Isolation and characterisation of a phenolic impurity in a commercial sample of duloxetine

A phenolic impurity of duloxetine hydrochloride was isolated and characterised (MS, NMR, X-ray-analysis).     

The efficacy of duloxetine in the treatment of premature ejaculation

Aim: Though premature ejaculation (PE) has been overshadowed by current attention given to erectile dysfunction, it is the most widespread form of male sexual dysfunction. Delayed or inhibited ejaculation, a known side effect of selective serotonin reuptake inhibitors (SSRIs), has made SSRIs potentially useful in the treatment of this disorder. In the present study, we examined the efficacy of duloxetine, an SSRI, in the treatment of PE. Method: The study included 20 married patients diagnosed with PE. The patients were randomly assigned to two groups, duloxetine (group I) and placebo (group II), each consisting of 10 patients. The effects on the ejaculatory function were estimated by the intravaginal ejaculation latency time. All patients were evaluated by using clinical global impression-improvement Scale (CGI-I). Results: The increase in the intravaginal ejaculation latency time in the duloxetine group was statistically significant than that of placebo group. Of group I patients, four (40%) were considered as “very much improved” and four (40%) “much improved” by CGI-I and only one of group II patients (10%) showed “much improved”. Conclusion: Duloxetine appears to be superior to placebo in the pharmacological treatment of PE when administered on a chronic basis.     

高压氧联合度洛西汀治疗卒中后抑郁状态疗效观察

目的：观察高压氧联合度洛西汀综合治疗卒中后抑郁状态（PSD）的疗效。方法：将86例明确PSD患者随机分为治疗组46例和对照组40例,治疗组接受高压氧联合度洛西汀治疗,对照组接受度洛西汀冶疗,分别于治疗前,治疗后3、6个月末进行HAMD抑郁量表、神经功能缺损程度（NIHSS）和日常生活活动能力（ADL）评分。结果：两组病例在治疗前、后,HAMD评分和NIHSS评分降低,ADL评分增加（P〈0.05）;组间比较,3个月时两组各项评分差异无统计学意义（P〉0.05）,6个月时治疗组各项评分优于对照组（P〈0.05）。结论：高压氧联合度洛西汀治疗能有效提高度洛西汀对PSD的疗效。     

HPLC法检测盐酸度洛西汀中有关物质及对映异构体

目的建立了HPLC法检查盐酸度洛西汀的有关物质及对映异构体。方法测定有关物质时采用SHIM-PACK VP-ODS柱,以0.05mol·L^-1磷酸二氢钾溶液（用磷酸调至pH2.5）-（甲醇∶四氢呋喃,35∶10）（50∶50）为流动相,检测波长230 nm。对映体检查时采用CHIRAL CELOD-RH色谱柱,以0.01 mol·L^-1磷酸二氢钾溶液（用磷酸调至pH2.3）-乙腈（65∶35）为流动相,检测波长230 nm。结果与结论在选定的色谱条件下,盐酸度洛西汀与盐酸左旋度洛西汀及有关物质分离完全,可用于本品的质量控制。     

Switching to duloxetine in selective serotonin reuptake inhibitor non- and partial-responders: effects on painful physical symptoms of depression

Painful physical symptoms (PPS) are common in patients with depression. Our objective was to evaluate the presence of PPS in a sample of SSRI non- or partial-responders with MDD and examine the effect of a switch to duloxetine on those PPS. Outpatients who met criteria for MDD despite having taken an SSRI antidepressant for at least 6 weeks, and who had a Hamilton depression rating scale total score of at least 15 and a clinical global impression of severity score of at least 3, were randomized to switch to duloxetine by either a direct switch or a start-taper switch method. PPS were assessed at baseline and at the study endpoint using various measures including six visual analog scales (VAS) for pain (overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake), the pain subscale of the symptom questionnaire-somatic subscale, and the bodily pain subscale of the short form-36 item health survey. Clinically significant levels of pain (mean baseline VAS scores >30 mm) were seen across all VAS pain measures prior to switching. Switch to duloxetine was associated with significant improvements on all pain measures regardless of switch method, and there was evidence for an earlier reduction in pain in the start-taper switch group. In summary, MDD patients who were non- or partial-responders to SSRI treatment were found to have clinically significant pain which improved significantly following switch to duloxetine regardless of the switch method utilized.     

