Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression.

Background: To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression. Methods: Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling.Patients were randomized to 8 weeks of quetiapine extended release(XR) 300 mg daily monotherapy or placebo.The primary out come measure was changed from baseline to Week 8 in MADRS total score. Results: Quetiapine XR 300 mg once daily(N=133)showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1(p<0.001)through to Week 8 (p<0.001).Mean change in MADRS total score at Week 8 was 17.4 in the quetiapine XR group and -11.9 in the placebo group(p<0.001). Response (≥ 50% reduction in MADRS total score)and remission (MADRS total score ≤12)rates at Week 8 were significantly higher with quetiapine XR compared with placebo (p<0.001 and p<0.05, respectively).Quetiapine XR improved core symptoms of depression. The most common adverse events associated with quetiapine XR were dry mouth, somnolence,and sedation. Greater weight gain was observed inpatients on quetiapine XR relative to placebo. Limitations: Fewer patients with bipolar II disorder included, only one fixed dose tested and the lack of an active comparator. Conclusions: Quetiapine XR(300 mg)once daily monotherapy was significantly more effective than placebo for treating episodes of depression in bipolar I disorder, throughout the 8-week study,with significance observed as early as Day 7.Adverse events were consistent with the known effects of quetiapine.

Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial.

BACKGROUND: Bipolar disorder, a highly recurrent and chronic condition, often necessitates periods of hospitalization and requires lifelong treatment with medication. It is characterized by alternating episodes of mania and depression. Given the severity of mania, physicians must be able to control symptoms rapidly. OBJECTIVE: The purpose of this pivotal, Phase III trial was to evaluate the efficacy and tolerability of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy in improving manic symptoms in patients with bipolar I disorder. METHODS: This was a 3-week, randomized, parallel-group, double-blind, placebo-controlled study. Patients aged 18 to 65 years with bipolar I disorder (most recent episode manic or mixed; with or without rapid cycling) were randomized to receive placebo or quetiapine XR monotherapy once daily (300 mg on day 1; 600 mg on day 2; flexible dosing, 400-800 mg, from day 3 through day 22 [study end point, week 3]). The primary outcome measure was the change from baseline to study end in the Young Mania Rating Scale (YMRS) total score. Secondary outcome measures included the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, YMRS response (≥50% reduction in YMRS) and remission (YMRS score ≤12 at final visit) rates, and change from baseline to week 3 in Clinical Global Impression-Bipolar-Severity of Illness (CGI-BP-S) and CGI-BP-Change (CGI-BP-C) scores. Safety profile and tolerability evaluations included monitoring of adverse events, clinical laboratory values, vital signs, extrapyramidal symptoms (including akathisia), and electrocardiogram results. RESULTS: Compared with placebo (n = 159), quetiapine XR monotherapy (n = 149; mean daily dose, 604 mg) significantly improved manic symptoms starting at day 4 (first assessment; P < 0.001), with sustained improvement to study end (week 3; P < 0.001). MADRS scores showed greater improvement from baseline to study end with quetiapine XR than with placebo (P = 0.004). Response and remission rates were significantly greater (P < 0.01) with quetiapine XR than with placebo at study end. Quetiapine XR also resulted in significant improvements over placebo in CGI-BP-S and CGI-BP-C scores (P < 0.001 and P < 0.001, respectively). Adverse events were mild to moderate in intensity; the most common ones associated with quetiapine XR were sedation, dry mouth, and somnolence. CONCLUSION: This 3-week trial suggests that quetiapine XR (400-800 mg) once-daily monotherapy is efficacious (from day 4) and generally well tolerated in patients with manic or mixed episodes of bipolar I disorder.

Dalteparin, a low-molecular-weight heparin, promotes angiogenesis mediated by heparin-binding VEGF-A in vivo.

Tumors are angiogenesis dependent and vascular endothelial growth factor-A (VEGF-A), a heparin-binding protein, is a key angiogenic factor. As chemotherapy and co-treatment with anticoagulant low-molecular-weight heparin (LMWH) are common in cancer patients, we investigated whether angiogenesis in vivo mediated by VEGF-A is modulated by metronomic-type treatment with: (i) the LMWH dalteparin; (ii) low-dosage cytostatic epirubicin; or (iii) a combination of these two drugs. Using the quantitative rat mesentery angiogenesis assay, in which angiogenesis was induced by intraperitoneal injection of very low doses of VEGF, dalteparin sodium (Fragmin(®) ) and epirubicin (Farmorubicin(®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days. Dalteparin was administered at 27, 80, or 240 IU/kg/day, i.e., doses that reflect the clinical usage of this drug, while epirubicin was given at the well-tolerated dosage of 0.4 mg/kg/day. While dalteparin significantly stimulated angiogenesis in an inversely dose-dependent manner, epirubicin did not significantly affect angiogenesis. However, concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis. The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo. The fact that co-treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect.

