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Sample records for antiangiogenic drug assessed

  1. Antiangiogenic drugs and advanced proliferative diabetic retinopathy

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    Jefferson Augusto Santana Ribeiro

    2011-04-01

    Full Text Available Advanced diabetic retinopathy with tractional retinal detachment or persistent vitreous hemorrhage often requires surgical treatment with pars plana vitrectomy. Despite advances in vitrectomy, surgery for complications of diabetic retinopathy can be a challenge and may be impaired by intense fibrovascular proliferation. Antiangiogenic drugs have been used for the treatment of diabetic retinopathy because of their inhibitory action on vascular endothelial growth factor. In this review, we discuss aspects related to the adjuvant use of these drugs in vitrectomy for complications of diabetic retinopathy. Bevacizumab shows beneficial effects regarding the surgical technique facilitation, but its long-term benefit still needs to be studied.

  2. Statistical Controversies in Clinical Research: Limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events. A meta-analysis.

    Science.gov (United States)

    Trone, J C; Ollier, E; Chapelle, C; Bertoletti, L; Cucherat, M; Mismetti, P; Magné, N; Laporte, S

    2018-02-05

    Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. We searched Medline, Cochrane, ClinicalTrials.gov databases, and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (OR) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of odds ratio (ROR), by dividing the OR values obtained in open-label trials by those obtained in DB trials. The literature-based meta-analysis included 166 trials (72,024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 (95% CI 2.12-2.73; P events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials. © The Author 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  3. Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

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    Terence C. Tang

    2010-03-01

    Full Text Available Hepatocellular carcinoma (HCC is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG, which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX, UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.

  4. Cholestane derivatives as antitumor and antiangiogenic drugs

    Czech Academy of Sciences Publication Activity Database

    Hoffmannová, L.; Steigerová, J.; Oklešťková, J.; Kohout, Ladislav; Chodounská, Hana; Hniličková, Jaroslava; Kasal, Alexander; Černý, Ivan; Kolář, Z.; Strnad, M.

    2010-01-01

    Roč. 35, SA (2010), s. 205-205 ISSN 0377-8282. [EFMC-ISMC 2010. International Symposium on Medicinal Chemistry /21./. 05.09.2010-09.09.2010, Brussels] R&D Projects: GA MŠk(CZ) LC06077; GA AV ČR KAN200200651 Institutional research plan: CEZ:AV0Z40550506 Keywords : cholestane derivatives * anticancer drugs Subject RIV: CC - Organic Chemistry

  5. Early Assessment of Colorectal Cancer Patients with Liver Metastases Treated with Antiangiogenic Drugs: The Role of Intravoxel Incoherent Motion in Diffusion-Weighted Imaging.

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    Vincenza Granata

    Full Text Available To assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM of Diffusion-weighted imaging (DWI in the assessment of liver metastases treated with targeted chemotherapy agents.12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC analysis were performed.24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively.IVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

  6. Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance.

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    Naito, Hisamichi; Wakabayashi, Taku; Kidoya, Hiroyasu; Muramatsu, Fumitaka; Takara, Kazuhiro; Eino, Daisuke; Yamane, Keitaro; Iba, Tomohiro; Takakura, Nobuyuki

    2016-06-01

    Angiogenesis plays a crucial role in tumor growth, with an undisputed contribution of resident endothelial cells (EC) to new blood vessels in the tumor. Here, we report the definition of a small population of vascular-resident stem/progenitor-like EC that contributes predominantly to new blood vessel formation in the tumor. Although the surface markers of this population are similar to other ECs, those from the lung vasculature possess colony-forming ability in vitro and contribute to angiogenesis in vivo These specific ECs actively proliferate in lung tumors, and the percentage of this population significantly increases in the tumor vasculature relative to normal lung tissue. Using genetic recombination and bone marrow transplant models, we show that these cells are phenotypically true ECs and do not originate from hematopoietic cells. After treatment of tumors with antiangiogenic drugs, these specific ECs selectively survived and remained in the tumor. Together, our results established that ECs in the peripheral vasculature are heterogeneous and that stem/progenitor-like ECs play an indispensable role in tumor angiogenesis as EC-supplying cells. The lack of susceptibility of these ECs to antiangiogenic drugs may account for resistance of the tumor to this drug type. Thus, inhibiting these ECs might provide a promising strategy to overcome antiangiogenic drug resistance. Cancer Res; 76(11); 3200-10. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

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    R.-D. Hofheinz

    2016-01-01

    Full Text Available Background. In metastatic colorectal cancer (mCRC, continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS and progression-free survival (PFS. Secondary endpoints were the impact of continuing antiangiogenic drugs (i in subgroups, (ii in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors, and (iii on remission rates and prevention of progression. Results. Eight studies (3,668 patients were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75 and OS (HR 0.83; 95%-CI, 0.76–0.89. PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58. Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

  8. Multi-parametric assessment of the anti-angiogenic effects of liposomal glucocorticoids

    NARCIS (Netherlands)

    Kluza, Ewelina; Heisen, Marieke; Schmid, Sophie; van der Schaft, Daisy W. J.; Schiffelers, Raymond M.; Storm, Gert; ter Haar Romeny, Bart M.; Strijkers, Gustav J.; Nicolay, Klaas

    2011-01-01

    Inflammation plays a prominent role in tumor growth. Anti-inflammatory drugs have therefore been proposed as anti-cancer therapeutics. In this study, we determined the anti-angiogenic activity of a single dose of liposomal prednisolone phosphate (PLP-L), by monitoring tumor vascular function and

  9. An ex vivo model for anti-angiogenic drug testing on intact microvascular networks.

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    Mohammad S Azimi

    Full Text Available New models of angiogenesis that mimic the complexity of real microvascular networks are needed. Recently, our laboratory demonstrated that cultured rat mesentery tissues contain viable microvascular networks and could be used to probe pericyte-endothelial cell interactions. The objective of this study was to demonstrate the efficacy of the rat mesentery culture model for anti-angiogenic drug testing by time-lapse quantification of network growth. Mesenteric windows were harvested from adult rats, secured in place with an insert, and cultured for 3 days according to 3 experimental groups: 1 10% serum (angiogenesis control, 2 10% serum + sunitinib (SU11248, and 3 10% serum + bevacizumab. Labeling with FITC conjugated BSI-lectin on Day 0 and 3 identified endothelial cells along blood and lymphatic microvascular networks. Comparison between day 0 (before and 3 (after in networks stimulated by 10% serum demonstrated a dramatic increase in vascular density and capillary sprouting. Growing networks contained proliferating endothelial cells and NG2+ vascular pericytes. Media supplementation with sunitinib (SU11248 or bevacizumab both inhibited the network angiogenic responses. The comparison of the same networks before and after treatment enabled the identification of tissue specific responses. Our results establish, for the first time, the ability to evaluate an anti-angiogenic drug based on time-lapse imaging on an intact microvascular network in an ex vivo scenario.

  10. Age-Related Macular Degeneration: Clinical Findings following Treatment with Antiangiogenic Drugs

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    Ricardo Casaroli-Marano

    2014-01-01

    Full Text Available Purpose. To survey the management of patients with neovascular age-related macular degeneration (nvAMD in Spain. Methods. An observational retrospective multicenter study was conducted. The variables analyzed were sociodemographic characteristics, foveal and macular thickness, visual acuity (VA, type of treatment, number of injections, and the initial administration of a loading dose of an antiangiogenic drug. Results. 208 patients were followed up during 23.4 months in average. During the first and second years, patients received a mean of 4.5±1.8 and 1.6±2.1 injections of antiangiogenic drugs, and 5.4±2.8 and 3.6±2.2 follow-up visits were performed, respectively. The highest improvement in VA was observed at 3 months of follow-up, followed by a decrease in the response that stabilized above baseline values until the end of the study. Patients who received an initial loading dose presented greater VA gains than those without. Conclusions. Our results suggest the need for a more standardized approach in the management and diagnosis of nvAMD receiving VEGF inhibitors. To achieve the visual outcomes reported in pivotal trials, an early diagnosis, proactive approach (more treating than follow-up visits, and a close monitoring might be the key to successfully manage nvAMD.

  11. Dynamic contrast-enhanced micro-CT on mice with mammary carcinoma for the assessment of antiangiogenic therapy response

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    Eisa, Fabian [University of Erlangen-Nuremberg, Institute of Medical Physics, Erlangen (Germany); University of Erlangen-Nuremberg, Graduate School in Advanced Optical Technologies (SAOT), Erlangen (Germany); Brauweiler, Robert; Hupfer, Martin; Nowak, Tristan; Kalender, Willi A. [University of Erlangen-Nuremberg, Institute of Medical Physics, Erlangen (Germany); Lotz, Laura; Hoffmann, Inge; Dittrich, Ralf; Beckmann, Matthias W. [University of Erlangen-Nuremberg, OB/GYN, University Hospital Erlangen, Erlangen (Germany); Wachter, David [University Hospital Erlangen, Institute of Pathology, Erlangen (Germany); Jost, Gregor; Pietsch, Hubertus [Bayer Pharma AG, Berlin (Germany)

    2012-04-15

    To evaluate the potential of in vivo dynamic contrast-enhanced micro-computed tomography (DCE micro-CT) for the assessment of antiangiogenic drug therapy response of mice with mammary carcinoma. 20 female mice with implanted MCF7 tumours were split into control group and therapy group treated with a known effective antiangiogenic drug. All mice underwent DCE micro-CT for the 3D analysis of functional parameters (relative blood volume [rBV], vascular permeability [K], area under the time-enhancement curve [AUC]) and morphology. All parameters were determined for total, peripheral and central tumour volumes of interest (VOIs). Immunohistochemistry was performed to characterise tumour vascularisation. 3D dose distributions were determined. The mean AUCs were significantly lower in therapy with P values of 0.012, 0.007 and 0.023 for total, peripheral and central tumour VOIs. K and rBV showed significant differences for the peripheral (P{sub per}{sup K} = 0.032, P{sub per}{sup rBV} = 0.029), but not for the total and central tumour VOIs (P{sub total}{sup K} = 0.108, P{sub central}{sup K} = 0.246, P{sub total}{sup rBV} = 0.093, P{sub central}{sup rBV} = 0.136). Mean tumour volume was significantly smaller in therapy (P{sub in} {sub vivo} = 0.001, P{sub ex} {sub vivo} = 0.005). Histology revealed greater vascularisation in the controls and central tumour necrosis. Doses ranged from 150 to 300 mGy. This study indicates the great potential of DCE micro-CT for early in vivo assessment of antiangiogenic drug therapy response. (orig.)

  12. Controlled delivery of antiangiogenic drug to human eye tissue using a MEMS device

    KAUST Repository

    Pirmoradi, Fatemeh Nazly

    2013-01-01

    We demonstrate an implantable MEMS drug delivery device to conduct controlled and on-demand, ex vivo drug transport to human eye tissue. Remotely operated drug delivery to human post-mortem eyes was performed via a MEMS device. The developed curved packaging cover conforms to the eyeball thereby preventing the eye tissue from contacting the actuating membrane. By pulsed operation of the device, using an externally applied magnetic field, the drug released from the device accumulates in a cavity adjacent to the tissue. As such, docetaxel (DTX), an antiangiogenic drug, diffuses through the eye tissue, from sclera and choroid to retina. DTX uptake by sclera and choroid were measured to be 1.93±0.66 and 7.24±0.37 μg/g tissue, respectively, after two hours in pulsed operation mode (10s on/off cycles) at 23°C. During this period, a total amount of 192 ng DTX diffused into the exposed tissue. This MEMS device shows great potential for the treatment of ocular posterior segment diseases such as diabetic retinopathy by introducing a novel way of drug administration to the eye. © 2013 IEEE.

  13. Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach

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    Chiara Bianca Maria Platania

    2015-10-01

    Full Text Available Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in-silico analysis of interaction of vascular endothelial growth factor A (VEGFA, the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein-protein docking and molecular dynamics (MD coupled to molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice.

  14. Assessment of the anti-angiogenic, anti-inflammatory and antinociceptive properties of ethyl vanillin.

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    Jung, Hyun-Joo; Song, Yun Seon; Kim, Kyunghoon; Lim, Chang-Jin; Park, Eun-Hee

    2010-02-01

    The present work aimed to assess novel pharmacological properties of ethyl vanillin (EVA) which is used as a flavoring agent for cakes, dessert, confectionary, etc. EVA exhibited an inhibitory activity in the chorioallantoic membrane angiogenesis. Anti-inflammatory activity of EVA was convinced using the two in vivo models, such as vascular permeability and air pouch models in mice. Antinociceptive activity of EVA was assessed using acetic acid-induced writhing model in mice. EVA suppressed production of nitric oxide and induction of inducible nitric oxide synthase in the lipopolysaccharide (LPS)-activated RAW264.7 macrophage cells. However, EVA could not suppress induction of cyclooxygenase-2 in the LPS-activated macrophages. EVA diminished reactive oxygen species level in the LPS-activated macrophages. EVA also suppressed enhanced matrix metalloproteinase-9 gelatinolytic activity in the LPSactivated RAW264.7 macrophage cells. EVA at the used concentrations couldn't diminish viability of the macrophage cells. Taken together, the anti-angiogenic, anti-inflammatory and anti-nociceptive properties of EVA are based on its suppressive effect on the production of nitric oxide possibly via decreasing the reactive oxygen species level.

  15. Contribution of tumor endothelial cells to drug resistance: anti-angiogenic tyrosine kinase inhibitors act as p-glycoprotein antagonists.

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    Bani, MariaRosa; Decio, Alessandra; Giavazzi, Raffaella; Ghilardi, Carmen

    2017-05-01

    Tumor endothelial cells (TEC) differ from the normal counterpart, in both gene expression and functionality. TEC may acquire drug resistance, a characteristic that is maintained in vitro. There is evidence that TEC are more resistant to chemotherapeutic drugs, substrates of ATP-binding cassette (ABC) transporters. TEC express p-glycoprotein (encoded by ABCB1), while no difference in other ABC transporters was revealed compared to normal endothelia. A class of tyrosine kinase inhibitors (TKI), used as angiostatic compounds, interferes with the ATPase activity of p-glycoprotein, thus impairing its functionality. The exposure of ovarian adenocarcinoma TEC to the TKIs sunitinib or sorafenib was found to abrogate resistance (proliferation and motility) to doxorubicin and paclitaxel in vitro, increasing intracellular drug accumulation. A similar effect has been reported by the p-glycoprotein inhibitor verapamil. No beneficial effect was observed in combination with cytotoxic drugs that are not p-glycoprotein substrates. The current paper reviews the mechanisms of TEC chemoresistance and shows the role of p-glycoprotein in mediating such resistance. Inhibition of p-glycoprotein by anti-angiogenic TKI might contribute to the beneficial effect of these small molecules, when combined with chemotherapy, in counteracting acquired drug resistance.

  16. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter [Department of Radiation Physics, Goeteborg University, Goeteborg 41345 (Sweden); Department of Oncology, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden); Department of Radiation Physics, Goeteborg University, Goeteborg, Sweden and Department of Nuclear Medicine, Sahlgrenska University Hospital, Goeteborg 41345 (Sweden)

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  17. A novel delivery vector for targeted delivery of the antiangiogenic drug paclitaxel to angiogenic blood vessels: TLTYTWS-conjugated PEG–PLA nanoparticles

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    Tan, Fei, E-mail: tanfeivip@126.com; Mo, Xiao-hui, E-mail: 675382206@qq.com [Shanghai Skin Disease Hospital (China); Zhao, Jian, E-mail: 22459402@qq.com [Karolinska University Hospital Solna, Department of Oncology-Pathology, Karolinska Institutet, CCK (Sweden); Liang, Hui, E-mail: nanotan@126.com [People' s Hospital of Longhua New District Shenzhen, Department of urology (China); Chen, Zhong-jian, E-mail: pfjk927627702@126.com; Wang, Xiu-li, E-mail: tanfeit@126.com [Shanghai Skin Disease Hospital (China)

    2017-02-15

    Antiangiogenesis has been widely accepted as an attractive strategy to combat tumor growth, invasion, and metastasis. An actively targeting nanoparticle-based drug delivery system (nano-DDS) would provide an alternative method to achieve antiangiogenic antitumor therapy. In the present study, our group fabricated novel nano-DDS, TLTYTWS (TS) peptide-modified poly(ethylene glycol)–poly(lactic acid) (PEG–PLA) nanoparticles (TS-NPs) encapsulating a drug with antiangiogenic potential, paclitaxel (Ptx) (TS-Ptx-NPs). The nanoparticles were uniformly spherical and had a unimodal particle size distribution and slightly negative zeta potential. TS-NPs accumulated significantly in human umbilical vein endothelial cells (HUVECs) via energy-dependent and caveolae- and lipid raft-mediated endocytosis and improved the antiproliferative, antimigratory, and antitube-forming abilities of paclitaxel in vitro. Following intravenous administration, TS-Ptx-NPs presented favorable pharmacokinetic profiles. Melanoma distribution assays confirmed that TS-NPs achieved higher accumulation and penetration at melanoma sites. These results collectively indicated that TLTYTWS-decorated nanoparticles can be considered to be a promising nano-DDS for chemotherapies targeting tumor angiogenesis and have great potential to improve the efficacy of antiangiogenic therapy in melanoma tumor-bearing nude mice.

  18. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    Science.gov (United States)

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  19. Synthesis and anti-angiogenic effect of conjugates between serum albumin and non-steroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Kjaer, B; Struve, C; Friis, T

    2010-01-01

    of investigating the anti-angiogenic efficiency of NSAID-HSA conjugates in vitro, three NSAIDs, aspirin, ibuprofen, and naproxen were conjugated to HSA using different concentrations of their N-hydroxysuccinimide esters. Conjugation ratios from 10 to 50 were achieved and the conjugates retained a growth inhibitory...

  20. Assessing antiangiogenic therapy response by DCE-MRI: development of a physiology driven multi-compartment model using population pharmacometrics.

    Directory of Open Access Journals (Sweden)

    Andreas Steingoetter

    Full Text Available Dynamic contrast enhanced (DCE- MRI is commonly applied for the monitoring of antiangiogenic therapy in oncology. Established pharmacokinetic (PK analysis methods of DCE-MRI data do not sufficiently reflect the complex anatomical and physiological constituents of the analyzed tissue. Hence, accepted endpoints such as Ktrans reflect an unknown multitude of local and global physiological effects often rendering an understanding of specific local drug effects impossible. In this work a novel multi-compartment PK model is presented, which for the first time allows the separation of local and systemic physiological effects. DCE-MRI data sets from multiple, simultaneously acquired tissues, i.e. spinal muscle, liver and tumor tissue, of hepatocellular carcinoma (HCC bearing rats were applied for model development. The full Markov chain Monte Carlo (MCMC Bayesian analysis method was applied for model parameter estimation and model selection was based on histological and anatomical considerations and numerical criteria. A population PK model (MTL3 model consisting of 3 measured and 6 latent (unobserved compartments was selected based on Bayesian chain plots, conditional weighted residuals, objective function values, standard errors of model parameters and the deviance information criterion. Covariate model building, which was based on the histology of tumor tissue, demonstrated that the MTL3 model was able to identify and separate tumor specific, i.e. local, and systemic, i.e. global, effects in the DCE-MRI data. The findings confirm the feasibility to develop physiology driven multi-compartment PK models from DCE-MRI data. The presented MTL3 model allowed the separation of a local, tumor specific therapy effect and thus has the potential for identification and specification of effectors of vascular and tissue physiology in antiangiogenic therapy monitoring.

  1. Early response assessment in patients with multiple myeloma during anti-angiogenic therapy using arterial spin labelling: first clinical results

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    Fenchel, Michael [Eberhard-Karls University, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany); Eberhard-Karls University, Department of Diagnostic and Interventional Neuroradiology, Tuebingen (Germany); Konaktchieva, Marina [Eberhard-Karls University, Department of Internal Medicine, Gastroenterology, Tuebingen (Germany); Weisel, Katja; Kraus, Sabina [Eberhard-Karls University, Department of Internal Medicine, Hematology, Tuebingen (Germany); Brodoefel, Harald; Claussen, Claus D.; Horger, Marius [Eberhard-Karls University, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany)

    2010-12-15

    To determine if arterial-spin-labelling (ASL) MRI can reliably detect early response to anti-angiogenic therapy in patients with multiple myeloma by comparison with clinical/haematological response. Nineteen consecutive patients (10 men; mean age 63.5 {+-} 9.1 years) were included in the present study. Inclusion criteria were diagnosis of stage III multiple myeloma and clinical indication for therapeutical administration of bortezomib or lenalidomide. We performed MRI on 3.0T MR in the baseline setting, 3 weeks after onset of therapy and after 8 weeks. Clinical responses were determined on the basis of international uniform response criteria in correlation with haematological parameters and medium-term patient outcome. MRI studies were performed after approval by the local institutional review board. Fifteen patients responded to anti-myeloma therapy; 4/19 patients were non-responders to therapy. Mean tumour perfusion assessed by ASL-MRI in a reference lesion was 220.7 {+-} 132.5 ml min{sup -1} 100 g{sup -1} at baseline, and decreased to 125.7 {+-} 86.3 (134.5 {+-} 150.9) ml min{sup -1} 100 g{sup -1} 3 (8) weeks after onset of therapy (P < 0.02). The mean decrease in paraproteinaemia at week 3 (8) was 52.3 {+-} 47.7% (58.2 {+-} 58.7%), whereas {beta}2-microglobulinaemia decreased by 20.3 {+-} 53.1% (23.3 {+-} 57.0%). Correlation of ASL perfusion with outcome was significant (P = 0.0037). ASL tumour perfusion measurements are a valuable surrogate parameter for early assessment of response to novel anti-angiogenic therapy. (orig.)

  2. Reappraising antiangiogenic therapy for breast cancer.

    Science.gov (United States)

    Kerbel, Robert S

    2011-10-01

    Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Broad spectrum antiangiogenic treatment for ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Ofra Benny

    2010-09-01

    Full Text Available Pathological neovascularization is a hallmark of late stage neovascular (wet age-related macular degeneration (AMD and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV, while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Lodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH, Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2. Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1. The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG assessing retinal and by histology.Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic

  4. Orthotopic animal model of pseudomyxoma peritonei: An in vivo model to test anti-angiogenic drug effects.

    Science.gov (United States)

    Dohan, Anthony; Lousquy, Ruben; Eveno, Clarisse; Goere, Diane; Broqueres-You, Dong; Kaci, Rachid; Lehmann-Che, Jacqueline; Launay, Jean-Marie; Soyer, Philippe; Bonnin, Philippe; Pocard, Marc

    2014-07-01

    Pseudomyxoma peritonei (PMP) is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was i.p. grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice a week either during tumor growth or after cytoreductive surgery. In vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler ultrasonography of the superior mesenteric artery revealed a twofold increase in blood flow velocity compared with tumor-free mice (P preclinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Perfusion CT allows prediction of therapy response in non-small cell lung cancer treated with conventional and anti-angiogenic chemotherapy.

    Science.gov (United States)

    Tacelli, Nunzia; Santangelo, Teresa; Scherpereel, Arnaud; Duhamel, Alain; Deken, Valérie; Klotz, Ernst; Cortot, Alexis; Lafitte, Jean-Jacques; Wallyn, Frédéric; Remy, Jacques; Remy-Jardin, Martine

    2013-08-01

    To determine whether CT can depict early perfusion changes in lung cancer treated by anti-angiogenic drugs, allowing prediction of response. Patients with non-small cell lung cancer, treated by conventional chemotherapy with (Group 1; n = 17) or without (Group 2; n = 23) anti-vascular endothelial growth factor (anti-VEGF) drug (bevacizumab) underwent CT perfusion before (TIME 0) and after 1 (TIME 1), 3 (TIME 2) and 6 (TIME 3) cycles of chemotherapy. The CT parameters evaluated included: (1) total tumour vascular volume (TVV) and total tumour extravascular flow (TEF); (2) RECIST (Response Evaluation Criteria in Solid Tumours) measurements. Tumour response was also assessed on the basis of the clinicians' overall evaluation. In Group 1, significant reduction in perfusion was identified between baseline and: (1) TIME 1 (TVV, P = 0.0395; TEF, P = 0.015); (2) TIME 2 (TVV, P = 0.0043; TEF, P Perfusion CT demonstrates early changes in lung cancer vascularity under anti-angiogenic chemotherapy that may help predict therapeutic response. • Perfusion CT has the potential of providing in vivo information about tumour vasculature. • CT depicts early and specific perfusion changes in NSCLC under anti-angiogenic drugs. • Specific therapeutic effects of anti-angiogenic drugs can be detected before tumour shrinkage. • Early perfusion changes can help predict therapeutic response to anti-angiogenic treatment. • Perfusion CT could be a non-invasive tool to monitor anti-angiogenic treatment.

  6. Synthesis and anti-angiogenic effect of conjugates between serum albumin and non-steroidal anti-inflammatory drugs

    DEFF Research Database (Denmark)

    Kjær, Birgitte; Struve, Casper; Friis, Tina

    2010-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit tumor growth and angiogenesis. Covalent linkage of naproxen to human serum albumin (HSA) has been shown to target it efficiently to the liver and this may potentially be exploited for liver-selective inhibition of angiogenesis. With the aim...

  7. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

    Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

    2010-01-01

    and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF...... tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria......ABSTRACT: Angiogenesis is an important component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive strategy for treatment of cancer. We describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development...

  8. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mauricio P. Pinto

    2016-09-01

    Full Text Available Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1 upregulation of compensatory/alternative pathways for angiogenesis; (2 vasculogenic mimicry; and (3 vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.

  9. Evaluation of Antiangiogenic Effects of a New Synthetic Candidate Drug KR-31831 on Xenografted Ovarian Carcinoma Using Dynamic Contrast Enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Je Hoon; Kim, Jae Hun; Im, Geun Ho; Heo, Hye Jung; Yoon, Se Ra; Lee, Jaewon; Lee, Jung Hee; Jeon, Pyoung [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2011-10-15

    The purpose of this research was to investigate the anti-angiogenic inhibitory effect of KR-31831, a newly developed anti-angiogenic agent, on an in vivo human ovarian carcinoma model using dynamic contrast-enhanced (DCE) MRI. Xenografted ovarian tumors were established by subcutaneous injection of SKOV3 cells into mice. The mice were treated daily with KR-31831 at 50 mg/kg for 21 days. Tumor tissues were excised corresponding to the DCE-MRI sections for evaluation of MVD with CD31 immunohistochemistry. All in vivo MRIs were performed on a 7.0 Tesla micro-MRI System. DCE-MRI was acquired prior to initiating treatment with KR-31831 and again on days 3 and 21 after treatment. The permeability parameters (K{sup trans}, v{sub e}, and v{sub p}) were estimated using a pharmacokinetic model. Qualitatively, the K{sup trans} parametric mapping showed different changes before and after treatment with KR-31831 in the treatment group. For quantification of this change, the median of K{sup trans} values were compared before and after treatments in the control and KR-31831-treated groups. A non-parametric statistical test (Wilcoxon signed-rank test) showed decreasing K{sup trans} values on day 21 compared to days 0 and 3 in the KR-31831-treated group (p < 0.05), whereas there was no significant difference in the control group (p = 0.84). Our results suggest that DCE-MRI can be a useful tool by which to evaluate the anti-angiogenic effect of KR-31831 on a xenografted human ovarian carcinoma model.

  10. Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles.

    Science.gov (United States)

    Malamas, Anthony S; Jin, Erlei; Gujrati, Maneesh; Lu, Zheng-Rong

    2016-07-05

    Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model. The RGD-targeted ECO/siHIF-1α nanoparticles resulted in over 50% reduction in tumor size after intravenous injection at a dose of 2.0 mg of siRNA/kg every 3 days for 3 weeks compared to a saline control. DCE-MRI revealed significant decline in vascularity and over a 70% reduction in the tumor blood flow, permeability-surface area product, and plasma volume fraction vascular parameters in the tumor treated with the targeted ECO/siHIF-1α nanoparticles. The treatment with targeted ECO/siRNA nanoparticles resulted in significant silencing of HIF-1α expression at the protein level, which also significantly suppressed the expression of VEGF, Glut-1, HKII, PDK-1, LDHA, and CAIX, which are all important players in tumor angiogenesis, glycolytic metabolism, and pH regulation. By possessing the ability to elicit a multifaceted effect on tumor biology, silencing HIF-1α with RGD-targeted ECO/siHIF-1α nanoparticles has great promise as a single therapy or in combination with traditional chemotherapy or radiation strategies to improve cancer treatment.

  11. Assessment of response to anti-angiogenic targeted therapy in pulmonary metastatic renal cell carcinoma: R2* value as a predictive biomarker

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Guangyu; Liu, Guiqin; Suo, Shiteng; Liu, Xiaosheng; Xu, Jianrong [Shanghai Jiao Tong University, Department of Radiology, Renji Hospital, School of Medicine, Shanghai (China); Kong, Wen; Zhang, Jin [Shanghai Jiao Tong University, Department of Urinary Surgery, Renji Hospital, School of Medicine, Shanghai (China); Qu, Jianxun [GE Healthcare, Shanghai (China)

    2017-09-15

    To evaluate the utility of MR R2*-mapping and the optimal time-point for assessing the response of pulmonary metastatic renal cell carcinoma (mRCC) to anti-angiogenic targeted therapy (aATT). The exploration-sample group and the validation-sample group consisted of 22 and 16 patients. The parameters of MR R2*-mapping, including the R2* value at each time-point (R2*{sub base}, R2*{sub 1cyc} and R2*{sub 2cyc}) and change between different time-points (R2*{sub (1cyc-base)/base}, R2*{sub (2cyc-base)/base} and R2*{sub (2cyc-1cyc)/1cyc}), were evaluated with a receiver-operating-characteristic analysis, and a cut-off value derived from the clinical outcome was applied to the Kaplan-Meier method to assess the value of R2* mapping and Response-Evaluation-Criteria in Solid Tumours (RECIST) during treatment evaluation. The inter-, intra-observer agreements and inter-scan consistency were excellent (p > 0.80). For the exploration-sample group, the areas under the curve for the parameters of MR R2* mapping were 0.55, 0.60, 0.83, 0.64, 0.88 and 0.83 for R2*{sub base}, R2*{sub 1cyc}, R2*{sub 2cyc}, R2*{sub (1cyc-base)/base}, R2*{sub (2cyc-base)/base} and R2*{sub (2cyc-1cyc)/1cyc.} For the validation-sample, R2*{sub (2cyc-base)/base} better predicted progression-free survival (p = 0.03) than RECIST and other R2* mapping parameters with a lower p value. Assessing aATT outcome based on changes in the R2* value between baseline and second treatment is more accurate than assessment at other time-points and assessment based on the RECIST. (orig.)

  12. Assessing the ability of the antiangiogenic and anticytokine agent thalidomide to modulate radiation-induced lung injury

    International Nuclear Information System (INIS)

    Anscher, Mitchell S.; Garst, Jennifer; Marks, Lawrence B.; Larrier, Nicole; Dunphy, Frank; Herndon, James E.; Clough, Robert B.S.; Marino, Christine R.N.; Vujaskovic, Zeljko; Zhou, Sumin; Dewhirst, Mark W.; Shafman, Timothy D.; Crawford, Jeffrey

    2006-01-01

    Purpose: Thalidomide has broad anticytokine properties, which might protect normal tissues in patients undergoing chemoradiotherapy. The purpose of this study was to determine the maximal tolerated dose of thalidomide when used in combination with vinorelbine plus thoracic radiotherapy. Methods and Materials: Eligible patients had inoperable Stage III non-small-cell lung cancer, a Karnofsky Performance Status ≥70, and life expectancy ≥6 months. Patients underwent pretreatment evaluation of lung function. Radiotherapy consisted of 66 Gy in 6.5 weeks. Vinorelbine was administered i.v. (5 mg/m 2 ) 3 times per week just before radiotherapy. Thalidomide was begun at 50 mg, p.o., on day 1 of chemoradiotherapy and continued once daily for 6 months. Side effects were scored using National Cancer Institute Common Toxicity Criteria. Results: Ten patients were enrolled. Of the first 6 patients, 2 developed major thrombotic events that were believed to be possibly related to thalidomide. The study was suspended and modified to require prophylactic anticoagulation. Of the last 4 patients, 2 developed dose-limiting toxicity attributable to thalidomide; both patients required a dose reduction of thalidomide to <50 mg/day. Because the drug is not available in an oral product providing <50 mg/day, the study was closed. Conclusions: The combination of thalidomide concurrently with thoracic radiotherapy and vinorelbine resulted in excessive toxicity

  13. Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality.

    Science.gov (United States)

    Lord, Simon; Funes, Juan M; Harris, Adrian L; Quintela-Fandino, Miguel

    2016-01-01

    Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.

  14. Anti-angiogenic activity and phytochemical screening of fruit fractions from Vitex agnus castus.

    Science.gov (United States)

    Certo, Giovanna; Costa, Rosaria; D'Angelo, Valeria; Russo, Marina; Albergamo, Ambrogina; Dugo, Giacomo; Germanò, Maria Paola

    2017-12-01

    Although the antitumour activity of Vitex agnus castus fruits has been already addressed, no work has yet assessed their anti-angiogenic potential. To this purpose, several extractive fractions of such fruits were tested on zebrafish embrios by EAP assay, so that only the bioactive fractions could be subsequently tested on the chick chorioallantoic membrane by CAM assay. Bioactive fractions were also phytochemically screened to identify those bioactive compounds responsible for anti-angiogenic activity. A marked inhibition of vessel formation was detected only in zebrafish embryos treated with chloroform or ethyl acetate fractions. Considering CAM assay, chloroform fraction induced a strong reduction of microvasculature and haemoglobin content; while lower anti-angiogenic effects of the ethyl acetate fraction were determined. Phytochemical analyses confirmed the presence of several bioactive anti-angiogenic compounds. Overall, obtained preliminary results highlighted a potential anti-angiogenic activity of V. agnus castus fruits.

  15. Novel concepts of antiangiogenic therapies in metastatic renal cell cancer.

    Science.gov (United States)

    Pichler, Renate; Heidegger, Isabel

    2017-01-01

    The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65-70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed.

  16. Tumor Oxygen Dynamics as a Prognostic Indicator of Effective Antiangiogenic Therapy

    National Research Council Canada - National Science Library

    Zhao, Dawen

    2003-01-01

    ...: so called angiogenesis. One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation, both during normal growth and following anti-angiogenic therapy...

  17. Tumor Oxygen Dynamics as a Prognostic Indicator of Effective Antiangiogenic Therapy

    National Research Council Canada - National Science Library

    Zhao, Dawen

    2002-01-01

    ...: so called angiogenesis. One major goal of this project is to fully understand and precisely assess the dynamic changes in blood perfusion and oxygenation, both during normal growth and following anti-angiogenic therapy...

  18. Antiangiogenic effects of marine sponge derived compounds on cancer.

    Science.gov (United States)

    Senthilkumar, Kalimuthu; Venkatesan, Jayachandran; Manivasagan, Panchanathan; Kim, Se-Kwon

    2013-11-01

    The term "angiogenic switch" refers to a time-restricted event during tumor progression where the balance between pro- and anti-angiogenic factors, resulting in the transition from dormant avascularized hyperplasia to outgrowing vascularized tumor and eventually to malignant tumor progression. Targeting angiogenesis and its mechanistic pathways are critical target for cancer therapy. Recently, marine derived compounds, plays major role in cancer research. Several sponge derived compounds such as alkaloids, terpenes, macrocylic lactone and polyketide are leading drugs in the treatment of different types of diseases including cancer. Those marine sponge compounds inhibit cancer cell proliferation and tumor angiogenesis. Hence, this review sheds light on angiogenic regulators and marine sponge derived antiangiogenic compounds for cancer. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. New perspectives in glioblastoma antiangiogenic therapy

    Directory of Open Access Journals (Sweden)

    Alisa Madalina Popescu

    2015-12-01

    Full Text Available Glioblastoma (GB is highly vascularised tumour, known to exhibit enhanced infiltrative potential. One of the characteristics of glioblastoma is microvascular proliferation surrounding necrotic areas, as a response to a hypoxic environment, which in turn increases the expression of angiogenic factors and their signalling pathways (RAS/RAF/ERK/MAPK pathway, PI3K/Akt signalling pathway and WTN signalling cascade. Currently, a small number of anti-angiogenic drugs, extending glioblastoma patients survival, are available for clinical use. Most medications are ineffective in clinical therapy of glioblastoma due to acquired malignant cells or intrinsic resistance, angiogenic receptors cross-activation and redundant intracellular signalling, or the inability of the drug to cross the blood-brain barrier and to reach its target in vivo . Researchers have also observed that GB tumours are different in many aspects, even when they derive from the same tissue, which is the reason for personalised therapy. An understanding of the molecular mechanisms regulating glioblastoma angiogenesis and invasion may be important in the future development of curative therapeutic approaches for the treatment of this devastating disease.

  20. Do not say ever never more: the ins and outs of antiangiogenic therapies.

    Science.gov (United States)

    Quesada, Ana R; Medina, Miguel Ángel; Muñoz-Chápuli, Ramón; Ponce, Ángel Luis G

    2010-01-01

    Angiogenesis has been described as one of the hallmarks of cancer, playing an essential role in tumor growth, invasion, and metastasis. Antiangiogenic therapy was initially perceived as a "magic bullet" that could eventually be used for the treatment of any type of cancer. For this reason inhibition of angiogenesis has become a major challenge in the development of new anticancer agents, with a countless number of antiangiogenic strategies being tested in preclinical and clinical trials. The initial pessimism about the usefulness of the antiangiogenic therapeutic approach for cancer, derived from the poor results obtained in clinical trials, turned into euphoria after the approvals of the anti-VEGF monoclonal antibody bevacizumab and the multitargeted tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib. Nowadays the clinical development of antiangiogenic therapies seems to be unstoppable, not only for cancer, but also for an increasing number of non-neoplasic angiogenesis-related diseases. Nevertheless, careful analysis of the clinical results reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months. This fact, combined with the high prices of the new antiangiogenic therapies have made a number of oncologists to doubt if they offer "good value". Moreover, recent experimental findings suggest that some antiangiogenic drugs could promote tumor invasiveness and metastasis. The success in the discovery and pharmacological development of future generations of angiogenesis inhibitors will benefit from further advances in the understanding of the mechanisms involved in human angiogenesis.

  1. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery.

    Directory of Open Access Journals (Sweden)

    Jean-Philip Truman

    2010-08-01

    elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.

  2. Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences.

    NARCIS (Netherlands)

    Broxterman, H.J.; Lankelma, J.; Hoekman, K.

    2003-01-01

    Intrinsic resistance to anticancer drugs, or resistance developed during chemotherapy, remains a major obstacle to successful treatment. This is the case both for resistance to cytotoxic agents, directed at malignant cells, and for resistance to anti-angiogenic agents, directed at non-malignant

  3. Assessment of Postoperative Analgesic Drug Efficacy

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Kloster; Gögenur, Ismail; Torup, Henrik

    2017-01-01

    , therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. METHODS: Data from a randomized, double......: Our analyses demonstrate that the applied statistical method may alter the statistical significance and estimates of effect size of analgesic outcome variables in postoperative pain trials. Our findings underline the importance of defining valid statistical methods for future analgesic drug trials. We...... drug efficacy....

  4. The role of tumor microenvironment in resistance to anti-angiogenic therapy

    Science.gov (United States)

    Ma, Shaolin; Pradeep, Sunila; Hu, Wei; Zhang, Dikai; Coleman, Robert; Sood, Anil

    2018-01-01

    Anti-angiogenic therapy has been demonstrated to increase progression-free survival in patients with many different solid cancers. Unfortunately, the benefit in overall survival is modest and the rapid emergence of drug resistance is a significant clinical problem. Over the last decade, several mechanisms have been identified to decipher the emergence of resistance. There is a multitude of changes within the tumor microenvironment (TME) in response to anti-angiogenic therapy that offers new therapeutic opportunities. In this review, we compile results from contemporary studies related to adaptive changes in the TME in the development of resistance to anti-angiogenic therapy. These include preclinical models of emerging resistance, dynamic changes in hypoxia signaling and stromal cells during treatment, and novel strategies to overcome resistance by targeting the TME. PMID:29560266

  5. Biomarkers in Tumor Angiogenesis and Anti-Angiogenic Therapy

    Science.gov (United States)

    Pircher, Andreas; Hilbe, Wolfgang; Heidegger, Isabel; Drevs, Joachim; Tichelli, André; Medinger, Michael

    2011-01-01

    Tumor angiogenesis has been identified to play a critical role in tumor growth and tumor progression, and is regulated by a balance of angiogenic and anti-angiogenic cytokines. Among them VEGF (vascular endothelial growth factor) and its signaling through its receptors are of crucial relevance. Inhibition of VEGF signaling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully established for the treatment of different cancer entities and multiple new drugs are being tested in clinical trials. However not all patients are likely to respond to these therapies, but to date there are no reliable biomarkers available to predict therapy response. Many studies integrated biomarker programs in their study protocols, thus several potential biomarkers have been identified which are currently under clinical investigation in prospective randomized studies. This review intends to give an overview of the described potential biomarkers as well as different imaging techniques such as ultrasound and magnetic resonance imaging that can indicate benefit, resistance and toxicity to anti-angiogenic therapies. PMID:22072937

  6. Assessment of cutaneous drug delivery using microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads

    2002-01-01

    During the last decade microdialysis has been successfully applied to assess cutaneous drug delivery of numerous substances, indicating the large potential for bioequivalence/bioavailability evaluation of topical formulations. The technique has been shown to be minimally invasive and supply...... pharmacokinetic information directly in the target organ for cutaneous drug delivery with high temporal resolution without further intervention with the tissue after implantation. However, there are a few challenges that need to be addressed before microdialysis can be regarded as a generally applicable routine...... technique for cutaneous drug delivery assessments. Firstly, the technique is currently not suitable for sampling of highly lipophilic compounds and, secondly, more studies are desirable for elucidation of the variables associated with the technique to increase reproducibility. The present literature...

  7. Antiangiogenic therapy for breast cancer

    DEFF Research Database (Denmark)

    Nielsen, D.L.; Andersson, M.; Andersen, Jon Alexander Lykkegaard

    2010-01-01

    and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF...... tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria...

  8. Talidomida: novas perspectivas para utilização como antiinflamatório, imunossupressor e antiangiogênico Thalidomide: new perspectives for its use as antiinflammatory, immunossupressive and antiangiogenic drug

    Directory of Open Access Journals (Sweden)

    Larissa de Godoy Borges

    2003-01-01

    Full Text Available Esta revisão tem como objetivo apresentar os novos usos da talidomida. O interesse por este fármaco é devido às suas propriedades antiinflamatórias, immunossupressoras, antiangiogênicas e até mesmo antivirais. Embora o seu mecanismo de ação seja desconhecido, resultados demonstram com sucesso o emprego deste fármaco no eritema nodoso leproso, mieloma múltiplo, doença enxerto-versus-hospedeiro e também como inibidor do vírus HIV e tratamento dos sintomas da Aids. O trabalho também mostra que apesar dos benefícios, a talidomida exige um controle muito rigoroso no que diz respeito à sua utilização e sua dispensação, devido às suas propriedades teratogênicas. Contudo, a talidomida constitui-se numa importante alternativa farmacêutica, sendo que o seu verdadeiro potencial ainda está sendo investigado.The new uses of thalidomide are reviewed. It has recently been used as antinflammatory, immunosuppressive, antiangiogenic, and antiviral agent. Although its mechanism of action is not yet understood, the advantage of its use in several diseases, such as erythema nodosum leprosum, multiple myeloma, and graft-versus-host-disease is evident. Owing to its teratogenic properties, the use of thalidomide must be very well controlled. However, thalidomide has become a very important alternative, with new applications being studied.

  9. Assessing the proarrhythmic potential of drugs

    DEFF Research Database (Denmark)

    Thomsen, Morten Bækgaard; Matz, Jørgen; Volders, Paul G A

    2006-01-01

    Torsades de pointes (TdP) is a potentially lethal cardiac arrhythmia that can occur as an unwanted adverse effect of various pharmacological therapies. Before a drug is approved for marketing, its effects on cardiac repolarisation are examined clinically and experimentally. This paper expresses...... the opinion that effects on repolarisation duration cannot directly be translated to risk of proarrhythmia. Current safety assessments of drugs only involve repolarisation assays, however the proarrhythmic profile can only be determined in the predisposed model. The availability of these proarrhythmic animal...... surrogate parameters possessing predictive power of TdP arrhythmia are reviewed. As these parameters are not developed to finalisation, any meaningful study of the proarrhythmic potential of a new drug will include evaluation in an integrated model of TdP arrhythmia....

  10. Antiangiogenic VEGF Isoform in Inflammatory Myopathies

    Directory of Open Access Journals (Sweden)

    Nila Volpi

    2013-01-01

    Full Text Available Objective. To investigate expression of vascular endothelial growth factor (VEGF antiangiogenic isoform A-165b on human muscle in idiopathic inflammatory myopathies (IIM and to compare distribution of angiogenic/antiangiogenic VEGFs, as isoforms shifts are described in other autoimmune disorders. Subjects and Methods. We analyzed VEGF-A165b and VEGF-A by western blot and immunohistochemistry on skeletal muscle biopsies from 21 patients affected with IIM (polymyositis, dermatomyositis, and inclusion body myositis and 6 control muscle samples. TGF-β, a prominent VEGF inductor, was analogously evaluated. Intergroup differences of western blot bands density were statistically examined. Endomysial vascularization, inflammatory score, and muscle regeneration, as pathological parameters of IIM, were quantitatively determined and their levels were confronted with VEGF expression. Results. VEGF-A165b was significantly upregulated in IIM, as well as TGF-β. VEGF-A was diffusely expressed on unaffected myofibers, whereas regenerating/atrophic myofibres strongly reacted for both VEGF-A isoforms. Most inflammatory cells and endomysial vessels expressed both isoforms. VEGF-A165b levels were in positive correlation to inflammatory score, endomysial vascularization, and TGF-β. Conclusions. Our findings indicate skeletal muscle expression of antiangiogenic VEGF-A165b and preferential upregulation in IIM, suggesting that modulation of VEGF-A isoforms may occur in myositides.

  11. Synthesis and Antiangiogenic Activity of N-Alkylated Levamisole Derivatives

    DEFF Research Database (Denmark)

    Hansen, Anders N.; Bendiksen, Christine D.; Sylvest, Lene

    2012-01-01

    less effective than antibody treatment and are also associated with serious side effects. The discovery of new chemotypes with efficient antiangiogenic activity is therefore of pertinent interest. (S)-Levamisole hydrochloride, an anthelminthic drug approved for human use and with a known clinical...... profile, was recently shown to be an inhibitor of angiogenesis in vitro and exhibited tumor growth inhibition in mice. Here we describe the synthesis and in vitro evaluation of a series of N-alkylated analogues of levamisole with the aim of characterizing structure-activity relationships with regard...... to inhibition of angiogenesis. N-Methyllevamisole and p-bromolevamisole proved more effective than the parent compound, (S)-levamisole hydrochloride, with respect to inhibition of angiogenesis and induction of undifferentiated cluster morphology in human umbilical vein endothelial cells grown in co...

  12. Antiangiogenic effects of AA-PMe on HUVECs in vitro and zebrafish in vivo

    Directory of Open Access Journals (Sweden)

    Jing Y

    2018-04-01

    Full Text Available Yue Jing,1,2,* Gang Wang,1,* Qi Xiao,1 Yachun Zhou,1 Yingjie Wei,3 Zhunan Gong1 1Center for New Drug Research and Development, College of Life Science, Nanjing Normal University, Nanjing, China; 2Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China; 3Key Laboratory of Oral Drug Delivery System of Chinese Materia Medica of State Administration of Traditional Chinese Medicine, Jiangsu Branch of China Academy of Chinese Medical Science, Nanjing, China *These authors contributed equally to this work Abstract: Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA has demonstrated anticancer properties and we suspect this might be attributable to an effect on angiogenesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl-L-proline methyl ester (AA-PMe, has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. Methods: In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs. First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline

  13. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery.

    Directory of Open Access Journals (Sweden)

    Jean-Philip Truman

    ceramide remains elevated while anti-angiogenic therapies fail without ceramide elevation, defining a ceramide rheostat that determines outcome of single dose radiotherapy. Understanding the temporal sequencing of anti-angiogenic drugs and radiation enables optimized radiosensitization and design of innovative radiosurgery clinical trials.

  14. Methods used to assess drug prescribing and dispensing ...

    African Journals Online (AJOL)

    In assessing drug sellers performance, various methods have been used to collect data from drug sellers and other non professional providers. Some of these methods include exit interviews for patients after purchase of drugs, observations to assess drug sellers/dispensers roles and consumers behaviour, interviews with ...

  15. Assessment of Postoperative Analgesic Drug Efficacy

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Kloster; Gögenur, Ismail; Torup, Henrik

    2017-01-01

    BACKGROUND: Pain intensity ratings and opioid consumption (OC) are ubiquitous indicators of pain in postoperative trials of the efficacy of interventional procedures. Unfortunately, consensus on the appropriate statistical handling of these outcomes has not been reached. The aim of this article was......, therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. METHODS: Data from a randomized, double...... also included an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC0-6/0-24 h). Also, estimation of effect size, generalized odds ratio of the individual analgesic outcome variables was performed. RESULTS: Sixty-one patients were included in the final data...

  16. Antiangiogenic ruthenium(ii) benzimidazole complexes, structure-based activation of distinct signaling pathways.

    Science.gov (United States)

    Lai, Haoqiang; Zhao, Zhennan; Li, Linlin; Zheng, Wenjie; Chen, Tianfeng

    2015-03-01

    Antiangiogenic therapy is considered to be a promising strategy for the treatment of cancers. VEGF and its receptors are important angiogenic factors involved in tumor growth. In the present study, the new ruthenium(ii) complexes containing 2,6-bis(benzimidazolyl)pyridine have been identified as potent antiangiogenic agents in vitro and in vivo, through activation of distinct antiangiogenic signaling pathways. Specifically, [Ru(bbp)(p-mpip)Cl]ClO4 (complex , bbp = 2,6-bis(benzimidazolyl)pyridine; p-mpip = 2-(4-methylphenyl)imidazo[4,5-f]-1,10-phenanthroline) exhibited the highest antiangiogenic activity, as evidenced by significant suppression of neovessel formation in chick chorioallantoic membranes and blockage of the angiogenesis in a matrigel plugs assay, which are significantly higher than those of the most accepted anti-metastasis ruthenium-based drug NAMI-A. Generally, these kinds of complexes induced the G0/G1cell cycle by inhibiting the formation of a Cyclin D1/CDK4 complex and CDK2 activation, through up regulation of the expression levels of p15(INK4B), p21(Cip1) and p27(Kip1). Moreover, the complexes also triggered intracellular DNA damage, and thus activated the phosphorylation of ATM, ATR, CHK1, Histone and p53. The suppression of Akt and ERK1/2 pathways reinforced the cell cycle perturbation effects of the complexes. Interestingly, complex displayed strong inhibition on the activation of VEGF and VEGFR-2 phosphorylation, which blocked the transmission of the mitogenic signal through Akt and ERK1/2 pathways, and thus enhanced cell cycle arrest. In contrast, we found that the most accepted anti-metastasis ruthenium based drug NAMI-A exerted lower antiangiogenic activity via activation of the DNA damage-mediated pathway, but showed no effects on VEGF and VEGFR-2 phosphorylation. Taken together, this study clearly demonstrates the distinct antiangiogenic mechanisms of metal complexes, and these kinds of complexes can be further developed as anti

  17. Perfusion CT allows prediction of therapy response in non-small cell lung cancer treated with conventional and anti-angiogenic chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Tacelli, Nunzia; Santangelo, Teresa; Remy, Jacques [University of Lille Nord de France, Department of Thoracic Imaging, Hospital Calmette (EA 2694), Lille (France); University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); Scherpereel, Arnaud; Cortot, Alexis; Wallyn, Frederic [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Pulmonary and Thoracic Oncology, Lille (France); Duhamel, Alain; Deken, Valerie [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Medical Statistics, Lille (France); Klotz, Ernst [Siemens Healthcare, Computed Tomography Division, Forchheim (Germany); Lafitte, Jean-Jacques [University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); University of Lille Nord de France, Department of Pulmonary and Thoracic Oncology, Lille (France); Pasteur Institute of Lille, INSERM unit 1019, CIIL, Lille (France); Remy-Jardin, Martine [University of Lille Nord de France, Department of Thoracic Imaging, Hospital Calmette (EA 2694), Lille (France); University of Lille Nord de France, Faculty of Medicine, Henri Warembourg, Lille (France); Hospital Calmette, Department of Thoracic Imaging, Lille cedex (France)

    2013-08-15

    To determine whether CT can depict early perfusion changes in lung cancer treated by anti-angiogenic drugs, allowing prediction of response. Patients with non-small cell lung cancer, treated by conventional chemotherapy with (Group 1; n = 17) or without (Group 2; n = 23) anti-vascular endothelial growth factor (anti-VEGF) drug (bevacizumab) underwent CT perfusion before (TIME 0) and after 1 (TIME 1), 3 (TIME 2) and 6 (TIME 3) cycles of chemotherapy. The CT parameters evaluated included: (1) total tumour vascular volume (TVV) and total tumour extravascular flow (TEF); (2) RECIST (Response Evaluation Criteria in Solid Tumours) measurements. Tumour response was also assessed on the basis of the clinicians' overall evaluation. In Group 1, significant reduction in perfusion was identified between baseline and: (1) TIME 1 (TVV, P = 0.0395; TEF, P = 0.015); (2) TIME 2 (TVV, P = 0.0043; TEF, P < 0.0001); (3) TIME 3 (TVV, P = 0.0034; TEF, P = 0.0005) without any significant change in Group 2. In Group 1: (1) the reduction in TVV at TIME 1 was significantly higher in responders versus non-responders at TIME 2 according to RECIST (P = 0.0128) and overall clinicians' evaluation (P = 0.0079); (2) all responders at TIME 2 had a concurrent decrease in TVV and TEF at TIME 1. Perfusion CT demonstrates early changes in lung cancer vascularity under anti-angiogenic chemotherapy that may help predict therapeutic response. (orig.)

  18. Assessing suicidal risk with antiepileptic drugs

    Directory of Open Access Journals (Sweden)

    Marco Mula

    2010-09-01

    Full Text Available Marco Mula2, Gail S Bell1, Josemir W Sander1,31Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, and National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, United Kingdom; 2Department of Clinical and Experimental Medicine, Division of Neurology, Amedeo Avogadro University, University Hospital Maggiore della Carità, Novara, Italy; 3SEIN – Epilepsy Institute in the Netherlands Foundation, Heemstede, The NetherlandsAbstract: Recently, the US Food and Drug Administration issued an alert about an increased risk for suicidality during treatment with antiepileptic drugs (AEDs for different indications, including epilepsy. We discuss the issue of suicide in epilepsy with special attention to AEDs and the assessment of suicide in people with epilepsy. It has been suggested that early medical treatment with AEDs might potentially reduce suicide risk of people with epilepsy, but it is of great importance that the choice of drug is tailored to the mental state of the patient. The issue of suicidality in epilepsy is likely to represent an example of how the underdiagnosis of psychiatric symptoms, the lack of input from professionals (eg, psychologists, social workers, and psychiatrists, and the delay in an optimized AED therapy may worsen the prognosis of the condition with the occurrence of severe complications such as suicide.Keywords: epilepsy, suicide, adverse effect, depression

  19. Assessment of Rational Prescribing of Antihypertensive Drug ...

    African Journals Online (AJOL)

    Results: The average number of drugs prescribed per encounter was 2.9. Encounters with injections were 0.5%. The percentage of drugs prescribed by generic name was 31.6%. All the drugs prescribed were from the National Essential Drugs List. Calcium antagonists were the most frequently used group of drugs (41.3%), ...

  20. Immuno-Expression of Endoglin and Smooth Muscle Actin in the Vessels of Brain Metastases. Is There a Rational for Anti-Angiogenic Therapy?

    Directory of Open Access Journals (Sweden)

    Valeria Barresi

    2014-04-01

    Full Text Available Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD, a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature in the tumor tissue of a series of BM derived from different primary tumors. By using immunohistochemistry against endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary tumor, as well as on its histotype. According to our results, BM from lung cancer displayed the highest MVD counts, while those from renal carcinoma had the lowest. Then, among BM from lung cancer, those from large cell and adenocarcinoma histotypes had significantly higher MVD counts than those originating from squamous cell carcinoma (p = 0.0043; p = 0.0063. Of note, MVD counts were inversely correlated with the maturation index of the endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA positive pericytes (r = −0.693; p < 0.0001. Accordingly, all the endoglin-positive vessels in BM from pulmonary squamous cell carcinoma and renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary tumors may account for their low sensitivity to anti-angiogenic therapies. Although our findings need to be validated in correlative studies with a clinical response, this should

  1. Better drug history taking: an assessment of the DRUGS mnemonic.

    Science.gov (United States)

    Hocking, G; Kalyanaraman, R; deMello, W F

    1998-06-01

    To improve drug history taking before anaesthesia, we have previously suggested a checklist with the mnemonic DRUGS (Doctor, Recreational, User, Gynaecological, Sensitivities). We have now tested this mnemonic in 1053 patients admitted for surgery, comparing the results with the information obtained in the original clerking. Use of the mnemonic yielded additional information in 621 patients (59%). Drugs which had gone unrecorded in routine clerking were detected in 24% of patients on medication. Of 199 patients with high alcohol intake, this feature had been recorded in only 38 (19%). Unprescribed medicines, being taken by 158, had been noted in only 31 (20%). Of women taking oral contraceptives or hormone replacement therapy, more than two-thirds had not given this information. Sensitivities had been recorded accurately in 100 patients but the mnemonic yielded relevant information in a further 85. On this evidence, use of the simple DRUGS mnemonic improves drug history taking in anaesthetic practice.

  2. Anti-angiogenic treatment of gastrointestinal malignancies.

    Science.gov (United States)

    Salmon, J Stuart; Lockhart, A Craig; Berlin, Jordan

    2005-01-01

    The scientific rationale to block angiogenesis as a treatment strategy for human cancer has been developed over the last 30 years, but is only now entering the clinical arena. Preclinical studies have demonstrated the importance of the vascular endothelial growth factor (VEGF) pathways in both physiologic and pathologic angiogenesis, and have led to the development of approaches to block its role in tumor angiogenesis. Bevacizumab is an antibody to VEGF and has been shown to prolong survival when given with chemotherapy in the treatment of metastatic colorectal cancer (CRC). Although this is the first anti-angiogenic treatment to be approved for the treatment of human epithelial malignancy, a number of other approaches currently are in development. Soluble chimeric receptors to sequester serum VEGF and monoclonal antibodies against VEGF receptors have both shown considerable promise in the laboratory and are being brought into clinical investigation. A number of small-molecule tyrosine kinase inhibitors that have activity against VEGF receptors also are in clinical trials. Although these novel treatments are being pioneered in CRC, anti-angiogenic approaches also are being tested in the treatment of other gastrointestinal malignancies. Anti-VEGF therapy has shown promise in such traditionally resistant tumors as pancreatic cancer and hepatocellular carcinoma. This review will examine the preclinical foundation and then focus on the clinical studies of anti-VEGF therapy in gastrointestinal cancers.

