Pharmacokinetic mechanisms for reduced toxicity of irinotecan by coadministered Thalidomide

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Gender-specific inhibition of platelet aggregation following omega-3 fatty acid supplementation

Background and Aims : Increased platelet aggregation is a major risk factor for heart attacks, stroke and thrombosis. Long chain omega-3 polyunsaturated fatty acids (LCn-3PUFA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) reduce platelet aggregation; however studies in the published literature involving EPA and/or DHA supplementation have yielded equivocal results. Recent in vitro studies have demonstrated that inhibition of platelet aggregation by LCn-3PUFA is gender specific. We examined the acute effects of dietary supplementation with EPA or DHA rich oils on platelet aggregation in healthy male and females.

Methods and Results : A blinded placebo controlled trial involving 15 male and 15 female subjects. Platelet aggregation was measured at 0, 2, 5 and 24 h post-supplementation with a single dose of either a placebo or EPA or DHA rich oil capsules. The relationship between LCn-3PUFA and platelet activity at each time point was examined according to gender vs. treatment. EPA was significantly the most effective in reducing platelet aggregation in males at 2, 5 and 24 h post-supplementation (−11%, −10.6%, −20.5% respectively) whereas DHA was not effective relative to placebo. In contrast, in females, DHA significantly reduced platelet aggregation at 24 h (−13.7%) while EPA was not effective. An inverse relationship between testosterone levels and platelet aggregation following EPA supplementation was observed.

Conclusion : Interactions between sex hormones and omega-3 fatty acids exist to differentially reduce platelet aggregation. For healthy individuals, males may benefit more from EPA supplementation while females are more responsive to DHA.

Systemic apomorphine alters HPA axis responses to interleukin-1β adminstration but not sound stress

Apomorphine is a dopamine receptor agonist that was recently licensed for the treatment of erectile dysfunction. However, although sexual activity can be stressful, there has been little investigation into whether treatments for erectile dysfunction affect stress responses. We have examined whether a single dose of apomorphine, sufficient to produce penile erections (50 μg/kg, i.a.), can alter basal or stress-induced plasma ACTH levels, or activity of central pathways thought to control the hypothalamic-pituitary-adrenal axis in rats. An immune challenge (interleukin-1β, 1 μg/kg, i.a.) was used as a physical stressor while sound stress (100 dB white noise, 30 min) was used as a psychological stressor. Intravascular administration of apomorphine had no effect on basal ACTH levels but did substantially increase the number of Fos-positive amygdala and nucleus tractus solitarius catecholamine cells. Administration of apomorphine prior to immune challenge augmented the normal ACTH response to this stressor at 90 min and there was a corresponding increase in the number of Fos-positive paraventricular nucleus corticotropin-releasing factor cells, paraventricular nucleus oxytocin cells and nucleus tractus solitarius catecholamine cells. However, apomorphine treatment did not alter ACTH or Fos responses to sound stress. These data suggest that erection-inducing levels of apomorphine interfere with hypothalamic-pituitary-adrenal axis inhibitory feedback mechanisms in response to a physical stressor, but have no effect on the response to a psychological stressor. Consequently, it is likely that apomorphine acts on a hypothalamic-pituitary-adrenal axis control pathway that is unique to physical stressors. A candidate for this site of action is the nucleus tractus solitarius catecholamine cell population and, in particular, A2 noradrenergic neurons.

Whey protein ingestion activates mTOR-dependent signalling after resistance exercise in young men : a double-blinded randomized controlled trial

The effect of resistance exercise with the ingestion of supplementary protein on the activation of the mTOR cascade, in human skeletal muscle has not been fully elucidated. In this study, the impact of a single bout of resistance exercise, immediately followed by a single dose of whey protein isolate (WPI) or placebo supplement, on the activation of mTOR signalling was analyzed. Young untrained men completed a maximal single-legged knee extension exercise bout and were randomized to ingest either WPI supplement (n = 7) or the placebo (n = 7). Muscle biopsies were taken from the vastus lateralis before, and 2, 4 and 24 hr post-exercise. WPI or placebo ingestion consumed immediately post-exercise had no impact on the phosphorylation of Akt (Ser⁴⁷³). However, WPI significantly enhanced phosphorylation of mTOR (Ser²⁴⁴⁸), 4E-BP1 (Thr^37/46) and p70S6K (Thr³⁸⁹) at 2 hr post-exercise. This study demonstrates that a single dose of WPI, when consumed in modest quantities, taken immediately after resistance exercise elicits an acute and transient activation of translation initiation within the exercised skeletal muscle.

