Safety,pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban,a factor Xa inhibitor,in healthy subjects

Aim

Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.

Method

This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).

Results

Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile.

Conclusion

Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.     

Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers

AIMS

To assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers.

METHODS

Three Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily [t.i.d. (n = 7)], 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9). Nine subjects received the approved orlistat dose (120 mg t.i.d.). Treatment was for 5 days, with a 2-day run-in period and 1-day post-treatment follow-up. The primary outcome measure was daily faecal fat excretion. Secondary outcomes included plasma lipid levels, tolerability [gastrointestinal adverse events (AEs)] and safety.

RESULTS

Cetilistat increased faecal fat excretion relative to baseline at all doses. Cetilistat was well tolerated, with gastrointestinal AEs the most common (51%). Steatorrhoea (oily stool) was more frequent in the orlistat group (4.11 events per subject) than in any cetilistat dose group (0.14–1.81 events per subject). Most AEs (98%) were mild or moderate in intensity.

CONCLUSIONS

Cetilistat increased dietary fat excretion in healthy volunteers receiving a controlled calorie diet. Cetilistat was well tolerated at all doses examined and tolerability appeared to be improved relative to orlistat. Faecal fat excretion in the cetilistat groups was at least comparable to the orlistat 120 mg t.i.d. group.     

Efficacy of a Non-Hormonal Treatment,BRN-01, on Menopausal Hot Flashes: A Multicenter,Randomized, Double-Blind,Placebo-Controlled Trial

Background

Homeopathic medicines have a place among the non-hormonal therapies for the treatment of hot flashes during the menopause.

Objective

The objective of this study was to evaluate the efficacy of the non-hormonal treatment BRN-01 in reducing hot flashes in menopausal women.

Study Design

This was a multicenter, randomized, double-blind, placebo-controlled study carried out between June 2010 and July 2011.

Setting

The study was conducted in 35 active centers in France (gynecologists in private practice).

Patients

One hundred and eight menopausal women, ≥50 years of age, were enrolled in the study. The eligibility criteria included menopause for <24 months and ≥5 hot flashes per day with a significant negative effect on the women’s professional and/or personal life.

Intervention

Treatment was either BRN-01 tablets, a registered homeopathic medicine containing Actaea racemosa (4 centesimal dilutions [4CH]), Arnica montana (4CH), Glonoinum (4CH), Lachesis mutus (5CH), and Sanguinaria canadensis (4CH), or identical placebo tablets, prepared by Laboratoires Boiron according to European Pharmacopoeia standards. Oral treatment (2 to 4 tablets per day) was started on day 3 after study enrollment and was continued for 12 weeks.

Main Outcome Measure

The main outcome measure was the hot flash score (HFS) compared before, during, and after treatment. Secondary outcome criteria were the quality of life (QoL) [measured using the Hot Flash Related Daily Interference Scale (HFRDIS)], severity of symptoms (measured using the Menopause Rating Scale), evolution of the mean dosage, and compliance. All adverse events (AEs) were recorded.

Results

One hundred and one women were included in the final analysis (intent-to-treat population: BRN-01, n = 50; placebo, n = 51). The global HFS over the 12 weeks, assessed as the area under the curve (AUC) adjusted for baseline values, was significantly lower in the BRN-01 group than in the placebo group (mean ± SD 88.2 ± 6.5 versus 107.2 ± 6.4; p = 0.0411). BRN-01 was well tolerated; the frequency of AEs was similar in the two treatment groups, and no serious AEs were attributable to BRN-01.

Conclusion

BRN-01 seemed to have a significant effect on the HFS, compared with placebo. According to the results of this clinical trial, BRN-01 may be considered a new therapeutic option with a safe profile for hot flashes in menopausal women who do not want or are not able to take hormone replacement therapy or other recognized treatments for this indication.Trial registration number (EudraCT): 2009-016959–21.     

The effects of sitaxentan on sildenafil pharmacokinetics and pharmacodynamics in healthy subjects

AIMS

This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers.

METHODS

Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period.

RESULTS

Sildenafil exposure was slightly higher [AUC_∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (E_max+) and maximum negative (E_max–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study.

CONCLUSION

The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.     

The effect of tafamidis on the QTc interval in healthy subjects

Aims

The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day⁻¹). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QT_c interval in healthy subjects.

Methods

This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic C_max of ∽20 µg ml⁻¹) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of  ≥ 14 days. Serial triplicate 12-lead electrocardiograms were performed. QT_c intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).