  3. Novel production method of innovative antiangiogenic and antitumor small peptides in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Setrerrahmane S

    2017-11-01

    Full Text Available Sarra Setrerrahmane,1 Jian Yu,1 Jingchao Hao,1,2 Heng Zheng,3 Hanmei Xu1,3 1The Engineering Research Center of Peptide Drug Discovery and Development, China Pharmaceutical University, Nanjing, Jiangsu, 2College of Pharmacy & the Provincial Key Laboratory of Natural Drug and Pharmacology, Kunming, Yunnan, 3State Key Laboratory of Natural Medicines, Ministry of Education, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China Background: Developing innovative drugs with potent efficacy, specificity, and high safety remains an ongoing task in antitumor therapy development. In the last few years, peptide drugs have become attractive agents in cancer therapy. HM-3, mainly with antiangiogenic effect, and AP25, with an additional antiproliferative effect, are two peptides designed in our laboratory targeting αvβ3 and α5β1 integrins, respectively. The low molecular weight of the two peptides renders their recombinant expression very difficult, and the complicated structure of AP25 makes its chemical synthesis restricted, which presents a big challenge for its development.Methods: Bifunctional peptides designed by the ligation of HM-3 and AP25, using linkers with different flexibility, were prepared using recombinant DNA technology in Escherichia coli. The fusion peptides were expressed in a modified auto-induction medium based on a mixture of glucose, glycerol, and lactose as carbon substrates and NH4+ as nitrogen source without any amino acid or other elements. Subsequently, the antiangiogenic, antiproliferative, and cell adhesion assays were conducted to evaluate the bioactivity of the two fusion peptides.Results: The peptides were successfully expressed in a soluble form without any induction, which allows the culture to reach higher cell density before protein expression occurs. Human umbilical vein endothelial cell migration assay and chick embryo chorioallantoic membrane assay showed, at low doses, a significantly

  4. Tratamento da forma neovascular de degeneração macular relacionada à idade com drogas antiangiogênicas Treatment of neovascular age-related macular degeneration with antiangiogenic drugs

    Directory of Open Access Journals (Sweden)

    Eduardo Büchele Rodrigues

    2006-10-01

    , whereas choroidal neovascularization (CNV represents an important manifestation suitable for treatment. The treatment of CNV has been a major focus of research in the past decades, and the first evidence-based established therapy was laser photocoagulation, which reduces the risk of visual loss in extrafoveal lesions. In the late 90's photodynamic therapy has been established as an efficient method for the treatment of predominantly classic and occult CNV. Additional therapies such as macular translocation, submacular surgery, and indocyanine-mediated prothrombosis are currently under investigation in large-scale clinical trials. Molecular biology has recently provided a better comprehension of the pathogenesis of ARMD, and vascular endothelial growth factor (VEGF was recognized as key mediator in the angiogenesis of CNV-formation. Therefore, the pharmacological approach rose as a key research area to treat CNV. The first FDA-approved agent for CNV-therapy is aptamer pegaptanib sodium (Macugen®, which inactivates the key angiogenic isoform VEGF165. Additional VEGF-blockers such as ranibizumab RhuFab V2 (Lucentis® and bevacizumab (Avastin® are under evaluation in major clinical studies. Impressive results of intravitreal bevacizumab were released recently. Moreover, the steroid-derived anecortave acetate as well as the corticosteroid triamcinolone acetate have been proposed as methods for treatment of wet-ARMD. This paper presents the rationale and principles of the pharmacologic antiangiogenic therapy for CNV in ARMD.

  5. An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

    Science.gov (United States)

    Fagiani, Ernesta; Bill, Ruben; Pisarsky, Laura; Ivanek, Robert; Rüegg, Curzio; Christofori, Gerhard

    2015-07-01

    Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer.

  6. Shark cartilage extracts as antiangiogenic agents: smart drinks or bitter pills?

    Science.gov (United States)

    Gingras, D; Renaud, A; Mousseau, N; Béliveau, R

    2000-01-01

    The use of crude cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of cartilage. We then presented the properties of AE-941, a novel standardized water-soluble extract derived from shark cartilage that represents less than 5% of the crude cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. EA-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer.

  7. Novel production method of innovative antiangiogenic and antitumor small peptides inEscherichia coli.

    Science.gov (United States)

    Setrerrahmane, Sarra; Yu, Jian; Hao, Jingchao; Zheng, Heng; Xu, Hanmei

    2017-01-01

    Developing innovative drugs with potent efficacy, specificity, and high safety remains an ongoing task in antitumor therapy development. In the last few years, peptide drugs have become attractive agents in cancer therapy. HM-3, mainly with antiangiogenic effect, and AP25, with an additional antiproliferative effect, are two peptides designed in our laboratory targeting α v β 3 and α 5 β 1 integrins, respectively. The low molecular weight of the two peptides renders their recombinant expression very difficult, and the complicated structure of AP25 makes its chemical synthesis restricted, which presents a big challenge for its development. Bifunctional peptides designed by the ligation of HM-3 and AP25, using linkers with different flexibility, were prepared using recombinant DNA technology in Escherichia coli . The fusion peptides were expressed in a modified auto-induction medium based on a mixture of glucose, glycerol, and lactose as carbon substrates and NH 4 + as nitrogen source without any amino acid or other elements. Subsequently, the antiangiogenic, antiproliferative, and cell adhesion assays were conducted to evaluate the bioactivity of the two fusion peptides. The peptides were successfully expressed in a soluble form without any induction, which allows the culture to reach higher cell density before protein expression occurs. Human umbilical vein endothelial cell migration assay and chick embryo chorioallantoic membrane assay showed, at low doses, a significantly increased antiangiogenic effect (>75%) of the purified products compared with the single molecules. Meanwhile, MTT assay confirmed their enhanced antitumor activity against gastric cancer cell line MGC-803; however, no significant effect was observed on hepatoma HepG2 cells and no cytotoxicity on normal human lens epithelial cell SRA01/04 and human epithelial esophageal cells. Bifunctional molecules with antiangiogenic and antiproliferative effects were obtained by using this technique

  8. Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel.

    Science.gov (United States)

    Wang, Hejing; Qian, Junmin; Zhang, Yaping; Xu, Weijun; Xiao, Juxiang; Suo, Aili

    2017-01-01

    -GMA hydrogel may offer an improved platform to minimize the gap between traditional tissue culture plates and clinical applicability. In addition, the anti-angiogenic efficacy of drugs such as Endostar and Bevacizumab can be more comprehensively studied and assessed in HECS-GMA hydrogels.

  9. California Drug and Alcohol Treatment Assessment (CALDATA-1991-1993)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The California Drug and Alcohol Treatment Assessment (CALDATA) was designed to study the costs, benefits, and effectiveness of the state's alcohol and drug treatment...

  10. Results of combined antiangiogenic activity on corneal neovascularization. Experimental and morphological study

    Directory of Open Access Journals (Sweden)

    V. R. Mamikpnyan

    2014-01-01

    Full Text Available Results of comparative experimental and morphological study of activity on corneal neovascularization in rabbit’s eye of photodynamic therapy with Photosense and antiangiogenic therapy with Avastin (bevacizumab alone, and in its combination are represented. The treatment was performed in regimens: 1 photodynamic therapy with Photosense (single intravenous injection in dose of 0.3 mg/kg 72 h prior to laser irradiation, power density of irradiation 500 mW/cm2, wavelength 675 nm; 2 drug antiangiogenic therapy with Avastin (single subconjuctival introduction at dose of 1.25 mg; 3 photodynamic therapy with Photosense (in described regimen in combination with subconjuctival introduction of Avastin at dose of 1.25 mg immediately prior to irradiation. Combined photodynamic therapy with antiangiogenic therapy allows to obtain almost complete occlusion in all regions of corneal neovascular bed with shorter time interval comparing with those for monoregimens. In case of blood flow retention in great vessels courses of combined modality treatment may be repeated. The absence of side-effects on surrounding tissues and the recovery of optical characteristics of cornea may allow to use this upcoming method in clinical practice. 

  11. Antiangiogenic therapies in urogenital malignancies: Fiction or fact?

    Science.gov (United States)

    Haidl, Friederike; Pfister, David; Heidenreich, Axel; Heidegger, Isabel

    2017-01-01

    The use of antiangiogenic agents in cancer therapy has become an attractive target in oncological research. However, concerning the uro-oncological field, current guidelines only recommend the use of antiangiogenic agents in metastatic renal cell cancer. Yet in recent years, several approaches for sequential treatment with angiogenesis inhibitors in other urogenital malignancies apart from renal cell cancer are ongoing. Thus, the present review article aims to provide an overview about clinical studies with antiangiogenic agents in prostate-, bladder-, testicular-, as well as penile cancer patients. For this, a literature search was conducted using Medline; moreover we performed a systematic review of data presented at this year's important urooncological meetings. Preliminary data revealed that there are several promising studies ongoing in prostate-, bladder-, testicular-, as well as penile cancer; however, larger studies should be conducted to optimize the use of antiangiogenic agents in clinical practice.

  12. NMR with Combined Antiangiogenic and Radiation Therapies - Breast Cancer

    National Research Council Canada - National Science Library

    Brown, Stephen

    2000-01-01

    The original goal of the present study was to determine optimal strategies for combining radiation and antiangiogenic therapies in spontaneous murine tumors and to evaluate the potential of Nuclear Magnetic Resonance (NMR...

  13. Optical Coherence Tomography and the Development of Antiangiogenic Therapies in Neovascular Age-Related Macular Degeneration

    Science.gov (United States)

    Rosenfeld, Philip J.

    2016-01-01

    Purpose To explain the pivotal role optical coherence tomography (OCT) imaging had in the development of antiangiogenic therapies for the treatment of neovascular age-related macular degeneration (nvAMD). Methods A historical literature review was combined with personal perspectives from the introduction of OCT imaging and the early clinical use of vascular endothelial growth factor (VEGF) inhibitors. Results At the time that OCT emerged, the gold standard for imaging of nvAMD was fluorescein angiography (FA), a time-consuming, dye-based, invasive technique that provided en face images of the retina and was used to characterize leakage, perfusion status, and the types of macular neovascularization (MNV). In comparison, OCT imaging was a fast, safe, noninvasive technique that complemented FA imaging by providing cross-sectional images of the macula. OCT was able to visualize and quantify the macular fluid that was associated with the presence of excess VEGF, which was identified by intraretinal fluid, subretinal fluid, and fluid under the retinal pigment epithelium (RPE). Clinicians quickly appreciated the benefits of OCT imaging for following macular fluid after anti-VEGF therapy. By observing the qualitative and quantitative changes in macular fluid depicted by OCT imaging, clinicians were empowered to compare anti-VEGF drugs and move from fixed-dosing regimens to patient-specific dosing strategies requiring fewer injections. Conclusions Optical coherence tomography imaging was adopted as a VEGF-meter, a method to detect excess VEGF, and evolved to become the gold standard imaging strategy for diagnosing nvAMD, assessing treatment responses to anti-VEGF drugs, deciding when to re-treat, and evaluating disease progression. PMID:27409464

  14. Anti-angiogenic potential of an ethanol extract of Annona atemoya seeds in vitro and in vivo.

    Science.gov (United States)

    Yi, Jin-Mu; Park, Jong-Shik; Lee, Jun; Hong, Jin Tae; Bang, Ok-Sun; Kim, No Soo

    2014-09-23

    Angiogenesis, which is initiated by certain tumor micro-environmental conditions and diverse protein factors, plays a pivotal role during tumor development and metastasis. Therefore, many efforts have been made to develop effective anti-angiogenic agents as anticancer therapeutics. In the current study, we investigated the anti-angiogenic potential of an ethanol extract of Annona atemoya seeds (EEAA) in vitro and in vivo. The anti-angiogenic potential of EEAA was evaluated using various in vitro/in vivo models, including cell proliferation, migration, and tube formation by human umbilical vascular endothelial cells (HUVECs); a Matrigel plug assay; and tumor-induced angiogenesis. The expression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF) was investigated using reverse transcription-polymerase chain reaction, immunoassays, and western blotting. EEAA was able to significantly inhibit the angiogenic properties of HUVECs in vitro as well as angiogenic factor-induced blood vessel formation in vivo. EEAA down-regulated the expression of VEGF and HIF-1alpha/2alpha at the mRNA and protein levels, respectively, in cancer cells under hypoxic conditions. EEAA shows a strong anti-angiogenic potential in both in vitro and in vivo systems, and we suggest that EEAA may be a valuable herbal source for anticancer drug development.

  15. Assessing website pharmacy drug quality: safer than you think?

    Directory of Open Access Journals (Sweden)

    Roger Bate

    Full Text Available BACKGROUND: Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA works with the National Association of Boards of Pharmacy (NABP to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality. METHODS AND FINDINGS: This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17 websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from "approved", "legally compliant" or "not recommended" websites (0 out of 86, whereas 8.6% (3 out of 35 failed from "highly not recommended" and unidentifiable websites. CONCLUSIONS: Of those drugs that could be assessed, all except Viagra(R passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by

  16. [Current problems in assessing drug prices].

    Science.gov (United States)

    Lucioni, C

    1989-01-01

    Two reasons provide historical justification for controlling drug prices: safeguarding the consumer and safeguarding public demand. Due to the increased presence of the "third payer" in public health systems this second reason has become more important. Nevertheless, over the last decade, a third purpose has attached to public control of prices: promotion of drug manufacturers economic development. The justification offered for this is that development of pharmaceutical companies contributes to the economic growth of the host country by creating employment, exports and research activity. The situations in Germany, Great Britain and United States are often cited in support of this thesis. As a model for price policy in Italy, however, it has not been successful. The rapid growth of prices in fact has not created greater employment and the foreign exchange deficit has risen rapidly. In other words the growing cost of drugs to the National Health Service has not produced hoped-for economic benefits. It would therefore be opportune to modify the mechanisms of price control by seeking a better balance in the interests involved (safeguarding public demand versus manufacturers economic growth). Methodologies available point to the evaluation of the therapeutic utility of a drug as a useful tool for this purpose. By this method the price of a new drug may only be higher than that of a drug already on the market if its therapeutic utility (which does not coincide only with clinical effectiveness) is greater. Appropriate evaluation techniques of benefits deriving from a new drug (cost-effectiveness and cost-utility) do exist and can be taken into consideration in a new method of calculating drug price.

  17. In vitro and in vivo anti-angiogenic activities of Panduratin A.

    Directory of Open Access Journals (Sweden)

    Siew-Li Lai

    Full Text Available Targeting angiogenesis has emerged as an attractive and promising strategy in anti-cancer therapeutic development. The present study investigates the anti-angiogenic potential of Panduratin A (PA, a natural chalcone isolated from Boesenbergia rotunda by using both in vitro and in vivo assays.PA exerted selective cytotoxicity on human umbilical vein endothelial cells (HUVECs with IC(50 value of 6.91 ± 0.85 µM when compared to human normal fibroblast and normal liver epithelial cells. Assessment of the growth kinetics by cell impedance-based Real-Time Cell Analyzer showed that PA induced both cytotoxic and cytostatic effects on HUVECs, depending on the concentration used. Results also showed that PA suppressed VEGF-induced survival and proliferation of HUVECs. Furthermore, endothelial cell migration, invasion, and morphogenesis or tube formation demonstrated significant time- and dose-dependent inhibition by PA. PA also suppressed matrix metalloproteinase-2 (MMP-2 secretion and attenuated its activation to intermediate and active MMP-2. In addition, PA suppressed F-actin stress fiber formation to prevent migration of the endothelial cells. More importantly, anti-angiogenic potential of PA was also evidenced in two in vivo models. PA inhibited neo-vessels formation in murine Matrigel plugs, and angiogenesis in zebrafish embryos.Taken together, our study demonstrated the distinctive anti-angiogenic properties of PA, both in vitro and in vivo. This report thus reveals another biological activity of PA in addition to its reported anti-inflammatory and anti-cancer activities, suggestive of PA's potential for development as an anti-angiogenic agent for cancer therapy.

  18. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM)

    Science.gov (United States)

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L.; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-01-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment. PMID:27706074

  19. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM).

    Science.gov (United States)

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-10-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

  20. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ in Multiple Myeloma (MM

    Directory of Open Access Journals (Sweden)

    Daniele Tibullo

    2016-10-01

    Full Text Available Multiple myeloma (MM is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC in the bone marrow (BM leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

  1. Rapid Assessment of Drugs of Abuse.

    Science.gov (United States)

    Wiencek, Joesph R; Colby, Jennifer M; Nichols, James H

    Laboratory testing for drugs of abuse has become standard practice in many settings both forensic and clinical. Urine is the predominant specimen, but other specimens are possible including hair, nails, sweat, and oral fluid. Point-of-care test kits provide for rapid analysis at the site where specimens are collected allowing for immediate action on the results. POCT is based on immunochromatography where the drug in the patient's sample competes with drug and antibody conjugates in the test to develop or block the development of a colored line. Most POCTs are visually interpreted in a few minutes. The potential for false positives is possible due to drug cross-reactivity with the antibodies in the test. False negatives are also possible due to dilution of the sample and the potential for adulteration or sample substitution by the patient. POCT shows more variability than central laboratory testing because of the variety of operators involved in the testing process, but POCT has good agreement for most tests with mass spectrometry provided comparable cutoffs and cross-reactivity of drugs/metabolites are considered. Validation of the test performance with the intended operators will identify potential interferences and operational issues before implementing the test in routine practice. POCT offers faster turnaround of test results provided the limitations and challenges of the test are considered. © 2017 Elsevier Inc. All rights reserved.

  2. Assessing Tumor Response to Treatment in Patients with Lung Cancer Using Dynamic Contrast-Enhanced CT

    DEFF Research Database (Denmark)

    Strauch, Louise S; Eriksen, Rie Ø; Sandgaard, Michael

    2016-01-01

    yielded 651 publications, and 16 articles were included in this study. The articles were divided into groups of treatment. In studies where patients were treated with systemic chemotherapy with or without anti-angiogenic drugs, four out of the seven studies found a significant decrease in permeability...... after treatment. Four out of five studies that measured blood flow post anti-angiogenic treatments found that blood flow was significantly decreased. DCE-CT may be a useful tool in assessing treatment response in patients with lung cancer. It seems that particularly permeability and blood flow...

  3. Assessing Outpatient Drug Abuse Treatment Programs.

    Science.gov (United States)

    Tims, Frank M.; And Others

    1992-01-01

    Data about outpatient treatment unit follow-up evaluations drawn from selected evaluation items in the recent National Drug Abuse Treatment Survey are reported. Directors and supervisors of 670 units completed surveys describing the follow-up studies. The majority of programs collecting follow-up data used the information for program change. (SLD)

  4. Implicit and Explicit Drug-Related Cognitions during Detoxification Treatment Are Associated with Drug Relapse: An Ecological Momentary Assessment Study

    Science.gov (United States)

    Marhe, Reshmi; Waters, Andrew J.; van de Wetering, Ben J. M.; Franken, Ingmar H. A.

    2013-01-01

    Objective: Relapse is a major problem in drug addiction treatment. Both drug craving and drug-related cognitions (e.g., attentional bias and implicit attitudes to drugs) may contribute to relapse. Using ecological momentary assessments, we examined whether craving and cognitions assessed during drug detoxification treatment were associated with…

  5. Hypothesis: primary antiangiogenic method proposed to treat early stage breast cancer

    International Nuclear Information System (INIS)

    Retsky, Michael W; Hrushesky, William JM; Gukas, Isaac D

    2009-01-01

    Women with Down syndrome very rarely develop breast cancer even though they now live to an age when it normally occurs. This may be related to the fact that Down syndrome persons have an additional copy of chromosome 21 where the gene that codes for the antiangiogenic protein Endostatin is located. Can this information lead to a primary antiangiogenic therapy for early stage breast cancer that indefinitely prolongs remission? A key question that arises is when is the initial angiogenic switch thrown in micrometastases? We have conjectured that avascular micrometastases are dormant and relatively stable if undisturbed but that for some patients angiogenesis is precipitated by surgery. We also proposed that angiogenesis of micrometastases very rarely occurs before surgical removal of the primary tumor. If that is so, it seems possible that we could suggest a primary antiangiogenic therapy but the problem then arises that starting a therapy before surgery would interfere with wound healing. The therapy must be initiated at least one day prior to surgical removal of the primary tumor and kept at a Down syndrome level perhaps indefinitely. That means the drug must have virtually no toxicity and not interfere meaningfully with wound healing. This specifically excludes drugs that significantly inhibit the VEGF pathway since that is important for wound healing and because these agents have some toxicity. Endostatin is apparently non-toxic and does not significantly interfere with wound healing since Down syndrome patients have no abnormal wound healing problems. We propose a therapy for early stage breast cancer consisting of Endostatin at or above Down syndrome levels starting at least one day before surgery and continuing at that level. This should prevent micrometastatic angiogenesis resulting from surgery or at any time later. Adjuvant chemotherapy or hormone therapy should not be necessary. This can be continued indefinitely since there is no acquired resistance that

  6. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

    Science.gov (United States)

    Winter, Ursula; Mena, Hebe A; Negrotto, Soledad; Arana, Eloisa; Pascual-Pasto, Guillem; Laurent, Viviana; Suñol, Mariona; Chantada, Guillermo L; Carcaboso, Angel M; Schaiquevich, Paula

    2016-01-01

    Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure) or metronomic (7-day continuous exposure) treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50) was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks) and metronomic (5 days a week for 2 weeks) topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23) was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p0.05). In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (pretinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced multidrug resistance mechanisms while apoptosis was the mechanism of cell death after both treatment

  7. Model-based, semiquantitative and time intensity curve shape analysis of dynamic contrast-enhanced MRI: a comparison in patients undergoing antiangiogenic treatment for recurrent glioma

    NARCIS (Netherlands)

    Lavini, Cristina; Verhoeff, Joost J. C.; Majoie, Charles B.; Stalpers, Lukas J. A.; Richel, Dick J.; Maas, Mario

    2011-01-01

    To compare time intensity curve (TIC)-shape analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data with model-based analysis and semiquantitative analysis in patients with high-grade glioma treated with the antiangiogenic drug bevacizumab. Fifteen patients had a pretreatment

  8. Synergistic effect of anti-angiogenic herbal composition (Meta-X) in combination with radiotherapy on the inhibition of tumor growth

    International Nuclear Information System (INIS)

    Han, Young Soo; Song, Jie Young; Yoon, Yeon Sook; Kim, Joon Sik; Park, Byung Young; Lee, Hee Suk; Kim, Min Yung

    2004-01-01

    Anti-angiogenic composition called Meta-X was made from herbal medicines that are currently used oral drugs for other indications. We examined biochemical properties of Meta-X, and synergistic effect of Meta-X combined with irradiation on the inhibition of tumor growth

  9. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer.

    Science.gov (United States)

    Pompas-Veganzones, N; Sandonis, V; Perez-Lanzac, Alberto; Beltran, M; Beardo, P; Juárez, A; Vazquez, F; Cozar, J M; Alvarez-Ossorio, J L; Sanchez-Carbayo, Marta

    2016-10-01

    Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed

  10. Modeling tumor-associated edema in gliomas during anti-angiogenic therapy and its impact on imageable tumor

    Directory of Open Access Journals (Sweden)

    Andrea eHawkins-Daarud

    2013-04-01

    Full Text Available Glioblastoma, the most aggressive form of primary brain tumor is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd and T2-weighted magnetic resonance imaging (MRI. Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically-driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor-cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR for tumors with lower proliferation rates.

  11. Assessment of Albendazole (an antiparasitic drug) effects on the ...

    African Journals Online (AJOL)

    Assessment of Albendazole (an antiparasitic drug) effects on the physiological activities of the cardiac, smooth and skeletal muscles of some experimental animals. Mohamed AA El-Rahman, Mohamed AA Omran, Ismail M Abdel-Nabi, Moustafa F Mohamed ...

  12. Benefit-Risk Assessment in Drug Development

    DEFF Research Database (Denmark)

    Sarac, Sinan

    This thesis covers the development, testing and use of an eight-step structured method for data-driven benefit-risk assessment. The aim of this thesis was to create a tailored method for the assessment of clinical data. The focus has been on three major aspects: (i) A simple preliminary method wa...

  13. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, R. D.; Wang, S. V.

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...... definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared...

  14. Suppression of autoimmune retinal inflammation by an antiangiogenic drug.

    Directory of Open Access Journals (Sweden)

    Takeru Yoshimura

    Full Text Available Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4(+ T cells that differentiate into effector T helper cells (Th1, Th2, and Th17 which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2 inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4(+ T cells, and a general normalization of the systemic immune reaction.

  15. Suppression of Autoimmune Retinal Inflammation by an Antiangiogenic Drug

    Science.gov (United States)

    Bazinet, Lauren; D’Amato, Robert J.

    2013-01-01

    Chronic and recurrent uveitis account for approximately 10% of legal blindness in the western world. Autoimmune uveitis is driven by activated CD4+ T cells that differentiate into effector T helper cells (Th1, Th2, and Th17) which release proinflammatory cytokines that damage the retina. In this study we investigated the effect of the methionine aminopeptidase 2 (MetAP2) inhibitor, Lodamin, on T cell activation and differentiation. MetAp2 is an enzyme which regulates cellular protein synthesis and is highly expressed in T cells. Lodamin was found to suppress T cell receptor (TCR) mediated T cell proliferation and reduced the production of Th1 and Th17 cells. Further, Lodamin suppressed overall inflammation in the mouse model of experimental autoimmune uveitis (EAU) by a six fold. This effect was attributed in part to a reduction in retinal proinflammatory cytokines, down regulation of MetAP2 expression in purified lymph node CD4+ T cells, and a general normalization of the systemic immune reaction. PMID:23785488

  16. Orphan drugs assessment in the centralised procedure.

    Science.gov (United States)

    Nisticò, Giuseppe

    2011-01-01

    On the basis of the author's experience as member of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and in order to facilitate the access of new orphan drugs to the patients, some suggestions were given. Among these the following should be taken into account by the regulatory bodies: 1) conditional approval or approval under exceptional circumstances should be granted more frequently; 2) the opinion of international societies for rare diseases should be taken into greater account by the EMA Committees; 3) the guidelines requirements should be interpreted more flexibly; 4) in comparison to the fulfilment of primary and secondary endpoints, the improvement of the quality of life should justify the approval of a new orphan drug; 5) the rigidity of guideline requirements should not prevail over the unmet medical need for severe and lethal rare disorders; 6) the statistical values of clinical data to the limit of significance should not prevail over the opinion of patients' associations and international scientific societies; 7) the current legislation should be amended.

  17. Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety

    Directory of Open Access Journals (Sweden)

    Welker MW

    2013-10-01

    Full Text Available Martin-Walter Welker, Joerg TrojanMedizinische Klinik 1, Universitätsklinikum Frankfurt, GermanyAbstract: Hepatocellular carcinoma (HCC is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety.Keywords: HCC, sorafenib, antiangiogenesis, TACE, MET

  18. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae chlorella pyrenoidosa

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    Objective: algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. Materials and Methods: lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). Results: VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. Conclusion: a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be

  19. Antiangiogenic Effects of VH02, a Novel Urea Derivative: In Vitro and in Vivo Studies

    Directory of Open Access Journals (Sweden)

    Suwadee Phowichit

    2016-09-01

    Full Text Available Vascular endothelial growth factor receptor 2 (VEGFR2 is a vital target for therapeutic intervention in cancer. We have recently described a computer-based drug design for a small molecule VEGFR2 inhibitor named VH02 (1-((1-(1H-indazol-6-yl-1H-1,2,3-triazol-4-ylmethyl-3-(3-chloromethylphenylurea. This study aimed to further explore the anti-angiogenic activity of VH02 both in vitro and in vivo. The in vitro assays include cell viability, capillary-like tube formation, MMP activity, and western blot analyses of signaling through VEGFR2 while the in vivo anti-angiogenic response were performed to evaluate the effect on vascularization in Matrigel plug applied in C57BL/6L mice. VH02 reduced angiogenesis behavior of EA.hy926 including cell viability, migration, adhesion, capillary-like tube formation, and MMP-2 activity induced by VEGF. Furthermore, VH02 regulated angiogenesis by directly inhibiting VEGFR2 on Tyr1175 signaling pathway leading to the inhibition of Akt-mediated cell survival and migration. Disruption of phosphorylation at VEGFR2-Tyr1175 by VH02 abolished FAK-Tyr397 signaling but not phosphorylation of p38 MAPK. This suggests that blockade of FAK by VH02 apparently associated with reduction of endothelial cell motility. Actin cytoskeleton rearrangement was diminished by VH02 in human endothelial cells. The anti-angiogenic effect of VH02 was confirmed in the in vivo model, revealing the reduction of vascular density in Matrigel plug after VH02 treatment. Additionally, the pericyte-like cells surrounding blood vessels in the plugs were significantly reduced as well as vascular density and p-Akt intensity. Our findings indicate that VH02 successfully inhibits VEGF-induced angiogenesis both in vitro and in vivo models. The compound could be further developed as an antiangiogenesis agent for cancer therapy.

  20. Evaluation of antiangiogenic and antiproliferative potential of the organic extract of green algae Chlorella pyrenoidosa.

    Science.gov (United States)

    Kyadari, Mahender; Fatma, Tasneem; Azad, Rajvardhan; Velpandian, Thirumurthy

    2013-01-01

    algae isolates obtained from fresh and marine resources could be one of the richest sources of novel bioactive secondary metabolites expected to have pharmaceutical significance for new drug development. This study was conducted to evaluate the antiangiogenic and antiproliferative activity of Chlorella pyrenoidosa in experimental models of angiogenesis and by MTT assay. lyophilized extract of C. pyrenoidosa was extracted using dichloromethane/methanol (2:1), concentrated and vacuum evaporated to obtain the dried extract. The crude extract was evaluated in the vascular endothelial growth factor (VEGF)-induced angiogenesis in in ovo chick chorioallantoic membrane assay (CAM) at various concentrations (n = 8) using thalidomide and normal saline as positive and untreated control groups, respectively. The crude extract was also subjected to the antiangiogenic activity in the silver nitrate/potassium nitrate cautery model of corneal neovascularization (CN) in rats where topical bevacizumab was used as a positive control. The vasculature was photographed and blood vessel density was quantified using Aphelion imaging software. The extract was also evaluated for its anti proliferative activity by microculture tetrazolium test (MTT) assay using HeLa cancer cell line (ATCC). VEGF increased the blood vessel density by 220% as compared to normal and thalidomide treatment decreased it to 67.2% in in ovo assay. In the in-vivo CN model, the mean neovascular density in the control group, the C. pyrenoidosa extract and bevacizumab group were found to be 100%, 59.02%, and 32.20%, respectively. The Chlorella pyrenoidosa extract negatively affected the viability of HeLa cells. An IC50 value of the extract was 570 μg/ml, respectively. a significant antiangiogenic activity was observed against VEGF-induced neovascularization and antiproliferative activity by MTT assay. In this study, it could be attributed that the activity may be due to the presence of secondary metabolites in the C

  1. Antiangiogenic Therapy in the Treatment of Recurrent Medulloblastoma in the Adult: Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Giuseppe Privitera

    2009-01-01

    Full Text Available Medulloblastoma is a rare tumor in central nervous system, with an even rarer occurrence in adulthood. The management of a recurrent disease is a medical challenge; chemotherapy has been used as the treatment of choice, while reirradiation has been employed in selected cases. We report the case of a 51-year-old man with recurrent medulloblastoma. He was treated with local reirradiation, chemotherapy, and antiangiogenic drug, with the latter giving the longer progression-free interval. The aim of this report is to show that recurrent medulloblastoma in adults can be approached with a multimodality treatment and that antiangiogenic therapy should have a role in the management of this disease.

  2. High-Throughput Cytochrome P450 Cocktail Inhibition Assay for Assessing Drug-Drug and Drug-Botanical Interactions.

    Science.gov (United States)

    Li, Guannan; Huang, Ke; Nikolic, Dejan; van Breemen, Richard B

    2015-11-01

    Detection of drug-drug interactions is essential during the early stages of drug discovery and development, and the understanding of drug-botanical interactions is important for the safe use of botanical dietary supplements. Among the different forms of drug interactions that are known, inhibition of cytochrome P450 (P450) enzymes is the most common cause of drug-drug or drug-botanical interactions. Therefore, a rapid and comprehensive mass spectrometry-based in vitro high-throughput P450 cocktail inhibition assay was developed that uses 10 substrates simultaneously against nine CYP isoforms. Including probe substrates for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and two probes targeting different binding sites of CYP3A4/5, this cocktail simultaneously assesses at least as many P450 enzymes as previous assays while remaining among the fastest due to short incubation times and rapid analysis using ultrahigh pressure liquid chromatography-tandem mass spectrometry. The method was validated using known inhibitors of each P450 enzyme and then shown to be useful not only for single-compound testing but also for the evaluation of potential drug-botanical interactions using the botanical dietary supplement licorice (Glycyrrhiza glabra) as an example. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Significance and challenges of stereoselectivity assessing methods in drug metabolism

    Directory of Open Access Journals (Sweden)

    Zhuowei Shen

    2016-02-01

    Full Text Available Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs is expensive. As a detector of chromatographic methods, mass spectrometry (MS is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

  4. Progress on Antiangiogenic Therapy for Patients with Malignant Glioma

    Directory of Open Access Journals (Sweden)

    Manmeet S. Ahluwalia

    2010-01-01

    Full Text Available Glioblastoma (GBM is the most common primary brain tumor occurring in America. Despite recent advances in therapeutics, the prognosis for patients with newly diagnosed GBM remains dismal. As these tumors characteristically show evidence of angiogenesis (neovascularization there has been great interest in developing anti-angiogenic therapeutic strategies for the treatment of patients with this disease and some anti-angiogenic agents have now been used for the treatment of patients with malignant glioma tumors. Although the results of these clinical trials are promising in that they indicate an initial therapeutic response, the anti-angiogenic therapies tested to date have not changed the overall survival of patients with malignant glioma tumors. This is due, in large part, to the development of resistance to these therapies. Ongoing research into key features of the neovasculature in malignant glioma tumors, as well as the general angiogenesis process, is suggesting additional molecules that may be targeted and an improved response when both the neovasculature and the tumor cells are targeted. Prevention of the development of resistance may require the development of anti-angiogenic strategies that induce apoptosis or cell death of the neovasculature, as well as an improved understanding of the potential roles of circulating endothelial progenitor cells and vascular co-option by tumor cells, in the development of resistance.

  5. Antiangiogenic Metargidin Peptide (AMEP) Gene Therapy in Disseminated Melanoma

    DEFF Research Database (Denmark)

    Spanggaard, Iben; Gehl, Julie

    2015-01-01

    Gene delivery by electroporation is an efficient method for transfecting genes into various tissues including tumors. Here we present the treatment protocol used in a phase 1 study on gene electrotransfer of plasmid DNA encoding an antiangiogenic peptide into cutaneous melanoma....

  6. Blood-Based Biomarkers for the Optimization of Anti-Angiogenic Therapies

    Directory of Open Access Journals (Sweden)

    Cristina Rabascio

    2010-05-01

    Full Text Available The dependence of tumor growth and metastasis on blood vessels makes tumor angiogenesis a rational target for therapy. Strategies have been pursued to inhibit neovascularization and to destroy existing tumor vessels, or both. These include direct targeting of endothelial cells, and indirect targeting by inhibiting the release of proangiogenic growth factors by cancer or stromal cells. Many patients benefit from antiangiogenic therapies; thus, development of noninvasive biomarkers of disease response and relapse is a crucial objective to aid in their management. A number of non-invasive tools are described with their potential benefits and limitations. We review currently available candidate biomarkers of anti-angiogenic agent effect. Including these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, and prediction of individual response. This has important consequences for the clinical use of angiogenesis inhibitors and for drug discovery, not only for optimizing the treatment of cancer, but possibly also for developing therapeutic approaches for various other diseases.

  7. In vitro and in vivo anti-angiogenic activity of girinimbine isolated from Murraya koenigii

    Directory of Open Access Journals (Sweden)

    Iman V

    2015-03-01

    Full Text Available Venoos Iman,1 Hamed Karimian,1 Syam Mohan,2 Yahya Hasan Hobani,2 Mohamed Ibrahim Noordin,1 Mohd Rais Mustafa,3 Suzita Mohd Noor41Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 2Medical Research Center, University of Jazan, Jazan, Saudi Arabia; 3Department of Pharmacology, Centre for Natural Products and Drug Discovery (CENAR, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 4Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, MalaysiaAbstract: Girinimbine is a carbazole alkaloid isolated from the stem bark and root of Murraya koenigii. Here we report that girinimbine is an inhibitor of angiogenic activity both in vitro and in vivo. MTT results showed that girinimbine inhibited proliferation of human umbilical vein endothelial cells, while results from endothelial cell invasion, migration, tube formation, and wound healing assays demonstrated significant time- and dose-dependent inhibition by girinimbine. A proteome profiler array done on girinimbine-treated human umbilical vein endothelial cells showed that girinimbine had mediated regulation of pro-angiogenic and anti-angiogenic proteins. The anti-angiogenic potential of girinimbine was also evidenced in vivo in the zebrafish embryo model wherein girinimbine inhibited neo vessel formation in zebrafish embryos following 24 hours of exposure. Together, these results showed that girinimbine could effectively suppress angiogenesis, suggestive of its therapeutic potential as a novel angiogenesis inhibitor. Keywords: angiogenesis, inhibitor, carbazole alkaloid, zebrafish

  8. [Educative game on drugs for blind individuals: development and assessment].

    Science.gov (United States)

    Mariano, Monaliza Ribeiro; Rebouças, Cristiana Brasil de Almeida; Pagliuca, Lorita Marlena Freitag

    2013-08-01

    Study aimed to develop and assess an educational game on psychoactive drugs accessible to blind individuals, conducted in three steps: development of the educative game, evaluation by three special education experts, and assessment by twelve blind individuals. As a result, a board game called Drugs: staying clean was developed. In the Alpha version, experts made suggestions regarding the game rules and instructions and the board base, including square texture, game pieces, and Braille writing. In Beta version, we proceeded to the assessment by the blind participants, who suggested changes in the square texture and the addition of Velcro-type material to fix the counters on the board. Then, the Gamma version was played by the last pairs of blind players and was considered by them to be adequate. In the evaluation of the experts, the game was appropriate, as it allowed access to information on psychoactive drugs in a ludic and playful manner.

  9. Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

    Science.gov (United States)

    Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.

    2014-01-01

    This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771

  10. Drug policy coordination: identifying and assessing dimensions of coordination.

    Science.gov (United States)

    Hughes, Caitlin Elizabeth; Ritter, Alison; Mabbitt, Nicholas

    2013-05-01

    Coordination has been recognised as a critical ingredient for successful drug policy governance. Yet what coordination means and how we assess the processes, outputs and outcomes of drug policy coordination is seldom defined. In this article we explore the utility of internationally recognised principles of good governance for examining aspects of drug policy coordination. We describe the development of an assessment tool, and pilot it in one context that has been both praised and criticised for its approach to drug policy coordination: Australia. Eight good governance principles of the United Nations Economic and Social Commission for Asia and the Pacific (which specify the need for policy processes to be participatory, responsive, equitable etc.), were adapted to drug policy coordination. A pilot survey was created to enable assessment of their perceived importance and perceived application and administered to 36 stakeholders from peak Australian advisory bodies. The instrument was shown to have high internal reliability and high face validity. Application to the Australian context suggested that the eight principles differed in importance, and that the most important principles were 'accountability' and 'participation'. Application also revealed perceived strengths and weaknesses in coordination, most notably, an apparent need to increase 'accountability' for stakeholder actions. The instrument requires further assessment of reliability and validity. Yet, at least within the Australian context, it starts to unpack normative statements about coordination to show perceptions of what coordination is, areas where improvement may be warranted and the degree of contestation amongst different players. Further application of the good governance lens within this and other contexts will progress the assessment of a fundamental yet neglected policy process and foster a more nuanced consideration of the possibilities for coordination in the drug policy "soup". Copyright

  11. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: Analysis of single-agent and combined modality approaches

    International Nuclear Information System (INIS)

    Beal, Kathryn; Abrey, Lauren E; Gutin, Philip H

    2011-01-01

    Surgical resection followed by radiotherapy and temozolomide in newly diagnosed glioblastoma can prolong survival, but it is not curative. For patients with disease progression after frontline therapy, there is no standard of care, although further surgery, chemotherapy, and radiotherapy may be used. Antiangiogenic therapies may be appropriate for treating glioblastomas because angiogenesis is critical to tumor growth. In a large, noncomparative phase II trial, bevacizumab was evaluated alone and with irinotecan in patients with recurrent glioblastoma; combination treatment was associated with an estimated 6-month progression-free survival (PFS) rate of 50.3%, a median overall survival of 8.9 months, and a response rate of 37.8%. Single-agent bevacizumab also exceeded the predetermined threshold of activity for salvage chemotherapy (6-month PFS rate, 15%), achieving a 6-month PFS rate of 42.6% (p < 0.0001). On the basis of these results and those from another phase II trial, the US Food and Drug Administration granted accelerated approval of single-agent bevacizumab for the treatment of glioblastoma that has progressed following prior therapy. Potential antiangiogenic agents-such as cilengitide and XL184-also show evidence of single-agent activity in recurrent glioblastoma. Moreover, the use of antiangiogenic agents with radiation at disease progression may improve the therapeutic ratio of single-modality approaches. Overall, these agents appear to be well tolerated, with adverse event profiles similar to those reported in studies of other solid tumors. Further research is needed to determine the role of antiangiogenic therapy in frontline treatment and to identify the optimal schedule and partnering agents for use in combination therapy

  12. [Interplay between marketing authorization and early benefit assessment of drugs].

    Science.gov (United States)

    Beinlich, Peggy; Müller-Berghaus, J; Sudhop, T; Vieths, S; Broich, K

    2015-03-01

    The early benefit assessment of newly approved drugs with new active substances or new applications that came into force on 1 January 2011 still presents a challenge to the parties involved. This article highlights the interplay between drug marketing approval and early benefit assessment. The constellation of a European, and even an international, largely harmonized, drug authorization process, with a mostly nationally regulated drug reimbursement situation causes inevitably friction, which could be reduced through joint advice discussions during the planning phase for pivotal studies. In 2013, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) provided 439 scientific advice procedures, compared with 98 advice meetings held at the Federal Joint Committee (G-BA), for 12 of which the BfArM or PEI provided written advice. The numbers of advice meetings held at the G-BA are increasing; however, the national competent authorities are involved in only a fraction of these. From the perspective of the national competent authorities, prompt and consistent involvement in the advice procedures regarding early benefit assessment would be useful and desirable.

  13. The Utility of a Population Approach in Drug-Drug Interaction Assessments: A Simulation Evaluation.

    Science.gov (United States)

    Wang, Diane D; Yu, Yanke; Kassir, Nastya; Zhu, Min; Hanley, William D; Earp, Justin C; Chow, Andrew T; Gupta, Manish; Hu, Chuanpu

    2017-10-01

    This study aims at evaluating the utility of the population pharmacokinetics approach in therapeutic protein drug-drug-interaction (DDI) assessment. Simulations were conducted for 2 representative victim drugs, methotrexate and trastuzumab, using a parallel-group design with and without the interaction drug. The effect of a perpetrator on the exposure of the victim drug is described as the ratio of clearance/apparent clearance of the victim drug given with or without the perpetrator. The power of DDI assessment was calculated as the percentage of runs with 90% confidence interval of the estimated DDI effect within 80% to 125% for the scenarios of no DDI, benchmarked with the noncompartmental approach with intensive sampling. The impact of the number of subjects, the number of sampling points per subject, sampling time error, and model misspecification on the power of DDI determination were evaluated. Results showed that with equal numbers of subjects in each arm, the population pharmacokinetics approach with sparse sampling may need about the same or a higher number of subjects compared to a noncompartmental approach in order to achieve similar power. Increasing the number of subjects, even if only in the study drug alone arm, can increase the power. Sampling or dosing time error had notable impacts on the power for methotrexate but not for trastuzumab. Model misspecification had no notable impacts on the power for trastuzumab. Overall, the population pharmacokinetics approach with sparse sampling built in phase 2/3 studies allows appropriate DDI assessment with adequate study design and analysis and can be considered as an alternative to dedicated DDI studies. © 2017, The American College of Clinical Pharmacology.

  14. Assessment of veterinary drug use and determination of ...

    African Journals Online (AJOL)

    A cross-sectional study was conducted between October 2009 and January 2010 to assess veterinary drug usage by broiler chicken farmers and to determine antimicrobial residues in broiler meat in Urban district, Zanzibar, Tanzania. Fifty five smallholder farmers were interviewed on types of antimicrobials, reasons for use, ...

  15. Assessment of patients' knowledge of their drug therapy in a ...

    African Journals Online (AJOL)

    Patients' knowledge of their medications is an important factor in ensuring adherence. Medication adherence is essential for rational drug use and derivation of optimal therapy. This study was conducted to assess knowledge of outpatients regarding their medications. A well structured questionnaire was administered to 200 ...

  16. Hypoxia upregulates Bcl-2 expression and suppresses interferon-gamma induced antiangiogenic activity in human tumor derived endothelial cells.

    LENUS (Irish Health Repository)

    Wang, Jiang Huai

    2012-02-03

    BACKGROUND: Hypoxia in solid tumors potentially stimulates angiogenesis by promoting vascular endothelial growth factor (VEGF) production and upregulating VEGF receptor expression. However, it is unknown whether hypoxia can modulate the effect of anti-angiogenic treatment on tumor-derived endothelium. METHODS: Human tumor-derived endothelial cells (HTDEC) were freshly isolated from surgically removed human colorectal tumors by collagenase\\/DNase digestion and Percol gradient sedimentation. Cell proliferation was assessed by measuring BrdU incorporation, and capillary tube formation was measured using Matrigel. Cell apoptosis was assessed by flow cytometry and ELISA, and Bcl-2 expression was detected by Western blot analysis. RESULTS: Under aerobic culture conditions (5% CO2 plus 21% O2) HTDEC expressed less Bcl-2 and were more susceptible to IFN-gamma-induced apoptosis with significant reductions in both cell proliferation and capillary tube formation, when compared with normal human macrovascular and microvascular EC. Following exposure of HTDEC to hypoxia (5% CO2 plus 2% O2), IFN-gamma-induced cell apoptosis, and antiangiogenic activity (i.e. an inhibition in cell proliferation and capillary tube formation) in HTDEC were markedly attenuated. This finding correlated with hypoxia-induced upregulation of Bcl-2 expression in HTDEC. CONCLUSIONS: These results indicate that hypoxia can protect HTDEC against IFN-gamma-mediated cell death and antiangiogenic activity, and suggest that improvement of tumor oxygenation may potentiate the efficacy of anti-cancer therapies specifically targeting the inhibition of tumor angiogenesis.

  17. Comparison of anti-angiogenic properties of pristine carbon nanoparticles

    DEFF Research Database (Denmark)

    Wierzbicki, Mateusz; Sawosz, Ewa; Grodzik, Marta

    2013-01-01

    nanoparticles decreased the expression of vascular endothelial growth factor receptor. These results provide new insights into the biological activity of carbon nanomaterials and emphasise the potential use of multi-wall nanotubes and diamond nanoparticles in anti-angiogenic tumour therapy.......Angiogenesis is vital for tumour formation, development and metastasis. Recent reports show that carbon nanomaterials inhibit various angiogenic signalling pathways and, therefore, can be potentially used in anti-angiogenic therapy. In the present study, we compared the effect of different carbon...... nanomaterials on blood vessel development. Diamond nanoparticles, graphite nanoparticles, graphene nanosheets, multi-wall nanotubes and C60 fullerenes were evaluated for their angiogenic activities using the in ovo chick embryo chorioallantoic membrane model. Diamond nanoparticles and multi-wall nanotubes...

  18. Assessment of the incidence of substandard drugs in developing countries.

    Science.gov (United States)

    Shakoor, O; Taylor, R B; Behrens, R H

    1997-09-01

    In a number of developing countries there is reportedly a high incidence of the availability of substandard drugs. The majority of these reports do not contain quantitative data to support these claims, nor do they describe the methodology employed for the quality assessment. Many assume counterfeiting as the reason for the poor quality and in some cases this is not justified. We collected 96 samples of chloroquine and selected antibacterials from Nigeria and Thailand in a controlled and methodical manner and analysed them using appropriately validated methods based on high-performance liquid chromatography capable of detecting drug-related impurities and quantifying active drug(s). The results indicate that 36.5% of the samples were substandard with respect to pharmacopoeial limits. Decomposition was the cause of poor quality in a number of the samples but overall, poor manufacturing appeared to be prevalent. The analyses generated little evidence to indicate fraudulent manufacturing. Treatment failure and drug-resistance are possible consequences of the use of substandard drugs.

  19. Critical Assessment of Implantable Drug Delivery Devices in Glaucoma Management

    Directory of Open Access Journals (Sweden)

    Dharani Manickavasagam

    2013-01-01

    Full Text Available Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure. However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a patient tolerability and acceptance, (b drug stability and drug release profiles, (c therapeutic efficacy, and (d toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma.

  20. Recent Advances in chemistry and pharmacology of 2-methoxyestradiol: An anticancer investigational drug.

    Science.gov (United States)

    Kumar, B Sathish; Raghuvanshi, Dushyant Singh; Hasanain, Mohammad; Alam, Sarfaraz; Sarkar, Jayanta; Mitra, Kalyan; Khan, Feroz; Negi, Arvind S

    2016-06-01

    2-Methoxyestradiol (2ME2), an estrogen hormone metabolite is a potential cancer chemotherapeutic agent. Presently, it is an investigational drug under various phases of clinical trials alone or in combination therapy. Its anticancer activity has been attributed to its antitubulin, antiangiogenic, pro-apoptotic and ROS induction properties. This anticancer drug candidate has been explored extensively in last twenty years for its detailed chemistry and pharmacology. Present review is an update of its chemistry and biological activity. It also extends an assessment of potential of 2ME2 and its analogues as possible anticancer drug in future. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Assessment of Drug Abuse in Iran’s Prisons

    Directory of Open Access Journals (Sweden)

    Jafar Bolhari

    2003-08-01

    Full Text Available Drugs are consumed in all prisons throughout the world in such a way that the matter has turned into a challenging issue for the governments. The current research seeks to determine the level of the spread of drug abuse among prison inmates in the country’s prisons. To name the other objectives pursued by this research one can refer to the distinction of demographic features of the abusers, determining the type of drugs distributed, the method of consumption in prisons, existence of high-risk behaviors and its level among prison inmates as well as taking into consideration the spread of mental disorders along with drug abuse. Such a research has been carried out in the form of a qualitative and quantitative study. The collection of the required data in the qualitative study was conducted by using detailed questionnaires and through interviews in four groups comprising male and female inmates who have committed drug-related crimes or other offences, prison wards as well as prison authorities. In the quantitative study that was conducted on male inmates questionnaires related to demographic and general specifications, the assessment of the situation of drug abuse and individuals’ view towards drug abuse as well as SCL-90-R were used. The group under study includes all prison inmates, prison wards and prison authorities in Iran. The individuals under study were selected from prisons in five different provinces using the cluster sample-taking and random methods. The number of individuals in the sample reached 1436 people. In order to clarify the outcome, frequency tables, mode, mediam, mean, standard deviation as well as X & Z tests were used. The result of the research implies that the comparison of drug abuse before and after entering the prison indicates a meaningful relationship.Meanwhile no meaningful difference was observed among age groups.

  2. Technology assessment and the Food and Drug Administration

    Science.gov (United States)

    Kaplan, A. H.; Becker, R. H.

    1972-01-01

    The statutory standards underlying the activities of the FDA, and the problems the Agency faces in decision making are discussed from a legal point of view. The premarketing clearance of new drugs and of food additives, the two most publicized and criticized areas of FDA activity, are used as illustrations. The importance of statutory standards in technology assessment in a regulatory setting is developed. The difficulties inherent in the formulation of meaningful standards are recognized. For foods, the words of the statute are inadequate, and for drugs, a statutory recognition of the various other objectives would be useful to the regulator and the regulated.

  3. Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids.

    Science.gov (United States)

    Ambrożak, Agnieszka; Steinebach, Christian; Gardner, Erin R; Beedie, Shaunna L; Schnakenburg, Gregor; Figg, William D; Gütschow, Michael

    2016-12-06

    The development of novel thalidomide derivatives as immunomodulatory and anti-angiogenic agents has revived over the last two decades. Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido-, tetrafluorophthalimido-, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine-activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti-angiogenic properties in an ex vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti-angiogenic activity. An opening of the five-membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen-bond networking, as revealed by comparative X-ray crystallographic analyses. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Ursula Winter

    Full Text Available Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure or metronomic (7-day continuous exposure treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50 was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks and metronomic (5 days a week for 2 weeks topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23 was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p0.05. In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (p<0.05. Continuous exposure to melphalan or topotecan increased the chemosensitivity of retinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced

  5. Condom use assessment of persons in drug abuse treatment.

    Science.gov (United States)

    Ross, Dana; Schumacher, Joseph E

    2004-12-01

    The purpose of this study was to objectively and quantitatively assess individual skill level of male condom use. This study developed a reliable and face valid assessment of correct male condom use based on Centers for Disease Control and Prevention criteria. Participants (N= 163) were recruited from persons in treatment for cocaine addiction. Condom use was assessed on the basis of correct completion of eight discrete steps. An overall score of 40% correct condom use indicated the need for training in this sample. Assessment showed training needs especially related to steps involving reduction of ejaculate leakage and steps related to potential hazards of nonoxynol-9 use. Frequency of condom use was also assessed; there was no correlation between frequency of condom use and condom use skill. Drug addiction treatment programs are encouraged to incorporate HIV risk reduction programs that teach condom use skills and use the CUDOS as an empirical measure of condom skill acquisition.

  6. Improvements in progression-free and overall survival due to the use of anti-angiogenic agents in gynecologic cancers.

    Science.gov (United States)

    Schmid, Bernd C; Oehler, Martin K

    2015-01-01

    In ovarian cancer (OC), the best established anti-angiogenic drug, bevacizumab, has demonstrated only modest prolonged progression free survival (PFS) and no increased overall survival (OS). The unanswered question is in which clinical situation bevacizumab might benefit ovarian cancer patients most. The cost-benefit analysis in the primary treatment was found not to be favorable but the use in the recurrent OC setting might be more compelling. Multi-targeted anti-angiogenic tyrosine kinase inhibitors (TKI) such as cediranib and pazopanib have shown some therapeutic benefits with improvements of PFS and OS in patients with platinum-sensitive as well as resistant OC, in whom there is a major need for novel therapies. Very promising is also the observed improvement of PFS in recurrent OC in patients when combining cediranib with the PARP inhibitor olaparib without giving additional chemotherapy. The anti-angiogenic agent trebananib has achieved similar results like TKI, but has a favorable toxicity profile which does not overlap with those of VEGF inhibitors. In cervical cancer the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent or metastatic chemotherapy-naive disease results in a significant increase in OS. Considering the lack of therapeutic options in this difficult clinical setting, the inclusion of bevacizumab most likely will become a new standard for recurrent cervical cancer. In uterine sarcomas as very aggressive malignancies with a substantial need for better therapies the observed improved PFS with sorafenib warrants further investigation. No data showing a convincing improvement of survival in endometrial cancer have been presented yet. In view of the limited PFS and OS benefit observed with anti-angiogenics in gynecologic oncology, increased morbidity due to side effects of this treatment resulting in loss of quality of life and also substantial costs have to be taken into consideration. Thorough case selection

  7. Physician assessments of drug seeking behavior: A mixed methods study.

    Directory of Open Access Journals (Sweden)

    Michael A Fischer

    Full Text Available Pain complaints are common, but clinicians are increasingly concerned about overuse of opioid pain medications. This may lead patients with actual pain to be stigmatized as "drug-seeking," or attempting to obtain medications they do not require medically. We assessed whether patient requests for specific opioid pain medication would lead physicians to classify them as drug-seeking and change management decisions.Mixed-methods analysis of interviews with 192 office-based primary care physicians after viewing video vignettes depicting patients presenting with back pain. For each presentation physicians were randomly assigned to see either an active request for a specific medication or a more general request for help with pain. The main outcome was assignment by the physician of "drug-seeking" as a potential diagnosis among patients presenting with back pain. Additional outcomes included other actions the physician would take and whether the physician would prescribe the medication requested. A potential diagnosis of drug-seeking behavior was included by 21% of physicians seeing a specific request for oxycodone vs. 3% for a general request for help with back pain(p<0.001. In multivariable models an active request was most strongly associated with a physician-assigned diagnosis of drug-seeking behavior(OR 8.10; 95% CI 2.11-31.15;p = 0.002; other major patient and physician characteristics, including gender and race, did not have strong associations with drug-seeking diagnosis. Physicians described short courses of opioid medications as a strategy for managing patients with pain while avoiding opioid overuse.When patients make a specific request for opioid pain medication, physicians are far more likely to suspect that they are drug-seeking. Physician suspicion of drug-seeking behavior did not vary by patient characteristics, including gender and race. The strategies used to assess patients further varied widely. These findings indicate a need for

  8. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor.

    Science.gov (United States)

    Kumar, Sushil; Mokhtari, Reza Bayat; Sheikh, Reihaneh; Wu, Bing; Zhang, Libo; Xu, Ping; Man, Shan; Oliveira, Indhira Dias; Yeger, Herman; Kerbel, Robert S; Baruchel, Sylvain

    2011-09-01

    Low dose metronomic (LDM) chemotherapy, combined with VEGF signaling pathway inhibitors, is a highly effective strategy to coordinately inhibit angiogenesis and tumor growth in many adult preclinical cancer models. We have tested the efficacies of daily oral LDM topotecan alone and in combination with pazopanib, a VEGF receptor inhibitor, in three pediatric extracranial solid tumor mouse models. In vitro dose-response study of topotecan and pazopanib was conducted on several neuroblastoma, osteosarcoma, and rhabdomyosarcoma cell lines. In vivo antitumor efficacies of the LDM topotecan and pazopanib as single agents and in combination were tested on 4 subcutaneous xenograft models and on 2 neuroblastoma metastatic models. Circulating angiogenic factors such as circulating endothelial cells (CEC), circulating endothelial pro genitor cells (CEP), and microvessel densities were used as surrogate biomarker markers of antiangiogenic activity. In vitro, topotecan caused a dose-dependent decrease in viabilities of all cell lines, while pazopanib did not. In vivo, combination of topotecan + pazopanib (TP + PZ) showed significant antitumor activity and significant enhancement in survival compared with the respective single agents in all models. Reductions in viable CEP and/or CEC levels and tumor microvessel density were correlated with tumor response and therefore confirmed the antiangiogenic activity of the regimens. Pharmacokinetic studies of both drugs did not reveal any drug-drug interaction. Metronomic administration of TP + PZ showed a statistically significant antitumor activity compared with respective single agents in pediatric tumor mouse models and represent a valid option as a maintenance therapy in aggressive pediatric solid tumors. ©2011 AACR.

  9. Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo.

    Science.gov (United States)

    Vasvari, Gergely P; Dyckhoff, Gerhard; Kashfi, Farzaneh; Lemke, Britt; Lohr, Jennifer; Helmke, Burkhard M; Schirrmacher, Volker; Plinkert, Peter K; Beckhove, Philipp; Herold-Mende, Christel C

    2007-10-15

    Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor-derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs. (c) 2007 Wiley-Liss, Inc.

