Land S.C.,University of Dundee |
Seminars in Cell and Developmental Biology | Year: 2014
The existence of a nutrient sensitive "autocatakinetic" regulator of embryonic tissue growth has been hypothesised since the early 20th century, beginning with pioneering work on the determinants of foetal size by the Australian physiologist, Thorburn Brailsford-Robertson. We now know that the mammalian target of rapamycin complexes (mTORC1 and 2) perform this essential function in all eukaryotic tissues by balancing nutrient and energy supply during the first stages of embryonic cleavage, the formation of embryonic stem cell layers and niches, the highly specified programmes of tissue growth during organogenesis and, at birth, paving the way for the first few breaths of life. This review provides a synopsis of the role of the mTOR complexes in each of these events, culminating in an analysis of lung branching morphogenesis as a way of demonstrating the central role mTOR in defining organ structural complexity. We conclude that the mTOR complexes satisfy the key requirements of a nutrient sensitive growth controller and can therefore be considered as Brailsford-Robertson's autocatakinetic centre that drives tissue growth programmes during foetal development. © 2014 The Authors.
Nalamachu S.,International Clinical Research Institute |
Hassman D.,Comprehensive Clinical Research |
Wallace M.S.,University of California at San Diego |
Dumble S.,Quantics Consulting Ltd |
And 2 more authors.
Current Medical Research and Opinion | Year: 2011
Background and objectives: Breakthrough cancer pain (BTcP) is a transient exacerbation of cancer pain in patients with otherwise stable, persistent background pain. This study evaluated the long-term effectiveness and tolerability of sublingual fentanyl orally disintegrating tablet (sublingual fentanyl ODT), for the treatment of BTcP in opioid-tolerant patients with cancer. Research design and methods: This was a non-randomized, open-label, multi-center, Phase III study conducted in opioid-tolerant patients (aged 17 years) with BTcP. The study comprised a 2-week titration phase, followed by a maintenance phase of up to 12 months. Patients self-administered sublingual fentanyl ODT for episodes of BTcP. Effectiveness was assessed using patients'â€™ global evaluation of medication (PGEM), the brief pain inventory (BPI) and the depression, anxiety and positive outlook scale (DAPOS). Adverse events were recorded throughout. Clinical trial registration: NCT00263575 (http://www.clinicaltrials.gov/). Results: Of 139 recruited patients, 69% identified an effective dose of sublingual fentanyl ODT (a dosage that successfully treated all episodes of BTcP over two consecutive days) and entered the maintenance phase, during which they were treated for a median of 149.0 days (mean dose 507.5μ g). The study recorded a significant increase in reported satisfaction with pain medication at the 6-month and end-of-study visits, compared to screening (pâ0.01). Evaluation of quality of life using BPI and DAPOS identified no deterioration in scores and significant improvements in certain parameters (p0.05). Sublingual fentanyl ODT was well tolerated, with no study drug-related deaths, and 49 patients (35.3%) experiencing 1 study drug-related adverse event. The most common of these included nausea (8.6%), constipation (5.8%) and somnolence (5.8%). There was no evidence of sublingual mucosal irritation due to the study medication. The pattern of adverse events was similar to that previously observed with transmucosal fentanyl. Conclusions: Sublingual fentanyl ODT was effective and well tolerated for the long-term treatment of BTcP in opioid-tolerant cancer patients. There was an increase in satisfaction with pain medication during the study, and sublingual fentanyl ODT showed an acceptable safety profile over 12 months of treatment. © 2011 Informa UK Ltd.
Jones T.H.,Barnsley Hospital |
Jones T.H.,University of Sheffield |
Arver S.,Karolinska University Hospital |
Behre H.M.,Martin Luther University of Halle Wittenberg |
And 8 more authors.
Diabetes Care | Year: 2011
OBJECTIVE - This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS - The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0-6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6-12). RESULTS - TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, -0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate. CONCLUSIONS - Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS. © 2011 by the American Diabetes Association.
Mason J.W.,University of Utah |
Mason J.W.,Spaulding Clinical Research |
Selness D.S.,Spaulding Clinical Research |
Moon T.E.,Spaulding Clinical Research |
And 4 more authors.
Clinical Cancer Research | Year: 2012
Purpose: The need for greater clarity about the effects of 5-HT 3 receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT 3 receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). Experimental Design: In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. Results: A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). Conclusion: GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.
Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: A randomized, double-blind, phase III study
Boccia R.V.,Center for Cancer and Blood Disorders |
Gordan L.N.,Gainesville Hematology Oncology Associates |
Clark G.,ProStrakan |
Howell J.D.,ProStrakan |
Grunberg S.M.,University of Vermont
Supportive Care in Cancer | Year: 2011
Purpose: A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Patients and methods: Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Results: Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. Conclusions: The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron. © 2010 The Author(s).
LennernAs B.,Gothenburg University |
Frank-Lissbrant I.,Gothenburg University |
LennernAs H.,Uppsala University |
KAlkner K.M.,Karolinska Hospital |
And 2 more authors.
Palliative Medicine | Year: 2010
In this study we evaluated the efficacy and tolerability of sublingual fentanyl (SLF) for breakthrough pain (BTP) in adult opioid-tolerant cancer patients. Patients received one dose of placebo, SLF 100, 200 and 400 μg in random order at four pain episodes. The primary efficacy endpoint was pain intensity difference (PID) from baseline. Twenty-seven patients received study medication. Overall PID increased significantly with SLF 400 μg versus placebo (8.57 mm, p <0.0001). Improvements were statistically different from placebo at 15 min (p = 0.005). SLF 100 and 200 μg showed a numerical trend towards improved pain relief. A dose that gave a clinically important reduction in pain (PID > 20 mm) was identified by 95% of patients. Reduced use of rescue medication (p < 0.001, SLF 400 μg) and improved global assessment of treatment (p = 0.0146, SLF 400 μg) confirmed these differences as clinically important. Nausea and dizziness were the most common treatment-related adverse effects. SLF appears to be a fast, effective and well-tolerated treatment for BTP. © 2010 The Author(s).
Vogel C.L.,University of Miami |
Johnston M.A.,GTx |
Capers C.,GTx |
Clinical Breast Cancer | Year: 2014
Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) > 40 years ago represented a revolutionary advance in the treatment of breast cancer. As a therapeutic class, SERMs have either estrogenic or antiestrogenic activity, depending on the target tissue and the hormonal environment. In breast tissue, SERMs are antiestrogenic, making them a major treatment option for women with hormone-sensitive breast cancer. Toremifene citrate was developed > 20 years ago with the goal of achieving efficacy similar to that of tamoxifen and with an improved safety profile. Although studies to date have not confirmed a clear safety advantage or disadvantage for toremifene, clinical data support the efficacy and safety of toremifene for the treatment of breast cancer in postmenopausal patients. Toremifene also has a pharmacokinetic profile and metabolic pathway different from that of tamoxifen, which may provide a therapeutic advantage in certain patients. In addition, because of the selective estrogenic effects of SERMs in bone and on lipid levels along with a different side effect profile compared with the aromatase inhibitors (AIs), toremifene is a viable option to the AIs for some patients. Despite a number of clinical trials and over 500,000 patient years of use, many oncologists have limited familiarity with toremifene data. This article will examine the rationale for the use of toremifene in the treatment of women with breast cancer and review data from 20 years of clinical experience with this agent. © 2014 Elsevier Inc. All rights reserved.
ProStrakan | Date: 2011-03-18
ProStrakan | Date: 2011-03-18