LONG-TERM PHYSICAL STABILITY, STERILITY, AND ANTI-VEGF BIOACTIVITY OF REPACKAGED BEVACIZUMAB IN 2-ML GLASS VIALS.

PURPOSE: Repackaged bevacizumab in single-dose, prefilled syringes for intravitreal injection is available, but with shelf life limited from 60 days to 90 days. For the Study of COmparative Treatments for REtinal Vein Occlusion 2 (SCORE2), 2-mL sterile glass vials were used rather than prefilled syringes to provide a longer shelf life for study supplies. METHODS: Repackaged bevacizumab in glass vials was tested at release and, for 1 lot, after 1, 3, 6, and 12 months for physical stability, including concentration, purity and appearance, and for sterility and endotoxins. Vials from 2 lots were tested at release and after 20 months and 21 months, respectively. One lot was tested at 21 months for anti-VEGF bioactivity compared with a fresh supply of commercial bevacizumab. RESULTS: Repackaged bevacizumab in 2-mL glass vials continued to meet all quality release specifications and remain sterile for up to 21 months. In addition, no degradation in anti-VEGF bioactivity was observed at 21 months compared with a fresh bevacizumab control. CONCLUSION: Bevacizumab can be repackaged into small, single-dose glass vials for intravitreal injection and the qualities of the commercial product maintained, including anti-VEGF bioactivity, for up to 21 months in refrigerated storage. Consideration should be given to repackaging bevacizumab for ophthalmic use in small glass vials as opposed to plastic syringes.

Rhodiola rosea versus sertraline for major depressive disorder: A randomized placebo-controlled trial.

BACKGROUND: We performed a proof of concept trial to evaluate relative safety and efficacy of Rhodiola rosea (R. rosea) versus sertraline for mild to moderate major depressive disorder. HYPOTHESIS: We hypothesize that R. rosea would have similar therapeutic effects as sertraline but with less adverse events. STUDY DESIGN: Phase II randomized placebo controlled clinical trial. METHODS: 57 subjects were randomized to 12 weeks of standardized R. rosea extract, sertraline, or placebo. Changes over time in Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and Clinical Global Impression Change (CGI/C) scores among groups were examined using mixed-effects models. RESULTS: Modest, albeit statistically non-significant, reductions were observed for HAM-D, BDI, and CGI/C scores for all treatment conditions with no significant difference between groups (p = 0.79, p = 0.28, and p = 0.17, respectively). The decline in HAM-D scores was greater for sertraline (-8.2, 95% confidence interval [CI], -12.7 to -3.6) versus R. rosea (-5.1, 95% CI: -8.8 to -1.3) and placebo (-4.6, 95% CI: -8.6 to -0.6). While the odds of improving (versus placebo) were greater for sertraline (1.90 [0.44-8.20]; odds ratio [95% CI]) than R. rosea (1.39 [0.38-5.04]), more subjects on sertraline reported adverse events (63.2%) than R. rosea (30.0%) or placebo (16.7%) (p = 0.012). CONCLUSIONS: Although R. rosea produced less antidepressant effect versus sertraline, it also resulted in significantly fewer adverse events and was better tolerated. These findings suggest that R. rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression.

Long-Term Chamomile Therapy of Generalized Anxiety Disorder: A Study Protocol for a Randomized, Double-Blind, Placebo- Controlled Trial.

