The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users

Rationale

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood.

Objective

This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women.

Methods

In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n?=?13) and nonuser controls (n?=?17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task.

Results

The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n?=?7), relative to controls (n?=?9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users.

Limitation

The group sizes were small, when males and females were considered separately.

Conclusions

Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.     

Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum

Rationale

It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings.

Objectives

To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum.

Methods

Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n?=?42 or 4 mg, n?=?24) or placebo (n?=?66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence.

Results

In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110)?=?1.28, p?=?0.20, $ \eta_{\mathrm{p}}^2 $ ?=?0.20] nor an effect of treatment [F(7,124)?=?0.45, p?=?0.87, $ \eta_{\mathrm{p}}^2 $ ?=?0.03]. There was an effect of time [F(21,110)?=?11.59, p?<?0.001, $ \eta_{\mathrm{p}}^2 $ ?=?0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence.

Conclusions

Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms.     

Effect of low-dose acute tryptophan depletion on the specificity of autobiographical memory in healthy subjects with a family history of depression

Rationale

Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to reduce specificity of autobiographical memory in patients who have recovered from a depressive episode.

Objectives

This study aimed to explore if reduced specificity of autobiographical memory with LD-ATD is common to other groups of individuals at risk of depression, specifically a healthy population with a family history of depression.

Methods

Nineteen healthy young adults with at least one first-degree relative with a history of major depression were recruited. LD-ATD drinks containing 1.15?g of tryptophan (T+) or no tryptophan (T?) were administered on two separate occasions, in a double blind random order crossover design. The Autobiographical Memory Test (AMT) was administered 5?h after drink administration.

Results

Analysis of variance revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. There was no within-subject main effect of LD-ATD on the memory task. However, there was a main effect of order of drink. Exploratory analysis of visit 1 data indicated a large between-subject effect (d?=?1.4) of LD-ATD on AMT with T? associated with less specificity in response to negative cue words (F(1, 17)?=?8.71, p?=?0.009).

Conclusions

Similar to findings following recovery from depression, LD-ATD can reduce specificity of AMT in the absence of lowered mood in healthy individuals with a strong family history of depression. These findings may reflect a 5-HT-dependent cognitive vulnerability to depression in different populations and warrant further research.     

Effects of short-term varenicline administration on cortisol in healthy, non-smoking adults: a randomized, double-blind, study

Rationale

Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves.

Objectives

Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic–pituitary–adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression.

Methods

In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility.

Results

Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F _1,32?=?0.405; P?=?0.529) or shape (F _2,31?=?0.110; P?=?0.164) of the cortisol awakening response.

Conclusions

Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions.     

Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment

Rationale

Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders.

Objectives

Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n?=?25), non-diagnosed suicides (n?=?13), and control subjects (n?=?35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n?=?25) and control subjects (n?=?25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed.

Results

No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (Δ?=?33?±?10 %, p?<?0.05) in the antipsychotic-treated subgroup (n?=?12) than in the antipsychotic-free subgroup (n?=?13). Immunodensities of plasma membrane RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects.

Conclusions

Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status.     

Serotonin depletion counteracts sex differences in anxiety-related behaviour in rat

Background

Numerous studies suggest (1) that a major physiological role of brain serotonin-containing neurons is to modulate sex steroid-driven behaviour such as sex and aggression, (2) that sex steroids influence brain serotonergic neurotransmission and (3) that brain serotonergic neurotransmission displays sexual dimorphism. Such observations indicate that an important task for brain serotonin is to either enhance or counteract sex differences in behaviour.

Methods

To test this hypothesis, we explored the effect of short-term serotonin depletion on the behaviour of adult male and female rats in a behavioural paradigm in which males and females have been shown to behave differently, i.e. the elevated plus maze.

Results

Two rounds of testing of untreated Wistar rats confirmed the previous observation that females make more entries into open arms (round 1, p?=?0.001; round 2, p?=?0.008) and spend more time on these arms (round 1, p?≤?0.001; round 2, p?=?0.006) than males; in addition, males displayed fewer entries into closed arms upon habituation, i.e. at the second round (p?≤?0.001) than did females. Administration of the tryptophan hydroxylase inhibitor para-chloro-phenylalanine, at a regimen (300 mg/kg/day for 3 days), markedly reducing brain content of serotonin, enhanced entries upon open arms (p?=?0.01) and time spent on open arms (p?=?0.004) in males but exerted no such effects in females (p?=?0.9 and p?=?0.9, respectively); moreover, it reduced entries into closed arms in females (p?≤?0.001) but not in males (p?=?0.1).

