Neuropathic pain affects ~ 6.9–10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, ...and pharmacokinetics of a voltage‐dependent and use‐dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo‐controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7‐day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax), area under the concentration‐time curve from predose to 24 hours postdose (AUC0–24), time to Cmax (Tmax), and terminal half‐life (t1/2), among others, were assessed. Drug‐related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug‐related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1–2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady‐state was achieved from day 5 onward. These data indicate that oral vixotrigine is well‐tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.
This meta-analysis of placebo-controlled paroxetine trials examines suicidality incidence in adults, focusing on disorder and age as potential risk factors. The findings are put in context with an ...efficacy meta-analysis of the same trial datasets.
GlaxoSmithKline paroxetine clinical trial database(s).
All double-blind, randomized, placebo-controlled, parallel-group studies of paroxetine therapy in adults enrolling at least 30 patients total were included in the analysis. The dataset comprised 14,911 patients from 61 trials.
Possible cases of suicidality were identified and blindly categorized by an expert panel, using methodology previously used by the US Food and Drug Administration. Incidences of suicidal behavior (preparatory act, suicide attempt, or completed suicide) and any suicidality (suicidal behavior or ideation) were compared between paroxetine and placebo. Efficacy assessments were based on standard depression rating scales (eg, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale) and Clinical Global Impressions Improvement scale (CGI-I) scores.
In the primary dataset, ie, all disorders combined, there were no significant differences between paroxetine and placebo for overall suicidality (suicidal behavior or ideation: n/n = 83/8,958 0.93% vs n/n = 65/5,953 1.09%, respectively; OR = 0.9 95% CI, 0.7-1.3; P = .649) or for suicidal behavior specifically (n/n = 50/8,958 0.56% vs n/n = 40/5,953 0.67%, respectively; OR = 1.2 95% CI, 0.8-1.9; P = .483). However, in patients with major depressive disorder (MDD), a greater incidence of suicidal behavior occurred in paroxetine-treated patients than in placebo-treated patients (n/n = 11/3,455 0.32% vs n/n = 1/1,978 0.05%, respectively; OR = 6.7 95% CI, 1.1-149.4; P = .058). Across all indications, a higher incidence of suicidal behavior occurred in paroxetine-treated versus placebo-treated adults aged 18 to 24 years (n/n = 17/776 2.19% vs n/n = 5/542 0.92%, respectively; OR = 2.4 95% CI, 0.9-7.3). In older age groups, no increase in suicidality was observed. Efficacy was demonstrated in all disorders evaluated, including MDD.
Across all disorders, overall suicidality incidence was similar between paroxetine and placebo. However, a higher frequency of suicidal behavior occurred with paroxetine in MDD, which was largely explained by the higher incidence in young adults. These data support the efficacy of paroxetine therapy; however, they also highlight the need for careful monitoring of suicidality during antidepressant therapy, particularly in younger adults.
Purpose
GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A
2
(Lp-PLA
2
), which was in development as a potential treatment for Alzheimer’s disease (AD). In order ...to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor,
18
FGSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.
Procedures
18
FGSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated,
18
Ftrifluoromethylation methodology. Healthy male subjects (
n
= 4, age range 34–42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of
18
FGSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (V
T
). Secondary PK and safety endpoints were also recorded.
Results
PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of
18
FGSK2647544 across all the ROIs examined. The mean whole brain V
T
was 0.56 (95 % CI, 0.41–0.72). Secondary PK parameters, C
max
(geometric mean) and T
max
(median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20–40 % of the parent compound
18
FGSK2647544 present after 120 min.
Conclusions
The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA
2
activity.
Trial Registration
Clintrials.gov: NCT01924858.
Vixotrigine is a state‐ and use‐dependent Nav1.7 channel blocker being investigated for the treatment of neuropathic pain conditions. This randomized, double‐blind, placebo‐controlled crossover trial ...was designed to evaluate changes in blood pressure with the administration of vixotrigine using ambulatory blood pressure monitoring (ABPM). Eligible participants were healthy adults 18 to 65 years of age without evidence of baseline systolic blood pressure (SBP) persistently > 140 mm Hg or diastolic blood pressure (DBP) persistently > 90 mm Hg. Vixotrigine (400 mg men, 300 mg women) or placebo was administered orally twice daily for 36 days. Following a 7‐day washout period, participants crossed over to the other treatment. Each dosing period was preceded by 1 inpatient visit and 1 outpatient baseline visit. Two 14‐hour inpatient ABPM sessions occurred on days 14 and 35, with a return to the clinic the morning of days 15 and 36 for initiation of outpatient ABPM, which assessed blood pressure and heart rate every 15 minutes. Adverse events were collected throughout the study. The primary end point was the change from baseline in 24‐hour mean SBP and DBP on day 36. Sixty participants were enrolled; 10 withdrew from the study owing to adverse events, investigator discretion, or withdrawal of consent. From baseline to day 36, mean changes in average SBP and DBP (vixotrigine treated) were ‐0.33 and 0.20 mm Hg, respectively. Adverse event rates were comparable for vixotrigine and placebo; the most common adverse events were headache, dizziness, and nausea. Vixotrigine administration is not associated with a clinically important increase in blood pressure.