Comparable effects of nicotine in smokers and nonsmokers on a prospective memory task

In a double-blind placebo-controlled study, we examined the effect of nicotine, a cholinergic agonist, on performance of a prospective memory (ProM) task in young adult volunteers.

Volunteers were required to complete an ongoing lexical decision task while maintaining the ProM task (responding with a different button press to items containing particular target letters). Half of the volunteers were smokers, half were nonsmokers. Half of each group received a single dose (1 mg) of nicotine nasal spray before completing the task; the remaining volunteers received a matched inactive placebo spray.

Nicotine improved performance on the ProM task when volunteers were able to devote resources to that task. Under a variant procedure, where volunteers completed a concurrent auditory monitoring task, ProM performance was impaired under nicotine. Results are discussed in terms of the resource model of ProM, and the arousal model of drug effects.

Impact of oral dexamethasone versus placebo after ED treatment of migraine with phenothiazines on the rate of recurrent headache: a randomised controlled trial

OBJECTIVE: Evidence suggests that the rate of recurrent headache after treatment of migraine in the emergency department (ED) is high. The mechanisms for this are unclear, but neurogenic inflammation may play a role. There is conflicting evidence about whether adjuvant dexamethasone reduces the rate of recurrent headache. The aim of this study was to compare the rate of recurrent headache in patients with migraine randomised to receive a single dose of oral dexamethasone or placebo at discharge after treatment in the ED with intravenous phenothiazine.

METHODS: A double-blind, randomised, placebo-controlled trial was conducted in the ED of three community teaching hospitals. Adult patients with physician-diagnosed migraine were treated with intravenous phenothiazine and at discharge were randomised to receive either 8 mg oral dexamethasone or placebo as a single dose. Follow-up was by telephone at 48-72 h and the proportion of patients with recurrent headache overall and in the subgroup with headache duration <24 h was recorded.

RESULTS: 63 patients (76% women) of median age 39 years were enrolled, 61 of whom (97%) completed follow-up. The pooled rate of recurrent headache was 33%. 32 were randomised to placebo and 31 to dexamethasone. The rate of recurrent headache in the dexamethasone and control groups was 27% (8/30) vs 39% (12/31) (relative risk (RR) 0.69, 95% CI 0.33 to 1.45, p = 0.47). For 40 patients with headache lasting <24 h the rate of recurrent headache in the dexamethasone and control groups was 15% (3/20) vs 45% (9/20), a reduction in absolute risk of 30% (RR 0.33, 95% CI 0.11 to 1.05, p = 0.08).

CONCLUSION: A single oral dose of dexamethasone following phenothiazine treatment for migraine in the ED did not reduce the rate of recurrent headache. There is weak evidence for a possible benefit in the subgroup who present within <24 h of symptom onset. A multicentre trial to confirm this finding is warranted.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial

Background Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking.

Aims To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health.

Method A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D3 (cholecalciferol) orally or placebo every autumn/winter for 3–5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression–Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants.

Results In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups.

Conclusions The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D3 is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Annual high-dose oral vitamin D and falls and fractures in older women : a randomized controlled trial

Context Improving vitamin D status may be an important modifiable risk factor to reduce falls and fractures; however, adherence to daily supplementation is typically poor.

Objective To determine whether a single annual dose of 500 000 IU of cholecalciferol administered orally to older women in autumn or winter would improve adherence and reduce the risk of falls and fracture.

Design, Setting, and Participants A double-blind, placebo-controlled trial of 2256 community-dwelling women, aged 70 years or older, considered to be at high risk of fracture were recruited from June 2003 to June 2005 and were randomly assigned to receive cholecalciferol or placebo each autumn to winter for 3 to 5 years. The study concluded in 2008.