Results

A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QT_cF between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin t_max of 3 h post-dose, confirming assay sensitivity. C_max and AUC(0,24 h) for tafamidis were 20.36 µg ml⁻¹ and 305.4 µg ml⁻¹ h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.

Conclusions

This thorough QT_c study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QT_c interval and is well-tolerated in healthy volunteers.     

Transcutaneous nicotine does not prevent postoperative nausea and vomiting: a randomized controlled trial

AIMS

There is empirical evidence that smokers are less likely to suffer from postoperative nausea and vomiting (PONV). We sought to investigate whether transcutaneus nicotine prevents PONV.

METHODS

Non-smokers receiving general anaesthesia for surgery were randomly allocated to Nicotinell® Patch 10 cm² (TTS 10), containing 17.5 mg of nicotine (average delivery rate, 7 mg 24 h⁻¹) or matching placebo patch. Patches were applied 1 h before surgery and were left in situ until 24 h after surgery (or until the first PONV symptoms occurred).

RESULTS

We randomized 90 patients (45 nicotine, 45 placebo). In the post-anaesthetic care unit, the incidence of nausea was 22.2% with nicotine and 24.4% with placebo (P= 0.80), and the incidence of vomiting was 20.0% with nicotine and 17.8% with placebo (P= 0.78). Cumulative 24 h incidence of nausea was 42.2% with nicotine and 40.0% with placebo (P= 0.83), and of vomiting was 31.1% with nicotine and 28.9% with placebo (P= 0.81). PONV episodes tended to occur earlier in the nicotine group. Postoperative headache occurred in 17.8% of patients treated with nicotine and in 15.6% with placebo (P= 0.49). More patients receiving nicotine reported a low quality of sleep during the first postoperative night (26.7% vs. 6.8% with placebo; P= 0.01).

CONCLUSIONS

Non-smokers receiving a prophylactic nicotine patch had a similar incidence of PONV during the first 24 h and tended to develop PONV symptoms earlier compared with controls. They had a significantly increased risk of insomnia during the first postoperative night.     

Effect of homeopathy on analgesic intake following knee ligament reconstruction: a phase III monocentre randomized placebo controlled study

Aims

The efficacy of homeopathy is still under debate. The objective of this study was to assess the efficacy of homeopathic treatment (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) on cumulated morphine intake delivered by PCA over 24 h after knee ligament reconstruction.

Methods

This was an add-on randomized controlled study with three parallel groups: a double-blind homeopathic or placebo arm and an open-label noninterventional control arm. Eligible patients were 18–60 years old candidates for surgery of the anterior cruciate ligament. Treatment was administered the evening before surgery and continued for 3 days. The primary end-point was cumulated morphine intake delivered by PCA during the first 24 h inferior or superior/equal to 10 mg day⁻¹.

Results

One hundred and fifty-eight patients were randomized (66 in the placebo arm, 67 in the homeopathic arm and 25 in the noninterventional group). There was no difference between the treated and the placebo group for primary end-point (mean (95% CI) 48% (35.8, 56.3), and 56% (43.7, 68.3), required less than 10 mg day⁻¹ of morphine in each group, respectively). The homeopathy treatment had no effect on morphine intake between 24 and 72 h or on the visual analogue pain scale, or on quality of life assessed by the SF-36 questionnaire. In addition, these parameters were not different in patients enrolled in the open-label noninterventional control arm.

Conclusions

The complex of homeopathy tested in this study was not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.

What is already known about this subject

• The efficacy of homeopathy is still under debate and a recent meta-analysis recommended further randomized double-blind clinical trials to identify any clinical situation in which homeopathy might be effective.

What this study adds

• The complex of homeopathy tested in this study (Arnica montana 5 CH, Bryonia alba 5 CH, Hypericum perforatum 5 CH and Ruta graveolens 3 DH) is not superior to placebo in reducing 24 h morphine consumption after knee ligament reconstruction.

     

Rapid Reduction in Use of Antidiabetic Medication after Laparoscopic Sleeve Gastrectomy: The Newfoundland and Labrador Bariatric Surgery Cohort (BaSCo) Study

Background:

Patients who have undergone bariatric surgery generally need fewer medications as they experience improvement in, or even resolution of, various medical conditions, including type 2 diabetes mellitus, hypertension, and dyslipidemia. Published data on changes in medication use after laparoscopic sleeve gastrectomy, a type of bariatric surgery that is growing in popularity, are limited.

