Evaluation of atomoxetine for first-line treatment of newly diagnosed,treatment-naïve children and adolescents with attention deficit/hyperactivity disorder

Abstract

Objective:

To test the hypothesis that first-line treatment with atomoxetine provides superior efficacy than placebo for up to 12 weeks in improving the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD).

Research design and methods:

This double-blind, randomized, placebo-controlled, parallel clinical trial included 151 treatment-naïve children (n?=?113) and adolescents (n?=?38) with newly diagnosed (≤3 months) ADHD. Atomoxetine dose was uptitrated from 0.5 to 1.2?mg/kg/day after two weeks. Outcome assessments included the ADHD Rating Scale-IV-Parent-reported Investigator-rated (ADHDRS-IV-Parent:Inv), the Clinical Global Impression of Severity of ADHD (CGI-ADHD-S), and the incidence of adverse events. Mixed-model repeated measures analysis was used to compare scale score changes between groups.

Clinical trial registration:

Trial registered at www.clinicaltrials.gov (study internal code: B4Z-XM-LYDM, identifier: NCT00191945).

Results:

Most patients were male (79.2%), of caucasian origin (96.0%) and severely ill (72.5%). Their mean age was 10.3 years. Atomoxetine-treated patients showed greater reductions from baseline to week 12 of total ADHDRS-IV-Parent:Inv score than placebo-treated patients (least square mean difference: ?7.9 [95% CI: ?11.0 to ?4.8], corresponding to a large effect size of 0.8). Between-group mean differences increased progressively with treatment exposure from week 6 to 12 (?2.7 [?4.9 to ?0.6] for total and ?1.6 [?2.9 to ?0.3] for inattention scores). At the end of the study, 50% of atomoxetine-treated patients (14% with placebo) showed a reduction ≥40% in total ADHDRS-IV-Parent:Inv score, and only 29% (46% with placebo) were severely ill (by CGI-ADHD-S). Treatment-related adverse events were significantly more frequent with atomoxetine (65.0%) than with placebo (37.3%), the most frequent being decreased appetite and somnolence. Only one case of decreased appetite was rated as severe. No patient discontinued treatment because of adverse events.

Conclusions:

A continued improvement of symptoms is expectable until 12 weeks in treatment-naïve ADHD patients treated with atomoxetine as first-line medication. Chief limitations are the small, national sample size and the absence of data beyond the 12-week time-point.     

A qualitative review of issues arising in the use of psycho­stimulant medications in patients with ADHD and co‑morbid substance use disorders

ABSTRACT

Objective: This review addresses the relationship between attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs), with an emphasis on factors that determine the potential for psychostimulant abuse. Strategies for identification and treatment of patients with ADHD who are at risk for, or have, co-morbid SUD are also addressed.

Research design and methods: The article was based on a qualitative review of current literature addressing co-morbid ADHD and SUD.

Discussion: Adolescent and adult patients with ADHD are at increased risk for SUD, as well as a number of other psychiatric disorders. Psychostimulant agents like methyl­phenidate (MPH) and mixed amphetamine salts (MAS) are effective first-line pharmacotherapies for ADHD; however, they are Schedule II controlled substances with a potential for abuse. Evidence suggests that treatment of ADHD during childhood with stimulant agents may reduce the risk of developing SUD later on. Factors associated with the highest risk of SUD in patients with ADHD include co-morbid antisocial personality disorder, bipolar disorder, an eating disorder, severe ADHD and/or antisocial behavior symptoms, and dropping out of school. Treatment initiation during adolescence or young adulthood also has been linked to increased risk of polydrug use and non-medical stimulant use, a pattern of behavior consistent with a risk of SUD development. Treatment plans for patients with ADHD and co-morbid SUD should include behavioral interventions, careful monitoring, and when appropriate, pharmacotherapy. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD. Long-acting stimulant formulations and non-stimulants, like atomoxetine or bupropion, have a lower potential for abuse, and provide several safe and effective treatment options for the development of a comprehensive manage­ment plan for patients with co-morbid ADHD and SUD.