Intervention 500 000 IU of cholecalciferol or placebo.

Main Outcome Measures Falls and fractures were ascertained using monthly calendars; details were confirmed by telephone interview. Fractures were radiologically confirmed. In a substudy, 137 randomly selected participants underwent serial blood sampling for 25-hydroxycholecalciferol and parathyroid hormone levels.

Results Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2892 times (rate, 83.4 per 100 person-years) while 769 women in the placebo group fell 2512 times (rate, 72.7 per 100 person-years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02-1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00-1.59; P = .047) vs the placebo group (rates per 100 person-years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.

Conclusion Among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.

ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals (N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively (P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

Single step preparation of meso-porous and reduced graphene oxide by gamma-ray irradiation in gaseous phase

A facile and highly efficient route to produce simultaneously porous and reduced graphene oxide by gamma ray irradiation in hydrogen is here demonstrated. Narrowly distributed nano-scale pores (average size of ∼3 nm and surface density >44,900 pore μm-2) were generated across 10 μm thick graphene oxide bucky-papers at a total irradiation dose of 500 kGy. The graphene oxide sheet reduction was confirmed to occur homogeneously across the structures by Fourier transform infrared spectroscopy and Raman analysis. This one-step, catalyst-free, high penetration and through-put technique, offers great promises potential for the mass production of reduced graphene oxide from cheap graphene oxide. © 2013 Elsevier Ltd. All rights reserved.

Acute mood but not cognitive improvements following administration of a single multivitamin and mineral supplement in healthy women aged 50 and above : a randomised controlled trial

A number of randomised controlled trials have indicated that multivitamin/mineral supplementation for a period of 4 weeks or greater can enhance mood and cognition. To date, no studies have investigated whether a single multivitamin dose can benefit mental function in older adults. This study investigated the acute effects of a single multivitamin and mineral and herbal (MVMH) supplement versus placebo on self ratings of mood and the performance of an effortful computerised cognitive battery in a sample of 76 healthy women aged 50-75 years. Mood was assessed using the depression anxiety stress scale (DASS), state trait anxiety inventory-state anxiety scale and visual analogue scales (VAS). Mood was rated at 1 h post supplementation and again after the competition of the cognitive assessments at 2 h post supplementation. It was demonstrated that the MVMH supplement improved overall DASS mood ratings; however, the most prominent effects appeared to be a reduction in ratings of perceived mental stress. These findings were confirmed using visual analogue scales, with these measures also demonstrating MVMH-related increased ratings of calmness. There were no benefits of the MVMH to mood ratings of depression and performance was not enhanced on the cognitive battery. Supplementation with a single multivitamin, mineral and herbal supplement reduces stress several hours after intake in healthy older people.

Predictors of vitamin D-containing supplement use in the Australian population and associations between dose and serum 25-hydroxyvitamin D concentrations

Despite concerns about vitamin D deficiency in the Australian population, little is known about the prevalence and predictors of vitamin D-containing supplement use. We described the use of vitamin D-containing supplements, and investigated associations between supplemental vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) concentrations, using a single 24-h dietary recall from the 2011-2013 Australian Health Survey (n = 12,153; ages ≥ 2 years). Multiple regression models were used to investigate predictors of vitamin D-containing supplement use in adults, and associations between dose and serum 25(OH)D concentrations/vitamin D sufficiency (≥50 nmol/L), adjusting for potential confounders. The prevalence of vitamin D-containing supplement use was 10%, 6% and 19% in children, adolescents and adults, respectively. Predictors of vitamin D-containing supplement use in adults included being female, advancing age, higher educational attainment, higher socio-economic status, not smoking, and greater physical activity. After adjusting for potential confounders, a 40 IU (1 µg) increase in vitamin D intake from supplements was associated with an increase of 0.41 nmol/L in serum 25(OH)D concentrations (95% CI 0.35, 0.47; p < 0.001). However, the prevalence of vitamin D-containing supplement use was generally low in the Australian population, particularly for single vitamin D supplements, with most supplement users obtaining only low levels of vitamin D from other supplement types.