Conclusions

Serotonin depletion abolishing the sex differences observed at baseline supports the theory that serotonin aids to uphold certain sex differences in behaviour.     

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Rational

It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia.

Objective

This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial.

Methods

Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45?years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6?mg/day) plus sildenafil (75?mg/day) and 20 to risperidone (6?mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS).

Results

Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F?=?4.77, df?=?1; P?=?0.03; F?=?5.91, df?=?1, P?=?0.02 respectively).

Conclusion

Therapy with 75?mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11).     

Effect of saffron on fluoxetine-induced sexual impairment in men: randomized double-blind placebo-controlled trial

Rationale

Saffron (Crocus sativus L.) has shown aphrodisiac effects in some animal and human studies.

Objectives

To assess the efficacy and tolerability of saffron in fluoxetine-related sexual dysfunction.

Methods

This was a 4-week randomized double-blind placebo-controlled study. Thirty-six married male patients with major depressive disorder whose depressive symptoms had been stabilized on fluoxetine and had subjective complaints of sexual impairment entered the study. The patients were randomly assigned to saffron (15?mg twice per day) or placebo for 4?weeks. International Index of Erectile Function scale was used to assess sexual function at baseline and weeks 2 and 4.

Results

Thirty patients finished the study. Baseline characteristics as well as baseline and final depressive symptoms scores were similar between the two groups. Effect of time?×?treatment interaction on the total score was significant [Greenhouse–Geisser-corrected, F (1.444, 40.434)?=?6.154, P?=?0.009]. By week 4, saffron resulted in significantly greater improvement in erectile function (P?P?=?0.001), and total scores (P?P?=?0.095), overall satisfaction (P?=?0.334), and sexual desire (P?=?0.517) domains scores. Nine patients (60%) in the saffron group and one patient (7%) in the placebo group achieved normal erectile function (score?>?25 on erectile function domain) at the end of the study (P value of Fisher’s exact test?=?0.005). Frequency of side effects were similar between the two groups.

Conclusions

Saffron is a tolerable and efficacious treatment for fluoxetine-related erectile dysfunction.     

Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial

Purpose

We investigated whether acetaminophen, given at 2?g/day and 3?g/day might potentiate the anticoagulant effect of warfarin.

Methods

Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2?g/day or 3?g/day) or placebo.

Results

The mean maximal INR increase was 0.70?±?0.49 and 0.67?±?0.62 in patients receiving acetaminophen at 2?g/day and 3?g/day, respectively (P?=?0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R ²?=?0.36, P?R ²?=?0.46, P?R ²?=?0.563, P?Conclusion Acetaminophen, at 2?g/day or 3?g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.     

Cortical glutathione levels in young people with bipolar disorder: a pilot study using magnetic resonance spectroscopy

Rationale

Glutathione (GSH) is a key scavenger for cellular free radicals, and patients with bipolar disorder may have lowered GSH levels in plasma and in post-mortem brain tissue.

Objectives

The objective of the current study was to use magnetic resonance spectroscopy (MRS) to measure cortical GSH levels in young people with bipolar disorder to determine if lowered GSH might be a useful biomarker of vulnerability to the illness.

Methods

We studied 13 patients with DSM-IV bipolar disorder and 11 healthy age-matched controls using proton MRS in conjunction with the SPECIAL acquisition technique. Voxels were placed in prefrontal and occipital cortex. All patients were clinically euthymic at the time of study and unmedicated. GSH and other relevant neurometabolites were measured relative to creatinine.

Results

There was no difference in GSH levels between bipolar participants and controls in either prefrontal or occipital cortex. Similarly, participants showed no difference from controls in other measured cortical metabolites including γ-aminobutyric acid, glutamate and N-acetylaspartate.

Conclusions

This pilot study suggests that levels of cortical GSH are unlikely to be a useful trait biomarker of bipolar disorder in young people with a history of relatively mild mood instability at an early stage of illness. Lowered GSH levels may be relevant to bipolar pathophysiology in more severely ill patients, particular those with significant current mood disturbance.     

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.     

Memory-related hippocampal functioning in ecstasy and amphetamine users

Rationale

Recreational use of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) has been associated with memory impairments. Functional neuroimaging studies with cross-sectional designs reported altered memory-related hippocampal functioning in ecstasy-polydrug users. However, differences might be pre-existing or related to the concomitant use of amphetamine.