Conclusions: The present review is neither exhaustive nor systematic. Moreover, the reviewed studies vary wide­ly with regards to methodology and patient populations. In light of these limitations, several conclusions are still warranted. Patients with ADHD are at increased risk for SUD. Under certain conditions, psychostimulants may be a pharmacologic option in the treatment of patients with co-morbid ADHD and SUD. However, clinicians should be mindful of the risks and benefits of this treatment approach in a high-risk population and should also bear in mind the labeling guidelines when working with this co-morbidity.     

Atomoxetine hydrochloride in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A placebo-controlled Italian study

ObjectiveThe primary aim of this study was to assess the efficacy of atomoxetine in improving ADHD and ODD symptoms in paediatric patients with ADHD and comorbid oppositional defiant disorder (ODD), non-responders to previous psychological intervention with parent support.MethodsThis was a multicentre, randomised, placebo-controlled trial conducted in patients aged 6–15 years, with ADHD and ODD diagnosed according to the DSM-IV criteria by a structured clinical interview (K-SADS-PL). Only subjects who are non-responders to a 6-week standardized parent training were randomised to atomoxetine (up to 1.2 mg/kg/day) or placebo (in a 3:1 ratio) for the following 8-week double blind phase.ResultsOnly 2 of the 156 patients enrolled for the parent support phase (92.9% of males; mean age: 9.9 years), improved after the parent training program; 139 patients were randomised for entering in the study and 137 were eligible for efficacy analysis. At the end of the randomised double blind phase, the mean changes in the Swanson, Nolan and Pelham Rating Scale-Revised (SNAP-IV) ADHD subscale were − 8.1 ± 9.2 and − 2.0 ± 4.7, respectively in the atomoxetine and in the placebo group (p < 0.001 between groups); changes in the ODD subscale were − 2.7 ± 4.1 and − 0.3 ± 2.6, respectively in the two groups (p = 0.001 between groups). The CGI-ADHD-S score decreased in the atomoxetine group (median change at endpoint: − 1.0) compared to no changes in the placebo group (p < 0.001 between groups). Statistically significant differences between groups, in favour of atomoxetine, were found in the CHIP-CE scores for risk avoidance domain, emotional comfort and individual risk avoidance subdomains. An improvement in all the subscales of Conners Parents (CPRS-R:S) and Teacher (CTRS-R:S) subscales was observed with atomoxetine, except in the cognitive problems subscale in the CTRS-R:S. Only 3 patients treated with atomoxetine discontinued the study due to adverse events. No clinically significant changes of body weight, height and vital signs were observed in both groups.ConclusionsTreatment with atomoxetine of children and adolescents with ADHD and ODD, who did not initially respond to parental support, was associated with improvements in symptoms of ADHD and ODD, and general health status. Atomoxetine was well tolerated.     

Modafinil in children and adolescents with attention-deficit/hyperactivity disorder:a preliminary 8-week,open-label study

ABSTRACT

Objective: In a 4-week, double-blind, placebo-controlled study, the attention-promoting agent modafinil improved symptoms of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents and was well tolerated. To assess the continued efficacy of modafinil and obtain additional safety data, an 8-week, open-label study was conducted as an extension to the double-blind study.

Method: Two hundred and twenty children and young adolescents (age range, 6–14 years) with ADHD who had completed 4 weeks of the double-blind period or had withdrawn for reasons other than an adverse event were enrolled. Patients received individually titrated doses of modafinil (100–400?mg), administered once daily or as a divided dose. Patients visited the clinic at open-label weeks 2, 4, and 8 for assessments of efficacy. Efficacy was assessed using the parent-or clinician-completed ADHD Rating Scale-IV (ADHD-RS-IV) Home Version, the parent-completed Conners' ADHD/DSM-IV Scale Parent Version (CADS-P), and the clinician-rated Clinical Global Impression of Improvement (CGI-I) scale. Adverse events were monitored.

