Julia Boyle

Randomized, Placebo-Controlled Comparison of Amitriptyline, Duloxetine, and Pregabalin in Patients With Chronic Diabetic Peripheral Neuropathic Pain Impact on pain, polysomnographic sleep, daytime functioning, and quality of life

OBJECTIVE Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP. RESEARCH DESIGN AND METHODS This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period. RESULTS All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group. CONCLUSIONS There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.

Regulatory approval and a first‐in‐human phase I clinical trial of a monoclonal antibody produced in transgenic tobacco plants

Although plant biotechnology has been widely investigated for the production of clinical-grade monoclonal antibodies, no antibody products derived from transgenic plants have yet been approved by pharmaceutical regulators for clinical testing. In the Pharma-Planta project, the HIV-neutralizing human monoclonal antibody 2G12 was expressed in transgenic tobacco (Nicotiana tabacum). The scientific, technical and regulatory demands of good manufacturing practice (GMP) were addressed by comprehensive molecular characterization of the transgene locus, confirmation of genetic and phenotypic stability over several generations of transgenic plants, and by establishing standard operating procedures for the creation of a master seed bank, plant cultivation, harvest, initial processing, downstream processing and purification. The project developed specifications for the plant-derived antibody (P2G12) as an active pharmaceutical ingredient (API) based on (i) the guidelines for the manufacture of monoclonal antibodies in cell culture systems; (ii) the draft European Medicines Agency Points to Consider document on quality requirements for APIs produced in transgenic plants; and (iii) de novo guidelines developed with European national regulators. From the resulting process, a GMP manufacturing authorization was issued by the competent authority in Germany for transgenic plant-derived monoclonal antibodies for use in a phase I clinical evaluation. Following preclinical evaluation and ethical approval, a clinical trial application was accepted by the UK national pharmaceutical regulator. A first-in-human, double-blind, placebo-controlled, randomized, dose-escalation phase I safety study of a single vaginal administration of P2G12 was carried out in healthy female subjects. The successful completion of the clinical trial marks a significant milestone in the commercial development of plant-derived pharmaceutical proteins.

Sedation and antihistamines: an update. Review of inter-drug differences using proportional impairment ratios

The use of antihistamines (AHs) has been associated with cognitive and psychomotor impairments, largely caused by the sedative properties of many of these drugs. Due to the ambulant nature of the population using AHs, it is important to evaluate these effects using standardised methodology and psychometric tests. A previous extensive review of the literature collated the results of studies of H1 receptor antagonists to determine the extent to which a particular AH produced impairments on a battery of psychometric tests by calculating a proportional impairment ratio for each AH.

Efficacy of a nicotine (4 mg)-containing lozenge on the cognitive impairment of nicotine withdrawal.

Objective: Controversy exists over the effect of tobacco deprivation in nicotine-dependent individuals and the efficacy of nicotine in reversing performance decrements. This studys aim was to assess the efficacy of nicotine (4-mg lozenge) versus placebo on aspects of cognitive and psychomotor performance, mood, and withdrawal symptoms in male and female established smokers. Methods: Male and female smokers (N = 22; mean age, 28.8 years), with a smoking history of more than 1 year and time to first cigarette of less than 30 minutes upon waking, were enrolled. Baseline measures were obtained at 17 hours of abstinence. At 18-hour abstinence, nicotine or placebo was administered every 2 hours over an 8-hour period. Cognitive and psychomotor performance measurements were taken 30 minutes after dose. Cognitive test battery included Rapid Visual Information Processing, Continuous Tracking Task, Critical Flicker Fusion, Choice Reaction Time, Stroop Test, and Sternbergs Short-term Memory Scanning Task. Withdrawal (Modified Minnesota Withdrawal Scale) and mood (Positive and Negative Affect Schedule) were also assessed. A mixed-models analysis of covariance was performed. Results: Compared with placebo nicotine (4 mg) significantly improved vigilance, divided attention, executive functioning, working memory, and sensorimotor performance in abstinent volunteers (P ≤ 0.05). Withdrawal symptoms including craving, difficulty concentrating, irritability, and restlessness were also attenuated, and affective state was improved after nicotine 4 mg administration. Conclusions: Compared with placebo, nicotine (4 mg) improved measures of vigilance, memory, and attention; improved mood; and reduced withdrawal symptoms. These findings suggest that repeated nicotine replacement therapy over a period of 8 hours can improve cognitive deficits associated with nicotine withdrawal.

Allergy medication in Japanese volunteers: treatment effect of single doses on nocturnal sleep architecture and next day residual effects.