LC-MS法测定人血浆中度洛西汀的浓度

目的:建立以液-质联用(LC-MS)法测定人血浆中度洛西汀浓度的方法。方法:血浆样品0.2mL,用乙腈沉淀蛋白2次,以20mmol·L-1乙酸铵溶液(pH3.5)-甲醇-乙腈(38∶20∶42)为流动相,用ThermoC18柱分离,采用LC-MS法测定10名健康志愿者单剂量口服盐酸度洛西汀肠溶胶囊22.4、44.8、67.2mg后的血药浓度。结果:度洛西汀血药浓度在0.78～100ng.mL-1范围内线性关系良好(r=0.9995);平均方法回收率为100.8%,日内RSD≤7.8%,日间RSD≤9.3%。结论:本方法准确、灵敏,适用于度洛西汀的药动学研究。     

Cost-Effectiveness Inferences from Bootstrap Quadrant Confidence Levels: Three Degrees of Dominance

ABSTRACT

When with at least 95% confidence a new treatment is shown to be not only less costly (LC), but also more effective (ME), than a current treatment, that new treatment can be said to “strictly dominate” the current treatment statistically. But what can be said when head-to-head treatment comparisons turn out to be less clear-cut than this? Here, we propose two additional sets of specific LC and/or ME confidence thresholds to define the concepts of “some dominance” and “much dominance.” Confidence levels associated with entire quadrants of the incremental cost–effectiveness (ICE) plane are easily computed using the same bootstrapping techniques used to estimate an “acceptability curve.” Our two proposed additional “degrees” of dominance, although less stringent than strict dominance, are nevertheless more stringent than commonly accepted approaches using ICE ratio or net benefit calculations.

To illustrate analysis concepts, we use data from a randomized, double-blind, placebo- and active comparator-controlled clinical registration trial for treatment of major depressive disorder (MDD). As is typical, our case study is rather small and short term, providing outcome information for a total of only 264 patients during their initial 8 weeks of acute-phase MDD treatment. Thus, we focus attention on sensitivity analyses, showing that the bootstrap distribution of cost-effectiveness uncertainty is robust across two alternative ways of measuring overall effectiveness and three alternative ways of imputing missing values.

Evaluation of the balance between cost and benefit is particularly difficult when a new pharmacological treatment is first introduced, yet information of this sort is highly desired by decision makers. We show that, even with only a relatively modest amount of clinical trial information, sensitivity analyses can still confirm that cost-effectiveness comparisons are being made in a consistent fashion. In contrast, extensive follow-up comparisons using data from actual clinical practice will almost always ultimately be needed to better inform health policy makers.     

Cost effectiveness of duloxetine compared with venlafaxine‐XR in the treatment of major depressive disorder

ABSTRACT

Purpose: To determine the cost effectiveness of duloxetine, a new serotonin norepinephrine reuptake inhibitor, when compared with venlafaxine‐XR in treating major depressive disorder.

Methods: A cost effectiveness analysis, using a decision tree modelled outpatient treatment over 6 months. Analytic perspectives were those of society (all direct and indirect costs) and the Ministry of Health of Ontario (MoH) as payer for all direct costs. Rates of success and dropouts were obtained from a meta-analysis of randomized placebo-controlled trials. Costs were taken from standard lists, adjusted to 2005 Canadian dollars; discounting was not applied. One-way sensitivity analyses were performed on monthly acquisition costs and success rates; Monte–Carlo analysis examined all parameters over 10?000 iterations.