BACKGROUND: Anxiety symptoms are among the most common reasons for consumers to use Complementary and Alternative Medicine (CAM) therapy. Although many botanicals have been proposed as putative remedies for anxiety symptoms, there has been a paucity of controlled trials of these remedies. A preliminary study of the anxiolytic effect of Chamomile (Matricaria recutita) in humans suggests that chamomile may have anxiolytic and antidepressant activity. We now seek to conduct a 5-year randomized, double-blind, placebo-substitution study to examine the short and long-term safety and efficacy of chamomile extract in Generalized Anxiety Disorder (GAD). METHODS/DESIGN: 180 subjects with moderate to severe GAD will receive initial open-label pharmaceutical-grade chamomile extract 500-1,500 mg daily for 8 weeks. Responders to treatment who remain well for an additional 4 weeks of consolidation therapy, will be randomized to double-blind continuation therapy with either chamomile extract 500-1,500 mg daily or placebo for an additional 26 weeks. The primary outcome will be the time to relapse during study continuation therapy in each treatment condition. Secondary outcomes will include the proportion of subjects in each treatment condition who relapse, as well as the proportion of subjects with treatment-emergent adverse events. Quality of life ratings will also be compared between treatment conditions during short and long-term therapy. DISCUSSION: Many individuals with mental disorders decline conventional therapy and seek CAM therapies for their symptoms. Thus, the identification of effective CAM therapy is of relevance to reducing the burden of mental illness. This study builds upon our prior findings of significant superiority of chamomile versus placebo in reducing GAD symptoms. We now extend these preliminary findings by conducting a randomized long-term safety and efficacy study of chamomile in GAD.

Chamomile (Matricaria recutita) may provide antidepressant activity in anxious, depressed humans: an exploratory study.

CONTEXT: Anxiety and depression are the most commonly reported psychiatric conditions and frequently occur as comorbid disorders. While the advent of conventional drug therapies has simplified treatment, a large segment of the population goes untreated or declines conventional therapy for financial, cultural, or personal reasons. Therefore, the identification of inexpensive and effective alternative therapies for anxiety and depression is of relevance to public health. OBJECTIVE: The current study explores data from a 2009 clinical chamomile trial in humans to determine if chamomile provides clinically meaningful antidepressant activity versus a placebo. DESIGN: In the 2009 randomized, double-blind, placebo-controlled study, the research team examined the antianxiety and antidepressant action of oral chamomile (Matricaria recutita) extract in participants with symptoms of comorbid anxiety and depression. SETTING: In the 2009 study, all of participants' evaluations took place at the Depression Research Unit at the University of Pennsylvania. The study drew participants from patients at the Department of Family Medicine and Community Health's primary care clinic at the University of Pennsylvania, Philadelphia. PARTICIPANTS: Of the 57 participants in the 2009 trial, 19 had anxiety with comorbid depression; 16 had anxiety with a past history of depression; and 22 had anxiety with no current or past depression. INTERVENTION: The intervention and placebo groups in the 2009 trial received identically appearing 220-mg capsules containing either pharmaceutical-grade chamomile extract standardized to a content of 1.2% apigenin or a placebo (ie, lactose monohydrate NF), respectively. OUTCOME MEASURES: In the current study, the research team used generalized estimating equations analysis to identify clinically meaningful changes over time in scores from the Hamilton Depression Rating (HAM-D) questionnaire among treatment groups. RESULTS: In the current study, the research team observed a significantly greater reduction over time in total HAM-D scores for chamomile vs placebo in all participants (P < .05). The team also observed a clinically meaningful but nonsignificant trend for a greater reduction in total HAM-D scores for chamomile vs placebo in participants with current comorbid depression (P = .062). When the team examined the HAM-D core mood item scores, it observed a significantly greater reduction over time for chamomile vs placebo in all participants (P < .05) and a clinically meaningful but nonsignificant trend for a greater reduction over time for chamomile vs placebo in participants without current or past depression (P = .06). CONCLUSION: Chamomile may provide clinically meaningful antidepressant activity that occurs in addition to its previously observed anxiolytic activity.