Objective

To prospectively investigate the specific effects of ecstasy on memory-related hippocampal functioning.

Methods

We used an associative memory task and functional magnetic resonance imaging (fMRI) in 40 ecstasy and/or amphetamine users at baseline (t1) and after 12 months (t2). At t1, all subjects had very limited amphetamine and/or ecstasy experience (less than 5 units lifetime dose). Based on the reported drug use at t2, subjects with continued ecstasy and/or amphetamine use (n?=?17) were compared to subjects who stopped use after t1 (n?=?12).

Results

Analysis of repeated measures revealed that encoding-related activity in the left parahippocampal gyrus changed differentially between the groups. Activity in this region increased in abstinent subjects from t1 to t2, however, decreased in subjects with continued use. Decreases within the left parahippocampal gyrus were associated with the use of ecstasy, but not amphetamine, during the follow-up period. However, there were no significant differences in memory performance.

Conclusions

The current findings suggest specific effects of ecstasy use on memory-related hippocampal functioning. However, alternative explanations such as (sub-)acute cannabis effects are conceivable.     

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial

Rational

Autism is associated with activation of the inflammatory response system.

Objective

This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autism

Methods

In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C.

Results

Significant time?×?treatment interaction was observed for Irritability (F (1.658, 63.021)?=?13.580, P?<?0.001), Lethargy/Social Withdrawal (F (1.948, 74.032)?=?16.811, P?<?0.001), and Stereotypic Behavior (F(1.742, 66.198)?=?12.104, P?<?0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424)?=?1.469, P?=?0.232), and Inappropriate Speech subscales (F (1.607, 61.075)?=?0.173, P?=?0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P?<?0.001), Lethargy/Social Withdrawal (P?<?0.001), and Stereotypic Behavior (P?<?0.00) but not in Hyperactivity/Noncompliance (P?=?0.202) and Inappropriate Speech (P?=?0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ ² (1)?=?5.227, P?=?0.022). Frequency of side effects was similar between the two groups.

Conclusions

Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir; IRCT138711091556N2)     

Effects of coffee on driving performance during prolonged simulated highway driving

Rationale

Coffee is often consumed to counteract driver sleepiness. There is limited information on the effects of a single low dose of coffee on prolonged highway driving in non-sleep deprived individuals.

Objectives

The aim of this study was to examine the effects of a single cup of coffee (80?mg caffeine) on simulated highway driving performance.

Methods

Non-sleep deprived healthy volunteers (n?=?24) participated in a double-blind, placebo-controlled, crossover study. After 2?h of monotonous highway driving, subjects received caffeinated or decaffeinated coffee during a 15-min break before continuing driving for another 2?h. The primary outcome measure was the standard deviation of lateral position (SDLP), reflecting the weaving of the car. Secondary outcome measures were speed variability, subjective sleepiness, and subjective driving performance.

Results

The results showed that caffeinated coffee significantly reduced SDLP as compared to decaffeinated coffee, both in the first (p?=?0.024) and second hour (p?=?0.019) after the break. Similarly, the standard deviation of speed (p?=?0.024; p?=?0.001), mental effort (p?=?0.003; p?=?0.023), and subjective sleepiness (p?=?0.001; p?=?0.002) were reduced in both the first and second hour after consuming caffeinated coffee. Subjective driving quality was significantly improved in the first hour after consuming caffeinated coffee (p?=?0.004).

Conclusions

These findings demonstrate a positive effect of one cup of caffeinated coffee on driving performance and subjective sleepiness during monotonous simulated highway driving.     

The effects of age at the onset of drinking to intoxication and chronic ethanol self-administration in male rhesus macaques

Rationale

Consumption of alcohol begins during late adolescence in a majority of humans, and the greatest drinking occurs at 18–25 years then decreases with age.

Objectives

The present study measured the differences in ethanol intake in relation to age at the onset of ethanol access among nonhuman primates to control for self-selection in humans and isolate age effects on heavy drinking.

Methods

Male rhesus macaques were assigned first access to ethanol during late adolescence (n?=?8), young adulthood (n?=?8), or early middle age (n?=?11). The monkeys were induced to drink ethanol (4 %?w/v in water) in increasing doses (water then 0.5, 1.0, 1.5 g/kg ethanol) using a fixed-time (FT) 300-s schedule of food delivery, followed by 22 h/day concurrent access to ethanol and water for 12 months. Age-matched controls consumed isocaloric maltose–dextrin solution yoked to the late adolescents expected to be rapidly maturing (n?=?4).