Results: Modafinil improved symptoms on all ADHD rating scales and subscales during the open-label extension. Mean change (baseline to final visit) in Total score on the ADHD-RS-IV was ?14.6 (95% CI: ?16.40 to ?12.70); and ?7.6 (95% CI: ?8.65 to ?6.62) and ?6.9 (95% CI: ?7.90 to ?5.94) in the Inattention and Hyperactivity–impulsivity scores, respectively. The mean Total score [SD] on the CADS-P decreased from baseline (74.4 [10.3]) to the final visit (63.2 [13.1]) (change: ?11.2, 95% CI: ?13.08 to ?9.65). Fiftythree percent of patients were rated as much or very much improved on the CGI-I. Insomnia (13%) and headache (10%) were the most common adverse events. No clinically meaningful changes were observed in physical examination findings, electrocardiography, blood pressure, pulse, or body temperature. Clinically significant changes (increase or decrease) in body weight of 7% or more were observed for 30 patients (14%), with decreases (mean, 3.2 kg) reported for 22 patients (10%) and increases (mean, 3.7 kg) reported for eight patients (4%).

Conclusion: Modafinil remained efficacious and well tolerated in children with ADHD, improving ADHD symptoms and overall clinical condition during the open-label study. Limitations of the study include open-label dosing and lack of a placebo control.     

Incidence and costs of polypharmacy: data from a randomized,double-blind,placebo-controlled study of risperidone and quetiapine in patients with schizophrenia or schizoaffective disorder

ABSTRACT

Objective: The use of adjunctive psychotropics and the costs of poly­pharmacy in patients randomized to receive risperidone or quetiapine were compared in a placebo-controlled double-blind study conducted in India, Romania, and the United States.

Methods: The efficacy and safety of risperidone, quetiapine, and placebo were compared in a 14-day monotherapy phase in patients experiencing an acute exacerbation of symptoms of schizophrenia or schizoaffective disorder. This was followed by a 28-day, additive-therapy phase during which addition of antipsychotics or other psychotropic medications was permitted. Risperidone was received by 153 patients in the monotherapy phase and 133 in the additive therapy phase, quetiapine by 156 and 122, respectively, and placebo by 73 and 53. Rates of polypharmacy were examined using the Cochran–Mantel–Haenszel, Kaplan–Meier, and Cox regression methods. Costs of poly­pharmacy were analyzed by non­parametric Wilcoxon 2-sample tests.

Results: Primary study results have been reported elsewhere (Potkin et al., Schizophr Res 2006;85:254-65). Mean (±SD) doses at the additive-therapy baseline were 4.7 ± 0.9?mg/day of risperidone and 579.0 ± 128.9?mg/day of quetiapine. Additional psychotropics were received by 36% of the risperidone group, 58% of the quetiapine group (?p < 0.01), and by 58% of the placebo group. Antipsychotics accounted for > 95% of the added psychotropics, the most common being olanzapine and haloperidol. The relative risk (quetiapine vs. risperidone) for antipsychotic polypharmacy was 1.90 (?p = 0.001; 95% CI 1.29, 2.80). The mean projected cost of additional antipsychotics per randomized patient during the additive-therapy phase was $57.03 in the risperidone group and $101.64 in the quetiapine group (?p < 0.01).

Conclusions: The results confirm earlier reports of higher rates of poly­pharmacy with quetiapine than with risperidone. The findings also reveal substantial between-treatment differences in costs associated with poly­pharmacy. Limitations of the study include that the study was of short duration and that a high proportion of patients were recruited from countries other than the United States.     

Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD)

Importance of the field: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a ‘first in class’ α_2A-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine.

Areas covered in this review: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial-responders are featured.

What the reader will gain: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited.

Take home message: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape.     

A 12-week,randomized, placebo-controlled trial assessing the safety and efficacy of oxymorphone extended release for opioid-naive patients with chronic low back pain

ABSTRACT

Objective: Determine the efficacy and tolerability of oxymorphone extended release (OPANA ER) in opioid-naive patients with moderate to severe chronic low back pain (CLBP).

Design and methods: Patients ≥ 18 years of age were titrated with oxymorphone ER (5- to 10?mg increments every 12?h, every 3–7 days) to a well-tolerated, stabilized dose. Patients were then randomized to continue their oxymorphone ER dose or receive placebo every 12?h for 12 weeks. Oxymorphone immediate release was available every 4–6?h, as needed, for the first 4 days and twice daily thereafter.

