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Land S.C.,University of Dundee | Scott C.L.,ProStrakan
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.

Vogel C.L.,University of Miami | Johnston M.A.,GTx | Capers C.,GTx | Braccia D.,ProStrakan
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.

Dobs A.S.,Johns Hopkins University | Mcgettigan J.,Quality of Life Medical and Research Center | Norwood P.,Valley Endocrine and Valley Research | Howell J.,ProStrakan | And 2 more authors.
Journal of Andrology | Year: 2012

Testosterone replacement therapy (TRT) can improve the symptoms, signs, and well being of hypogonadal men by restoring serum testosterone concentrations to physiologic levels. This multicenter, open-label noncomparative trial of men with hypogonadism evaluated the pharmacokinetic profile and safety of a novel testosterone 2% gel (FortestaTM Gel), administered once daily to the front and inner thighs at starting doses of 40 mg/d. The metered-dose delivery system allowed dose adjustments in 10-mg increments between 10 and 70 mg/d. Of the 149 patients enrolled, 138 patients (92.6%) completed the study and 129 patients (86.6%) were included in the efficacy analysis. On day 90, mean testosterone concentration (Cavg [0-24 hours] ± SD) was 438.6 ± 162.5 ng/dL. Overall, 100 (77.5%) patients achieved serum total testosterone concentrations within the normal physiologic range (≥300 and ≤1140 ng/dL). On day 90, mean testosterone Cmax (±SD) was 827.6 ± 356.5 ng/dL. On day 90, a total of 122 patients (94.6%) had Cmax levels of 1500 ng/dL or less and 2 patients (1.6%) had values between 1800 and 2500 ng/dL. Similar results for Cavg (0-24 hours) and Cmax were observed on day 35. All enrolled patients were included in the safety analysis. Testosterone 2% gel was generally well tolerated, with the most common adverse events (AE) being mild and moderate skin reactions. There were no serious AEs related to testosterone 2% gel. Once-daily testosterone 2% gel restored levels of testosterone in more than 75% of patients, with low risk of supraphysiologic testosterone levels. Patients may find this a suitable option for TRT because of its application site and low volume. © American Society of Andrology.

Nalamachu S.R.,International Clinical Research Institute | Rauck R.L.,Carolinas Pain Institute | Wallace M.S.,University of California at San Diego | Hassman D.,Comprehensive Clinical Research | Howell J.,ProStrakan
Pain Practice | Year: 2012

Objective: This analysis was conducted to determine the likelihood of identifying an effective dose of fentanyl sublingual tablet during the initial titration phase of 2 clinical trials, to characterize the actual effective dose in patients achieving successful titration, and to examine the relationship between baseline characteristics and likelihood of achieving an effective dose. Methods: Data were derived from 2 clinical trials (Study 1, n=131; Study 2, n=139) of fentanyl sublingual tablet in patients with cancer-associated breakthrough pain (BTP). Both trials comprised a 2-week titration phase and 12-month maintenance phase. The initial dose was 100μg, titrated to an effective dose (producing effective relief of all BTP episodes on 2 consecutive days) of 100 to 800μg. Results: A total of 270 patients entered the titration phase. Mean (SD) baseline BTP opioid dose was 25.7 (88.9)mg morphine equivalent, and mean baseline around-the-clock opioid dose was 196.5 (151.6) mg morphine equivalent. Using conservative criteria for determining effective dose, 174 patients (64.4%) were successfully titrated to an effective dose (mean [SD], 498.2 [234.8] μg). The most frequent (27.6%) effective dose was 800μg, and more than 85% of patients required an effective dose ≥300μg. There were no significant relationships between any baseline characteristics and titration success. Conclusion: Despite stringent criteria, 64.4% of patients achieved an effective dose of fentanyl sublingual tablet within the dose range of 100 to 800μg. Baseline characteristics were not identified to be associated with the likelihood of successful titration or with the actual effective dose of fentanyl sublingual tablet. © 2012 The Authors. Pain Practice © 2012 World Institute of Pain.

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.

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