Objective:

To determine whether patients took fewer medications for management of type 2 diabetes, hypertension, and dyslipidemia after laparoscopic sleeve gastrectomy, relative to preprocedure medications.

Methods:

In this prospective, single-centre cohort study, a nurse practitioner used standard medication reconciliation and study data-extraction forms to interview adult patients who had undergone laparoscopic sleeve gastrectomy and determine their medication use and pertinent demographic data. The data were analyzed using generalized estimating equations and standard statistical software. Outcome measures included changes in the use of antidiabetic, antihypertensive, and antilipemic medications at 1, 3, and 6 months after the surgery.

Results:

A total of 65 patients who underwent laparoscopic sleeve gastrectomy between May 2011 and January 2014 met the study inclusion criteria. Before surgery, the 30 patients with type 2 diabetes were taking an average of 1.9 antidiabetic medications. One month after the procedure, 15 (50%) had discontinued all antidiabetic medications, with a further decline at 3 and 6 months (p < 0.001 at each time point). Among the patients who were taking antihypertensives (n = 48) and antilipemics (n = 33) before surgery, the decline in use occurred at a more modest rate, with 6 (12%) and 2 (6%), respectively, discontinuing these medication classes within 1 month, and 12 (25%) (p = 0.001) and 8 (24%) (p = 0.015) having discontinued by 6 months.

Conclusions:

These findings suggest that patients with a history of type 2 diabetes mellitus, hypertension, and/or dyslipidemia who undergo laparoscopic sleeve gastrectomy are less likely to require disease-specific medications shortly after surgery.     

The potent calcitonin gene-related peptide receptor antagonist, telcagepant, does not affect nitroglycerin-induced vasodilation in healthy men

AIMS

To assess the effect of the calcitonin gene-related peptide (CGRP) receptor antagonist, telcagepant, on the haemodynamic response to sublingual nitroglycerin (NTG).

METHODS

Twenty-two healthy male volunteers participated in a randomized, placebo-controlled, double-blind, two-period, crossover study. Subjects received 500 mg telcagepant or placebo followed, 1.5 h later, by 0.4 mg NTG. To assess the haemodynamic response the following vascular parameters were measured: blood pressure, aortic augmentation index (AIx) and brachial artery diameter (BAD). Data are presented as mean (95% confidence interval, CI).

RESULTS

The aortic AIx following NTG decreased by −18.50 (−21.02, −15.98) % after telcagepant vs. −17.28 (−19.80, −14.76) % after placebo. The BAD fold increase following NTG was 1.14 (1.12, 1.17) after telcagepant vs. 1.13 (1.10, 1.15) after placebo. For both AIx and BAD, the hypothesis that telcagepant does not significantly affect the changes induced by NTG is supported (P < 0.0001). In addition, no vasoconstrictor effect of telcagepant could be demonstrated.

CONCLUSIONS

Telcagepant did not affect NTG-induced haemodynamic changes. These data suggest that NTG-induced vasodilation is not CGRP dependent.     

Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects

AIMS

To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine.

METHODS

In this open-label, randomized, two-way crossover study, 28 healthy subjects (18–55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration–time curve from 0 to infinity (AUC(0,∞)), maximum plasma concentration (C_max), time to C_max (t_max), and half-life (t_1/2), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine.

RESULTS

Concomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and C_max of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t_max or t_½. Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters.

CONCLUSION

Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.     

Antimicrobial Stewardship Programs: Comparison of a Program with Infectious Diseases Pharmacist Support to a Program with a Geographic Pharmacist Staffing Model

Background:

Stewardship of antimicrobial agents is an essential function of hospital pharmacies. The ideal pharmacist staffing model for antimicrobial stewardship programs is not known.

Objective:

To inform staffing decisions for antimicrobial stewardship teams, we aimed to compare an antimicrobial stewardship program with a dedicated Infectious Diseases (ID) pharmacist (Dedicated ID Pharmacist Hospital) to a program relying on ward pharmacists for stewardship activities (Geographic Model Hospital).

Methods:

We reviewed a randomly selected sample of 290 cases of inpatient parenteral antibiotic use. The electronic medical record was reviewed for compliance with indicators of appropriate antimicrobial stewardship.