  10. NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION

    Science.gov (United States)

    Emblem, Kyrre; Pinho, Marco; Chandra, Vyshak; Gerstner, Elizabeth; Stufflebeam, Steve; Sorenson, Greg; Harris, Gordon; Freedman, Rachel; Sohl, Jessica; Younger, Jerry; Krop, Ian; Winer, Eric; Lin, Nancy

    2014-01-01

    INTRODUCTION: As systemic therapy improves, brain metastases are increasingly common in patients with breast cancer. Unfortunately, effective therapy with durable control has remained elusive [1]. Combining bevacizumab and cyototoxic chemotherapy is an appealing approach as the anti-angiogenic effect of bevicizumab may improve delivery of cytotoxic drugs to brain tumors. METHODS: We conducted a Phase II study of patients with parenchymal brain metastasis treated with bevacizumab and carboplatin [2]. Patients could have any hormone receptor status or any number of prior therapies. Patients with HER2+ breast cancer also received trastuzamab. Correlative perfusion MRI scans to look at tumor perfusion, blood volume, vessel calibers and relative oxygen saturation (ΔSO2) levels were performed at baseline, day 1, and after 2 months of therapy [3, 4]. For consistency, the largest contrast-enhancing lesion in each patient visible on all three MR visits was selected for analysis. RESULTS: Thirty-eight patients were enrolled in the study of which 32 had, paired evaluable imaging datasets. Compared to baseline, 12/32 patients were identified as responders by a durable increase in ΔSO2 levels at day 1 and at 2 months above a 5% measurement error threshold. The remaining patients were identified by stable (15/32) or reduced (5/32) ΔSO2 levels. Patients responding to therapy showed increased tumor perfusion (Mann-Whitney; P10 µm) were seen across all patients. CONCLUSIONS: Similar to primary brain tumors [2, 3], perfusion MRI demonstrates that anti-angiogenic therapy can induce vascular normalization in a subset of patients with metastatic breast cancer to the brain. Our data indicate that the vascular response may also be associated with improved survival. [1] Lin NU, Lancet Oncol 2013 [2] Sorensen AG, Cancer Res 2012 [3] Emblem KE, Nat Med 2013

  11. Perforated Gastric Ulcer Associated with Anti-Angiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Diogo Libânio

    2017-08-01

    Full Text Available Anti-angiogenic therapy with bevacizumab, an inhibitor of vascular endothelial growth factor, is commonly used in metastatic colorectal cancer and is rarely associated with gastrointestinal perforation, perforation being more frequent in the primary tumor site or at the anastomotic level. We present the case of a 64-year-old male with stage IV rectal adenocarcinoma who was on palliative chemotherapy with FOLFOX and bevacizumab. After the 4th chemotherapy cycle, our patient started fever and epigastric pain. He was hemodynamically stable, and signs of peritoneal irritation were absent. There were no alterations in the abdominal X-ray, and C-reactive protein was markedly elevated. A CT scan revealed a de novo thickness in the gastric antrum. Upper digestive endoscopy showed an ulcerated 40-mm lesion in the angulus, with a 20-mm orifice communicating with an exsudative cavity revested by the omentum. A conservative approach was decided including fasting, broad-spectrum intravenous antibiotics, and proton-pump inhibitors. Subsequent gastroduodenal series showed no contrast extravasation, allowing the resumption of oral nutrition. Esophagogastroduodenoscopy after 8 weeks showed perforation closure. Biopsies did not show neoplastic cells or Heliobacter pylori infection. Although the success in the conservative management of perforation allowing the maintenance of palliative chemotherapy (without bevacizumab, the patient died after 4 months due to liver failure. The reported case shows an uncommon endoscopic finding due to a rare complication of anti-angiogenic therapy. Additionally, it reminds clinicians that a history of gastroduodenal ulcers should be actively sought before starting anti-angiogenic treatment and that suspicion for perforation should be high in these cases.

  12. [Comparison of anti-angiogenic effect in vitro between ranibizumab and bevacizumab].

    Science.gov (United States)

    Souto, Alexandre Cupello; Maricato, Juliana Terzi; Denapoli, Priscila Martins Andrade; Sallum, Juliana Maria Ferraz; Han, Sang Won

    2011-01-01

    To evaluate the comparative in-vitro antiangiogenic effect of Bevacizumab and Ranibizumab. Endothelial venous umbilical cells culture (ECV304) cultivated in F12 media with addition of 10% Fetal Bovine Serum, were plaqued and treated with clinically relevant concentrations of Bevacizumab and Ranibizumab just after the scratch done in the middle of the culture (scratch methodology). Measurements of the linear size of the area free of cell proliferation were done 24, 48 and 72 hours after the scratch day point. All the experiments were done in triplicate and statistical analysis were done with T-student test. Inhibitory effect was observed just at the concentrations of 0.5 and 0.7 mg/ml in both drugs. At 0.7 mg/ml, Ranibizumab demonstrated a more potent proliferative inhibitory effect than Bevacizumab. At the same concentration, Ranibizumab was three times more potent than Ranibizumab. Inhibitory effect was observed just in the first 24 hours for both drugs. Ranibizumab demonstrates an increased effect when compared to Bevacizumab and this is related more to the different molar rate of each drug than related to a real better proliferative inhibitory effect.

  13. The anti-angiogenic effect of dexamethasone in a murine hepatocellular carcinoma model by augmentation of gluconeogenesis pathway in malignant cells.

    Science.gov (United States)

    Shang, Fei; Liu, Mingming; Li, Bingwei; Zhang, Xiaoyan; Sheng, Youming; Liu, Shuying; Han, Jianqun; Li, Hongwei; Xiu, Ruijuan

    2016-05-01

    Angiogenesis is a long-term complex process involving various protein factors in hepatocellular carcinoma (HCC). Dexamethasone (Dex), considered as a synthetic glucocorticoid drug in clinical therapy, has been reported to have the therapeutic efficacy against liver cancer by intervention of abnormal glycolysis. In this study, we investigated the anti-angiogenic effect of Dex in murine liver cancer and attempted to demonstrate the potential mechanism. The malignant cells H22 were treated with Dex. Western blotting was used to explore the expression of PEPCK and G6Pase which were the two key enzymes that regulated gluconeogenesis. The supernatants from cultured H22 treated by Dex were collected and co-cultured with HUVECs. In vitro, migration assay, transwell assay and tube formation assay were performed to assess for migration, proliferation and tube formation abilities of HUVECs, respectively. In situ murine hepatoma model with green fluorescent protein markers (HepG2-GFP) was constructed to determine angiogenesis after treatment by Dex. PEPCK and G6Pase were almost deficient in H22 compared with normal liver cells NCTC-1469 (P gluconeogenesis could be restored significantly (P gluconeogenesis pathway.

  14. Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia.

    Science.gov (United States)

    Nayeri, Unzila A; Buhimschi, Irina A; Laky, Christine A; Cross, Sarah N; Duzyj, Christina M; Ramma, Wenda; Sibai, Baha M; Funai, Edmund F; Ahmed, Asif; Buhimschi, Catalin S

    2014-06-01

    Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

  15. Drug interactions evaluation: An integrated part of risk assessment of therapeutics

    International Nuclear Information System (INIS)

    Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping; Huang, Shiew-Mei

    2010-01-01

    Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industry and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.

  16. Epigenetics and cancer: implications for drug discovery and safety assessment

    International Nuclear Information System (INIS)

    Moggs, Jonathan G.; Goodman, Jay I.; Trosko, James E.; Roberts, Ruth A.

    2004-01-01

    It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Research conducted over the last two decades has led to the paradigm that chemicals can cause cancer either by damaging DNA or by altering cellular growth, probably via receptor-mediated changes in gene expression. However, recent evidence suggests that gene expression can be altered markedly via several diverse epigenetic mechanisms that can lead to permanent or reversible changes in cellular behavior. Key molecular events underlying these mechanisms include the alteration of DNA methylation and chromatin, and changes in the function of cell surface molecules. Thus, for example, DNA methyltransferase enzymes together with chromatin-associated proteins such as histone modifying enzymes and remodelling factors can modify the genetic code and contribute to the establishment and maintenance of altered epigenetic states. This is relevant to many types of toxicity including but not limited to cancer. In this paper, we describe the potential for interplay between genetic alteration and epigenetic changes in cell growth regulation and discuss the implications for drug discovery and safety assessment

  17. Evaluation of high frequency ultrasound methods and contrast agents for characterising tumor response to anti-angiogenic treatment

    Energy Technology Data Exchange (ETDEWEB)

    Rix, Anne, E-mail: arix@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Lederle, Wiltrud, E-mail: wlederle@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Siepmann, Monica, E-mail: monica.siepmann@rub.de [Department of Medical Engineering, Universitätstraße 150, 44780 Bochum, Ruhr-University Bochum, Bochum (Germany); Fokong, Stanley, E-mail: sfokong@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Behrendt, Florian F., E-mail: fbehrendt@ukaachen.de [Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Bzyl, Jessica, E-mail: jbzyl@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Grouls, Christoph, E-mail: cgrouls@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Kiessling, Fabian, E-mail: fkiessling@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Palmowski, Moritz, E-mail: mpalmowski@ukaachen.de [Department of Experimental Molecular Imaging, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany); Department of Nuclear Medicine, Pauwelsstrasse 30, 52074 Aachen, RWTH-Aachen University, Aachen (Germany)

    2012-10-15

    Purpose: To compare non-enhanced and contrast-enhanced high-frequency 3D Doppler ultrasound with contrast-enhanced 2D and 3D B-mode imaging for assessing tumor vascularity during antiangiogenic treatment using soft-shell and hard-shell microbubbles. Materials and methods: Antiangiogenic therapy effects (SU11248) on vascularity of subcutaneous epidermoid-carcinoma xenografts (A431) in female CD1 nude mice were investigated longitudinally using non-enhanced and contrast-enhanced 3D Doppler at 25 MHz. Additionally, contrast-enhanced 2D and 3D B-mode scans were performed by injecting hard-shell (poly-butyl-cyanoacrylate-based) and soft-shell (phospholipid-based) microbubbles. Suitability of both contrast agents for high frequency imaging and the sensitivity of the different ultrasound methods to assess early antiangiogenic therapy effects were investigated. Ultrasound data were validated by immunohistology. Results: Hard-shell microbubbles induced higher signal intensity changes in tumors than soft-shell microbubbles in 2D B-mode measurements (424 ± 7 vs. 169 ± 8 A.U.; p < 0.01). In 3D measurements, signals of soft-shell microbubbles were hardly above the background (5.48 ± 4.57 vs. 3.86 ± 2.92 A.U.), while signals from hard-shell microbubbles were sufficiently high (30.5 ± 8.06 A.U). Using hard-shell microbubbles 2D and 3D B-mode imaging depicted a significant decrease in tumor vascularity during antiangiogenic therapy from day 1 on. Using soft-shell microbubbles significant therapy effects were observed at day 4 after therapy in 2D B-mode imaging but could not be detected in the 3D mode. With non-enhanced and contrast-enhanced Doppler imaging significant differences between treated and untreated tumors were found from day 2 on. Conclusion: Hard-shell microbubble-enhanced 2D and 3D B-mode ultrasound achieved highest sensitivity for assessing therapy effects on tumor vascularisation and were superior to B-mode ultrasound with soft-shell microbubbles and to Doppler

  18. Anti-angiogenic therapy and radioimmunotherapy in colon cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kinuya, Seigo; Yokoyama, Kunihiko; Michigishi, Takatoshi; Tonami, Norihisa [Dept. of Nuclear Medicine, Kanazawa Univ. (Japan); Kawashima, Atsuhiro [Dept. of Pathology (I), Kanazawa Univ. School of Medicine, Kanazawa, Ishikawa (Japan); Kudo, Miho; Kasahara, Yoshihito [Dept. of Pediatrics, Kanazawa University School of Medicine, Kanazawa, Ishikawa (Japan); Watanabe, Naoto [Dept. of Radiology, Toyama Medical and Pharmaceutical University, Toyama (Japan); Shuke, Noriyuki [Dept. of Radiology, Asahikawa Medical College, Asahikawa (Japan); Bunko, Hisashi [Medical Informatics, Kanazawa University Hospital, Kanazawa (Japan)

    2001-09-01

    Angiogenesis is critical to the growth and metastatic process of malignant tumors. An endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), displays anti-angiogenic and anti-tumorigenic effects. The purpose of this investigation was to determine whether exogenously administered 2-ME would enhance the efficacy of radioimmunotherapy (RIT). Experimental RIT with 4.63 MBq of {sup 131}I-A7, an IgG1 anti-colorectal monoclonal antibody, was conducted in mice xenografted with LS180 human colon cancer cells. 2-ME suspended in 0.5% carboxymethylcellulose was administered daily at a dose of 75 mg/kg per day. 2-ME administration suppressed tumor growth and improved the efficacy of RIT in comparison to RIT alone. Tumor volumes on day 13, expressed as a ratio relative to the initial volume, were 12.7{+-}2.95 in the nontreated control, 4.73{+-}0.89 with 2-ME, 3.05{+-}0.37 with RIT and 0.97{+-}0.20 with RIT+2-ME. Immunohistochemistry of tumor sections stained with an antibody against factor VIII demonstrated a decrease in microvessel number within tumors treated with 2-ME (7.9{+-}0.8/200 x field) as compared with that in control tumors (29.9{+-}2.5). Cell proliferation assay at increasing concentrations of 2-ME showed direct cytotoxicity of 2-ME in vitro at 5 {mu}M and greater. In conclusion, 2-ME enhanced the efficacy of RIT with {sup 131}I-A7 via inhibition of angiogenesis within the xenografts. The direct cytotoxicity of 2-ME appears to have contributed to this improvement. Anti-angiogenic therapy may prolong the dormancy of microscopic metastases while RIT may exterminate this population of cells. Therefore, the combined treatment may improve the therapeutic outcome of patients with disseminated cancer. (orig.)

  19. Quantification of serial changes in cerebral blood volume and metabolism in patients with recurrent glioblastoma undergoing antiangiogenic therapy

    Energy Technology Data Exchange (ETDEWEB)

    Stadlbauer, Andreas, E-mail: andi@nmr.at [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen (Germany); Department of Radiology and Nuclear Medicine, Medical University Vienna, Währinger Gürtel 18-20, A-1097 Vienna (Austria); Pichler, Petra [First Department of Internal Medicine, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Poelten (Austria); Karl, Marianne [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Brandner, Sebastian [Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, D-91054 Erlangen (Germany); Lerch, Claudia [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria); Renner, Bertold [Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nürnberg, Erlangen (Germany); Heinz, Gertraud [Institute of Medical Radiology, University Clinic of St. Pölten, Propst Führer-Straße 4, A-3100 St. Pölten (Austria)

    2015-06-15

    Highlights: • Antiangiogenic therapy can lead to a decreased in CBV in normal brain tissue. • Responding and pseudoresponding lesions to AAT showed a similar CBV decrease. • Cho and NAA allowed for a distinction of responding and pseudoresponding lesions. • Cr ratios are not suited for evaluation of antiangiogenic therapy response. • Responders to AAT may have an increased risk for remote progression of the GBM. - Abstract: Objectives: To evaluate the usefulness of quantitative advanced magnetic resonance imaging (MRI) methods for assessment of antiangiogenic therapy (AAT) response in recurrent glioblastoma multiforme (GBM). Methods: Eighteen patients with recurrent GBM received bevacizumab and 18 patients served as control group. Baseline MRI and two follow-up examinations were acquired every 3–5 months using dynamic susceptibility-weighted contrast (DSC) perfusion MRI and {sup 1}H-MR spectroscopic imaging ({sup 1}H-MRSI). Maps of absolute cerebral blood volume (aCBV) were coregistered with choline (Cho) and N-acetyl-aspartate (NAA) concentrations and compared to usually used relative parameters as well as controls. Results: Perfusion significantly decreased in responding and pseudoresponding GBMs but also in normal appearing brain after AAT onset. Cho and NAA concentrations were superior to Cr-ratios in lesion differentiation and showed a clear gap between responding and pseudoresponding lesions. Responders to AAT exceptionally frequently (6 out of 8 patients) showed remote GBM progression. Conclusions: Quantification of CBV reveals changes in normal brain perfusion due to AAT, which were not described so far. DSC perfusion MRI seems not to be suitable for differentiation between response and pseudoresponse to AAT. However, absolute quantification of brain metabolites may allow for distinction due to a clear gap at 6–9 months after therapy onset.

  20. Probing cardiac repolarization reserve in drug safety assessment

    NARCIS (Netherlands)

    Nalos, L.

    2011-01-01

    Excessive prolongation of cardiac repolarization, manifested as QT prolongation on ECG, is common unwanted side effect of many drugs and drug candidates. Prolongation of QT interval may lead to life threatening cardiac arrhythmia – Torsade de Point (TdP). Number of drugs was withdrawn from the

  1. Clinical relevance of drug-drug interactions : a structured assessment procedure.

    NARCIS (Netherlands)

    Roon, E.N. van; Flikweert, S.; Comte, M. le; Langendijk, P.N.; Kwee-Zuiderwijk, W.J.; Smits, P.; Brouwers, J.R.B.J.

    2005-01-01

    INTRODUCTION: Computerised drug interaction surveillance systems (CIS) may be helpful in detecting clinically significant drug interactions. Experience with CIS reveals that they often yield alerts with questionable clinical significance, fail to provide relevant information on risk factors for the

  2. Clinical relevance of drug-drug interactions - A structured assessment procedure

    NARCIS (Netherlands)

    van Roon, EN; Flikweert, S; le Comte, M; Langendijk, PNJ; Kwee-Zuiderwijk, WJM; Smits, P; Brouwers, JRBJ

    2005-01-01

    Introduction: Computerised drug interaction surveillance systems (CIS) may be helpful in detecting clinically significant drug interactions. Experience with CIS C, reveals that they often yield alerts with questionable clinical significance, fail to provide relevant information on risk factors for

  3. Dual-Energy CT in Patients Treated with Anti-Angiogenic Agents for Non-Small Cell Lung Cancer: New Method of Monitoring Tumor Response?

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yoo Na; Lee, Ho Yun; Lee, Kyung Soo; Chung, Myung Jin; Ahn, Myung Ju; Park, Keun Chil; Kim, Tae Sung; Yi, Chin A [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Seo, Joon Beom [Dept. of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2012-11-15

    To evaluate tumor responses in patients treated with anti-angiogenic agents for non-small cell lung cancer (NSCLC) by assessing intratumoral changes using a dual-energy CT (DECT) (based on Choi's criteria) and to compare it to traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Ten NSCLC patients treated with bevacizumab underwent DECT. Tumor responses to anti-angiogenic therapy were assessed and compared with the baseline CT results using both RECIST (size changes only) and Choi's criteria (reflecting net tumor enhancement). Kappa statistics was used to evaluate agreements between tumor responses assessed by RECIST and Choi's criteria. The weighted {kappa} value for the comparison of tumor responses between the RECIST and Choi's criteria was 0.72. Of 31 target lesions (21 solid nodules, 8 lymph nodes, and two ground-glass opacity nodules [GGNs]), five lesions (16%) showed discordant responses between RECIST and Choi's criteria. Iodine-enhanced images allowed for a distinction between tumor enhancement and hemorrhagic response (detected in 14% [4 of 29, excluding GGNs] of target lesions on virtual nonenhanced images). DECT may serve as a useful tool for response evaluation after anti-angiogenic treatment in NSCLC patients by providing information on the net enhancement of target lesions without obtaining non-enhanced images.

  4. An assessment of drug testing within the construction industry.

    Science.gov (United States)

    Gerber, Jonathan K; Yacoubian, George S

    2002-01-01

    Drug testing in the workplace has gone from virtual nonexistence to widespread employer acceptance during the past two decades. This growth is particularly significant for the construction industry. High rates of alcohol and other drug use, coupled with the high-risk, safety-sensitive nature of the industry, have prompted the development of a variety of drug surveillance and prevention strategies. Despite this growing vigilance, no scholarly works have examined the impact of drug-related policies in the construction industry. To address this limitation, we investigate the efficacy of workplace drug-testing programs in reducing injury incident rates and workers' compensation experience-rating modification factors (MODs) within the construction industry. Analyses indicate that companies with drug-testing programs experienced a 51 percent reduction in incident rates within two years of implementation. Moreover, companies that drug test their employees experienced a significant reduction in their MODs. Policy implications are discussed in light of the current findings.

  5. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Laura Pisarsky

    2016-05-01

    Full Text Available Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

  6. Assessment of socioeconomic consequences of drug abuse in the Ural federal district

    Directory of Open Access Journals (Sweden)

    Inessa Aleksandrovna Gurban

    2013-06-01

    Full Text Available The paper considers issues of the assessment of the socioeconomic consequences of drug abuse in today’s conditions, which have the following features — the approaching of drug-dealers to legalize the drug market, develop the illegal drug market and their analogs and derivatives by the introduction of modern production technologies and distribution of psychoactive agents. Key tendencies observed in the contemporary world in the field of dynamics of the drug market development, which are reflected in the regions of Russia including the Ural Federal District are revealed. The procedure of assessment of socioeconomic expenses of drug abuse including assessment of drug consumers’ expenses and their surrounding people; and also; maintenance costs of the state bodies supervising drug trafficking; expenses for health care and other social expenses connected to drug use; damage to individuals of drug abuse distribution; expenses of private institutions and establishments; socioeconomic impact of drug abuse distribution. The technique uses a tool allowing to carry out a calculation (a heroin equivalent, i.e. the drugs withdrawn by law enforcement agencies and the subsequent calculation of the corresponding number of consumers of each type of drug. This method is aimed at increasing the accuracy of estimates received. On the basis of results calculated according to offered technique, the shares of socioeconomic expenses of drug abuse concerning the income of the cumulative consolidated budget and a gross regional product of the Ural Federal District are defined.

  7. Drugs for rare diseases: mixed assessment in Europe.

    Science.gov (United States)

    2007-02-01

    (1) Worldwide, there are an estimated 6000 to 7000 rare diseases. Patients face special difficulties in obtaining an accurate diagnosis, adequate information about the disease, and access to qualified specialists. (2) Drug companies do not spontaneously conduct research on drugs for rare diseases, mainly because of the limited market for each indication. Only a few dozen of these drugs were available in France before 2000. (3) In 2000 the European Union adopted a Regulation, based on experience in the United States, aimed at promoting the development of drugs for patients suffering from rare diseases, i.e. 'orphan drugs'. (4) In Europe, orphan drug status can be granted when the prevalence of the disease does not exceed 5 cases per 10 000 inhabitants (or when it is more frequent but profitability is likely to be inadequate). (5) Companies that market an orphan drug receive a variety of financial assistance as well as a 10-year marketing monopoly. (6) Between April 2000 and April 2005, 268 medicinal products received European orphan drug status and 22 were granted European marketing authorization. (7) Access to these drugs varies greatly from one European Union Member State to another, mainly because of the high annual treatment costs (up to 300 000 euros per patient). Worldwide sales of the orphan drug imatinib reached more than two thousand million dollars in 2005. (8) Our systematic analyses (see the New Products column of our French edition la revue Prescrire) show that only 5 drugs which received European orphan drug status before May 2005 were for diseases for which there had previously been no treatment. (9) Clinical evaluation of orphan drugs is hindered by the small number of patients available for clinical trials. Some orphan drugs are adequately tested before being brought to market. Others are not compared to existing treatments. In many cases, surrogate criteria are used instead of clinical endpoints. These methodological flaws are in no way limited to

  8. Anti-angiogenic activity of the methanol extract and its fractions of Ulmus davidiana var. japonica.

    Science.gov (United States)

    Jung, Hyun-Joo; Jeon, Hye-Jin; Lim, Eun-Ju; Ahn, Eun-Kyoung; Song, Yun Seon; Lee, Sanghyun; Shin, Kuk Hyun; Lim, Chang-Jin; Park, Eun-Hee

    2007-06-13

    This study aimed to elucidate anti-angiogenic activity of Ulmus davidiana var. japonica that has been widely used in folk medicine. The methanol extract (UDE) of Ulmus davidiana var. japonica concentration-dependently displayed a strong inhibition in the chick chorioallantoic membrane (CAM) angiogenesis. The n-butanol fraction of UDE and subsequent 30% MeOH subfraction were identified to be most responsible for the anti-angiogenic activity.

  9. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    OpenAIRE

    Pisarsky Laura; Bill Ruben; Fagiani Ernesta; Dimeloe Sarah; Goosen Ryan William; Hagmann Jorg; Hess Christoph; Christofori Gerhard

    2016-01-01

    Summary Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and?sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward...

  10. Sprouting strategies and dead ends in anti-angiogenic targeting of NETs.

    Science.gov (United States)

    Carrasco, Patricia; Zuazo-Gaztelu, Iratxe; Casanovas, Oriol

    2017-07-01

    Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that arise from cells of the neuroendocrine system. NETs are characterized by being highly vascularized tumors that produce large amounts of proangiogenic factors. Due to their complexity and heterogeneity, progress in the development of successful therapeutic approaches has been limited. For instance, standard chemotherapy-based therapies have proven to be poorly selective for tumor cells and toxic for normal tissues. Considering the urge to develop an efficient therapy to treat NET patients, vascular targeting has been proposed as a new approach to block tumor growth. This review provides an update of the mechanisms regulating different components of vessels and their contribution to tumor progression in order to develop new therapeutic drugs. Following the description of classical anti-angiogenic therapies that target VEGF pathway, new angiogenic targets such as PDGFs, EGFs, FGFs and semaphorins are further explored. Based on recent research in the field, the combination of therapies that target multiple and different components of vessel formation would be the best approach to specifically target NETs and inhibit tumor growth. © 2017 The authors.

  11. Methodological Issues in Assessing the Impact of Prenatal Drug Exposure

    Directory of Open Access Journals (Sweden)

    Carolien Konijnenberg

    2015-01-01

    Full Text Available Prenatal drug exposure is a common public health concern that can result in perinatal complications, birth defects, and developmental disorders. The growing literature regarding the effects of prenatal exposure to specific drugs such as tobacco, alcohol, cocaine, and heroin is often conflicting and constantly changing. This review discusses several reasons why the effects of prenatal drug exposure are so difficult to determine, including variations in dose, timing, duration of exposure, polydrug use, unreliable measures of drug exposure, latent or “sleeper” effects, genetic factors, and socioenvironmental influences. In addition to providing research guidelines, this review also aims to help clinicians and policy makers to identify the strengths and weaknesses in studies investigating the effects of prenatal drug exposure. This knowledge may be used to make better informed decisions regarding the appropriate treatment for pregnant, drug-dependent women and their children.

  12. Assessment of pharmacokinetic drug-drug interaction between pradigastat and atazanavir or probenecid.

    Science.gov (United States)

    Mendonza, Anisha; Hanna, Imad; Meyers, Dan; Koo, Phillip; Neelakantham, Srikanth; Zhu, Bing; Majumdar, Tapan; Rebello, Sam; Sunkara, Gangadhar; Chen, Jin

    2016-03-01

    Pradigastat, a novel diacylglycerol acyltransferase-1 inhibitor, has activity in common metabolic diseases associated with abnormal accumulation of triglycerides. In vitro studies suggest that glucuronidation is the predominant metabolism pathway for elimination of pradigastat in humans and confirmed the role of uridine 5'-diphosphoglucuronosyltransferase (UGT) enzymes, UGT1A1, -1A3, and -2B7. The in vitro studies using atazanavir as a selective inhibitor of UGT1A1 and -1A3 indicated that these enzymes contribute ∼55% toward the overall glucuronidation pathway. Therefore, a clinical study was conducted to assess the potential for drug interaction between pradigastat and probenecid (purported general UGT inhibitor) or atazanavir (selective UGT1A1, -1A3 inhibitor). The study included 2 parallel cohorts, each with 3 sequential treatment periods and 22 healthy subjects per cohort. The 90%CI of the geometric mean ratios for Cmax,ss and AUCτ,ss of pradigastat were within 0.80-1.25 when administered in combination with probenecid. However, the Cmax,ss and AUCτ,ss of pradigastat decreased by 31% (90%CI: 0.62-0.78) and 26% (0.67-0.82), respectively, when administered in combination with atazanavir. This magnitude of decrease in pradigastat steady-state exposure is not considered clinically relevant. Pradigastat was well tolerated by all subjects, either alone or in combination with atazanavir or probenecid. © 2015, The American College of Clinical Pharmacology.

  13. Antiangiogenic Agent Might Upgrade tumor Cell Sensitivity to Ionizing Radiation

    International Nuclear Information System (INIS)

    Badr, N.M.S.A.

    2013-01-01

    The understanding of the fundamental role of angiogenesis and metastasis in cancer growth has led to tremendous interest in research regarding its regulatory mechanisms and clinical implications in the management of cancer. The present study was conducted to evaluate the influence of the angiogenic regulators modification on the tumor growth and the cell sensitivity to ionizing radiation targeting the improvement of cancer therapeutic protocols. Accordingly, the antiangiogenic activity of apigenin and selenium was tested in vitro via MTT assay. The action of Apigenin and or Selenium was examined in vivo by using a model of solid tumor carcinoma (EAC). The growth rate of solid tumor in all experimental groups was measured by Caliper. The irradiated mice were exposed to 6.5 Gy of gamma rays. Apigenin 50 mg/kg body weight and selenium 5 μg per mice were daily administrated for 14 consecutive days after tumor volume reached 1mm 3 . The angiogenic activators TNF-α (key cytokine) in spleen, serum MMP 2 and MMP 9, liver and tumor NO, the lipid peroxidation (LPx) and angiogenic inhibitor TIMP-1 in spleen as well as, antioxidant markers (CAT, SOD, GPX) in tumor and liver tissue and DNA fragmentation in splenocytes were estimated to monitor efficacy of Apigenin and selenium in cancer treatment strategy. All parameters were determined as a time course on days 16 and 22 after tumor volume reached 1mm 3 . The using of MTT assay on EAC cells shows inhibition in EAC cell proliferation after the incubation with apigenin and /or selenium. The administration of apigenin and /or selenium to mice bearing tumor and to irradiated mice bearing tumor reduce significantly the TNF-α expression, MMP 2,9 , NO , LPx level and increased the antioxidant enzymes (GPx , SOD and CAT) activities. The DNA fragmentation and the antiangiogenic factors TIMP-1 were significantly increased when compared with their values in mice bearing tumor or in irradiated mice bearing tumor. From the results

  14. Exploring the role of anti-angiogenic therapies in prostate cancer: results from the phase 3 trial of sunitinib

    Directory of Open Access Journals (Sweden)

    Himisha Beltran

    2014-08-01

    Full Text Available Prostate cancer is a leading cause of cancer death in men. Despite recent advances in our understanding and treatment of advanced disease, no systemic therapy is curative and new therapies are needed. Targeting angiogenesis is an attractive therapeutic strategy, as angiogenic pathways are upregulated in prostate tumors similar to other malignancies due to imbalance of pro- and anti-angiogenic factors secreted by tumor, endothelial and stromal cells and increased neovasculature. [1] Vascular endothelial growth factor (VEGF is the most well-characterized pro-angiogenenic factor, with several small molecule inhibitors (sunitinib, sorafenib, pazopanib, axitinib, others, antibodies (bevacizumab and other drugs that target the VEGF pathway approved and/or in development for the treatment of a wide range of tumor types.

  15. Prevalence and assessment of factors contributing to adverse drug ...

    African Journals Online (AJOL)

    BACKGROUND: Adverse drug reactions account for the highest proportion among the causes of morbidity and mortality in clinical wards and are posing a considerable challenge. Hence, the objective of this study was to find out the prevalence of adverse drug reactions and the factors which contribute to their prevalence.

  16. Assessment of drug usage and antimicrobial residues in milk on ...

    African Journals Online (AJOL)

    Milk samples were also collected for evaluation of antimicrobial drug residues using three tests; the Delvotest® SP, agar well diffusion and agar plate disc assays. On the day of farm visit, 25.4% of study farms had various drugs used to treat animals, categorised as antimicrobials (54.2%), anthelmintics (25.0%), ...

  17. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    have an effective means of monitoring the quality of generic drug products in the market. This results in widespread ... countries. Marketing of such drugs has been widely reported in Africa, Asia, and Latin America. © CNCS .... three-fourth of the plate. The plate was dried in air for 15 minutes and examined under UV-light,.

  18. Assessment and use of drug information references in Utah pharmacies.

    Science.gov (United States)

    Moorman, Krystal L; Macdonald, Elyse A; Trovato, Anthony; Tak, Casey R

    2017-01-01

    To determine which drug references Utah pharmacists use most frequently. To determine which types of drug information questions are most commonly asked, and whether Utah pharmacists have access to adequate references to respond to these questions. A 19-question survey was created using Qualtrics, LLC (Provo, Utah) software. An electronic survey link was sent to 1,431 pharmacists with a valid e-mail address listed in the Department of Professional Licensing database. Questions focused on available references in the participant's pharmacy, how current the references are, and the participant's use of the references. Surveys were analyzed for participants practicing in either community or hospital pharmacies in the state of Utah. A total of 147 responses were included in the analysis. Approximately 44% of respondents practiced in the community, and 56% practiced in a hospital setting. The most commonly used references by Utah pharmacists are Micromedex, Lexicomp, UpToDate, Clinical Pharmacology, and Drug Facts & Comparisons. Pharmacists in the community frequently receive questions related to adverse drug reactions, drug interactions, and over-the-counter medications. Pharmacists in the hospital frequently receive questions relating to dosage and administration, drug interactions, and adverse drug reactions. About 89% of community pharmacists and 96% of hospital pharmacists feel available references are adequate to answer the questions they receive. Utah pharmacists generally use large reference suites to answer drug information questions. The majority of pharmacists consider the references available to them to be adequate to answer the questions they receive.

  19. Antiangiogenic effects of AA-PMe on HUVECs in vitro and zebrafish in vivo.

    Science.gov (United States)

    Jing, Yue; Wang, Gang; Xiao, Qi; Zhou, Yachun; Wei, Yingjie; Gong, Zhunan

    2018-01-01

    Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA) has demonstrated anticancer properties and we suspect this might be attributable to an effect on angio-genesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-L-proline methyl ester (AA-PMe), has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear. In this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF) present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP) transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline phosphatase assay. VEGFR2 expression in whole embryos following AA-PMe treatment was also determined. We found AA-PMe decreased cell viability and inhibited migration and tube formation in a dose-dependent manner in HUVECs. Similarly, AA-PMe disrupted the formation of intersegmental vessels, the dorsal aorta, and the posterior cardinal vein in zebrafish embryos. Both in vitro and in vivo AA-PMe surpassed AA in its ability to block angiogenesis by suppressing VEGF-induced phosphorylation of VEGFR2 and disrupting downstream extracellular regulated protein kinase and AKT signaling. For the first time

  20. Maternal hair and neonatal meconium to assess gestational consumption and prenatal exposure to drugs of abuse and psychoactive drugs.

    Science.gov (United States)

    Cortes, Laura; Almeida, Laura; Sabra, Sally; Muniesa, Marta; Busardo, Francesco Paolo; Garcia-Algar, Oscar; Gomez-Roig, Maria Dolores

    2018-04-05

    In the last two decades, the consumption of drugs of abuse among women of childbearing age has experienced a significant increase and results from analyses of surveys concerning maternal intake of psychoactive prescription drugs during pregnancy indicate that the rates of intake are increasing each year. Analyses of biological matrices such as maternal hair and neonatal meconium have recently been used for assessment of gestational consumption and consequent prenatal exposure to drugs of abuse in high-risk groups of women METHODS: Maternal hair and neonatal meconium were analyzed by validated chromatographic mass spectrometric methodologies to disclose gestational use of drugs of abuse and psychoactive prescription drugs and consequent prenatal exposure in a cohort of 513 mother-newborn dyads at the Sant Joan de Déu Barcelona Hospital, Spain, during 2012- 2013. A total of 3.9% the women reported drugs of abuse or prescription psychoactive drug consumption at any time during pregnancy. The prevalence of gestational consumption and consequent prenatal exposure to drugs of abuse (e.g. cannabis, cocaine and MDMA) was 1.2% in maternal hair and 0.4% in meconium; that of psychoactive prescription drugs (e.g. venlafaxine, citalopram, fluoxetine, clomipramine) was 1.7% in maternal hair and 1.2% in meconium. The prevalence of drugs of abuse and prescription psychoactive drug consumption was lower in our specific cohort of Spanish pregnant women than in other cohorts such as those from U.S. or Denmark. Analysis of materno-fetal matrices provides a viable alternative to study prenatal exposure to these substances and develop specific social and health intervention recommendations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Drug detection in breath: non-invasive assessment of illicit or pharmaceutical drugs.

    Science.gov (United States)

    Trefz, Phillip; Kamysek, Svend; Fuchs, Patricia; Sukul, Pritam; Schubert, Jochen K; Miekisch, Wolfram

    2017-03-20

    Breath analysis not only holds great potential for the development of new non-invasive diagnostic methods, but also for the identification and follow up of drug levels in breath. This is of interest for both, forensic and medical science. On the one hand, the detection of drugs of abuse in exhaled breath-similar to the well-known breath alcohol tests-would be highly desirable as an alternative to blood or urine analysis in situations such as police controls for drugged driving. The non-invasive detection of drugs and their metabolites is thus of great interest in forensic science, especially since marijuana is becoming legalized in certain parts of the US and the EU. The detection and monitoring of medical drugs in exhaled breath without the need of drawing blood samples on the other hand, is of high relevance in the clinical environment. This could facilitate a more precise medication and enable therapy control without any burden to the patient. Furthermore, it could be a step towards personalized medicine. This review gives an overview of the current state of drug detection in breath, including both volatile and non-volatile substances. The review is divided into two sections. The first section deals with qualitative detection of drugs (drugs of abuse), while the second is related to quantitative drug detection (medical drugs). Chances and limitations are discussed for both aspects. The detection of the intravenous anesthetic propofol is presented as a detailed example that demonstrates the potential, requirements, pitfalls and limitations of therapeutic drug monitoring by means of breath analysis.

  2. Clinician impression versus prescription drug monitoring program criteria in the assessment of drug-seeking behavior in the emergency department.

    Science.gov (United States)

    Weiner, Scott G; Griggs, Christopher A; Mitchell, Patricia M; Langlois, Breanne K; Friedman, Franklin D; Moore, Rebecca L; Lin, Shuo Cheng; Nelson, Kerrie P; Feldman, James A

    2013-10-01

    We compare emergency provider impression of drug-seeking behavior with objective criteria from a state prescription drug monitoring program, assess change in opioid pain reliever prescribing after prescription drug monitoring program review, and examine clinical factors associated with suspected drug-seeking behavior. This was a prospective observational study of emergency providers assessing a convenience sample of patients aged 18 to 64 years who presented to either of 2 academic medical centers with chief complaint of back pain, dental pain, or headache. Drug-seeking behavior was objectively defined as present when a patient had greater than or equal to 4 opioid prescriptions by greater than or equal to 4 providers in the 12 months before emergency department evaluation. Emergency providers completed data forms recording their impression of the likelihood of drug-seeking behavior, patient characteristics, and plan for prescribing pre- and post-prescription drug monitoring program review. Descriptive statistics were generated. We calculated agreement between emergency provider impression of drug-seeking behavior and prescription drug monitoring program definition, and sensitivity, specificity, and positive predictive value of emergency provider impression, using prescription drug monitoring program criteria as the criterion standard. A multivariate logistic regression analysis was conducted to determine clinical factors associated with drug-seeking behavior. Thirty-eight emergency providers with prescription drug monitoring program access participated. There were 544 patient visits entered into the study from June 2011 to January 2013. There was fair agreement between emergency provider impression of drug-seeking behavior and prescription drug monitoring program (κ=0.30). Emergency providers had sensitivity 63.2% (95% confidence interval [CI] 54.8% to 71.7%), specificity 72.7% (95% CI 68.4% to 77.0%), and positive predictive value 41.2% (95% CI 34.4% to 48

  3. Assessing the Persuasiveness of Drug Abuse Information. Drug Abuse Information Research Project.

    Science.gov (United States)

    McEwen, William J.; Wittbold, George H.

    The magnitude of the effect television has on young people's lives makes it an important source of drug abuse information, but there is a question as to whether or not such information is persuasive. Some studies indicate that viewer response to anti-drug television commercials falls into four judgmental dimensions: relevant persuasion, negative…

  4. [Governance of drug advertising control: assessment of misleading advertising penalties].

    Science.gov (United States)

    Chakroun, R

    2013-04-01

    Loyal promotion of the pharmaceutical industry has been challenged by stakeholders. Drug advertising is the easiest point to assess. Based on the agency theory, our objective was to describe the governance of advertising control when it was misleading and the terms of penalties within the framework of the contradictory process between the industry and the regulatory authorities. We conducted a thorough analysis of the contents of the minutes of the Board of Control of advertising from April 2007 to May 2010. The amounts of penalties were analyzed according to three criteria: the timing of the examination procedure (first session versus second session), the nature of the penalty (ban versus notice of change) and the company's defense strategy (written response versus presence of company representatives). Thirty-nine reports involving 62 projects to ban advertisements were analyzed. The first two causes of penalties were off label promotion and non-objective use of study results to support claims. The Committee issued 47 advertising bans (76%) and 15 formal notices of change (24%). When the defense strategy of the company involved the presence of representatives, there was a significant reduction of votes in favor of a ban (68% versus 81%, Pstrategy did not influence the nature of the penalty (Chi(2)=2.05; P=n.s). These results should be put into perspective considering the fact that the qualitative composition of the commission was not free of potential conflicts of interest and that, moreover, only 10% of the penalty projects were reviewed. In addition, advertising control does not address the issue of the loyalty of the sales forces. Finally, our results open perspectives for research and managerial applications for the governance of advertising controls. Copyright © 2013. Published by Elsevier Masson SAS.

  5. Test systems in drug discovery for hazard identification and risk assessment of human drug-induced liver injury.

    Science.gov (United States)

    Weaver, Richard J; Betts, Catherine; Blomme, Eric A G; Gerets, Helga H J; Gjervig Jensen, Klaus; Hewitt, Philip G; Juhila, Satu; Labbe, Gilles; Liguori, Michael J; Mesens, Natalie; Ogese, Monday O; Persson, Mikael; Snoeys, Jan; Stevens, James L; Walker, Tracy; Park, B Kevin

    2017-07-01

    The liver is an important target for drug-induced toxicities. Early detection of hepatotoxic drugs requires use of well-characterized test systems, yet current knowledge, gaps and limitations of tests employed remains an important issue for drug development. Areas Covered: The current state of the science, understanding and application of test systems in use for the detection of drug-induced cytotoxicity, mitochondrial toxicity, cholestasis and inflammation is summarized. The test systems highlighted herein cover mostly in vitro and some in vivo models and endpoint measurements used in the assessment of small molecule toxic liabilities. Opportunities for research efforts in areas necessitating the development of specific tests and improved mechanistic understanding are highlighted. Expert Opinion: Use of in vitro test systems for safety optimization will remain a core activity in drug discovery. Substantial inroads have been made with a number of assays established for human Drug-induced Liver Injury. There nevertheless remain significant gaps with a need for improved in vitro tools and novel tests to address specific mechanisms of human Drug-Induced Liver Injury. Progress in these areas will necessitate not only models fit for application, but also mechanistic understanding of how chemical insult on the liver occurs in order to identify translational and quantifiable readouts for decision-making.

  6. Assessment of different polymers and drug loads for fused deposition modeling of drug loaded implants.

    Science.gov (United States)

    Kempin, Wiebke; Franz, Christian; Koster, Lynn-Christine; Schneider, Felix; Bogdahn, Malte; Weitschies, Werner; Seidlitz, Anne

    2017-06-01

    The 3D printing technique of fused deposition modeling® (FDM) has lately come into focus as a potential fabrication technique for pharmaceutical dosage forms and medical devices that allows the preparation of delivery systems with nearly any shape. This is particular promising for implants administered at application sites with a high anatomical variability where an individual shape adaption appears reasonable. In this work different polymers (Eudragit®RS, polycaprolactone (PCL), poly(l-lactide) (PLLA) and ethyl cellulose (EC)) were evaluated with respect to their suitability for FDM of drug loaded implants and their drug release behaviour was evaluated. The fluorescent dye quinine was used as a model drug to visualize drug distribution in filaments and implants. Quinine loaded filaments were produced by solvent casting and subsequent hot melt extrusion (HME) and model implants were printed as hollow cylinders using a standard FDM printer. Parameters were found at which model implants (hollow cylinders, outer diameter 4-5mm, height 3mm) could be produced from all tested polymers. The drug release which was examined by incubation of the printed implants in phosphate buffered saline solution (PBS) pH 7.4 was highly dependent on the used polymer. The fastest relative drug release of approximately 76% in 51days was observed for PCL and the lowest for Eudragit®RS and EC with less than 5% of quinine release in 78 and 100days, respectively. For PCL further filaments were prepared with different quinine loads ranging from 2.5% to 25% and thermal analysis proved the presence of a solid dispersion of quinine in the polymer for all tested concentrations. Increasing the drug load also increased the overall percentage of drug released to the medium since nearly the same absolute amount of quinine remained trapped in PCL at the end of drug release studies. This knowledge is valuable for future developments of printed implants with a desired drug release profile that might be

  7. Drug delivery system innovation and Health Technology Assessment: Upgrading from Clinical to Technological Assessment.

    Science.gov (United States)

    Panzitta, Michele; Bruno, Giorgio; Giovagnoli, Stefano; Mendicino, Francesca R; Ricci, Maurizio

    2015-11-30

    Health Technology Assessment (HTA) is a multidisciplinary health political instrument that evaluates the consequences, mainly clinical and economical, of a health care technology; the HTA aim is to produce and spread information on scientific and technological innovation for health political decision making process. Drug delivery systems (DDS), such as nanocarriers, are technologically complex but they have pivotal relevance in therapeutic innovation. The HTA process, as commonly applied to conventional drug evaluation, should upgrade to a full pharmaceutical assessment, considering the DDS complexity. This is useful to study more in depth the clinical outcome and to broaden its critical assessment toward pharmaceutical issues affecting the patient and not measured by the current clinical evidence approach. We draw out the expertise necessary to perform the pharmaceutical assessment and we propose a format to evaluate the DDS technological topics such as formulation and mechanism of action, physicochemical characteristics, manufacturing process. We integrated the above-mentioned three points in the Evidence Based Medicine approach, which is data source for any HTA process. In this regard, the introduction of a Pharmaceutics Expert figure in the HTA could be fundamental to grant a more detailed evaluation of medicine product characteristics and performances and to help optimizing DDS features to overcome R&D drawbacks. Some aspects of product development, such as manufacturing processes, should be part of the HTA as innovative manufacturing processes allow new products to reach more effectively patient bedside. HTA so upgraded may encourage resource allocating payers to invest in innovative technologies and providers to focus on innovative material properties and manufacturing processes, thus contributing to bring more medicines in therapy in a sustainable manner. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

    Science.gov (United States)

    Pantziarka, Pan; Hutchinson, Lisa; André, Nicolas; Benzekry, Sébastien; Bertolini, Francesco; Bhattacharjee, Atanu; Chiplunkar, Shubhada; Duda, Dan G; Gota, Vikram; Gupta, Sudeep; Joshi, Amit; Kannan, Sadhana; Kerbel, Robert; Kieran, Mark; Palazzo, Antonella; Parikh, Aparna; Pasquier, Eddy; Patil, Vijay; Prabhash, Kumar; Shaked, Yuval; Sholler, Giselle Saulnier; Sterba, Jaroslav; Waxman, David J; Banavali, Shripad

    2016-01-01

    The 5 th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6 th - 8 th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

  9. Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

    DEFF Research Database (Denmark)

    Săftoiu, Adrian; Vilmann, Peter

    2011-01-01

    Angiogenesis has a critical role in primary tumor growth and the development of metastases. Several angiogenesis inhibitors were recently developed, being a very attractive target for digestive tumor therapy. However, individualized therapy should not only be based on the pre-treatment imaging...... of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers, used for the longitudinal monitoring of the effects of chemo-radiotherapy (including anti-angiogenic therapies), as well as for the precise targeting of drugs...... through molecular-based drug-delivery systems....

  10. Antiangiogenic activity of 2-deoxy-D-glucose.

    Directory of Open Access Journals (Sweden)

    Jaime R Merchan

    2010-10-01

    Full Text Available During tumor angiogenesis, endothelial cells (ECs are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG on in vitro and in vivo angiogenesis were investigated.In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR, which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay. Thus, 2-DG's effects on ECs appeared primarily due to inhibition of LLOs synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LH(BETAT(AG transgenic retinoblastoma model.In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies.

  11. Drug use patterns and predictors among homeless youth: results of an ecological momentary assessment.

    Science.gov (United States)

    Santa Maria, Diane; Padhye, Nikhil; Yang, Yijiong; Gallardo, Kathryn; Santos, Glenn-Milo; Jung, Julie; Businelle, Michael

    2017-12-29

    Alcohol and drug use is associated with significant morbidity and mortality and is highly prevalent among homeless youth. Ecological Momentary Assessments (EMA) have been used to examine the effect of urges on drug use, though not among homeless youth. We assessed the patterns of drug use and the correlation between real-time contextual factors and drug use using EMA collected daily. We identified predictors of drug use among a sample of homeless youth 18-25 years old in Houston, Texas. Homeless youth (n = 66, 62% male) were recruited from a drop-in center between September 2015 and May 2016. We used generalized linear mixed models and cross-validation methods to determine the best predictive model of drug use. The overall drug use was high: 61% and 32% of participants reported using drugs or alcohol at least one day, respectively. Marijuana and synthetic marijuana use (i.e., Kush, K2, incense packs) were reported most frequently; 86% and 13% of the total drug use EMAs, respectfully. Drug use urge was reported on 26% of days and was the highest on drug use days. Drug use was predicted by discrimination, pornography use, alcohol use, and urges for drugs, alcohol, and to steal. EMA can be used to predict drug use among homeless youth. Drug use treatment among homeless youth should address the role of experiencing discrimination, pornography and alcohol use, and urge management strategies on drug use. Research is needed to determine if EMA informed just-in-time interventions targeting these predictors can reduce use.

  12. Anti-angiogenic activity of a new andrographolide derivative in zebrafish and HUVECs.

    Science.gov (United States)

    Li, Jingjing; Peng, Yuran; Li, Shang; Sun, Yicheng; Chan, Judy Yuet-Wa; Cui, Guozhen; Wang, Decai; Zhou, Guo-Chun; Lee, Simon Ming-Yuen

    2016-10-15

    Andrographolide is among the most promising anti-tumor and anti-angiogenic components in Andrographis paniculata but its poor bioavailability and limited efficacy pose difficulties for its therapeutic development. Therefore, improving its pharmaceutical features and potency, by modifying its chemical structure, is desirable. In the present study, a new andrographolide derivative (AGP-40) was synthesized and characterized for its anti-angiogenic properties. Human umbilical vein endothelial cells (HUVECs) and zebrafish models were used to identify the anti-angiogenic activity of AGP-40. AGP-40 significantly suppressed the formation of blood vessels in zebrafish and inhibited proliferation, migration and tube formation in vitro. The anti-angiogenic effects of AGP-40 are at least partially mediated via the PI3K/Akt and MEK/Erk(1/2) signaling pathways. Furthermore, AGP-40 exhibited stronger anti-proliferative effects than andrographolide against A549, HepG2, Hela cancer cell lines. This study is the first to demonstrate the promising anti-angiogenic activity of the new andrographolide derivative AGP-40. Our results indicate that AGP-40 could serve as a potential therapeutic agent for the treatment and prevention of diseases associated with excessive angiogenesis. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality.

    Science.gov (United States)

    McIntyre, Alan; Harris, Adrian L

    2015-04-01

    Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6-8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table 1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

  14. Risk assessment for drugs of abuse in the Dutch watercycle.

    NARCIS (Netherlands)

    van der Aa, M.; Bijlsma, L.; Emke, E.; Dijkman, E.; van Nuijs, A.L.N.; van de Ven, B.M.; Hernández, F.; Versteegh, A.; de Voogt, P.

    2013-01-01

    A screening campaign of drugs of abuse (DOA) and their relevant metabolites in the aqueous environment was performed in the Netherlands. The presence of DOA, together with the potential risks for the environment and the possible human exposure to these compounds through consumption of drinking water

  15. Using technology to assess and intervene with illicit drug-using persons at risk for HIV.

    Science.gov (United States)

    Horvath, Keith J; Lammert, Sara; LeGrand, Sara; Muessig, Kathryn E; Bauermeister, José A

    2017-09-01

    This review describes recent literature on novel ways technology is used for assessment of illicit drug use and HIV risk behaviours, suggestions for optimizing intervention acceptability, and recently completed and ongoing technology-based interventions for drug-using persons at risk for HIV and others with high rates of drug use and HIV risk behaviour. Among studies (n = 5) comparing technology-based to traditional assessment methods, those using Ecological Momentary Assessment (EMA) had high rates of reported drug use and high concordance with traditional assessment methods. The two recent studies assessing the acceptability of mHealth approaches overall demonstrate high interest in these approaches. Current or in-progress technology-based interventions (n = 8) are delivered using mobile apps (n = 5), text messaging (n = 2) and computers (n = 1). Most intervention studies are in progress or do not report intervention outcomes; the results from one efficacy trial showed significantly higher HIV testing rates among persons in need of drug treatment. Studies are needed to continually assess technology adoption and intervention preferences among drug-using populations to ensure that interventions are appropriately matched to users. Large-scale technology-based intervention trials to assess the efficacy of these approaches, as well as the impact of individual intervention components, on drug use and other high-risk behaviours are recommended.

  16. Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

    Directory of Open Access Journals (Sweden)

    Johanna Weiss

    2014-12-01

    Full Text Available Dovitinib (TKI-258 is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1 inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2 by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM. Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3, and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

  17. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

    Science.gov (United States)

    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-01-01

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID:26956051

  18. Model driven optimization of antiangiogenics + cytotoxics combination: application to breast cancer mice treated with bevacizumab + paclitaxel doublet leads to reduced tumor growth and fewer metastasis.

    Science.gov (United States)

    Mollard, Severine; Ciccolini, Joseph; Imbs, Diane-Charlotte; El Cheikh, Raouf; Barbolosi, Dominique; Benzekry, Sebastien

    2017-04-04

    Bevacizumab is the first-in-class antiangiogenic drug and is almost always administrated in combination with cytotoxics. Reports have shown that bevacizumab could induce a transient phase of vascular normalization, thus ensuring a better drug delivery when cytotoxics administration is adjuvant. However, determining the best sequence remains challenging. We have developed a mathematical model describing the impact of antiangiogenics on tumor vasculature. A 3.4 days gap between bevacizumab and paclitaxel was first proposed by our model. To test its relevance, 84 mice were orthotopically xenografted with human MDA-231Luc+ refractory breast cancer cells. Two sets of experiments were performed, based upon different bevacizumab dosing (10 or 20 mg/kg) and inter-cycle intervals (7 or 10 days), comprising several combinations with paclitaxel. Results showed that scheduling bevacizumab 3 days before paclitaxel improved antitumor efficacy (48% reduction in tumor size compared with concomitant dosing, p optimal gap of 2.2 days. Our experimental data suggest that current concomitant dosing between bevacizumab and paclitaxel could be a sub-optimal strategy at bedside. In addition, this proof of concept study suggests that mathematical modelling could help to identify the optimal interval among a variety of possible alternate treatment modalities, thus refining the way experimental or clinical studies are conducted.

  19. Surveying Teens in School to Assess the Prevalence of Problematic Drug Use

    Science.gov (United States)

    Falck, Russel S.; Nahhas, Ramzi W.; Li, Linna; Carlson, Robert G.

    2012-01-01

    Background: Illicit drug use by school-aged teens can adversely affect their health and academic achievement. This study used a survey administered in schools to assess the prevalence of problematic drug use among teenagers in a Midwestern community. Methods: Self-report data were collected from 11th- and 12th-grade students (N = 3974) in 16…

  20. Correlation of antiangiogenic, antioxidant and cytotoxic activities of some Sudanese medicinal plants with phenolic and flavonoid contents.

    Science.gov (United States)

    Hassan, Loiy Elsir A; Ahamed, Mohamed B Khadeer; Majid, Aman S Abdul; Baharetha, Hussein M; Muslim, Nahdzatul S; Nassar, Zeyad D; Majid, Amin M S Abdul

    2014-10-20

    Consumption of medicinal plants to overcome diseases is traditionally belongs to the characteristics of most cultures on this earth. Sudan has been a host and cradle to various ancient civilizations and developed a vast knowledge on traditional medicinal plants. The present study was undertaken to evaluate the antioxidant, antiangiogenic and cytotoxic activities of six Sudanese medicinal plants which have been traditionally used to treat neoplasia. Further the biological activities were correlated with phytochemical contents of the plant extracts. Different parts of the plants were subjected to sequential extraction method. Cytotoxicity of the extracts was determined by dimethylthiazol-2-yl)- 2,5diphenyl tetrazolium bromide (MTT) assay on 2 human cancer (colon and breast) and normal (endothelial and colon fibroblast) cells. Anti-angiogenic potential was tested using ex vivo rat aortic ring assay. DPPH (1,1-diphenyl-2-picrylhydrazyl) assay was conducted to screen the antioxidant capabilities of the extracts. Finally, total phenolic and flavonoid contents were estimated in the extracts using colorimetric assays. The results indicated that out of 6 plants tested, 4 plants (Nicotiana glauca, Tephrosia apollinea, Combretum hartmannianum and Tamarix nilotica) exhibited remarkable anti-angiogenic activity by inhibiting the sprouting of microvessels more than 60%. However, the most potent antiangiogenic effect was recorded by ethanol extract of T. apollinea (94.62%). In addition, the plants exhibited significant antiproliferative effects against human breast (MCF-7) and colon (HCT 116) cancer cells while being non-cytotoxic to the tested normal cells. The IC50 values determined for C. hartmannianum, N. gluaca and T. apollinea against MCF-7 cells were 8.48, 10.78 and 29.36 μg/ml, respectively. Whereas, the IC50 values estimated for N. gluaca, T. apollinea and C. hartmannianum against HCT 116 cells were 5.4, 20.2 and 27.2 μg/ml, respectively. These results were more or

  1. ADC histograms predict response to anti-angiogenic therapy in patients with recurrent high-grade glioma

    Energy Technology Data Exchange (ETDEWEB)

    Nowosielski, Martha; Tinkhauser, Gerd; Stockhammer, Guenther [Innsbruck Medical University, Department of Neurology, Innsbruck (Austria); Recheis, Wolfgang; Schocke, Michael; Gotwald, Thaddaeus [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria); Goebel, Georg [Innsbruck Medical University, Department of Medical Statistics, Informatics and Health Economics, Innsbruck (Austria); Gueler, Oezguer [Innsbruck Medical University, 4D Visualization Laboratory, University Clinic of Oto-, Rhino- and Laryngology, Innsbruck (Austria); Kostron, Herwig [Innsbruck Medical University, Department of Neurosurgery, Innsbruck (Austria); Hutterer, Markus [Innsbruck Medical University, Department of Neurology, Innsbruck (Austria); Paracelsus Medical University Salzburg-Christian Doppler Hospital, Department of Neurology, Salzburg (Austria)

    2011-04-15

    The purpose of this study is to evaluate apparent diffusion coefficient (ADC) maps to distinguish anti-vascular and anti-tumor effects in the course of anti-angiogenic treatment of recurrent high-grade gliomas (rHGG) as compared to standard magnetic resonance imaging (MRI). This retrospective study analyzed ADC maps from diffusion-weighted MRI in 14 rHGG patients during bevacizumab/irinotecan (B/I) therapy. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences and of hyperintense T2 lesions (hT2) were calculated. hT2 were defined as regions of interest (ROI) and registered to corresponding ADC maps (hT2-ADC). Histograms were calculated from hT2-ADC ROIs. Thereafter, histogram asymmetry termed ''skewness'' was calculated and compared to progression-free survival (PFS) as defined by the Response Assessment Neuro-Oncology (RANO) Working Group criteria. At 8-12 weeks follow-up, seven (50%) patients showed a partial response, three (21.4%) patients were stable, and four (28.6%) patients progressed according to RANO criteria. hT2-ADC histograms demonstrated statistically significant changes in skewness in relation to PFS at 6 months. Patients with increasing skewness (n = 11) following B/I therapy had significantly shorter PFS than did patients with decreasing or stable skewness values (n = 3, median percentage change in skewness 54% versus -3%, p = 0.04). In rHGG patients, the change in ADC histogram skewness may be predictive for treatment response early in the course of anti-angiogenic therapy and more sensitive than treatment assessment based solely on RANO criteria. (orig.)