Results: Sixty-three percent of patients (205/325) were titrated to a stabilized dose of oxymorphone ER, most (203/205) within 1 month. During titration, 18% discontinued from adverse events (AEs) and 1% from lack of efficacy. For patients completing titration, average pain intensity decreased from 69.4?mm at screening to 22.7?mm (?p < 0.0001). After random­ization, 68% of oxymorphone ER and 47% of placebo patients completed 12 weeks of double-blind treatment. Approximately 8% of patients in each group discontinued because of AEs. Placebo patients discontinued significantly sooner from lack of efficacy than those receiving oxymorphone ER (?p < 0.0001). Pain intensity increased significantly more in the placebo group (least squares [LS] mean change 26.9 ± 2.4 [median 28.0]) than in the oxymorphone ER group (LS mean change 10.0 ± 2.4 [median 2.0]; p < 0.0001). Oxymorphone ER was generally well tolerated without unexpected AEs. Although limitations of a randomized withdrawal study include the potential for unblinding and opioid withdrawal in placebo patients, opioid withdrawal was limited to two patients in the placebo group and one in the oxymorphone ER group.

Conclusions: Stabilized doses of oxymorphone ER were generally safe and effective over a 12?week double-blind treatment period in opioid-naive patients with CLBP.     

A double-blind,randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension

ABSTRACT

Objectives: The objective of this study was to evaluate the effects of losartan ± hydrochlorothiazide (HCTZ) versus placebo in obese patients with systolic and diastolic hypertension.

Research design and methods: Randomized patients (n = 261) were non-diabetic with systolic blood pressure (SBP) ≥ 140 and ≤ 180?mmHg and diastolic BP (DBP) ≥ 95 and ≤ 115?mmHg, body mass index > 30?kg/m², and waist circumference > 40 (males)/> 35 (females)?inches. Patients were randomized to placebo or a forced titration of losartan 50?mg titrated at 4-week intervals to losartan 100?mg, losartan 100?mg/HCTZ 12.5?mg, and losartan 100?mg/HCTZ 25?mg. Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks. Secondary measurements were change from baseline in BPs at 8 and 16 weeks, percent responders at 12 and 16 weeks, and safety/tolerability. Post-hoc analyses were BP at 4 weeks and achieve­ment of controlled BP (SBP < 140 and/or DBP < 90?mmHg) at 12 and 16 weeks.

Results: Losartan 50?mg reduced BP from 151.6/99.2?mmHg at baseline to 140.1/89.8?mmHg at week 4 (post hoc), 139.5/89.6?mmHg with losartan 100?mg at week 8 (secondary), 134.3/85.9?mmHg with losartan 100?mg/HCTZ 12.5?mg at week 12 (primary), and 132.1/84.9?mmHg with losartan 100?mg/HCTZ50?mg at week 16 (secondary) (all p < 0.05). Rates of clinical adverse experi­ences were similar between treatment groups. A limitation of these analyses is the relatively rapid rate of study drug titration, which may not have allowed for the evaluation of the full treatment effect at each titration step.

Conclusions: We conclude that losartan alone or in combination with HCTZ was generally well tolerated and effective in the treatment of elevated systolic and diastolic BP in obese patients with hypertension.     

Update on atomoxetine in the treatment of attention-deficit/hyperactivity disorder

Background: Atomoxetine, an inhibitor of, the presynaptic transporter of norepinephrine, was approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children aged 6 years and older, adolescents and adults in the USA in 2002, and in Europe, first in the UK and then by mutual recognition in several countries during 2003 and 2004. Since that time, the use of atomoxetine has spread globally and extensive additional research has been conducted evaluating its efficacy and safety. Objective: The objective of this review is to provide a summary of the available data on atomoxetine, with an emphasis on postmarketing clinical research, which is helping to clarify the role of this agent in ADHD pharmacotherapy. Methods: Recent as well as long-term safety and efficacy data are reviewed, with an emphasis on comparison with long-acting psychostimulants, ADHD in special populations and in patients with psychiatric comorbidities. Results/conclusion: Atomoxetine is an effective acute and long-term pharmacotherapy for ADHD, and may play a particular role in the treatment of patients with comorbid disorders and those who have failed or are unable to tolerate stimulants.     

A Randomized,Double-Blind,Placebo-Controlled Phase 2 Study of α4β2 Agonist ABT-894 in Adults with ADHD

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners'' Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.     