Results

Young adult monkeys had the greatest daily ethanol intake and blood-ethanol concentration (BEC). Only late adolescents escalated their intake (ethanol, not water) during the second compared to the first 6 months of access. On average, plasma testosterone level was consistent with age differences in maturation and tended to increase throughout the experiment more for control than ethanol-drinking adolescent monkeys.

Conclusions

Young adulthood in nonhuman primates strongly disposes toward heavy drinking, which is independent of sociocultural factors present in humans. Ethanol drinking to intoxication during the critical period of late adolescence is associated with escalation to heavy drinking.     

Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, double-blind, placebo-controlled trial

Rationale

Epidemiological studies have suggested a beneficial effect of fish oil supplementation in halting the initial progression of Alzheimer’s disease. However, it remains unclear whether fish oil affects cognitive function in older people with mild cognitive impairment (MCI).

Objectives

This study investigated the effects of fish oil supplementation on cognitive function in elderly person with MCI.

Methods

This was a 12-month, randomised, double-blind, placebo-controlled study using fish oil supplementation with concentrated docosahexaenoic acid (DHA). Thirty six low-socioeconomic-status elderly subjects with MCI were randomly assigned to receive either concentrated DHA fish oil (n?=?18) or placebo (n?=?18) capsules. The changes of memory, psychomotor speed, executive function and attention, and visual-constructive skills were assessed using cognitive tests. Secondary outcomes were safety and tolerability of the DHA concentrate.

Results

The fish oil group showed significant improvement in short-term and working memory (F?=?9.890; ηp ²?=?0.254; p?<?0.0001), immediate verbal memory (F?=?3.715; ηp ²?=?0.114; p?<?0.05) and delayed recall capability (F?=?3.986; ηp ²?=?0.121; p?<?0.05). The 12-month change in memory (p?<?0.01) was significantly better in the fish oil group. Fish oil consumption was well tolerated, and the side effects were minimal and self-limiting.

Conclusions

This study suggested the potential role of fish oil to improve memory function in MCI subjects. Studies with larger sample sizes, longer intervention periods, different fish oil dosages and genetic determinations should be investigated before definite recommendations can be made.     

Effect of treatment with pravastatin or ezetimibe on endothelial function in patients with moderate hypercholesterolemia

Background/Aim

Statin treatment improves endothelial function. It is matter of debate, however, if this effect of statins is due to their action on low-density lipoprotein cholesterol (LDL-C) or to other non-lipidic (pleiotropic) effects. The aim of this study was to evaluate whether the effect of pravastatin on endothelial function is mediated by pleiotropic effects. We therefore compared the effect of pravastatin and ezetimibe, a cholesterol absorption inhibitor, at doses yielding similar reductions in LDL-C and examined the effect of the two treatments on flow-mediated dilation (FMD) in hypercholesterolemic subjects.

Methods

A total of 33 moderately hypercholesterolemic patients were randomized into three treatment groups to receive ezetimibe 10 mg/day (n?=?10), pravastatin 10 mg/day (n?=?13) or no treatment (control, n?=?10) for 6 weeks. To assess endothelial function, we determined FMD of the brachial artery non-invasively by high-resolution ultrasound before and after treatment.

Results

Ezetimibe and pravastatin treatment reduced LDL-C (mean ± standard error) to a similar extent (?20.6 ± 4.1 vs. ?24.1 ± 4.0 %, respectively; P?=?0.4771), while no decrease was observed in the control group. FMD increased significantly after treatment with ezetimibe (from 11.4 ± 5.7 to 16.8 ± 3.6 %; P?=?0.022) and with pravastatin (from 13.7 ± 4.9 to 17.5 ± 4.4 %; P?=?0.0466), but not in the control group. There were no differences in the endothelial function changes between the two treatment groups.

Conclusions

In this study, two treatments that lower cholesterol via different mechanisms improved endothelial function to a similar extent, suggesting that the observed effect can be explained by the reduction of cholesterol levels.     

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.     

Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson’s disease patients

Purpose

To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity.

Methods

The study included 52 Parkinson’s disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR.

Results

The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P?=?0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94–8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P?=?0.014; OR 9.33, 95 % CI 1.71–50.78).

Conclusions

In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.