  2. Assessment of new cardiovascular drugs : Relationships between considerations, professional characteristics, and prescribing

    NARCIS (Netherlands)

    Wieringa, NF; Denig, P; de Graeff, PA; Vos, R

    2001-01-01

    Objectives: To study considerations used by professional and academic leaders to assess the position of new cardiovascular drugs in the therapeutic regimen in relationship to professional characteristics and the level of prescribing. Methods: Interviews with 39 internists, cardiologists, general

  3. Assessment of herbal drugs for promising anti-Candida activity.

    Science.gov (United States)

    Soliman, Sameh S M; Semreen, Mohammad H; El-Keblawy, Ali A; Abdullah, Arbab; Uppuluri, Priya; Ibrahim, Ashraf S

    2017-05-08

    Microbial infections are diverse and cause serious human diseases. Candida albicans infections are serious healthcare-related infections that are complicated by its morphological switching from yeast to hyphae, resistant biofilm formation and mixed infections with bacteria. Due to the increase in drug resistance to currently used antimicrobial agents and the presence of undesirable side effects, the need for safe and effective novel therapies is important. Compounds derived from plants are known for their medicinal properties including antimicrobial activities. The purpose of the study was to compare and evaluate the anti-Candida activities of several medicinal plants in order for the selection of a herbal drug for human use as effective antimicrobial. The selection was taking into considerations two important parameters; parameters related to the selected drug including activity, stability, solubility and toxicity and parameters related to the pathogen including its different dynamic growth and its accompanied secondary bacterial infections. Seven different plants including Avicennia marina (Qurm), Fagonia indica (Shoka'a), Lawsania inermis (Henna), Portulaca oleracea (Baq'lah), Salvadora persica (Souwak), Ziziphus spina- Christi (Sidr) and Asphodelus tenuifolius (Kufer) were ground and extracted with ethanol. The ethanol extracts were evaporated and the residual extract dissolved in water prior to testing against Candida albicans in its different morphologies. The antibacterial and cytotoxic effects of the plants extracts were also tested. Out of the seven tested plants, L. inermis and P. oleracea showed significant anti-Candida activity with MIC ~10 μg/mL. Furthermore, both plant extracts were able to inhibit C. albicans growth at its dynamic growth phases including biofilm formation and age resistance. Accompanied secondary bacterial infections can complicate Candida pathogenesis. L. inermis and P. oleracea extracts showed effective antibacterial activities

  4. Development of a rational scale to assess the harm of drugs of potential misuse.

    Science.gov (United States)

    Nutt, David; King, Leslie A; Saulsbury, William; Blakemore, Colin

    2007-03-24

    Drug misuse and abuse are major health problems. Harmful drugs are regulated according to classification systems that purport to relate to the harms and risks of each drug. However, the methodology and processes underlying classification systems are generally neither specified nor transparent, which reduces confidence in their accuracy and undermines health education messages. We developed and explored the feasibility of the use of a nine-category matrix of harm, with an expert delphic procedure, to assess the harms of a range of illicit drugs in an evidence-based fashion. We also included five legal drugs of misuse (alcohol, khat, solvents, alkyl nitrites, and tobacco) and one that has since been classified (ketamine) for reference. The process proved practicable, and yielded roughly similar scores and rankings of drug harm when used by two separate groups of experts. The ranking of drugs produced by our assessment of harm differed from those used by current regulatory systems. Our methodology offers a systematic framework and process that could be used by national and international regulatory bodies to assess the harm of current and future drugs of abuse.

  5. Assessment of Web-Based Consumer Reviews as a Resource for Drug Performance

    Science.gov (United States)

    Adusumalli, Swarnaseetha; Lee, HueyTyng; Hoi, Qiangze; Koo, Si-Lin; Tan, Iain Beehuat

    2015-01-01

    Background Some health websites provide a public forum for consumers to post ratings and reviews on drugs. Drug reviews are easily accessible and comprehensible, unlike clinical trials and published literature. Because the public increasingly uses the Internet as a source of medical information, it is important to know whether such information is reliable. Objective We aim to examine whether Web-based consumer drug ratings and reviews can be used as a resource to compare drug performance. Methods We analyzed 103,411 consumer-generated reviews on 615 drugs used to treat 249 disease conditions from the health website WebMD. Statistical analysis identified 427 drug pairs from 24 conditions for which two drugs treating the same condition had significantly and substantially different satisfaction ratings (with at least a half-point difference between Web-based ratings and Paddictive properties were rated higher than their counterparts in Web-based reviews, and (3) second-line or alternative drugs were rated higher. In addition, Web-based ratings indicated drug delivery problems. If FDA black box warning labels are used to resolve disagreements between publications and online trends, the concordance rate increases to 71% (55/77) (Pmanufacturers to assess the performance of a drug. However, one should be cautious to rely solely on consumer reviews as ratings can be strongly influenced by the consumer experience. PMID:26319108

  6. Effect of safety issues with HIV drugs on the approval process of other drugs in the same class: an analysis of European Public Assessment Reports.

    Science.gov (United States)

    Arnardottir, Arna H; Haaijer-Ruskamp, Flora M; Straus, Sabine M J; de Graeff, Pieter A; Mol, Peter G M

    2011-11-01

    Knowledge on the safety of new medicines is limited at the time of market entry. Nearly half of all drugs used to treat HIV registered in the EU required ≥1 Direct Healthcare Professional Communication (DHPC) in the past 10 years for safety issues identified post-approval. The aim was to evaluate the extent to which regulators and industry have addressed the risk of safety issues for HIV drugs based on prior experience with other drugs in the same class and whether doing so impacts development time of these drugs. HIV drugs receiving ≥1 DHPC in the Netherlands between January 1999 and December 2008 were identified. Each drug with a DHPC ('index' drug) was paired with subsequently approved HIV drug(s) in the same class (Anatomical Therapeutic Chemical [ATC] 4th level) ['follow-on' drugs]. Characteristics of safety issues were extracted from the DHPCs of the 'index' drugs. European Public Assessment Reports (EPARs) were reviewed regarding whether the safety issues had been considered during development and approval. Consideration of previously identified safety issues in 'follow-on' drug applications was assessed regarding attention paid to adverse drug reaction (ADR) symptoms in pre-marketing studies, Summary of Product Characteristics (SmPC) and postmarketing commitments, and whether size of the safety population was in accordance with Regulatory guidelines. 'Index' drugs were also paired with drugs in the same class already on the market ('older' drugs). For 'older' drugs, we identified whether the safety issue led to appropriate changes in the current SmPC (January 2011) compared with the SmPC at the time of marketing authorization. Clinical development time was assessed using time from first patent application to market authorization as proxy, and comparison was made between 'index' and 'follow-on' drugs. For 9 (43%) of the 21 centrally authorized HIV drugs, 11 serious safety issues that required a DHPC were identified. Two drugs were excluded from our

  7. Synthesis and biological evaluations of cytotoxic and antiangiogenic triterpenoids-jacaranone conjugates

    DEFF Research Database (Denmark)

    Sun, Hua; Yue, Partick Y. K.; Wang, Shao Rong

    2016-01-01

    showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted...

  8. Biological evaluation of tubulysin A: A potential anticancer and antiangiogenic natural product

    NARCIS (Netherlands)

    Kaur, Gurmeet; Hollingshead, Melinda; Holbeck, Susan; Schauer-Vukašinović, Vesna; Camalier, Richard F.; Dömling, Alexander; Agarwal, Seema

    2006-01-01

    Tubulysin A (tubA) is a natural product isolated from a strain of myxobacteria that has been shown to depolymerize microtubules and induce mitotic arrest. The potential of tubA as an anticancer and antiangiogenic agent is explored in the present study. tubA shows potent antiproliferative activity in

  9. The anti-proliferative and anti-angiogenic effect of the methanol extract from brittle star.

    Science.gov (United States)

    Baharara, Javad; Amini, Elaheh; Mousavi, Marzieh

    2015-04-01

    Anti-angiogenic therapy is a crucial step in cancer treatment. The discovery of new anti-angiogenic compounds from marine organisms has become an attractive concept in anti-cancer therapy. Because little data correlated to the pro- and anti-angiogenic efficacies of Ophiuroidea, which include brittle star, the current study was designed to explore the anti-angiogenic potential of brittle star methanol extract in vitro and in vivo. The anti-proliferative effect of brittle star extract on A2780cp cells was examined by MTT assays, and transcriptional expression of VEGF and b-FGF was evaluated by RT-PCR. In an in vivo model, 40 fertilized Ross eggs were divided into control and three experimental groups. The experimental groups were incubated with brittle star extract at concentrations of 25, 50 and 100 µg/ml, and photographed by photo-stereomicroscopy. Ultimately, numbers and lengths of vessels were measured by Image J software. Data were analyzed with SPSS software (pstar extract exerted a dose- and time-dependent anti-proliferative effect on A2780cp cancer cells. In addition, VEGF and b-FGF expression decreased with brittle star methanol extract treatment. Macroscopic evaluations revealed significant changes in the second and third experimental group compared to controls (pstar methanol extract in vitro and in vivo confer novel insight into the application of natural marine products in angiogenesis-related pathologies.

  10. Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

    Science.gov (United States)

    Hsiao, Hsiu-Ling; Langenickel, Thomas Heiko; Greeley, Michael; Roberts, John; Zhou, Wei; Pal, Parasar; Rebello, Sam; Rajman, Iris; Sunkara, Gangadhar

    2015-11-01

    LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies. © 2015, The American College of Clinical Pharmacology.

  11. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    requirements for the registration, assessment, marketing, authorization, and quality control of .... The mobile phase was consisted of a mixture of methanol, dichloromethane, ammonia and acetonitrile. (40:40:20:10) as stated in BP 2004. A test solution of 0.05% w/v was prepared by mixing 750 ml of water with powdered ...

  12. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    ABSTRACT. An attempt was made to assess the quality and compare the physicochemical equivalence of six brands of ciprofloxacin tablets marketed in Tigray, Ethiopia. Six brands of ciprofloxacin tablets were used in the study. Identity, weight uniformity test, disintegration test, dissolution test and assay for the content of ...

  13. Quality Assessment of the Commonly Prescribed Antimicrobial Drug ...

    African Journals Online (AJOL)

    An attempt was made to assess the quality and compare the physicochemical equivalence of six brands of ciprofloxacin tablets marketed in Tigray, Ethiopia. Six brands of ciprofloxacin tablets were used in the study. Identity, weight uniformity test, disintegration test, dissolution test and assay for the content of active ...

  14. Assessment of Web-Based Consumer Reviews as a Resource for Drug Performance.

    Science.gov (United States)

    Adusumalli, Swarnaseetha; Lee, HueyTyng; Hoi, Qiangze; Koo, Si-Lin; Tan, Iain Beehuat; Ng, Pauline Crystal

    2015-08-28

    Some health websites provide a public forum for consumers to post ratings and reviews on drugs. Drug reviews are easily accessible and comprehensible, unlike clinical trials and published literature. Because the public increasingly uses the Internet as a source of medical information, it is important to know whether such information is reliable. We aim to examine whether Web-based consumer drug ratings and reviews can be used as a resource to compare drug performance. We analyzed 103,411 consumer-generated reviews on 615 drugs used to treat 249 disease conditions from the health website WebMD. Statistical analysis identified 427 drug pairs from 24 conditions for which two drugs treating the same condition had significantly and substantially different satisfaction ratings (with at least a half-point difference between Web-based ratings and PGoogle Scholar were searched for publications that were assessed for concordance with findings online. Scientific literature was found for 77 out of the 427 drug pairs and compared to findings online. Nearly two-thirds (48/77, 62%) of the online drug trends with at least a half-point difference in online ratings were supported by published literature (P=.02). For a 1-point online rating difference, the concordance rate increased to 68% (15/22) (P=.07). The discrepancies between scientific literature and findings online were further examined to obtain more insights into the usability of Web-based consumer-generated reviews. We discovered that (1) drugs with FDA black box warnings or used off-label were rated poorly in Web-based reviews, (2) drugs with addictive properties were rated higher than their counterparts in Web-based reviews, and (3) second-line or alternative drugs were rated higher. In addition, Web-based ratings indicated drug delivery problems. If FDA black box warning labels are used to resolve disagreements between publications and online trends, the concordance rate increases to 71% (55/77) (Prating difference and

  15. Spatial and Temporal Assessment on Drug Addiction Using Multivariate Analysis and GIS

    International Nuclear Information System (INIS)

    Mohd Ekhwan Toriman; Mohd Ekhwan Toriman; Siti Nor Fazillah Abdullah; Izwan Arif Azizan; Mohd Khairul Amri Kamarudin; Roslan Umar; Nasir Mohamad

    2015-01-01

    There is a need for managing and displaying drug addiction phenomena and trend at both spatial and temporal scales. Spatial and temporal assessment on drug addiction in Terengganu was undertaken to understand the geographical area of district in the same cluster, in addition, identify the hot spot area of this problem and analysis the trend of drug addiction. Data used were topography map of Terengganu and number of drug addicted person in Terengganu by district within 10 years (2004-2013). Number of drug addicted person by district were mapped using Geographic Information system and analysed using a combination of multivariate analysis which is cluster analysis were applied to the database in order to validate the correlation between data in the same cluster. Result showed a cluster analysis for number of drug addiction by district generated three clusters which are Besut and Kuala Terengganu in cluster 1 named moderate drug addicted person (MDA), Dungun, Marang, Setiu and Hulu Terengganu in cluster 2 named lower drug addicted person (LDA) and Kemaman in cluster 3 named high drug addicted person(HDA). This analysis indicates that cluster 3 which is Kemaman is a hot spot area. These results were beneficial for stakeholder to monitor and manage this problem especially in the hot spot area which needs to be emphasized. (author)

  16. Validation of a behavioral economic purchase task for assessing drug abuse liability.

    Science.gov (United States)

    MacKillop, James; Goldenson, Nicholas I; Kirkpatrick, Matthew G; Leventhal, Adam M

    2018-01-05

    Behavioral economic purchase tasks quantify drug demand (i.e. reinforcing value of a drug) and have been used extensively to assess the value of various drugs among current users. However, purchase tasks have been rarely used with unfamiliar drugs to address a compound's abuse liability, and the current study sought to validate the paradigm in this capacity. Using a double-blind placebo-controlled within-subjects drug challenge design, the study evaluated differential drug demand on an experimental drug purchase task for a 20 mg dose of oral D-amphetamine (versus placebo), a prototypic psychostimulant, in 98 stimulant-naïve participants. Compared with placebo, amphetamine significantly increased intensity, breakpoint and O max , and significantly decreased elasticity. Mechanistic analyses revealed that O max and breakpoint mediated the relationship between subjective drug effects and 'willingness to take again', a putative indicator of liability via motivation for future drug-seeking behavior. These findings validate the purchase task paradigm for quantifying the reinforcing value and, in turn, abuse liability of unfamiliar compounds, providing a foundation for a variety of future applications. © 2018 Society for the Study of Addiction.

  17. Training Needs of Rehabilitation Counselors concerning Alcohol and Other Drugs Abuse Assessment and Treatment

    Science.gov (United States)

    Ong, Lee Za; Cardoso, Elizabeth; Chan, Fong; Chronister, Julie; Chou, Chih Chin

    2007-01-01

    Forty-two rehabilitation counselors participated in a study regarding perceived training needs concerning alcohol and other drug abuse (AODA) treatment and assessment. Participants reported that 85% of consumers with whom they worked had AODA issues, yet over half rated their graduate training in AODA treatment and assessment as poor, and their…

  18. Establishing the Validity of the Personality Assessment Inventory Drug and Alcohol Scales in a Corrections Sample

    Science.gov (United States)

    Patry, Marc W.; Magaletta, Philip R.; Diamond, Pamela M.; Weinman, Beth A.

    2011-01-01

    Although not originally designed for implementation in correctional settings, researchers and clinicians have begun to use the Personality Assessment Inventory (PAI) to assess offenders. A relatively small number of studies have made attempts to validate the alcohol and drug abuse scales of the PAI, and only a very few studies have validated those…

  19. Molecular Interaction and Computational Analytical Studies of Pinocembrin for its Antiangiogenic Potential Targeting VEGFR-2: A Persuader of Metastasis.

    Science.gov (United States)

    Sharma, Neha; Sharma, Mala; Shakeel, Eram; Jamal, Qazi M Sajid; Kamal, Mohammad A; Sayeed, Usman; Khan, Mohammad K A; Siddiqui, Mohammad H; Arif, Jamal M; Akhtar, Salman

    2018-04-16

    Designing a novel antagonist against VEGFR-2 is being applied currently to inhibit cancer growth and metastasis. Because of the unexpected side effects incurred by the contemporary anticancer medications, the focus has been laid towards identifying natural compounds that might carry the potential to inhibit tumor progression. VEGR-2 remains an important target for anticancer drug development as it is the master regulator of vascular growth. The study focuses on virtual screening of compounds from plants of Asteraceae family that bears antiangiogenic potential and thus, inhibiting VEGFR-2 using a computational approach. Structures of phytochemicals were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, VEGFR-2 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytochemicals of the Asteraceae family and the filtered compounds were further promoted for molecular docking and MD simulation analysis. The study extends towards the SOM analysis of Pinocembrin to predict the possible toxic and non-toxic in vivo metabolites via in silico tools (Xenosite Web and PASS online server) Results: The docking results revealed promising inhibitory potential of Pinocembrin against VEGFR-2 with binding energy of -8.50 kcal/mole as compared to its known inhibitors Sorafenib and YLT192 having binding energy of -6.49 kcal/mole and -8.02 kcal/mol respectively. Further, molecular dynamics (MD) simulations for 10ns were conducted for optimization, flexibility prediction, and determination of folded VEGFR-2 stability. The Hsp90-Pinocembrin complex was found to be quite stable with RMSD value of 0.2nm. Pinocembrin was found to be metabolically stable undergoing phase I metabolism with non-toxic metabolites compared to the standard drug Sorafenib and YLT192. Obtained results propose Pinocembrin as a multi-targeted novel lead compound that bears

  20. Assessing drug abusers with the Millon Clinical Multiaxial Inventory: a review.

    Science.gov (United States)

    Craig, R J; Weinberg, D

    1992-01-01

    This paper reviews studies that used the Millon Clinical Multiaxial Inventory with drug abusers. Although the test has been used with over 2000 such patients in the published literature, there is still a dearth of basic research with the MCMI with this population. Preliminary evidence suggests that the Personality Disorder Scales are quite useful to assess personality styles of drug abusers, but the Clinical Syndrome Scales present some problems. Specifically, the Drug Dependence Scale has had difficulty in reliably "detecting" drug addicted individuals who were in treatment for drug abuse. However, a reliable modal MCMI profile among this population seems to exist, although cluster research suggests several subtypes, each with different personality styles. MCMI computer-narrative reports may overdiagnose paranoid disorder and under diagnose antisocial disorders among this population.

  1. Sex, drugs, and HIV: rapid assessment of HIV risk behaviors among street-based drug using sex workers in Durban, South Africa.

    Science.gov (United States)

    Needle, Richard; Kroeger, Karen; Belani, Hrishikesh; Achrekar, Angeli; Parry, Charles D; Dewing, Sarah

    2008-11-01

    South Africa is experiencing significant changes in patterns of illicit drug use, including increasing injection and non-injection drug use, and the use of drugs by persons engaged in sex work, both of which could further expand the HIV/AIDS epidemic. In 2005, a rapid ethnographic assessment was conducted in Durban, South Africa, to learn more about patterns of drug use and HIV risk behaviors among drug-using, street-based sex workers. Field teams recruited 52 current injection and non-injection drug users for key informant interviews and focus groups, and they conducted mapping and observation in identified high-risk neighborhoods. Key informants were offered free, voluntary counseling and HIV rapid testing. The results of the assessment indicate that in this population, drugs play an organizing role in patterns of daily activities, with sex work closely linked to the buying, selling, and using of drugs. Participants reported using multiple drugs including crack cocaine, heroin, Ecstasy and Mandrax, and their choices were based on their expectations about the functional role and behavioral and pharmacological properties of the drugs. The organization of sex work and patterns of drug use differ by gender, with males exercising more control over daily routines and drug and sexual transactions than females. Activities of female sex workers are subject to considerable control by individual pimps, many of whom also function as landlords and drug dealers. A strong hold over the overlapping economies of drugs and sex work by a few individuals extends to control of the physical and social settings in which sex is exchanged and drugs are sold and used as well as the terms under which sex work is carried out. The potential for accelerated HIV spread is considerable given the evidence of overlapping drug-using and sexual risk behaviors and the mixing patterns across drug and sexual risk networks.

  2. Assessment of Adverse Drug Reactions Based on Spontaneous Signals at Secondary Care Public Hospital.

    Science.gov (United States)

    Ponnusankar, S; Tejaswini, M; Chaitanya, M

    2015-01-01

    Adverse drug reactions are considered to be among the leading causes of morbidity and mortality. Approximately 5-25% of hospital admissions are due to adverse drug reactions and 6-15% of hospitalized patients experience serious adverse drug reactions, causing significant prolongation of hospital stay. Thus this study was aimed at determining adverse drug reactions by conducting spontaneous reporting in secondary care Govt. District Head Quarters Hospital at Ooty. A prospective Spontaneous Adverse Drug Reaction reporting study was conducted over a period of 12 months from July 2012 to June 2013. The assessment, categorization, causality, severity and preventability were assessed using standard criteria. A total of 47 suspected adverse drug reactions were reported during the study period. Over all incidences was 1.29% among the study population. Antibiotics (31.91%) were the class of drug most commonly involved, while ciprofloxacin (14.89%) was the most frequently reported. Type H (Hypersensitivity) reactions (51.06%) accounted for majority of the reports and a greater share of the adverse drug reactions are probable (89.36%) based on causality assessment. Mild reactions accounted 82.97% based on modified Hartwig and Siegel severity scale. In 76.59% of the reports, the reaction was considered to be preventable based on Schumock and Thornton preventability scale. The implementation of monitoring based on spontaneous reporting will be useful for the detection and evaluation is associated with increase in morbidity and duration of hospitalization. This study also has established the vital role of clinical pharmacist in the adverse drug reaction monitoring program.

  3. Theoretical Assessment of Fluorinated Phospholipids in the Design of Liposomal Drug-Delivery Systems

    DEFF Research Database (Denmark)

    Madsen, Jesper J.united st; Fristrup, Peter; Peters, Günther H.J.

    2016-01-01

    ,alpha-difluoro (F-2-ProAEL) conjugates of (R)-1-O-hexadecyl-2-palmitoyl-sn-glycero-3-phoshocholineglycerol (ProAEL). Our results provide a theoretical assessment of the potential usefulness of these fluorinated lipids in the rational design of liposomal drug-delivery systems. The a-fluorine-substituted phospholipid...... properties and that are still subjects for important and pharmaceutically proven drug-delivery mechanisms....

  4. The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance.

    Science.gov (United States)

    Selen, Arzu; Dickinson, Paul A; Müllertz, Anette; Crison, John R; Mistry, Hitesh B; Cruañes, Maria T; Martinez, Marilyn N; Lennernäs, Hans; Wigal, Tim L; Swinney, David C; Polli, James E; Serajuddin, Abu T M; Cook, Jack A; Dressman, Jennifer B

    2014-11-01

    The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  5. Influence of drugs of abuse and alcohol upon patients admitted to acute psychiatric wards: physician's assessment compared to blood drug concentrations.

    Science.gov (United States)

    Mordal, Jon; Medhus, Sigrid; Holm, Bjørn; Mørland, Jørg; Bramness, Jørgen G

    2013-06-01

    In acute psychiatric services, rapid and accurate detection of psychoactive substance intake may be required for appropriate diagnosis and intervention. The aim of this study was to investigate the relationship between (a) drug influence as assessed by physicians and (b) blood drug concentrations among patients admitted to acute psychiatric wards. We also explored the possible effects of age, sex, and psychotic symptoms on physician's assessment of drug influence. In a cross-sectional study, the sample comprised 271 consecutive admissions from 2 acute psychiatric wards. At admission, the physician on call performed an overall judgment of drug influence. Psychotic symptoms were assessed with the positive subscale of the Positive and Negative Syndrome Scale. Blood samples were screened for a wide range of psychoactive substances, and quantitative results were used to calculate blood drug concentration scores. Patients were judged as being under the influence of drugs and/or alcohol in 28% of the 271 admissions. Psychoactive substances were detected in 56% of the blood samples. Altogether, 15 different substances were found; up to 8 substances were found in samples from 1 patient. Markedly elevated blood drug concentration scores were estimated for 15% of the patients. Physician's assessment was positively related to the blood drug concentration scores (r = 0.52; P < 0.001), to symptoms of excitement, and to the detection of alcohol, cannabis, and amphetamines. The study demonstrates the major impact of alcohol and drugs in acute psychiatric settings and illustrates the challenging nature of the initial clinical assessment.

  6. [Requirements for drug approval and additional benefits assessment: Regulatory aspects and experiences].

    Science.gov (United States)

    Broich, K; Löbker, W; Schulte, A; Beinlich, P; Müller, T

    2016-04-01

    The early assessment of benefits of newly approved drugs with novel active substances or new applications, which came into force on 1 January 2011 still represents a challenge to all parties involved. This article highlights the definitions, regulatory requirements and interaction between drug marketing approval and early assessment of benefits in Germany. The constellation of an extensively harmonized European and even international drug authorization process with a predominantly national regulation of drug reimbursement situation inevitably causes friction, which could be markedly reduced through early joint advisory discussions during the planning phase for pivotal clinical trials. During the year 2015 the Federal Institute for Drugs and Medical Devices (BfArM) carried out 300 scientific advice procedures of which 34 were concerned with applications in the field of indications for the central nervous system (CNS). In comparison 98 advisory meetings were held by the Federal Joint Committee (G-BA) of which the BfArM provided advice in 12 instances and in 2 cases on CNS indications. Study design, endpoints and appropriate comparative therapies are the key issues in exchanges and discussions between the BfArM, the G‑BA and applicants. Under these aspects the BfArM and G‑BA promote an early and consistent involvement in early advice procedures regarding the prerequisites for drug approval and assessment of additional benefits.

  7. Surgical hemostatic agents: assessment of drugs and medical devices.

    Science.gov (United States)

    Aubourg, R; Putzolu, J; Bouche, S; Galmiche, H; Denis, C; d'Andon, A; Maitrot, D; Partensky, C

    2011-12-01

    Surgical hemostatic agents are indicated to improve hemostasis when conventional techniques (compression, sutures or electrocoagulation) are inadequate. The National French Authority for Health (Haute Autorité de santé [HAS]) set out to assess these products (medical devices and agents) to determine their optimal utility. This evaluation included one class of products containing some form of human fibrinogen and thrombin and eight classes of medical devices and automated devices to prepare autologous fibrin. The assessment was based on a systematic review of the literature and expert opinion of health care professionals. The main measures of effectiveness of hemostatic agents were the success rate as expressed in terms of the time necessary to obtain adequate hemostasis, the volume of intra and/or postoperative blood loss, the need for blood transfusions, complication rate, duration of operations and hospital stay. A meta-analysis and 52 controlled randomized studies were selected involving cardiac or vascular surgery (19), ENT surgery (11), gastrointestinal surgery (5), urology (4), orthopedic surgery (4). Approximately half of the studies retained in this analysis evaluated blood derived agents (fibrin sealants) while the other half evaluated medical devices. The working group considered that there is not any evidence that these surgical hemostatic agents decrease the rates of transfusion, complications, reoperation, mortality, duration of operation and/or hospital stay. The working group considered that the use of surgical hemostatic agents to improve the safety of hemostasis in the absence of identified bleeding as an alternative to adequate conventional hemostasis was not justified. Surgical hemostatic agents can be used in ad hoc settings, as a complement to conventional methods to control persistent bleeding after conventional hemostatic techniques, or when abundant bleeding has led to biologic hemostatic disorders. The working group also distinguished

  8. Miniaturized screening of polymers for amorphous drug stabilization (SPADS): rapid assessment of solid dispersion systems.

    Science.gov (United States)

    Wyttenbach, Nicole; Janas, Christine; Siam, Monira; Lauer, Matthias Eckhard; Jacob, Laurence; Scheubel, Emmanuel; Page, Susanne

    2013-08-01

    Development of a novel, rapid, miniaturized approach to identify amorphous solid dispersions with maximum supersaturation and solid state stability. Three different miniaturized assays are combined in a 2-step decision process to assess the supersaturation potential and drug-polymer miscibility and stability of amorphous compositions. Step 1: SPADS dissolution assay. Drug dissolution is determined in 96-well plates to detect systems that generate and maintain supersaturation. Promising combinations graduate to step 2. Step 2: SPADS interaction and SPADS imaging assays. FTIR microspectroscopy is used to study intermolecular interactions. Atomic force microscopy is applied to analyze molecular homogeneity and stability. Based on the screening results, selected drug-polymer combinations were also prepared by spray-drying and characterized by classical dissolution tests and a 6-month physical stability study. From the 7 different polymers and 4 drug loads tested, EUDRAGIT E PO at a drug load of 20% performed best for the model drug CETP(2). The classical dissolution and stability tests confirmed the results from the miniaturized assays. The results demonstrate that the SPADS approach is a useful de-risking tool allowing the rapid, rational, time- and cost-effective identification of polymers and drug loads with appropriate dual function in supersaturation performance and amorphous drug stabilization. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Rapid assessment response (RAR study: drug use and health risk - Pretoria, South Africa

    Directory of Open Access Journals (Sweden)

    Trautmann Franz

    2011-06-01

    Full Text Available Abstract Background Within a ten year period South Africa has developed a substantial illicit drug market. Data on HIV risk among drug using populations clearly indicate high levels of HIV risk behaviour due to the sharing of injecting equipment and/or drug-related unprotected sex. While there is international evidence on and experience with adequate responses, limited responses addressing drug use and drug-use-related HIV and other health risks are witnessed in South Africa. This study aimed to explore the emerging problem of drug-related HIV transmission and to stimulate the development of adequate health services for the drug users, by linking international expertise and local research. Methods A Rapid Assessment and Response (RAR methodology was adopted for the study. For individual and focus group interviews a semi-structured questionnaire was utilised that addressed key issues. Interviews were conducted with a total of 84 key informant (KI participants, 63 drug user KI participants (49 males, 14 females and 21 KI service providers (8 male, 13 female. Results and Discussion Adverse living conditions and poor education levels were cited as making access to treatment harder, especially for those living in disadvantaged areas. Heroin was found to be the substance most available and used in a problematic way within the Pretoria area. Participants were not fully aware of the concrete health risks involved in drug use, and the vague ideas held appear not to allow for concrete measures to protect themselves. Knowledge with regards to substance related HIV/AIDS transmission is not yet widespread, with some information sources disseminating incorrect or unspecific information. Conclusions The implementation of pragmatic harm-reduction and other evidence-based public health care policies that are designed to reduce the harmful consequences associated with substance use and HIV/AIDS should be considered. HIV testing and treatment services also need to

  10. Human Laboratory Settings for Assessing Drug Craving Implications for the Evaluation of Treatment Efficacy

    Directory of Open Access Journals (Sweden)

    Zahra Alam Mehrjerdi

    2011-04-01

    Full Text Available Research on assessing craving in laboratory settings often involves inducing and then measuring craving in subjects. Cue-induced craving is studied in laboratory settings using the cue reactivity paradigm, in which drug-related photos, videos, evocative scripts, olfactory cues, and paraphernalia may induce craving. Cue-induced craving evoked by drug-related stimuli could be associated with relapse and recurrence of drug addiction. In this article, the authors review different methods of assessing craving in laboratory settings and explain how human laboratory settings can bridge the gap between randomized clinical trials (RCTs and animal models on pharmacological treatments for drug dependence. The brief reviewed literature provides strong evidence that laboratory-based studies of craving may improve our understanding of how subjective reports of drug craving are related to objective measures of drug abuse and laboratory settings provide an opportunity to measure the degree to which they co-vary during pharmacological interventions. This issue has important implications inclinical studies.

  11. Human Laboratory Settings for Assessing Drug Craving; Implications for the Evaluation of Treatment Efficacy

    Directory of Open Access Journals (Sweden)

    Zahra Alam Mehrjerdi

    2011-04-01

    Full Text Available Research on assessing craving in laboratory settings often involves inducing and then measuring craving in subjects. Cue-induced craving is studied in laboratory settings using the cue reactivity paradigm, in which drug-related photos, videos, evocative scripts, olfactory cues, and paraphernalia may induce craving. Cue-induced craving evoked by drug-related stimuli could be associated with relapse and recurrence of drug addiction. In this article, the authors review different methods of assessing craving in laboratory settings and explain how human laboratory settings can bridge the gap between randomized clinical trials (RCTs and animal models on pharmacological treatments for drug dependence. The brief reviewed literature provides strong evidence that laboratory-based studies of craving may improve our understanding of how subjective reports of drug craving are related to objective measures of drug abuse and laboratory settings provide an opportunity to measure the degree to which they co-vary during pharmacological interventions. This issue has important implications inclinical studies.

  12. A multiple biomarker assay for quality assessment of botanical drugs using a versatile microfluidic chip.

    Science.gov (United States)

    Li, Zhen-Hao; Ai, Ni; Yu, Lawrence X; Qian, Zhong-Zhi; Cheng, Yi-Yu

    2017-09-25

    Quality control is critical for ensuring the safety and effectiveness of drugs. Current quality control method for botanical drugs is mainly based on chemical testing. However, chemical testing alone may not be sufficient as it may not capture all constituents of botanical drugs. Therefore, it is necessary to establish a bioassay correlating with the drug's known mechanism of action to ensure its potency and activity. Herein we developed a multiple biomarker assay to assess the quality of botanicals using microfluidics, where enzyme inhibition was employed to indicate the drug's activity and thereby evaluate biological consistency. This approach was exemplified on QiShenYiQi Pills using thrombin and angiotensin converting enzyme as "quality biomarkers". Our results demonstrated that there existed variations in potency across different batches of the intermediates and preparations. Compared with chromatographic fingerprinting, the bioassay provided better discrimination ability for some abnormal samples. Moreover, the chip could function as "affinity chromatography" to identify bioactive phytochemicals bound to the enzymes. This work proposed a multiple-biomarker strategy for quality assessment of botanical drugs, while demonstrating for the first time the feasibility of microfluidics in this field.

  13. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

    Science.gov (United States)

    Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

    2007-01-04

    The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

  14. Antiangiogenic agents and the skin: cutaneous adverse effects of sorafenib, sunitinib, and bevacizumab.

    Science.gov (United States)

    Ara, M; Pastushenko, E

    2014-12-01

    As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients' quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life-threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents. Copyright © 2013 Elsevier España, S.L.U. y AEDV. All rights reserved.

  15. The paradoxical pro- and antiangiogenic actions of resveratrol: therapeutic applications in cancer and diabetes.

    Science.gov (United States)

    Kamaleddin, Mohammad Amin

    2016-12-01

    Resveratrol, a polyphenol found in grapes, peanuts, and red wine, plays different roles in diseases such as cancer and diabetes. Existing information indicates that resveratrol provides cardioprotection, as evidenced by superior postischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes associated with resveratrol treatment in animal models. Cardiovascular benefits are experienced in humans with routine but not acute consumption of red wine. In this concise review, the paradoxical pro- and antiangiogenic effects of resveratrol are described, and different roles for resveratrol in the formation of new blood vessels are explained through different mechanisms. It is hypothesized that the effects of resveratrol on different cell types are not only dependent on its concentration but also on the physical and chemical conditions surrounding cells. The findings discussed herein shed light on potential therapeutic proapoptotic and antiangiogenic applications of low-dose resveratrol treatment in the prevention and treatment of different diseases. © 2016 New York Academy of Sciences.

  16. Angiogenic and anti-angiogenic factor gene transcript level quantitation by quantitative real time PCR in patients with hepatocellular carcinoma.

    Science.gov (United States)

    Sharma, Bal Krishan; Srinivasan, Radhika; Kapil, Shweta; Singla, Bhupesh; Chawla, Yogesh Kumar; Chakraborti, Anuradha; Saini, Nitin; Duseja, Ajay; Das, Ashim; Kalra, Naveen; Dhiman, Radha Krishan

    2013-10-01

    Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. The aim of this study was to quantify the expression of angiogenic (VEGF, HIF-1α, Angiopiotein-2) and anti-angiogenic (endostatin, angiostatin and Thrombospondin-1) factors and to discern their clinical relevance. A total 90 patients (67 HCC, 9 cirrhosis and 14 chronic hepatitis) were enrolled in the study. Tissue transcript levels of angiogenic (VEGF, HIF-1α, Ang-2) and anti-angiogenic (endostatin, angiostatin and TSP-1) factors were analyzed by quantitative real time-polymerase chain reaction (qRT-PCR) in the tissue samples. The tissue transcript levels of VEGF, HIF-1α and endostatin were found to be significantly higher in HCC in comparison to cirrhosis and chronic hepatitis. Although Ang-2, angiostatin and TSP-1 tissue transcript levels were higher in HCC group than the others groups but the difference was not statistically significant. In univariate analysis both VEGF and HIF-1α were found to be associated with poor survival of HCC patients. Multivariate analysis by the cox proportional hazard model revealed only VEGF as an independent factor predicting poor survival of the HCC patients. Angiogenic and anti-angiogenic factors are all highly expressed in HCC patients. Upregulation of tissue anti-angiogenic factors indicates the urgency for the alternative of anti-angiogenic therapies.

  17. A Novel Chronic Opioid Monitoring Tool to Assess Prescription Drug Steady State Levels in Oral Fluid.

    Science.gov (United States)

    Shaparin, Naum; Mehta, Neel; Kunkel, Frank; Stripp, Richard; Borg, Damon; Kolb, Elizabeth

    2017-11-01

    Interpretation limitations of urine drug testing and the invasiveness of blood toxicology have motivated the desire for the development of simpler methods to assess biologically active drug levels on an individualized patient basis. Oral fluid is a matrix well-suited for the challenge because collections are based on simple noninvasive procedures and drug concentrations better correlate to blood drug levels as oral fluid is a filtrate of the blood. Well-established pharmacokinetic models were utilized to generate oral fluid steady state concentration ranges to assess the interpretive value of the alternative matrix to monitor steady state plasma oxycodone levels. Paired oral fluid and plasma samples were collected from patients chronically prescribed oxycodone and quantitatively analyzed by liquid chromatography tandem mass spectrometry. Steady state plasma concentration ranges were calculated for each donor and converted to an equivalent range in oral fluid. Measured plasma and oral fluid oxycodone concentrations were compared with respective matrix-matched steady state ranges, using each plasma steady state classification as the control. A high degree of correlation was observed between matrices when classifying donors according to expected steady state oxycodone concentration. Agreement between plasma and oral fluid steady state classifications was observed in 75.6% of paired samples. This study supports novel application of basic pharmacokinetic knowledge to the pain management industry, simplifying and improving individualized drug monitoring and risk assessment through the use of oral fluid drug testing. Many benefits of established therapeutic drug monitoring in plasma can be realized in oral fluid for patients chronically prescribed oxycodone at steady state. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  18. Simulated drug discovery process to conduct a synoptic assessment of pharmacy students.

    Science.gov (United States)

    Richardson, Alan; Curtis, Anthony D M; Moss, Gary P; Pearson, Russell J; White, Simon; Rutten, Frank J M; Perumal, Dhaya; Maddock, Katie

    2014-03-12

    OBJECTIVE. To implement and assess a task-based learning exercise that prompts pharmacy students to integrate their understanding of different disciplines. DESIGN. Master of pharmacy (MPharm degree) students were provided with simulated information from several preclinical science and from clinical trials and asked to synthesize this into a marketing authorization application for a new drug. Students made a link to pharmacy practice by creating an advice leaflet for pharmacists. ASSESSMENT. Students' ability to integrate information from different disciplines was evaluated by oral examination. In 2 successive academic years, 96% and 82% of students demonstrated an integrated understanding of their proposed new drug. Students indicated in a survey that their understanding of the links between different subjects improved. CONCLUSION. Simulated drug discovery provides a learning environment that emphasizes the connectivity of the preclinical sciences with each other and the practice of pharmacy.

  19. Challenges and advances in the assessment of the disposition of antibody‐drug conjugates

    Science.gov (United States)

    Iyer, Suhasini

    2015-01-01

    Abstract Antibody‐drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and to minimize toxicity in patients. Significant progress has been made in recent years in this area, however, many fundamental questions still remain. This review discusses factors to consider while assessing the disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed. © 2015 Genentech Inc. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:25904406

  20. Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy.

    Science.gov (United States)

    Zhang, Li; Takara, Kazuhiro; Yamakawa, Daishi; Kidoya, Hiroyasu; Takakura, Nobuyuki

    2016-01-01

    Antiangiogenic agents transiently normalize tumor vessel structure and improve vessel function, thereby providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy. Currently, there are no reliable predictors or markers reflecting this vessel normalization window during antiangiogenic therapy. Apelin, the expression of which is regulated by hypoxia, and which has well-described roles in tumor progression, is an easily measured secreted protein. Here, we show that apelin can be used as a marker for the vessel normalization window during antiangiogenic therapy. Mice bearing s.c. tumors resulting from inoculation of the colon adenocarcinoma cell line HT29 were treated with a single injection of bevacizumab, a mAb neutralizing vascular endothelial growth factor. Tumor growth, vessel density, pericyte coverage, tumor hypoxia, and small molecule delivery were determined at four different times after treatment with bevacizumab (days 1, 3, 5, and 8). Tumor growth and vessel density were significantly reduced after bevacizumab treatment, which also significantly increased tumor vessel maturity, and improved tumor hypoxia and small molecule delivery between days 3 and 5. These effects abated by day 8, suggesting that a time window for vessel normalization was opened between days 3 and 5 during bevacizumab treatment in this model. Apelin mRNA expression and plasma apelin levels decreased transiently at day 5 post-treatment, coinciding with vessel normalization. Thus, apelin is a potential indicator of the vessel normalization window during antiangiogenic therapy. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  1. Anti-angiogenic effect of curcumin, curcumin ethylenediamine derivative and curcumin ethylenediamine manganese complex

    OpenAIRE

    SUNTORNSUK, Leena; Koizumi, Keiichi; Saitoh, Yurika; Nakamura, ElianeShizuka; KAMMASUD, Naparat; VAJARAGUPTA, Opa; Saiki, Ikuo

    2004-01-01

    We investigated the anti-angiogenic effect of curcumin, curcumin ethylenediamine derivative (curcumin ED) and curcumin ethylenediamine manganese complex (curcumin EDMn) through the inhibition of the formation of tube-like structures by human umbilical vascular endothelial cells (HUVEC). Curcumin, curcumin ED, curcumin EDMn did not show cytotoxicity to HUVEC at concentrations equal and lower than 10 μM. At the concentration of 10 μM,curcumin, curcumin ED and curcumin EDMn inhibited the tube fo...

  2. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  3. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    International Nuclear Information System (INIS)

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  4. Campania preventability assessment committee: a focus on the preventability of the contrast media adverse drug reactions.

    Science.gov (United States)

    Sessa, Maurizio; Rossi, Claudia; Rafaniello, Concetta; Mascolo, Annamaria; Cimmaruta, Daniela; Scavone, Cristina; Fiorentino, Sonia; Grassi, Enrico; Reginelli, Alfonso; Rotondo, Antonio; Sportiello, Liberata

    2016-12-01

    The current study aims to assess the preventability of the contrast media adverse drug reactions reported through the Campania spontaneous reporting system, identifying the possible limitations emerged in this type of evaluation. All the individual case safety reports validated by the Campania Pharmacovigilance Regional Centre from July 2012 to September 2015 were screened to select those that reported contrast media as suspected drug. Campania Preventability Assessment Committee, in collaboration with clinicians specialized in Radiology, assessed the preventability according to the P-Method, through a case-by-case approach. From July 2012 to September 2015, 13798 cases were inserted by pharmacovigilance managers in the Italian Pharmacovigilance Network database (in the geographical contest of the Campania Region), of which 67 reported contrast media as suspected drug. Five preventable cases were found. The most reported causes for preventability were the inappropriate drug use for the case clinical conditions and the absence of the preventive measure administrated prior to the contrast media administration. Several limitations were found in the evaluation of the critical criteria for the preventability assessment. Educational initiatives will be organized directly to the healthcare professionals involved in the contrast media administration, to promote an appropriate use of the contrast media.

  5. Legacy data sharing to improve drug safety assessment: the eTOX project

    DEFF Research Database (Denmark)

    Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas

    2017-01-01

    The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the...

  6. Legacy data sharing to improve drug safety assessment : the eTOX project

    NARCIS (Netherlands)

    Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas; Díaz, Carlos; Cases, Montserrat; Pastor, Manuel; Marc, Philippe; Wichard, Joerg; Briggs, Katharine; Watson, David K; Kleinöder, Thomas; Yang, Chihae; Amberg, Alexander; Beaumont, Maria; Brookes, Anthony J; Brunak, Søren; Cronin, Mark T D; Ecker, Gerhard F; Escher, Sylvia; Greene, Nigel; Guzmán, Antonio; Hersey, Anne; Jacques, Pascale; Lammens, Lieve; Mestres, Jordi; Muster, Wolfgang; Northeved, Helle; Pinches, Marc; Saiz, Javier; Sajot, Nicolas; Valencia, Alfonso; van der Lei, Johan; Vermeulen, Nico P E; Vock, Esther; Wolber, Gerhard; Zamora, Ismael

    2017-01-01

    The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the

  7. Comparison of indicators assessing the quality of drug prescribing for asthma

    NARCIS (Netherlands)

    Veninga, C.C.M.; Denig, P.; Pont, L.G.; Haaijer-Ruskamp, F.M.

    Objective. To compare different indicators for assessing the quality of drug prescribing and establish their agreement in identifying doctors who may not adhere to treatment guidelines. Data Sources/Study Setting. Data from 181 general practitioners (GPs) from The Netherlands. The case of asthma is

  8. Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Yoojoo Lim

    Full Text Available Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear.Tumor attenuation as measured by Hounsfield units (HU in contrast-enhanced computed tomography (CT and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80 treated with regorafenib in a prospective study.141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%-20.7%. Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson's r = 0.37, p = 0.002. Among 53 patients with lung metastases, 17 (32.1% developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50 and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13.Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies.

  9. Clinical Implication of Anti-Angiogenic Effect of Regorafenib in Metastatic Colorectal Cancer

    Science.gov (United States)

    Yoon, Jeong Hee; Lee, Jeong Min; Lee, Jung Min; Paeng, Jin Chul; Won, Jae-Kyung; Kang, Gyeong Hoon; Jeong, Seung-Yong; Park, Kyu Joo; Lee, Kyung-Hun; Kim, Jee Hyun; Kim, Tae-You

    2015-01-01

    Background Regorafenib induces distinct radiological changes that represent its anti-angiogenic effect. However, clinical implication of the changes is unclear. Methods Tumor attenuation as measured by Hounsfield units (HU) in contrast-enhanced computed tomography (CT) and cavitary changes of lung metastases were analyzed in association with treatment outcome of metastatic colorectal cancer patients (N = 80) treated with regorafenib in a prospective study. Results 141 lesions in 72 patients were analyzed with HU. After 2 cycles of regorafenib, 87.5% of patients showed decrease of HU (Median change -23.9%, range -61.5%–20.7%). Lesional attenuation change was modestly associated with metabolic changes of 18-fluoro-deoxyglucose positron emission tomography-CT (Pearson’s r = 0.37, p = 0.002). Among 53 patients with lung metastases, 17 (32.1%) developed cavitary changes. There were no differences in disease control rate, progression-free survival, or overall survival according to the radiological changes. At the time of progressive disease (PD) according to RECIST 1.1, HU was lower than baseline in 86.0% (43/50) and cavitary change of lung metastasis persisted without refilling in 84.6% (11/13). Conclusion Regorafenib showed prominent anti-angiogenic effect in colorectal cancer, but the changes were not associated with treatment outcome. However, the anti-angiogenic effects persisted at the time of PD, which suggests that we may need to develop new treatment strategies. PMID:26671465

  10. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Zhao, Mei [Department of Pharmacy, Shanghai Institute of Health Sciences and Health School Attached to SJTU-SM, 279 Zhouzhu Road, Shanghai 201318 (China); Liu, Ya-Rong; Liu, Hai-Jun [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Fang, Chao, E-mail: fangchao100@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China); Chen, Hong-Zhuan, E-mail: hongzhuan_chen@hotmail.com [Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025 (China)

    2014-11-15

    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC.

  11. Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues.

    Science.gov (United States)

    Nuti, Elisa; Bassani, Barbara; Camodeca, Caterina; Rosalia, Lea; Cantelmo, AnnaRita; Gallo, Cristina; Baci, Denisa; Bruno, Antonino; Orlandini, Elisabetta; Nencetti, Susanna; Noonan, Douglas M; Albini, Adriana; Rossello, Armando

    2017-09-29

    Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 μM concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R 2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Drug prescribing data used in the assessment of general practitioners’ treatment of asthma and urinary tract infection – Experience from the European Drug Education Project

    Directory of Open Access Journals (Sweden)

    Per Lagerløv

    2009-11-01

    Full Text Available  ABSTRACTDescribing drug treatment given by general practitioners, and quantifying changes in their prescribingbehaviour due to educational intervention, were important parts of the method developed and appliedby the European Drug Education Project. Based on the physicians’ prescription data, individual patientswere defined as having either asthma or urinary tract infections. Prescribing indicators were establishedfor assessing the quality (acceptable or unacceptable of the drug treatment. The diagnose definitionsand prescribing indicators are discussed in more detail in relation to feeding back individual prescribingdata to educational groups of physicians to improve the quality of their drug therapy.

  13. Questionnaire of core beliefs related to drug use and craving for assessment of relapse risk.

    Science.gov (United States)

    Martínez-González, José Miguel; Vilar López, Raquel; Lozano-Rojas, Oscar; Verdejo-García, Antonio

    2017-07-12

    This study was aimed at designing a questionnaire for the assessment of addiction-related core beliefs and craving. The sample comprised 215 patients (85.8% males and 14.2% females) in treatment for dependence to alcohol (40%), cocaine (36.3%) and cannabis (23.7%). Descriptive statistics were used to characterize the sample. Variance, regression and factorial analyses were conducted to study the questionnaire structure and its relation with variables such as abstinence and craving. Items about drug-related beliefs yielded a four-factor structure: what patient think that they could not do without drug use, lack of withdrawal, conditions required to use drugs again, and use of drugs as the only way to feel good. Items related to craving yielded three factors: negative emotions as precipitants of drug use, positive emotions, and difficulties attributed to coping with craving. Furthermore, beliefs were more important to predict craving than abstinence time. The present questionnaire allows to assess a set of significant factors to design prevention relapse programs.

  14. Antitumour and antiangiogenic activities of [Pt(O,O′‐acac)(γ‐acac)(DMS)] in a xenograft model of human renal cell carcinoma

    Science.gov (United States)

    Vetrugno, C; Biagioni, F; Calabriso, N; Calierno, M T; Fornai, F; De Pascali, S A; Marsigliante, S; Fanizzi, F P

    2016-01-01

    Background and Purpose It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O′‐acac)(γ‐acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non‐genomic targets, on human renal carcinoma and compared them with those of the well‐established anticancer drug, cisplatin. Experimental Approach Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki‐1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs. Key Results Treatment of the Caki‐1 cells with cisplatin or [Pt(DMS)] resulted in a dose‐dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours. Conclusions and Implications The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing. PMID:27351124

  15. Antitumour and antiangiogenic activities of [Pt(O,O'-acac)(γ-acac)(DMS)] in a xenograft model of human renal cell carcinoma.

    Science.gov (United States)

    Muscella, A; Vetrugno, C; Biagioni, F; Calabriso, N; Calierno, M T; Fornai, F; De Pascali, S A; Marsigliante, S; Fanizzi, F P

    2016-09-01

    It is thought that the mechanism of action of anticancer chemotherapeutic agents is mainly due to a direct inhibition of tumour cell proliferation. In tumour specimens, the endothelial cell proliferation rate increases, suggesting that the therapeutic effects of anticancer agents could also be attributed to inhibition of tumour angiogenesis. Hence, we investigated the potential effects of [Pt(O,O'-acac)(γ-acac)(DMS)] ([Pt(DMS)]), a new platinum drug for non-genomic targets, on human renal carcinoma and compared them with those of the well-established anticancer drug, cisplatin. Tumour growth, tumour cell proliferation and microvessel density were investigated in a xenograft model of renal cell carcinoma, developed by injecting Caki-1 cells into BALB/c nude mice. The antiangiogenic potential of compounds was also investigated using HUVECs. Treatment of the Caki-1 cells with cisplatin or [Pt(DMS)] resulted in a dose-dependent inhibition of cell survival, but the cytotoxicity of [Pt(DMS)] was approximately fivefold greater than that of cisplatin. [Pt(DMS)] was much more effective than cisplatin at inhibiting tumour growth, proliferation and angiogenesis in vivo, as well as migration, tube formation and MMP1, MMP2 and MMP9 secretion of endothelial cells in vitro. Whereas, cisplatin exerted a greater cytotoxic effect on HUVECs, but did not affect tube formation or the migration of endothelial cells. In addition, treatment of the xenograft mice with [Pt(DMS)] decreased VEGF, MMP1 and MMP2 expressions in tumours. The antiangiogenic and antitumour activities of [Pt(DMS)] provide a solid starting point for its validation as a suitable candidate for further pharmacological testing. © 2016 The British Pharmacological Society.

  16. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.

    Science.gov (United States)

    Zhang, Tianyu; Li, Si-Yang; Converse, Paul J; Grosset, Jacques H; Nuermberger, Eric L

    2013-01-01

    Buruli ulcer (BU) caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments. For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU) counts for a panel of drugs with various mechanisms of action. Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound, and costs

  17. Medical prescriptions falsified by the patients: a 12-year national monitoring to assess prescription drug diversion.

    Science.gov (United States)

    Jouanjus, Emilie; Guernec, Grégory; Lapeyre-Mestre, Maryse

    2018-02-13

    Diversion of prescription drugs is difficult to assess in quality and quantity. This study aimed to characterize diversion of prescription drugs in France through a comparative analysis of falsified prescriptions collected during three periods from 2001 to 2012. The data recorded in a national program which records all falsified prescriptions presented to community pharmacies were studied. Included data regarded: subjects, prescription forms, and drugs. Description of the dataset in three periods (2001-2004, 2005-2008, and 2009-2012) was completed with clustering analyses to characterize profiles of prescriptions and subjects associated with the most reported drugs. The 4469 falsified prescriptions concerned most often females (51.6%). Average age was 46.5 years. Zolpidem, bromazepam, and buprenorphine were the most frequent drugs. Alone, 13 drugs (1.7%, 13/772) represented more than 40% of the total reports (3055/7272). They were associated with three diversion profiles: (i) buprenorphine, flunitrazepam, and morphine were mentioned on overlapping secure prescription forms presented by young men; (ii) alprazolam, bromazepam, zolpidem, codeine/acetaminophen were mentioned on simple prescription forms presented by experienced women; and (iii) acetaminophen and lorazepam were mentioned on modified prescription forms presented by elderly subjects. Clonazepam, clorazepate, dextropropoxyphene, zopiclone moved between those profiles. The patterns of falsified prescriptions provided in this study contribute to enhance the scientific knowledge on the most diverted prescription drugs. The latter follow distinct trajectories across time depending on their pharmacology (including their abuse/addiction potential) and on their regulation's history. The close and continuous analysis of falsified prescriptions is an excellent way to monitor prescription drug diversion. © 2018 Société Française de Pharmacologie et de Thérapeutique.

  18. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.

    Directory of Open Access Journals (Sweden)

    Tianyu Zhang

    Full Text Available Buruli ulcer (BU caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound

  19. Micropharmacology: An In Silico Approach for Assessing Drug Efficacy Within a Tumor Tissue.

    Science.gov (United States)

    Karolak, Aleksandra; Rejniak, Katarzyna A

    2018-02-08

    Systemic chemotherapy is one of the main anticancer treatments used for most kinds of clinically diagnosed tumors. However, the efficacy of these drugs can be hampered by the physical attributes of the tumor tissue, such as tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, tumor metabolic gradients, and non-uniform expression of the cell membrane receptors. This can impede the transport of therapeutic agents to tumor cells in sufficient quantities. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine ways to improve drug delivery on a cell-to-tissue scale (single-cell pharmacology), we developed the microscale pharmacokinetics/pharmacodynamics (microPKPD) modeling framework. Our model is modular and can be adjusted to include only the mathematical equations that are crucial for a biological problem under consideration. This modularity makes the model applicable to a broad range of pharmacological cases. As an illustration, we present two specific applications of the microPKPD methodology that help to identify optimal drug properties. The hypoxia-activated drugs example uses continuous drug concentrations, diffusive-advective transport through the tumor interstitium, and passive transmembrane drug uptake. The targeted therapy example represents drug molecules as discrete particles that move by diffusion and actively bind to cell receptors. The proposed modeling approach takes into account the explicit tumor tissue morphology, its metabolic landscape and/or specific receptor distribution. All these tumor attributes can be assessed from patients' diagnostic biopsies; thus, the proposed methodology can be developed into a tool suitable for personalized medicine, such as neoadjuvant chemotherapy.

  20. Assessment of clinical risk factors for drug-resistant epilepsy in children and teenagers

    Directory of Open Access Journals (Sweden)

    Marta Kasprzyk

    2014-09-01

    Full Text Available Introduction: Epilepsy is one of the most common neurological illnesses occurring in children. In approximately 20–30% of cases it is drug-resistant. Aim of the research: To assess the already-known risk factors, analyse the rarely described ones, and find new causes of epilepsy drug resistance in children, taking into account the level of impact of each factor. Material and methods : The study comprised 152 of all 383 children hospitalised in 2012 at the Neurology Department of the Polish Mother’s Memorial Hospital in Lodz due to epilepsy. Based on medical documentation, neurological examination, and our own questionnaire, we divided patients into two groups: drug-resistant epilepsy or drug-sensitive epilepsy. We compared the type, level of influence, and prevalence of different factors. For statistical analysis, the 2 test was used. Statistical significance was set at p < 0.05. Results: Drug-resistant epilepsy was found in 64 patients (42.1%, and drug-sensitive epilepsy was found in 88 patients (57.9%. Factors that were most probable to cause drug resistance included: high prevalence of seizures (Cramer’s V = 0.66, type of epileptic syndrome (V = 0.62, psychomotor developmental delay (V = 0.62, and occurrence of status epilepticus (V = 0.6. Factors such as infections of CNS in early childhood, repeated severe infections of airways in childhood, and mother’s infectious diseases with high fever during pregnancy were rare or non occurring (Cramer’s V = 0.41, 0.32, and 0.31, respectively. Conclusions : The study confirmed the previously known causes of drug resistance and indicated the significance of underestimated inflammatory and infectious factors involving pyrexia, in children and also in mothers during pregnancy.

  1. Assessment of the quality and quantity of drug-drug interaction studies in recent NDA submissions: study design and data analysis issues.

    Science.gov (United States)

    Huang, S M; Lesko, L J; Williams, R L

    1999-10-01

    This report investigates the quality and quantity of drug-drug interaction studies in recent new drug applications (NDAs). Eighty-nine studies contained in 14 NDAs submitted between December 1995 and November 1996 to the U.S. Food and Drug Administration (FDA) were reviewed. The results indicated that the median number of clinical drug-drug interaction studies per NDA was 6, almost double that of a 1994-1995 survey. In vitro metabolism data were present in 70% of the submissions. More than 50% of the submissions contained interaction studies using a battery of drugs (cimetidine, digoxin, or warfarin) without optimal use of the in vitro metabolism or in vivo mass balance data. Various study designs using a median number of 12 subjects were employed in the evaluation of drug-drug interactions. Some of the important study design factors such as dose size, dosing regimen, dosing duration, and timing of coadministration were considered, although not consistently, by the sponsors in their study design. Seventy-five percent of the studies used normal, healthy male subjects, and 25% used patients for whom the new molecular entities were intended. In 33% of the studies, female subjects were also recruited. Although the majority (80%) of the submissions still used p-values to determine the significance of drug interactions, 30% used a more relevant equivalence approach with 90% confidence intervals for key pharmacokinetic and/or pharmacodynamic parameter ratios to assess the extent of drug interactions. Overall, 82% of the studies concluded no interaction. Although population pharmacokinetic analysis can be a useful tool in studying drug-drug interactions, only 21% of the submissions used this approach. In summary, this assessment reveals that the quantity and quality of drug-drug interaction studies in NDAs have improved over the years. These improvements, as well as others that can be implemented, should result in more informative labeling and better patient care. FDA

  2. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis

    NARCIS (Netherlands)

    Kamp, Jasper; Bolhuis, Mathieu S.; Tiberi, Simon; Akkerman, Onno W.; Centis, Rosella; de lange, Wiel C.; Kosterink, Jos G.; van der Werf, Tjip S.; Migliori, Giovanni B.; Alffenaar, Jan-Willem C.