Long-term safety,tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis

ABSTRACT

Background: Renin–angiotensin system (RAS) blockade with ACE inhibitor and/or angiotensin receptor blocker therapy can lead to increased potassium levels, hence the need to assess dual blockade involving a direct renin inhibitor. Here we report the results of a pre-planned 6-month interim analysis of a long-term, open-label study examining the safety, tolerability and efficacy of the aliskiren/valsartan 300/320-mg combination in patients with hyper­tension.

Methods: A total of 601 patients with hyper­tension (msDBP ≥?90 and <?110?mmHg) received a combination of aliskiren/valsartan 150/160?mg for 2 weeks followed by forced titration to aliskiren/valsartan 300/320?mg once daily for a targeted duration of 52 weeks. Optional hydrochlorothiazide (HCTZ) addition was allowed from week 8 for inadequate BP control (≥?140/90?mmHg). The primary objective was to assess the safety of combination therapy; potassium elevations were a pre-defined safety outcome. BP was measured at regular intervals during the study.

Results: At the 6-month cut-off date, 512 patients (85.2%) were still ongoing with study treatment, and 192 patients had received at least one dose of HCTZ add-on during this period. Combination therapy was generally well-tolerated; the most commonly reported adverse events were headache (7.5%), dizziness (7.3%) and nasopharyngitis (7.2%). Ten patients (2.5%) receiving aliskiren/valsartan and two patients (1.0%) receiving aliskiren/valsartan/HCTZ had serum potassium elevations >?5.5?mmol/L. Only one patient (0.2%) exhibited potassium levels ≥?6.0?mmol/L during this period and the patient was treated with aliskiren/valsartan. Mean msSBP/DBP reductions of 22.3/14.4?mmHg were observed at 6-month endpoint (LOCF analysis) and 73.4% of patients achieved BP control (<?140/90?mmHg; LOCF).

Conclusions: Although lack of an active comparator group is a limitation of the study, our findings show that long-term treatment with the aliskiren/valsartan 300/320-mg combin­ation provided clinically significant BP lowering, was well-tolerated and was associated with a very low rate of potassium elevations in patients with hyper­tension.     

Duloxetine versus escitalopram and placebo: an 8-month,double-blind trial in patients with major depressive disorder

ABSTRACT

Background: Duloxetine and escitalopram were compared in an 8-month, randomized, double-blind, placebo-controlled trial in adult outpatients meeting DSM?IV criteria for major depressive disorder (MDD). The results regarding the primary objective of the study (onset of antidepressant action) have been previously published. The current paper focuses on the longer-term (8-month) comparisons of efficacy and safety between duloxetine and escitalopram.

Research design and methods: Upon completion of the 8-week, fixed-dose, placebo-controlled, acute-treatment phase (duloxetine 60?mg/day (n = 273), escitalopram 10?mg/day (n = 274), placebo (n = 137)), patients remaining in the duloxetine (n = 188) and escitalopram (n = 208) groups were eligible for double-blind dose increases (duloxetine to 120?mg/day, escitalopram to 20?mg/day), and placebo non-responders were eligible for double-blind rescue to active drug.

Main outcome measures: Efficacy was primarily assessed using the HAMD₁₇. Safety/tolerability assess­ments included spontaneously reported adverse events (AEs), overall rates and reasons for discontinuation, laboratory analyses, and vital signs.