Results:

At the hospital staffed by a dedicated ID pharmacist, 96.8% of patients received initial antimicrobial therapy that adhered to local treatment guidelines compared to 87% of patients at the hospital that assigned antimicrobial stewardship duties to ward pharmacists (P < .002). Therapy was modified within 24 hours of availability of laboratory data in 86.7% of cases at the Dedicated ID Pharmacist Hospital versus 72.6% of cases at the Geographic Model Hospital (P < .03). When a patient’s illness was determined not to be caused by a bacterial infection, antibiotics were discontinued in 78.0% of cases at the Dedicated ID Pharmacist Hospital and in 33.3% of cases at the Geographic Model Hospital (P < .0002).

Conclusion:

An antimicrobial stewardship program with a dedicated ID pharmacist was associated with greater adherence to recommended antimicrobial therapy practices when compared to a stewardship program that relied on ward pharmacists.     

A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01)1

Aims

The pharmacokinetic (PK) similarity between PF-05280014, a proposed trastuzumab biosimilar, trastuzumab sourced from European Union (trastuzumab-EU) or from United States (trastuzumab-US) was evaluated. Safety and immunogenicity were also assessed.

Methods

In this phase 1, double-blind trial ({"type":"clinical-trial","attrs":{"text":"NCT01603264","term_id":"NCT01603264"}}NCT01603264), 105 healthy male volunteers were randomized 1:1:1 to receive a single 6 mg kg⁻¹ intravenous dose of PF-05280014, trastuzumab-EU, or trastuzumab-US, and evaluated for 70 days. Drug concentration–time data were analyzed by non-compartmental methods. PK similarity for the comparisons of PF-05280014 to each of trastuzumab-EU and trastuzumab-US, and trastuzumab-EU to trastuzumab-US were determined using the standard 80.00% to 125.00% bioequivalence criteria.

Results

Baseline demographics for the 101 subjects evaluable for PK were similar across all arms. The three products exhibited similar PK profiles with target-mediated disposition. The 90% CIs for the ratios of C_max, and AUC_(0,∞) were within 80.00% to 125.00% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms with treatment-related AEs reported by 71.4%, 68.6% and 65.7% subjects in the PF-05280014, trastuzumab-EU, and trastuzumab-US arms, respectively. The most common AEs were infusion-related reactions, headache, chills, pyrexia and nausea. The AE term ‘pyrexia’ was numerically greater in the PF-05280014 arm. All post-dose samples, except 1, tested negative for anti-drug antibodies (ADA).

Conclusions

This study demonstrates PK similarity among PF-05280014, trastuzumab-EU and trastuzumab-US. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab.     

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UVB-inflamed and normal skin

Aims

Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV_B-inflamed skin.

Methods

This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO₂-laser on normal and UV_B-inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types.

Results

Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV_B-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml⁻¹ for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings.

Conclusions

TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation.     

Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects

AIMS

To assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson''s disease and restless legs syndrome, without the problem of the confounding factors related to the disease.

METHODS

Placebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 ± 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled.

RESULTS

Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [−6.1 min (−9.8, −2.4), P = 0.002] and 5 h 30 min [−5.6 min (−7.7, −3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning.

CONCLUSIONS

These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.     

Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial

Aim

The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep.

Methods

In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day⁻¹ vs. placebo during 12 months. The primary endpoint quality of life parameter ‘vitality’ was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations.

Results

Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group.

Conclusions

The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6–12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.     

Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial

Aim

We compared the efficacy of melatonin and placebo as adjuvants in the withdrawal of patients from long term temazepam, zopiclone or zolpidem (here ‘BZD’) use.

Methods

A double-blind, placebo-controlled, randomized trial was conducted in a primary health care outpatient clinic. Ninety-two men or women (≥55 years) with primary insomnia and chronic BZD use received controlled release melatonin 2 mg (CRM) (n = 46) or placebo (n = 46) during the 1 month withdrawal from BZDs. Psychosocial support was provided. Follow-up continued for up to 6 months. Successful BZD withdrawal by the end of 1 month was confirmed by BZD plasma determinations, while reduction in BZD use and abstinence continuing for 6 months were noted.

Results

There were two drop-outs on CRM and one on placebo. After a 1 month withdrawal, 31 participants (67%; 95% CI 54, 81) on CRM and 39 (85%; 74, 95) on placebo had withdrawn completely (intention-to-treat analysis between groups, P = 0.051; per protocol P = 0.043). Reduction in BZD use was similar or even more rare in the CRM than in the placebo group (P = 0.052 per protocol). After 6 months, 14 participants in the CRM group and 20 in the placebo group remained non-users of BZD (NS between groups). BZD doses were higher in the CRM than in the placebo group at the end of the 6 month follow-up (P = 0.025). Withdrawal symptoms did not differ between the groups.