    Linezolid is used increasingly for the treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis (TB). However, linezolid can cause severe adverse events, such as peripheral and optical neuropathy or thrombocytopenia related to higher drug exposure. This study aimed

  3. Antiangiogenic Effect of Ficus deltoidea Jack Standardised Leaf ...

    African Journals Online (AJOL)

    cancer cell lines was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Results: In rat ... cytotoxicity against breast and colon cancer cells while demonstrating non-cytotoxic activity against normal endothelial cells. .... ventilated cages with 12 h of light as well as food and water were ...

  4. Assessment of a micropatterned hepatocyte coculture system to generate major human excretory and circulating drug metabolites.

    Science.gov (United States)

    Wang, Wendy WeiWei; Khetani, Salman R; Krzyzewski, Stacy; Duignan, David B; Obach, R Scott

    2010-10-01

    Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites.

  5. Assessment of Sexual Dysfunction Symptoms in Female Drug Users: Standardized vs. Unstandardized Methods.

    Science.gov (United States)

    Diehl, Alessandra; Rassool, G Hussein; dos Santos, Manoel Antônio; Pillon, Sandra Cristina; Laranjeira, Ronaldo

    2016-01-01

    The aim of this study is to evaluate whether there is a difference in the identified prevalence between the assessment of symptoms of sexual dysfunction in female drug users using a standardized scale and by means of a nonstandardized set of questions about sexual dysfunctions. A cross-sectional study was conducted with two groups of substance-dependent women using the Drug Abuse Screening Test, the Short Alcohol Dependence Data questionnaire, the Fagerström Test for Nicotine Dependence for the evaluation of the severity of dependence, and the Arizona Sexual Experience Scale. In both groups, the severity of dependence and the prevalence of symptoms of sexual dysfunctions in women were similar. The use of standardized and nonstandardized instruments to assess sexual dysfunction symptoms is an essential resource for the provision of good-quality care to this clientele.

  6. Penduliflaworosin, a Diterpenoid from Croton crassifolius, Exerts Anti-Angiogenic Effect via VEGF Receptor-2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yeyin Liang

    2017-01-01

    Full Text Available Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR-2 has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs. Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments.

  7. Raman and infrared techniques for fighting drug-related crime: a preliminary assessment

    Science.gov (United States)

    Valussi, Silvia; Underhill, Mark

    2006-09-01

    A proof-of-concept hand-held Raman spectrometer and a commercial portable system based on Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) were assessed for the rapid, "at scene" analysis of illicit drugs. The objectives of such an assessment were twofold: 1) to determine the suitability of the systems in practical forensic casework and 2) to determine the potential of the use of such systems in covert operations. Data obtained are promising and demonstrate the potential advantages and limitations of the use of these techniques in these fields of operation.

  8. Drug interaction at hERG channel: In vitro assessment of the electrophysiological consequences of drug combinations and comparison against theoretical models.

    Science.gov (United States)

    Wiśniowska, Barbara; Lisowski, Bartosz; Kulig, Magdalena; Polak, Sebastian

    2018-04-01

    Drugs carry a proarrhythmic risk, which gets even greater when they are used in combination. In vitro assessment of the proarrhythmic potential of drugs is limited to one compound and thus neglects the potential of drug-drug interactions, including those involving active metabolites. Here we present the results of an in vitro study of potential drug-drug interactions at the level of the hERG channel for the combination of up to three compounds: loratadine, desloratadine and ketoconazole. Experiments were performed at room temperature on an automated patch-clamp device CytoPatch 2, with the use of heterogeneously, stably transfected HEK cells. Single drugs, pairs and triplets were used. The results provided as the inhibition of the I Kr current for pairs were compared against the calculated theoretical interaction. Models applied to calculate the combined effect of inhibitory actions of simultaneously given drugs include: (1) simple additive model with a maximal inhibition limit of 1 (all channels blocked in 100%); (2) Bliss independence; and (3) Loewe additivity. The observed IC 50 values for loratadine, desloratadine and ketoconazole were 5.15, 1.95 and 0.74 μm respectively. For the combination of drugs tested in pairs, the effect was concentration dependent. In lower concentrations, the synergistic effect was observed, while for the highest tested concentrations it was subadditive. To triple the effect, it was subadditive regardless of concentrations. The square root of sum of squares of differences between the observed and predicted total inhibition was calculated to assess the theoretical interaction models. For most of the drugs, the allotopic model offered the best fit. Copyright © 2017 John Wiley & Sons, Ltd.

  9. Modernizing methodology for the WHO assessment of substances for the international drug control conventions.

    Science.gov (United States)

    Danenberg, E; Sorge, L A; Wieniawski, W; Elliott, S; Amato, L; Scholten, W K

    2013-08-01

    The WHO Executive Board revised the guidance that governs the procedures for the WHO review of psychoactive substances for international drug control in 2010. To meet the standards defined in these guidelines, the current evaluation methodology at WHO must be an evidence-based assessment. We describe the history of substance evaluation from 1912 to the present and the development of the evaluation methods over time including a description of the current assessment system, using reports from WHO and its predecessor, the League of Nations. Furthermore, we describe the current review system. We found that some substances under international control were never reviewed; other substances were reviewed decades ago. We argue that assessments do not have unlimited validity, and therefore, substances need to be re-assessed periodically, as already recommended by the Expert Committee on Drug Dependence in 1982. We propose that the evaluation time be shortened; that the influence of the route of administration and/or dosage form of the preparation is considered in the evaluation; and we recommend studying national and regional assessment systems and adopting their best practices. With this article, we make a case for the inclusion of systematic review and other methods of comprehensive analysis of substance evaluation to arrive at a process of equal rigour and quality as already applied by WHO for the development of treatment guidelines. Copyright © 2013 World Health Organization. Published by Elsevier Ireland Ltd.. All rights reserved.

  10. New Anti-angiogenic Leading Structure Discovered in the Fruit of Cimicifuga yunnanensis

    Science.gov (United States)

    Nian, Yin; Yang, Jing; Liu, Tong-Yang; Luo, Ying; Zhang, Ji-Hong; Qiu, Ming-Hua

    2015-03-01

    Cimyunnins A-C (1-3), characterized with an unusual fused cyclopentenone ring G, together with cimyunnin D (4), possessing a highly rearranged γ-lactone ring F, were characterized from the fruit of Cimicifuga yunnanensis. Their structures were elucidated by spectroscopic analysis, X-ray diffraction, and density functional theory calculations. In addition, cimyunnin A exhibited comparable anti-angiogenic activities to those of sunitinib, a clinically-used first-line angiogenesis inhibitor, in the in vitro and ex vivo studies.

  11. Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Cui Y

    2016-11-01

    Full Text Available Yanfen Cui,1,* Caiyuan Zhang,1,* Ran Luo,1 Huanhuan Liu,1 Zhongyang Zhang,1 Tianyong Xu,2 Yong Zhang,2 Dengbin Wang11Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 2MR Advanced Application and Research Center, GE Healthcare China, Shanghai, People’s Republic of China *These authors contributed equally to this workPurpose: Arginine-glycine-aspartic acid (RGD-based nanoprobes allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA-coated ultrasmall superparamagnetic iron oxide (USPIO (referred to as RGD-PAA-USPIO in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC xenograft model by magnetic resonance imaging (MRI.Materials and methods: The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group.Results: The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvβ3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P<0.05.Conclusion: This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in

  12. The native structure of annexin A2 peptides in hydrophilic environment determines their anti-angiogenic effects.

    Science.gov (United States)

    Raddum, Aase M; Hollås, Hanne; Shumilin, Igor A; Henklein, Petra; Kretsinger, Robert; Fossen, Torgils; Vedeler, Anni

    2015-05-01

    The progression of aggressive cancer occurs via angiogenesis and metastasis makes these processes important targets for the development of anti-cancer agents. However, recent studies have raised the concern that selective inhibition of angiogenesis results in a switch towards increased tumour growth and metastasis. Since Annexin A2 (AnxA2) is involved in both angiogenesis and metastasis, it may serve as an ideal target for the simultaneous inhibition of both processes. Based on the discovery that domains I (D(I)) and IV (D(IV)) of AnxA2 are potent inhibitors of angiogenesis, we designed seven peptides derived from these domains based on AnxA2 crystal structures. The peptides were expressed as fusion peptides to increase their folding and solubility. Light scattering, far-UV circular dichroism and thermal transition analyses were employed to investigate their aggregation tendencies, α-helical propensity and stability, respectively. 2,2,2-trifluoroethanol (50%) increased the α-helical propensities of all peptides, indicating that they may favour a hydrophobic environment, but did not enhance their thermal stability. D(I)-P2 appears to be the most stable and folded peptide in a hydrophilic environment. The secondary structure of D(I)-P2 was confirmed by nuclear magnetic resonance spectra. The effect of the seven AnxA2 peptides on the formation and integrity of capillary-like networks was studied in a co-culture system mimicking many of the angiogenesis-related processes. Notably, D(I)-P2 inhibited significantly network formation in this system, indicating that the folded D(I)-P2 peptide interferes with vascular endothelial growth factor-dependent pro-angiogenic processes. Thus, this peptide has the potential of being developed further as an anti-angiogenic drug. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data.

    Science.gov (United States)

    Williams, John; Bialer, Meir; Johannessen, Svein I; Krämer, Günther; Levy, René; Mattson, Richard H; Perucca, Emilio; Patsalos, Philip N; Wilson, John F

    2003-01-01

    To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs). Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy. The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry. With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.

  14. The practice of pre-marketing safety assessment in drug development.

    Science.gov (United States)

    Chuang-Stein, Christy; Xia, H Amy

    2013-01-01

    The last 15 years have seen a substantial increase in efforts devoted to safety assessment by statisticians in the pharmaceutical industry. While some of these efforts were driven by regulations and public demand for safer products, much of the motivation came from the realization that there is a strong need for a systematic approach to safety planning, evaluation, and reporting at the program level throughout the drug development life cycle. An efficient process can help us identify safety signals early and afford us the opportunity to develop effective risk minimization plan early in the development cycle. This awareness has led many pharmaceutical sponsors to set up internal systems and structures to effectively conduct safety assessment at all levels (patient, study, and program). In addition to process, tools have emerged that are designed to enhance data review and pattern recognition. In this paper, we describe advancements in the practice of safety assessment during the premarketing phase of drug development. In particular, we share examples of safety assessment practice at our respective companies, some of which are based on recommendations from industry-initiated working groups on best practice in recent years.

  15. Rapamycin/DiR loaded lipid-polyaniline nanoparticles for dual-modal imaging guided enhanced photothermal and antiangiogenic combination therapy.

    Science.gov (United States)

    Wang, Jinping; Guo, Fang; Yu, Meng; Liu, Li; Tan, Fengping; Yan, Ran; Li, Nan

    2016-09-10

    Imaging-guided photothermal therapy (PTT) has promising application for treating tumors. Nevertheless, so far imaging-guided photothermal drug-delivery systems have been developed with limited success for tumor chemo-photothermal therapy. In this study, as the proof-of-concept, a stimuli-responsive tumor-targeting rapamycin/DiR loaded lipid-polyaniline nanoparticle (RDLPNP) for dual-modal imaging-guided enhanced PTT efficacy is reported for the first time. In this system, polyaniline (PANI) with π-π electronic conjugated system and effective photothermal efficiency is chosen as the appropriate model receptor of fluorescence resonance energy transfer (FRET), and loaded cyanine probe (e.g., 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide, DiR) acts as the donor of near-infrared fluorescence (NIRF). In addition, rapamycin (RAPA), which is used as the antiangiogenesis chemotherapeutic drug, can cutdown the tumor vessels and delay tumor growth obviously. After intravenous treatment of RDLPNPs into Hela tumor bearing mice, fluorescent (from DiR) and enhanced photoacoustic (from DLPNPs) signals were found in tumor site over time, which reached to peak at the 6h time point. After irradiating with an NIR laser, a good anti-tumor effect was observed owing to the enhanced photothermal and antiangiogenic effect of RDLPNPs. These results show that the multifunctional nanoparticle can be used as a promising imaging-guided photothermal drug delivery nanoplatform for cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Rapid assessment of drug use and sexual HIV risk patterns among ...

    African Journals Online (AJOL)

    Non-injection drug use (mainly cannabis, methaqualone, crack cocaine and crystal methamphetamine) and injection drug use (mainly heroin) was occurring in these cities. Drug users report selling sex for money to buy drugs, and CSWs used drugs before, during and after sex. Most (70%) of the drug-using KIs offered HIV ...

  17. Imaging anti-angiogenic treatment response with DCE-VCT, DCE-MRI and DWI in an animal model of breast cancer bone metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Baeuerle, Tobias [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: t.baeuerle@dkfz-heidelberg.de; Bartling, Soenke [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: s.bartling@dkfz-heidelberg.de; Berger, Martin [Unit of Chemotherapy and Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: m.berger@dkfz-heidelberg.de; Schmitt-Graeff, Annette [Institute of Pathology, University of Freiburg, Postfach 214, 79002 Freiburg (Germany)], E-mail: annette.schmitt-graeff@uniklinik-freiburg.de; Hilbig, Heidegard [Institute of Anatomy, University of Leipzig, Liebigstrasse 13, 04103 Leipzig (Germany)], E-mail: Heidegard.Hilbig@medizin.uni-leipzig.de; Kauczor, Hans-Ulrich [Department of Diagnostic and Interventional Radiology, Radiologische Klinik, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg (Germany)], E-mail: hans-ulrich.kauczor@med.uni-heidelberg.de; Delorme, Stefan [Department of Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)], E-mail: s.delorme@dkfz-heidelberg.de; Kiessling, Fabian [Department of Medical Physics in Radiology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Department of Experimental Molecular Imaging, RWTH Aachen, Pauwelsstrasse 20, 52074 Aachen (Germany)], E-mail: fkiessling@ukaachen.de

    2010-02-15

    As current classification systems for the assessment of treatment response in bone metastasis do not meet the needs of oncologists, new imaging biomarkers are desirable. Therefore, the diagnostic impact of dynamic contrast enhanced (DCE)-volumetric computed tomography (VCT) (descriptive analysis), DCE-MRI (two-compartment model) and diffusion weighted imaging (DWI) for monitoring anti-angiogenic therapy effects of the VEGF antibody bevacizumab in breast cancer bone metastases in rats was studied. Nude rats (n = 8 animals treated with bevacizumab and n = 9 untreated control rats) with site-specific osteolytic bone metastasis of the hind leg were imaged with a 1.5 T clinical MRI-scanner in an animal coil as well as in a volumetric CT-scanner at days 30, 40, 50 and 60 after inoculation of MDA-MB-231 human breast cancer cells. From these data, osteolytic lesion size (OLS), peak enhancement (PE), area under the curve (AUC), amplitude (A), exchange rate constant (k{sub ep}) and apparent diffusion coefficient (ADC) were determined in bone metastases. Prior to changes in OLS (p {<=} 0.05 at days 50 and 60) there was already a significant decrease in PE, AUC and A (p {<=} 0.05 at days 40-60) in treated animals compared to controls. However, for k{sub ep} and ADC there were no significant differences between the groups at any time point (p > 0.05 at days 40-60). In conclusion, anti-angiogenic treatment response in osteolytic breast cancer bone metastases can be assessed early with surrogate markers of vascularization, while DWI appears to be insensitive.

  18. Differential expression of anti-angiogenic factors and guidance genes in the developing macula.

    Science.gov (United States)

    Kozulin, Peter; Natoli, Riccardo; O'Brien, Keely M Bumsted; Madigan, Michele C; Provis, Jan M

    2009-01-01

    The primate retina contains a specialized, cone-rich macula, which mediates high acuity and color vision. The spatial resolution provided by the neural retina at the macula is optimized by stereotyped retinal blood vessel and ganglion cell axon patterning, which radiate away from the macula and reduce shadowing of macular photoreceptors. However, the genes that mediate these specializations, and the reasons for the vulnerability of the macula to degenerative disease, remain obscure. The aim of this study was to identify novel genes that may influence retinal vascular patterning and definition of the foveal avascular area. We used RNA from human fetal retinas at 19-20 weeks of gestation (WG; n=4) to measure differential gene expression in the macula, a region nasal to disc (nasal) and in the surrounding retina (surround) by hybridization to 12 GeneChip microarrays (HG-U133 Plus 2.0). The raw data was subjected to quality control assessment and preprocessing, using GC-RMA. We then used ANOVA analysis (Partek) Genomic Suite 6.3) and clustering (DAVID website) to identify the most highly represented genes clustered according to "biological process." The neural retina is fully differentiated at the macula at 19-20 WG, while neuronal progenitor cells are present throughout the rest of the retina. We therefore excluded genes associated with the cell cycle, and markers of differentiated neurons, from further analyses. Significantly regulated genes (pmacula versus surround" and "macula versus nasal." KEGG pathway clustering of the filtered gene lists identified 25 axon guidance-related genes that are differentially regulated in the macula. Furthermore, we found significant upregulation of three anti-angiogenic factors in the macula: pigment epithelium derived factor (PEDF), natriuretic peptide precurusor B (NPPB), and collagen type IValpha2. Differential expression of several members of the ephrin and semaphorin axon guidance gene families, PEDF, and NPPB was verified by

  19. Evolution of health technology assessment: best practices of the pan-Canadian Oncology Drug Review

    Directory of Open Access Journals (Sweden)

    Rocchi A

    2015-06-01

    Full Text Available Angela Rocchi,1 Isabelle Chabot,2 Judith Glennie3 1Athena Research Inc., Burlington, ON, 2EvAccess Inc., Vaudreuil-Dorion, QC, 3JL Glennie Consulting Inc., Aurora, ON, Canada Background: In 2007, Canada chose to develop a separate and distinct path for oncology drug health technology assessment (HTA. In 2013, the decision was made to transfer the pan-Canadian Oncology Drug Review (pCODR to the Canadian Agency for Drugs and Technologies in Health (CADTH, to align the pCODR and CADTH Common Drug Review processes while building on the best practices of both. The objective of this research was to conduct an examination of the best practices established by the pCODR. Methods: A qualitative research approach was taken to assess the policies, processes, and practices of the pCODR, based on internationally accepted best practice “principles” in HTA, with a particular focus on stakeholder engagement. Publicly available information regarding the approach of the pCODR was used to gauge the agency's performance against these principles. In addition, stakeholder observations and real-world experiences were gathered through key informant interviews to be inclusive of perspectives from patient advocacy groups, provincial and/or cancer agency decision-makers, community and academic oncologists, industry, expert committee members, and health economists. Results: This analysis indicated that, through the pCODR, oncology stakeholders have had a voice in and have come to trust the quality and relevance of oncology HTA as a vital tool to ensure the best decisions for Canadians with cancer and their health care system. It could be expected that adoption of the principles and processes of the pCODR would bring a similar level of engagement and trust to other HTA organizations in Canada and elsewhere. Conclusion: The results of this research led to recommendations for improvement and potential extrapolation of these best practices to other HTA organizations

  20. Assessment of postoperative changes in antihypertensive drug consumption in patients with primary aldosteronism using the defined daily dose

    Directory of Open Access Journals (Sweden)

    Takanobu Utsumi

    2014-10-01

    Conclusion: The defined daily dose is a useful tool for assessing total changes in the consumption of antihypertensive drugs in patients with primary aldosteronism. Using the defined daily dose, clinicians could explain in detail to patients with primary aldosteronism the predicted postoperative change in antihypertensive drug consumption.

  1. A Challenge for Diagnosing Acute Liver Injury with Concomitant/Sequential Exposure to Multiple Drugs: Can Causality Assessment Scales Be Utilized to Identify the Offending Drug?

    Directory of Open Access Journals (Sweden)

    Roxanne Lim

    2014-01-01

    Full Text Available Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM, Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis.

  2. [Assessing the added benefit of new ophthalmic drugs : Which additional insights can be extracted from the early benefit assessment?

    Science.gov (United States)

    Appelrath, M; Glaeske, G

    2017-12-01

    Until now six ophthalmic agents have undergone the German early benefit assessment according to § 35a Social Security Code (SGB) V in a total of eleven indications. Only one agent (ocriplasmin) was recognized by the Federal Joint Committee as having an added benefit based on submitted study data for a subpopulation (indication of a considerable added benefit, limited for 5 years) and another agent, idebenone, received an added benefit due to its orphan drug designation (proof of a not quantifiable added benefit, limited for 2 years). All remaining agents (aflibercept, bromfenac, nepafenac and tafluprost/timolol) were not recognized as having an added benefit. The analysis showed that there was a lack of suitable evidence. Some reasons for the inappropriateness of the conducted trials for the usage in the early benefit assessment are the comparative therapy, the patient population included or the dosage regimens. For two agents (bromfenac and nepafenac) the pharmaceutical company did not even submit a value dossier. The examples from ophthalmology illustrate the methodological and procedural shortcomings of the assessment process and that results of an early benefit assessment should be interpreted with caution.

  3. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    Full Text Available Objectives: Advancements in nanotechnology have led to nanoparticle (NP use in various fields of medicine. Although the potential of NPs is promising, the lack of documented evidence on the toxicological effects of NPs is concerning. A few studies have documented that homeopathy uses NPs. Unfortunately, very few sound scientific studies have explored the toxic effects of homeopathic drugs. Citing this lack of high-quality scientific evidence, regulatory agencies have been reluctant to endorse homeopathic treatment as an alternative or adjunct treatment. This study aimed to enhance our insight into the impact of commercially-available homeopathic drugs, to study the presence of NPs in those drugs and any deleterious effects they might have, and to determine the distribution pattern of NPs in zebrafish embryos (Danio rerio. Methods: Homeopathic dilutions were studied using high-resolution transmission electron microscopy with selected area electron diffraction (SAED. For the toxicity assessment on Zebrafish, embryos were exposed to a test solution from 4 - 6 hours post-fertilization, and embryos/larvae were assessed up to 5 days post-fertilization (dpf for viability and morphology. Toxicity was recorded in terms of mortality, hatching delay, phenotypic defects and metal accumulation. Around 5 dpf was found to be the optimum developmental stage for evaluation. Results: The present study aimed to conclusively prove the presence of NPs in all high dilutions of homeopathic drugs. Embryonic zebrafish were exposed to three homeopathic drugs with two potencies (30CH, 200CH during early embryogenesis. The resulting morphological and cellular responses were observed. Exposure to these potencies produced no visibly significant malformations, pericardial edema, and mortality and no necrotic and apoptotic cellular death. Conclusion: Our findings clearly demonstrate that no toxic effects were observed for these three homeopathic drugs at the potencies and

  4. Parental and offspring assessment of driving capability under the influence of drugs or alcohol: gender and inter-generational differences.

    Science.gov (United States)

    Rosenbloom, Tova; Beigel, Ariela; Perlman, Amotz; Eldror, Ehud

    2010-11-01

    The current study set to examine whether there are inter-generational and gender-based differences between family members self-assessing their ability to drive under normal conditions and while under the influence of either alcohol or drugs. Participants were 135 young-adults and both their parents, consisting 45 family triads, who received self-assessment questionnaires relating to their driving skills in various road scenarios. Each family triad was randomly assigned to one of three groups: either requested to base the assessments on normal driving conditions, or under the influence of either drugs or alcohol, thus forming a control group, and two experimental groups (alcohol and drugs), respectively. The findings indicate the assessments of both the alcohol and drugs groups were more severe than those of the control group. The alcohol group assessments were less strict than the drug group assessment (non-significantly). Inter-generational differences indicated that the parents' driving-skills assessments were lower than those of their offspring, corresponding with previous findings (Elkind, 1967; Finn and Bragg, 1986). A significant within-subject interaction has been found between the respondent's gender and familial relations regarding the self-assessment of driving skills: male respondents assessed better driving skills compared to the self estimates of both parents (which did not significantly differ). In contrast, female respondents' estimates did not differ from their fathers' and both fathers' and daughters' estimates were significantly higher than that of the mothers in each family. 2010 Elsevier Ltd. All rights reserved.

  5. Cognitive and social learning models of drug dependence: implications for the assessment of tobacco dependence in adolescents.

    Science.gov (United States)

    Brandon, Thomas H; Herzog, Thaddeus A; Irvin, Jennifer E; Gwaltney, Chad J

    2004-06-01

    This paper is part of a series that has the goal of identifying potential approaches toward developing new instruments for assessing tobacco dependence among adolescents. The fundamental assumption underlying the series is that contemporary theories of drug dependence offer a rich source of opportunities for the development of theoretically based assessment tools. The present paper focuses on cognitive and social-learning models of drug dependence and the implications of these models for novel assessment instruments. In particular, the paper focuses on Mark Goldman's model of drug expectancies, Albert Bandura's model of self-efficacy, Thomas Wills's model of stress and coping and Stephen Tiffany's cognitive-processing model of drug urges and cravings. In addition to traditional self-report measures, naturalistic and laboratory-based assessments are identified that may yield information relevant to multi-dimensional measurement of tobacco dependence.

  6. Post-marketing access to orphan drugs: a critical analysis of health technology assessment and reimbursement decision-making considerations

    Directory of Open Access Journals (Sweden)

    Iskrov G

    2014-01-01

    Full Text Available Georgi Iskrov, Rumen Stefanov Department of Social Medicine and Public Health, Medical University of Plovdiv, Plovdiv, Bulgaria Abstract: This study aims to explore the current rationale of post-marketing access to orphan drugs. As access to orphan medicinal products depends on assessment and appraisal by health authorities, this article is focused on health technology assessment (HTA and reimbursement decision-making considerations for orphan drugs. A critical analysis may identify important factors that could predetermine the combined outcomes of these two processes. Following this objective, an analytical framework was developed, comprising three overlaying issues: to outline what is currently done and what needs to be done in the field of HTA of orphan drugs, to synthesize important variables relevant to the reimbursement decision-making about orphan drugs, and to unveil relationships between theory and practice. Methods for economic evaluation, cost-effectiveness threshold, budget impact, uncertainty of evidence, criteria in reimbursement decision-making, and HTA research agenda are all explored and discussed from an orphan drug perspective. Reimbursement decision-making for orphan drugs is a debate of policy priorities, health system specifics, and societal attitudes. Health authorities need to pursue a multidisciplinary analysis on a range of criteria, ensuring an explicit understanding of the trade-offs for decisions related to eligibility for reimbursement. The only reasonable way to accept a higher valuation of orphan drug benefits is if these are demonstrated empirically. Rarity means that the quality of orphan drug evidence is not the same as for conventional therapies. Closing this gap is another crucial point for the timely access to these products. The generation of evidence goes far beyond pre-market authorization trials and requires transnational cooperation and coordination. Early constructive dialogue among orphan drug

  7. Assessing behavioral patterns of Internet addiction and drug abuse among high school students.

    Science.gov (United States)

    Nemati, Zeinab; Matlabi, Hossein

    2017-01-01

    Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents' addiction extracts high cost on health care, educational failure and mental health services. The aim of this study was to assess the behavioral patterns of Internet and drug addiction among urban and rural students in Urmia, Iran. A sectional and descriptive-analytical approach with stratified sampling method was employed to recruit 385 high school students from urban and rural areas. The Internet Addiction Test (IAT) and the Addiction Acknowledgement Scale (AAS) were used for data collection. The total score of Internet addiction among the students was 41.72 ± 17.41. Approximately two-third of the students were not addicted to the Internet. The mean score of the AAS was 1.87 ± 1.23 among boys and 1.75 ± 1.31 among girls. Moreover, 8.31% of the students were prone to abusing substances. A statistically significant relationship was found between mother's literacy level and Internet addiction behavior of students ( p =0.009). Concentrating on adolescents' behavioral patterns and their tendency toward misusing Internet and drugs is a notable procedure. Therefore, focusing on adolescents' health and institutionalizing appropriate training programs for adolescents and their families are vital.

  8. Toxicological assessment of drugs that affect the endocrine system in puberty-related disorders.

    Science.gov (United States)

    Maranghi, Francesca; Tassinari, Roberta; Mantovani, Alberto

    2013-10-01

    Toxicologists must ensure that clinical risk-to-benefit analysis should be made both for genders and age groups, with any treatment. Puberty concerns physiological changes leading to organism's maturation. Pubertal growth disorders are increasing in last decades: besides causing physical and psychological distress, they may signal underlying endocrine-metabolic abnormalities with serious health consequences later on. Therapeutic approaches for some health conditions in childhood and adolescence are considered. The authors discuss how some diseases and treatments can impact pubertal growth. The authors look at particular immunological disorders such as asthma and how both the disease and treatment affects pubertal growth. They also discuss how the provision of available data can help to assess the dose-response of the drug, in these cases, and minimize the chance of side effects. The authors also discuss pediatric inflammatory bowel disease and how both the disease and treatment can mitigate the growth delay. Last, but not least, the authors discuss how the effects of the drugs used in the treatment of psychiatric disorders may accentuate endocrine issues in juvenile patients. Hyperprolactinemia induction by some antipsychotics is highlighted as an example. Appropriate risk-benefit analysis of drugs prescribed during childhood and adolescence and intended to be used in the long term is required. Furthermore, future treatment strategies and safer compounds development should be supported by the knowledge of mechanisms underlying adverse side effects in pubertal growth and development.

  9. Are drug companies living up to their human rights responsibilities? Moving toward assessment.

    Science.gov (United States)

    Gruskin, Sofia; Raad, Zyde

    2010-09-28

    The human rights responsibilities of drug companies have been considered for years by nongovernmental organizations, but were most sharply defined in a report by the UN Special Rapporteur on the right to health, submitted to the United Nations General Assembly in August 2008. The "Human Rights Guidelines for Pharmaceutical Companies in relation to Access to Medicines" include responsibilities for transparency, management, monitoring and accountability, pricing, and ethical marketing, and against lobbying for more protection in intellectual property laws, applying for patents for trivial modifications of existing medicines, inappropriate drug promotion, and excessive pricing. Two years after the release of the Guidelines, the PLoS Medicine Debate asks whether drug companies are living up to their human rights responsibilities. Sofia Gruskin and Zyde Raad from the Harvard School of Public Health say more assessment is needed of such responsibilities; Geralyn Ritter, Vice President of Global Public Policy and Corporate Responsibility at Merck & Co. argues that multiple stakeholders could do more to help States deliver the right to health; and Paul Hunt and Rajat Khosla introduce Mr. Hunt's work as the UN Special Rapporteur on the right to the highest attainable standard of health, regarding the human rights responsibilities of pharmaceutical companies and access to medicines.

  10. [Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example].

    Science.gov (United States)

    Rüther, E; Hellweg, R; Janetzky, W

    2012-12-01

    After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Post-marketing access to orphan drugs: a critical analysis of health technology assessment and reimbursement decision-making considerations

    OpenAIRE

    Iskrov, Georgi; Stefanov,Rumen

    2014-01-01

    Georgi Iskrov, Rumen Stefanov Department of Social Medicine and Public Health, Medical University of Plovdiv, Plovdiv, Bulgaria Abstract: This study aims to explore the current rationale of post-marketing access to orphan drugs. As access to orphan medicinal products depends on assessment and appraisal by health authorities, this article is focused on health technology assessment (HTA) and reimbursement decision-making considerations for orphan drugs. A critical analysis may identify importa...

  12. Assessing behavioral patterns of Internet addiction and drug abuse among high school students

    Directory of Open Access Journals (Sweden)

    Nemati Z

    2017-01-01

    Full Text Available Zeinab Nemati, Hossein Matlabi Department of Health Education and Promotion, Faculty of Health Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Background: Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents’ addiction extracts high cost on health care, educational failure and mental health services. Objectives: The aim of this study was to assess the behavioral patterns of Internet and drug addiction among urban and rural students in Urmia, Iran. Methods: A sectional and descriptive–analytical approach with stratified sampling method was employed to recruit 385 high school students from urban and rural areas. The Internet Addiction Test (IAT and the Addiction Acknowledgement Scale (AAS were used for data collection. Results: The total score of Internet addiction among the students was 41.72 ± 17.41. Approximately two-third of the students were not addicted to the Internet. The mean score of the AAS was 1.87 ± 1.23 among boys and 1.75 ± 1.31 among girls. Moreover, 8.31% of the students were prone to abusing substances. A statistically significant relationship was found between mother’s literacy level and Internet addiction behavior of students (p=0.009. Conclusion: Concentrating on adolescents’ behavioral patterns and their tendency toward misusing Internet and drugs is a notable procedure. Therefore, focusing on adolescents’ health and institutionalizing appropriate training programs for adolescents and their families are vital. Keywords: Internet, drug abuse, adolescence, addiction, behavior

  13. Histologic Assessment of Drug-Eluting Grafts Related to Implantation Site

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Tille

    2016-02-01

    Full Text Available Drug-eluting vascular prostheses represent a new direction in vascular surgery to reduce early thrombosis and late intimal hyperplasia for small calibre grafts. Subcutaneous implantation in rats is a rapid and cost-effective screening model to assess the drug-elution effect and could, to some extent, be useful to forecast results for vascular prostheses. We compared biological and histological responses to scaffolds in different implantation sites. Polycaprolactone (PCL, paclitaxel-loaded PCL (PCL-PTX and dexamethasone-loaded PCL (PCL-DXM electrospun scaffolds were implanted subcutaneously and in an infrarenal abdominal aortic model in rats for up to 12 weeks. At the conclusion of the study, a histological analysis was performed. Cellular graft invasion revealed differences in the progression of cellular infiltration between PCL-PTX and PCL/PCL-DXM groups in both models. Cell infiltration increased over time in the aortic model compared to the subcutaneous model for all groups. Cell counting revealed major differences in fibroblast, macrophage and giant cell graft colonisation in all groups and models over time. Macrophages and giant cells increased in the PCL aortic model; whereas in the subcutaneous model these cell types increased only after three weeks or even decreased in the drug-eluting PCL groups. Other major findings were observed only in the aortic replacement such as extracellular matrix deposition and neo-angiogenesis. The subcutaneous implant model can be used for screening, especially when drug-eluting effects are studied. However, major histological differences were observed in cell type reaction and depth of cell penetration compared to the aortic model. Our results demonstrate that the implantation site is a critical determinant of the biological response.

  14. Limitations of in vitro assessments of the drug interaction potential of botanical supplements.

    Science.gov (United States)

    Markowitz, John S; Zhu, Hao-Jie

    2012-09-01

    Although there are inherent and recognized limitations of in vitro screening methodologies to assess conventional drug-drug interactions (DDIs) per industry guidelines and those adopted by independent laboratories, further limitations are being appreciated which are unique to the evaluation of botanical products and potential DDIs in which they may participate. Among the larger issues faced are the uncertainty in assigning hepatic concentrations of multiple constituents and their potential metabolites, accounting for oral bioavailability, distribution, first-pass metabolism and active metabolites. Furthermore, the wide variability in the chemical composition of commercially available botanical supplement formulations continues to be a major concern, and manufacturing standards or enforcement thereof is essentially nonexistent in most countries. Differing formulations, unspecified product excipients, administration and absorption of the therapeutic ingredient(s) of a standardized dosage form, the very presence and/or concentration of one or more phytoconstituents within a supplement are typically unknown and nontarget entities. A further issue is the absence of authentic analytical standards, and the inability to accurately screen the entities as mixtures to even approximate typical scenarios, which may occur following the ingestion of dietary supplements, adds additional layers of complexity to experimental design and difficulty in interpreting experimental results. Multiple challenges exist in experimental methodologies employed in performing in vitro research with conventional pharmaceuticals and those unique to botanical extracts. These obstacles prevent the investigators from effectively utilizing high-throughput models to accomplish more than essentially "flag" suspected sources of drug interactions which must be further evaluated in vivo, at present, in order to confirm clinical significance. This review is intended to discuss the problems and challenges in

  15. Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy.

    Science.gov (United States)

    Cavero, Icilio; Guillon, Jean-Michel

    2014-01-01

    The rhythmic opening and tightly closing of cardiac valve leaflets are cardiac cyclic events imposing to blood a unidirectional course along the vascular tree. Drugs with 5-HT2B agonism properties can seriously compromise this biological function critical for hemodynamic efficiency as their intrinsic pro-fibrotic effects can, with time, make valvular coaptation blood regurgitant. Cardiac valve anatomy, physiology and pathology as well as 5-HT2B receptor properties (coupling, effects mediated, biased agonism) are briefly exposed. Approaches to unveil 5-HT2B receptor liability of drug candidates are detailed. In silico computational models can rapidly probe molecules for chemical signatures associated with 5-HT2B receptor affinity. In vitro radioligand competition assays allow quantifying receptor binding capacity (Ki, IC50), the pharmacological nature (agonism, antagonism) of which can be ascertained from cytosolic second messenger (inositol phosphates, Ca(++), MAPK2) changes. Potencies calculated from the latter data may exhibit variability as they are dependent upon the readout measured and the experimental conditions (e.g., receptor density level of cell material expressing human 5-HT2B receptors). The in vivo valvulopathy effects of 5-HT2B receptor agonists can be assessed by echocardiographic measurements and valve histology in rats chronically treated with the candidate drug. Finally, safety margins derived from from nonclinical and clinical data are evaluated in terms of the readout, usefulness and scientific reliability. The Safety Pharmacology toolbox for detecting possible 5-HT2B receptor agonism liabilities of candidate drugs requires meticulous optimization and validation of all its (in silico, in vitro and in vivo) components to perfect its human predictability power. In particular, since 5-HT2B receptor agonism is biased in nature, the most predictive readout(s) of valvular liability should be identified and prioritized in keeping with best scientific

  16. Assessment of antibacterial drug residues in milk for consumption in Kosovo.

    Science.gov (United States)

    Rama, Adem; Lucatello, Lorena; Benetti, Cristiana; Galina, Guglielmo; Bajraktari, Drita

    2017-07-01

    The objective of this study was to assess the occurrence of drug residues in the raw milk collected from individual farms and milk collection points during 2009-2010 in six different major regions of Kosovo (Prishtinë, Gjilan, Mitrovicë, Pejë, Gjakovë, Prizren). In the present study, a total of 1734 raw milk samples were collected, and qualitatively screened with two different tests, the Delvotest SP assay and an enzyme-linked receptor-binding assay (SNAP). Overall, 106 (6.11%) out of 1734 samples examined with Delvotest SP contained possible drug residues (5.12% and 7.51% of samples from 2009 and 2010, respectively). All suspect samples were further analyzed by three distinct enzyme-linked receptor-binding assays specific for β-lactams (new β-lactam test), tetracyclines (SNAP tetracycline test), and sulfonamides (SNAP sulfamethazine test). Only the new SNAP β-lactam test detected residues in 40 out of 52 samples in 2009 and 54 out of 54 suspect samples in 2010. A confirmatory method based on liquid chromatography-tandem mass spectrometry was used to confirm the presence of β-lactam drug residues in samples detected by the enzyme-linked receptor-binding assay. Amoxicillin, penicillin G, and cloxacillin were the most frequently detected residues and were in a concentration range between 2.1 μg/kg and 1973 μg/kg. Seventeen of the positive samples exceeded the maximum residue levels for one or more β-lactam drug. The highest number of positive milk samples came from the Pejë Region (58.8%) and Gjakovë Region (23.5%), and the lowest number of positive samples originated from Gjilan (5.88%), with no positive samples detected in two regions, Mitrovicë and Prizren. Copyright © 2016. Published by Elsevier B.V.

  17. Personalized risk assessment of drug-related harm is associated with health outcomes.

    Directory of Open Access Journals (Sweden)

    Andrea A Jones

    Full Text Available The Independent Scientific Committee on Drugs (ISCD assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS would be associated with poor health outcomes in polysubstance users.A prospective community sample (n=293 of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes.Polysubstance use was pervasive (95.8%, as was multimorbid illness (median 3, possible range 0-12. The median CHS was 2845 (interquartile range 1865-3977. Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07-2.01, p = 0.02, and persistent hepatitis C infection (OR 1.29, 95% CI 1.02-1.67, p = 0.04. The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13-1.67, p = 0.001. The amount spent on drugs increased 1.51-fold (1.40-1.62, p < 0.001 and the odds of having committed a crime increased 1.74-fold (1.46-2.10, p < 0.001. Multimorbid illness increased 1.43-fold (95% CI 1.26-1.63, p < 0.001.Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.

  18. Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy.

    Science.gov (United States)

    Dominietto, Marco; Dobosz, Michael; Bürgi, Sandra; Renner, Anja; Zahlmann, Gudrun; Scheuer, Werner; Rudin, Markus

    2017-07-01

    This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity. Murine glioma cells have been inoculated into the right brain frontal lobe of 16 mice. Anti-VEGF antibody was administered to a first group (n = 8), while a second group (n = 8) received a placebo. Magnetic resonance acquisitions, performed at days 10, 12, 15 and 23 following the implantation, allowed the derivation of a three-dimensional features dataset characterising tumour heterogeneity. Three-dimensional ultramicroscopy and standard histochemistry analysis have been performed to verify in vivo results. Placebo-treated mice displayed a highly-vascularised area at the tumour periphery, a monolithic necrotic core and a chaotic dense vasculature across the entire tumour. In contrast, the B20-treated group did not show any highly vascularised regions and presents a fragmented necrotic core. A significant reduction of the number of vessel segments smaller than 17 μm has been observed. There was no difference in overall tumour volume and growth rate between the two groups. Region-specific analysis revealed that VEGF inhibition affects only: (1) highly angiogenic compartments expressing high levels of VEGF and characterised by small capillaries, and also (2) the formation and structure of necrotic regions. These effects appear to be transient and limited in time. • VEGF inhibition affects only the highly angiogenic region and small capillaries network • VEGF inhibition is transient in time • Tumour volume is not affected by anti-angiogenic treatment • VEGF inhibition also influences the architecture of necrotic regions.

  19. A comprehensive approach to benefit-risk assessment in drug development

    DEFF Research Database (Denmark)

    Sarac, Sinan B; Rasmussen, Christian H; Rasmussen, Morten A.

    2012-01-01

    Major regulatory agencies, for example, FDA and EMA, have started to request comprehensive benefit-risk analyses of pharmaceutical products prior to approval or labelling expansion. The purpose of this study is to develop a generally applicable and reliable data-driven benefit-risk assessment...... method, where two or more drugs/doses can be compared. Our aim is to formulate an approach that is simple to apply, allows direct comparison of different types of risks and benefits, and is tailored for application in different disease areas both during clinical development and in the marketing approval......) discussion and formulation of an overall conclusion. To reduce the impact of subjective judgements, scores are assigned to each criterion on the basis of objective information (data) wherever possible. The proposed benefit-risk evaluation approach offers comprehensive, data-driven assessments that can...

  20. Therapeutic Drug Monitoring of Second-Generation Antipsychotics for the Estimation of Early Drug Effect in First-Episode Psychosis: A Cross-sectional Assessment.

    Science.gov (United States)

    Bustillo, Mariana; Zabala, Arantzazu; Querejeta, Imanol; Carton, Jaione I; Mentxaka, Oiane; González-Pinto, Ana; García, Sainza; Meana, J Javier; Eguiluz, J Ignacio; Segarra, Rafael

    2018-04-01

    Studies on therapeutic drug monitoring (TDM) of second-generation antipsychotics (SGAs) have provided conflicting results regarding the association between dose, plasma concentrations, and drug effect and have focused rather on analyzing how individual drugs work. No study has attempted to process data from different SGAs globally to offer a panoramic view of the utility of TDM in clinical practice, and data on patients with first-episode psychosis (FEP) are lacking. This study aimed to assess the relationship between dose, plasma concentrations, and drug effect in a sample of patients with FEP, regardless of the SGA prescribed. Data from 64 compliant patients treated with the same SGA during a 2-month follow-up were recorded. Clinical symptoms were assessed using the Positive and Negative Symptoms Scale and the Montgomery-Åsberg Depression Rating Scale. Adverse effects were rated using the Udvalg für Kliniske Undersogelser scale. SGA doses were standardized to chlorpromazine equivalents, and patients were classified into 3 different ranges according to their plasma concentrations (subtherapeutic, therapeutic, and supratherapeutic). Plasma concentration ranges were proportionally related to dose. Patients with supratherapeutic plasma concentrations were treated with doses significantly higher than those with subtherapeutic concentrations. Dose and plasma concentrations were not associated with early drug effect. TDM seems unable to accurately estimate the early effects of SGAs in FEP. Ours is the first study to categorize plasma concentrations of SGAs into ranges for joint processing of data from a larger number of patients.

  1. EEG in non-clinical drug safety assessments: Current and emerging considerations.

    Science.gov (United States)

    Authier, Simon; Delatte, Marcus S; Kallman, Mary-Jeanne; Stevens, Joanne; Markgraf, Carrie

    2016-01-01

    Electroencephalogram (EEG) data in nonclinical species can play a critical role in the successful evaluation of a compound during drug development, particularly in the evaluation of seizure potential and for monitoring changes in sleep. Yet, while non-invasive electrocardiogram (ECG) monitoring is commonly included in preclinical safety studies, pre-dose or post-dose EEG assessments are not. Industry practices as they relate to preclinical seizure liability and sleep assessments are not well characterized and the extent of preclinical EEG testing varies between organizations. In the current paper, we discuss the various aspects of preclinical EEG to characterize drug-induced seizure risk and sleep disturbances, as well as describe the use of these data in a regulatory context. An overview of EEG technology-its correct application and its limitations, as well as best practices for setting up the animal models is presented. Sleep and seizure detection are discussed in detail. A regulatory perspective on the use of EEG data is provided and, tying together the previous topics is a discussion of the translational aspects of EEG. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  2. IMPACT OF HEALTH TECHNOLOGY ASSESSMENT IN LITIGATION CONCERNING ACCESS TO HIGH-COST DRUGS.

    Science.gov (United States)

    Aleman, Alicia; Perez Galan, Ana

    2017-01-01

    The impact of health technology assessment (HTA) in the judicialization of the right of health has not been deeply studied in Latin American countries. The purpose of this study is to review the process of judicialization of the access to high cost drugs in Uruguay and assess the impact HTAs have had on this process. The methodology used for this study included a comprehensive literature search in electronic databases, local journals, internal documents developed in the Ministry of Health, as well as conducting interviews with key informants. Judicialization of the access of high cost drugs has been increasing since 2010. The strategy of the Ministry of Health of Uruguay to decrease this problem included the organization of roundtables with judges and other stakeholders on the basis of HTA, the training of defense lawyers in the use and interpretation of HTA, and the participation of a professional who develops HTA in the preparation of the defense arguments. A year after the implementation of this strategy, 25 percent of writs of protection were won by the Ministry of Health. Even though the strategy implemented was effective in reducing the loss of litigations, it was not effective in reducing the growing number of writs of protection. It is essential to address this problem in a broad debate and to promote understanding between the parties.

  3. VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment

    Directory of Open Access Journals (Sweden)

    Skowronski Karolina

    2010-12-01

    Full Text Available Abstract Background Targeting tumor vasculature is a strategy with great promise in the treatment of many cancers. However, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results clinically. Among the possible reasons for this may be heterogeneous expression of the target protein. Methods Double immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal and WM239 (melanoma xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1-/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker α-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1α and immunohistochemistry of CA-IX. Results VEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93% and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60% xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on α-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased

  4. VEGFR2 heterogeneity and response to anti-angiogenic low dose metronomic cyclophosphamide treatment

    International Nuclear Information System (INIS)

    Patten, Steven G; Adamcic, Una; Lacombe, Kristen; Minhas, Kanwal; Skowronski, Karolina; Coomber, Brenda L

    2010-01-01

    Targeting tumor vasculature is a strategy with great promise in the treatment of many cancers. However, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results clinically. Among the possible reasons for this may be heterogeneous expression of the target protein. Double immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal) and WM239 (melanoma) xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1 -/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker α-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1α and immunohistochemistry of CA-IX. VEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD) in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93%) and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60%) xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on α-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased stabilization of colorectal microvessels, but no

  5. Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical.

    Science.gov (United States)

    Andersen, Lars Peter Kloster; Gögenur, Ismail; Torup, Henrik; Rosenberg, Jacob; Werner, Mads Utke

    2017-09-01

    Pain intensity ratings and opioid consumption (OC) are ubiquitous indicators of pain in postoperative trials of the efficacy of interventional procedures. Unfortunately, consensus on the appropriate statistical handling of these outcomes has not been reached. The aim of this article was, therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. Data from a randomized, double-blind, placebo-controlled study investigating the analgesic efficacy of a regional anesthetic block following a major elective surgical procedure were analyzed. The original data included measurements of pain intensity (visual analog scale [VAS]) at rest and during coughing (VAS0/2/4/6/12/18/24 h) and OC0-6/0-24 h administered by patient-controlled analgesia. The statistical analyses included comparisons of discrete pain intensity scores (VAS0/2/4/6/12/18/24 h), summary measures of pain intensity ratings (area under the curve [AUC]-VAS0-6/0-24 h; mean VAS0-6/0-24 h), and OC0-6/0-24 h. Finally, the analyses also included an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC0-6/0-24 h). Also, estimation of effect size, generalized odds ratio of the individual analgesic outcome variables was performed. Sixty-one patients were included in the final data analysis. Discrete pain intensity ratings differed significantly between the treatment groups at specific postoperative time points, but appropriate correction for multiple comparisons eliminated some of these differences. AUC-VAS0-6 h differed significantly at rest and during coughing, while no difference was found for AUC-VAS0-24 h. In contrast, mean VAS0-6 h and VAS0-24 h differed significantly between treatment groups at rest and during coughing. OC0-6/0-24 h differed significantly between the

  6. Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs.

    Science.gov (United States)

    Neuhaus, W; Mandikova, J; Pawlowitsch, R; Linz, B; Bennani-Baiti, B; Lauer, R; Lachmann, B; Noe, C R

    2012-05-01

    In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of

  7. [HTA-Perspective: Challenges in the early assessment of new oncological drugs].

    Science.gov (United States)

    Wild, Claudia; Nachtnebel, Anna

    2013-01-01

    Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). Copyright © 2013. Published by Elsevier GmbH.

  8. Evolution of health technology assessment: best practices of the pan-Canadian Oncology Drug Review.

    Science.gov (United States)

    Rocchi, Angela; Chabot, Isabelle; Glennie, Judith

    2015-01-01

    In 2007, Canada chose to develop a separate and distinct path for oncology drug health technology assessment (HTA). In 2013, the decision was made to transfer the pan-Canadian Oncology Drug Review (pCODR) to the Canadian Agency for Drugs and Technologies in Health (CADTH), to align the pCODR and CADTH Common Drug Review processes while building on the best practices of both. The objective of this research was to conduct an examination of the best practices established by the pCODR. A qualitative research approach was taken to assess the policies, processes, and practices of the pCODR, based on internationally accepted best practice "principles" in HTA, with a particular focus on stakeholder engagement. Publicly available information regarding the approach of the pCODR was used to gauge the agency's performance against these principles. In addition, stakeholder observations and real-world experiences were gathered through key informant interviews to be inclusive of perspectives from patient advocacy groups, provincial and/or cancer agency decision-makers, community and academic oncologists, industry, expert committee members, and health economists. This analysis indicated that, through the pCODR, oncology stakeholders have had a voice in and have come to trust the quality and relevance of oncology HTA as a vital tool to ensure the best decisions for Canadians with cancer and their health care system. It could be expected that adoption of the principles and processes of the pCODR would bring a similar level of engagement and trust to other HTA organizations in Canada and elsewhere. The results of this research led to recommendations for improvement and potential extrapolation of these best practices to other HTA organizations worldwide, along with suggestions for continued evolution of the pCODR in conjunction with its integration into the CADTH. It is clear that the transition of the pCODR to CADTH provides an opportunity for practices initiated by the pCODR to

  9. Assessment of the expectancy, seriousness and severity of adverse drug reactions reported for chronic obstructive pulmonary disease therapy.

    Science.gov (United States)

    Petrova, Guenka; Stoimenova, Assena; Dimitrova, Maria; Kamusheva, Maria; Petrova, Daniela; Georgiev, Ognian

    2017-01-01

    Adverse drug reactions can cause increased morbidity and mortality, and therefore information needs to be studied systematically. Little is known about the adverse drug reactions for chronic obstructive pulmonary disease therapy. The goal of this study is to assess the expectedness, seriousness and severity of adverse drug reactions during chronic obstructive pulmonary disease therapy based on their reporting in the national pharmacovigilance system. This was a prospective, observational, 1-year, real-life study about the pharmacotherapy of a sample of 390 chronic obstructive pulmonary disease patients. Prescribed medicines were systematized and national pharmacovigilance databases were searched for reported adverse drug reactions. The expectedness was evaluated through the review of the summary of product characteristics, the seriousness was evaluated by the clinicians based on the life threatening nature of the adverse drug reactions, and the severity was evaluated through Hartwig's Severity Assessment Scale. Descriptive statistics of the reported adverse drug reactions was performed and the relative risk of developing an adverse drug reaction with all international non-proprietary names included in the analysis was calculated. Results confirm that the chronic obstructive pulmonary disease is a disease with high appearance of adverse drug reactions, and causes many additional costs to the healthcare system. Unexpected and severe adverse drug reactions are frequent. A total of 4.8% of adverse drug reactions were evaluated as life threatening. Majority of adverse drug reactions are classified in Levels 1 (32.6%), 2 (26.4%) and 3 (19%) according to Hartwig's Severity Assessment Scale. Approximately 22% of reported adverse drug reactions affect people's everyday life to a greater extent and require additional therapy which might further increase the risk. The relative risk of developing an adverse drug reaction was highest for novphyllin (relative risk = 0

  10. Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment.

    Science.gov (United States)

    Polak, Sebastian; Fijorek, Kamil; Glinka, Anna; Wisniowska, Barbara; Mendyk, Aleksander

    2012-01-01

    The anatomical and histological parameters of the human ventricle depend on many factors including age and sex. Myocyte volume and electric capacitance are significant physiological parameters of left ventricle cardiomyocyte mathematical models. They allow the assessment of inter-individual variability during in vitro-in vivo extrapolation of the drug cardiotoxic effect. The current research was carried out to analyze the relationship between age, human left ventricle cardiomyocyte volume, and electric capacitance in a healthy population. In order to collect data describing cardiomyocyte volume and membrane area, literature searches were performed. It was assumed that the cardiomyocyte volume (VOL) and area (AREA) distribution have non-negative support and are skewed to the right. A log-linear model with constant variance was used. A simulation study was run to assess the influence of physiological parameters on action potential duration. The coefficient of determination for the proposed model R(2) = 0.95, that is, 95% of the variability observed in log cardiomyocyte volume can be explained by the estimated regression equation. To allow simple calculation and model performance validation, a simple Excel file was developed (Supplementary material). To the best of our knowledge, there is no other model available, combining age, cardiomyocyte volume, and area. The main limitations of the proposed models result from the assumptions made at the data analysis stage. The limited amount of information available in the literature and the lack of differentiation between sexes results in one common equation. The developed model is a part of the computational system for drug cardiotoxicity assessment.

  11. Bisphosphonate-related osteonecrosis of jaw (BRONJ: an anti-angiogenic side-effect?

    Directory of Open Access Journals (Sweden)

    Petcu Eugen B

    2012-07-01

    Full Text Available Abstract Bisphosphonates are recommended in the treatment of osteoporosis and some cancers, in which case they prevent the appearance of bone metastasis. The patients taking bisphosphonates are at increased risk of developing bisphosphonate-related osteonecrosis of jaw (BRONJ which is characterised by the presence of an un-healing wound after dental surgery. BRONJ might represent an anti-angiogenic side effect. However, the real number of patients with BRONJ might be higher than currently recorded. Considering the differential diagnosis which includes various primary and secondary cancers, a correct histopathological diagnosis is very important. The morphological criteria for diagnosis of BRONJ are highlighted in this material. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1813972972323288

  12. Aminopeptidase N inhibition could be involved in the anti-angiogenic effect of dobesilates

    Directory of Open Access Journals (Sweden)

    Farsa Oldřich

    2015-01-01

    Full Text Available Calcium, magnesium and zinc 2,5-dihydroxybenzenesulfonates (dobesilates were synthesized by sulfonation of hydroquinone with sulfuric acid under mild conditions. To form the salts, neutralization with calcium carbonate followed by cation exchange by means of magnesium or zinc sulfates was performed. The dobesilates were characterized by standard spectral methods and by AAS for metal content and then tested for inhibitory activity against aminopeptidase N. Calcium and magnesium 2,5-dihydroxybenzene sulfonates exhibited rather weak inhibitory activity to aminopeptidase N as demonstrated by IC50 values of 978.0 and 832.1 mmol l-1 respectively while zinc 2,5-dihydroxybenzene sulfonate reached the more significant inhibitory activity characterized by IC50 77.4 mmol l-1. The inhibitory activity results suggest that the inhibition of aminopeptidase N could play a role in the anti-angiogenic activity of 2,5-dihydroxybenzenesulfonates.

  13. Antiangiogenic properties of cafestol, a coffee diterpene, in human umbilical vein endothelial cells

    International Nuclear Information System (INIS)

    Wang, Shuaiyu; Yoon, Yeo Cho; Sung, Mi-Jeong; Hur, Haeng-Jeon; Park, Jae-Ho

    2012-01-01

    Highlights: ► Cafestol inhibits tube formation and migration of VEGF-stimulated HUVEC. ► Cafestol inhibits phosphorylation of FAK and Akt. ► Cafestol decreases NO production. -- Abstract: As angiogenesis plays important roles in tumor growth and metastasis, searching for antiangiogenic compounds is a promising tactic for treating cancers. Cafestol, a diterpene found mainly in unfiltered coffee, provides benefit through varied biological activity, including antitumorigenic, antioxidative, and anti-inflammatory effects. This study aimed to investigate the effects of cafestol on angiogenesis and to uncover the associated mechanism. We show that cafestol inhibits angiogenesis of human umbilical vascular endothelial cells. This inhibition affects the following specific steps of the angiogenic process: proliferation, migration, and tube formation. The inhibitory effects of cafestol are accompanied by decreasing phosphorylation of FAK and Akt and by a decrease in nitric oxide production. Overall, cafestol inhibits angiogenesis by affecting the angiogenic signaling pathway.

  14. A biomimetic collagen derived peptide exhibits anti-angiogenic activity in triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Elena V Rosca

    Full Text Available We investigated the application of a mimetic 20 amino acid peptide derived from type IV collagen for treatment of breast cancer. We showed that the peptide induced a decrease of proliferation, adhesion, and migration of endothelial and tumor cells in vitro. We also observed an inhibition of triple negative MDA-MB-231 xenograft growth by 75% relative to control when administered intraperitoneally for 27 days at 10 mg/kg. We monitored in vivo the changes in vascular properties throughout the treatment using MRI and found that the vascular volume and permeability surface area product decreased significantly. The treatment also resulted in an increase of caspase-3 activity and in a reduction of microvascular density. The multiple mode of action of this peptide, i.e., anti-angiogenic, and anti-tumorigenic, makes it a viable candidate as a therapeutic agent as a monotherapy or in combination with other compounds.