Results: Both drugs demonstrated similar remission rates over the course of the study, with the probability of remission reaching 70% (duloxetine) and 75% (escitalo­pram) at 8 months (?p = 0.44). Similar improvement was observed for both duloxetine and escitalopram on efficacy measures with the exception of the sleep subscale of the HAMD₁₇, wherein escitalopram had a statistically signif­icant advantage over duloxetine in improving sleep. Over the entire 8-month study, discontinuation rates differed significantly for duloxetine (62%) compared with escitalo­pram (55%; p = 0.02). Rates of discontinuation due to AEs did not differ significantly between duloxetine (12.8%), escitalopram (12.0%), and placebo (10.2%) (?p > 0.05 all pairwise comparisons). AEs associated with duloxetine tended to emerge early in treatment (e.g., nausea, dry mouth), whereas AEs associated with escitalopram tended to emerge later in treatment (e.g., diarrhea, weight increase). The incidence of sustained hypertension was similar between drugs (1.5 vs. 1.1% patients for dulox­etine and escitalopram, respectively). Statistically signif­icant drug differences were identified in the mean changes from baseline to study endpoint for pulse (+3.05 beats per minute (bpm), duloxetine; –0.89?bpm, escitalopram; p < 0.001) and systolic blood pressure (+3.73?mmHg, duloxetine; +0.31?mmHg, escitalopram; p < 0.05), but not diastolic blood pressure (+0.81?mmHg, duloxetine; –0.24?mmHg, escitalopram; p = 0.27). At 8 months, mean change in weight was significantly higher for escitalopram compared with duloxetine (+0.61?kg, duloxetine; +1.83?kg, escitalopram; p < 0.05), however, the incidence of treatment-emergent abnormal weight gain (≥?7% increase in weight from baseline) was similar between drugs and was significantly greater for both duloxetine and escitalopram compared with placebo.

Limitations: Because so few patients on placebo (n = 15), in comparison to duloxetine (n = 104) or escitalopram (n = 123), completed the entire 8-month study, the power to detect a difference between the active treatments and placebo after 8 weeks was significantly decreased and very likely insufficient.

Conclusion: Throughout the 8-month study, similar improvement was observed for both duloxetine and escitalopram on most efficacy measures with the exception of the sleep subscale of the HAMD₁₇. Drug differences were identified in safety/tolerability measures.     

European,randomized, phase 3 study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder

This study evaluated the efficacy and safety of lisdexamfetamine dimesylate (LDX) compared with placebo in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in Europe. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference arm. Patients (6–17 years old) with a baseline ADHD Rating Scale version IV (ADHD-RS-IV) total score ≥28 were randomized (1:1:1) to dose-optimized LDX (30, 50, or 70 mg/day), OROS-MPH (18, 36, or 54 mg/day) or placebo for 7 weeks. Primary and key secondary efficacy measures were the investigator-rated ADHD-RS-IV and the Clinical Global Impressions-Improvement (CGI-I) rating, respectively. Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Of 336 patients randomized, 196 completed the study. The difference between LDX and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was ?18.6 (95% confidence interval [CI]: ?21.5 to ?15.7) (p<0.001; effect size, 1.80). The difference between OROS-MPH and placebo in least squares mean change in ADHD-RS-IV total score from baseline to endpoint was ?13.0 (95% CI: ?15.9 to ?10.2) (p<0.001; effect size, 1.26). The proportions (95% CI) of patients showing improvement (CGI-I of 1 or 2) at endpoint were 78% (70–86), 14% (8–21), and 61% (51–70) for LDX, placebo, and OROS-MPH. The most common TEAEs for LDX were decreased appetite, headache, and insomnia. Mean changes in vital signs were modest and consistent with the known profile of LDX. LDX was effective and generally well tolerated in children and adolescents with ADHD.     

Efficacy and safety of valsartan 160/HCTZ 25 mg in fixed combination in hypertensive patients not controlled by candesartan 32 mg plus HCTZ 25 mg in free combination

ABSTRACT

Objective: Free combination hypertension medication is associated with a lower compliance and less persistence compared to fixed combination therapy and can, there­fore, be associated with insufficient blood pressure reductions. This non-randomized study investigated whether valsartan 160?mg/ hydrochlorothiazide 25?mg (Val 160/HCTZ 25) in fixed dose combination could provide additional blood pressure control in hypertensive patients not adequately controlled by the free combination of candesartan 32?mg plus HCTZ 25?mg.

Research design and methods: One hundred and ninety-seven patients with a mean sitting diastolic blood pressure (MSDBP) between 100 and 110?mmHg entered a 4-week treatment phase with 32?mg of candesartan in free combination with 25?mg of HCTZ once daily. One hundred and thirty-eight patients with uncontrolled BP at Week 4, entered a second 4-week treatment phase with Val160/ HCTZ 25 once daily.

Main outcome measures: The primary efficacy parameter was the reduction in MSDBP at trough between Week 4 and Week 8 in the intent-to-treat population.