Conclusions

Gradual dose reduction of BZDs combined with CRM or placebo, and psychosocial support produced high short term and moderate long term BZD abstinence. CRM showed no withdrawal benefit compared with placebo.     

The effect of allopurinol on the cerebral vasculature of patients with subcortical stroke; a randomized trial

AIMS

New preventative strategies for stroke are required. One promising strategy is uric acid reduction and xanthine oxidase inhibition with allopurinol. We sought to investigate whether allopurinol improves cerebrovascular reactivity (CVR) following subcortical stroke.

METHODS

We performed a randomized, double-blind, controlled study to investigate the effect of a 3-month course of 300 mg allopurinol once daily vs. placebo on CVR in individuals with recent (within 6 months) subcortical stroke. Participants were randomized on a 1 : 1 basis. CVR was defined as the percentage change in middle cerebral artery flow velocity following an intravenous injection of 15 mg kg⁻¹ of acetazolamide. Our primary end-point was the CVR difference between baseline and 3 months. Secondary end-points included measures of peripheral vascular reactivity and blood markers of inflammation and endothelial activation.

RESULTS

We enrolled 50 participants; 45 completed the protocol. Baseline serum urate was 0.35 mmol l⁻¹ (SD 0.1) and 0.34 mmol l⁻¹ (SD 0.1) in the allopurinol and placebo groups, respectively. There were no serious adverse events related to treatment. CVR did not change following treatment with allopurinol [median CVR change 0.89% after allopurinol (n= 20) and −0.68% after placebo (n= 25); 95% confidence interval for estimated difference in medians −13.4, 25.5, P= 0.64]. Urate was significantly lowered by allopurinol but no change in other secondary end-points was seen.

CONCLUSION

Xanthine oxidase inhibition with allopurinol has previously been shown to improve cerebrovascular function, but no benefit was seen in this study. It may therefore be that previous encouraging findings will not translate into important clinical benefits.     

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic,in a first-in-human study

Aims

The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM).

Methods

T2DM subjects (glycosylated haemoglobin: 7.0–10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5–200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride – an early marker of drug activity.

Results

No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5–7.7 h and 66.5– 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups.

Conclusions

Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.     

Assessment of antitussive efficacy of dextromethorphan in smoking related cough: objective vs. subjective measures

AIMS

Using an established model of smokers cough we measured the antitussive effects of dextromethorphan compared with placebo.

METHODS

The study was a randomized, double-blind placebo controlled, crossover comparison of 22 mg 0.8 ml⁻¹ dextromethorphan delivered pregastrically with matched placebo. Objective and subjective measurements of cough were recorded. Subjective measures included a daily diary record of cough symptoms and the Leicester quality of life questionnaire. Cough frequency was recorded using a manual cough counter. The objective measure of cough reflex sensitivity was the citric acid, dose–response cough challenge.

RESULTS

Dextromethorphan was significantly associated with an increase in the concentration of citric acid eliciting an average of two coughs/inhalation (C2) when compared with placebo, 1 h post dose by 0.49 mM (95% CI 0.05, 0.45, geometric mean 3.09) compared with placebo 0.24 mM (geometric mean 1.74) P < 0.05 and at 2 h 0.57 mM (95% CI 0.01, 0.43, geometric mean 3.75) compared with placebo 0.34 mM (geometric mean 2.19) P < 0.05). There was a highly significant improvement in the subjective data when compared with baseline. However, there was no significant difference between placebo and active treatment. No correlation was seen between cough sensitivity to citric acid and recorded cough counts or symptoms. When both subjective and objective data were compared with screening data there was evidence of a marked ‘placebo’ effect.

CONCLUSIONS

The objective measure of cough sensitivity demonstrates dextromethorphan effectively diminishes the cough reflex sensitivity. However, subjective measures do not support this. Other studies support these findings, which may represent a profound sensitivity of the cough reflex to higher influences.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Dextromethorphan is widely used as a cough suppressant in over the counter medications.
• Its efficacy in altering cough reflex sensitivity has been shown in healthy volunteers. In contrast evidence for an effect on clinically important cough is poor.

WHAT THIS STUDY ADDS

• A significant decrease in evoked cough was seen with dextromethorphan compared with placebo. However, both placebo and active treatment improved subjective data to a similar degree.
• We doubt the validity of currently used objective tests in the investigation of antitussives.