  15. Evaluation, partial characterization and purification of acetylcholine esterase enzyme and antiangiogenic activity from marine sponges

    Directory of Open Access Journals (Sweden)

    Maushmi Shailesh Kumar

    2014-11-01

    Full Text Available Objective: To test three marine sponges Halichondria glabrata Keller, 1891; Spirastrella pachyspira (S. pachyspira Levi, 1958 and Cliona lobata Hancock, 1849 for the presence of the acetylcholinesterase (AChE in both young and developed samples from western coastal area of India. S. pachyspira methanolic extract was selected for anti/pro angiogenic activity. Methods: They were evaluated for AChE activity using Ellman’s assay based on production of yellow colored 5-thio-2-nitrobenzoate. Purification of the enzyme was planned using ammonium sulphate precipitation and characterization by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Chorioallantoic membrane (ChAM assay model was used for angiogenic/ antiangiogenic testing. Results: All the three sponges showed good specific enzyme activity and S. pachyspira contained maximum specific enzyme activity. Sixty percent of ammonium sulphate precipitation of crude protein sample gave single band at 66 kDa corresponding to the true AChE. ChAM assay was performed at 62.5, 125.0 and 250.0 µg/mL. Dosage beyond 250 µg/mL extract showed toxic response with anti angiogenic activity at all the concentrations. Conclusions: AChE activity was detected in all samples. Extract showed good anti-angiogenic response at 62.5 µg/mL. Extract was highly toxic affecting microvasculature of ChAM as well as normal growth and development of the embryo at 500 µg/mL. With further characterization of bioactive compounds from the extract of S. pachyspira, the compounds can be developed for anti tumor activity.

  16. Anti-angiogenic and anti-inflammatory properties of kahweol, a coffee diterpene.

    Directory of Open Access Journals (Sweden)

    Casimiro Cárdenas

    Full Text Available BACKGROUND: Epidemiological studies have shown that unfiltered coffee consumption is associated with a low incidence of cancer. This study aims to identify the effects of kahweol, an antioxidant diterpene contained in unfiltered coffee, on angiogenesis and key inflammatory molecules. METHODOLOGY/PRINCIPAL FINDINGS: The experimental procedures included in vivo angiogenesis assays (both the chicken and quail choriallantoic membrane assay and the angiogenesis assay with fluorescent zebrafish, the ex vivo mouse aortic ring assay and the in vitro analysis of the effects of treatment of human endothelial cells with kahweol in cell growth, cell viability, cell migration and zymographic assays, as well as the tube formation assay on Matrigel. Additionally, two inflammation markers were determined, namely, the expression levels of cyclooxygenase 2 and the levels of secreted monocyte chemoattractant protein-1. We show for the first time that kahweol is an anti-angiogenic compound with inhibitory effects in two in vivo and one ex vivo angiogenesis models, with effects on specific steps of the angiogenic process: endothelial cell proliferation, migration, invasion and tube formation on Matrigel. We also demonstrate the inhibitory effect of kahweol on the endothelial cell potential to remodel extracellular matrix by targeting two key molecules involved in the process, MMP-2 and uPA. Finally, the anti-inflammatory potential of this compound is demonstrated by its inhibition of both COX-2 expression and MCP-1 secretion in endothelial cells. CONCLUSION/SIGNIFICANCE: Taken together, our data indicate that, indeed, kahweol behaves as an anti-inflammatory and anti-angiogenic compound with potential use in antitumoral therapies. These data may contribute to the explanation of the reported antitumoral effects of kahweol, including the recent epidemiological meta-analysis showing that drinking coffee could decrease the risk of certain cancers.

  17. Definition of the "Drug-Angiogenic-Activity-Index" that allows the quantification of the positive and negative angiogenic active drugs: a study based on the chorioallantoic membrane model.

    Science.gov (United States)

    Demir, Resit; Peros, Georgios; Hohenberger, Werner

    2011-06-01

    Since the introduction of the angiogenic therapy by Folkman et al. in the 1970'ies many antiangiogenic drugs were identified. Only few of them are still now in clinical use. Also the Vascular Endothelial Growth Factor (VEGF), the cytokine with the highest angiogenic activity, has been identified. Its antagonist, Bevacizumab, is produced and admitted for the angiogenic therapy in first line for metastatic colorectal cancer. When we look at preclinical studies, they fail of in vivo models that define the "Drug-Angiogenic-Activity-Index" of angiogenic or antiangiogenic drugs. This work proposes a possible standardized procedure to define the "Drug Angiogenic Activity Index" by counting the vascular intersections (VIS) on the Chorioallantoic Membrane after drug application. The equation was defined as follows: {ΔVIS[Drug]-ΔVIS[Control]} / Δ VIS[Control]. For VEGF a Drug-Angiogenic-Activity-Index of 0.92 was found and for Bevacizumab a -1. This means almost that double of the naturally angiogenic activity was achieved by VEGF on the Chorioallantoic membrane. A complete blocking of naturally angiogenic activity was observed after Bevacizumabs application. Establishing the "Drug-Angiogenic-Activity-Index" in the preclinical phase will give us an impact of effectiveness for the new constructed antiangiogenic drugs like the impact of effectiveness in the cortisone family.

  18. Dimethyl sulfoxide-caused changes in pro- and anti-angiogenic factor levels could contribute to an anti-angiogenic response in HeLa cells.

    Science.gov (United States)

    Şimşek, Ece; Aydemir, Esra Arslan; İmir, Nilüfer; Koçak, Orhan; Kuruoğlu, Aykut; Fışkın, Kayahan

    2015-10-01

    Dimethyl sulfoxide (DMSO) is widely used in biological research as a general solvent. While it has been previously demonstrated that DMSO possesses a wide range of pharmacological effects, there is no published work regarding the effects of DMSO on pro-angiogenic factor levels. This study was designed to investigate the possible effects of DMSO on the levels of three pro-angiogenic factors released from HeLa cells in vitro. Cells were treated with two different and previously determined concentrations of DMSO. The cytotoxic effects of DMSO concentrations on HeLa cells were determined via MTT. Survival rates of DMSO-treated cells were determined by Invitrogen live/dead viability/cytotoxicity kit and trypan blue exclusion assay. Changes in the pro-angiogenic levels in media were evaluated by Cayman's Substance P Enzyme Immunoassay ELISA kit. Vascular endothelial growth factor ELISA kit and interferon gamma ELISA kit for substance P, VEGF and IFNγ respectively. Changes in substance P levels were corrected by standard western blotting. Changes in VEGF and IFNγ levels were corrected both by western blot and real time PCR. Treatment with 1.4 μM DMSO caused a time-dependent inhibition of cell proliferation at 24, 48 and 72 h. 1.4 μM DMSO caused a significant reduction in VEGF levels at 72 h of incubation and sharp increases in IFNγ levels at both 48 and 72 h of incubation. According to real time PCR analyses, DMSO (1.4 μM) exhibited an inhibitory effect on VEGF but acted as an augmenter of IFNγ release on HeLa cells in vitro. This is the first report showing that the general solvent DMSO suppressed HeLa cell proliferation, decreased the levels of two pro-angiogenic factors (substance P and VEGF) and increased the release of an anti-angiogenic factor IFNγ in vitro. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. [Assessing drug targeting of Yougui Pill, Zuogui Pill, and their disassembled prescriptions using infrared thermography].

    Science.gov (United States)

    Zheng, Xia; Deng, Yan-Li; Li, Qi-Jia; Lu, Hua

    2014-04-01

    To dynamically assess drug targeting of Yougui Pill (YP) and Zuogui Pill (ZP) using infrared thermography. In this self-control experiment, five healthy volunteers were recruited. By using infrared thermography 10 to 11 thermal images of different body locations were taken from each participant after they took warm water, YP, ZP, and their dissembled prescriptions at 30, 70, 100, 130, and 160 min, respectively. The heat values in the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) were statistically analyzed after scanning for 125 times. Administration of YP and its disassembled prescriptions enhanced the heat value of the locations of the Du channel and Shenque (CV8), but did no enhance the heat value of the lower quadrant abdomen at 30 min. Administration of ZP and its disassembled prescriptions reduced the heat value in the locations of the lower quadrant abdomen, uterus, Du channel, and Shenque (CV8) at each time point. The drug targeting of ZP and YP focused on the locations of the Du channel and Shenque (CV8), not on the locations of the lower quadrant abdomen or uterus.

  20. Non-steroidal anti-inflammatory drug prescriptions in hospital inpatients: are we assessing the risks?

    LENUS (Irish Health Repository)

    Kitchen, J

    2012-02-01

    AIM: To determine non-steroidal anti-inflammatory drug (NSAID) prescribing practices in a tertiary referral hospital. METHODS: A single time-point audit of drug kardexes and clinical notes of n = 388 patients on 2 July 2008 was carried out assessing demographics, gastrointestinal and coronary heart disease risk factors, renal function and co-prescribed medications. RESULTS: Fifty-seven of 388 (14.7%) hospital patients were on NSAIDs. Forty-nine were prescribed NSAID after admission. Nineteen (32.2%) were on regular NSAID (11\\/19 on PPI) and 38 patients were on PRN NSAID (12\\/38 on PPI). Seventeen of 49 patients were on other medications associated with gastrointestinal bleeding (10\\/17 were on PPI). Nineteen patients (33.3%) were >60 years. Eight patients had three or four risk factors for gastrointestinal bleeding; six were on PPI. Thirteen patients had two risks; 7 were on PPI. Six of 19 patients with one risk factor were on PPI. 40.3% had stage 2\\/3 chronic kidney disease. 35.1% had ischaemic heart disease. CONCLUSIONS: NSAIDs and PPIs are often prescribed inappropriately.

  1. Complacent and conflicting scientific expertise in British and American drug regulation: clinical risk assessment of triazolam.

    Science.gov (United States)

    Abraham, J; Sheppard, J

    1999-12-01

    This paper presents a case study in the production and interpretation of regulatory science, focusing on the conflicting British and American clinical risk assessments of triazolam (Halcion) - the most controversial sleeping pill in the world. The regulation of triazolam is shown to be more permissive in the USA than in the UK. Six principal socio-political factors are put forward to explain this; differential regulatory trust; regulators' socio-technical data selections; medico-scientific disciplinary influences; organizational and professional interests; conflicts of interest of expert advisers; and the growth of the neo-liberal regulatory state. The risk assessments of both the British and American regulatory agencies are shown to be complacent relative to technical standards which the agencies themselves later accepted. It is suggested that, when the interests of pharmaceutical manufacturers and patients diverge, regulatory assessments are crucially affected by whether regulators are predisposed to award the benefit of the scientific doubts to the manufacturers or patients, and by the balance of such predispositions both within and between regulatory institutions of scientific expertise. The triazolam case indicates that the amount of trust placed in the pharmaceutical industry by the British American regulatory systems may hamper detection of flaws in manufacturers' medical data in a timely manner and, as a consequence, compromise patients' interests. Some policy implications for drug regulation are sketched.

  2. Assessing Miniaturized Sensor Performance using Supervised Learning, with Application to Drug and Explosive Detection

    DEFF Research Database (Denmark)

    Alstrøm, Tommy Sonne

    This Ph.D. thesis titled “Assessing Miniaturized Sensor Performance using Supervised Learning, with Application to Drug and Explosive Detection” is a part of the strategic research project “Miniaturized sensors for explosives detection in air” funded by the Danish Agency for Science and Technology...... before the sensor responses can be applied to supervised learning algorithms. The technologies used for sensing consist of Calorimetry, Cantilevers, Chemoselective compounds, Quartz Crystal Microbalance and Surface Enhanced Raman Scattering. Each of the sensors have their own strength and weaknesses...... and Gaussian Processes. Often, there is no tradition for using these methods in the communities of the prescribed sensors. Here, a method of too much complexity is often undesired so it is a balance when to utilize more sophisticated methods. For this reason, an array of methods that only discriminate between...

  3. Antibacterial drugs in products originating from aquaculture: assessing the risks to public welfare

    Directory of Open Access Journals (Sweden)

    G. RIGOS

    2010-02-01

    Full Text Available As aquaculture expands to meet human demand and compensate for pessimistic forecasts of fisheries catches, usage of antibacterial agents to combat or forestall bacterial diseases is still a necessity, although effective vaccines and improved hygiene have aided drastically to this battle. The hazards for the consumer perspective arising from the imprudent use of such chemicals can be detrimental especially if the residues persist above legal tolerance. These may include selection and dissemination of resistant bacteria, disruption of the colonization barrier in the human intestinal flora and allergic reactions. In cases that unlawful drugs reached the consumer via consumption of aquatic products, human health may be jeopardized even further. The present review article assesses these risks on human health.

  4. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    International Nuclear Information System (INIS)

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-01-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I Na ) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I Na , this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E max 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two out of three

  5. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  6. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    International Nuclear Information System (INIS)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

    2013-01-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

  7. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    Energy Technology Data Exchange (ETDEWEB)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

    2013-12-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na{sub v}1.5 sodium and Ca{sub v}1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on

  8. Tumor microvascular changes in antiangiogenic treatment : Assessment by magnetic resonance contrast media of different molecular weights

    NARCIS (Netherlands)

    Turetschek, K; Preda, A; Novikov, [No Value; Brasch, RC; Weinmann, HJ; Wunderbaldinger, P; Roberts, TPL

    Purpose: To test magnetic resonance (MR) contrast media of different molecular weights (MWs) for their potential to characterize noninvasively microvascular changes in an experimental tumor treatment model. Materials and Methods: MD-MBA-435, a poorly differentiated human breast cancer cell line, was

  9. Development of a questionnaire to assess drug abuse among high school students of Isfahan province, Iran: An action research

    Directory of Open Access Journals (Sweden)

    Nahid Geramian

    2014-01-01

    Conclusions: According to the obtained results, the designed questionnaire is capable to assess the drug abuse status among high school students of Isfahan Province. Regarding the importance of teenage years in forming the future behaviors of adolescents and the opportunities provided at schools, it is prudent to pay more attention to interventions in this age group in order to increase their knowledge and correct their attitude toward illegal drugs and strengthening their confidence in this regard. These interventions can have an important role in decreasing the rate of drug abuse in this age group and consequently in the whole community.

  10. Use of the over-the-counter drugs by adults and an assessment of the impact of advertisements on consumers

    Directory of Open Access Journals (Sweden)

    Monika Szpringer

    2015-03-01

    Full Text Available Introduction: During the last few years there has been a considerable value growth in the demand for the so-called over-the-counter drugs (OTC, available without doctor’s prescription. Using OTC drugs is related to self-treatment, aimed at mitigating first symptoms of a cold, flu, or various types of pain. The omnipresent advertisements for OTC drugs encourage and contribute to the elevated demand. Unfortunately, the marketing techniques used in advertisements fail to provide reliable and objective information to the viewers about specific products. Aim of the research: To determine the respondents’ opinions on using OTC drugs and to assess how advertisements influence the consumers’ needs. Material and methods : The study was conducted by means of a diagnostic survey using a questionnaire. For the purpose of the study, the authors prepared a survey questionnaire, which was used as a research tool. The study included 114 respondents, falling within an age bracket of 18–66 years. Results : The most frequently used OTC drugs were painkillers and medicines for cold and flu symptoms (68.33% of women and 59.09% of men. The drugs were usually bought in pharmacies and grocery/convenience stores. Conclusions: Taking OTC drugs is a widespread phenomenon, both in women and men. The obtained results clearly indicate that advertisements have a considerable impact upon target groups and contribute to increased consumption of OTC drugs.

  11. Age related changes in fractional elimination pathways for drugs: assessing the impact of variable ontogeny on metabolic drug-drug interactions.

    Science.gov (United States)

    Salem, Farzaneh; Johnson, Trevor N; Barter, Zoe E; Leeder, J Steven; Rostami-Hodjegan, Amin

    2013-08-01

    The magnitude of any metabolic drug-drug interactions (DDIs) depends on fractional importance of inhibited pathway which may not necessarily be the same in young children when compared to adults. The ontogeny pattern of cytochrome P450 (CYP) enzymes (CYPs 1A2, 2B6, 2C8, 2C9, 2C18/19, 2D6, 2E1, 3A4) and renal function were analyzed systematically. Bootstrap methodology was used to account for variability, and to define the age range over which statistical differences existed between each pair of specific pathways. A number of DDIs were simulated (Simcyp Pediatric v12) for virtual compounds to highlight effects of age on fractional elimination and consequent magnitude of DDI. For a theoretical drug metabolized 50% by each of CYP2D6 and CYP3A4 pathways at birth, co-administration of ketoconazole (3 mg/kg) resulted in a 1.65-fold difference between inhibited versus uninhibited AUC compared to 2.4-fold in 1 year olds and 3.2-fold in adults. Conversely, neonates could be more sensitive to DDI than adults in certain scenarios. Thus, extrapolation from adult data may not be applicable across all pediatric age groups. The use of pediatric physiologically based pharmacokinetic (p-PBPK) models may offer an interim solution to uncovering potential periods of vulnerability to DDI where there are no existing clinical data derived from children. © The Author(s) 2013.

  12. Assessment of interactions of efavirenz solid drug nanoparticles with human immunological and haematological systems.

    Science.gov (United States)

    Liptrott, Neill J; Giardiello, Marco; McDonald, Tom O; Rannard, Steve P; Owen, Andrew

    2018-03-15

    Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations. Here we have conducted a preclinical evaluation of efavirenz SDN to assess their potential interaction with these systems. Platelet aggregation and activation, plasma coagulation, haemolysis, complement activation, T cell functionality and phenotype, monocyte derived macrophage functionality, and NK cell function were assessed in primary healthy volunteer samples treated with either aqueous efavirenz or efavirenz SDN. Efavirenz SDNs were shown not to interfere with any of the systems studied in terms of immunostimulation nor immunosuppression. Although efavirenz aqueous solution was shown to cause significant haemolysis ex vivo, efavirenz SDNs did not. No other interaction with haematological systems was observed. Efavirenz SDNs have been demonstrated to be immunologically and haematologically inert in the utilised assays. Taken collectively, along with the recent observation that lopinavir SDN formulations did not impact immunological responses, these data indicate that this type of nanoformulation does not elicit immunological consequences seen with other types of nanomaterial. The methodologies presented here provide a framework for pre-emptive preclinical characterisation of nanoparticle safety.

  13. MRI and image quantitation for drug assessment - growth effects of anabolic steroids and precursors.

    Science.gov (United States)

    Tang, Haiying; Wu, Ed; Vasselli, Joseph

    2005-01-01

    MRI and image quantitation play an expanding role in modern drug research, because MRI offers high resolution and non-invasive ability, and provides excellent soft tissue contrast. Moreover, with development of effective image segmentation and analysis methods, in-vivo and serial tissue growth measurements could be assessed. In the study, MR image acquisition and analysis protocol were established and validated for investigating the effects of anabolic steroids and precursors on muscle growth and body composition in a guinea pig model. Semi-automatic and interactive segmentation methods were developed to accurately label the tissue of interest for tissue volume estimation. In addition, a longitudinal tissue area outlining procedure was proposed for study of tissue geometric features in relation to tissue growth. Finally, a fully automatic data retrieval and analysis scheme was implemented to facilitate the overall huge amount of image quantitation, statistical analysis, as well as study group comparisons. As a result, highly significant differences in muscle and organ growth were detected between intact and castrated guinea pigs using the selected anabolic steroids, indicating the viability of employing such protocol to assess other anabolic steroids. Furthermore, the anabolic potential of selected steroid precursors and their effects on muscle growth, in comparison with that in respective positive control groups of castrated guinea pigs, were evaluated with the proposed protocol.

  14. Health Technology Assessment Of Orphan Drugs : The example of Pompe disease

    NARCIS (Netherlands)

    T.A. Kanters (Tim A.)

    2016-01-01

    markdownabstractIn recent decades, the development of orphan drugs, i.e. drugs for rare diseases, is stimulated by regulations in various countries. However, the generally high prices of orphan drugs confront policy makers with difficult reimbursement decisions. The orphan disease investigated in

  15. Assessing anti-malarial drug effects ex vivo using the haemozoin detection assay

    NARCIS (Netherlands)

    Rebelo, Maria; Tempera, Carolina; Fernandes, José F.; Grobusch, Martin P.; Hänscheid, Thomas

    2015-01-01

    In vitro sensitivity assays are crucial to detect and monitor drug resistance. Plasmodium falciparum has developed resistance to almost all anti-malarial drugs. Although different in vitro drug assays are available, some of their inherent characteristics limit their application, especially in the

  16. Mid-Term Assessment of the EU Drugs Strategy 2013–2020 and Final Evaluation of the Action Plan on Drugs 2013–2016

    Science.gov (United States)

    Emilie, Balbirnie; Matthew, Davies; Emma, Disley; Cristina Gonzalez, Monsalve; Stephen, Hartka; Stijn, Hoorens; Kristy, Kruithof; Martin, Sacher; Jirka, Taylor

    2018-01-01

    Abstract The aim of the EU Drugs Strategy 2013–2020 is to contribute to a reduction in drug demand and drug supply within the EU. The Strategy has so far been implemented by an Action Plan covering the period 2013–2016. This article sets out the findings of an evaluation that assesses the degree of implementation of the Strategy and the Action Plan in terms of outputs and, where possible, impacts. It looks at the extent to which the objectives of the Strategy have been achieved. The evaluation aims to provide evidence to support the European Commission's decision about whether to propose a new Action Plan for the period 2017–2020 and, if so, what changes would be needed compared to the current plan. Through applying a mixed-methods approach, the evaluation examined the effectiveness, efficiency, relevance and coherence of the actions undertaken on the basis of the EU Drugs Strategy and the Action Plan, as well as their EU added value. The evaluation makes 20 recommendations, addressed to the European Commission, Member States, the European Council and other stakeholders. The key recommendation for the Commission is that a new Action Plan should be implemented for the period 2017–2020. This should be an updated version of the current Action Plan, rather than taking a new approach or introducing more new actions. PMID:29416944

  17. Mid-Term Assessment of the EU Drugs Strategy 2013-2020 and Final Evaluation of the Action Plan on Drugs 2013-2016: Final report.

    Science.gov (United States)

    Emilie, Balbirnie; Matthew, Davies; Emma, Disley; Cristina Gonzalez, Monsalve; Stephen, Hartka; Stijn, Hoorens; Kristy, Kruithof; Martin, Sacher; Jirka, Taylor

    2018-01-01

    The aim of the EU Drugs Strategy 2013-2020 is to contribute to a reduction in drug demand and drug supply within the EU. The Strategy has so far been implemented by an Action Plan covering the period 2013-2016. This article sets out the findings of an evaluation that assesses the degree of implementation of the Strategy and the Action Plan in terms of outputs and, where possible, impacts. It looks at the extent to which the objectives of the Strategy have been achieved. The evaluation aims to provide evidence to support the European Commission's decision about whether to propose a new Action Plan for the period 2017-2020 and, if so, what changes would be needed compared to the current plan. Through applying a mixed-methods approach, the evaluation examined the effectiveness, efficiency, relevance and coherence of the actions undertaken on the basis of the EU Drugs Strategy and the Action Plan, as well as their EU added value. The evaluation makes 20 recommendations, addressed to the European Commission, Member States, the European Council and other stakeholders. The key recommendation for the Commission is that a new Action Plan should be implemented for the period 2017-2020. This should be an updated version of the current Action Plan, rather than taking a new approach or introducing more new actions.

  18. Vixapatin (VP12, a C-Type Lectin-Protein from Vipera xantina palestinae Venom: Characterization as a Novel Anti-angiogenic Compound

    Directory of Open Access Journals (Sweden)

    Philip Lazarovici

    2012-10-01

    Full Text Available A C-type lectin-like protein (CTL, originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim of the present study was to prove the possibility that this protein is also a potent novel anti-angiogenic compound. Using an adhesion assay, we demonstrated that Vixapatin selectively and potently inhibited the α2 mediated adhesion of K562 over-expressing cells, with IC50 of 3 nM. 3 nM Vixapatin blocked proliferation of human dermal microvascular endothelial cells (HDMEC; 25 nM inhibited collagen I induced migration of human fibrosarcoma HT-1080 cells; and 50 nM rat C6 glioma and human breast carcinoma MDA-MB-231 cells. 1 µM Vixapatin reduced HDMEC tube formation by 75% in a Matrigel assay. Furthermore, 1 µM Vixapatin decreased by 70% bFGF-induced physiological angiogenesis, and by 94% C6 glioma-induced pathological angiogenesis, in shell-less embryonic quail chorioallantoic membrane assay. Vixapatin’s ability to inhibit all steps of the angiogenesis process suggest that it is a novel pharmacological tool for studying α2β1 integrin mediated angiogenesis and a lead compound for the development of a novel anti-angiogenic/angiostatic/anti-cancer drug.

  19. In vitro and in vivo antiangiogenic activity of a novel deca-peptide derived from human tissue-type plasminogen activator kringle 2

    Energy Technology Data Exchange (ETDEWEB)

    Su, Li; Xu, Xun; Zhao, Hui; Gu, Qing [Department of Ophthalmology, Shanghai First People' s Hospital, Affiliate of Shanghai Jiaotong University, No. 100 Haining Road, Shanghai 200080 (China); Zou, Haidong, E-mail: zouhaidong@hotmail.com [Department of Ophthalmology, Shanghai First People' s Hospital, Affiliate of Shanghai Jiaotong University, No. 100 Haining Road, Shanghai 200080 (China)

    2010-06-11

    A synthetic deca-peptide corresponding to the amino acid sequence Arg{sup 54}-Trp{sup 63} of human tissue-type plasminogen activator (t-PA) kringle 2 domain, named TKII-10, is produced and tested for its ability to inhibit endothelial cell proliferation, migration, tube formation in vitro, and angiogenesis in vivo. At the same time, another peptide TKII-10S composed of the same 10 amino acids as TKII-10, but in a different sequence, is also produced and tested. The results show that TKII-10 potently inhibits VEGF-stimulated endothelial cell migration and tube formation in a dose-dependent, as well as sequence-dependent, manner in vitro while it is inactive in inhibiting endothelial cell proliferation. Furthermore, TKII-10 potently inhibits angiogenesis in chick chorioallantoic membrane and mouse cornea. The middle four amino acids DGDA in their sequence play an important role in TKII-10 angiogenesis inhibition{sub .} These results suggest that TKII-10 is a novel angiogenesis inhibitor that may serve as a prototype for antiangiogenic drug development.

  20. Physicochemical properties and in vitro cytotoxicity of iron oxide-based nanoparticles modified with antiangiogenic and antitumor peptide A7R

    Energy Technology Data Exchange (ETDEWEB)

    Niescioruk, Anna; Nieciecka, Dorota; Puszko, Anna K.; Królikowska, Agata [University of Warsaw, Faculty of Chemistry (Poland); Kosson, Piotr [Polish Academy of Sciences, Department of Neuropeptides, Mossakowski Medical Research Centre (Poland); Perret, Gerard Y. [Université Paris 13, Sorbonne Paris Cité (France); Krysinski, Pawel; Misicka, Aleksandra, E-mail: misicka@chem.uw.edu.pl [University of Warsaw, Faculty of Chemistry (Poland)

    2017-05-15

    Superparamagnetic iron oxide-based nanoparticles (SPIONs) are promising carriers as targeted drug delivery vehicles, because they can be guided to their target with the help of an external magnetic field. Functionalization of nanoparticles’ surface with molecules, which bind with high affinity to receptors on target tissue significantly facilitates delivery of coated nanoparticles to their targeted site. Here, we demonstrate conjugation of an antiangiogenic and antitumor peptide ATWLPPR (A7R) to SPIONs modified with sebacic acid (SPIONs-SA). Successful conjugation was confirmed by various analytical techniques (FTIR, SERS, SEM-EDS, TEM, TGA). Cell cytotoxicity studies, against two cell lines (HUVEC and MDA-MB-231) indicated that SPIONs modified with A7R reduced HUVEC cell viability at concentrations higher than 0.01 mg Fe/mL, in comparison to cells that were exposed to either the nanoparticles modified with sebacic acid or A7R peptide solely, what might be partially caused by a process of internalization.

  1. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease.

    Science.gov (United States)

    Fanelli, F; Cannavale, A; Gazzetti, M; Lucatelli, P; Wlderk, A; Cirelli, C; d'Adamo, A; Salvatori, F M

    2014-08-01

    This study was designed to assess the effect of calcium on the efficacy of DEB during revascularization of steno-obstructive SFA lesions. Sixty patients with de novo lesions of the superficial femoral artery underwent endovascular treatment with drug eluting balloons (DEB). DEB was selected according to vessel reference diameter (1:1). In case of residual stenosis > 50 % or flow-limiting dissection, postdilatation with conventional balloon or provisional stenting was done. Patients were classified into eight groups according to circumferential distribution of calcium on CT-angiography axial images (from 0° to 360°) and to its length (length  3 cm) evaluated with digital-subtraction-angiography. Ankle-brachial index (ABI), late lumen loss (LLL), target lesion revascularization (TLR), primary (PP) and secondary (SP) patency, major adverse events (MAE), and Rutherford shift were evaluated at 1-year follow-up and correlated with the amount of calcium. Revascularization was successful in all cases. Flow-limiting dissection occurred in five cases (8.3 %) with a higher circumferential degree of calcium and solved in three cases with postdilatation and in the other two with provisional stenting. DEB effect was lower in patients with higher degree of calcium (>270° vs. <90°): ABI 0.71 ± 0.07 versus 0.92 ± 0.07; LLL 0.75 ± 0.21 versus 0.45 ± 0.1; PP 50 versus 100 %; SP 50 versus 100 %; TLR 25 versus 0 %; MAE 25 versus 0 %. Calcium represents a barrier to optimal drug absorption. Circumferential distribution seems to be the most influencing factor with the worst effect noticed in 360° calcium presence.

  2. The role of health technology assessment bodies in shaping drug development.

    Science.gov (United States)

    Ciani, Oriana; Jommi, Claudio

    2014-01-01

    The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.

  3. Assessment of an Innovative Voluntary Substance Abuse Treatment Program Designed to Replace Compulsory Drug Detention Centers in Malaysia.

    Science.gov (United States)

    Khan, Farrah; Krishnan, Archana; Ghani, Mansur A; Wickersham, Jeffrey A; Fu, Jeannia J; Lim, Sin How; Dhaliwal, Sangeeth Kaur; Kamarulzaman, Adeeba; Altice, Frederick L

    2018-01-28

    As part of an ongoing initiative by the Malaysian government to implement alternative approaches to involuntary detention of people who use drugs, the National Anti-Drug Agency has created new voluntary drug treatment programs known as Cure and Care (C&C) Centers that provide free access to addiction treatment services, including methadone maintenance therapy, integrated with social and health services.   We evaluated early treatment outcomes and client satisfaction among patients accessing C&C treatment and ancillary services at Malaysia's second C&C Center located in Kota Bharu, Kelantan. In June-July 2012, a cross-sectional convenience survey of 96 C&C inpatients and outpatients who entered treatment >30 days previously was conducted to assess drug use, criminal justice experience, medical co-morbidities, motivation for seeking treatment, and attitudes towards the C&C. Drug use was compared for the 30-day-period before C&C entry and the 30-day-period before the interview. Self-reported drug use levels decreased significantly among both inpatient and outpatient clients after enrolling in C&C treatment. Higher levels of past drug use, lower levels of social support, and more severe mental health issues were reported by participants who were previously imprisoned. Self-reported satisfaction with C&C treatment services was high. Conclusions/Importance: Preliminary evidence of reduced drug use and high levels of client satisfaction among C&C clients provide support for Malaysia's ongoing transition from compulsory drug detention centers (CDDCs) to these voluntary drug treatment centers. If C&C centers are successful, Malaysia plans to gradually transition away from CDDCs entirely.

  4. Health technology assessment of new drugs for rare disorders in Canada: impact of disease prevalence and cost.

    Science.gov (United States)

    Rawson, Nigel S B

    2017-03-23

    Authors from the Canadian Agency for Drugs and Technologies in Health (CADTH) presented an analysis of submissions to the Common Drug Review (CDR) between 2004 and February 3, 2016 for drugs for rare disorders (disorders with a prevalence of cost in the CDR reports varied with the prevalence of the disorder treated by the drug grouped into three decreasing categories: 10, ≤10 to >1, and ≤1 per 100,000. As the prevalence of the treated disorder decreased, the median daily cost of the drug, the negative recommendation rate and the proportion of submissions with statements in the CDR reports highlighting the cost of the drug increased, while the proportion of submissions with acceptable evidence of clinical efficacy decreased. Moreover, although the CADTH authors reported that only two submissions received a negative recommendation due to a "lack of cost-effectiveness/high cost," high cost was mentioned in the CDR reports of 15 drugs with negative recommendations, all for disorders with a prevalence of ≤10 per 100,000. The aggregated analysis of CDR submissions for drugs for disorders with wide ranging prevalence rates concealed information of concern to patients. The negative reimbursement recommendation rate and the significance of cost in the CDR assessments increased as the prevalence of the treated disorder decreased. Since 2012, the manner in which high cost drugs for rare disorders have been dealt with by the CDR has changed. Cost has ceased to be a factor in negative recommendations but is included in criteria accompanying positive recommendations. This trend is associated with the integration of the CDR process with the system for price negotiation between public drug plans and pharmaceutical companies.

  5. The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents.

    Science.gov (United States)

    Lagae, Lieven

    2017-06-01

    It has long been recognised that uncontrolled childhood epilepsy is detrimental to cognition and behaviour, impacting on a patient's ability to succeed academically. Patients who experience more frequent and serious seizures are at greater risk for cognitive decline, emphasising the need for more effective epilepsy treatments to bring seizures under control. That said, although more effective antiepileptic drugs (AEDs) have the potential to limit the impact of uncontrolled seizures on cognitive and behavioural function, recently it has been acknowledged that deficits in these functions may be caused by AEDs themselves. The cognitive and behavioural effects of older-generation AEDs have been determined largely from AE reporting rather than from specific assessment. Recently, clinical trials of newer-generation AEDs, such as topiramate, levetiracetam and perampanel, have included standardised neuropsychological tests as outcome measures to assess their impact on cognition and behaviour in children and adolescents. However, to understand how we may limit the cognitive and behavioural side effects of AEDs, it is necessary for us to gain a fuller, more accurate, characterisation of their true impact. Such insight will depend on sophisticated and standardised approaches to the design of AED clinical trials. This review provides a general overview of our current understanding of the impact of both epilepsy and AEDs on cognition and behaviour, before focusing on the AEDs for which more detailed assessment, using standardised cognitive and behavioural measures, has been undertaken. We will then go on to discuss the key elements in the design of future AED clinical trials to address current unmet needs.

  6. An Evidence-Based Assessment of the Clinical Significance of Drug-Drug Interactions Between Disease-Modifying Antirheumatic Drugs and Non-Antirheumatic Drugs According to Rheumatologists and Pharmacists

    NARCIS (Netherlands)

    van Roon, Eric N.; van den Bemt, Patricia M. L. A.; Jansen, Tim L. Th. A.; Houtman, Nella M.; van de Laar, Mart A. F. J.; Brouwers, Jacobus R. B. J.

    Background: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a

  7. Vasculatures in Tumors Growing From Preirradiated Tissues: Formed by Vasculogenesis and Resistant to Radiation and Antiangiogenic Therapy

    International Nuclear Information System (INIS)

    Chen, Fang-Hsin; Chiang, Chi-Shiun; Wang, Chun-Chieh; Fu, Sheng-Yung; Tsai, Chien-Sheng; Jung, Shih-Ming; Wen, Chih-Jen; Lee, Chung-Chi; Hong, Ji-Hong

    2011-01-01

    Purpose: To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy. Methods and Materials: Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein-tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay. Results: The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions. Conclusions: This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy.

  8. Phytochemical screening, antioxidant, anti-inflammatory and antiangiogenic activities of Lophira procera A. Chev. (Ochnaceae medicinal plant from Gabon

    Directory of Open Access Journals (Sweden)

    Rick-Leonid Ngoua-Meye-Misso

    2018-03-01

    Full Text Available The objective of this study was to perform phytochemical screening, to determine the content of phenolic compound, to evaluate antioxidant, anti-inflammatory and antiangiogenic activities of ethanol, water-ethanol and water extracts of Lophira procera. Antioxidant activity was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH and phosphomolybdenum assay, anti-inflammatory activity by proteins denaturation inhibition and membranes stabilization test and antiangiogenic activity by chicken chorioallantoic membrane (CAM method. The results showed that this plant is rich in saponins, polyphenols, tannins, total flavonoids, proanthocyanidins and coumarins. Extracts presented a strong antioxidant activity (IC50 values of 5.452 ± 0.119 μg/mL and 6.346 ± 0.544 μg/mL and respective AAI of 9.173 ± 0.203 and 7.919 ± 0.711. Excellent anti-inflammatory activity was also observed (IC50 = 16.952 ± 1.897 and IC50 = 23.172 ± 0.066 μg/mL for inhibition of protein denaturation and membrane stabilization respectively. Finally, extracts manifested a very good anti-angiogenic activity (with inhibitions ranging from 57.142 ± 0.124% to 100%. These biological activities are certainly due to high content of phenolic compound. This is the first study to report the phytochemical screening, the content of phenolic compound, the antioxidant, anti-inflammatory and antiangiogenic activities of extract derived from Lophira procera. The use of this plant in traditional medicine against ulcers, breast cancer, kidney and dental pain is therefore justified and its potential as a candidate for bioactive therapeutic molecule.

  9. Assessing the drug release from nanoparticles: Overcoming the shortcomings of dialysis by using novel optical techniques and a mathematical model.

    Science.gov (United States)

    Xie, Li; Beyer, Susanne; Vogel, Vitali; Wacker, Matthias G; Mäntele, Werner

    2015-07-05

    The aim of the present investigation was to develop a reliable method which can be applied to the measurement of in vitro drug release from nanocarriers. Since the limited membrane transport is one major obstacle to the assessment of drug release with dialysis techniques, the determination of this parameter was our objective. Therefore, a novel drug release automatic monitoring system (DREAMS) was designed to conduct continuous measurements during the dialysis process. Moreover, a mathematical model was used for evaluation of the experimental data. This combination of mathematical and analytical tools enabled the quantification of the total amount of free drug in the system. Eudragit(®) RS 100 nanoparticles loaded with the model compound 5,10,15,20-tetrakis(m-hydroxypheny)chlorin (mTHPC) were investigated and the drug release was continuously monitored by using a fluorescence spectrometer that is part of the setup. Free drug and drug-loaded nanoparticles were tested to discriminate between the two formulations. In addition, two types of membranes composed of different materials were evaluated and the kinetics of membrane transport was determined. The data obtained from the apparatus were further treated by a mathematical model, which yielded distinguishable release profiles between samples of different compositions. The method offers a promising option for release testing of nanoparticles. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Anti-angiogenic effect of triptolide in rheumatoid arthritis by targeting angiogenic cascade.

    Directory of Open Access Journals (Sweden)

    Xiangying Kong

    Full Text Available Rheumatoid arthritis (RA is characterized by a pre-vascular seriously inflammatory phase, followed by a vascular phase with high increase in vessel growth. Since angiogenesis has been considered as an essential event in perpetuating inflammatory and immune responses, as well as supporting pannus growth and development of RA, inhibition of angiogenesis has been proposed as a novel therapeutic strategy for RA. Triptolide, a diterpenoid triepoxide from Tripterygium wilfordii Hook F, has been extensively used in treatment of RA patients. It also acts as a small molecule inhibitor of tumor angiogenesis in several cancer types. However, it is unclear whether triptolide possesses an anti-angiogenic effect in RA. To address this problem, we constructed collagen-induced arthritis (CIA model using DA rats by the injection of bovine type II collagen. Then, CIA rats were treated with triptolide (11-45 µg/kg/day starting on the day 1 after first immunization. The arthritis scores (P<0.05 and the arthritis incidence (P<0.05 of inflamed joints were both significantly decreased in triptolide-treated CIA rats compared to vehicle CIA rats. More interestingly, doses of 11~45 µg/kg triptolide could markedly reduce the capillaries, small, medium and large vessel density in synovial membrane tissues of inflamed joints (all P<0.05. Moreover, triptolide inhibited matrigel-induced cell adhesion of HFLS-RA and HUVEC. It also disrupted tube formation of HUVEC on matrigel and suppressed the VEGF-induced chemotactic migration of HFLS-RA and HUVEC, respectively. Furthermore, triptolide significantly reduced the expression of angiogenic activators including TNF-α, IL-17, VEGF, VEGFR, Ang-1, Ang-2 and Tie2, as well as suppressed the IL1-β-induced phosphorylated of ERK, p38 and JNK at protein levels. In conclusion, our data suggest for the first time that triptolide may possess anti-angiogenic effect in RA both in vivo and in vitro assay systems by downregulating the

  11. Do anti-angiogenic VEGF (VEGFxxxb isoforms exist? A cautionary tale.

    Directory of Open Access Journals (Sweden)

    Sheila Harris

    Full Text Available Splicing of the human vascular endothelial growth factor-A (VEGF-A gene has been reported to generate angiogenic (VEGFxxx and anti-angiogenic (VEGFxxxb isoforms. Corresponding VEGFxxxb isoforms have also been reported in rat and mouse. We examined VEGFxxxb expression in mouse fibrosarcoma cell lines expressing all or individual VEGF isoforms (VEGF120, 164 or 188, grown in vitro and in vivo, and compared results with those from normal mouse and human tissues. Importantly, genetic construction of VEGF164 and VEGF188 expressing fibrosarcomas, in which exon 7 is fused to the conventional exon 8, precludes VEGFxxxb splicing from occurring. Thus, these two fibrosarcoma cell lines provided endogenous negative controls. Using RT-PCR we show that primers designed to simultaneously amplify VEGFxxx and VEGFxxxb isoforms amplified only VEGFxxx variants in both species. Moreover, only VEGFxxx species were generated when mouse podocytes were treated with TGFβ-1, a reported activator of VEGFxxxb splice selection in human podocytes. A VEGF164/120 heteroduplex species was identified as a PCR artefact, specifically in mouse. VEGFxxxb isoform-specific PCR did amplify putative VEGFxxxb species in mouse and human tissues, but unexpectedly also in VEGF188 and VEGF164 fibrosarcoma cells and tumours, where splicing to produce true VEGFxxxb isoforms cannot occur. Moreover, these products were only consistently generated using reverse primers spanning more than 5 bases across the 8b/7 or 8b/5 splice junctions. Primer annealing to VEGFxxx transcripts and amplification of exon 8b primer 'tails' explained the artefactual generation of VEGFxxxb products, since the same products were generated when the PCR reactions were performed with cDNA from VEGF164/VEGF188 'knock-in' vectors used in the generation of single VEGF isoform-expressing transgenic mice from which the fibrosarcoma lines were developed. Collectively, our results highlight important pitfalls in data

  12. Selection and utilization of assessment instruments in substance abuse treatment trials: the National Drug Abuse Treatment Clinical Trials Network experience

    Directory of Open Access Journals (Sweden)

    Rosa C

    2012-07-01

    Full Text Available Carmen Rosa, Udi Ghitza, Betty TaiCenter for the Clinical Trials Network, National Institute on Drug Abuse, Bethesda, MD, USAAbstract: Based on recommendations from a US Institute of Medicine report, the National Institute on Drug Abuse established the National Drug Abuse Treatment Clinical Trials Network (CTN in 1999, to accelerate the translation of science-based addiction treatment research into community-based practice, and to improve the quality of addiction treatment, using science as the vehicle. One of the CTN's primary tasks is to serve as a platform to forge bi-directional communications and collaborations between providers and scientists, to enhance the relevance of research, which generates empirical results that impact practice. Among many obstacles in moving research into real-world settings, this commentary mainly describes challenges and iterative experiences in regard to how the CTN develops its research protocols, with focus on how the CTN study teams select and utilize assessment instruments, which can reasonably balance the interests of both research scientists and practicing providers when applied in CTN trials. This commentary also discusses the process by which the CTN further selects a core set of common assessment instruments that may be applied across all trials, to allow easier cross-study analyses of comparable data.Keywords: addiction, assessment, drug abuse treatment, drug dependence, NIDA Clinical Trials Network, substance use disorder

  13. Dual energy CT allows for improved characterization of response to antiangiogenic treatment in patients with metastatic renal cell cancer

    Energy Technology Data Exchange (ETDEWEB)

    Hellbach, K.; Sterzik, A.; Sommer, W.; Karpitschka, M.; Hummel, N.; Ingrisch, M.; Graser, A. [Ludwig-Maximilians-University Hospital Munich, Department of Clinical Radiology, Muenchen (Germany); Casuscelli, J.; Staehler, Michael [Ludwig-Maximilians-University Hospital Munich, Department of Urology, Muenchen (Germany); Schlemmer, M. [Krankenhaus Barmherzige Brueder Muenchen, Department of Palliative Care, Muenchen (Germany)

    2017-06-15

    To evaluate the potential role of dual energy CT (DECT) to visualize antiangiogenic treatment effects in patients with metastatic renal cell cancer (mRCC) while treated with tyrosine-kinase inhibitors (TKI). 26 patients with mRCC underwent baseline and follow-up single-phase abdominal contrast enhanced DECT scans. Scans were performed immediately before and 10 weeks after start of treatment with TKI. Virtual non-enhanced (VNE) and colour coded iodine images were generated. 44 metastases were measured at the two time points. Hounsfield unit (HU) values for VNE and iodine density (ID) as well as iodine content (IC) in mg/ml of tissue were derived. These values were compared to the venous phase DECT density (CTD) of the lesions. Values before and after treatment were compared using a paired Student's t test. Between baseline and follow up, mean CTD and DECT-derived ID both showed a significant reduction (p < 0.005). The relative reduction measured in percent was significantly greater for ID than for CTD (49.8 ± 36,3 % vs. 29.5 ± 20.8 %, p < 0.005). IC was also significantly reduced under antiangiogenic treatment (p < 0.0001). Dual energy CT-based quantification of iodine content of mRCC metastases allows for significantly more sensitive and reproducible detection of antiangiogenic treatment effects. (orig.)

  14. Assessment of adherence to drug and non-drug treatments and its changes under the influence of an education program in patients with rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    E V Orlova

    2012-01-01

    Full Text Available Objective: to assess awareness of drug and non-drug treatments for rheumatoid arthritis (RA and compliance in patients before and after their participation in an education program, as well as the survival of the knowledge and the need for retraining. Subjects and methods. The study included 43 patients with RA: 23 study group patients were trained according to an education program (Rheumatoid Arthritis Health School, 20 patients formed a control group. The education program consisted of 4 daily 90-min studies. Adherence to drug and non-drug treatments was assessed at baseline and at 3 and 6 months. Results. In the study group, the basic therapy remained stably high (about 100% within 6 months. At 3 months after studies, nonsteroidal anti-inflammatory drugs could be discontinued in 23.8% (p < 0.05. After 6 months, the proportion of patients using laser therapy increased by 57.1% (p < 0.01 and accounted for 47.8%; the use of electric and ultrasound treatments showed a 55.6% increase (p < 0.01 and was 60.9%. The number of patients who were compliant to the procedures for shaping a correct functional stereotype increased by 14 and 10 times following 3 and 6 months (60.9% and 43.5%, respectively; p < 0.01. After 3 months, there was a rise in the number of patients using hand ortheses by 75.0% (30.4%; p < 0.01; knee ortheses by 50.0% (39.1%; p < 0.01; individual inner soles by 71.4% (52.2%; p < 0.01; and walking sticks and crutches by 60.0% (34.8%; p < 0.01. Following 6 months, the positive changes remained only after the relative use of inner soles (60.9% and support means (34.8%; p < 0.05. The number of patients who regularly did physical activity increased by 5.3 (69.6%; р < 0.01 and 3.7 (47.8%; p < 0.01 times at 3 and 6 months, respectively. The trend in the control group was less pronounced, determining statistically significant differences between the groups in most indicators (р < 0.05. Conclusion. The education program retains high

  15. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    International Nuclear Information System (INIS)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y.

    2014-01-01

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  16. Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Nanjun; Tengstrand, Elizabeth A.; Chourb, Lisa; Hsieh, Frank Y., E-mail: frank.hsieh@nextcea.com

    2014-09-15

    The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann–Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings. - Highlights: • A reliable biomarker of drug-induced phospholipidosis (DIPL) is needed for humans. • Di-22:6-BMP is specific/sensitive for DIPL in animals as published in literatures. • The di-22:6-BMP biomarker can be validated for humans via NPC patients. • DIPL

  17. Metabolic impact of anti-angiogenic agents on U87 glioma cells.

    Directory of Open Access Journals (Sweden)

    Tanja Mesti

    Full Text Available BACKGROUND: Glioma cells not only secrete high levels of vascular endothelial growth factor (VEGF but also express VEGF receptors (VEGFR, supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev or VEGFR Tyrosine Kinase Inhibitor (TKI, is poorly known. MATERIAL AND METHODS: U87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS. RESULTS: U87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells. CONCLUSION: Although both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS might be a valuable marker to assess drug cytotoxicity.

  18. Risk of drug-related problems for various antibiotics in hospital: assessment by use of a novel method.

    Science.gov (United States)

    Blix, Hege Salvesen; Viktil, Kirsten K; Moger, Tron Anders; Reikvam, Aasmund

    2008-08-01

    To investigate the use of antibiotics in hospitals, to explore drug-related problems (DRPs) linked to antibiotics and to introduce a novel way of expressing the risks accompanying use of various antibiotics. Patients from internal medicine departments in four Norwegian hospitals were prospectively included in 2002. Demographics, drugs used, medical history, laboratory data and clinical/pharmacological risk factors were recorded. DRPs were identified by clinical pharmacists and assessed in multidisciplinary hospital teams. A new term, the drug risk ratio, was established and defined as the number of times the antibiotic was associated with DRPs in relation to the number of times it was used. Out of the 668 patients included, 283 patients (42%) used antibiotics (AB users). AB users were older (76.2 vs. 73.9), used more drugs on admission (5.1 vs. 4.4) and had more DRPs (3.0 vs. 2.2) than non-users. The DRP categories no further need for drug, non-optimal drug and non-optimal dose were most frequently observed. The drug risk ratio, calculated for 12 antibiotic groups, was highest for aminoglycosides (0.77), beta-lactamase-resistant penicillins (0.56), macrolides (0.54) and quinolones (0.48) and lowest for first- and third-generation cephalosporins, 0.17 and 0.13, respectively. Nearly half of the hospitalised patients were prescribed antibiotics and antibiotic associated DRPs occurred frequently. The drug risk ratio for the different antibiotic groups varied with a factor of six from the lowest to the highest. A high drug risk ratio would alert of antibiotics which require heightened awareness when going to be used in clinical practice.

  19. The relevance of polymeric synthetic membranes in topical formulation assessment and drug diffusion study.

    Science.gov (United States)

    Ng, Shiow-Fern; Rouse, Jennifer J; Sanderson, Francis D; Eccleston, Gillian M

    2012-03-01

    Synthetic membranes are composed of thin sheets of polymeric macromolecules that can control the passage of components through them. Generally, synthetic membranes used in drug diffusion studies have one of two functions: skin simulation or quality control. Synthetic membranes for skin simulation, such as the silicone-based membranes polydimethylsiloxane and Carbosil, are generally hydrophobic and rate limiting, imitating the stratum corneum. In contrast, synthetic membranes for quality control, such as cellulose esters and polysulfone, are required to act as a support rather than a barrier. These synthetic membranes also often contain pores; hence, they are called porous membranes. The significance of Franz diffusion studies and synthetic membranes in quality control studies involves an understanding of the fundamentals of synthetic membranes. This article provides a general overview of synthetic membranes, including a brief background of the history and the common applications of synthetic membranes. This review then explores the types of synthetic membranes, the transport mechanisms across them, and their relevance in choosing a synthetic membrane in Franz diffusion cell studies for formulation assessment purposes.

  20. Usage of Failure Mode & EffectAnalysis Method (FMEA forsafety assessment in a drug manufacture

    Directory of Open Access Journals (Sweden)

    Y Nazari

    2006-04-01

    Full Text Available Background and Aims: This study was hold in purpose of recognizing and controlling workplacehazards in production units of a drag ManufactureMethod:So for recognition and assessment of hazards, FMEA Method was used. FMEASystematically investigates the effects of equipment and system failures leading often toequipment design improvements. At first the level of the study defined as system. Then accordingto observations, accident statistic, and interview with managers, supervisory, and workers highrisk system were determiner. So the boundaries of the system established and informationregarding the relevant Components, their function and interactions gathered. To preventConfusion between Similar pieces of equipment, a unique system identifier developed. After thatall failure modes and their causes for each equipment or system listed, the immediate effects ofeach failure mode and interactive effect on other equipment or system was described too. Riskpriority number was determined according to global and local criteriaResults: After all some actions and solution proposed to reduce the likelihood and severity offailures and raise their delectability.Conclusion :This study illustrated that although of the first step drug manufacture may seem safe,but there are still many hazardous condition that could cause serious accidents, The result proposedit is necessary: (1 to develop comprehensive manual for periodical and regular inspection ofinstruments of workplaces in purpose of recognize unknown failures and their causes, (2 developa comprehensive program for systems maintenance and repair, and (3 conduct worker training.

  1. Holographic electron density shape theorem and its role in drug design and toxicological risk assessment.

    Science.gov (United States)

    Mezey, P G

    1999-01-01

    Each complete, boundaryless molecular electron density is fully determined by any nonzero volume piece of the electron density cloud. This inherent feature of molecules, called the "holographic" property of molecular electron densities, provides a strong foundation for the local, quantum chemical shape analysis of various functional groups, pharmacophores, and other local molecular moieties. A proof is presented for the relevant molecular shape theorem, the "holographic electron density shape theorem", and the role of this theorem in quantum chemical, quantitative shape-activity relations (QShAR) is discussed. The quantum chemical methods of molecular shape analysis can be extended to ab initio quality electron densities of macromolecules, such as proteins, as well as to local molecular moieties, such as functional groups or pharmacophores, based on the transferability and additivity of local, fuzzy density fragments and the associated local density matrixes within the framework of the ADMA (Adjustable Density Matrix Assembler) approach. In addition to new results on chemical bonding and the development of macromolecular force methods, the new methodologies are also applicable to QShAR studies in computer-aided drug discovery and in toxicological risk assessment.

  2. Assessment of the effects of antihistamine drugs on mood, sleep quality, sleepiness, and dream anxiety.

    Science.gov (United States)

    Ozdemir, Pinar Guzel; Karadag, Ayşe Serap; Selvi, Yavuz; Boysan, Murat; Bilgili, Serap Gunes; Aydin, Adem; Onder, Sevda

    2014-08-01

    There are limited comparative studies on classic and new-generation antihistamines that affect sleep quality and mood. The purpose of this study was to determine and compare the effects of classic and new-generation antihistamines on sleep quality, daytime sleepiness, dream anxiety, and mood. Ninety-two patients with chronic pruritus completed study in the dermatology outpatient clinic. Treatments with regular recommended therapeutic doses were administered. The effects of antihistaminic drugs on mood, daytime sleepiness, dream anxiety, and sleep quality were assessed on the first day and 1 month after. Outpatients who received cetirizine and hydroxyzine treatments reported higher scores on the depression, anxiety, and fatigue sub-scales than those who received desloratadine, levocetirizine, and rupatadine. Pheniramine and rupatadine were found to be associated with daytime sleepiness and better sleep quality. UKU side effects scale scores were significantly elevated among outpatients receiving pheniramine. Classic antihistamines increased daytime sleepiness and decreased the sleep quality scores. New-generation antihistamines reduced sleep latency and dream anxiety, and increased daytime sleepiness and sleep quality. Both antihistamines, significantly increased daytime sleepiness and nocturnal sleep quality. Daytime sleepiness was significantly predicted by rupadatine and pheniramine treatment. Cetirizine and hydroxyzine, seem to have negative influences on mood states. Given the extensive use of antihistamines in clinical settings, these results should be more elaborately examined in further studies.

  3. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics

    DEFF Research Database (Denmark)

    Kreilgaard, Mads; Kemme, M J; Burggraaf, J

    2001-01-01

    The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil-in-water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method....

  4. Scanning electron microscopic assessment of coating irregularities and their precursors in unexpanded durable polymer-based drug-eluting stents

    NARCIS (Netherlands)

    Basalus, M.W.; Tandjung, K.; Tandjung, K.; van Westen, T.; Sen, H.; van der Jagt, P.K.N.; Grijpma, Dirk W.; van Apeldoorn, Aart A.; von Birgelen, Clemens

    2012-01-01

    Objectives: To assess and quantify coating irregularities on unexpanded and expanded durable polymer-based drug-eluting stents (DES) to gain insights into the origin of coating irregularities. Background: Previous scanning electron microscopy (SEM) studies in various expanded DES revealed

  5. Relevance of Campus Climate for Alcohol and Other Drug Use among LGBTQ Community College Students: A Statewide Qualitative Assessment

    Science.gov (United States)

    Manning, Patricia; Pring, Lauren; Glider, Peggy

    2012-01-01

    Literature suggests that individuals who identify as LGBTQ may engage in more alcohol and other drug (AOD) use/abuse than others. Little data is available about these populations on college campuses where AOD use may be seen as part of the general campus climate and culture. This article will describe a qualitative needs assessment conducted on 10…

  6. Viola tricolor Induces Apoptosis in Cancer Cells and Exhibits Antiangiogenic Activity on Chicken Chorioallantoic Membrane

    Directory of Open Access Journals (Sweden)

    Hamid Reza Sadeghnia

    2014-01-01

    Full Text Available In the present study, the cytotoxic and apoptogenic properties of hydroalcoholic extract and ethyl acetate (EtOAc, n-butanol, and water fractions (0–800 μg/mL of Viola tricolor were investigated in Neuro2a mouse neuroblastoma and MCF-7 human breast cancer cells. In addition, antiangiogenic effect of EtOAc fraction was evaluated on chicken chorioallantoic membrane (CAM. The quality of EtOAc fraction was also characterized using high performance liquid chromatography (HPLC fingerprint. Cytotoxicity assay revealed that EtOAc fraction was the most potent among all fractions with maximal effect on MCF-7 and minimal toxicity against normal murine fibroblast L929 cells. Apoptosis induction by EtOAc fraction was confirmed by increased sub-G1 peak of propidium iodide (PI stained cells. This fraction triggered the apoptotic pathway by increased Bax/Bcl-2 ratio and cleaved caspase-3 level. Moreover, treatment with EtOAc fraction significantly decreased the diameter of vessels on CAM, while the number of newly formed blood vessels was not suppressed significantly. Analysis of quality of EtOAc fraction using HPLC fingerprint showed six major peaks with different retention times. The results of the present study suggest that V. tricolor has potential anticancer property by inducing apoptosis and inhibiting angiogenesis.

  7. Antiangiogenic activity of 11,11'-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola

    International Nuclear Information System (INIS)

    Chen Yi; Zhang Yixiang; Li Meihong; Zhao Weimin; Shi Yuhua; Miao Zehong; Zhang Xiongwen; Lin Liping; Ding Jian

    2005-01-01

    The fungus Shiraia bambusicola yields the phytochemical 11,11'-dideoxyverticillin, which has been shown to possess potent anticancer activity both in vitro and in vivo. In this study, we reveal that 11,11'-dideoxyverticillin has anti-angiogenic activities and explore the potential mechanisms for this effect. Treatment with 11,11'-dideoxyverticillin inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) with IC 50 values of 0.17 ± 0.05 μM for VEGF-stimulated cells and 0.39 ± 0.08 μM for serum-stimulated cells. 11,11'-Dideoxyverticillin also antagonized the antiapoptotic effects of VEGF on serum-deprived HUVECs, inhibited VEGF-induced HUVEC migration in vitro, and blocked serum-induced HUVEC tube formation. Moreover, 11,11'-dideoxyverticillin completely blocked VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice. In addition, 11,11'-dideoxyverticillin decreased VEGF secretion by MDA-MB-468 breast cancer cells, and significantly suppressed VEGF-induced tyrosine phosphorylation of Flt-1 and KDR/Flk-1. This inhibition of receptor phosphorylation was correlated with a marked decrease in VEGF-triggered pERK activation and a dramatic increase in pP38 MAPK, but no apparent change in pAkt. Together, these findings strongly suggest that 11,11'-dideoxyverticillin is a structurally novel angiogenesis inhibitor

  8. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases.