Results: At baseline, MSDBP was 103.0 ± 2.8?mmHg. After Week 4, MSDBP had decreased to 93.8 ± 4.5?mmHg. Subsequent treatment with Val 160/HCTZ 25 for 4 weeks reduced MSDBP to 88.7 ± 8.6?mmHg. This represented an additional decrease in MSDBP of 5.1 ± 7.9?mmHg (?p < 0.0001). Val 160/ HCTZ 25 reduced mean sitting systolic BP by 3.4 ± 13.0?mmHg (?p = 0.0029).

Conclusions: The fixed dose combination of valsartan 160/HCTZ 25?mg provided a statistically and clinically significant additional BP reduction in patients not controlled by the free combination of candesartan 32?mg and HCTZ 25?mg.     

Lens opacities in children using methylphenidate hydrochloride

Purpose: To assess clinical findings of eye examination in children having attention deficit hyperactivity disorder (ADHD) administered with methylphenidate hydrochloride.

Methods: Fifty-seven consecutive patients diagnosed of ADHD and administered with oral methylphenidate hydrochloride treatment for at least one year were involved in this study (Group 1). Sixty healthy subjects (Group 2) having demographic features similar to group 1 were involved as a control group. All patients underwent detailed ophthalmological examination.

Results: One hundred and seventeen consecutive subjects with a mean age of 11.2?±?2.4?years (7–18?years) were enrolled. Fifty-seven consecutive patient (32 males, 25 females) under oral methylphenidate hydrochloride treatment (Group 1) and 60 healthy control subjects (30 males, 30 females) (Group 2)) were recruited for this prospective study. The mean methylphenidate hydrochloride dosage was 0.9?±?0.1?mg/kg/day and the mean duration of methylphenidate hydrochloride usage was for 2.73?±?0.73?years (1–7?years). High intraocular pressure was not observed in any of the patients in our study. We detected lens opacities in five eyes of five patients in group 1 (p?=?0.019). The patient with the highest degree of cataract formation had been using MPH for 84?months and this patient’s cataract score was P4.

Conclusion: Long-term use of methylphenidate may cause lens opacities. In particular, patients who have been using methylphenidate for more than two years should go for regular eye examination.     

Effects of calcitriol on bone mineral density in patients treated with esomeprazole

Context: Proton pump inhibitor (PPI) increases the risk of decrease in bone mineral density (BMD). However, whether calcitrol improves this situation is unknown.

Objective: The current study investigates the effects of calcitriol on BMD in patients with esomeprazole therapy.

Materials and methods: Three hundred and eighty-six participants with gastrointestinal ulcerations were enrolled and randomly assigned into controlled and supplemented groups. Participants in the controlled group were prescribed esomeprazole (20?mg/qd), while the supplemented group was prescribed esomeprazole (20?mg/qd) and calcitriol (2.5?μg/qd). BMD, serum levels of calcium, carboxy-terminal collagen crosslinks (CTX), and alkaline-phosphatase (ALP) were assessed.

Results: (1) No significant between-group difference of age, gender, smoking, previous glucocorticoid use and hemoglobin level was found; (2) after 10.6?±?0.8?d of PPI therapy, BMD T score in the controlled group was slightly increased compared with initial (?1.25?±?0.08 versus ?1.28?±?0.06, p?=?0.084), while there was no change in the supplemented group (?1.25?±?0.05 versus ?1.26?±?0.03, p?=?0.308); (3) during study termination, calcium level in the supplemented group was slightly higher than the controlled group (2.05?±?0.03?mmol/L versus 2.01?±?0.05?mmol/L, p?=?0.073), while no significant differences of CTX (366.57?±?43.71?pg/mL versus 373.15?±?50.23?pg/mL, p?=?0.036) and ALP were found among these two groups (50.47?±?9.32?U/L versus 52.23?±?10.45?U/L, p?=?0.075).

Conclusion: Patients with gastrointestinal ulcerations with esomeprazole therapy, calcitriol supplement showed no efficacy on BMD changes.     

A phase 1, double-blind,placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis

ABSTRACT

Objective: To evaluate safety, pharmacokinetics, pharmacodynamics, and clinical response of single subcutaneous (SC) administrations of a human mono­clonal antibody against the p40 subunit of IL?12/23 (IL?12/23 mAb) in subjects with moderate-to-severe psoriasis.

