Ginkgolic Acid Inhibits Herpes Simplex Virus Type 1 Skin Infection and Prevents Zosteriform Spread in Mice.

Herpes simplex virus type 1 (HSV-1) causes a lifelong latent infection with an estimated global prevalence of 66%. Primary and recurrent HSV infections are characterized by a tingling sensation, followed by an eruption of vesicles, which can cause painful erosions. Commonly used antiviral drugs against HSV infection are nucleoside analogues including acyclovir (ACV), famciclovir, and valacyclovir. Although these nucleoside analogues reduce morbidity and mortality in immunocompetent individuals, ACV-resistant HSV strains (ACVR-HSV) have been isolated from immunocompromised patients. Thus, ACVR-HSV infection poses a critical emerging public health concern. Recently, we reported that ginkgolic acid (GA) inhibits HSV-1 by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we showed GA affords a broad spectrum of fusion inhibition of all three classes of fusion proteins, including those of HIV, Ebola, influenza A and Epstein Barr viruses. Here we report GA's antiviral activity against HSV-1 skin infection in BALB/cJ mice. GA-treated mice demonstrated a significantly reduced mortality rate and decreased infection scores compared to controls treated with dimethylsulfoxide (DMSO)-vehicle. Furthermore, GA efficiently inhibited ACVR-HSV-1 strain 17+ in vitro and in vivo. Since GA's mechanism of action includes virucidal activity and fusion inhibition, it is expected to work alone or synergistically with other anti-viral drugs, and we anticipate it to be effective against additional cutaneous and potentially systemic viral infections.

Exploratory meta-analysis on lisdexamfetamine versus placebo in adult ADHD.

BACKGROUND: Recent studies have promised that lisdexamfetamine (LDX) is effective in the treatment of adults with attention-deficit hyperactivity disorder (ADHD). OBJECTIVES: This systematic review was undertaken to summarize LDX efficacy, acceptability, and tolerability in adult ADHD. All randomized controlled trials (RCTs) of lisdexamfetamine compared with placebo were included for synthesis. Clinical trials published between January 1991 and January 2014 were evaluated. METHODS: The database of MEDLINE(®), EMBASE™, CINAHL(®), PsycINFO(®) and Cochrane Controlled Trials Register were searched in January 2014. Studies were also searched in ClinicalTrials.gov and the EU Clinical Trials Register database. Study eligibility criteria, participants, and interventions were considered. All RCTs of LDX vs placebo reporting final results of: 1) severity of ADHD symptoms and executive function deficit, 2) response or remission rates, 3) overall discontinuation rate, or 4) discontinuation rate due to adverse events were included. The language of the papers was not restricted. All abstracts of studies gathered from the database were examined. After excluding irrelevant trials, the full text version of relevant studies were assessed and extracted for outcomes of interest. Examination of risks of bias, based on the Cochrane bias assessment, was carried out. The efficacy outcomes consisted of the mean end point or change scores for ADHD rating scales, the response rate, and the remission rate. The overall discontinuation rate and the discontinuation rate due to adverse events were measured for acceptability and tolerability, respectively. A random effect model was applied for the synthesis of relative risks (RRs), and weighted mean differences or standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: A total of 806 final study or safety participants were included. The dosage of lisdexamfetamine was 30 to 70 mg/day. The pooled mean scores of mean change and mean end point scores between LDX- and placebo-treated groups also had a significant difference (SMD [95% CI] of -0.97 [-1.15, -0.78], I(2)=18%). The pooled response rates for adult ADHD between the two groups had a significant difference (RR [95% CI] of 1.99 [1.50, 2.63], I(2)=0%). Based on the Behavior Rating Inventory of Executive Function - Adult version (BRIEF-A), the pooled end point mean scores for the Global Executive Composite (GEC) for the LDX-treated groups was greater than that of placebo-treated groups (MD [95% CI] of -9.20 [-14.11, -4.29], I(2)=34%). The pooled overall discontinuation rates between the two groups had no significant difference (RR [95% CI] of 0.82 [0.59, 1.14], I(2)=0%). Similarly, the pooled discontinuation rates due to adverse events between the two groups was not significantly different (RR [95% CI] of 1.77 [0.71, 4.40], I(2)=0%). CONCLUSION: The number of included studies was limited (five RCTs), but based on this meta-analysis, LDX is efficacious and well tolerated in the treatment of adult ADHD. Additionally, it also improved the executive function deficits in this population. However, its acceptability is no higher than placebo. These findings should be carefully interpreted and considered as preliminary outcomes. To confirm these results, further studies are warranted. LDX is a viable alternative psychostimulant for adult ADHD.

Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials.

BACKGROUND: Schizophrenia and bipolar depression trials suggest that quetiapine may have an antidepressant effect. OBJECTIVES: This meta-analysis aimed to determine the efficacy, acceptability and tolerability of quetiapine treatment for major depressive disorder (MDD). Only the randomized controlled trials (RCTs) comparison between quetiapine and placebo were included. The authors searched such clinical trials carried out between 1991 and February 2012. DATA SOURCES: MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in February 2012. Study populations comprised adults with MDD or major depression. STUDY ELIGIBLE CRITERIA, PARTICIPANTS AND INTERVENTIONS: Eligible studies were randomized, placebo-controlled trials of quetiapine monotherapy carried out in adults with MDD and presenting endpoint outcomes relevant to: i) depression severity, ii) response rate, iii) overall discontinuation rate, or iv) discontinuation rate due to adverse events. No language restriction was applied. STUDY APPRAISAL AND SYNTHESIS METHODS: All abstracts identified by the electronic searches were examined. The full reports of relevant studies were assessed, and the data of interest were extracted. Based on the Cochrane methods of bias assessment, risks of bias were determined. The studies with two risks or less were included. The efficacy outcomes were the mean change scores of depression rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate was considered as a measure of acceptability. The discontinuation rate due to adverse events was a measure of tolerability. Relative risks (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were computed by using a random effect model. RESULTS: A total of 1,497 participants in three RCTs were included. All trials examined the quetiapine extended-release (XR). The pooled mean change scores of the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D) of the quetiapine-treated group were higher than those of the placebo-treated group with the WMDs (95%CI) of -3.37 (-3.95, -2.79) and -2.46 (-3.47, -1.45), respectively. All studies defined the response and remission as ≥ 50% reduction of the MADRS total score and the MADRS total score of ≤8 at endpoint, respectively. The overall response and remission rates were significantly greater in the quetiapine-treated group with RRs (95%CIs) of 1.44 (1.26, 1.64) and 1.37 (1.12, 1.68), respectively. The pooled discontinuation rate was not significantly different between groups with an RR (95%CI) of 1.16 (0.97, 1.39). The pooled discontinuation rate due to adverse event was greater in the quetiapine group with an RR (95%CI) of 2.90 (1.87, 4.48). With respect to sleep time, the pooled mean change Pittsburgh Sleep Quality Index (PSQI) scores of the quetiapine-treated group was also significantly higher than that of the placebo-treated group [WMD (95%CI) of -1.21 (-1.81, -0.61)]. LIMITATIONS: Variety of quetiapine XR doses and the small number of RCTs were key limitations of this meta-analysis. CONCLUSIONS: Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for adult patients with MDD. The high dropout rate due to adverse events suggests that some MDD patients may not be able to tolerate quetiapine XR. Due to the balance of its efficacy benefit and risk of side effects, as the overall discontinuation rate shown, the acceptability of this agent is not more than placebo. These results should be viewed as the very preliminary one. Further studies in this area are warranted. IMPLICATION OF KEY FINDINGS: Quetiapine may be an alternative antidepressant. However, both risk and benefit of this agent should be taken into account for an individual patient with MDD.

Bupropion for adults with attention-deficit hyperactivity disorder: meta-analysis of randomized, placebo-controlled trials.