    Science.gov (United States)

    Lançon, Allan; Frazzi, Raffaele; Latruffe, Norbert

    2016-03-02

    Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  9. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases

    Directory of Open Access Journals (Sweden)

    Allan Lançon

    2016-03-01

    Full Text Available Resveratrol (3,4′,5 trihydroxy-trans-stilbene is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  10. Fibrocyte-like cells mediate acquired resistance to anti-angiogenic therapy with bevacizumab

    Science.gov (United States)

    Mitsuhashi, Atsushi; Goto, Hisatsugu; Saijo, Atsuro; Trung, Van The; Aono, Yoshinori; Ogino, Hirokazu; Kuramoto, Takuya; Tabata, Sho; Uehara, Hisanori; Izumi, Keisuke; Yoshida, Mitsuteru; Kobayashi, Hiroaki; Takahashi, Hidefusa; Gotoh, Masashi; Kakiuchi, Soji; Hanibuchi, Masaki; Yano, Seiji; Yokomise, Hiroyasu; Sakiyama, Shoji; Nishioka, Yasuhiko

    2015-01-01

    Bevacizumab exerts anti-angiogenic effects in cancer patients by inhibiting vascular endothelial growth factor (VEGF). However, its use is still limited due to the development of resistance to the treatment. Such resistance can be regulated by various factors, although the underlying mechanisms remain incompletely understood. Here we show that bone marrow-derived fibrocyte-like cells, defined as alpha-1 type I collagen-positive and CXCR4-positive cells, contribute to the acquired resistance to bevacizumab. In mouse models of malignant pleural mesothelioma and lung cancer, fibrocyte-like cells mediate the resistance to bevacizumab as the main producer of fibroblast growth factor 2. In clinical specimens of lung cancer, the number of fibrocyte-like cells is significantly increased in bevacizumab-treated tumours, and correlates with the number of treatment cycles, as well as CD31-positive vessels. Our results identify fibrocyte-like cells as a promising cell biomarker and a potential therapeutic target to overcome resistance to anti-VEGF therapy. PMID:26635184

  11. Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI.

    Directory of Open Access Journals (Sweden)

    Wenlian Zhu

    Full Text Available Solid tumor vasculature is highly heterogeneous, which presents challenges to antiangiogenic intervention as well as the evaluation of its therapeutic efficacy. The aim of this study is to evaluate the spatial tumor vascular changes due to bevacizumab/paclitaxel therapy using a combination approach of MR angiography and DCE-MRI method.Tumor vasculature of MCF-7 breast tumor mouse xenografts was studied by a combination of MR angiography and DCE-MRI with albumin-Gd-DTPA. Tumor macroscopic vasculature was extracted from the early enhanced images. Tumor microvascular parameters were obtained from the pharmacokinetic modeling of the DCE-MRI data. A spatial analysis of the microvascular parameters based on the macroscopic vasculature was used to evaluate the changes of the heterogeneous vasculature induced by a 12 day bevacizumab/paclitaxel treatment in mice bearing MCF-7 breast tumor.Macroscopic vessels that feed the tumors were not affected by the bevacizumab/paclitaxel combination therapy. A higher portion of the tumors was within close proximity of these macroscopic vessels after the treatment, concomitant with tumor growth retardation. There was a significant decrease in microvascular permeability and vascular volume in the tumor regions near these vessels.Bevacizumab/paclitaxel combination therapy did not block the blood supply to the MCF-7 breast tumor. Such finding is consistent with the modest survival benefits of adding bevacizumab to current treatment regimens for some types of cancers.

  12. Patterns of Innovation in Alzheimer's Disease Drug Development: A Strategic Assessment Based on Technological Maturity.

    Science.gov (United States)

    Beierlein, Jennifer M; McNamee, Laura M; Walsh, Michael J; Ledley, Fred D

    2015-08-01

    This article examines the current status of translational science for Alzheimer's disease (AD) drug discovery by using an analytical model of technology maturation. Previous studies using this model have demonstrated that nascent scientific insights and inventions generate few successful leads or new products until achieving a requisite level of maturity. This article assessed whether recent failures and successes in AD research follow patterns of innovation observed in other sectors. The bibliometric-based Technology Innovation Maturation Evaluation model was used to quantify the characteristic S-curve of growth for AD-related technologies, including acetylcholinesterase, N-methyl-d-aspartate (NMDA) receptors, B-amyloid, amyloid precursor protein, presenilin, amyloid precursor protein secretases, apolipoprotein E4, and transactive response DNA binding protein 43 kDa (TDP-43). This model quantifies the accumulation of knowledge as a metric for technological maturity, and it identifies the point of initiation of an exponential growth stage and the point at which growth slows as the technology is established. In contrast to the long-established acetylcholinesterase and NMDA receptor technologies, we found that amyloid-related technologies reached the established point only after 2000, and that the more recent technologies (eg, TDP-43) have not yet approached this point. The first approvals for new molecular entities targeting acetylcholinesterase and the NMDA receptor occurred an average of 22 years after the respective technologies were established, with only memantine (which was phenotypically discovered) entering clinical trials before this point. In contrast, the 6 lead compounds targeting the formation of amyloid plaques that failed in Phase III trials between 2009 and 2014 all entered clinical trials before the respective target technologies were established. This analysis suggests that AD drug discovery has followed a predictable pattern of innovation in which

  13. Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

    Science.gov (United States)

    Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

    2017-01-01

    Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

  14. The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery.

    Science.gov (United States)

    Thomas, Craig E; Will, Yvonne

    2012-02-01

    Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies. Given the lengthy development time frames of drugs in the pharmaceutical industry, the authors believe that the impact of new technologies on attrition is best measured as a function of the quality and timeliness of candidate compounds entering development. The authors provide an overview of in silico and in vitro models, as well as more complex approaches such as 'omics,' and where they are best positioned within the drug discovery process. It is important to take away that not all technologies should be applied to all projects. Technologies vary widely in their validation state, throughput and cost. A thoughtful combination of validated and emerging technologies is crucial in identifying the most promising candidates to move to proof-of-concept testing in humans. In spite of the challenges inherent in applying new technologies to drug discovery, the successes and recognition that we cannot continue to rely on safety assessment practices used for decades have led to rather dramatic strategy shifts and fostered partnerships across government agencies and industry. We are optimistic that these efforts will ultimately benefit patients by delivering effective and safe medications in a timely fashion.

  15. A stepwise protocol for drug permeation assessment that combines heat-separated porcine ear epidermis and vertical diffusion cells

    Directory of Open Access Journals (Sweden)

    Pantelić Ivana

    2018-01-01

    Full Text Available After decades long absence of an official consensus on the most appropriate evaluation method for in vitro skin performance of topical semisolid drugs, United States Pharmacopoeia (USP 39 finally suggested three types of testing equipment; however, all these provide data on drug release using inert synthetic membranes. Considering the need for a readily available membrane that would be more structurally similar to human skin, this paper provides a detailed protocol of a method for drug permeation assessment that uses heat-separated porcine ear epidermis and modified Franz diffusion cells. Phases that were shown to be critical for variability of the results are identified (e.g., membrane preparation, and process parameters optimized. Applicability of the method was tested on four cream samples loaded with aceclofenac as a model drug. Sample compositions were designed in such a way to provide „large“ variations (variation of the main stabilizer: natural-origin versus synthetic emulsifier and relatively „minor“ variations (co-solvent variation: none/isopropanol/glycerol. The developed protocol is a straightforward and reliable in vitro test for the evaluation of rate and extent of drug delivery into/through the skin. Moreover, this protocol may be routinely applied even in averagely equipped laboratories during formulation development or preliminary bioequivalence assessment of generic topical semisolids. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. TR34031

  16. Bridging the boundaries between scientists and clinicians-mechanistic hypotheses and patient stories in risk assessment of drugs.

    Science.gov (United States)

    Rocca, Elena

    2017-02-01

    The cultural divide between scientists and clinicians has been described as undermining the advance of medical science, by hindering the production of practice-relevant research and of research-informed clinical decisions. Here, I consider the field of post-marketing risk assessment of drugs as an example of strict interdependence between basic biomedical research, clinical research, and clinical evaluation and show how it would benefit from a closer collaboration between scientists and clinicians. The risk assessment of drugs after their marketing relies on spontaneous adverse effect reports to drug agencies and on peer-reviewed case reports. I emphasize the importance of qualitative analysis of such reports for the improvement of mechanistic understanding of harmful effects of drugs. I argue that mechanistic explanations of drug effects are at least as important as determination of their frequency, in order to establish causation. An ideal risk assessment, then, verifies not only the frequency of undesired effects but also why and how the harm happens. For this purpose, the frequency or novelty of the unintended outcome, although contextually indicative, should not determine the epistemic value of a report. Details about the context that generated an unexpected outcome, instead, can offer the chance of improving causal understanding about how the intervention works. This is illustrated through examples from medical research. Mechanistic understanding is a domain of joint collaboration among (1) clinicians, in charge of detailed, qualitative reporting of patient stories about side effects, (2) qualitative clinical researchers, in charge of analyzing clinical contexts or harmful effects and formulating explanatory hypotheses, and (3) basic biomedical researchers, in charge of verifying such hypotheses. In addition, direct information flow can on one side focus clinicians' attention on knowledge gaps about drugs/effects where more research is needed, while on the

  17. Pancreatic Safety of Incretin-Based Drugs - FDA and EMA Assessment

    NARCIS (Netherlands)

    Egan, Amy G.; Blind, Eberhard; Dunder, Kristina; de Graeff, Pieter A.; Hummer, B. Timothy; Bourcier, Todd; Rosebraugh, Curtis

    2014-01-01

    After evaluating a safety signal regarding pancreatitis and pancreatic cancer in patients using incretin-based drugs, the Food and Drug Administration and the European Medicines Agency conclude that assertions of a causal association are inconsistent with the data. With approximately 25.8 million

  18. In Silico Systems Pharmacology to Assess Drug's Therapeutic and Toxic Effects

    DEFF Research Database (Denmark)

    Orozco, Alejandro Aguayo; Audouze, Karine; Brunak, Soren

    2016-01-01

    For many years, the "one target, one drug" paradigm has been the driving force behind developments in pharmaceutical research. With the recent advances in molecular biology and genomics technologies, the focus is shifting toward "drug-holistic" systems based approaches (i.e. systems pharmacology)...

  19. School-Based Drug Prevention Program: Quantitative Assessment of Life Skills Training Elementary School Program

    Science.gov (United States)

    Kindle, Silverlene J.

    2013-01-01

    Since the 1960s long-term studies have documented nation-wide patterns of adolescent smoking, drinking and illicit drug use. The federal government responded by passing the Safe and Drug Free Schools and Communities Act, which funded school-based prevention programs. The problem for school counselors in a Georgia Public School District was…

  20. A Multiyear Assessment of Public Response to a Statewide Drug Take-Back and Disposal Campaign, 2010 to 2012.

    Science.gov (United States)

    Yanovitzky, Itzhak

    2017-08-01

    This study is the first to analyze public response to a drug take-back program, the American Medicine Chest Challenge, in a single state over a period of 3 years (2010-2012). The study utilized a three-wave repeated cross-sectional design and an annual phone survey conducted with a representative sample of adults ( N = 906 in 2010, N = 907 in 2011, and N = 906 in 2012), which assessed exposure to the campaign, drug disposal behaviors, possible mediators of campaign effects (risk appraisal, personal agency, normative influence, and interpersonal talk), and potential confounders. Logistic regression and causal mediation analysis were employed to estimate confounder-adjusted direct and mediated effects of the campaign. Results showed that the campaign reached a sizable portion (50% to 60%) of state adults and that campaign exposure was associated with increased likelihood of having conversations with others about this topic. About 55% of all adults in the state reported taking at least one of the actions recommended by the campaign, and campaign exposure was associated with increased likelihood of disposing of prescription drugs at a drug collection day event (adjusted odds ratio = 4) and of talking to a child about the risks associated with prescription drug abuse (adjusted odds ratio = 2). The causal mediation analysis demonstrated that the campaign influenced audiences by reinforcing their efficacy to safely dispose of prescription drugs, but also potentially by stimulating conversations among community members about this topic. Drug take-back campaigns can be an effective mechanism to decrease the availability of prescription drugs in communities.

  1. Drug and herb induced liver injury: Council for International Organizations of Medical Sciences scale for causality assessment.

    Science.gov (United States)

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schwarzenboeck, Alexander; Schulze, Johannes; Eickhoff, Axel

    2014-01-27

    Causality assessment of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI) is hampered by the lack of a standardized approach to be used by attending physicians and at various subsequent evaluating levels. The aim of this review was to analyze the suitability of the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale as a standard tool for causality assessment in DILI and HILI cases. PubMed database was searched for the following terms: drug induced liver injury; herb induced liver injury; DILI causality assessment; and HILI causality assessment. The strength of the CIOMS lies in its potential as a standardized scale for DILI and HILI causality assessment. Other advantages include its liver specificity and its validation for hepatotoxicity with excellent sensitivity, specificity and predictive validity, based on cases with a positive reexposure test. This scale allows prospective collection of all relevant data required for a valid causality assessment. It does not require expert knowledge in hepatotoxicity and its results may subsequently be refined. Weaknesses of the CIOMS scale include the limited exclusion of alternative causes and qualitatively graded risk factors. In conclusion, CIOMS appears to be suitable as a standard scale for attending physicians, regulatory agencies, expert panels and other scientists to provide a standardized, reproducible causality assessment in suspected DILI and HILI cases, applicable primarily at all assessing levels involved.

  2. Optimizing Clinical Drug Product Performance: Applying Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid.

    Science.gov (United States)

    Dickinson, Paul A; Kesisoglou, Filippos; Flanagan, Talia; Martinez, Marilyn N; Mistry, Hitesh B; Crison, John R; Polli, James E; Cruañes, Maria T; Serajuddin, Abu T M; Müllertz, Anette; Cook, Jack A; Selen, Arzu

    2016-11-01

    The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well-formulated critical questions and well-designed and conducted integrated studies. This commentary describes and illustrates application of the BioRAM Scoring Grid, a companion to the BioRAM strategy, which guides implementation of such an integrated strategy encompassing 12 critical areas and 6 assessment stages. Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe that BioRAM is going to have a broad-reaching impact, influencing drug development and leading to unique collaborations influencing how we learn, and leverage and share knowledge. Published by Elsevier Inc.

  3. Single-item measure for assessing quality of life in children with drug-resistant epilepsy.

    Science.gov (United States)

    Conway, Lauryn; Widjaja, Elysa; Smith, Mary Lou

    2018-03-01

    The current study investigated the psychometric properties of a single-item quality of life (QOL) measure, the Global Quality of Life in Childhood Epilepsy question (G-QOLCE), in children with drug-resistant epilepsy. Data came from the Impact of Pediatric Epilepsy Surgery on Health-Related Quality of Life Study (PESQOL), a multicenter prospective cohort study (n = 118) with observations collected at baseline and at 6 months of follow-up on children aged 4-18 years. QOL was measured with the QOLCE-76 and KIDSCREEN-27. The G-QOLCE was an overall QOL question derived from the QOLCE-76. Construct validity and reliability were assessed with Spearman's correlation and intraclass correlation coefficient (ICC). Responsiveness was examined through distribution-based and anchor-based methods. The G-QOLCE showed moderate (r ≥ 0.30) to strong (r ≥ 0.50) correlations with composite scores, and most subscales of the QOLCE-76 and KIDSCREEN-27 at baseline and 6-month follow-up. The G-QOLCE had moderate test-retest reliability (ICC range: 0.49-0.72) and was able to detect clinically important change in patients' QOL (standardized response mean: 0.38; probability of change: 0.65; Guyatt's responsiveness statistics: 0.62 and 0.78). Caregiver anxiety and family functioning contributed most strongly to G-QOLCE scores over time. Results offer promising preliminary evidence regarding the validity, reliability, and responsiveness of the proposed single-item QOL measure. The G-QOLCE is a potentially useful tool that can be feasibly administered in a busy clinical setting to evaluate clinical status and impact of treatment outcomes in pediatric epilepsy.

  4. Assessing prescription drug abuse using functional principal component analysis (FPCA) of wastewater data.

    Science.gov (United States)

    Salvatore, Stefania; Røislien, Jo; Baz-Lomba, Jose A; Bramness, Jørgen G

    2017-03-01

    Wastewater-based epidemiology is an alternative method for estimating the collective drug use in a community. We applied functional data analysis, a statistical framework developed for analysing curve data, to investigate weekly temporal patterns in wastewater measurements of three prescription drugs with known abuse potential: methadone, oxazepam and methylphenidate, comparing them to positive and negative control drugs. Sewage samples were collected in February 2014 from a wastewater treatment plant in Oslo, Norway. The weekly pattern of each drug was extracted by fitting of generalized additive models, using trigonometric functions to model the cyclic behaviour. From the weekly component, the main temporal features were then extracted using functional principal component analysis. Results are presented through the functional principal components (FPCs) and corresponding FPC scores. Clinically, the most important weekly feature of the wastewater-based epidemiology data was the second FPC, representing the difference between average midweek level and a peak during the weekend, representing possible recreational use of a drug in the weekend. Estimated scores on this FPC indicated recreational use of methylphenidate, with a high weekend peak, but not for methadone and oxazepam. The functional principal component analysis uncovered clinically important temporal features of the weekly patterns of the use of prescription drugs detected from wastewater analysis. This may be used as a post-marketing surveillance method to monitor prescription drugs with abuse potential. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Assessment of club patrons' alcohol and drug use: the use of biological markers.

    Science.gov (United States)

    Miller, Brenda A; Byrnes, Hilary F; Branner, Amy C; Voas, Robert; Johnson, Mark B

    2013-11-01

    Young adulthood (ages 18-25 years) represents a time when high-risk behaviors, including alcohol and drug use, peak. Electronic music dance events (EMDEs) featured at clubs provide an ecologic niche for these high-risk behaviors. This paper examines the prevalence of alcohol and drug use among EMDE patrons. Examination of personal characteristics associated with exit levels of alcohol and drug use identifies important indicators of risk taking for prevention strategies. Data were collected anonymously during 2010-2012 from 2028 patrons as they entered and exited clubs in the San Francisco Bay area featuring EMDEs. Nearly half were aged ≤25 years. Biological measures of drug and alcohol and self-reported personal characteristics were attained. Analyses were completed in 2012. At entrance, more than one fifth of patrons were positive for drug use and one fourth arrived either impaired (blood alcohol concentration [BAC]: 0.05%-0.079%) or intoxicated (BAC: >0.08%) by alcohol. At exit, one fourth tested positive for drugs, and nearly half were impaired or intoxicated by alcohol. Individual characteristics that were important for levels of risk included prior alcohol use behaviors, sexual identity, ethnic/racial identity, and transportation to the event. Gender did not differentiate for alcohol use but fewer women used drugs. Findings confirm the importance of targeting EMDEs for prevention efforts. EMDEs attract young working adults who are engaged in heavy alcohol and/or drug use. Targeting these social settings for delivering public health prevention strategies regarding alcohol and drug use and related harm is indicated by the findings. © 2013 American Journal of Preventive Medicine.

  6. The use of GLIM and the bootstrap in assessing a clinical trial of two drugs.

    Science.gov (United States)

    Mapleson, W W

    1986-01-01

    An approach is described for estimating the dose of a new drug which is equipotent to an established dose of an old drug. The approach is basically that of the parallel-line assay but it can allow for concomitant variables and, by exploiting the facilities available in the statistical computer package GLIM (generalized linear interactive modelling), the approach can be applied when the residuals conform to one of a number of distributions and, with suitable safeguards, to continuous, discrete and even 'scored' responses. In some circumstances, it is necessary to obtain confidence limits by Efron's 'bootstrap' technique. The method is illustrated with results from a trial of two premedicant drugs in children.

  7. An Assessment of Alcohol and Drug Education/Prevention Programs in the United States Army

    Science.gov (United States)

    1973-12-01

    paraphernalia such as exotic pipes, black lights, psychedelic posters, and the like. These elements of the drug culture must be considered when one...methods used were successf-il in curbing hard drug use, and that the benefits outweigh the costs, we recommend that the Army implemeni the program on a...Research ProbI~t • KI•773-3 ,’AN_ ASSESSMENIT OF ALCOHOL AND DRUG - EDUCATIONP/ EVENTIOON PROGRAMS IN THE UNITED STATES ARMY. 0t -.. -’. "--,’- D D

  8. Development and psychometric testing the Health of Body, Mind and Spirit Scale for assessing individuals who have drug abuse histories.

    Science.gov (United States)

    Sun, Fan-Ko; Chiang, Chun-Ying; Lu, Chu-Yun; Yu, Pei-Jane; Liao, Tzu-Chiao; Lan, Chu-Mei

    2018-03-01

    To develop the Health of Body, Mind and Spirit Scale (HBMSS), which was designed to assess drug abusers' health condition. Helping drug abusers to become healthy is important to healthcare professionals. However, no instrument exists to assess drug abusers' state of health. A cross-sectional questionnaire survey was implemented to examine the validity of the HBMSS. Data were collected from 2015-2016 at one drug abuse prevention centre in Taiwan. Participants (N = 320) who had abused drugs were invited to complete a preliminary 64-item version of the HBMSS. An item analysis, criterion-related validity analysis (using the Relapse Prediction Scale [RPS] score), split-half reliability testing and confirmatory factor analysis (CFA) were conducted to examine the psychometric properties of the HBMSS. The final version of the HBMSS contained 15 items that were divided into three subscales: the health of the body, mind and spirit. Cronbach's α and split-half reliability coefficients were all above .85. The factor loading of each item was between .74-.95. The HBMSS had satisfactory criterion-related validity with the RPS score (r = -.50, p < .001). A second-order CFA was conducted on the HBMSS. The fit indexes were good, χ 2  = 184.060, df = 94, χ 2 /df = 1.958 (p = .000). The entire HBMSS and the subscales had satisfactory reliability and validity. Healthcare professionals could use the HBMSS to evaluate the condition of the health of individuals with a drug abuse history. © 2017 John Wiley & Sons Ltd.

  9. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  10. Quantification of antiangiogenic treatment effects on tissue heterogeneity in glioma tumour xenograft model using a combination of DCE-MRI and 3D-ultramicroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Dominietto, Marco [University and ETH Zurich, Institute for Biomedical Engineering, Zurich (Switzerland); University of Basel, Biomaterials Science Center, Allschwil (Switzerland); Dobosz, Michael; Renner, Anja; Scheuer, Werner [Roche Innovation Center Penzberg, Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Penzberg (Germany); Buergi, Sandra; Rudin, Markus [University and ETH Zurich, Institute for Biomedical Engineering, Zurich (Switzerland); Zahlmann, Gudrun [pRED, Oncology DTA, Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel (Switzerland)

    2017-07-15

    This study aimed at assessing the effects of an anti-angiogenic treatment, which neutralises vascular endothelial growth factor (VEGF), on tumour heterogeneity. Murine glioma cells have been inoculated into the right brain frontal lobe of 16 mice. Anti-VEGF antibody was administered to a first group (n = 8), while a second group (n = 8) received a placebo. Magnetic resonance acquisitions, performed at days 10, 12, 15 and 23 following the implantation, allowed the derivation of a three-dimensional features dataset characterising tumour heterogeneity. Three-dimensional ultramicroscopy and standard histochemistry analysis have been performed to verify in vivo results. Placebo-treated mice displayed a highly-vascularised area at the tumour periphery, a monolithic necrotic core and a chaotic dense vasculature across the entire tumour. In contrast, the B20-treated group did not show any highly vascularised regions and presents a fragmented necrotic core. A significant reduction of the number of vessel segments smaller than 17 μm has been observed. There was no difference in overall tumour volume and growth rate between the two groups. Region-specific analysis revealed that VEGF inhibition affects only: (1) highly angiogenic compartments expressing high levels of VEGF and characterised by small capillaries, and also (2) the formation and structure of necrotic regions. These effects appear to be transient and limited in time. (orig.)

  11. Multiparametric Monitoring of Early Response to Antiangiogenic Therapy: A Sequential Perfusion CT and PET/CT Study in a Rabbit VX2 Tumor Model

    Directory of Open Access Journals (Sweden)

    Jung Im Kim

    2014-01-01

    Full Text Available Objectives. To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Methods. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group or saline infusion (control group. Perfusion CT was analyzed to calculate blood flow (BF, blood volume (BV, and permeability surface area product (PS; FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG, entropy, and homogeneity. The flow-metabolic ratio (FMR was also calculated and immunohistochemical analysis of microvessel density (MVD was performed. Results. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. Conclusions. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.

  12. Multiparametric monitoring of early response to antiangiogenic therapy: a sequential perfusion CT and PET/CT study in a rabbit VX2 tumor model.

    Science.gov (United States)

    Kim, Jung Im; Lee, Hyun-Ju; Kim, Young Jae; Kim, Kwang Gi; Lee, Kyung Won; Lee, Jae Ho; Lee, Hak Jong; Lee, Won Woo

    2014-01-01

    To perform dual analysis of tumor perfusion and glucose metabolism using perfusion CT and FDG-PET/CT for the purpose of monitoring the early response to bevacizumab therapy in rabbit VX2 tumor models and to assess added value of FDG-PET to perfusion CT. Twenty-four VX2 carcinoma tumors implanted in bilateral back muscles of 12 rabbits were evaluated. Serial concurrent perfusion CT and FDG-PET/CT were performed before and 3, 7, and 14 days after bevacizumab therapy (treatment group) or saline infusion (control group). Perfusion CT was analyzed to calculate blood flow (BF), blood volume (BV), and permeability surface area product (PS); FDG-PET was analyzed to calculate SUVmax, SUVmean, total lesion glycolysis (TLG), entropy, and homogeneity. The flow-metabolic ratio (FMR) was also calculated and immunohistochemical analysis of microvessel density (MVD) was performed. On day 14, BF and BV in the treatment group were significantly lower than in the control group. There were no significant differences in all FDG-PET-derived parameters between both groups. In the treatment group, FMR prominently decreased after therapy and was positively correlated with MVD. In VX2 tumors, FMR could provide further insight into the early antiangiogenic effect reflecting a mismatch in intratumor blood flow and metabolism.

  13. Methodological approach to determine minor, considerable, and major treatment effects in the early benefit assessment of new drugs.

    Science.gov (United States)

    Skipka, Guido; Wieseler, Beate; Kaiser, Thomas; Thomas, Stefanie; Bender, Ralf; Windeler, Jürgen; Lange, Stefan

    2016-01-01

    At the beginning of 2011, the early benefit assessment of new drugs was introduced in Germany with the Act on the Reform of the Market for Medicinal Products (AMNOG). The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this type of assessment, which examines whether a new drug shows an added benefit (a positive patient-relevant treatment effect) over the current standard therapy. IQWiG is required to assess the extent of added benefit on the basis of a dossier submitted by the pharmaceutical company responsible. In this context, IQWiG was faced with the task of developing a transparent and plausible approach for operationalizing how to determine the extent of added benefit. In the case of an added benefit, the law specifies three main extent categories (minor, considerable, major). To restrict value judgements to a minimum in the first stage of the assessment process, an explicit and abstract operationalization was needed. The present paper is limited to the situation of binary data (analysis of 2 × 2 tables), using the relative risk as an effect measure. For the treatment effect to be classified as a minor, considerable, or major added benefit, the methodological approach stipulates that the (two-sided) 95% confidence interval of the effect must exceed a specified distance to the zero effect. In summary, we assume that our approach provides a robust, transparent, and thus predictable foundation to determine minor, considerable, and major treatment effects on binary outcomes in the early benefit assessment of new drugs in Germany. After a decision on the added benefit of a new drug by G-BA, the classification of added benefit is used to inform pricing negotiations between the umbrella organization of statutory health insurance and the pharmaceutical companies. © 2015 The Authors. Biometrical Journal Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  14. The role of semaphorin 4D as a potential biomarker for antiangiogenic therapy in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Ding X

    2016-03-01

    Full Text Available Xiaojie Ding,1,2,* Lijuan Qiu,1,2,* Lijuan Zhang,3 Juemin Xi,1,2 Duo Li,1,2 Xinwei Huang,1,2 Yujiao Zhao,1,2 Xiaodang Wang,1,2 Qiangming Sun1,2 1Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 2Molecular Epidemiology Joint Laboratory, Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, 3Department of Pathology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Provincial Tumor Hospital, Kunming, People’s Republic of China*These authors contributed equally to this workBackground: Semaphorin 4D (Sema4D belongs to the class IV semaphorins, and accumulating evidence has indicated that its elevated level may be one strategy by which tumors evade current antiangiogenic therapies. The biological roles of Sema4D in colorectal cancer (CRC, however, remain largely undefined. This study was designed to investigate the effects of Sema4D on tumor angiogenesis and growth in CRC, especially in different vascular endothelial growth factor (VEGF backgrounds.Methods: The expression of Sema4D in human CRC was evaluated by immunohistochemical analysis of tumors and their matching normal control tissues. The expression level of Sema4D and VEGF was investigated in different CRC cell lines. To evaluate the contributions of Sema4D to tumor-induced angiogenesis, two CRC cell lines with opposite VEGF backgrounds were infected with lentiviruses expressing Sema4D or Sema4D short hairpin RNA, followed by in vitro migration and in vivo tumor angiogenic assays.Results: Immunohistochemical analysis of human CRC revealed high levels of Sema4D in a cell surface pattern. In all, 84.85% of CRC samples analyzed exhibited moderate to strong Sema4D expression. The positive ratios of Sema4D staining for well, moderately, and poorly differentiated cancers were 71.43%, 96.67%, and 77.27%, respectively. Sema4D is highly expressed in five different CRC cell lines, while VEGF

  15. Health technology assessment of drugs for rare diseases: insights, trends, and reasons for negative recommendations from the CADTH common drug review.

    Science.gov (United States)

    Janoudi, Ghayath; Amegatse, William; McIntosh, Brendan; Sehgal, Chander; Richter, Trevor

    2016-12-01

    A shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency. A public database (cadth.ca) was screened to identify DRD submissions to CDR. A diseases prevalence of ≤50 per 100,000 people was considered a rare disease. We calculated descriptive statistics for prevalence, study design, study size, treatment cost, reimbursement recommendation types, and reasons for negative reimbursement recommendations. From 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%). The number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD

  16. Ecotoxicity and genotoxicity assessment of cytotoxic antineoplastic drugs and their metabolites

    Czech Academy of Sciences Publication Activity Database

    Zounková, R.; Kovalová, L.; Bláha, Luděk; Dott, W.

    2010-01-01

    Roč. 81, č. 2 (2010), s. 253-260 ISSN 0045-6535 Institutional research plan: CEZ:AV0Z60050516 Keywords : cytotoxic drugs * ecotoxicity * metabolite Subject RIV: EF - Botanics Impact factor: 3.155, year: 2010

  17. Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography

    DEFF Research Database (Denmark)

    Taniwaki, Masanori; Radu, Maria D; Zaugg, Serge

    2016-01-01

    BACKGROUND: The pathomechanisms underlying very late stent thrombosis (VLST) after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography, we investigated potential causes of this adverse event. METHODS AND RESULTS: Between August 2010 and Decemb...

  18. Progression of retinal pigment epithelial atrophy in antiangiogenic therapy of neovascular age-related macular degeneration.

    Science.gov (United States)

    Schütze, Christopher; Wedl, Manuela; Baumann, Bernhard; Pircher, Michael; Hitzenberger, Christoph K; Schmidt-Erfurth, Ursula

    2015-06-01

    To monitor retinal pigment epithelial (RPE) atrophy progression during antiangiogenic therapy of neovascular age-related macular degeneration (AMD) over 2 years using polarization-sensitive optical coherence tomography (OCT). Prospective interventional case series. setting: Clinical practice. Thirty patients (31 eyes) with treatment-naïve neovascular AMD. Standard intravitreal therapy (0.5 mg ranibizumab) was administered monthly during the first year and pro re nata (PRN; as-needed) during the second year. Spectral-domain (SD) OCT and polarization-sensitive OCT (selectively imaging the RPE) examinations were performed at baseline and at 1, 3, 6, 12, and 24 months using a standardized protocol. RPE-related changes were evaluated using a semi-automated polarization-sensitive OCT segmentation algorithm and correlated with SD OCT and fundus autofluorescence (FAF) findings. RPE response, geographic atrophy (GA) progression. Atrophic RPE changes included RPE thinning, RPE porosity, focal RPE atrophy, and development of GA. Early RPE loss (ie, RPE porosity, focal atrophy) increased progressively during initial monthly treatment and remained stable during subsequent PRN-based therapy. GA developed in 61% of eyes at month 24. Mean GA area increased from 0.77 mm(2) at 12 months to 1.10 mm(2) (standard deviation = 1.09 mm(2)) at 24 months. Reactive accumulation of RPE-related material at the lesion borders increased until month 3 and subsequently decreased. Progressive RPE atrophy and GA developed in the majority of eyes. RPE migration signifies certain RPE plasticity. Polarization-sensitive OCT specifically images RPE-related changes in neovascular AMD, contrary to conventional imaging methods. Polarization-sensitive OCT allows for precisely monitoring the sequence of RPE-related morphologic changes. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Narayana, Ashwatha, E-mail: ashwatha.narayana@nyumc.org [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Kunnakkat, Saroj D. [Department of Radiation Oncology, New York University Langone Medical Center, New York, NY (United States); Medabalmi, Praveen [Department of Biostatistics, New York University Langone Medical Center, New York, NY (United States); Golfinos, John; Parker, Erik [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Knopp, Edmond [Department of Radiology, New York University Langone Medical Center, New York, NY (United States); Zagzag, David [Department of Pathology, New York University Langone Medical Center, New York, NY (United States); Eagan, Patricia [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States); Gruber, Deborah [Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Gruber, Michael L. [Department of Neurosurgery, New York University Langone Medical Center, New York, NY (United States); Department of Neuro-Oncology, New York University Langone Medical Center, New York, NY (United States); Atlantic Health System, Overlook Hospital, Summit, NJ (United States)

    2012-01-01

    Purpose: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. Methods and Materials: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. Results: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R{sup 2} = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). Conclusion: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

  20. In vitro, in vivo and pharmacokinetic assessment of amikacin sulphate laden polymeric nanoparticles meant for controlled ocular drug delivery

    Science.gov (United States)

    Sharma, Upendra Kumar; Verma, Amita; Prajapati, Sunil Kuamr; Pandey, Himanshu; Pandey, Avinash C.

    2015-02-01

    The rationale of current exploration was to formulate positively charged amikacin-loaded polymeric nanoparticles providing a controlled release attribute. Amikacin sulphate-loaded nanoparticles were prepared by w/o/w emulsification solvent evaporation approach succeeded by high-pressure homogenization. Two bioadhesive positively charged polymers, Eudragit® RS 100 and Eudragit® RL 100, were used in the blend, with variable ratios of drug and polymer. The formulations were assessed in terms of particle size and zeta potential. Thermal gravimetric analysis was brought out on the samples of drug, polymer and drug polymer complex. Drug loading and release attributes of the nanoparticles were scrutinized and antimicrobial activity in contrast to Staphylococcus aureus was appraised. Ocular irritation test, in vivo ocular retention study, in vivo release profile (permeation study) and in vivo antibacterial activity of polymeric nanosuspensions were executed. No rupture consequence but a lengthened drug release was contemplated from all formulations. Amikacin sulphate release from the polymeric nanoparticles reflected a better fit with Korsmeyer-Peppas model. In the course of the antibacterial activity of nanoparticles against S. aureus, formulation AE1 displays the most prominent inhibitory effect as compared with marketed formulation of amikacin sulphate.

  1. Assessment of prescribing information for generic drugs manufactured in the Middle East and marketed in Saudi Arabia

    International Nuclear Information System (INIS)

    Gebran, N.; Al-Haldari, K.

    2006-01-01

    Little research has assessed the quality of manufacturer provided prescribing information or documented difference in key aspects of drug information among different marketed generic products of the same drug particularly in Middle East and Arabian Gulf. We assessed the quality of written prescribing information for selected generic drugs marketed in Saudi Arabia and manufactured in various countries of Middle East. We assessed the correctness and completeness of information pertaining to indications, dosage cautions/contraindications, side effects and drug interactions in 37 packages inserts for generic products registered in Saudi Arabia and manufactured in the Middle East, including atenolol (6 inserts), fluoxetine (4 inserts), ciprofloxacin (11 inserts), melformin (7 inserts) and omeprazole (9 inserts). We also described deficiencies in quality and quantity of manufacturers provided information that could be misleading to patients and prescribes. We found substantial disagreement in information between generic packages inserts versus the British National Formulary and the package insert of the brand product marketed in Saudi Arabia. A cumulative average of 63.16% of drug information indicators were in agreement with these standard references. Section headings with the least conformity with study references were those related to dosage (57, 28%) and side effects (54+-30%). Our results indicate that national authorities should implement appropriate measures aimed at removing misleading and incorrect information in generic package inserts and incorporating crucial prescribing information that is missing. National authorities in the Middle East and Arabian Gulf should strengthen collaboration and information interchange among each other and with international agencies to maintain common quality standards for delivering information through package inserts. (author)

  2. Illicit Drug Use Among South Korean Offenders: Assessing the Generality of Social Learning Theory.

    Science.gov (United States)

    Yun, Minwoo; Kim, Eunyoung

    2015-10-01

    Since the mid-1990s, illicit drug use has become a problem in Korean society. This trend is likely due to the rapid globalization and expansion that occurred with the Internet revolution, which led to greater numbers of people socially learning about drug culture. The current study attempts to uncover criminogenic causality of such social learning about drug use by studying adult felony drug offenders in South Korea. The data used for the study were obtained from self-reported surveys, originally collected by the Korean Institution of Criminology (KIC). The final sample comprised 1,452 felony offenders convicted of illicit drug use, and their responses were analyzed with a set of multiple logistic regression tests. The current study found supportive evidence for the generalizability of social learning theory from the sample of the South Korean adult drug offenders. We argue that the current study provides additional empirical evidence that supports the generalizability of social learning theory. © The Author(s) 2014.

  3. Assessment of drug disposition in the perfused rat brain by statistical moment analysis

    Energy Technology Data Exchange (ETDEWEB)

    Sakane, T.; Nakatsu, M.; Yamamoto, A.; Hashida, M.; Sezaki, H.; Yamashita, S.; Nadai, T. (Faculty of Pharmaceutical Sciences, Setsunan University, Osaka (Japan))

    1991-06-01

    Drug disposition in the brain was investigated by statistical moment analysis using an improved in situ brain perfusion technique. The right cerebral hemisphere of the rat was perfused in situ. The drug and inulin were injected into the right internal carotid artery as a rapid bolus and the venous outflow curve at the posterior facial vein was obtained. The infusion rate was adjusted to minimize the flow of perfusion fluid into the left hemisphere. The obtained disposition parameters were characteristics and considered to reflect the physicochemical properties of each drug. Antipyrine showed a small degree of initial uptake. Therefore, its apparent distribution volume (Vi) and apparent intrinsic clearance (CLint,i) were small. Diazepam showed large degrees of both influx and efflux and, thus, a large Vi. Water showed parameters intermediate between those of antipyrine and those of diazepam. Imipramine, desipramine, and propranolol showed a large CLint,i compared with those of the other drugs. The extraction ratio of propranolol significantly decreased with increasing concentrations of unlabeled propranolol in the perfusion fluid. These findings may be explained partly by the tissue binding of these drugs. In conclusion, the present method is useful for studying drug disposition in the brain.

  4. Assessment of drug disposition in the perfused rat brain by statistical moment analysis

    International Nuclear Information System (INIS)

    Sakane, T.; Nakatsu, M.; Yamamoto, A.; Hashida, M.; Sezaki, H.; Yamashita, S.; Nadai, T.

    1991-01-01

    Drug disposition in the brain was investigated by statistical moment analysis using an improved in situ brain perfusion technique. The right cerebral hemisphere of the rat was perfused in situ. The drug and inulin were injected into the right internal carotid artery as a rapid bolus and the venous outflow curve at the posterior facial vein was obtained. The infusion rate was adjusted to minimize the flow of perfusion fluid into the left hemisphere. The obtained disposition parameters were characteristics and considered to reflect the physicochemical properties of each drug. Antipyrine showed a small degree of initial uptake. Therefore, its apparent distribution volume (Vi) and apparent intrinsic clearance (CLint,i) were small. Diazepam showed large degrees of both influx and efflux and, thus, a large Vi. Water showed parameters intermediate between those of antipyrine and those of diazepam. Imipramine, desipramine, and propranolol showed a large CLint,i compared with those of the other drugs. The extraction ratio of propranolol significantly decreased with increasing concentrations of unlabeled propranolol in the perfusion fluid. These findings may be explained partly by the tissue binding of these drugs. In conclusion, the present method is useful for studying drug disposition in the brain

  5. A qualitative assessment of the challenges of WHO prequalification for anti-malarial drugs in China.

    Science.gov (United States)

    Huang, Yangmu; Pan, Ke; Peng, Danlu; Stergachis, Andy

    2018-04-03

    While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China.

  6. Assessment of Pseudomonas aeruginosa N5,N10-methylenetetrahydrofolate dehydrogenase-cyclohydrolase as a potential antibacterial drug target.

    Directory of Open Access Journals (Sweden)

    Thomas C Eadsforth

    Full Text Available The bifunctional enzyme methylenetetrahydrofolate dehydrogenase - cyclohydrolase (FolD is identified as a potential drug target in Gram-negative bacteria, in particular the troublesome Pseudomonas aeruginosa. In order to provide a comprehensive and realistic assessment of the potential of this target for drug discovery we generated a highly efficient recombinant protein production system and purification protocol, characterized the enzyme, carried out screening of two commercial compound libraries by differential scanning fluorimetry, developed a high-throughput enzyme assay and prosecuted a screening campaign against almost 80,000 compounds. The crystal structure of P. aeruginosa FolD was determined at 2.2 Å resolution and provided a template for an assessment of druggability and for modelling of ligand complexes as well as for comparisons with the human enzyme. New FolD inhibitors were identified and characterized but the weak levels of enzyme inhibition suggest that these compounds are not optimal starting points for future development. Furthermore, the close similarity of the bacterial and human enzyme structures suggest that selective inhibition might be difficult to attain. In conclusion, although the preliminary biological data indicates that FolD represents a valuable target for the development of new antibacterial drugs, indeed spurred us to investigate it, our screening results and structural data suggest that this would be a difficult enzyme to target with respect to developing the appropriate lead molecules required to underpin a serious drug discovery effort.

  7. Assessing the potential impact of artemisinin and partner drug resistance in sub-Saharan Africa.

    Science.gov (United States)

    Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Okell, Lucy C

    2016-01-06

    Artemisinin and partner drug resistant malaria parasites have emerged in Southeast Asia. If resistance were to emerge in Africa it could have a devastating impact on malaria-related morbidity and mortality. This study estimates the potential impact of artemisinin and partner drug resistance on disease burden in Africa if it were to emerge. Using data from Asia and Africa, five possible artemisinin and partner drug resistance scenarios are characterized. An individual-based malaria transmission model is used to estimate the impact of each resistance scenario on clinical incidence and parasite prevalence across Africa. Artemisinin resistance is characterized by slow parasite clearance and partner drug resistance is associated with late clinical failure or late parasitological failure. Scenarios with high levels of recrudescent infections resulted in far greater increases in clinical incidence compared to scenarios with high levels of slow parasite clearance. Across Africa, it is estimated that artemisinin and partner drug resistance at levels similar to those observed in Oddar Meanchey province in Cambodia could result in an additional 78 million cases over a 5 year period, a 7% increase in cases compared to a scenario with no resistance. A scenario with high levels of slow clearance but no recrudescence resulted in an additional 10 million additional cases over the same period. Artemisinin resistance is potentially a more pressing concern than partner drug resistance due to the lack of viable alternatives. However, it is predicted that a failing partner drug will result in greater increases in malaria cases and morbidity than would be observed from artemisinin resistance only.

  8. Antioxidant and Antiangiogenic Properties, and Gas Chromatographic-Time of Flight Analysis of Sonchus arvensis Leaves Extracts

    International Nuclear Information System (INIS)

    Itam, A.; Shah, A. M.; Majid, A.; Ismail, Z.

    2015-01-01

    Sonchus arvensis L. (Asteraceae) is one of the medicinal herbs used in traditional medicines, in which the leaf extract was used as a diuretic, lithotriptic and antiurolithiasis agent. The leaves of S. arvensis reported contain several compounds, including a variety of flavonoids, terpenoids and sterol, even this plant also contain silica and potassium. Flavonoids are secondary metabolite compound which have ability as antioxidant. In this study, the aims are to determine of antioxidants and antiangiogenic properties, and phytoconstituents quantitative of aqueous and methanol extracts of S. arvensis leaves. The antioxidant properties were studied using 1,1-Diphenyl-2-picrylhydrazyl (DPPH) free radical, xanthine oxidase and beta-carotene-linoleate models system. Furthermore, the antiangiogenic property was evaluated using ex vivo rat aorta ring assay. Quantitative determination of extracts phytoconstituents were carried out by using Gas Chromatographic-Time of Flight (GC-TOF) mass spectrophotometric methods. The results showed that the aqueous and methanol extracts have ability as antioxidant which is antioxidant activities of aqueous extracts on DPPH radical and inhibition of xanthine oxidase activity are higher than that of methanol extracts. Meanwhile antioxidant activity using beta-carotene-linoleate model system of S. arvensis aqueous extract is lower than that of methanol extracts. Nevertheless, the differences of these antioxidant activities are not significant. Antiangiogenic property of aqueous extract is also higher than that of methanol extract which is measured at 100 meu g mL/sup -1/ of extracts. This indicates that there is correlation between antioxidant activity and antiangigenic property, exhibiting that this plant possesses the potential to prevent or cure the diseases that related to angiogenesis such as cancer. (author)

  9. Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its antiproliferative and antiangiogenic activity in vitro

    Science.gov (United States)

    Dasgupta, P; Mukherjee, R

    2000-01-01

    The therapeutic potential of the somatostatin analogue RC-160 having antiproliferative activity, is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid were conjugated to the N-terminal residue of RC-160. The lipophilized derivatives of RC-160 were synthesized, purified by reverse phase HPLC and characterized by ES-mass spectroscopy. The antiproliferative activity of lipophilized derivatives of RC-160 on the growth of MIA-PaCa2 (human pancreatic carcinoma), DU145 (human prostate carcinoma), ECV304 (human umbilical chord endothelioma), as well as their antiangiogenic activity was evaluated in vitro. The relative stability of myristoyl-RC-160 towards degradation by proteases and serum was also determined. Myristoyl-RC-160 exhibited significantly higher antiproliferative efficacy than RC-160, on the above cell lines (P<0.01). Receptor binding assays, demonstrated that the affinity of RC-160 towards somatostatin receptors remains unaltered by myristoylation. Unlike RC-160, the myristoylated derivative was found to have significantly greater resistance to protease and serum degradation (P<0.01). Myristoyl-RC-160 exhibited significantly greater antiproliferative activity on ECV304, than RC-160 (P<0.01). Myristoyl RC-160 could also inhibit capillary tube formation more efficiently than RC-160 in a dose dependent manner, suggesting that it possessed enhanced antiangiogenic activity in vitro (P<0.001). Lipophilization of RC-160 with long chain fatty acids like myristic acid endows it with improved antiproliferative and antiangiogenic activity, stability and therapeutic index. PMID:10694208

  10. Apigenin-induced nitric oxide production involves calcium-activated potassium channels and is responsible for antiangiogenic effects.

    Science.gov (United States)

    Erdogan, A; Most, A K; Wienecke, B; Fehsecke, A; Leckband, C; Voss, R; Grebe, M T; Tillmanns, H; Schaefer, C A; Kuhlmann, C R W

    2007-08-01

    The dietary flavonoid apigenin (Api) has been demonstrated to exert multiple beneficial effects upon the vascular endothelium. The aim of this study was to examine whether Ca(2+)-activated K(+) channels (K(Ca)) are involved in endothelial nitric oxide (NO) production and antiangiogenic effects. Endothelial NO generation was monitored using a cyclic guanosine monophosphate radioimmunoassay. K(Ca) activity and changes of the intracellular Ca(2+) concentration [Ca(2+)](i) were analyzed using the fluorescent dyes bis-barbituric acid oxonol, potassium-binding benzofuran isophthalate, and fluo-3. The endothelial angiogenic parameters measured were cell proliferation, [(3)H]-thymidine incorporation, and cell migration (scratch assay). Akt phosphorylation was examined using immunohistochemistry. Api caused a concentration-dependent increase in cyclic guanosine monophosphate levels, with a maximum effect at a concentration of 1 mum. Api-induced hyperpolarization was blocked by the small and large conductance K(Ca) inhibitors apamin and iberiotoxin, respectively. Furthermore, apamin and iberiotoxin blocked the late, long-lasting plateau phase of the Api-induced biphasic increase of [Ca(2+)](i). Inhibition of Ca(2+) signaling and the K(Ca) blockade both blocked NO production. Prevention of all three (NO, Ca(2+), and K(Ca) signaling) reversed the antiangiogenic effects of Api under both basal and basic fibroblast growth factor-induced culture conditions. Basic fibroblast growth factor-induced Akt phosphorylation was also reduced by Api. Based on our experimental results we propose the following signaling cascade for the effects of Api on endothelial cell signaling. Api activates small and large conductance K(Ca), leading to a hyperpolarization that is followed by a Ca(2+) influx. The increase of [Ca(2+)](i) is responsible for an increased NO production that mediates the antiangiogenic effects of Api via Akt dephosphorylation.

  11. Assessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development

    Directory of Open Access Journals (Sweden)

    Zaloumis Sophie

    2012-08-01

    Full Text Available Abstract Background Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD model for predicting within-host parasite response was performed. Methods Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50, derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. Results The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle. The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i

  12. Novel peptide-specific quantitative structure-activity relationship (QSAR) analysis applied to collagen IV peptides with antiangiogenic activity.

    Science.gov (United States)

    Rivera, Corban G; Rosca, Elena V; Pandey, Niranjan B; Koskimaki, Jacob E; Bader, Joel S; Popel, Aleksander S

    2011-10-13

    Angiogenesis is the growth of new blood vessels from existing vasculature. Excessive vascularization is associated with a number of diseases including cancer. Antiangiogenic therapies have the potential to stunt cancer progression. Peptides derived from type IV collagen are potent inhibitors of angiogenesis. We wanted to gain a better understanding of collagen IV structure-activity relationships using a ligand-based approach. We developed novel peptide-specific QSAR models to study the activity of the peptides in endothelial cell proliferation, migration, and adhesion inhibition assays. We found that the models produced quantitatively accurate predictions of activity and provided insight into collagen IV derived peptide structure-activity relationships.

  13. The use of toxicokinetics for the safety assessment of drugs acting in the brain.

    Science.gov (United States)

    Campbell, D B

    1995-01-01

    Pharmacological and toxicological studies undertaken on drugs that affect the brain are frequently performed in disparate species under various experimental conditions, at doses often greatly in excess of those expected to be administered to humans, and the findings are extrapolated implicitly or explicitly with scant regard to differences in the biodisposition of the drugs. Such considerations are necessary since: 1. Species; 2. Strain; 3. Gender; 4. Route; 5. Dose; 6. Frequency and time of administration; 7. Temperature; 8. Coadministration of drugs; and 9. Surgical manipulation are but some of the factors that have been shown to influence the kinetics and metabolism of drugs. This article, using MDMA and other phenylethylamines as examples, provides evidence for the need to measure the exposure of the drugs and their active metabolites in blood and brain (toxicokinetics) in order that conclusions based only on dynamic, biochemical, or histological evidence are more pertinent. Further, the combined use of toxicokinetic-dynamic modeling can lead to a better appreciation of the mechanisms involved and a more useful approach to the calculation of safety margins.

  14. Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

    DEFF Research Database (Denmark)

    Saftoiu, Adrian; Vilmann, Peter; Săftoiu, Adrian

    2011-01-01

    evaluation, but also on sensitive monitoring of microvascular changes during treatment. State-of-the-art imaging techniques have the potential to visualize and characterize angiogenesis, although the technology and methodologies employed are recent and need further validation. The aim of this series......Angiogenesis has a critical role in primary tumor growth and the development of metastases. Several angiogenesis inhibitors were recently developed, being a very attractive target for digestive tumor therapy. However, individualized therapy should not only be based on the pre-treatment imaging...... of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers, used for the longitudinal monitoring of the effects of chemo-radiotherapy (including anti-angiogenic therapies), as well as for the precise targeting of drugs...

  15. EO-199, a specific antagonist of antiarrhythmic drugs: Assessment by binding experiments and in vivo studies

    Energy Technology Data Exchange (ETDEWEB)

    Oppenheimer, E.; Harel, G.; Lipinsky, D.; Sarne, Y. (Tel-Aviv Univ. (Israel))

    1991-01-01

    EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class I{sub A}). EO-199 did not block significantly the activity of a class I{sub B} antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of ({sup 3}H)EO-122 to rate heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (I{sub A}) but not lidocaine (I{sub B}), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

  16. [Assessment of legal awareness regarding illicit drug use among Kraków university students].

    Science.gov (United States)

    Morawska, Jowanka; Krawczyk, Elzbieta; Satora, Leszek

    2005-01-01

    Social survey is a very important source of information concerned with planing the preventive strategy and protecting against problems relevant to the use of psychoactive substances. The survey covered a group of 211 first-year students from five colleges in Kraków. The students showed weak awareness of law. The respondents are of the opinion that the rules dealing with the addiction issue have been too liberal thus far. The emphasis should be put on enforcing the anti-drug law. Otherwise it will not became a powerful weapon to counteract the drug addiction. According to the opinion of respondents the trade and delivery of drugs are highly disapproving and they require inflicting stringent punishments. The results of our analysis are the integral part of Kraków model to help addicted to psychoactive substances and of prevention activities referred to the students of colleges.

  17. Exploiting Surface Plasmon Resonance (SPR Technology for the Identification of Fibroblast Growth Factor-2 (FGF2 Antagonists Endowed with Antiangiogenic Activity

    Directory of Open Access Journals (Sweden)

    Marco Presta

    2009-08-01

    Full Text Available Angiogenesis, the process of new blood vessel formation, is implicated in various physiological/pathological conditions, including embryonic development, inflammation and tumor growth. Fibroblast growth factor-2 (FGF2 is a heparin-binding angiogenic growth factor involved in various physiopathological processes, including tumor neovascularization. Accordingly, FGF2 is considered a target for antiangiogenic therapies. Thus, numerous natural/synthetic compounds have been tested for their capacity to bind and sequester FGF2 in the extracellular environment preventing its interaction with cellular receptors. We have exploited surface plasmon resonance (SPR technique in search for antiangiogenic FGF2 binders/antagonists. In this review we will summarize our experience in SPR-based angiogenesis research, with the aim to validate SPR as a first line screening for the identification of antiangiogenic compounds.

  18. Irradiation-induced angiosarcoma and anti-angiogenic therapy: A therapeutic hope?

    Energy Technology Data Exchange (ETDEWEB)

    Azzariti, Amalia, E-mail: a.azzariti@oncologico.bari.it [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Porcelli, Letizia [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Mangia, Anita; Saponaro, Concetta [Functional Biomorphology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Quatrale, Anna E. [Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Popescu, Ondina S. [Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Strippoli, Sabino [Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Simone, Gianni [Department of Pathology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Paradiso, Angelo [Experimental Medical Oncology, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy); Guida, Michele [Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Viale O. Flacco, 65, 70124 Bari (Italy)

    2014-02-15

    Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF–VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach

  19. Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions.

    Science.gov (United States)

    Pereira-Leite, Catarina; Nunes, Cláudia; Reis, Salette

    2013-10-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs-induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.

    Science.gov (United States)

    Matsuda, Yoshiki; Konno, Yoshihiro; Hashimoto, Takashi; Nagai, Mika; Taguchi, Takayuki; Satsukawa, Masahiro; Yamashita, Shinji

    2013-08-01

    The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

  1. Assessment of the Drug Interaction Potential of Unconjugated and GalNAc3-Conjugated 2'-MOE-ASOs.

    Science.gov (United States)

    Shemesh, Colby S; Yu, Rosie Z; Warren, Mark S; Liu, Michael; Jahic, Mirza; Nichols, Brandon; Post, Noah; Lin, Song; Norris, Daniel A; Hurh, Eunju; Huang, Jane; Watanabe, Tanya; Henry, Scott P; Wang, Yanfeng

    2017-12-15

    Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE-ASOs), including a single triantennary N-acetyl galactosamine (GalNAc 3 )-conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE-ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored. The inhibition on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 and induction on CYP1A2, CYP2B6, and CYP3A4 were investigated in cryopreserved hepatocytes using up to 100 μM of each ASO. No significant inhibition (half maximal inhibitory concentration [IC 50 ] > 100 μM) or induction was observed based on either enzymatic phenotype or mRNA levels. In addition, transporter interaction studies were conducted with nine major transporters per recommendations from regulatory guidances and included three hepatic uptake transporters, organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3; three renal uptake transporters, organic anion transporter 1 (OAT1), OAT3, and OCT2; and three efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP). None of the four ASOs (10 μM) were substrates of any of the nine transporters, with uptake drug molecules via any major CYP enzyme or drug transporters at clinically relevant exposures. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  2. Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone).

    Science.gov (United States)

    Chen, Xin; Fadda, Hala M; Aburub, Aktham; Mishra, Dinesh; Pinal, Rodolfo

    2015-10-15

    The log-linear cosolvency model was applied for estimating the solubility of four drugs: ritonavir, griseofulvin, itraconazole and ketoconazole in poly(vinylpyrrolidone) (PVP). Cosolvent mixtures consisted of PVP mixed in different proportions with N-ethylpyrrolidone, which served as the monomeric analogue of the repeating unit of the polymer. Solubility in the monomer-polymer mixtures was determined by HPLC. As the configuration of the solvating unit in the solvent mixture changed from entirely monomeric to increasingly polymeric, the solubility of the drugs decreased in a fashion that follows the log-linear cosolvency model. The linear relationship was used to obtain estimates for the solubility of the drugs in the different grades of PVP. The solubility of the drugs in PVP is low (from solubility in PVP (w/w). Mixing with the monomer is most favorable for griseofulvin among the four drugs. However, the detrimental effect of polymerization on its solubility is more pronounced than for ritonavir. The mixing of itraconazole with the monomer is more favorable than the mixing of ketoconazole. However, despite the molecular similarity between ketaconazole and itraconazole, the solubility of the latter is particularly affected by the polymeric configuration of the solvating unit, to the point of exhibiting differences in solubility resulting from the chain length of the grade of PVP used. The log-linear cosolvency model is a useful tool for estimating the solubility of the drugs in the polymer at room temperature, while providing quantitative information on the differences in mixing behavior of the four model compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Assessment of anti-arrhythmic activity of antipsychotic drugs in an animal model

    DEFF Research Database (Denmark)

    Mow, Tomas; Frederiksen, Kristen; Thomsen, Morten B.

    2015-01-01

    limited experimental information exists about the effects of α1-adrenergic receptor activity of antipsychotic drugs in pro-arrhythmic models, we have decided to investigate this. In this study we show that four antipsychotic drugs all have high affinity for α1-adrenergic receptor (sertindole>risperidone>haloperidol>olanzapine......) and all block IKr (sertindole>haloperidol>risperidone>olanzapine). In canine Purkinje fibres, α1-adrenergic stimulation prolonged action potential duration; however, the stimulation does not cause afterdepolarizations, even in the presence of dofetilide-induced delayed repolarization. We showed...