The impact of type 1 diabetes (T1D) on patient’s lives has been described in the literature, but little insight exists on the experience of newly diagnosed pediatric patients. This timeframe is ...unique for clinical reasons (honeymoon period) and psychosocial reasons (adapting to living with T1D). This project aimed to identify concepts core to describing the experience of pediatric patients in the first two years of T1D and organize them into a framework.
Based on literature and clinician input, a semi-structured interview guide was developed. Patients (n=29) ages 7-17 recruited by an agency and childrenwithdiabetes.com participated in face-to-face (age <10) or phone interviews. Interviews were recorded, transcribed, and inductively coded using ATLAS.ti software. Detailed concepts were categorized into overarching domains reflecting their conceptual underpinning to design the framework.
The sample mean age was 12 years, and was 48% male and 72% white. The interviews confirmed symptoms of hyper and hypoglycemia already described in the literature, but above all, they provided in-depth information as to how symptoms and impacts are experienced within the first two years of T1D diagnosis.
The proposed conceptual framework includes symptoms, impacts, and disease management. Symptoms include hyper and hypoglycemia. Impacts include peers, school, sports, emotions, diet, preoccupation with the disease, conflict with parents (adolescents only) and parental supervision (children only). Disease management focused on checking blood glucose, giving insulin, carrying supplies, the pain of treatment, and adapting to management of the disease over time.
This study highlights the impact of T1D within the first two years of diagnosis in pediatric patients. It provides a conceptual foundation for the measurement of the benefit of medical or psychosocial interventions and monitoring while patients and their caregivers assimilate to the implications of the disease on their day-to-day lives.
Disclosure
E. Senior: Employee; Self; UCB, Inc. R. Fong: Employee; Self; UCB, Inc.. A. Christian: None. J.T. Markowitz: None. S. Strzok: None. T. Schmidt: None. K. Harris: Employee; Self; UCB, Inc.. P. Marquis: None.
Background: Alitretinoin is approved for the treatment of adults with severe chronic hand eczema (CHE) refractory to potent topical steroids. In the 6 years since launch, approximately 250 000 ...patients have been treated with alitretinoin. Objective: To compare the postmarketing safety surveillance experience of alitretinoin with data from clinical trials and key safety issues with other retinoids. Methods: An integrated safety analysis of the pivotal studies of alitretinoin and postmarketing adverse event (AE) reports received since approval for alitretinoin were analyzed. Results: In the pivotal trials, headache, erythema, nausea, increased blood triglycerides and increased blood creatinine phosphokinase were the most frequently reported AEs. Headache, hyperlipidemia and nausea were also frequently reported postmarketing AEs, but depression was relatively more frequently reported than in the pivotal trials. Inflammatory bowel disease and benign intracranial hypertension were rare, and very few cases have been reported in postmarketing surveillance. There have been no reports of teratogenicity in humans consequent to fetal exposure. Conclusions: Safety data collected in pivotal trials and postmarketing surveillance suggest that alitretinoin is well tolerated by patients with CHE with a relatively low incidence of serious reactions. The adverse reaction profile is congruent with reported effects of other marketed oral retinoids.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase ...A2 (Lp-PLA2) inhibitor).
Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2.
Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively.
GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. .
Event-related potentials to binaural complex tones
were recorded from 40 depressed outpatients and 22 normal
control participants at 30 electrode sites. Patients did
not differ from control ...participants in N1 or P3 amplitude
but showed greater N2. N2 was greater over right than over
the left hemisphere at lateral sites in patients and control
participants. A P3 asymmetry was found for control participants
and patients with low scores on a physical anhedonia scale,
but not for patients with high anhedonia scores. Topographic
(local Laplacian) maps corresponding to P3 showed greater
radial current flow over right than over left central regions
in control participants. Patients with high anhedonia did
not show this asymmetry, whereas patients with low anhedonia
showed an intermediate asymmetry. These findings support
the hypothesis that anhedonic depression is associated
with dysfunction of right hemisphere mechanisms mediating
the processing of complex pitch information.
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