AIM: The aim of this study was to systematically review the efficacy, acceptability and tolerability of bupropion in comparison to placebo. Only randomized-controlled trials were included in the meta-analysis. METHODS: MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in October 2010. Study populations comprised adults with any subtype of attention-deficit hyperactivity disorder, attention-deficit disorder, hyperkinetic disorder, minimal brain dysfunction, minimal cerebral dysfunction or minor cerebral dysfunction. Efficacy outcomes were pooled mean changed scores of the ADHD rating scale (ADHD-RS) and the overall response rates. The overall discontinuation rate was considered as the measure of acceptability. RESULTS: A total of 349 participants (n for bupropion treatment = 175) in five published randomized, controlled trials were included. Bupropion sustained- or extended-release was the experimental treatment in all studies. The pooled mean changed score of the ADHD-RS of the bupropion-treated group was greater than that of the placebo-treated group with a weighted mean difference (95%CI) of 5.08 (3.13-7.03). The overall response rate of the bupropion-treated group was significantly greater than that of placebo-treated groups with a relative risk (95%CI) of 1.67 (1.23-2.26). However, the pooled overall discontinuation rate and the pooled discontinuation rate due to adverse events were not significantly different between groups with a relative risk (95%CI) of 1.11 (0.71-1.72) and 0.87 (0.08-9.79), respectively. CONCLUSION: The evidence suggests that bupropion is superior to placebo and effective for the treatment of ADHD in adults. However, its acceptability and tolerability were not significantly higher than those of placebo.

Efficacy and safety of direct transition to risperidone long-acting injectable in patients treated with various antipsychotic therapies.

The maintained antipsychotic efficacy of risperidone long-acting injectable (RLAI) was investigated in patients with schizophrenia or other psychoses who were transitioned directly from their previous antipsychotic medication. Patients symptomatically stable, but considered to require a treatment change, received 25 mg of RLAI (increased to 37.5 or 50 mg, if necessary) every 2 weeks for 6 months. Assessments included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression-Severity (CGI-S), Global Assessment of Functioning (GAF), SF-36 Health-Related Quality of Life Questionnaire and Extrapyramidal Symptoms Rating Scale (ESRS). Of 1876 patients enrolled, 74% completed the 6-month study. The most frequent reasons for treatment change were non-compliance (38%), insufficient efficacy (33%) and side-effects (26%). There was a significant reduction from baseline to endpoint in mean total PANSS score and in the scores on all PANSS subscales and symptom factors (P<0.001). CGI-S improved significantly, as did mean GAF score, all factors on the SF-36 and patient satisfaction with treatment. Scores on ESRS showed significant, sustained improvements throughout the study period. Direct initiation of RLAI was effective and well tolerated. RLAI provides an advancement in the treatment options available for a wide range of patients requiring long-term antipsychotic therapy.

Clinical experience with the long-acting injectable formulation of the atypical antipsychotic, risperidone.

BACKGROUND: To detail specific effects of long-acting risperidone on individuals with schizophrenia and their way of life in a series of four cases. METHOD: Four patients with schizophrenia were selected from four different psychiatric centres. Patients were established on an oral dose of risperidone (1-4 mg/day) for 2 weeks. Based on their oral dose, they then received intramuscular injections of 25 mg or 50 mg of long-acting risperidone every 2 weeks, which could be adjusted according to clinical response. Assessments of efficacy (Positive And Negative Syndrome Scale, Clinical Global Impression-Severity) and safety (Extrapyramidal Symptom Rating Scale) were made at intervals throughout a 1-year period. RESULTS: Patients demonstrated a variety of reasons for receiving a long-acting injectable antipsychotic drug, including insufficient control of symptoms, adverse events and convenience. After 1 year of treatment with long-acting risperidone, all patients showed improvements in their symptoms of schizophrenia over their original stable condition, and benefited from a considerable reduction or total disappearance of pre-existing extrapyramidal symptoms. Patients were more socially interactive, with no signs of sedation, fatigue, confusion, depression or anxiety, and none were considered to have relapsed or to require hospitalisation. Three of the four patients were considered to have had no signs of illness after 1 year, one of whom had returned to college and another to work. They demonstrate that patients can be switched from oral and depot medications without problems. There was little pain or discomfort and no inflammatory response experienced at the injection site. CONCLUSION: The cases demonstrate the suitability of long-acting risperidone in patients benefiting from long-term treatment and suggest its potential in all patients who are at risk of relapse.