  4. Comparison of Individual and Pooled Stool Samples for the Assessment of Soil-Transmitted Helminth Infection Intensity and Drug Efficacy

    Science.gov (United States)

    Mekonnen, Zeleke; Meka, Selima; Ayana, Mio; Bogers, Johannes; Vercruysse, Jozef; Levecke, Bruno

    2013-01-01

    Background In veterinary parasitology samples are often pooled for a rapid assessment of infection intensity and drug efficacy. Currently, studies evaluating this strategy in large-scale drug administration programs to control human soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm), are absent. Therefore, we developed and evaluated a pooling strategy to assess intensity of STH infections and drug efficacy. Methods/Principal Findings Stool samples from 840 children attending 14 primary schools in Jimma, Ethiopia were pooled (pool sizes of 10, 20, and 60) to evaluate the infection intensity of STHs. In addition, the efficacy of a single dose of mebendazole (500 mg) in terms of fecal egg count reduction (FECR; synonym of egg reduction rate) was evaluated in 600 children from two of these schools. Individual and pooled samples were examined with the McMaster egg counting method. For each of the three STHs, we found a significant positive correlation between mean fecal egg counts (FECs) of individual stool samples and FEC of pooled stool samples, ranging from 0.62 to 0.98. Only for A. lumbricoides was any significant difference in mean FEC of the individual and pooled samples found. For this STH species, pools of 60 samples resulted in significantly higher FECs. FECR for the different number of samples pooled was comparable in all pool sizes, except for hookworm. For this parasite, pools of 10 and 60 samples provided significantly higher FECR results. Conclusion/Significance This study highlights that pooling stool samples holds promise as a strategy for rapidly assessing infection intensity and efficacy of administered drugs in programs to control human STHs. However, further research is required to determine when and how pooling of stool samples can be cost-effectively applied along a control program, and to verify whether this approach is also applicable to other NTDs. PMID:23696905

  5. Assessment of Quality of Sleep and Use of Drugs with Sedating Properties in Adult Patients Hospitalized in Hamadan Ekbatan Hospital

    Directory of Open Access Journals (Sweden)

    F. Zeraati

    2010-01-01

    Full Text Available Introduction & Objective: Hospitalization can significantly disrupt sleeping patterns. considering the prevalence of insomnia and widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted this study to assess the quality of sleep and hypnotic drug use in hospitalized adult patients in 2007.Materials & Methods: This descriptive analytical cross-sectional study involved an assessment of sleep quality for patients whose consent had been obtained when admitted to the internal ward of Hamadan Ekbatan hospital. The Pittsburg sleep quality index (PSQI was used to measure the quality of sleep in patients and completed at the time of admission and discharge. Also the relation of factors such as age, sex. Marital status, education and sedating drug use prior to and during hospitalization with sleep quality were assessed. 300 patients entered this study and completed PSQI sleep questionnaires two twice, at the time of admission & discharge. Results: At the time of admission only 36% of patients had good sleep quality (PSQI score <5 while this percent decreased to 18.3% at the time of discharge. Mean global PSQI score was 7.6 at the time of admission versus 9.4 at the time of discharge indicating the patients’ worse sleep quality at the time of discharge (Pv<0.05. 23% of patients received hypnotic drugs while in the hospital with no evidence of preadmission hypnotic use. Benzodiazepines were prescribed for all of them.Conclusion: Quality of sleep at the time of discharge was significantly worse than it at the time of admission and it seems that despite widespread use of sedative drug in the hospital , there are still patients with poor sleep quality in the hospital.

  6. Assessment Of Pattern Of Non-steroidal Anti-Inflammatory Drugs ...

    African Journals Online (AJOL)

    Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of pains. Self-medication is a common practice all over the world. Unwanted effects from use of this class of medication could pose health challenges. This study evaluated the prevalence and pattern of inappropriate use of NSAIDs among ...

  7. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

    NARCIS (Netherlands)

    Mesens, N.; Crawfordb, A.D.; Menke, A.; Hung, P.D.; Goethem, F. van; Nuyts, R.; Hansen, E.; Wolterbeek, A.; Gompel, J. van; Witte, P. de; Esguerra, C.V.

    2015-01-01

    Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for

  8. Niche markets and evidence assessment in transition: a critical review of proposed drug reforms.

    Science.gov (United States)

    Gibson, Shannon G; Lemmens, Trudo

    2014-01-01

    In response to rising demands and treatment costs, and the need to achieve better value for money in the face of tight fiscal constraints, both the National Health Service and the public drug reimbursement system are undergoing important reforms. Concurrently, the pharmaceutical sector itself is also alleged to be experiencing significant changes, perhaps most notably, a decline of the blockbuster model of drug development and a growing focus on niche market products. As pharmaceutical development strategies evolve and the resulting drug products become more complex, regulatory and policy responses must be able to evolve along with them. We explore how in numerous jurisdictions, including the UK, proposals for 'adaptive licensing' on the regulatory side and 'performance-based risk sharing agreements' on the funding side are shifting the focus of drug regulation and reimbursement towards more incremental access to new therapies and more post-market evidence generation. However, serious questions remain about how such reforms can be successfully implemented and whether they can balance demands for earlier access to promising new therapies with the need for robust evidence on safety, efficacy, and cost-effectiveness. © The Author 2014. Published by Oxford University Press; all rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. In silico Assessment of Drug-like Properties of Alkaloids from Areca ...

    African Journals Online (AJOL)

    Purpose: To investigate in silico the drug-like properties of alkaloids (arecoline, arecaidine, guvacine, guvacoline, isoguvacine, arecolidine and homoarecoline) obtained from the fruits of Areca catechu L (areca nut). Methods: All chemical structures were re-drawn using Chemdraw Ultra 11.0. Furthermore, software including ...

  10. The in vitro Assessment of Drug Resistant Malaria In Makurdi, North ...

    African Journals Online (AJOL)

    antimalarial drugs, against Plasmodium falciparum isolates in Makurdi, North Central Nigeria. The standard schizonts growth inhibition assays was used to study the in vitro activities of quinine, artesunate, and amodiaquine against 146 isolates in children aged 2-14 years. 100 % of isolates were in vitro sensitive to quinine, ...

  11. Transmission assessment surveys (TAS) to define endpoints for lymphatic filariasis mass drug administration

    DEFF Research Database (Denmark)

    Chu, Brian K.; Deming, Michael; Biritwum, Nana-Kwadwo

    2013-01-01

    Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached...

  12. Bioavailability assessment of hydroxymethylglutaryl coenzyme A reductase inhibitor utilizing pulsatile drug delivery system: a pilot study.

    Science.gov (United States)

    Taha, Ehab I

    2016-09-01

    Chronotherapy or pulsatile drug delivery system could be achieved by increasing drug plasma concentration exactly at the time of disease incidence. Cholesterol synthesis shows a circadian rhythm being high at late night and early in the morning. Simvastatin (SIM) inhibits hydroxymethylglutaryl coenzyme A reductase, which is responsible for cholesterol synthesis. In this study, SIM lipid-based formulation filled in gelatin capsules and coated with aqueous Eudragit® S100 dispersion was prepared for chronotherapeutic treatment of hypercholesterolemia. The pharmacokinetic parameters of SIM capsules were studied in human volunteers after a single oral dose and compared with that of Zocor® tablets as a reference in a randomized cross-over study. Pharmacokinetic parameters such as AUC 0-∞ , C max , T max , t 1/2 and elimination rate constant were determined from plasma concentration-time profile for both formulations. The tested formulation had the ability to delay drug absorption and provide higher drug concentrations from 3 up to 10 h after oral administration compared to that of commercial tablets. The data in this study revealed that the prepared formulation could be effective in chronotherapeutic treatment of hypercholesterolemia. Moreover, the tested formulation was found to enhance SIM bioavailability by 29% over the reference tablets.

  13. Integrated cardiac safety: assessment methodologies for noncardiac drugs in discovery, development, and postmarketing surveillance

    National Research Council Canada - National Science Library

    Turner, J. Rick; Durham, Todd A

    2009-01-01

    ... PROTEOMICS AND TRANSCRIPTOMICS 2.8 GENE EXPRESSION 2.9 PROTEINS 2.10 CELLS 2.11 CELL MEMBRANES 2.12 PROTEINS IN CELL MEMBRANES 2.13 ION CHANNELS 2.14 RECEPTORS ADVERSE DRUG REACTIONS MELANOGASTER 25 ...

  14. Assessment of laser-induced release of drugs from liposomes: An in vitro study

    International Nuclear Information System (INIS)

    Khoobehi, B.; Char, C.A.; Peyman, G.A.

    1990-01-01

    We evaluated the characteristics of laser-induced release of an antimetabolite (cytosine arabinoside) from temperature-sensitive liposomes. Previous work had shown that a laser would induce breakdown of liposomes when a dye was encapsulated within the liposomes. The present investigation was performed to determine if release could be induced from liposomes that did not contain dye. In vitro, dynamic studies of the release of the drug from liposomes diluted in blood (flowing in a capillary tube at 40 microns/min) were conducted using an argon dye laser operating either in the blue-green mode (488/514 nm) or in the dye mode (577 nm). A radio-labeled marker was used to monitor the drug release. The results showed that the drug could indeed be released from liposomes that did not contain dye, at energy levels that are not likely to be harmful to the tissue. At identical power levels, the release of the drug was greater at 577 nm than at 488/514 nm, probably owing to the greater light absorbance of hemoglobin at the longer wavelength. The results indicate the potential for the site-specific release of a variety of molecules in the ocular vasculature

  15. Comparative assessment of saliva and plasma for drug bioavailability and bioequivalence studies in humans

    Directory of Open Access Journals (Sweden)

    Nasir M. Idkaidek

    2017-07-01

    Conclusion: Our results suggest that there is a potential in BA/BE studies for saliva to be considered as a surrogate for plasma concentration, which goes along with drug regulations. The use of saliva instead of plasma in such studies makes them non-invasive, easy and with a lower clinical burden.

  16. Assessment of drug treatment quality in two Danish health-care centres

    DEFF Research Database (Denmark)

    Andersen, Stig Ejdrup; Edfors, Kajsa

    2011-01-01

    Bridging the primary and secondary sector, health-care centres aim to reduce morbidity and prevent further hospitalization in patients with chronic heart diseases. The aim of this study was to describe the quality of drug treatment in patients with chronic heart diseases in two Copenhagen health-care...

  17. Assessment of veterinary drug retail outlets in two rural areas of ...

    African Journals Online (AJOL)

    Veterinary retail shops have emerged as important players in the provision of animal health services. However, diseases such as helminthiasis continue to occur with a high proportion in Nigerian livestock, despite the availability of veterinary drug retail outlets. A cross sectional survey was carried out in Tsaragi and Lafiagi ...

  18. 78 FR 36787 - Rechanneling the Current Cardiac Risk Paradigm: Arrhythmia Risk Assessment During Drug...

    Science.gov (United States)

    2013-06-19

    ... method as an alternative to clinical Thorough QT studies. The workshop, which will seek input from all... workshop. SUMMARY: The Food and Drug Administration (FDA), the Cardiac Safety Research Consortium, and the... parameters for an appropriate, strong, nonclinical proarrthymia screening method as an alternative to...

  19. Development and oral bioavailability assessment of a supersaturated self-microemulsifying drug delivery system (SMEDDS) of albendazole.

    Science.gov (United States)

    Mukherjee, Tusharmouli; Plakogiannis, Fotios M

    2010-09-01

    Albendazole's (ABZ) poor aqueous solubility is a major determinant of its variable therapeutic response (20-50%). The purpose of this study was to develop and optimize the composition of a self-microemulsifying drug delivery system (SMEDDS) of ABZ and assess its oral pharmacokinetics in rabbits. A D-optimal mixture design of experiments was used to select the levels of constraints of the formulation variables. The predicted composition was optimized using four responses: dispersion performance, droplet sizes, dissolution efficiency (DE) and time for 85% drug release (t(85%)). The optimal composition of the ABZ-SMEDDS formulation, with approximately 5 mg/g drug loading of ABZ, was predicted to be Cremophor EL (30% w/w), Tween 80 (15% w/w), Capmul PG-8 (10% w/w) and acidified PEG 400 (45% w/w). An increase of 63% in the relative bioavailability compared with the commercial suspension was obtained with ABZ-SMEDDS as measured by albendazole sulfoxide (ABZSO) plasma levels. The area under the curve (AUC(0-->24h)) and the peak plasma concentration (C(max)) of ABZ-SMEDDS was higher than those obtained with the commercial suspension by 56% and 52%, respectively. This study demonstrates a strategy for the development of a supersaturated SMEDDS formulation of a drug with low aqueous solubility.

  20. Rapid Assessment Response (RAR) study: drug use, health and systemic risks--Emthonjeni Correctional Centre, Pretoria, South Africa.

    Science.gov (United States)

    Dos Santos, Monika M L; Trautmann, Franz; Wolvaardt, Gustaaf; Palakatsela, Romeo

    2014-04-03

    Correctional centre populations are one of the populations most at risk of contracting HIV infection for many reasons, such as unprotected sex, violence, rape and tattooing with contaminated equipment. Specific data on drug users in correctional centres is not available for the majority of countries, including South Africa. The study aimed to identify the attitudes and knowledge of key informant (KI) offender and correctional centre staff regarding drug use, health and systemic-related problems so as to facilitate the long-term planning of activities in the field of drug-use prevention and systems strengthening in correctional centres, including suggestions for the development of appropriate intervention and rehabilitation programmes. A Rapid Assessment Response (RAR) methodology was adopted which included observation, mapping of service providers (SP), KI interviews (staff and offenders) and focus groups (FGs). The study was implemented in Emthonjeni Youth Correctional Centre, Pretoria, South Africa. Fifteen KI staff participants were interviewed and 45 KI offenders. Drug use is fairly prevalent in the centre, with tobacco most commonly smoked, followed by cannabis and heroin. The banning of tobacco has also led to black-market features such as transactional sex, violence, gangsterism and smuggling in order to obtain mainly prohibited tobacco products, as well as illicit substances. HIV, health and systemic-related risk reduction within the Correctional Service sector needs to focus on measures such as improvement of staff capacity and security measures, deregulation of tobacco products and the development and implementation of comprehensive health promotion programmes.

  1. Drug Repositioning for Preeclampsia Therapeutics by In Vitro Screening: Phosphodiesterase-5 Inhibitor Vardenafil Restores Endothelial Dysfunction via Induction of Placental Growth Factor.

    Science.gov (United States)

    Kakigano, Aiko; Tomimatsu, Takuji; Mimura, Kazuya; Kanayama, Tomoko; Fujita, Satoko; Minato, Kenji; Kumasawa, Keiichi; Taniguchi, Yukiko; Kanagawa, Takeshi; Endo, Masayuki; Ishihara, Tomoaki; Namba, Takushi; Mizushima, Tohru; Kimura, Tadashi

    2015-10-01

    We screened a library of 528 approved drugs to identify candidate compounds with therapeutic potential as preeclampsia treatments via their proangiogenic properties. Using human umbilical vein endothelial cells (HUVECs), we assessed whether the screened drugs induced placental growth factor (PIGF) and restored damaged endothelial cell function. Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure levels of PlGF in conditioned media treated with each drug (100 µmol/L) in the drug library. Tube formation assays were performed using HUVECs to evaluate the angiogenic effects of drugs that induced PlGF. We also performed ELISA, quantitative reverse transcription polymerase chain reaction, and tube formation assays after treatment with a range of concentrations of the candidate drug. Of the drugs that induced PlGF, vardenafil was the only compound that significantly facilitated tube formation in comparison with the control cells (P Treatment with vardenafil at concentrations of 50, 100, and 250 µmol/L increased expression of PlGF in a dose-dependent manner. Vardenafil (250 µmol/L) significantly improved tube formation which was inhibited in the presence of soluble fms-like tyrosine kinase 1 (100 ng/mL) and/or soluble endoglin (100 ng/mL). Production of PlGF from HUVECs in the presence of sera derived from patients with preeclampsia was significantly elevated by administration of vardenafil (250 µmol/L). By assessing drug repositioning through screening a library of approved drugs, we identified vardenafil as a potential protective agent against preeclampsia. The therapeutic mechanism of vardenafil may involve inhibition of the systemic maternal antiangiogenic state that leads to preeclampsia, in addition to its vasodilating effect. As concentrations used are high and unlikely to be useful clinically, further work is needed before testing it in humans. © The Author(s) 2015.

  2. A cross-sectional national survey assessing self-reported drug intake behavior, contact with the primary sector and drug treatment among service users of Danish drug consumption rooms

    DEFF Research Database (Denmark)

    Toth, Eva Charlotte; Tegner, Jette; Lauridsen, Sigurd

    2016-01-01

    non-EU citizens. As drug intake method, 63 % injected drugs in a vein, 7 % sniffed, and 37 % smoked. Of drugs used in the DCR, 49 % used cocaine, 41 % heroin, 16 % a mix of heroin and cocaine, and 16 % used methadone. Participants who smoked drugs made significantly less use of drug rehabilitation...

  3. Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations

    Directory of Open Access Journals (Sweden)

    Ludovica Ciuffreda

    2009-08-01

    Full Text Available The Raf/MEK/ERK pathway is an importantmediator of tumor cell proliferation and angiogenesis. Here, weinvestigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC50 in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G1-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27KIP1 and apoptosis (Bcl-2 and survivin regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.

  4. Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF

    International Nuclear Information System (INIS)

    Belakavadi, Madesh; Prabhakar, B.T.; Salimath, Bharathi P.

    2005-01-01

    Butyrate, a short-chain fatty acid produced in the colon, induces cell cycle arrest, differentiation, and apoptosis in transformed cell lines. In this report, we study the effects of butyrate (BuA) on the growth of Ehrlich ascites tumor (EAT) cells in vivo. BuA, when injected intraperitoneally (i.p) into mice, inhibited proliferation of EAT cells. Further, induction of apoptosis in EAT cells was monitored by nuclear condensation, annexin-V staining, DNA fragmentation, and translocation of caspase-activated DNase into nucleus upon BuA-treatment. Ac-DEVD-CHO, a caspase-3 inhibitor, completely inhibited BuA-induced apoptosis, indicating that activation of caspase-3 mediates the apoptotic pathway in EAT cells. The proapoptotic effect of BuA also reflects on the antiangiogenic pathway in EAT cells. The antiangiogenic effect of BuA in vivo was demonstrated by the downregulation of the secretion of VEGF in EAT cells. CD31 immunohistochemical staining of peritoneum sections clearly indicated a potential angioinhibitory effect of BuA in EAT cells. These results suggest that BuA, besides regulating other fundamental cellular processes, is able to modulate the expression/secretion of the key angiogenic growth factor VEGF in EAT cells

  5. Ferulic Acid Exerts Anti-Angiogenic and Anti-Tumor Activity by Targeting Fibroblast Growth Factor Receptor 1-Mediated Angiogenesis.

    Science.gov (United States)

    Yang, Guang-Wei; Jiang, Jin-Song; Lu, Wei-Qin

    2015-10-12

    Most anti-angiogenic therapies currently being evaluated target the vascular endothelial growth factor (VEGF) pathway; however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here, we identified ferulic acid as a novel fibroblast growth factor receptor 1 (FGFR1) inhibitor and a novel agent with potential anti-angiogenic and anti-cancer activities. Ferulic acid demonstrated inhibition of endothelial cell proliferation, migration and tube formation in response to basic fibroblast growth factor 1 (FGF1). In ex vivo and in vivo angiogenesis assays, ferulic acid suppressed FGF1-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of ferulic acid on different molecular components and found that ferulic acid suppressed FGF1-triggered activation of FGFR1 and phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) signaling. Moreover, ferulic acid directly inhibited proliferation and blocked the PI3K-Akt pathway in melanoma cell. In vivo, using a melanoma xenograft model, ferulic acid showed growth-inhibitory activity associated with inhibition of angiogenesis. Taken together, our results indicate that ferulic acid targets the FGFR1-mediated PI3K-Akt signaling pathway, leading to the suppression of melanoma growth and angiogenesis.

  6. Evaluation of anti-HIF and anti-angiogenic properties of honokiol for the treatment of ocular neovascular diseases.

    Directory of Open Access Journals (Sweden)

    Divya Teja Vavilala

    Full Text Available Pathological activation of the hypoxia-inducible-factor (HIF pathway leading to expression of pro-angiogenic genes, such as vascular endothelial growth factor (VEGF, is the fundamental cause of neovascularization in ocular ischemic diseases and cancers. We have shown that pure honokiol inhibits the HIF pathway and hypoxia-mediated expression of pro-angiogenic genes in a number of cancer and retinal pigment epithelial (RPE cell lines. The crude extracts, containing honokiol, from Magnolia plants have been used for thousands of years in the traditional oriental medicine for a number of health benefits. We have recently demonstrated that daily intraperitoneal injection of honokiol starting at postnatal day (P 12 in an oxygen induced retinopathy mouse model significantly reduced retinal neovascularization at P17. Here, we evaluate the mechanism of HIF inhibition by honokiol in RPE cells. Using chromatin immunoprecipitation experiments, we demonstrate that honokiol inhibits binding of HIF to hypoxia-response elements present on VEGF promoter. We further show using a number of in vitro angiogenesis assays that, in addition to anti-HIF effect, honokiol manifests potent anti-angiogenic effect on human retinal micro vascular endothelial cells. Our results suggest that honokiol possesses potent anti-HIF and anti-angiogenic properties. These properties of honokiol make it an ideal therapeutic agent for the treatment of ocular neovascular diseases and solid tumors.

  7. Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors

    Directory of Open Access Journals (Sweden)

    Anne Louise Askou

    Full Text Available Lentivirus-based gene delivery vectors carrying multiple gene cassettes are powerful tools in gene transfer studies and gene therapy, allowing coexpression of multiple therapeutic factors and, if desired, fluorescent reporters. Current strategies to express transgenes and microRNA (miRNA clusters from a single vector have certain limitations that affect transgene expression levels and/or vector titers. In this study, we describe a novel vector design that facilitates combined expression of therapeutic RNA- and protein-based antiangiogenic factors as well as a fluorescent reporter from back-to-back RNApolII-driven expression cassettes. This configuration allows effective production of intron-embedded miRNAs that are released upon transduction of target cells. Exploiting such multigenic lentiviral vectors, we demonstrate robust miRNA-directed downregulation of vascular endothelial growth factor (VEGF expression, leading to reduced angiogenesis, and parallel impairment of angiogenic pathways by codelivering the gene encoding pigment epithelium-derived factor (PEDF. Notably, subretinal injections of lentiviral vectors reveal efficient retinal pigment epithelium-specific gene expression driven by the VMD2 promoter, verifying that multigenic lentiviral vectors can be produced with high titers sufficient for in vivo applications. Altogether, our results suggest the potential applicability of combined miRNA- and protein-encoding lentiviral vectors in antiangiogenic gene therapy, including new combination therapies for amelioration of age-related macular degeneration.

  8. Chemical characterisation and the anti-inflammatory, anti-angiogenic and antibacterial properties of date fruit (Phoenix dactylifera L.).

    Science.gov (United States)

    Taleb, Hajer; Maddocks, Sarah E; Morris, R Keith; Kanekanian, Ara D

    2016-12-24

    Date fruit, Phoenix dactylifera L. has traditionally been used as a medicine in many cultures for the treatment of a range of ailments such as stomach and intestinal disorders, fever, oedema, bronchitis and wound healing. The present review aims to summarise the traditional use and application of P. dactylifera date fruit in different ethnomedical systems, additionally the botany and phytochemistry are identified. Critical evaluation of in vitro and in vitro studies examining date fruit in relation to anti-inflammatory, anti-angiogenic and antimicrobial activities are outlined. The ethnomedical use of P. dactylifera in the treatment of inflammatory disease has been previously identified and reported. Furthermore, date fruit and date fruit co-products such as date syrup are rich sources of polyphenols, anthocyanins, sterols and carotenoids. In vitro studies have demonstrated that date fruit exhibits antibacterial, anti-inflammatory and anti-angiogenic activity. The recent interest in the identification of the numerous health benefits of dates using in vitro and in vivo studies have confirmed that date fruit and date syrup have beneficial health effects that can be attributed to the presence of natural bioactive compounds. Date fruit and date syrup have therapeutic properties, which have the potential to be beneficial to health. However, more investigations are needed to quantify and validate these effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Out-patient drug policy by clinical assessment rather than financial constraints? The gate-keeping function of the out-patient drug reimbursement system in The Netherlands

    NARCIS (Netherlands)

    Pronk, Marja H.; Bonsel, Gouke J.

    2004-01-01

    Since 1991, the Dutch Price Reference System (DPRS) has aimed at a growth reduction of out-patient drug costs without loss of medical quality. New drugs are excluded unless they pass legally anchored clinical criteria, i.e. substitutability with accepted drugs (DPRS-list 1a, implies a reimbursement

  10. The Drug Abuse Prevention and Control Act of 1970: Retrospective Assessments of Disparate Treatment and Consequential Impact.

    Science.gov (United States)

    Yamatani, Hide; Feit, Marvin; Mann, Aaron

    2017-01-01

    Although the basic paradigm of the U.S. federal drug policy targeting the supply and demand reduction has not changed since its enactment in 1970, there have been seriously undesirable disparate treatments and impacts among various population groups. Although U.S. Congress could not define what is discrimination, it did provide two major criteria for the assessment of discriminatory practices as follows: (a) disparate treatment-basing a key decision on association with any of the five prohibited individual's demographic classifications (race, color, religion, sex, or national origin); and (b) disparate impact-correlation between any of the five prohibited demographic classifications and the key outcomes. In reference to those criteria, this article describes evidence-based indicators of national failure of the Comprehensive Drug Abuse Prevention and Control Act.

  11. The utilisation of short-lived radionuclides in the assessment of formulation and in vivo disposition of drugs

    International Nuclear Information System (INIS)

    Digenis, G.A.

    1982-01-01

    The utilisation of short-lived radionuclides in the assessment of drug formulations, and the in vivo distribution of drugs is discussed. Disintegration of tablets and capsules as a function of the formulation, and gastric emptying are important. The applicability of perturbed angular correlation to the study of the dissolution of water soluble substances from solid dosages in man is shown. Examples are given to illustrate how external scintigraphy can be applied to study the tissue distribution of 18 F-haloperidol, 82 Br-bromperidol, in rat and monkey. 11 C, L-andD-phenylalanine in rats, 11 C, D-leucine in mice with human colon tumours; 13 N-nitrosoureas and 13 N-nitroso-carbamates. (U.K.)

  12. Assessment of tobramycin RIA for drug monitoring and dosage regimen. Comparison with other assay technics

    International Nuclear Information System (INIS)

    Takahashi, S.; Shinozaki, K.; Tsujino, D.; Ohhara, H.; Tanaka, Y.; Arai, S.; Someya, K.; Sasaki, Y.

    1983-01-01

    Because of wide range of inter-individual difference of pharmacokinetic parameter, importance of monitoring blood concentration of aminoglycoside antibiotics in each patient has been recognized. With the purpose to use for monitoring of serum tobramycin (TOB) levels and for adequate dosage regimen RIA of TOB was evaluated in comparison with other assay technics. Gamma Coat TOB RIA kits (Clinical Assay-Travenol Japan) were used for RIA of TOB. The TOB concentrations in the same samples were also measured by two kinds of enzyme immunoassay (EIA) (EMIT EIA and SLFIA EIA), High Performance Liquid Chromatography (HPLC) and bioassay (BA). RIA of TOB is a useful assay method with high sensitivity and reasonably good precision to be used for drug monitoring and adequate dosage regimen. Modification of the method for rapid assay of a small number of samples will increase the clinical usefulness in individualized drug monitoring

  13. Prescription drug monitoring program inquiry in psychiatric assessment: detection of high rates of opioid prescribing to a dual diagnosis population.

    Science.gov (United States)

    Hackman, Daniel T; Greene, Marion S; Fernandes, Taya J; Brown, Ashley M; Wright, Eric R; Chambers, R Andrew

    2014-07-01

    An epidemic of prescription drug abuse is disproportionately impacting the mentally ill. We examined the utility of a state prescription drug monitoring database for assessing recent controlled substance prescribing to patients presenting for dual diagnosis treatment. In a community mental health center that provides integrated dual diagnosis care, we queried the Indiana Scheduled Prescription Electronic Collection and Tracking (INSPECT) system for all cases that were open as of August 2, 2011, and had been practitioner-diagnosed (per DSM-IV criteria) by January 2, 2012. INSPECT provided a record of controlled substance dispensations to each patient; diagnostic evaluation was conducted blind from prescription data compilation covering the prior 12 months. Demographic data, insurance status, and DSM-IV diagnoses were compiled from the clinic's electronic medical record. The sample (N = 201) was 51% female, 56% white, and two-thirds uninsured. Over 80% were dually diagnosed with substance use disorders and psychotic, mood, or anxiety disorders. Nicotine and alcohol disorders were identified in most, with about a third diagnosed with cannabis, cocaine, or opioid disorders. A majority of patients (n = 115) had been prescribed opioids in the prior year, with nearly 1 in 5 prescribed an opioid and benzodiazepine simultaneously. Patients were dispensed a mean of 4 opioid prescriptions and 213 opioid pills. More opioid prescriptions correlated with opioid dependence (OR = 1.08; 95% CI, 1.016-1.145), and more prescribers correlated with personality disorder diagnoses (OR = 1.112; 95% CI, 1.001-1.235). Higher rates and riskier patterns of controlled substance prescribing were identified in patients with Medicaid/Medicare insurance compared to uninsured patients. Prescription drug monitoring is a powerful tool for assessing addictions and high frequencies of patient exposures to prescribed opioids in a dual diagnosis clinic. Improved prevention and treatment strategies for

  14. Dual isotope technique for in vivo quantitative assessment of intra-arterial(IA) drug delivery to hepatic metastases

    International Nuclear Information System (INIS)

    Line, B.R.; Harper, G.; Armstrong, M.; Ruckdeschel, J.

    1984-01-01

    Qualitative Tc-99m macro-aggregated albumin (MAA) scans can evaluate both IA catheter placement and regional hepatic perfusion. The authors report a new, dual isotope technique for the quantitative assessment of IA drug delivery to hepatic metastases (mets). Four patients (pts) with colon cancer metastatic to liver were treated for two week cycles with continuous IA 5-fluoro-2'-deoxyuridine (FUDR) infusion via an implantable pump (INFUSAID) at a dose of 0.1 to 0.3 mg/kg/d. At four week intervals each patient had quantitative hepatic imaging studies with Tc-99m SC to estimate met volume followed immediately by Tc-99m MAA through the pump to map drug distribution. MAA was distinguished from SC by computer subtraction and a distribution index (DI) expressed as the ratio of MAA in tumor vs normal tissues was determined. The lesion volume and DI were used to calculate the amount of FUDR delivered to tumor during treatment. Marked variability was found in the DI and chemotherapy delivered to tumor tissue between and within different pts. Pretreatment DIs were estimated to be 54%, 20%, 15%, and 1%. One pt demonstrated a drop in relative blood flow from a pretreatment DI of 54% to 49% at 4 weeks, and 37% at 8 weeks. The pt with the least DI (1.1%-5.0%) had the largest tumor burden (900 gm) and the smallest FUDR tumor delivery (0.2-1.1 ng/gm/min). The pt with the smallest tumor burden (80 gm) had the greatest FUDR delivery (14.8-22.1 ng/gm/min). This imaging technique provides quantitative estimates of tumor size and relative perfusion which can evaluate drug delivery to tumor and refine the assessment of both antitumor drug activity and toxicity of IA hepatic chemotherapy

  15. Assessing behavioral patterns of Internet addiction and drug abuse among high school students

    OpenAIRE

    Nemati, Zeinab; Matlabi, Hossein

    2017-01-01

    Zeinab Nemati, Hossein Matlabi Department of Health Education and Promotion, Faculty of Health Sciences, Tabriz University of Medical Sciences, Tabriz, Iran Background: Internet addiction and drug abuse isolate adolescents from their family and friends and cause damage to their health, relations, emotions, and spirit. In the society, adolescents’ addiction extracts high cost on health care, educational failure and mental health services. Objectives: The aim of this study wa...

  16. Innovator Organizations in New Drug Development: Assessing the Sustainability of the Biopharmaceutical Industry.

    Science.gov (United States)

    Kinch, Michael S; Moore, Ryan

    2016-06-23

    The way new medicines are discovered and brought to market has fundamentally changed over the last 30 years. Our previous analysis showed that biotechnology companies had contributed significantly to the US Food and Drug Administration approval of new molecular entities up to the mid-1980s, when the trends started to decline. Although intriguing, the focus on biotechnology necessarily precluded the wider question of how the biopharmaceutical industry has been delivering on its goals to develop new drugs. Here, we present a comprehensive analysis of all biopharmaceutical innovators and uncover unexpected findings. The present biopharmaceutical industry grew steadily from 1800 to 1950 and then stagnated for two decades, before a burst of growth attributable to the biotechnology revolution took place; but consolidation has reduced the number of active and independent innovators to a level not experienced since 1945. The trajectories and trends we observe raise fundamental questions about biopharmaceutical innovators and the sustainability of the drug-development enterprise. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Molecular Docking Assessment of Efficacy of Different Clinically Used Arsenic Chelator Drugs

    Directory of Open Access Journals (Sweden)

    Durjoy Majumder

    2013-01-01

    Full Text Available Arsenic contamination of ground water has become a global problem affecting specially, south-east Asian countries like Bangladesh and eastern parts of India. It also affects South America and some parts of the US. Different organs of the physiological system are affected due to contamination of inorganic arsenic in water. Animal studies with different chelators are not very conclusive as far as the multi/differential organ effect(s of arsenic is concerned. Our docking study establishes the molecular rationale of blood test for early detection of arsenic toxicity; as arsenic has a high affinity to albumin, a plasma protein and actin, a structural protein of all cells including Red Blood Cells. This study also shows that there is a little possibility of male reproductive organs toxicity by different forms of inorganic arsenic; however, female reproductive system is very much susceptible to sodium-arsenite. Through comparative analysis regarding the chelating effectiveness among the available arsenic chelator drugs, meso-2,3 dimercaptosuccinic acid (DMSA and in some cases lipoic acid is the most preferred choice of drug for removing of arsenic deposits. This computational method actually reinforces the clinical finding regarding DMSA as the most preferred drug in removal of arsenic deposits from majority of the human tissues.

  18. The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs.

    Science.gov (United States)

    Bax, Hannelore I; Bakker-Woudenberg, Irma A J M; de Vogel, Corné P; van der Meijden, Aart; Verbon, Annelies; de Steenwinkel, Jurriaan E M

    2017-07-01

    Novel treatment strategies for tuberculosis are urgently needed. Many different preclinical models assessing anti-tuberculosis drug activity are available, but it is yet unclear which combination of models is most predictive of clinical treatment efficacy. The aim of this study was to determine the role of our in vitro time kill-kinetics assay as an asset to a predictive preclinical modeling framework assessing anti-tuberculosis drug activity. The concentration- and time-dependent mycobacterial killing capacities of six anti-tuberculosis drugs were determined during exposure as single drugs or in dual, triple and quadruple combinations towards a Mycobacterium tuberculosis Beijing genotype strain and drug resistance was assessed. Streptomycin, rifampicin and isoniazid were most active against fast-growing M. tuberculosis. Isoniazid with rifampicin or high dose ethambutol were the only synergistic drug combinations. The addition of rifampicin or streptomycin to isoniazid prevented isoniazid resistance. In vitro ranking showed agreement with early bactericidal activity in tuberculosis patients for some but not all anti-tuberculosis drugs. The time-kill kinetics assay provides important information on the mycobacterial killing dynamics of anti-tuberculosis drugs during the early phase of drug exposure. As such, this assay is a valuable component of the preclinical modeling framework. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. An investigation into solvent-membrane interactions when assessing drug release from organic vehicles using regenerated cellulose membranes.

    Science.gov (United States)

    Reid, Monica L; Brown, Marc B; Moss, Gary P; Jones, Stuart A

    2008-09-01

    The influence of organic solvents on artificial membranes when assessing drug release from topical formulations is, generally, poorly characterised yet current guidelines require no characterisation of the membrane before, during or after an experiment. Therefore, the aim of this study was to determine the effect of solvent-membrane interactions when using in-vitro Franz cell methods for the assessment of corticosteroid release and to assess compliance or otherwise with Higuchi's equation. The rate of beclometasone dipropionate monohydrate (BDP) and betamethasone 17-valerate (BMV) release across a regenerated cellulose membrane (RCM), from both saturated solutions and commercial formulations, was determined. Increasing the ratio of organic solvent, compared with aqueous phase, in the donor fluid (DF) resulted in up to a 416-fold increase in steady-state flux. Further, alterations in the receiver fluid (RF) composition caused, in some cases, 337-fold increases in flux. Analysis indicated that the RCM remained chemically unchanged, that its pore size remained constant and that no drug partitioned into the membrane, regardless of the DF or RF employed. However, it was observed that the organic solvents had a thinning effect on the RCM, resulting in enhanced flux, which was potentially due to the variation in the diffusional path length. Such findings raise issues of the veracity of data produced from any membrane release study involving a comparison of formulations with differing solvent content.

  20. [Optimization and assessment of a reverse hybridization system for the detection of HBV drug-resistant mutations].

    Science.gov (United States)

    Liu, Yan-chen; Huang, Ai-long; Hu, Yuan; Hu, Jie-li; Lai, Guo-qi; Zhang, Wen-lu

    2011-12-01

    To establish a detection method for HBV drug-resistant mutations related to lamivudine, adefovir and entecavir by optimization and assessment of reverse hybridization system. 26 degenerated probes covering 10 drug-resistant hotspots of 3 drugs were synthesized and immobilized on the same positively charged nylon membrane. PCR products labeled with digoxigenin were hybridized with corresponding probes. To improve the sensitivity and specificity, 4 reaction steps of reverse hybridization were optimized including the number of labeled digoxigenin, the energy intensity of UV cross-linking, hybridization and stringency wash conditions. To prove the feasibility, the specificity, sensitivity and accuracy of this system were assessed respectively. Sensitive and specific results are obtained by the optimization of the following 4 reaction steps: the primers labeled with 3 digoxigenin, energy intensity of UV cross-linking for 1500 x 0.1 mJ/cm², hybridization at 42 degrees C and stringency wash with 0.5 x SSC and 0.1% SDS solution at 44 degrees C for 30 min. In the assessment of system, the majority of probes have high specificity. The quantity of PCR product with a concentration of 10 ng/μl or above can be detected by this method. The concordant rate between reverse hybridization and direct sequencing is 93.9% in the clinical sample test. Though the specificity of several probes needs to be improved further, it is a simple, rapid and sensitive method which can detect HBV resistant mutations related to lamivudine, adefovir and entecavir simultaneously. Due to the short distance between 180 and 181, likewise 202 and 204, the sequence of the same probe covers two codon positions, and hybridization will be interfered by each other. To avoid such interference, the possible solution is that probes are designed by arranging and combining various forms of two near codons.

  1. Early health technology assessments in pharmacogenomics: a case example in cardiovascular drugs

    NARCIS (Netherlands)

    Geenen, Joost W.; Baranova, Ekaterina V.; Asselbergs, Folkert W.; de Boer, Anthonius; Vreman, Rick A.; Palmer, Colin Na; Maitland-van der Zee, Anke H.; Hövels, Anke M.

    2017-01-01

    Aim: To assess the required characteristics (cost, sensitivity and specificity) of a pharmacogenomic test for being a cost-effective prevention of angiotensin-converting enzyme inhibitors induced angioedema. Furthermore, we assessed the influence of only testing high-risk populations. Materials &

  2. Molecular targeted therapy in modern oncology: Imaging assessment of treatment response and toxicities

    Energy Technology Data Exchange (ETDEWEB)

    Krajewski, Katherine M.; Braschi-Amirfarzan, Marta; DiPiro, Pamela J.; Jagannathan, Jyothi P.; Shinagare, Atul B. [Dept. of of Imaging, Dana Farber Cancer Institute, Boston (United States)

    2017-01-15

    Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities.

  3. An assessment of the relationship between the World Health Organization HIV drug resistance early warning indicators and HIV drug resistance acquisition.

    Science.gov (United States)

    St-Jean, M; Harrigan, P R; Sereda, P; Montaner, Jsg; Lima, V D

    2017-05-01

    The World Health Organization (WHO)'s HIV drug resistance (HIVDR) early warning indicators (EWIs) measure antiretroviral therapy (ART)-site factors associated with HIVDR prevention, without HIVDR laboratory testing. We assessed the relationship between EWIs and HIVDR acquisition using data from British Columbia, Canada. Eligible patients were ART-naïve, were ≥ 19 years old, had initiated ART between 1 January 2000 and 31 December 2012, had ≥ 15 months of follow-up, and were without transmitted HIVDR. Patients were followed for acquired HIVDR until 31 March 2014, the last contact date, or death. We built logistic regression models to assess the associations and predictive ability of individual indicators and of the EWI Score (the number of indicators for which a patient did not meet the criteria) on HIVDR acquisition (to any class of HIVDR, lamivudine (3TC)/emtricitabine (FTC), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors (PIs)]). All explored EWIs were associated with at least one class of HIVDR, with the exception of 'ART prescribing practices'. We observed a dose-response relationship between acquiring HIVDR to any antiretroviral class and an increasing EWI score in our predictive logistic regression model. The area under the curve was 0.848 (excellent discrimination). The adjusted odds ratios for acquiring any class of HIVDR for an EWI score of 1, 2 and ≥ 3 versus 0 were 2.30 [95% confidence Interval (CI) 1.21-4.38], 3.35 (95% CI: 1.86-6.03) and 7.26 (95% CI: 4.18-12.61), respectively. Several EWIs were associated with and predictive of HIVDR, supporting the WHO EWIs as a component of the HIVDR prevention method in settings where HIVDR testing is not routinely or widely available. © 2016 British HIV Association.

  4. A First Assessment of Mycobacterium tuberculosis Genetic Diversity and Drug-Resistance Patterns in Twelve Caribbean Territories

    Directory of Open Access Journals (Sweden)

    Julie Millet

    2014-01-01

    Full Text Available With the exception of some French-speaking islands, data on tuberculosis (TB in the Caribbean are scarce. In this study, we report a first assessment of genetic diversity of a convenience sample of Mycobacterium tuberculosis strains received from twelve Caribbean territories by spoligotyping and describe their drug-resistance patterns. Of the 480 isolates, 40 (8.3% isolates showed resistance to at least one anti-TB drug. The proportion of drug-resistant strains was significantly higher in The Bahamas (21.4%; P=0.02, and Guyana (27.5%; P<0.0001, while it was significantly lower in Jamaica (2.4%; P=0.03 than in other countries of the present study. Regarding genetic diversity, 104 distinct spoligotype patterns were observed: 49 corresponded to clustered strains (2 to 93 strains per cluster, while 55 remained unclustered among which 16 patterns were not reported previously. Combining the study results with regional data retrieved from the international SITVIT2 database underlined a connection between frequency of certain M. tuberculosis phylogenetic lineages and the language spoken, suggesting historical (colonial and ongoing links (trade, tourism, and migratory flows with European countries with which they shared a common past.

  5. Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer

    DEFF Research Database (Denmark)

    Siemann, D W; Chaplin, D J; Horsman, M R

    2017-01-01

    Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting a...

  6. Time until initiation of tumor growth is an effective measure of the anti-angiogenic effect of TNP-470 on human glioblastoma in nude mice

    DEFF Research Database (Denmark)

    Kragh, M; Spang-Thomsen, M; Kristjansen, P E

    1999-01-01

    We examined the effect of the anti-angiogenic compound TNP-470 on early tumor growth characteristics following subcutaneous implantation of 1 mm3 tissue blocks of human glioblastoma U87, in nude mice. The mice received daily injections with TNP-470, 7 mg/kg, from one day before until either 3, 7...

  7. Venous return curve and its application to assessment of the effect of cardiovascular drugs

    Energy Technology Data Exchange (ETDEWEB)

    Nagashima, Kenshi; Gotoh, Kohshi; Yagi, Yasuo (Gifu Univ. (Japan). Faculty of Medicine) (and others)

    1990-01-01

    In an effort to obtain a venous return curve, occlusion plethysmography with radionuclide was performed in the forearm of 24 patients with various heart diseases. Radionuclide angiocardiography was performed and during the equilibrium phase the region of interest was created over the forearm for repeated venous occlusions. Specific compliance in the vein of the forearm was obtained by drawing the radionuclide count-venous pressure curve from changes in venous pressure and radioactivity of the forearm. Compliance of human systemic veins was then obtained based on some hypotheses. Mean systemic pressure (Pms) was estimated. In addition, right auricular pressure and cardiac output were obtained for drawing part of the venous return curve. In a study of the effect of cardiovascular drugs on the venous return curve, Pms was found to be significantly decreased by the administration of nitroglycerin. Furthermore, systemic venous return curve moved to the leftward. In contrast, nifedipine did not have any influence on Pms in Class I of cardiovascular function; and systemic venous return curve moved clockwise by the administration of the drug. In the case of Class II or III, nifedipine caused the systemic venous return curve to move clockwise with decreasing Pms. (N.K.).

  8. Cationic Albumin Nanoparticles for Enhanced Drug Delivery to Treat Breast Cancer: Preparation and In Vitro Assessment

    Directory of Open Access Journals (Sweden)

    Sana Abbasi

    2012-01-01

    Full Text Available Most anticancer drugs are greatly limited by the serious side effects that they cause. Doxorubicin (DOX is an antineoplastic agent, commonly used against breast cancer. However, it may lead to irreversible cardiotoxicity, which could even result in congestive heart failure. In order to avoid these harmful side effects to the patients and to improve the therapeutic efficacy of doxorubicin, we developed DOX-loaded polyethylenimine- (PEI- enhanced human serum albumin (HSA nanoparticles. The formed nanoparticles were ~137 nm in size with a surface zeta potential of ~+15 mV, prepared using 20 μg of PEI added per mg of HSA. Cytotoxicity was not observed with empty PEI-enhanced HSA nanoparticles, formed with low-molecular weight (25 kDa PEI, indicating biocompatibility and safety of the nanoparticle formulation. Under optimized transfection conditions, approximately 80% of cells were transfected with HSA nanoparticles containing tetramethylrhodamine-conjugated bovine serum albumin. Conclusively, PEI-enhanced HSA nanoparticles show potential for developing into an effective carrier for anticancer drugs.

  9. Performance of an in-house human immunodeficiency virus type 1 genotyping system for assessment of drug resistance in Cuba.

    Science.gov (United States)

    Alemán, Yoan; Vinken, Lore; Kourí, Vivian; Pérez, Lissette; Álvarez, Alina; Abrahantes, Yeissel; Fonseca, Carlos; Pérez, Jorge; Correa, Consuelo; Soto, Yudira; Schrooten, Yoeri; Vandamme, Anne-Mieke; Van Laethem, Kristel

    2015-01-01

    As commercial human immunodeficiency virus type 1 drug resistance assays are expensive, they are not commonly used in resource-limited settings. Hence, a more affordable in-house procedure was set up taking into account the specific epidemiological and economic circumstances of Cuba. The performance characteristics of the in-house assay were evaluated using clinical samples with various subtypes and resistance patterns. The lower limit of amplification was determined on dilutions series of 20 clinical isolates and ranged from 84 to 529 RNA copies/mL. For the assessment of trueness, 14 clinical samples were analyzed and the ViroSeq HIV-1 Genotyping System v2.0 was used as the reference standard. The mean nucleotide sequence identity between the two assays was 98.7% ± 1.0. Additionally, 99.0% of the amino acids at drug resistance positions were identical. The sensitivity and specificity in detecting drug resistance mutations was respectively 94.1% and 99.5%. Only few discordances in drug resistance interpretation patterns were observed. The repeatability and reproducibility were evaluated using 10 clinical samples with 3 replicates per sample. The in-house test was very precise as nucleotide sequence identity among paired nucleotide sequences ranged from 98.7% to 99.9%. The acceptance criteria were met by the in-house test for all performance characteristics, demonstrating a high degree of accuracy. Subsequently, the applicability in routine clinical practice was evaluated on 380 plasma samples. The amplification success rate was 91% and good quality consensus sequences encoding the entire protease and the first 335 codons in reverse transcriptase could be obtained for 99% of the successful amplicons. The reagent cost per sample using the in-house procedure was around € 80 per genotyping attempt. Overall, the in-house assay provided good results, was feasible with equipment and reagents available in Cuba and was half as expensive as commercial assays.

  10. Performance of an in-house human immunodeficiency virus type 1 genotyping system for assessment of drug resistance in Cuba.

    Directory of Open Access Journals (Sweden)

    Yoan Alemán

    Full Text Available As commercial human immunodeficiency virus type 1 drug resistance assays are expensive, they are not commonly used in resource-limited settings. Hence, a more affordable in-house procedure was set up taking into account the specific epidemiological and economic circumstances of Cuba. The performance characteristics of the in-house assay were evaluated using clinical samples with various subtypes and resistance patterns. The lower limit of amplification was determined on dilutions series of 20 clinical isolates and ranged from 84 to 529 RNA copies/mL. For the assessment of trueness, 14 clinical samples were analyzed and the ViroSeq HIV-1 Genotyping System v2.0 was used as the reference standard. The mean nucleotide sequence identity between the two assays was 98.7% ± 1.0. Additionally, 99.0% of the amino acids at drug resistance positions were identical. The sensitivity and specificity in detecting drug resistance mutations was respectively 94.1% and 99.5%. Only few discordances in drug resistance interpretation patterns were observed. The repeatability and reproducibility were evaluated using 10 clinical samples with 3 replicates per sample. The in-house test was very precise as nucleotide sequence identity among paired nucleotide sequences ranged from 98.7% to 99.9%. The acceptance criteria were met by the in-house test for all performance characteristics, demonstrating a high degree of accuracy. Subsequently, the applicability in routine clinical practice was evaluated on 380 plasma samples. The amplification success rate was 91% and good quality consensus sequences encoding the entire protease and the first 335 codons in reverse transcriptase could be obtained for 99% of the successful amplicons. The reagent cost per sample using the in-house procedure was around € 80 per genotyping attempt. Overall, the in-house assay provided good results, was feasible with equipment and reagents available in Cuba and was half as expensive as commercial

  11. 75 FR 4400 - Draft Guidance for Industry on Assessment of Abuse Potential of Drugs; Availability

    Science.gov (United States)

    2010-01-27

    ..., and Cosmetic Act, an abuse potential assessment is part of the general evaluation of the safety and..., prescribing, advertising, manufacturing, promotion, marketing, and use in the practice of medicine. Not...

  12. Assessment of MEKC suitability for residue drug monitoring on pharmaceutical manufacturing equipment

    CSIR Research Space (South Africa)

    Boca, MB

    2008-03-01

    Full Text Available The suitability of micellar electrokinetic chromatography for the simultaneous trace determination of several compounds (sulfamethoxazole, trimethoprim, sulfanilic acid, sulfanilamide, 3,4,5-trimethoxybenzoic acid and nonoxynol-9) was assessed...

  13. Clinical Assessment of Drug Adjunctive Therapy Effects in Association with Chronic Generalized Periodontitis and Osteoporotic Disease*

    Directory of Open Access Journals (Sweden)

    Ursarescu Irina-Georgeta

    2015-11-01

    Full Text Available Aim: The present study proposes an assessment of the clinical effects on periodontal level generated by the adjunctive periodontal therapy with sub-antimicrobial doses of doxycycline in patients with chronic periodontitis and osteoporosis.

  14. The evaluation of anti-angiogenic treatment effects for implanted rabbit VX2 breast tumors using functional multi-slice spiral computed tomography (f-MSCT)

    Energy Technology Data Exchange (ETDEWEB)

    Lei Zhen, E-mail: leizhen2004@163.com [Department of Anatomy, Chinese Medical University, No. 92, Beiermalu Road, Heping District, Shenyang, 110001 (China) and Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Ma Heji, E-mail: maheji9831@sina.com [Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Xu Na, E-mail: xuna821230@sohu.com [Department of Radiology, The First Hospital of Liaoning Medical College, No. 2, Wuduan, Renmin Street, Jinzhou, 121001 (China); Xi Huanjiu, E-mail: xihuanjiu2004@yahoo.cn [Anthropology Institute, Liaoning Medical College, No. 40, Sanduan, Songpo Rd, Jinzhou, 121001 (China)

    2011-05-15

    Objective: Investigate the benefit of functional multi-slice spiral computed tomography (f-MSCT) perfusion imaging in the non-invasive assessment of targeted anti-angiogenesis therapy on an implanted rabbit VX2 breast tumor model. Method: 69 female pure New Zealand white rabbits were randomly assigned to one of the 4 groups and received treatment accordingly: control (saline), Endostar, neoadjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5-Fluorouracil, CEF), combination therapy (Endostar and CEF). After 2 weeks of treatment, f-MSCT perfusion scannings were performed for all rabbits and information about blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (SP) was collected. After perfusion imaging, tumor tissues were sampled for immunohistochemistry and the Western blot test of VEGF protein expression. Results: (1) The VEGF expression level, measured by immunohistochemistry and Western blot, decreased by treatment group (control > Endostar > CEF > combination therapy). The same was true for the mean BF, BV, MTT and PS, which decreased from the control group to the combination therapy group gradually. The mean MTT level increased in reverse order from the control to the combination therapy group. The difference between any 2 groups on these measures was statistically significant (P < 0.05). (2) There was moderate positive correlation between VEGF expression and BE, BV, or PS level (P < 0.05) and a negative correlation between VEGF expression and MTT level for all 4 groups (P < 0.05). Conclusion: Therefore, f-MSCT can be used as a non-invasive approach to evaluate the effect of anti-angiogenic therapy for implanted rabbit VX2 breast tumors.

  15. The evaluation of anti-angiogenic treatment effects for implanted rabbit VX2 breast tumors using functional multi-slice spiral computed tomography (f-MSCT)

    International Nuclear Information System (INIS)

    Lei Zhen; Ma Heji; Xu Na; Xi Huanjiu

    2011-01-01

    Objective: Investigate the benefit of functional multi-slice spiral computed tomography (f-MSCT) perfusion imaging in the non-invasive assessment of targeted anti-angiogenesis therapy on an implanted rabbit VX2 breast tumor model. Method: 69 female pure New Zealand white rabbits were randomly assigned to one of the 4 groups and received treatment accordingly: control (saline), Endostar, neoadjuvant chemotherapy (Cyclophosphamide, Epirubicin and 5-Fluorouracil, CEF), combination therapy (Endostar and CEF). After 2 weeks of treatment, f-MSCT perfusion scannings were performed for all rabbits and information about blood flow (BF), blood volume (BV), mean transit time (MTT) and surface permeability (SP) was collected. After perfusion imaging, tumor tissues were sampled for immunohistochemistry and the Western blot test of VEGF protein expression. Results: (1) The VEGF expression level, measured by immunohistochemistry and Western blot, decreased by treatment group (control > Endostar > CEF > combination therapy). The same was true for the mean BF, BV, MTT and PS, which decreased from the control group to the combination therapy group gradually. The mean MTT level increased in reverse order from the control to the combination therapy group. The difference between any 2 groups on these measures was statistically significant (P < 0.05). (2) There was moderate positive correlation between VEGF expression and BE, BV, or PS level (P < 0.05) and a negative correlation between VEGF expression and MTT level for all 4 groups (P < 0.05). Conclusion: Therefore, f-MSCT can be used as a non-invasive approach to evaluate the effect of anti-angiogenic therapy for implanted rabbit VX2 breast tumors.

  16. Early biomarkers from dynamic contrast-enhanced magnetic resonance imaging to predict the response to antiangiogenic therapy in high-grade gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Piludu, Francesca; Vidiri, Antonello [Regina Elena National Cancer Institute, Radiology and Diagnostic Imaging Department, Rome (Italy); Marzi, Simona [Regina Elena National Cancer Institute, Medical Physics Laboratory, Rome (Italy); Pace, Andrea; Villani, Veronica [Regina Elena National Cancer Institute, Neurology Division, Rome (Italy); Fabi, Alessandra [Regina Elena National Cancer Institute, Oncology Department, Rome (Italy); Carapella, Carmine Maria [Regina Elena National Cancer Institute, Oncologic Surgery Department, Rome (Italy); Terrenato, Irene [Regina Elena National Cancer Institute, Biostatistics-Scientific Direction, Rome (Italy); Antenucci, Anna [Regina Elena National Cancer Institute, Clinical Pathology, Rome (Italy)

    2015-12-15

    The aim of this study is to investigate whether early changes in tumor volume and perfusion measurements derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may predict response to antiangiogenic therapy in recurrent high-grade gliomas. Twenty-seven patients who received bevacizumab every 3 weeks were enrolled in the study. For each patient, three MRI scans were performed: at baseline, after the first dose, and after the fourth dose of bevacizumab. The entire tumor volume (V{sub tot}), as well as contrast-enhanced and noncontrast-enhanced tumor subvolumes (V{sub CE-T1} and V{sub NON-CE-T1}, respectively) were outlined using post-contrast T1-weighted images as a guide for the tumor location. Histogram analysis of normalized IAUGC (nIAUGC) and transfer constant K{sup trans} maps were performed. Each patient was classified as a responder patient if he/she had a partial response or a stable disease or as a nonresponder patient if he/she had progressive disease. Responding patients showed a larger reduction in V{sub NON-CE-T1} after a single dose, compared to nonresponding patients. Tumor subvolumes with increased values of nIAUGC and K{sup trans}, after a single dose, significantly differed between responders and nonresponders. The radiological response was found to be significantly associated to the clinical outcome. After a single dose, V{sub tot} was predictive of overall survival (OS), while V{sub CE-T1} showed a tendency of correlation with OS. Tumor subvolumes with increased nIAUGC and K{sup trans} showed the potential for improving the diagnostic accuracy of DCE. Early assessments of the entire tumor volume, including necrotic areas, may provide complementary information of tumor behavior in response to anti-VEGF therapies and is worth further investigation. (orig.)

  17. An assessment of quality of sleep and the use of drugs with sedating properties in hospitalized adult patients

    Directory of Open Access Journals (Sweden)

    Naumann Terryn

    2004-03-01

    Full Text Available Abstract Background Hospitalization can significantly disrupt sleeping patterns. In consideration of the previous reports of insomnia and apparent widespread use of benzodiazepines and other hypnotics in hospitalized patients, we conducted a study to assess quality of sleep and hypnotic drug use in our acute care adult patient population. The primary objectives of this study were to assess sleep disturbance and its determinants including the use of drugs with sedating properties. Methods This single-centre prospective study involved an assessment of sleep quality for consenting patients admitted to the general medicine and family practice units of an acute care Canadian hospital. A validated Verran and Snyder-Halpern (VSH Sleep Scale measuring sleep disturbance, sleep effectiveness, and sleep supplementation was completed daily by patients and scores were compared to population statistics. Patients were also asked to identify factors influencing sleep while in hospital, and sedating drug use prior to and during hospitalization was also assessed. Results During the 70-day study period, 100 patients completed at least one sleep questionnaire. There was a relatively even distribution of males versus females, most patients were in their 8th decade of life, retired, and suffered from multiple chronic diseases. The median self-reported pre-admission sleep duration for participants was 8 hours and our review of PharmaNetR profiles revealed that 35 (35% patients had received a dispensed prescription for a hypnotic or antidepressant drug in the 3-month period prior to admission. Benzodiazepines were the most common sedating drugs prescribed. Over 300 sleep disturbance, effective and supplementation scores were completed. Sleep disturbance scores across all study days ranged 16–681, sleep effectiveness scores ranged 54–402, while sleep supplementation scores ranged between 0–358. Patients tended to have worse sleep scores as compared to healthy non

  18. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  19. Assessment of abuse liability of Tramadol among experienced drug users: Double-blind crossover randomized controlled trial.

    Science.gov (United States)

    Das, Mrinmay; Jain, Raka; Dhawan, Anju; Kaur, Amandeep

    Tramadol is a widely used opioid analgesic. Different preclinical, clinical, and postmarketing surveillance studies show conflicting results regarding abuse potential of this drug. A randomized double-blind complete crossover study was conducted at National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi. Total subjects were 10, comprising total 120 observations (each subject assessed at baseline, 5, 45, and 240 minutes). Subjects with history of substance abuse were included after detoxification and informed consent. Assessment was done using modified single dose opiate questionnaire, morphine benzedrine group (MBG), pentobarbital chlorpromazine alcohol group (PCAG), and two bipolar visual analogue scales (VAS) after administration of three drugs-Tramadol (100 mg), Buprenorphine (0.6 mg), and Placebo (Normal Saline) intramuscularly, at 5-day interval. In intra-group analysis, there was statistically significant increase in scores of all four scales from baseline to all three time points after Tramadol and Buprenorphine administration. In inter-group analysis, statistically higher scores were seen for Buprenorphine in comparison t