Methods: Twenty-one subjects were enrolled sequentially into 4 dose cohorts (0.27, 0.675, 1.35, and 2.7?mg/kg) and randomized to IL?12/23 mAb or placebo in a 4:1 ratio. Laboratory/clinical parameters and pharm­acokinetics were evaluated through Week 24; mRNA cytokine expression was measured in psoriatic plaques at Week 1.

Results: Mostly mild adverse events and no serious adverse events were reported. The pharmacokinetics (C_max and AUC) of IL?12/23 mAb increased in an approximately dose-proportional manner. Of the 17 subjects who received IL?12/23 mAb, 13 achieved PASI 75 (compared with no placebo subjects). mRNA expression of IL?8, IL?18, and IFN?γ in psoriatic plaques decreased in subjects with sustained Psoriasis Area and Severity Index (PASI) improvement.

Limitations: Interpretation of results is limited due to the small sample size in each dose cohort.

Conclusion: A single SC administration of IL?12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.     

Ceramide lipid-based nanosuspension for enhanced delivery of docetaxel with synergistic antitumor efficiency

Ceramide (CE), a bioactive lipid with tumor suppression, has been widely used as a drug carrier and enhancer for cancer therapy. CE-based combination therapy was prone to be attractive in cancer therapy. In our previous study, the combination of CE and docetaxel (DTX) was proved to be an effective strategy for cancer therapy. To further improve the antitumor efficiency of DTX, the CE lipid-based nanosuspensions (LNS) was prepared for the delivery of DTX to exhibit synergistic therapeutic effect. The enhanced delivery and synergistic therapeutic effect of DTX-loaded CE-LNS (CE?+?DTX-LNS) were evaluated. CE?+?DTX-LNS exhibited spherical or ellipsoidal shape, uniform particle size distribution (108.1?±?3.8?nm), sustained release characteristics and good stability in vitro. Notably, CE?+?DTX-LNS could effectively co-localize CE and DTX into same tumor cell and subsequently play synergistic cell damage effect compared with CE-LNS?+?DTX-LNS (p?in vivo fluorescence imaging results showed that CE?+?DTX-LNS could effectively prolong the in vivo circulation time and enhance the accumulation in tumor sites. Moreover, the antitumor efficacy of CE?+?DTX-LNS observed in B16 murine melanoma model was 93.94?±?2.77%, significantly higher than that of CE-LNS, DTX-LNS, Duopafei® (p?p?相似文献   

Efficacy and safety of HL301 in the treatment of acute bronchitis and acute exacerbation of chronic bronchitis: a phase 2, randomized,double-blind,placebo-controlled,multicenter study

Purpose: The efficacy and safety of Chinese herbs for symptomatic treatment of bronchitis is not well established. We evaluated the efficacy and safety of a combination product of seven herbs (HL301) for the treatment of acute bronchitis (AB) and acute exacerbation of chronic bronchitis (AECB) using a randomized, double-blind, placebo-controlled, multicenter trial design.

Methods: A total of 160 patients with AB or with AECB were randomized to receive placebo or one of three doses of HL301 (0.6?g/day, 1.2?g/day, or 1.8?g/day) for a total of 7 days. The primary study endpoint was the change in bronchitis severity score (BSS) from the baseline visit (visit 2) to the end of treatment visit (visit 3). Other efficacy variables were percentage BSS systemic sign efficacy after treatment and change in individual BSS parameters after treatment.

Findings: Changes in BSS from visit 2 to visit 3 in the three treatment groups (4.63?±?2.24, 4.08?±?1.63, and 4.15?±?1.74 in the HL301 0.6?g/day, 1.2?g/day, and 1.8?g/day groups, respectively) were higher than that of the placebo group (2.88?±?2.57) in the per protocol set (PPS) (P?P?Implications: Three different doses of HL301 (0.6?g/day, 1.2?g/day, and 1.8?g/day) were effective in decreasing the BSS index compared to placebo. HL301 may be effective for symptomatic treatment of both AB and AECB.

Limitations: Essential components of HL301 have not been delineated in the study and patients with AB and AECB were indiscriminately enrolled in the present study. Respective evaluation of the efficacy of HL301 for AB and AECB will be necessary in the future.