A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II).

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of quetiapine and paroxetine monotherapy for major depression in bipolar disorder. METHOD: 740 patients (478 bipolar I, 262 bipolar II) with major depressive episodes (DSM-IV) were randomly assigned to quetiapine 300 mg/d (n = 245), quetiapine 600 mg/d (n = 247), paroxetine 20 mg/d (n = 122), or placebo (n = 126) for 8 weeks. The primary end point was the change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from May 2005 to May 2007. RESULTS: Mean MADRS score change from baseline at 8 weeks was -16.19 for quetiapine 300 mg, -16.31 for quetiapine 600 mg, -13.76 for paroxetine, and -12.60 for placebo (P < .001 for both quetiapine doses, P = .313 for paroxetine, vs placebo). Quetiapine-treated (both doses), but not paroxetine-treated, patients showed significantly greater improvements (P < or = .05) in most secondary outcomes measures at week 8 versus the placebo group. Paroxetine significantly improved Hamilton Anxiety Rating Scale scores versus placebo (P < .05) but not MADRS or Hamilton Depression Rating Scale (HDRS) scores. Both quetiapine doses were associated with greater improvements than paroxetine for MADRS and HDRS scores. The most common adverse events were dry mouth, somnolence, sedation, and dizziness with quetiapine (both doses) and dry mouth, sedation, headache, insomnia, and nausea with paroxetine. The incidence of treatment-emergent mania/hypomania was lower with quetiapine compared with paroxetine and placebo. CONCLUSIONS: Quetiapine (300 or 600 mg/d), but not paroxetine, was more effective than placebo for treating acute depressive episodes in bipolar I and II disorder. Quetiapine treatment was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119652.

Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression.

BACKGROUND: To evaluate the effectiveness of quetiapine extended release once daily in bipolar depression. METHODS: Double-blind, placebo-controlled study in acutely depressed adults with bipolar I or II disorder, with or without rapid cycling. Patients were randomized to 8 weeks of quetiapine extended release (XR) 300 mg daily monotherapy or placebo. The primary outcome measure was change from baseline to Week 8 in MADRS total score. RESULTS: Quetiapine XR 300 mg once daily (N=133) showed significantly greater improvement in depressive symptoms compared with placebo (N=137) from Week 1 (p<0.001) through to Week 8 (p<0.001). Mean change in MADRS total score at Week 8 was -17.4 in the quetiapine XR group and -11.9 in the placebo group (p<0.001). Response (>or=50 reduction in MADRS total score) and remission (MADRS total score

The complex between tPA and PAI-1: risk factor for myocardial infarction as studied in the SHEEP project.

INTRODUCTION: The tPA/PAI-1 complex seems to be an important biochemical marker for myocardial reinfarction. Therefore we explored the distribution, correlation and interaction of plasma concentrations of tPA/PAI-1 complex in all available patients and matched controls in the Stockholm Heart Epidemiology Program (SHEEP). METHODS AND PATIENTS: The SHEEP study is a case control study of 2246 patients with a first myocardial infarction (MI), of which 1267 surviving patients were subjected to blood sampling about 3 months after MI and compared with a control group, matched for age, sex and living area within the Stockholm County. The study consists of 886 (591 men and 295 women) patients and 1198 (753 men and 445 women) matched controls, who were all analysed for plasma tPA/PAI-1 complex. RESULTS: The plasma concentration of tPA/PAI-1 complex was significantly associated with the risk for MI, for both genders. Synergistic interactions were observed in men for the co exposure to high plasma tPA/PAI-1 complex concentrations in combination with smoking (OR=4.6) or diabetes mellitus (OR=7.9). Synergism was also seen in combination with exposure to serum hypercholesterolemia or increased levels of apolipoprotein B. An antagonistic effect of the co exposure to high tPA/PAI-1 complex and hypertension was found among men with a similar tendency among women, but an antagonistic effect of increased waist/hip ratio was only observed among the women. CONCLUSIONS: Measuring the plasma concentration of tPA/PAI-1 complex might be of practical value in assessing risk of MI for both genders, especially in those who are smokers or in patients with manifest diabetes mellitus.