ABSTRACT Objectives: To evaluate the acute effects of two histamine H1-receptor antagonists on nocturnal sleep architecture and on next day cognitive function and psychomotor performance. Methods: This was a single-site, randomized, double-blind, 3-way crossover study, comparing the effects of a single dose of chlorpheniramine (6 mg), fexofenadine (120 mg) and placebo in 18 healthy (male and female) Japanese volunteers aged 20–55 years. Volunteers were resident for 3 days and each period was separated by a minimum 5‐day washout period. The three treatments were administered at 23.00 h. Overnight sleep was measured from 23.00 h to 07.00 h using polysomnography. Residual effects were studied at 07.00 h and 9.00 h the next morning, with the latency to sleep (sleep latency test) measured at 09.30 h. Results: Compared with placebo, chlorpheniramine increased the latencies to sleep onset and rapid eye movement (REM) sleep ( p ≤ 0.05 for both), and reduced the duration of REM sleep ( p ≤ 0.01), but this was not observed with fexofenadine. As far as residual effects the next morning were concerned there were decrements in performance with chlorpheniramine, but not with fexofenadine. Chlorpheniramine 6 mg impaired divided attention ( p < 0.001), vigilance ( p < 0.05), working memory ( p < 0.0001) and sensori-motor performance ( p < 0.01), and the latency to daytime sleep was reduced ( p < 0.0001). Six adverse events possibly related to study medication were reported during the study, three of which were related to placebo, two to fexofenadine and one to chlorpheniramine. Conclusion: These findings suggest that a single nocturnal dose of fexofenadine has advantages over the first-generation antihistamine chlorpheniramine, being free of disruption of night-time sleep and detrimental effects on cognitive performance the next day. It is likely that this advantage will remain with chronic ingestion, but this would need to be confirmed.

Acute Alertness‐Promoting Effects of a Novel Histamine Subtype‐3 Receptor Inverse Agonist in Healthy Sleep‐Deprived Male Volunteers

The alertness‐promoting effect of MK‐0249 (10 or 50 mg), a histamine subtype‐3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double‐blind, double‐dummy, placebo‐ and modafinil‐ (200 mg) controlled, four‐period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK‐0249 50 mg (5.17 min; P = 0.008), and MK‐0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK‐0249). The alertness‐promoting effect with the use of MK‐0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.

Randomised clinical trial investigating the specificity of a novel skin test (C-Tb) for diagnosis of M. tuberculosis infection.

Background Tuberculin skin testing is simple and relatively inexpensive, but the specificity of PPD is affected by BCG vaccination. Objective Determine optimal dose and specificity of recombinant ESAT-6 and CFP-10 (C-Tb) produced in Lactococcus lactis for diagnosis of M. tuberculosis infection. Methods In a dose finding phase I trial 0.01 or 0.1 µg preserved and unpreserved C-Tb was injected by Mantoux technique in 38 patients with active tuberculosis and induration responses measured. In a phase II specificity trial in 151 uninfected, BCG vaccinated participants 0.1 µg C-Tb was compared to 2 TU PPD. Results 0.1 µg C-Tb gave a median induration of 15 mm after 2 days. Phenol preservation did not affect the response. The specificity of C-Tb was 99.3% (95% CI 96–100%) regarding indurations ≥5 mm as a positive outcome. This was higher than the specificity of PPD (63% using a cut-off of 5 mm or 92% using a cut-off of 15 mm to adjust for non-specific BCG responses). Local adverse reactions following C-Tb injection included transient itching and discomfort as expected components of the immune response. Conclusion C-Tb offers a simple and convenient skin test to diagnose M. tuberculosis infection using a single, universal cut-off unaffected by BCG vaccination. Trial Registration ClinicalTrials.gov NCT01033929 and NCT01241188.

Next-day residual effects of gaboxadol and flurazepam administered at bedtime: a randomized double-blind study in healthy elderly subjects.

To evaluate the next‐day residual effects of the novel hypnotic, gaboxadol, following bedtime dosing in healthy elderly subjects.

The Effects of Rhodiola rosea L. Extract on Anxiety, Stress, Cognition and Other Mood Symptoms

This trial evaluated the impact of a Rhodiola rosea L. extract on self‐reported anxiety, stress, cognition, and other mood symptoms. Eighty mildly anxious participants were randomized into two different groups of either Rhodiola rosea L (2 × 200 mg dose Vitano®, 1 tablet taken before breakfast and 1tablet before lunch) or a control condition (no treatment). Self‐report measures and cognitive tests were completed at four testing sessions over a period of 14 days. Relative to the controls, the experimental group demonstrated a significant reduction in self‐reported, anxiety, stress, anger, confusion and depression at 14 days and a significant improvements in total mood. No relevant differences in cognitive performance between the groups were observed. Rhodiola rosea L (Vitano®) presented a favourable safety tolerability profile. Although this was a non‐placebo controlled trial, it is unlikely that the findings were the result of placebo effects as changes appeared gradual and were specific to certain psychological measures. However, we cannot determine a causal relationship; further investigations are recommended to support the effects of Rhodiola rosea L. extract on stress related symptoms. Copyright

Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18–45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p ≤ 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.