Randomized, double-blind, placebo-controlled trial of Cimicifuga racemosa (black cohosh) in women with anxiety disorder due to menopause.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled, parallel group trial of the efficacy and tolerability of Cimicifuga racemosa (black cohosh) extract for the treatment of anxiety disorder due to menopause. We hypothesized that black cohosh would be superior to placebo in reducing anxiety symptoms of menopause, with a comparable tolerability profile to placebo. MATERIALS AND METHODS: Subjects were randomized to therapy with either pharmaceutical-grade black cohosh extract (n = 15) or placebo (n = 13) for up to 12 weeks. The primary outcome measure was changed over time in total Hamilton Anxiety Rating Scale (HAM-A) scores. Secondary outcomes included a change in scores on the Beck Anxiety Inventory, Green Climacteric Scale (GCS), and Psychological General Well-Being Index (PGWBI) and the proportion of patients with a change of 50% or higher in baseline HAM-A scores. RESULTS: There was neither a significant group difference in change over time in total HAM-A scores (P = 0.294) nor a group difference in the proportion of subjects with a reduction of 50% or higher in baseline HAM-A scores at study end point (P = 0.79). There was a significantly greater reduction in the total GCS scores during placebo (vs black cohosh; P = 0.035) but no group difference in change over time in the GCS subscale scores or in the PGWBI (P = 0.140). One subject (3.6%) taking black cohosh discontinued treatment because of adverse events. CONCLUSIONS: We found no statistically significant anxiolytic effect of black cohosh (vs placebo). However, small sample size, choice of black cohosh preparation, and dosage used may have been limiting factors producing negative results.

A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita (chamomile) extract therapy for generalized anxiety disorder.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled efficacy and tolerability trial of Matricaria recutita (chamomile) extract therapy in patients with mild to moderate generalized anxiety disorder (GAD). We hypothesized that chamomile would be superior to placebo in reducing GAD symptoms with a comparable tolerability profile. MATERIALS AND METHODS: Sixty-one outpatients with mild to moderate GAD were enrolled, and 57 were randomized to either double-blind chamomile extract (n = 28) or placebo therapy (n = 29) for 8 weeks. The study was powered to detect a statistically significant and clinically meaningful group difference in change over time in total Hamilton Anxiety Rating (HAM-A) scores. Secondary outcomes included change in the Beck Anxiety Inventory, Psychological Well Being, and Clinical Global Impression Severity scores and the proportion of patients with 50% reduction or more in baseline HAM-A score. RESULTS: We observed a significantly greater reduction in mean total HAM-A score during chamomile versus placebo therapy (P = 0.047). Although the study was not powered to identify small to moderate differences in secondary outcomes, we observed a positive change in all secondary outcomes in the same direction as the primary outcome measure. One patient in each treatment group discontinued therapy for adverse events. The proportion of patients experiencing 0, 1, 2, or 3 adverse events or more was not significantly different between groups (P = 0.417). CONCLUSIONS: This is the first controlled clinical trial of chamomile extract for GAD. The results suggest that chamomile may have modest anxiolytic activity in patients with mild to moderate GAD. Future studies are needed to replicate these observations.

A phase I study of SPI-077 (Stealth liposomal cisplatin) concurrent with radiation therapy for locally advanced head and neck cancer.

BACKGROUND: Liposomal cisplatin preparations have two potential advantages over the free drug when combined with radiation therapy (RT): 1) selective tumor localization, improving the therapeutic ratio, and 2) prolonged half-life, allowing more radiosensitization. We performed a Phase I study of Stealth liposomal cisplatin (SPI-077) concurrent with RT for head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with Stage IVa/b HNSCC were treated with SPI-077, given intravenously twice two weeks apart, concurrent with RT (60-72 Gy in 6-7 weeks). The SPI-077 dose was escalated in standard phase I design. RESULTS: Twenty patients received 38 doses of SPI-077, escalated from 20-200 mg/m2 in six dose levels. Two of these patients received one dose because of reversible Grade 3 liver toxicity or rash. Three patients had a Grade 1, and one had a Grade 2 infusion reaction. Four patients had transiently elevated transaminases: Grade I (n = 1), Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3 neutropenia occurred in one patient. There was no ototoxicity, neurotoxicity, or nephrotoxicity. In-field radiation skin and mucosal toxicities did not appear to be intensified. Ten of 17 patients (59%) finishing treatment achieved initial complete response. CONCLUSIONS: Systemic and in-field radiation toxicities of SPI-077 were minimal. Infusion reactions were minimized with a slower and more dilute initial infusion. Further dose escalation was stopped in the absence of dose-limiting toxicity to address the reformulation of the liposomally bound cisplatin. Nonetheless, this study shows that high doses of SPI-077 can be given safely. The potentially beneficial therapeutic ratio suggests that liposomal radiosensitizer preparations warrant further investigation.