The role of fine excipient particles in adhesive mixtures for inhalation

Despite the fact that adding fines improve the drug dispersion performance during inhalation, the scarcity of mechanistic insight into the formulation process, independent of the aerosolization, has kept the dispute on the underlying improvement mechanism open. We therefore simulate ternary formulations (carrier, drug, fines) in a vibrational cell to explore the mixing mechanism and the effect of particle size and loading ratio of fines on formulation performance. Results suggest that the buffer theory is a critical contributory mechanism since it curtails the carrier\u27s collision rate and, therefore, decreases agglomerate breakage. Consequently, relatively larger drug aggregates are formed over the carrier, which eventually experiences greater detachment forces. A simple dispersion test is performed to evaluate drug detachment rate at wall-collision. An excess of cohesive fines, or using larger fines, diminishes the rotational kinetic energy of coarse particles by lumping them together. This reduces drug agglomerate breakage and leads to poor mixing

Interaction between c-jun and Androgen Receptor Determines the Outcome of Taxane Therapy in Castration Resistant Prostate Cancer

Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients

Геофизические закономерности локализации месторождений углеводородов Баренцево-Карского региона

Background: Rising serum levels of prostate-specific antigen (PSA) after radical prostatectomy are indicative of recurrent prostate cancer. This double-blind, placebo-controlled phase II study evaluated the anti-tumour activity of the anti-epithelial cell adhesion molecule (EpCAM) antibody adecatumumab in delaying biochemical disease progression. Patients and Methods: Prostate cancer patients with increasing serum PSA levels following radical prostatectomy were randomized to low- (2 mg/kg) or high-dose adecatumumab (6 mg/kg) or placebo. The primary efficacy endpoint was the mean change from baseline in total serum PSA at week 24. Secondary endpoints included PSA response rate, prolongation of serum PSA doubling time and time to biochemical disease progression. Results: The primary and secondary endpoints of the study were not met in the predefined analyses. In a retrospective analysis of patients with baseline PSA <= 1 ng/ml and a high EpCAM expression, both the mean increase in PSA from baseline to week 24 and the PSA doubling time at week 15 were significantly improved in the high-dose adecatumumab group compared with the placebo group. Most frequent treatment-related clinical adverse events were gastrointestinal (diarrhoea and nausea) or general events (chills), showing a dose dependency but no grade 3/4 intensity in any patient. Conclusion: In men with rising PSA levels after radical prostatectomy and no evidence of clinical relapse, adecatumumab delayed disease progression in a subgroup of patients with baseline PSA levels <= 1 ng/ml and high EpCAM-expressing tumours. Copyright (C) 2010 S. Karger AG, Base

HIF1 alpha isoforms in benign and malignant prostate tissue and their correlation to neuroendocrine differentiation

Background: Neuroendocrine (NE) differentiation in prostate cancer has been correlated with a poor prognosis and hormone refractory disease. In a previous report, we demonstrated the presence of immunoreactive cytoplasmic hypoxia inducible factor 1 alpha (HIF1 alpha), in both benign and malignant NE prostate cells. HIF1 alpha and HIF1 beta are two subunits of HIF1, a transcription factor important for angiogenesis. The aim of this study was to elucidate whether the cytoplasmic stabilization of HIF1 alpha in androgen independent NE differentiated prostate cancer is due to the presence of certain HIF1 alpha isoforms.Methods: We studied the HIF1 alpha isoforms present in 8 cases of benign prostate hyperplasia (BPH) and 43 cases of prostate cancer with and without NE differentiation using RT-PCR, sequencing analysis, immunohistochemistry and in situ hybridization.Results: We identified multiple isoforms in both benign and malignant prostate tissues. One of these isoforms, HIF1 alpha 1.2, which was previously reported to be testis specific, was found in 86% of NE-differentiated prostate tumors, 92% of HIF1 alpha immunoreactive prostate tumors and 100% of cases of benign prostate hyperplasia. Immunohistochemistry and in situ hybridization results showed that this isoform corresponds to the cytoplasmic HIF1 alpha present in androgen-independent NE cells of benign and malignant prostate tissue and co-localizes with immunoreactive cytoplasmic HIF1 beta.Conclusion: Our results indicate that the cytoplasmic stabilization of HIF1 alpha in NE-differentiated cells in benign and malignant prostate tissue is due to presence of an HIF1 alpha isoform, HIF1 alpha 1.2. Co-localization of this isoform with HIF1 beta indicates that the HIF1 alpha 1.2 isoform might sequester HIF1 beta in the cytoplasm

Pathophysiology of bone metastases in prostate cancer

Objective: Men with advanced prostate cancer are at high risk for bone metastases that result in significant skeletal morbidity. This review discusses the pathophysiology of bone metastases in prostate cancer. Methods: Relevant information was identified through searches of published studies, abstracts from scientific meetings, and review articles. Results: Bone metastases are common in patients with advanced cancer. Numerous growth factors present in the bone matrix are released during bone remodeling, potentially providing a fertile environment for the growth of tumor cells. Factors such as parathyroid hormone-related protein and interleukin-6 stimulate osteoclast-mediated bone resorption, thus enhancing the release of bone-derived growth factors. Prostate cancer cells secrete factors, including protease-activated receptor 1, that are involved in the multistep process of tumor cell detachment and migration to bone and factors that stimulate osteoblast-mediated bone formation, such as transforming growth factor-beta and bone morphogenetic proteins. In addition, prostate cancer cells produce endothelin-1, a peptide under intense investigation that stimulates the proliferation of osteoblasts and is thought to play a role in the development of osteoblastic bone lesions. These tumor-derived factors cause dysregulation of normal bone remodeling. Interactions between prostate tumor cells and the bone typically result in the formation of osteoblastic lesions characterized by increased osteolysis and uncoupled new bone formation. Preclinical evidence suggests that zoledronic acid has antitumor activity in animal models of prostate cancer. Conclusions: Bone metastasis is a complex process involving multiple molecular interactions between tumor cells and the bone microenvironment resulting in disruption of bone remodeling. In patients with prostate cancer, bone lesions are primarily osteoblastic, but are also associated with increased osteolytic activity, resulting in marked increases in bone turnover and clinically significant morbidity. (C) 2004 Elsevier B.V. All rights reserved

Intermittent androgen deprivation therapy in patients with prostate cancer : Connecting the dots

Intermittent androgen deprivation therapy (IADT) is now being increasingly opted by the treating physicians and patients with prostate cancer. The most common reason driving this is the availability of an off-treatment period to the patients that provides some relief from treatment-related side-effects, and reduced treatment costs. IADT may also delay the progression to castration-resistant prostate cancer. However, the use of IADT in the setting of prostate cancer has not been strongly substantiated by data from clinical trials. Multiple factors seem to contribute towards this inadequacy of supportive data for the use of IADT in patients with prostate cancer, e.g., population characteristics (both demographic and clinical), study design, treatment regimen, on- and off-treatment criteria, duration of active treatment, endpoints, and analysis. The present review article focuses on seven clinical trials that evaluated the efficacy of IADT vs. continuous androgen deprivation therapy for the treatment of prostate cancer. The results from these clinical trials have been discussed in light of the factors that may impact the treatment outcomes, especially the disease (tumor) burden. Based on evidence, potential candidate population for IADT has been suggested along with recommendations for the use of IADT in patients with prostate cancer