Results: From both perspectives, outcomes all numerically favoured venlafaxine‐XR (Expected success = 53% and 57%; symptom-free days [SFDs] = 52.72 and 57.03 for duloxetine and venlafaxine‐XR, respectively). Total expected costs/patient treated were, Can$7081 and Can$6551 (MoH), Can$20?987 and Can$19?997 (societal perspective), for duloxetine and venlafaxine‐XR, respectively. Expected costs/SFD were Can$134 and Can$115 (MoH) and Can$398 and Can$351 (societal viewpoint) for duloxetine and venlafaxine‐XR, respectively. Although results were sensitive to changes in success rate within the 95% CI, Monte–Carlo analyses using the ICER (incremental cost effectiveness ratio) as outcome found venlafaxine‐XR was dominant in approximately 78% of scenarios in both perspectives.

Conclusions: Differences in pharmacoeconomic outcomes found were modest, but in all cases, favoured venlafaxine‐XR over duloxetine. Therefore, a possible advantage may exist at the population level in the treatment of major depressive disorder in Canada. Ultimately, a head to head study of the two drugs would be needed to confirm these findings.     

Duloxetine 60 mg once-daily in the treatment of painful physical symptoms in patients with major depressive disorder

BACKGROUND: While emotional symptoms such as depressed mood and loss of interest have traditionally been considered to constitute the core symptoms of major depressive disorder (MDD), the prevalence and importance of painful physical symptoms such as back pain, abdominal pain, and musculoskeletal pain is becoming increasingly appreciated. Antidepressants possessing dual serotonin/norepinephrine (5-HT/NE) reuptake inhibition may demonstrate greater efficacy in the alleviation of pain. The efficacy of duloxetine, a balanced and potent dual reuptake inhibitor of 5-HT and NE, was evaluated within a cohort of depressed patients with associated painful physical symptoms. METHODS: In this multicenter, double-blind, placebo-controlled study, patients meeting DSM-IV criteria for MDD were randomized to receive placebo (N=141) or duloxetine 60 mg QD (N=141). Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD17) total score 15, a Clinical Global Impression of Severity (CGI-S) score 4, and a Brief Pain Inventory (BPI) Average Pain score 2 at baseline. The primary efficacy measure was the BPI Average Pain score, while secondary measures included other BPI items, the HAMD17 total score, CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQSS). Safety was evaluated by recording treatment-emergent adverse events (spontaneously reported), vital signs, and laboratory analytes. RESULTS: Mean changes in BPI Average Pain for duloxetine- and placebo-treated patients differed significantly at most visits, but only approached significance at endpoint p=0.066. For the main effect of treatment (pooling all visits), significant advantages for duloxetine-treated patients were found in 10 of 11 assessed BPI pain severity and pain interference items, in addition to VAS overall pain and back pain. Mean changes in pain measures for duloxetine-treated patients corresponded to improvements of 25-50%, compared with 19-39% for placebo. Mean changes at endpoint in depression rating scales (HAMD17, CGI-S, PGI-I) did not differ significantly between duloxetine and placebo treatment groups due to unusually high placebo response. The magnitude of placebo treatment effects (as measured by HAMD17 total score and Maier subscale) was significantly smaller in patients with 1 previous depressive episode, compared to those patients with no previous episodes. In patients with 1 previous depressive episode the advantage of duloxetine over placebo was similar to previous studies. Rates of discontinuation due to adverse events were 14.2% vs. 2.1% for duloxetine and placebo, respectively p<0.001. Treatment-emergent adverse events reported at a significantly higher rate by duloxetine-treated patients included nausea, dry mouth, fatigue, and decreased appetite. CONCLUSIONS: In this study, duloxetine (60 mg QD) was shown to be an effective treatment for the painful physical symptoms which are frequently associated with depression. Improvements in pain severity occurred independently of changes in depressive symptom severity.