

In this study, we assessed mercury (Hg) exposure in several tissues (brain, liver, and breast and primary feathers) in bald eagles (Haliaeetus leucocephalus) collected from across five Great Lakes states (Iowa, Michigan, Minnesota, Ohio, and Wisconsin) between 2002–2010, and assessed relationships between brain Hg and neurochemical receptors (NMDA and GABA_A) and enzymes (glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)). Brain total Hg (THg) levels (dry weight basis) averaged 2.80 μg/g (range: 0.2–34.01), and levels were highest in Michigan birds. THg levels in liver (r _p  = 0.805) and breast feathers (r _p  = 0.611) significantly correlated with those in brain. Brain Hg was not associated with binding to the GABA_A receptor. Brain THg and inorganic Hg (IHg) were significantly positively correlated with GS activity (THg r _p  = 0.190; IHg r _p  = 0.188) and negatively correlated with NMDA receptor levels (THg r _p  = −0245; IHg r _p  = −0.282), and IHg was negatively correlated with GAD activity (r _s  = −0.196). We also report upon Hg demethylation and relationships between Hg and Se in brain and liver. These results suggest that bald eagles in the Great Lakes region are exposed to Hg at levels capable of causing subclinical neurological damage, and that when tissue burdens are related to proposed avian thresholds approximately 14–27% of eagles studied here may be at risk.     

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Background  Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus. Methods  Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). Results  There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC_0–12 in groups of patients treated with MMF or everolimus (R ² 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC_0–12 in patients treated with MMF (R ² = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC_0–12 in patients treated with everolimus (R ² = 0.24). Conclusion  Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.